Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
</div>
 
</div>
−
{{#lst:Section editor transclusions|sarcoma}}
+
{{#lst:Section editor transclusions|heme}}
−
<big>'''Note: certain regimens have been moved to dedicated pages:
 
−
*'''[[Ewing sarcoma, pediatric|Pediatric Ewing sarcoma]]
 
−
</big>
 
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
=Guidelines=
 
=Guidelines=
−
==[http://www.esmo.org/ ESMO]==
+
==ASH==
−
*'''2014:''' [http://annonc.oxfordjournals.org/content/25/suppl_3/iii113.full.pdf+html Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/25210081 PubMed]
+
*'''2019:''' Neunert et al. [https://ashpublications.org/bloodadvances/article/3/23/3829/429213/American-Society-of-Hematology-2019-guidelines-for American Society of Hematology 2019 guidelines for immune thrombocytopenia]
−
==ESMO/PaedCan/EURACAN==
+
===Older===
−
*'''2018:''' Casali et al. [https://www.esmo.org/Guidelines/Sarcoma-and-GIST/Bone-Sarcomas Bone sarcomas: ESMO–PaedCan–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*'''2011:''' Neunert et al. [http://www.bloodjournal.org/content/117/16/4190 The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia]
−
==[https://www.nccn.org/ NCCN]==
+
==BSH==
−
*[https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf NCCN Guidelines - Bone Cancer]
+
*'''2019:''' Hill et al. [https://doi.org/10.1111/bjh.15735 The prevention of glucocorticoid-induced osteoporosis in patients with immune thrombocytopenia receiving steroids: a British Society for Haematology Good Practice Paper]
−
=Neoadjuvant therapy=
+
=="How I Treat"==
−
==EVAIA {{#subobject:4d4fee|Regimen=1}}==
+
*'''2021:''' Ghanima et al. [https://doi.org/10.1182/blood.2021010968 How I treat primary ITP in adult patients who are unresponsive to or dependent on corticosteroid treatment]
−
EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin
+
=Initial therapy=
 +
==Dexamethasone monotherapy {{#subobject:7c8c62|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:11e269|Variant=1}}===
+
===Regimen variant #1 {{#subobject:666055|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
+
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]
−
|1992-1997
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
|[[#Prednisone_monotherapy|Prednisone]]
−
|[[#VAIA|VAIA]]
+
| style="background-color:#1a9850" |Superior CR rate
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
 
|-
 
|-
 
|}
 
|}
−
''Note: This regimen is intended for high-risk patients.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
+
'''4-day course'''
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of mesna
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 4 cycles'''
 
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible.
+
*If platelets remained below 30 x 10<sup>9</sup>/L or bleeding by day 10, course is repeated once
−
*For patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: [[External beam radiotherapy]] 54.4 Gy, then adjuvant [[#EVAIA_2|EVAIA]]
+
</div></div><br>
−
*For patients with a good histologic response: [[External beam radiotherapy]] 44.8 Gy, then adjuvant [[#EVAIA_2|EVAIA]]
 
−
*Additional details about particular clinical scenarios can be found in the original reference
 
−
</div></div>
 
−
===References===
 
−
# '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
==VACA {{#subobject:4a10e9|Regimen=1}}==
 
−
VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:72ab30|Variant=1}}===
+
===Regimen variant #2 {{#subobject:678fa4|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|-
 +
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Prednisone_monotherapy|Prednisone]]
 +
| style="background-color:#91cf60" |Seems to have superior responding patients maintaining remission for at least 6 mo
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunosuppressive therapy, part 1====
 +
*[[Prednisone (Sterapred)]] 1 mg/kg/day PO for 7 days
 +
====Immunosuppressive therapy, part 2====
 +
*[[Dexamethasone (Decadron)]] 0.6 mg/kg/day (route not specified) for days 1 to 4
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3 {{#subobject:19f4e9|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa030254 Cheng et al. 2003]
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunosuppressive therapy====
 +
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 +
'''4-day course'''
 +
''Patients who had an initial response, but whose platelets dropped below 30 x 10<sup>9</sup>/L within 6 months received:''
 +
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
 +
*[[Prednisone (Sterapred)]] 15 mg PO once per day, starting on day 5, "with gradual tapering"
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, monthly dexamethasone {{#subobject:f892de|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa020890 Grier et al. 2003 (INT-0091)]
+
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]
−
|1988-1992
+
| style="background-color:#91cf61" |Phase 2
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VACA.2FIE|VACA/IE]]
 
−
|style="background-color:#d73027"|Inferior OS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: The survival disadvantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
+
*Patients who had platelet counts of less than or equal to 20 x 10<sup>9</sup>/L between cycles received [[Prednisone (Sterapred)]] 0.25 mg/kg PO once per day "between courses"
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup>
+
'''28-day cycle for 6 cycles'''
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] after [[Cyclophosphamide (Cytoxan)]] for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
 
−
'''21-day cycle for 17 cycles'''
 
−
''Local therapy is planned to take place on week 12, as follows:''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Surgical_resection|Surgery]] can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
 
−
**For residual tumor after surgery: 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
 
−
*If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:c30ab5|Variant=1}}===
+
===Regimen variant #5, bi-weekly dexamethasone {{#subobject:8ac5fe|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
+
|[http://www.bloodjournal.org/content/109/4/1401.long Mazzucconi et al. 2007]
−
|style="background-color:#91cf61"|Non-randomized
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Note: This regimen is intended for standard risk patients.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+
*[[Dexamethasone (Decadron)]] by the following criteria:
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
+
**Adults: 40 mg IV or PO once per day on days 1 to 4
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43
+
**Patients less than 15 years old: 20 mg/m<sup>2</sup> (maximum dose of 40 mg) IV or PO once per day on days 1 to 4
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
+
**Patients who had platelet counts of less than or equal to 30 x 10<sup>9</sup>/L between cycles and/or who had bleeding related to thrombocytopenia received 0.035 mg/kg PO once per day "between courses"
−
====Supportive therapy====
+
'''14-day cycle for 4 cycles'''
−
*[[Mesna (Mesnex)]] "as appropriate"
 
−
'''9-week "block", then proceed to local therapy:'''
 
−
====Local therapy====
 
−
*Complete [[Surgery#Surgical_resection|surgical removal]] of tumors is done when possible.
 
−
*Patients not undergoing surgery: [[External beam radiotherapy]] 60 Gy to the tumor bulk, with the tumor-bearing compartment receiving at least 44.8 Gy
 
−
*Patients with incomplete surgical resection or poor histologic response: [[External beam radiotherapy]] 44.8 Gy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#VACA_2|VACA]]
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
+
# Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, Wong WS, Cheng G. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med. 2003 Aug 28;349(9):831-6. [https://doi.org/10.1056/NEJMoa030254 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12944568 PubMed] content property of [http://hemonc.org HemOnc.org]
−
# '''INT-0091:''' Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS; CCG; POG. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. [https://doi.org/10.1056/NEJMoa020890 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12594313 PubMed]
+
# Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, Vianelli N, Avvisati G, Rodeghiero F, Amendola A, Baronci C, Carbone C, Quattrin S, Fioritoni G, D'Alfonso G, Mandelli F; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007 Feb 15;109(4):1401-7. Epub 2006 Oct 31. [http://www.bloodjournal.org/content/109/4/1401.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17077333 PubMed]
−
==VACA/IE {{#subobject:ed89d8|Regimen=1}}==
+
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]
−
VACA/IE: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide
+
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26480931 PubMed]
 +
==Dexamethasone & Eltrombopag {{#subobject:910687|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol {{#subobject:2f582d|Variant=1}}===
+
===Regimen {{#subobject:470504|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa020890 Grier et al. 2003 (INT-0091)]
+
|[http://www.bloodjournal.org/content/123/25/3906.long Gómez-Almaguer et al. 2014]
−
|1988-1992
+
| style="background-color:#ffffbe" |Pilot, <20 pts reported
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#VACA|VACA]]
 
−
|style="background-color:#1a9850"|Superior OS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: The survival advantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, VACA portion====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
+
====Growth factor therapy====
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup>
+
*[[Eltrombopag (Promacta)]] 50 mg PO once per day on days 5 to 33
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
+
'''5-week course'''
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] after [[Cyclophosphamide (Cytoxan)]] for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
 
−
'''21-day cycle, alternating with IE, for 17 total cycles of chemotherapy'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
'''21-day cycle, alternating with VACA, for 17 total cycles of chemotherapy'''
 
−
''Local therapy is planned to take place on week 12, as follows:''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Surgical_resection|Surgery]] can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
 
−
**For residual tumor after surgery, 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
 
−
*If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''INT-0091:''' Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. [https://doi.org/10.1056/NEJMoa020890 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12594313 PubMed]
+
<!-- Presented in an abstract form at the 55th meeting of the American Society of Hematology, New Orleans, LA, December 2013. -->
−
==VAIA {{#subobject:84f65e|Regimen=1}}==
+
# Gómez-Almaguer D, Herrera-Rojas MA, Jaime-Pérez JC, Gómez-De León A, Cantú-Rodríguez OG, Gutiérrez-Aguirre CH, Tarín-Arzaga L, Hernández-Reyes J, Ruiz-Arguelles GJ. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014 Jun 19;123(25):3906-8. Epub 2014 May 6. [http://www.bloodjournal.org/content/123/25/3906.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24802773 PubMed]
−
VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>A</u>'''ctinomycin-D (Dactinomycin)
+
==Dexamethasone & Mycophenolate mofetil {{#subobject:5f56yh|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:195911|Variant=1}}===
+
===Regimen {{#subobject:5yh112|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
+
|[https://doi.org/10.1056/nejmoa2100596 Bradbury et al. 2021 (FLIGHT)]
−
|1992-1997
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#1a9851"|Phase 3 (C)
+
|1. [[#Dexamethasone_monotherapy|Dexamethasone]]<br> 2. [[#Prednisolone_monotherapy_88|Prednisolone]]
−
|[[#EVAIA|EVAIA (high-risk)]]
+
| style="background-color:#1a9850" |Superior treatment failure
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
 
|-
 
|-
 
|}
 
|}
−
''Note: high-risk patients were randomized to this regimen versus EVAIA. Standard-risk patients were not randomized at this point of the protocol.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
+
*[[Dexamethasone (Decadron)]]
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
+
*[[Mycophenolate mofetil (CellCept)]]
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
</div></div>
−
**Note: primary reference does not comment about the use of mesna
+
===References===
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
+
#'''FLIGHT:''' Bradbury CA, Pell J, Hill Q, Bagot C, Cooper N, Ingram J, Breheny K, Kandiyali R, Rayment R, Evans G, Talks K, Thomas I, Greenwood R. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia. N Engl J Med. 2021 Sep 2;385(10):885-895. [https://doi.org/10.1056/nejmoa2100596 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34469646/ PubMed] NCT03156452
−
'''21-day cycle for 4 cycles, then proceed to local therapy:'''
+
==Dexamethasone & Rituximab {{#subobject:b9a6ee|Regimen=1}}==
−
====Local therapy====
 
−
*[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible.
 
−
*For patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: [[External beam radiotherapy]] 54.4 Gy
 
−
*For patients with a good histologic response: [[External beam radiotherapy]] 44.8 Gy
 
−
*Additional details about particular clinical scenarios can be found in the original reference
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*High-risk patients: Adjuvant [[#VAIA_2|VAIA]]
 
−
*Standard-risk patients: Adjuvant [[#VAIA_2|VAIA]] versus [[#VACA_2|VACA]]
 
−
</div></div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:fc21ca|Variant=1}}===
+
===Regimen ("R+3Dex") {{#subobject:d05adc|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
+
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]
−
|style="background-color:#91cf61"|Non-randomized
+
| style="background-color:#ffffbe" |Retrospective
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunosuppressive therapy====
 +
*[[Dexamethasone (Decadron)]] 28 mg/m<sup>2</sup>/day (maximum dose of 40 mg) on days 1 to 4
 +
*[[Rituximab (Rituxan)]] as follows:
 +
**Cycles 1 & 2: 375 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''14-day cycle for 3 cycles'''
 +
</div></div>
 +
===References===
 +
# '''Abstract: Retrospective:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]
 +
==Intravenous immunoglobulin monotherapy {{#subobject:ea894c|Regimen=1}}==
 +
IVIG: '''<u>I</u>'''ntra'''<u>V</u>'''enous '''<u>I</u>'''mmuno'''<u>G</u>'''lobulin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9134b2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
 +
|[https://doi.org/10.1046/j.1365-2141.1999.01766.x Godeau et al. 1999]
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Intravenous_immunoglobulin_monotherapy|IVIG]]; 0.5 g/kg
 +
| style="background-color:#1a9850" |Superior response rate
 
|}
 
|}
−
''Note: This regimen is intended for high risk patients.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
 
 
====Supportive therapy====
 
====Supportive therapy====
−
*[[Mesna (Mesnex)]] "as appropriate"
+
*[[Intravenous immunoglobulin (IVIG)]] 1000 mg/kg IV once on day 1
−
'''9-week "block", then proceed to local therapy:'''
+
'''One dose'''
−
====Local therapy====
 
−
*Complete [[Surgery#Surgical_resection|surgical removal]] of tumors is done when possible.
 
−
*Patients not undergoing surgery: [[External beam radiotherapy]] 60 Gy to the tumor bulk, with the tumor-bearing compartment receiving at least 44.8 Gy
 
−
*Patients with incomplete surgical resection or poor histologic response: [[External beam radiotherapy]] 44.8 Gy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#VAIA_2|VAIA]]
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
+
# Imbach P, Wagner HP, Berchtold W, Gaedicke G, Hirt A, Joller P, Mueller-Eckhardt C, Müller B, Rossi E, Barandun S. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet. 1985 Aug 31;2(8453):464-8. [https://doi.org/10.1016/s0140-6736(85)90400-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2863492 PubMed]
−
# '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
+
# Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, Gent M. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993 Dec;123(6):989-95. [https://doi.org/10.1016/s0022-3476(05)80400-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8229536 PubMed]
−
#'''CWS/RMS-96:''' Sparber-Sauer M, Ferrari A, Kosztyla D, Ladenstein R, Cecchetto G, Kazanowska B, Scarzello G, Ljungman G, Milano GM, Niggli F, Alaggio R, Vokuhl C, Casanova M, Klingebiel T, Zin A, Koscielniak E, Bisogno G. Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer. 2022 Sep;69(9):e29691. Epub 2022 Apr 19. [https://doi.org/10.1002/pbc.29691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35441463/ PubMed]
+
# Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, de Veber B, Israels S, Kobrinsky N, Luke B. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994 Sep 10;344(8924):703-7. [https://doi.org/10.1016/s0140-6736(94)92205-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7915773 PubMed]
−
==VDC/IE {{#subobject:5bcde5|Regimen=1}}==
+
# Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 05 and 1 g/kg bw. Br J Haematol. 1999 Dec;107(4):716-9. [https://doi.org/10.1046/j.1365-2141.1999.01766.x link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10606875 PubMed]
−
VDC/IE: '''<u>V</u>'''incristine, '''<u>D</u>'''oxorubicin, '''<u>C</u>'''yclophosphamide, alternating with '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide
+
# Godeau B, Chevret S, Varet B, Lefrère F, Zini JM, Bassompierre F, Chèze S, Legouffe E, Hulin C, Grange MJ, Fain O, Bierling P; French ATIP Study Group. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet. 2002 Jan 5;359(9300):23-9. [https://doi.org/10.1016/S0140-6736(02)07275-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11809183 PubMed]
−
<br>VAdriaC/IE: '''<u>V</u>'''incristine, '''<u>Adria</u>'''mycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, alternating with '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide
+
# '''TIKI:''' Heitink-Pollé KMJ, Uiterwaal CSPM, Porcelijn L, Tamminga RYJ, Smiers FJ, van Woerden NL, Wesseling J, Vidarsson G, Laarhoven AG, de Haas M, Bruin MCA; TIKI Investigators. Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial. Blood. 2018 Aug 30;132(9):883-891. Epub 2018 Jun 26. [http://www.bloodjournal.org/content/132/9/883.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/29945954 PubMed]
 +
==Mycophenolate mofetil & Prednisolone {{#subobject:5f5dab|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, q2wk {{#subobject:47963f|Variant=1}}===
+
===Regimen {{#subobject:dacj12|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ Womer et al. 2012 (AEWS0031)]
+
|[https://doi.org/10.1056/nejmoa2100596 Bradbury et al. 2021 (FLIGHT)]
−
|2001-2005
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
|1. [[#Dexamethasone_monotherapy|Dexamethasone]]<br> 2. [[#Prenisolone_monotherapy_88|Prednisolone]]
−
|[[#VDC.2FIE|VDC/IE]]; standard
+
| style="background-color:#1a9850" |Superior treatment failure
−
| style="background-color:#91cf60" |Seems to have superior EFS
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, VDC portion====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] as follows:
+
*[[Mycophenolate mofetil (CellCept)]]
−
**Cycles 1, 3, 5: 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Prednisolone (Millipred)]]
−
*[[Doxorubicin (Adriamycin)]] as follows:
+
</div></div>
−
**Cycles 1, 3, 5: 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
===References===
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
+
#'''FLIGHT:''' Bradbury CA, Pell J, Hill Q, Bagot C, Cooper N, Ingram J, Breheny K, Kandiyali R, Rayment R, Evans G, Talks K, Thomas I, Greenwood R. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia. N Engl J Med. 2021 Sep 2;385(10):885-895. [https://doi.org/10.1056/nejmoa2100596 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34469646/ PubMed] NCT03156452
−
**Cycles 1, 3, 5: 1200 mg/m<sup>2</sup> IV once on day 1
+
==Prednisone monotherapy {{#subobject:5f27f2|Regimen=1}}==
−
====Supportive therapy, VDC portion====
 
−
*[[Mesna (Mesnex)]] as follows:
 
−
**Cycles 1, 3, 5: with [[Cyclophosphamide (Cytoxan)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]] as follows:
 
−
**Cycles 1, 3, 5: Schedule not specified
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] as follows:
 
−
**Cycles 2, 4, 6: 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] as follows:
 
−
**Cycles 2, 4, 6: 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy, IE portion====
 
−
*[[Mesna (Mesnex)]] as follows:
 
−
**Cycles 2, 4, 6: with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]] as follows:
 
−
**Cycles 2, 4, 6: Schedule not specified
 
−
'''14-day cycle for 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Local therapy, then adjuvant [[#VDC.2FIE_88|VDC/IE]]
 
−
</div></div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol variant #2, q2wk with extra vincristine {{#subobject:4ug63f|Variant=1}}===
+
===Regimen variant #1 {{#subobject:d3c7eb|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677904/ Leavey et al. 2021 (COG AEWS1031)]
+
|[http://www.bloodjournal.org/content/127/3/296.long Wei et al. 2015]
−
|2010-2016
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|style="background-color:#1a9851"|Phase 3 (C)
+
|[[#Dexamethasone_monotherapy|Dexamethasone]]
−
|[[#VDC.2FIE.2FVTC_99|VDC/IE/VTC]]
+
| style="background-color:#d73027" |Inferior CR rate
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: the only difference between this and the variant above is the additional dose of vincristine in the second week of each VDC cycle.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, VDC portion====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
+
*[[Prednisone (Sterapred)]] as follows:
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
**Days 1 to 28: 1 mg/kg/day PO
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
+
**Day 29 onwards: tapered over 4 to 6 weeks with a goal of maintenance dosing less than 15 mg/day or "complete termination"
−
====Supportive therapy====
+
***Taper schedule determined by treating physician
−
*[[Filgrastim (Neupogen)]]
 
−
'''14-day cycle, alternating with IE, for 6 total cycles of chemotherapy'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''14-day cycle, alternating with VDC, for 6 total cycles of chemotherapy'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Local therapy, then [[#VDC.2FIE_88|VDC/IE]] continuation
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol variant #3, q3wk {{#subobject:6c6df0|Variant=1}}===
+
===Regimen variant #2 {{#subobject:7c003e|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ Womer et al. 2012 (AEWS0031)]
+
|[http://www.bloodjournal.org/content/122/21/325 Matschke et al. 2013]
−
|2001-2005
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|style="background-color:#1a9851"|Phase 3 (C)
+
|[[#Dexamethasone_monotherapy|Dexamethasone]]
−
|[[#VDC.2FIE|VDC/IE]]; dose-intense
+
| style="background-color:#fc8d59" |Seems to have inferior responding patients maintaining remission for at least 6 mo
−
| style="background-color:#fc8d59" |Seems to have inferior EFS
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, VDC portion====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Prednisone (Sterapred)]] as follows:
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
**Weeks 1 to 2: 1 mg/kg/day PO
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
+
**Weeks 3 to 19: Tapered over 19 weeks with a goal of maintenance dosing less than 7.5 mg/day at the end of week 19
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Cyclophosphamide (Cytoxan)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''21-day cycle, alternating with IE, for 4 total cycles of chemotherapy'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''21-day cycle, alternating with VDC, for 4 total cycles of chemotherapy'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Local therapy, then adjuvant [[#VDC.2FIE_88|VDC/IE]]
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''AEWS0031:''' Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR; Children's Oncology Group. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012 Nov 20;30(33):4148-54. Epub 2012 Oct 22. Erratum in: J Clin Oncol. 2015 Mar 1;33(7):814. Dosage error in article text. [https://doi.org/10.1200/JCO.2011.41.5703 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23091096 PubMed] NCT00006734
+
# Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, Gent M. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993 Dec;123(6):989-95. [https://doi.org/10.1016/s0022-3476(05)80400-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8229536 PubMed]
−
# '''COG AEWS1031:''' Leavey PJ, Laack NN, Krailo MD, Buxton A, Randall RL, DuBois SG, Reed DR, Grier HE, Hawkins DS, Pawel B, Nadel H, Womer RB, Letson GD, Bernstein M, Brown K, Maciej A, Chuba P, Ahmed AA, Indelicato DJ, Wang D, Marina N, Gorlick R, Janeway KA, Mascarenhas L. Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report. J Clin Oncol. 2021 Dec 20;39(36):4029-4038. Epub 2021 Oct 15. [https://doi.org/10.1200/jco.21.00358 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677904/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34652968 PubMed] NCT01231906
+
# Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, de Veber B, Israels S, Kobrinsky N, Luke B. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994 Sep 10;344(8924):703-7. [https://doi.org/10.1016/s0140-6736(94)92205-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7915773 PubMed]
−
==VIDE {{#subobject:be5278|Regimen=1}}==
+
# '''Abstract:''' Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. [http://www.bloodjournal.org/content/122/21/325 link to abstract]
−
VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide
+
# Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/127/3/296.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26480931 PubMed]
 +
==RhIG monotherapy {{#subobject:3ab9b6|Regimen=1}}==
 +
RhIG: '''<u>Rh</u>'''o(D) '''<u>I</u>'''mmune '''<u>G</u>'''lobulin
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:6b3582|Variant=1}}===
+
===Regimen variant #1, 25 mcg/kg {{#subobject:8335a6|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 50%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://doi.org/10.1002/pbc.20820 Juergens et al. 2006 (EURO-E.W.I.N.G. 99)]
+
|[http://www.bloodjournal.org/content/77/9/1884 Bussel et al. 1991]
−
|NR in abstract
+
| style="background-color:#91cf61" |Phase 2
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[https://doi.org/10.1200/jco.21.01942 Koch et al. 2022 (Ewing 2008R3)]
 
−
|2009-2018
 
−
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Eligibility: RhD-positive.''
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV push once on day 1
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 1 to 3 hours once per day on days 1 to 3
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
 
====Supportive therapy====
 
====Supportive therapy====
−
*[[Mesna (Mesnex)]] 1000 mg/m<sup>2</sup> IV push once on day 1; 60 minutes prior to [[Ifosfamide (Ifex)]], then 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours (total dose per cycle: 10,000 mg/m<sup>2</sup>)
+
*[[Rho(D) immune globulin (RhoGAM)]] 25 mcg/kg IV once on day 1, repeated as needed on days 3 & 4
−
*2 to 3 liters/m<sup>2</sup> hydration per day
+
'''4-day course'''
−
*Recommended, but not required: [[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 4 to 13, starting 24 hours after completion of chemotherapy
 
−
'''21-day cycle for 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*EURO-E.W.I.N.G. 99: Further therapy is dictated by patient characteristics & response; details can be found in the primary reference
 
−
*Ewing 2008R3: Surgery when feasible, then [[#VAC_88|VAC]] x 8 or [[#VAI|VAI]] x 8, then [[#Treosulfan_.26_Melphalan.2C_then_auto_HSCT_99|Treosulfan & Melphalan, then auto HSCT]] versus [[#Observation_88|No further treatment]]
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:bd4d04|Variant=1}}===
+
===Regimen variant #2, 50 mcg/kg {{#subobject:487067|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 25%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
+
|[https://doi.org/10.1046/j.1365-2141.2001.02627.x Newman et al. 2001]
−
|NR in abstract
+
| style="background-color:#91cf61" |Randomized Phase 2, <20 pts (C)
−
|style="background-color:#91cf61"|Phase 2
+
|[[#RhIG_monotherapy|Rho(D)]]; 75 mcg/kg
 +
| style="background-color:#fc8d59" |Seems to have inferior platelet effect
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''
−
====Chemotherapy====
+
====Supportive therapy====
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Rho(D) immune globulin (RhoGAM)]] 50 mcg/kg IV once on day 1
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
 
====Supportive therapy====
 
====Supportive therapy====
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m<sup>2</sup>)
+
*[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1, prior to therapy
−
'''21-day cycle for up to 6 cycles'''
+
*[[Prednisone (Sterapred)]] 20 mg PO once on day 1, prior to therapy
−
</div>
+
'''One dose; can be repeated if required to increase platelet count'''
−
<div class="toccolours" style="background-color:#cbd5e7">
+
</div></div><br>
−
====Subsequent treatment====
 
−
*Patients with resectable localized disease: complete [[Surgery#Surgical_resection|surgical removal]] of tumors when possible, then adjuvant [[#VAI|VAI]]
 
−
*Patients with unresectable localized disease: [[#VAI|VAI & RT]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
# '''EURO-E.W.I.N.G. 99:''' Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-EWING 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. [https://doi.org/10.1002/pbc.20820 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16572419 PubMed]
 
−
# '''Euro-EWING99-R1:''' Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. [https://doi.org/10.1200/JCO.2013.54.4833 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/24982464 PubMed] NCT00020566
 
−
#'''Ewing 2008R3:''' Koch R, Gelderblom H, Haveman L, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Eich HT, Renard M, Hauser P, Burdach S, Bovee J, Bonar F, Reichardt P, Kruseova J, Hardes J, Kühne T, Kessler T, Collaud S, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Hong A, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Metzler M, Hartmann W, Hjorth L, Bhadri V, Dirksen U. High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. J Clin Oncol. 2022 Jul 20;40(21):2307-2320. Epub 2022 Apr 15. [https://doi.org/10.1200/jco.21.01942 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/35427190/ PubMed] NCT00987636
 
−
=Adjuvant therapy=
 
−
==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}==
 
−
BuMel: '''<u>Bu</u>'''sulfan & '''<u>Mel</u>'''phalan
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:75d2e0|Variant=1}}===
+
===Regimen variant #3, 75 mcg/kg {{#subobject:b30788|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997]
+
|[https://doi.org/10.1046/j.1365-2141.2001.02627.x Newman et al. 2001]
−
|NR
+
| style="background-color:#91cf61" |Randomized Phase 2, <20 pts (E-esc)
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
+
|[[#RhIG_monotherapy|Rho(D)]]; 50 mcg/kg
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#91cf60" |Seems to have superior platelet effect
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090/ Whelan et al. 2018 (R2Loc)]
 
−
|2000-2015
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Ewing_sarcoma#VAI|VAI]]
 
−
| style="background-color:#91cf60" |Seems to have superior OS
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
+
''Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 10<sup>9</sup>/L.''
−
====Preceding treatment====
+
====Supportive therapy====
−
*[[#VIDE|VIDE]] x 6, then [[Surgery#Surgical_resection|surgery]], then [[#VAI|VAI]] x 1
+
*[[Rho(D) immune globulin (RhoGAM)]] 75 mcg/kg IV once on day 1
−
{{#lst:Autologous HSCT|75d2e0}}
+
====Supportive therapy====
 +
*[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1, prior to therapy
 +
*[[Prednisone (Sterapred)]] 20 mg PO once on day 1, prior to therapy
 +
'''One dose; can be repeated if required to increase platelet count'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. [https://doi.org/10.1038/sj.bmt.1700992 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9404924 PubMed]
+
# Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 1;77(9):1884-93. [http://www.bloodjournal.org/content/77/9/1884 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1850307 PubMed]  
−
# '''R2Loc:''' Whelan J, Le Deley MC, Dirksen U, Le Teuff G, Brennan B, Gaspar N, Hawkins DS, Amler S, Bauer S, Bielack S, Blay JY, Burdach S, Castex MP, Dilloo D, Eggert A, Gelderblom H, Gentet JC, Hartmann W, Hassenpflug WA, Hjorth L, Jimenez M, Klingebiel T, Kontny U, Kruseova J, Ladenstein R, Laurence V, Lervat C, Marec-Berard P, Marreaud S, Michon J, Morland B, Paulussen M, Ranft A, Reichardt P, van den Berg H, Wheatley K, Judson I, Lewis I, Craft A, Juergens H, Oberlin O; Euro-EWING-99 and EWING-2008 Investigators. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-EWING99 and Ewing-2008. J Clin Oncol. 2018 Nov 1;36(31):3110-9. Epub 2018 Sep 6. [https://doi.org/10.1200/JCO.2018.78.2516 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30188789 PubMed] NCT00020566
+
# Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/day of iv anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/day in adults with immune thrombocytopenic purpura. Br J Haematol. 2001 Mar;112(4):1076-8. [https://doi.org/10.1046/j.1365-2141.2001.02627.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11298610 PubMed]
−
==EVAIA {{#subobject:a56448|Regimen=1}}==
+
==TT4 {{#subobject:d5ad89|Regimen=1}}==
−
EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin
+
TT4: '''<u>T</u>'''riple '''<u>T</u>'''herapy (4?)
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:342685|Variant=1}}===
+
===Regimen {{#subobject:be2a8d|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ Choi et al. 2015]
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Note: This regimen is intended for high-risk patients.''
+
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''
−
<div class="toccolours" style="background-color:#cbd5e8">
+
====Immunosuppressive therapy====
−
====Preceding treatment====
+
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1 to 4
−
*Neoadjuvant [[#EVAIA|EVAIA]] and [[Surgery#Surgical_resection|local therapy]]
+
*[[Cyclosporine|Cyclosporine A]] 2.5 to 3 mg/kg/day PO on days 1 to 28
−
</div>
+
**Dose adjusted for target trough of 200 to 400 mcg/L
−
<div class="toccolours" style="background-color:#b3e2cd">
+
*[[Rituximab (Rituxan)]] 100 mg IV once per day on days 7, 14, 21, 28
−
====Chemotherapy====
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of Mesna (Mesnex)
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 10 cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
+
# Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood. 2015 Jul 23;126(4):500-3. Epub 2015 May 13. [http://www.bloodjournal.org/content/126/4/500.long link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560338/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25972158 PubMed]
−
 
+
=Relapsed or refractory=
−
==VACA {{#subobject:f92366|Regimen=1}}==
+
==ATRA & Danazol {{#subobject:43e110|Regimen=1}}==
−
VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:835ca4|Variant=1}}===
+
===Regimen {{#subobject:077574|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
+
|[https://doi.org/10.1016/S2352-3026(17)30170-9 Feng et al. 2017 (U1111-1132-6877)]
−
|1992-1997
+
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+
|[[#Danazol_monotherapy|Danazol]]
−
|[[#VAIA_2|VAIA]]
+
| style="background-color:#1a9850" |Superior 12-month sustained response
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen was intended for standard-risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VAIA|VAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
+
*[[All-trans retinoic acid (ATRA)]] 10 mg PO twice per day
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
+
====Endocrine therapy====
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
+
*[[Danazol (Danocrine)]] 200 mg PO twice per day
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
+
'''16-week course'''
−
'''21-day cycle for 10 cycles'''
+
</div></div>
−
</div></div><br>
+
===References===
 +
# '''U1111-1132-6877:''' Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://doi.org/10.1016/S2352-3026(17)30170-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28917657 PubMed] NCT01667263
 +
==Avatrombopag monotherapy {{#subobject:c8da29|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:26bab6|Variant=1}}===
+
===Regimen {{#subobject:1aab54|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
+
|[https://doi.org/10.1111/bjh.15573 Jurczak et al. 2018 (E5501-G000-302)]
−
|style="background-color:#91cf61"|Non-randomized
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior cumulative weeks of platelet response
 
|-
 
|-
 
|}
 
|}
−
''Note: This regimen is intended for standard risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VACA|VACA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Growth factor therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+
*[[Avatrombopag (Doptelet)]]
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
+
</div></div>
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43
+
===References===
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
+
# Bussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, Tang S, McIntosh J. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014 Jun 19;123(25):3887-94. Epub 2014 May 6. [http://www.bloodjournal.org/content/123/25/3887.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/24802775 PubMed]
−
====Supportive therapy====
+
# '''E5501-G000-302:''' Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, Allen LF. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018 Nov;183(3):479-490. Epub 2018 Sep 7. [https://doi.org/10.1111/bjh.15573 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30191972 PubMed]
−
*[[Mesna (Mesnex)]] "as appropriate"
+
==Cyclosporine monotherapy {{#subobject:4d3847|Regimen=1}}==
−
'''9-week "block" for 3 blocks'''
 
−
</div></div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3 {{#subobject:26bab6|Variant=1}}===
+
===Regimen {{#subobject:df1b55|Variant=1}}===
−
{| class="wikitable" style="width: 60%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 50%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://www.ejcancer.com/article/S0959-8049(97)00043-9/pdf Craft et al. 1997 (ET-1)]
+
|[http://www.bloodjournal.org/content/99/4/1482 Emilia et al. 2002]
−
|1978-1986
+
| style="background-color:#ffffbe" |Pilot, <20 pts
−
|style="background-color:#91cf61"|Non-randomized (RT)
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.''
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]]
+
*[[Cyclosporine|Cyclosporine A]] as follows:
−
*[[Doxorubicin (Adriamycin)]]
+
**Days 1 to 6: 5 mg/kg/day PO split into twice per day dosing
−
*[[Cyclophosphamide (Cytoxan)]]
+
**Day 7 onwards: 2.5 to 3 mg/kg/day PO with dose adjusted for target trough of 200 to 400 mcg/L
−
*[[Dactinomycin (Cosmegen)]]
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''ET-1:''' Craft AW, Cotterill SJ, Bullimore JA, Pearson D; United Kingdom Children's Cancer Study Group; Medical Research Council Bone Sarcoma Working Party. Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). Eur J Cancer. 1997 Jun;33(7):1061-9. [https://www.ejcancer.com/article/S0959-8049(97)00043-9/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/9376188 PubMed]
+
# Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, Ferrara L, D'Apollo N, Potenza L, Bertesi M, Torelli G. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002 Feb 15;99(4):1482-5. [http://www.bloodjournal.org/content/99/4/1482 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11830504 PubMed]
−
# '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
+
==Danazol monotherapy {{#subobject:e7bf80|Regimen=1}}==
−
# '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
==VAI {{#subobject:560a3d|Regimen=1}}==
 
−
VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide
 
−
<br>IVA: '''<u>I</u>'''fosfamide, '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, capped dactinomycin {{#subobject:9b2e40|Variant=1}}===
+
===Regimen {{#subobject:9a63e6|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|-
 +
|[https://doi.org/10.1056/NEJM198306093082306 Ahn et al. 1983]
 +
| style="background-color:#91cf61" |Pilot, >20 pts
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2013.54.4833 Le Deley et al. 2014 (Euro-EWING99-R1)]
+
|[https://doi.org/10.1016/S2352-3026(17)30170-9 Feng et al. 2017 (U1111-1132-6877)]
−
|2000-2010
+
| style="background-color:#1a9851" |Randomized Phase 2 (C)
−
| style="background-color:#1a9851" |Phase 3 (C)
+
|[[#ATRA_.26_Danazol|ATRA & Danazol]]
−
|[[#VAC_99|VAC]]
+
| style="background-color:#d73027" |Inferior 12-month sustained response
−
| style="background-color:#ffffbf" |Inconclusive whether non-inferior EFS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+
''Note: Ahn et al. 1983 gave a range of 200 mg PO from two to four times per day; the dose below is from U1111-1132-6877''
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VIDE|VIDE]] x 6, then complete [[Surgery#Surgical_resection|surgical excision]] if feasible; radiotherapy if surgery incomplete or infeasible
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Endocrine therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Danazol (Danocrine)]] 200 mg PO twice per day
−
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> (maximum dose of 1.5 mg) IV once per day on days 1 & 2
+
'''16-week course'''
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
</div></div>
−
====Supportive therapy====
+
===References===
−
*[[Mesna (Mesnex)]] is not described
+
# Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med. 1983 Jun 9;308(23):1396-9. [https://doi.org/10.1056/NEJM198306093082306 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6682484 PubMed]
−
'''21-day cycle for 8 cycles'''
+
# '''U1111-1132-6877:''' Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. [https://doi.org/10.1016/S2352-3026(17)30170-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28917657 PubMed] NCT01667263
−
</div></div><br>
+
==Dexamethasone monotherapy {{#subobject:a6cd06|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, uncapped dactinomycin {{#subobject:ddb896|Variant=1}}===
+
===Regimen {{#subobject:8c260f|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
+
|[https://doi.org/10.1056/NEJM199406023302203 Andersen 1994]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#ffffbe" |Pilot, <20 pts
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VIDE|VIDE]] and [[Surgery#Surgical_resection|local therapy]] if it was possible
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
−
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
'''28-day cycles for 6 cycles'''
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*If appropriate, concurrent radiation therapy given sometime during the first 3 cycles
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for up to 8 cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
+
# Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994 Jun 2;330(22):1560-4. [https://doi.org/10.1056/NEJM199406023302203 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8177245 PubMed]
−
# '''Euro-EWING99-R1:''' Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. [https://doi.org/10.1200/JCO.2013.54.4833 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24982464 PubMed] NCT00020566
+
==Dexamethasone & Rituximab {{#subobject:52f32|Regimen=1}}==
−
==VAIA {{#subobject:05e476|Regimen=1}}==
 
−
VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>A</u>'''ctinomycin-D (Dactinomycin)
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:f72b80|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
 
−
|1992-1997
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VACA_2|VACA (standard-risk)]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
−
|-
 
−
|}
 
−
''Note: standard-risk patients were randomized to this regimen versus VACA. High-risk patients were not randomized at this point of the protocol.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VAIA|VAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of mesna
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 10 cycles'''
 
−
</div></div><br>
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:7bd984|Variant=1}}===
+
===Regimen ("R+3Dex") {{#subobject:abae3b|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
+
|[http://www.bloodjournal.org/content/122/21/2310 Imahiyerobo et al. 2013]
−
|style="background-color:#91cf61"|Non-randomized
+
| style="background-color:#ffffbe" |Retrospective
 
|-
 
|-
 
|}
 
|}
−
''Note: This regimen is intended for high risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VAIA|VAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+
*[[Dexamethasone (Decadron)]] 28 mg/m<sup>2</sup>/day (maximum dose of 40 mg) on days 1 to 4
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
+
*[[Rituximab (Rituxan)]] as follows:
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44
+
**Cycles 1 & 2: 375 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
+
'''14-day cycle for 3 cycles'''
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] "as appropriate"
 
−
'''9-week "block" for 3 blocks'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''CESS 86:''' Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
+
# '''Abstract:''' Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. [http://www.bloodjournal.org/content/122/21/2310 link to abstract]
−
# '''EICESS-92:''' Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
+
==Eltrombopag monotherapy {{#subobject:170bd|Regimen=1}}==
−
=Relapsed or refractory or metastatic=
 
−
==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, PO busulfan, mel 140 mg/m<sup>2</sup> {{#subobject:75d2e0|Variant=1}}===
+
===Regimen variant #1 {{#subobject:90336c|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 25%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997]
+
|[https://doi.org/10.1016/S0140-6736(15)61107-2 Grainger et al. 2015 (PETIT2)]
−
|NR
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
+
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior durable platelet response
 
|-
 
|-
 
|}
 
|}
−
{{#lst:Autologous HSCT|75d2e0}}
+
''This regimen was intended for pediatric patients.''
 +
====Growth factor therapy====
 +
*[[Eltrombopag (Promacta)]] with starting dose by the following criteria:
 +
**Age 6 to 17, weighing at least 27kg, non-east Asian: 50 mg PO once per day
 +
**Age 6 to 17, weighing at least 27kg, east Asian: 25 mg PO once per day
 +
**Age 6 to 17, weighing less than 27kg, non-east Asian: 37.5 mg PO once per day
 +
**Age 6 to 17, weighing less than 27kg, east Asian: 25 mg PO once per day
 +
**Age 1 to 5, non-east Asian: 1.2 mg/kg/day oral suspension
 +
**Age 1 to 5, east Asian: 0.8 mg/kg/day oral suspension
 +
'''Dose adjusted to a maximum of 75 mg/day, with temporary discontinuation for platelet count greater than 400 x 10<sup>9</sup>/L'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, PO busulfan, mel 160 mg/m<sup>2</sup> {{#subobject:75d2e1|Variant=1}}===
+
===Regimen variant #2 {{#subobject:5912e7|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 25%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997]
+
|[https://doi.org/10.1016/S0140-6736(09)60402-5 Bussel et al. 2009 (TRA100773)]
−
|NR
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
+
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior plt count of greater than or equal to 50 x 10<sup>9</sup>/L on day 43
 
|-
 
|-
 
|}
 
|}
−
{{#lst:Autologous HSCT|75d2e1}}
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Growth factor therapy====
 +
*[[Eltrombopag (Promacta)]] 50 mg (starting dose) PO once per day
 +
'''The dose could be increased from 50 mg to 75 mg after 3 weeks in patients whose platelet counts were less than 50 x 10<sup>9</sup>/L. Treatment was discontinued in patients who attained a platelet count greater than 200 x 10<sup>9</sup>/L'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3, IV busulfan {{#subobject:a61951|Variant=1}}===
+
===Regimen variant #3 {{#subobject:9ac7d2|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
+
|[https://doi.org/10.1016/S0140-6736(10)60959-2 Cheng et al. 2010 (RAISE-ITP)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior RR
 
|-
 
|-
 
|}
 
|}
−
''Note that melphalan is reported as given on day 2 (not day -2) in the original reference but this is surely an error.''
+
''Note: this trial should not be confused with the trial by the same name in colorectal cancer.''
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#VAI_2|VAI]] x 1 or more cycles
 
−
{{#lst:Autologous HSCT|a61951}}
 
−
</div></div>
 
−
===References===
 
−
# Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. [https://doi.org/10.1038/sj.bmt.1700992 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9404924 PubMed]
 
−
# Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
==Cyclophosphamide & Topotecan {{#subobject:2535b6|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, standard-dose {{#subobject:f13281|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.15.3463 Saylors et al. 2001]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Growth factor therapy====
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
+
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with dose modifications:
−
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given second'''
+
**Increase to 75 mg PO once per day allowed after day 22 for patients with platelet counts lower than 50 x 10<sup>9</sup>/L
−
====Supportive therapy====
+
**Decrease to 25 mg PO once per day required for platelets counts between 200 and 400 x 10<sup>9</sup>/L
−
*500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
+
**Drug was held for platelet count greater than 400 x 10<sup>9</sup>/L, until platelet count dropped below 150 x 10<sup>9</sup>/L
−
*[[:Category:Emesis_prevention|Antiemetics]] once per day on days 1 to 5, prior to chemotherapy
+
'''6-month course'''
−
*3 liters/m<sup>2</sup> IV or PO over 24 hours after chemotherapy
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 1500/uL above nadir
 
−
'''21-day cycle for 12 to 14 cycles'''
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, standard-dose with local therapy {{#subobject:c531e2|Variant=1}}===
+
===Regimen variant #4 {{#subobject:b1f517|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1002/pbc.20719 Hunold et al. 2006]
+
|[https://doi.org/10.1056/NEJMoa073275 Bussel et al. 2007 (TRA100773)]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior RR
 
|-
 
|-
 
|}
 
|}
−
''Note: Some guidelines state that vincristine can be added to this regimen. No primary reference for this is available.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Growth factor therapy====
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
+
*[[Eltrombopag (Promacta)]] 50 mg PO once per day
−
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
+
'''Up to 6-week course'''
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]], antiemetics, fluids, and [[Filgrastim (Neupogen)]] "according to institutional standards"
 
−
'''21-day cycle for 12 to 14 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Surgical candidate lesions: [[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible.
 
−
*All other lesions: [[External beam radiotherapy]]
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3, high-dose {{#subobject:230266|Variant=1}}===
+
===Regimen variant #5 {{#subobject:55f69d|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1002/1096-911X%2820001101%2935:5%3C468::AID-MPO5%3E3.0.CO;2-P Kushner et al. 2000]
+
|[http://www.bloodjournal.org/content/121/3/537.long Saleh et al. 2012 (EXTEND)]
−
|style="background-color:#91cf61"|Non-randomized
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Growth factor therapy====
−
*[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given second''' (total dose per cycle: 4200 mg/m<sup>2</sup>)
+
*[[Eltrombopag (Promacta)]] 50 mg PO once per day, with adjustments:
−
**Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 140 mg/kg)
+
''Dose and schedule were individualized with the goal of achieving and maintaining platelets between 50 and 200 x 10<sup>9</sup>/L.''
−
*[[Topotecan (Hycamtin)]] 2 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given third''' (total dose per cycle: 6 mg/m<sup>2</sup>)
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 2100 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given first''' (total dose per cycle: 6300 mg/m<sup>2</sup>)
 
−
**Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 210 mg/kg)
 
−
***If body surface area less than 1 m<sup>2</sup>, mesna is given in 500 mL NS over 24 hours
 
−
***If body surface area is at least 1 m<sup>2</sup>, mesna is given in 1000 mL NS over 24 hours
 
−
*On day 1, prior to chemotherapy, 20 mL/kg NS IV over 30 minutes, then D5 1/2 NS with 15 mEq KCl per 500 mL at 200 mL/m<sup>2</sup>/H until urine specific gravity less than 1.010, then start mesna & cyclophosphamide
 
−
*Additional hydration fluid on days 1 & 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3000 mL/m<sup>2</sup>/24 hours
 
−
*Additional hydration fluid on day 3 at 150 mL/m<sup>2</sup>/hour for 6 to 12 hours after completion of cyclophosphamide infusion
 
−
*Cyclophosphamide is given in D5NS with 10 mEq potassium chloride (KCl) and 5 mg [[Furosemide (Lasix)]] per 500 mL fluid. 500 mL total volume is used for patients with body surface area less than 1 m<sup>2</sup>; 1000 mL total volume is used for patients with BSA of at least 1 m<sup>2</sup>
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 5, to continue until ANC is at least 1000/uL
 
−
'''Subsequent cycles to start when ANC greater than 1000/uL and platelets greater than 75 x 10<sup>9</sup>/L'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000 Nov;35(5):468-74. [https://doi.org/10.1002/1096-911X%2820001101%2935:5%3C468::AID-MPO5%3E3.0.CO;2-P link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11070479 PubMed]
+
# '''TRA100773:''' Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. [https://doi.org/10.1056/NEJMoa073275 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18046028 PubMed] NCT00102739
−
# Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. [https://doi.org/10.1200/jco.2001.19.15.3463 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11481351 PubMed]
+
# '''TRA100773:''' Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://doi.org/10.1016/S0140-6736(09)60402-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19231632 PubMed] NCT00102739
−
# Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006 Nov;47(6):795-800. [https://doi.org/10.1002/pbc.20719 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16411206 PubMed]
+
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://doi.org/10.1016/S0140-6736(10)60959-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20739054 PubMed] NCT00370331
−
==Docetaxel & Gemcitabine {{#subobject:f4062c|Regimen=1}}==
+
# '''EXTEND:''' Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537-45. Epub 2012 Nov 20. [http://www.bloodjournal.org/content/121/3/537.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23169778 PubMed]
 +
# '''PETIT2:''' Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://doi.org/10.1016/S0140-6736(15)61107-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26231455 PubMed] NCT01520909
 +
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://doi.org/10.1111/bjh.14380 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27734464 PubMed]
 +
==Fostamatinib monotherapy {{#subobject:ddb228|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a99189|Variant=1}}===
+
===Regimen {{#subobject:85221f|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
!style="width: 20%"|Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055608/ Bussel et al. 2018 (FIT1)]
 +
|2014-2016
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior stable response
 
|-
 
|-
−
|[https://doi.org/10.1002/cncr.23586 Navid et al. 2008]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055608/ Bussel et al. 2018 (FIT2)]
−
|style="background-color:#ffffbe"|Retrospective
+
|2015-2016
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior stable response
 
|-
 
|-
 
|}
 
|}
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. Only 2 of the 22 patients in this retrospective review had Ewing sarcoma.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Targeted therapy====
−
*[[Docetaxel (Taxotere)]] 75 to 100 mg/m<sup>2</sup> IV over 60 minutes once on day 8, '''given second'''
+
*[[Fostamatinib (Tavalisse)]] 100 mg PO twice per day  
−
*[[Gemcitabine (Gemzar)]] 675 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8, '''given first on day 8'''
+
**Dose may be increased to 150 mg PO twice per day after 4 weeks if needed to achieve platelet count of at least 50
−
====Supportive therapy====
+
'''24-week course'''
−
*[[Ondansetron (Zofran)]] once per day on days 1 & 8, prior to chemotherapy
 
−
*[[Dexamethasone (Decadron)]] starting either the day before or the day of [[Docetaxel (Taxotere)]], and continued for 2 days after [[Docetaxel (Taxotere)]]
 
−
*H1 or H2 blockers such as [[Diphenhydramine (Benadryl)]] and [[Ranitidine (Zantac)]] prior to chemotherapy on days 1 & 8 per physician discretion
 
−
*Some patients received [[Filgrastim (Neupogen)]] starting on day 9
 
−
'''21-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. [https://doi.org/10.1002/cncr.23586 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18484657 PubMed]
+
# '''FIT1:''' Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, Hellmann A, Windyga J, Sivcheva L, Khalafallah AA, Zaja F, Cooper N, Markovtsov V, Zayed H, Duliege AM. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018 Jul;93(7):921-930. Epub 2018 May 15. [https://doi.org/10.1002/ajh.25125 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055608/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29696684 PubMed] NCT02076399
−
==ICE {{#subobject:456f0a|Regimen=1}}==
+
# '''FIT2:''' Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, Hellmann A, Windyga J, Sivcheva L, Khalafallah AA, Zaja F, Cooper N, Markovtsov V, Zayed H, Duliege AM. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018 Jul;93(7):921-930. Epub 2018 May 15. [https://doi.org/10.1002/ajh.25125 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055608/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29696684 PubMed] NCT02076412
−
ICE: '''<u>I</u>'''fosfamide, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide
+
# '''Review:''' Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018 Jan;10(1):9-25. [https://www.futuremedicine.com/doi/10.2217/imt-2017-0097?url_ver=Z39.88-2003 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967793 PubMed]
 +
==Mycophenolate mofetil monotherapy {{#subobject:ddb338|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:d99fb7|Variant=1}}===
+
===Regimen {{#subobject:850f1f|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005]
+
|[https://doi.org/10.1111/bjh.13622 Taylor et al. 2015]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#ffffbe" |Retrospective
 
|-
 
|-
 
|}
 
|}
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. The reference did not mention [[Mesna (Mesnex)]] being used.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
*[[Mycophenolate mofetil (CellCept)]] 1 gm/day PO
−
*[[Carboplatin (Paraplatin)]] 400 mg/m<sup>2</sup> IV "for 2 days"
+
'''Continued indefinitely'''
−
**Note: the reference did not explicitly say which 2 days carboplatin should be given on
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*Depending on the study the patients were enrolled on, they received one of the following:
 
−
**CCG-0894: [[Filgrastim (Neupogen)]] 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/uL, or until ANC is at least 1000/uL post nadir, whichever comes later
 
−
**CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m<sup>2</sup> SC once per day or 500 mcg/m<sup>2</sup> SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/uL or platelet count is at least 900 x 10<sup>9</sup>/L for 2 days between days 13 to 18, or until ANC is at least 1000/uL and platelet count is at least 100 x 10<sup>9</sup>/L, whichever comes later
 
−
**CCG-0931: [[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/uL, and IL-6 is continued until platelets are at least 100 x 10<sup>9</sup>/L for 2 consecutive days or until day 35, whichever comes sooner.
 
−
'''21-day cycles''', with next cycle starting as soon as ANC is at least 1000/uL and platelet count is at least 100 x 10<sup>9</sup>/L
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Resection of disease was allowed after 4 cycles based on patient's response to ICE
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. [https://doi.org/10.1002/pbc.20227 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15503297 PubMed]
+
# '''Retrospective:''' Taylor A, Neave L, Solanki S, Westwood JP, Terrinonive I, McGuckin S, Kothari J, Cooper N, Stasi R, Scully M. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol. 2015 Nov;171(4):625-30. Epub 2015 Aug 6. [https://doi.org/10.1111/bjh.13622 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26250874 PubMed]
−
==IE {{#subobject:ba75ef|Regimen=1}}==
+
==Placebo==  
−
IE: '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:4cd5c8|Variant=1}}===
+
===Regimen===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.1987.5.8.1191 Miser et al. 1987]
+
|[https://doi.org/10.1016/S0140-6736(08)60203-2 Kuter et al. 2008 (Amgen 20030105)]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Romiplostim_monotherapy|Romiplostim]]
 +
| style="background-color:#d73027" |Inferior durable platelet response
 
|-
 
|-
−
|}
+
|[https://doi.org/10.1016/S0140-6736(08)60203-2 Kuter et al. 2008 (Amgen 20030212)]
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
+
| style="background-color:#1a9851" |Phase 3 (C)
−
<div class="toccolours" style="background-color:#b3e2cd">
+
|[[#Romiplostim_monotherapy|Romiplostim]]
−
====Chemotherapy====
+
| style="background-color:#d73027" |Inferior durable platelet response
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second, with loading dose of mesna'''
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 360 mg/m<sup>2</sup> IV loading dose over 1 hour, '''given with [[Ifosfamide (Ifex)]]''', then 120 mg/m<sup>2</sup>/hour IV over 3 hours, then 360 mg/m<sup>2</sup> IV or PO over 15 minutes every 3 hours for 6 doses, '''given at hours 5, 8, 11, 14, 17, 20'''
 
−
'''21-day cycle for 12 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*For patients responding to therapy after 4 cycles: local therapy with [[Surgery#Surgical_resection|surgery]] or radiation is used to try to achieve a complete remission.
 
−
**Radiation therapy consisted of 1.8 Gy fractions given for a total dose of 50 to 55 Gy.
 
−
</div></div>
 
−
===References===
 
−
# Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, Wesley R, Magrath I. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987 Aug;5(8):1191-8. [https://doi.org/10.1200/jco.1987.5.8.1191 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3114435 PubMed]
 
−
==Irinotecan & Temozolomide {{#subobject:2e2a5c|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:c62d11|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[http://clincancerres.aacrjournals.org/content/10/3/840.long Wagner et al. 2004]
+
|[https://doi.org/10.1016/S0140-6736(09)60402-5 Bussel et al. 2009 (TRA100773)]
−
|style="background-color:#ffffbe"|Phase 1, <20 pts
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Eltrombopag_monotherapy|Eltrombopag]]
 +
| style="background-color:#d73027" |Inferior RR
 
|-
 
|-
−
|}
+
|[https://doi.org/10.1016/S0140-6736(10)60959-2 Cheng et al. 2010 (RAISE-ITP)]
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available. Note that irinotecan 15 mg/m<sup>2</sup> was also studied, but this dose was not recommended due to dose-limiting toxicities of diarrhea and infection.''
+
| style="background-color:#1a9851" |Phase 3 (C)
−
<div class="toccolours" style="background-color:#b3e2cd">
+
|[[#Eltrombopag_monotherapy|Eltrombopag]]
−
====Chemotherapy====
+
| style="background-color:#d73027" |Inferior RR
−
*[[Irinotecan (Camptosar)]] 10 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 8 to 12, '''given second on days 1 to 5, 1 hour after temozolomide'''
 
−
*[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*[[Loperamide (Imodium)]] prn diarrhea
 
−
'''28-day cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:620185|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://doi.org/10.1002/pbc.22206 Casey et al. 2009]
+
|[https://doi.org/10.1016/S0140-6736(14)61495-1 Ghanima et al. 2015 (RITP)]
−
|style="background-color:#ffffbe"|Retrospective
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Rituximab_monotherapy|Rituximab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of rate of treatment failure within 78 weeks
 
|-
 
|-
−
|}
+
|[https://doi.org/10.1016/S0140-6736(15)61107-2 Grainger et al. 2015 (PETIT2)]
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
+
| style="background-color:#1a9851" |Phase 3 (C)
−
<div class="toccolours" style="background-color:#b3e2cd">
+
|[[#Eltrombopag_monotherapy|Eltrombopag]]
−
====Chemotherapy====
+
| style="background-color:#d73027" |Inferior durable platelet response
−
*[[Irinotecan (Camptosar)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, 8 to 12, '''given second on days 1 to 5, 1 hour after temozolomide'''
 
−
*[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*[[Cefixime (Suprax)]] prophylaxis starting 1 to 2 days prior to [[Irinotecan (Camptosar)]], continuing until the completion of each cycle
 
−
*Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg PO three times per day during [[Irinotecan (Camptosar)]] therapy
 
−
*[[Loperamide (Imodium)]] prn diarrhea
 
−
*Patient "advised to maintain hydration"
 
−
'''21-day cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''Phase I:''' Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004 Feb 1;10(3):840-8. [http://clincancerres.aacrjournals.org/content/10/3/840.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14871959 PubMed]
 
−
# '''Retrospective:''' Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007 Feb;48(2):132-9. [https://doi.org/10.1002/pbc.20697 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16317751 PubMed]
 
−
# '''Retrospective:''' Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, Meyers PA. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009 Dec;53(6):1029-34. [https://doi.org/10.1002/pbc.22206 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19637327 PubMed]
 
−
==TC, then IE, VDoxoC, VEC {{#subobject:c31c79|Regimen=1}}==
 
−
TC, then IE, VDoxoC, VEC: '''<u>T</u>'''opotecan, '''<u>C</u>'''yclophosphamide followed by '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide, then '''<u>V</u>'''incristine, '''<u>Doxo</u>'''rubicin, '''<u>C</u>'''yclophosphamide, then '''<u>V</u>'''incristine, '''<u>E</u>'''toposide, '''<u>C</u>'''yclophosphamide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:87b074|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2005.02.1717 Bernstein et al. 2006 (POG 9457)]
+
|[https://doi.org/10.1016/S0140-6736(16)00279-8 Tarantino et al. 2016 (Amgen 20080279)]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Romiplostim_monotherapy|Romiplostim]]
 +
| style="background-color:#d73027" |Inferior durable platelet response
 
|-
 
|-
 
|}
 
|}
−
''Note: This is a complex regimen, and it is suggested to refer to the primary reference and figure 1 for the protocol schema. One arm of patients in this trial received [[Amifostine (Ethyol)]], but its usage is not described below since it did not result in improved outcomes. Treatment starts with an optional topotecan window for stable patients without significantly impaired function or life-threatening disease:''
+
''No active treatment; used as a comparator arm and here for reference purposes only. Note that RAISE should not be confused with the trial by the same name in colorectal cancer.''
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, topotecan window====
 
−
*[[Topotecan (Hycamtin)]] 2.4 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/uL above nadir
 
−
'''5-day course, followed by upfront window, starting at week 0:'''
 
−
====Chemotherapy, upfront window====
 
−
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*Prehydration with 500 mL/m<sup>2</sup> D5 1/4 NS
 
−
*1500 mL/m<sup>2</sup> IV or PO hydration continuous for 24 hours after chemotherapy
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/uL above nadir
 
−
'''21-day cycle for up to 2 cycles'''
 
−
''Patients with progression after the first cycle moved immediately to induction therapy; others proceeded to induction after the second cycle, starting at week 6 with IE:''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] as follows:
 
−
**Cycle 1: 3600 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, after etoposide'''
 
−
***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS
 
−
**Cycles 2 & 3: 2800 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, after etoposide'''
 
−
***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 minutes once per day on days 1 to 5, '''given first, before ifosfamide'''
 
−
**Administered in 250 mL/m<sup>2</sup> of D5 1/2 NS
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 4000 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*"Vigorous hydration"
 
−
*Antiemetics
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for a total of 3 cycles, alternating with VDoxoC'''
 
−
====Chemotherapy, VDoxoC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV bolus once per day on days 1, 8, 15, '''given first'''
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given third''' (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
**Administered in 2400 mL/m<sup>2</sup>/day (4800 mL/m<sup>2</sup> total volume) of D5 1/2 NS
 
−
*[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, '''given second'''
 
−
**Administered in 200 mL/m<sup>2</sup> D5 1/2 NS
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 2400 mg/m<sup>2</sup> total dose IV; exact schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 4, 24 hours after chemotherapy is complete
 
−
'''21-day cycle for a total of 2 cycles, alternating with IE'''
 
−
''Local therapy for primary disease along with ongoing chemotherapy starts at week 21:''
 
−
====Chemotherapy, primary, VDoxoC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]], dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 1 cycle, followed by local control:'''
 
−
====Local therapy, after week 21====
 
−
*Choice of modality between surgical and radiation therapy options is at the discretion of the provider
 
−
*Patients treated with radiation alone received [[External beam radiotherapy]] 45 Gy in 1.8 Gy fractions to the initial tumor volume; additional treatment up to a total of 55.8 Gy was administered to original bony tumors and the postinduction chemotherapy soft tissue volumes plus a 2 cm margin
 
−
*See primary reference for details about radiation therapy in a variety of clinical scenarios
 
−
====Chemotherapy, primary, VEC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*Use of [[Mesna (Mesnex)]] not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 2 cycles, followed by:'''
 
−
====Chemotherapy, continuation, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 2100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]], dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for a total of 2 cycles, alternating with VDoxoC'''
 
−
====Chemotherapy, continuation, VDoxoC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 1 cycle, in between IE'''
 
−
''Local therapy for metastatic disease along with ongoing chemotherapy starts at week 39:''
 
−
====Chemotherapy, metastases, VDoxoC potion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
**Note: the day 8 dose is not described in the text but is described in figure 1
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 1 cycle, followed by local control of metastatic disease:'''
 
−
====Local therapy, metastatic disease (after week 39)====
 
−
*Choice of modality between surgical and radiation therapy options is at the discretion of the provider
 
−
*[[External beam radiotherapy]] could be used to treat up to three sites of metastatic disease
 
−
*See primary reference for details about radiation therapy in a variety of clinical scenarios
 
−
====Chemotherapy, metastases, VEC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*Use of [[Mesna (Mesnex)]] not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 2 cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''POG 9457:''' Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group; Children's Oncology Group. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006 Jan 1;24(1):152-9. [https://doi.org/10.1200/jco.2005.02.1717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16382125 PubMed] NCT00002643
+
# '''Amgen 20030105:''' Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://doi.org/10.1016/S0140-6736(08)60203-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18242413 PubMed] NCT00102323
−
==VAdCA {{#subobject:dd0198|Regimen=1}}==
+
# '''Amgen 20030212:''' Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://doi.org/10.1016/S0140-6736(08)60203-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18242413 PubMed] NCT00102336
−
VAdCA: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin
+
# '''TRA100773:''' Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. [https://doi.org/10.1016/S0140-6736(09)60402-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19231632 PubMed] NCT00102739
 +
# '''RAISE:''' Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. [https://doi.org/10.1016/S0140-6736(10)60959-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20739054 PubMed] NCT00370331
 +
# '''RITP:''' Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4. [https://doi.org/10.1016/S0140-6736(14)61495-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25662413 PubMed] NCT00344149
 +
# '''PETIT2:''' Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. [https://doi.org/10.1016/S0140-6736(15)61107-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26231455 PubMed] NCT01520909
 +
# '''Amgen 20080279:''' Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://doi.org/10.1016/S0140-6736(16)00279-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27103127 PubMed] NCT01444417
 +
# Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. [https://doi.org/10.1111/bjh.14380 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27734464 PubMed]
 +
==Rituximab monotherapy {{#subobject:d7d211|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cb5fae|Variant=1}}===
+
===Regimen {{#subobject:128a52|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|-
 +
|[http://www.bloodjournal.org/content/112/4/999.long Godeau et al. 2008]
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2004.01.041 Miser et al. 2004]
+
|[https://doi.org/10.1016/S0140-6736(14)61495-1 Ghanima et al. 2015 (RITP)]
−
|1988-1992
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#1a9851"|Phase 3 (C)
+
|[[#Placebo|Placebo]]
−
|[[#VAdCA.2FIE|VAdCA/IE]]
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of rate of treatment failure within 78 weeks
−
|style="background-color:#ffffbf"|Did not meet primary endpoints of EFS/OS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.''
+
''Patients in Godeau et al. 2008 had "ITP lasting 6 or more months before inclusion; at least 1 previous treatment for ITP; and platelet count less than 30 × 10<sup>9</sup>/L at inclusion" and were candidates for splenectomy."''
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Immunosuppressive therapy====
−
====Chemotherapy====
+
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1
+
====Supportive therapy====
−
**Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 uses a capped dose and is from the same trial
+
*(per Godeau et al. 2008):
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
+
*Patients received Streptococcus pneumoniae and Haemophilus influenzae vaccination at least 2 weeks before the first dose of [[Rituximab (Rituxan)]]
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses)
+
*[[Acetaminophen (Tylenol)]] 1000 mg once per day on days 1, 8, 15, 22, prior to [[Rituximab (Rituxan)]]
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
+
*[[Methylprednisolone (Solumedrol)]] 60 mg IV once per day on days 1, 8, 15, 22, prior to [[Rituximab (Rituxan)]]
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
+
'''4-week course'''
−
'''21-day cycle for 17 cycles'''
 
−
''Local therapy is planned to take place on week 9, as follows:''
 
−
====Local therapy====
 
−
*[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible.
 
−
*[[External beam radiotherapy]] to all metastatic sites of disease in addition to any radiation planned for primary tumor.
 
−
*If only radiation therapy is used, [[External beam radiotherapy]] 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
 
−
*Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. [https://doi.org/10.1200/jco.2004.01.041 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15254055 PubMed]
+
# Godeau B, Porcher R, Fain O, Lefrère F, Fenaux P, Cheze S, Vekhoff A, Chauveheid MP, Stirnemann J, Galicier L, Bourgeois E, Haiat S, Varet B, Leporrier M, Papo T, Khellaf M, Michel M, Bierling P. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008 Aug 15;112(4):999-1004. [http://www.bloodjournal.org/content/112/4/999.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18463354 PubMed]
−
==VAdCA/IE {{#subobject:a6863c|Regimen=1}}==
+
# '''Prospective cohort:''' Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, Kanter J, Neufeld E, Taube T, Ramenghi U, Shenoy S, Ward MJ, Mihatov N, Patel VL, Bierling P, Lesser M, Cooper N, Bussel JB. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012 Jun 21;119(25):5989-95. [http://www.bloodjournal.org/content/119/25/5989.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383014/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22566601 PubMed]
−
VAdCA/IE: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide
+
# '''RITP:''' Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4.[https://doi.org/10.1016/S0140-6736(14)61495-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25662413 PubMed] NCT00344149
 +
==Romiplostim monotherapy {{#subobject:a6df46|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol {{#subobject:a2770e|Variant=1}}===
+
===Regimen {{#subobject:8b8d3b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 25%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2004.01.041 Miser et al. 2004]
+
|[https://doi.org/10.1016/S0140-6736(08)60203-2 Kuter et al. 2008 (Amgen 20030105)]
−
|1988-1992
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
|[[#Placebo|Placebo]]
−
|[[#VAdCA|VAdCA]]
+
| style="background-color:#1a9850" |Superior durable platelet response
−
|style="background-color:#ffffbf"|Did not meet primary endpoints of EFS/OS
 
 
|-
 
|-
−
|}
+
|[https://doi.org/10.1016/S0140-6736(08)60203-2 Kuter et al. 2008 (Amgen 20030212)]
−
''Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.''
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
<div class="toccolours" style="background-color:#b3e2cd">
+
|[[#Placebo|Placebo]]
−
====Chemotherapy, VAdCA portion====
+
| style="background-color:#1a9850" |Superior durable platelet response
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once on day 1
 
−
**Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 uses a capped dose and is from the same trial
 
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
'''21-day cycle, alternating with IE, for 17 total cycles'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
'''21-day cycle, alternating with VAC, for 17 total cycles'''
 
−
''Local therapy is planned to take place on week 9, as follows:''
 
−
====Local therapy====
 
−
*[[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible.
 
−
*[[External beam radiotherapy]] to all metastatic sites of disease in addition to any radiation planned for primary tumor.
 
−
*If only radiation therapy is used, [[External beam radiotherapy]] 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
 
−
*Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"
 
−
</div></div>
 
−
===References===
 
−
# Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. [https://doi.org/10.1200/jco.2004.01.041 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15254055 PubMed]
 
−
==VAI {{#subobject:547404|Regimen=1}}==
 
−
VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:020e4c|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
+
|[https://doi.org/10.1016/S0140-6736(16)00279-8 Tarantino et al. 2016 (Amgen 20080279)]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior durable platelet response
 
|-
 
|-
 
|}
 
|}
−
''Note: This protocol was intended for patients with metastatic disease. The reference does not clearly describe how many cycles of VAI might be used.''
+
''Patients in Amgen 20030105 had undergone splenectomy. Patients in Amgen 20080279 were younger than 18 years old at time of study entry; see paper for details on dose titration.''
−
<div class="toccolours" style="background-color:#cbd5e8">
+
====Growth factor therapy====
−
====Preceding treatment====
+
*[[Romiplostim (Nplate)]] 1 mcg/kg SC once per day on days 1, 8, 15, 22
−
*[[#VIDE_2|VIDE]] for up to 6 cycles
+
'''28-day cycles'''
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for one or more cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Busulfan_.26_Melphalan.2C_then_auto_HSCT|Busulfan & Melphalan, then auto HSCT]]
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
+
# '''Amgen 20030105:''' Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://doi.org/10.1016/S0140-6736(08)60203-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18242413 PubMed] NCT00102323
−
# '''R2Pulm:''' Dirksen U, Brennan B, Le Deley MC, Cozic N, van den Berg H, Bhadri V, Brichard B, Claude L, Craft A, Amler S, Gaspar N, Gelderblom H, Goldsby R, Gorlick R, Grier HE, Guinbretiere JM, Hauser P, Hjorth L, Janeway K, Juergens H, Judson I, Krailo M, Kruseova J, Kuehne T, Ladenstein R, Lervat C, Lessnick SL, Lewis I, Linassier C, Marec-Berard P, Marina N, Morland B, Pacquement H, Paulussen M, Randall RL, Ranft A, Le Teuff G, Wheatley K, Whelan J, Womer R, Oberlin O, Hawkins DS; Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators. High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol. 2019 Dec 1;37(34):3192-3202. Epub 2019 Sep 25. [https://doi.org/10.1200/JCO.19.00915 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881099/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31553693 PubMed] NCT00987636
+
# '''Amgen 20030212:''' Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [https://doi.org/10.1016/S0140-6736(08)60203-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18242413 PubMed] NCT00102336
−
==VIDE {{#subobject:737059|Regimen=1}}==
+
# '''Amgen 20080279:''' Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. [https://doi.org/10.1016/S0140-6736(16)00279-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27103127 PubMed] NCT01444417
−
VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide
+
== Vinblastine-loaded platelets ==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:2601fd|Variant=1}}===
+
===Regimen ===
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 1,192: Line 791:
 
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
+
|[https://doi.org/10.1056/NEJM197805182982001 Ahn et al. 1978]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#ffffbe" |Phase 1
−
|ORR: 88%
+
|CR in 6 of 11 patients
−
|-
 
 
|}
 
|}
−
''Note: This protocol was intended for patients with metastatic disease.''
+
=== Reference ===
−
<div class="toccolours" style="background-color:#b3e2cd">
+
# '''Phase 1:''' Ahn YS, Byrnes JJ, Harrington WJ, Cayer ML, Smith DS, Brunskill DE, Pall LM. New England Journal of Medicine. 1978; 298:1101-1107. [https://doi.org/10.1056/NEJM197805182982001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/565464 PubMed]
−
====Chemotherapy====
+
[[Category:Immune thrombocytopenia regimens]]
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for up to 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#VAI_2|VAI]], then [[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|HD with auto HSCT]]
 
−
</div></div>
 
−
===References===
 
−
# Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
[[Category:Ewing sarcoma regimens]]
 
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
−
[[Category:Bone sarcomas]]
+
[[Category:Autoimmune hematologic conditions]]
−
[[Category:Pediatric solid tumors]]
+
[[Category:Bleeding disorders]]
 +
[[Category:Cytopenias]]
 +
[[Category:Clinical pharmacology]]

Revision as of 12:11, 17 October 2022

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Section editor transclusions

0 regimens on this page
0 variants on this page


Guidelines

ASH

Older

BSH

"How I Treat"

Initial therapy

Dexamethasone monotherapy

Regimen variant #1

Study Evidence Comparator Efficacy
Wei et al. 2015 Phase 3 (E-esc) Prednisone Superior CR rate

Immunosuppressive therapy

4-day course

Subsequent treatment

  • If platelets remained below 30 x 109/L or bleeding by day 10, course is repeated once


Regimen variant #2

Study Evidence Comparator Efficacy
Matschke et al. 2013 Phase 3 (E-esc) Prednisone Seems to have superior responding patients maintaining remission for at least 6 mo

Immunosuppressive therapy, part 1

Immunosuppressive therapy, part 2

21-day cycle for 6 cycles


Regimen variant #3

Study Evidence
Cheng et al. 2003 Phase 2

Immunosuppressive therapy

4-day course Patients who had an initial response, but whose platelets dropped below 30 x 109/L within 6 months received:


Regimen variant #4, monthly dexamethasone

Study Evidence
Mazzucconi et al. 2007 Phase 2

Immunosuppressive therapy

28-day cycle for 6 cycles


Regimen variant #5, bi-weekly dexamethasone

Study Evidence
Mazzucconi et al. 2007 Phase 2

Immunosuppressive therapy

  • Dexamethasone (Decadron) by the following criteria:
    • Adults: 40 mg IV or PO once per day on days 1 to 4
    • Patients less than 15 years old: 20 mg/m2 (maximum dose of 40 mg) IV or PO once per day on days 1 to 4
    • Patients who had platelet counts of less than or equal to 30 x 109/L between cycles and/or who had bleeding related to thrombocytopenia received 0.035 mg/kg PO once per day "between courses"

14-day cycle for 4 cycles

References

  1. Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, Wong WS, Cheng G. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med. 2003 Aug 28;349(9):831-6. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  2. Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, Vianelli N, Avvisati G, Rodeghiero F, Amendola A, Baronci C, Carbone C, Quattrin S, Fioritoni G, D'Alfonso G, Mandelli F; Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007 Feb 15;109(4):1401-7. Epub 2006 Oct 31. link to original article contains dosing details in manuscript PubMed
  3. Abstract: Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. link to abstract
  4. Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. link to original article contains dosing details in manuscript PubMed

Dexamethasone & Eltrombopag

Regimen

Study Evidence
Gómez-Almaguer et al. 2014 Pilot, <20 pts reported

Immunosuppressive therapy

Growth factor therapy

5-week course

References

  1. Gómez-Almaguer D, Herrera-Rojas MA, Jaime-Pérez JC, Gómez-De León A, Cantú-Rodríguez OG, Gutiérrez-Aguirre CH, Tarín-Arzaga L, Hernández-Reyes J, Ruiz-Arguelles GJ. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014 Jun 19;123(25):3906-8. Epub 2014 May 6. link to original article contains dosing details in manuscript PubMed

Dexamethasone & Mycophenolate mofetil

Regimen

Study Evidence Comparator Efficacy
Bradbury et al. 2021 (FLIGHT) Phase 3 (E-esc) 1. Dexamethasone
2. Prednisolone 		Superior treatment failure

Immunosuppressive therapy

References

  1. FLIGHT: Bradbury CA, Pell J, Hill Q, Bagot C, Cooper N, Ingram J, Breheny K, Kandiyali R, Rayment R, Evans G, Talks K, Thomas I, Greenwood R. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia. N Engl J Med. 2021 Sep 2;385(10):885-895. link to original article PubMed NCT03156452

Dexamethasone & Rituximab

Regimen ("R+3Dex")

Study Evidence
Imahiyerobo et al. 2013 Retrospective

Immunosuppressive therapy

14-day cycle for 3 cycles

References

  1. Abstract: Retrospective: Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. link to abstract

Intravenous immunoglobulin monotherapy

IVIG: IntraVenous ImmunoGlobulin

Regimen

Study Evidence Comparator Efficacy
Godeau et al. 1999 Phase 3 (E-esc) IVIG; 0.5 g/kg Superior response rate

Supportive therapy

One dose

References

  1. Imbach P, Wagner HP, Berchtold W, Gaedicke G, Hirt A, Joller P, Mueller-Eckhardt C, Müller B, Rossi E, Barandun S. Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet. 1985 Aug 31;2(8453):464-8. link to original article PubMed
  2. Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, Gent M. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993 Dec;123(6):989-95. link to original article PubMed
  3. Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, de Veber B, Israels S, Kobrinsky N, Luke B. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994 Sep 10;344(8924):703-7. link to original article PubMed
  4. Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 05 and 1 g/kg bw. Br J Haematol. 1999 Dec;107(4):716-9. link to original article contains dosing details in abstract PubMed
  5. Godeau B, Chevret S, Varet B, Lefrère F, Zini JM, Bassompierre F, Chèze S, Legouffe E, Hulin C, Grange MJ, Fain O, Bierling P; French ATIP Study Group. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet. 2002 Jan 5;359(9300):23-9. link to original article PubMed
  6. TIKI: Heitink-Pollé KMJ, Uiterwaal CSPM, Porcelijn L, Tamminga RYJ, Smiers FJ, van Woerden NL, Wesseling J, Vidarsson G, Laarhoven AG, de Haas M, Bruin MCA; TIKI Investigators. Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial. Blood. 2018 Aug 30;132(9):883-891. Epub 2018 Jun 26. link to original article PubMed

Mycophenolate mofetil & Prednisolone

Regimen

Study Evidence Comparator Efficacy
Bradbury et al. 2021 (FLIGHT) Phase 3 (E-esc) 1. Dexamethasone
2. Prednisolone 		Superior treatment failure

Immunosuppressive therapy

References

  1. FLIGHT: Bradbury CA, Pell J, Hill Q, Bagot C, Cooper N, Ingram J, Breheny K, Kandiyali R, Rayment R, Evans G, Talks K, Thomas I, Greenwood R. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia. N Engl J Med. 2021 Sep 2;385(10):885-895. link to original article PubMed NCT03156452

Prednisone monotherapy

Regimen variant #1

Study Evidence Comparator Efficacy
Wei et al. 2015 Phase 3 (C) Dexamethasone Inferior CR rate

Immunosuppressive therapy

  • Prednisone (Sterapred) as follows:
    • Days 1 to 28: 1 mg/kg/day PO
    • Day 29 onwards: tapered over 4 to 6 weeks with a goal of maintenance dosing less than 15 mg/day or "complete termination"
      • Taper schedule determined by treating physician


Regimen variant #2

Study Evidence Comparator Efficacy
Matschke et al. 2013 Phase 3 (C) Dexamethasone Seems to have inferior responding patients maintaining remission for at least 6 mo

Immunosuppressive therapy

  • Prednisone (Sterapred) as follows:
    • Weeks 1 to 2: 1 mg/kg/day PO
    • Weeks 3 to 19: Tapered over 19 weeks with a goal of maintenance dosing less than 7.5 mg/day at the end of week 19

References

  1. Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, Gent M. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993 Dec;123(6):989-95. link to original article PubMed
  2. Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, de Veber B, Israels S, Kobrinsky N, Luke B. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994 Sep 10;344(8924):703-7. link to original article PubMed
  3. Abstract: Johannes Matschke, Hannes Müller-Beißenhirtz, Ilona Vester, Bernd Hertenstein, Lewin Eisele, Hildegard Lax, Claudia Ose, Ulrich Dührsen. A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment Naïve Patients With Idiopathic Thrombocytopenic Purpura. Blood Nov 2013,122(21)325. link to abstract
  4. Wei Y, Ji XB, Wang YW, Wang JX, Yang EQ, Wang ZC, Sang YQ, Bi ZM, Ren CA, Zhou F, Liu GQ, Peng J, Hou M. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. Blood. 2016 Jan 21;127(3):296-302. Epub 2015 Oct 19. link to original article contains dosing details in manuscript PubMed

RhIG monotherapy

RhIG: Rho(D) Immune Globulin

Regimen variant #1, 25 mcg/kg

Study Evidence
Bussel et al. 1991 Phase 2

Eligibility: RhD-positive.

Supportive therapy

4-day course


Regimen variant #2, 50 mcg/kg

Study Evidence Comparator Efficacy
Newman et al. 2001 Randomized Phase 2, <20 pts (C) Rho(D); 75 mcg/kg Seems to have inferior platelet effect

Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 109/L.

Supportive therapy

Supportive therapy

One dose; can be repeated if required to increase platelet count


Regimen variant #3, 75 mcg/kg

Study Evidence Comparator Efficacy
Newman et al. 2001 Randomized Phase 2, <20 pts (E-esc) Rho(D); 50 mcg/kg Seems to have superior platelet effect

Eligibility: RhD-positive, adult, HIV-negative, non-splenectomized, platelet count less than or equal to 30 x 109/L.

Supportive therapy

Supportive therapy

One dose; can be repeated if required to increase platelet count

References

  1. Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 1;77(9):1884-93. link to original article contains dosing details in manuscript PubMed
  2. Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/day of iv anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/day in adults with immune thrombocytopenic purpura. Br J Haematol. 2001 Mar;112(4):1076-8. link to original article contains dosing details in manuscript PubMed

TT4

TT4: Triple Therapy (4?)

Regimen

Study Evidence
Choi et al. 2015 Phase 2

The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.

Immunosuppressive therapy

References

  1. Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood. 2015 Jul 23;126(4):500-3. Epub 2015 May 13. link to original article contains dosing details in abstract link to PMC article PubMed

Relapsed or refractory

ATRA & Danazol

Regimen

Study Evidence Comparator Efficacy
Feng et al. 2017 (U1111-1132-6877) Randomized Phase 2 (E-esc) Danazol Superior 12-month sustained response

Targeted therapy

Endocrine therapy

16-week course

References

  1. U1111-1132-6877: Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. link to original article contains dosing details in abstract PubMed NCT01667263

Avatrombopag monotherapy

Regimen

Study Evidence Comparator Efficacy
Jurczak et al. 2018 (E5501-G000-302) Phase 3 (E-esc) Placebo Superior cumulative weeks of platelet response

Growth factor therapy

References

  1. Bussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, Tang S, McIntosh J. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014 Jun 19;123(25):3887-94. Epub 2014 May 6. link to original article PubMed
  2. E5501-G000-302: Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, Allen LF. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018 Nov;183(3):479-490. Epub 2018 Sep 7. link to original article PubMed

Cyclosporine monotherapy

Regimen

Study Evidence
Emilia et al. 2002 Pilot, <20 pts

The authors do not specify whether modified or non-modified cyclosporine was used in this protocol. Please contact them for clarifications.

Immunosuppressive therapy

  • Cyclosporine A as follows:
    • Days 1 to 6: 5 mg/kg/day PO split into twice per day dosing
    • Day 7 onwards: 2.5 to 3 mg/kg/day PO with dose adjusted for target trough of 200 to 400 mcg/L

References

  1. Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, Ferrara L, D'Apollo N, Potenza L, Bertesi M, Torelli G. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood. 2002 Feb 15;99(4):1482-5. link to original article contains dosing details in manuscript PubMed

Danazol monotherapy

Regimen

Study Evidence Comparator Efficacy
Ahn et al. 1983 Pilot, >20 pts
Feng et al. 2017 (U1111-1132-6877) Randomized Phase 2 (C) ATRA & Danazol Inferior 12-month sustained response

Note: Ahn et al. 1983 gave a range of 200 mg PO from two to four times per day; the dose below is from U1111-1132-6877

Endocrine therapy

16-week course

References

  1. Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med. 1983 Jun 9;308(23):1396-9. link to original article contains dosing details in manuscript PubMed
  2. U1111-1132-6877: Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, Shen JL, Wang JW, Xu LP, Liu KY, Huang XJ, Zhang XH. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial. Lancet Haematol. 2017 Oct;4(10):e487-e496. Epub 2017 Sep 13. link to original article contains dosing details in abstract PubMed NCT01667263

Dexamethasone monotherapy

Regimen

Study Evidence
Andersen 1994 Pilot, <20 pts

Immunosuppressive therapy

28-day cycles for 6 cycles

References

  1. Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994 Jun 2;330(22):1560-4. link to original article contains dosing details in manuscript PubMed

Dexamethasone & Rituximab

Regimen ("R+3Dex")

Study Evidence
Imahiyerobo et al. 2013 Retrospective

Immunosuppressive therapy

14-day cycle for 3 cycles

References

  1. Abstract: Allison Imahiyerobo, Micha Thompson, Marina Izak Karaev, Waleed Ghanima, James B Bussel. Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years. Blood Nov 2013,122(21)2310. link to abstract

Eltrombopag monotherapy

Regimen variant #1

Study Evidence Comparator Efficacy
Grainger et al. 2015 (PETIT2) Phase 3 (E-esc) Placebo Superior durable platelet response

This regimen was intended for pediatric patients.

Growth factor therapy

  • Eltrombopag (Promacta) with starting dose by the following criteria:
    • Age 6 to 17, weighing at least 27kg, non-east Asian: 50 mg PO once per day
    • Age 6 to 17, weighing at least 27kg, east Asian: 25 mg PO once per day
    • Age 6 to 17, weighing less than 27kg, non-east Asian: 37.5 mg PO once per day
    • Age 6 to 17, weighing less than 27kg, east Asian: 25 mg PO once per day
    • Age 1 to 5, non-east Asian: 1.2 mg/kg/day oral suspension
    • Age 1 to 5, east Asian: 0.8 mg/kg/day oral suspension

Dose adjusted to a maximum of 75 mg/day, with temporary discontinuation for platelet count greater than 400 x 109/L


Regimen variant #2

Study Evidence Comparator Efficacy
Bussel et al. 2009 (TRA100773) Phase 3 (E-esc) Placebo Superior plt count of greater than or equal to 50 x 109/L on day 43

Growth factor therapy

The dose could be increased from 50 mg to 75 mg after 3 weeks in patients whose platelet counts were less than 50 x 109/L. Treatment was discontinued in patients who attained a platelet count greater than 200 x 109/L


Regimen variant #3

Study Evidence Comparator Efficacy
Cheng et al. 2010 (RAISE-ITP) Phase 3 (E-esc) Placebo Superior RR

Note: this trial should not be confused with the trial by the same name in colorectal cancer.

Growth factor therapy

  • Eltrombopag (Promacta) 50 mg PO once per day, with dose modifications:
    • Increase to 75 mg PO once per day allowed after day 22 for patients with platelet counts lower than 50 x 109/L
    • Decrease to 25 mg PO once per day required for platelets counts between 200 and 400 x 109/L
    • Drug was held for platelet count greater than 400 x 109/L, until platelet count dropped below 150 x 109/L

6-month course


Regimen variant #4

Study Evidence Comparator Efficacy
Bussel et al. 2007 (TRA100773) Phase 3 (E-esc) Placebo Superior RR

Growth factor therapy

Up to 6-week course


Regimen variant #5

Study Evidence
Saleh et al. 2012 (EXTEND) Phase 2

Growth factor therapy

Dose and schedule were individualized with the goal of achieving and maintaining platelets between 50 and 200 x 109/L.

References

  1. TRA100773: Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. link to original article PubMed NCT00102739
  2. TRA100773: Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. link to original article contains dosing details in manuscript PubMed NCT00102739
  3. RAISE: Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. link to original article contains dosing details in manuscript PubMed NCT00370331
  4. EXTEND: Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537-45. Epub 2012 Nov 20. link to original article contains dosing details in manuscript PubMed
  5. PETIT2: Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. link to original article contains dosing details in manuscript PubMed NCT01520909
  6. Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. link to original article PubMed

Fostamatinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bussel et al. 2018 (FIT1) 2014-2016 Phase 3 (E-esc) Placebo Superior stable response
Bussel et al. 2018 (FIT2) 2015-2016 Phase 3 (E-esc) Placebo Superior stable response

Targeted therapy

  • Fostamatinib (Tavalisse) 100 mg PO twice per day
    • Dose may be increased to 150 mg PO twice per day after 4 weeks if needed to achieve platelet count of at least 50

24-week course

References

  1. FIT1: Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, Hellmann A, Windyga J, Sivcheva L, Khalafallah AA, Zaja F, Cooper N, Markovtsov V, Zayed H, Duliege AM. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018 Jul;93(7):921-930. Epub 2018 May 15. link to original article link to PMC article PubMed NCT02076399
  2. FIT2: Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, Hellmann A, Windyga J, Sivcheva L, Khalafallah AA, Zaja F, Cooper N, Markovtsov V, Zayed H, Duliege AM. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018 Jul;93(7):921-930. Epub 2018 May 15. link to original article link to PMC article PubMed NCT02076412
  3. Review: Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018 Jan;10(1):9-25. link to original article PubMed

Mycophenolate mofetil monotherapy

Regimen

Study Evidence
Taylor et al. 2015 Retrospective

Immunosuppressive therapy

Continued indefinitely

References

  1. Retrospective: Taylor A, Neave L, Solanki S, Westwood JP, Terrinonive I, McGuckin S, Kothari J, Cooper N, Stasi R, Scully M. Mycophenolate mofetil therapy for severe immune thrombocytopenia. Br J Haematol. 2015 Nov;171(4):625-30. Epub 2015 Aug 6. link to original article PubMed

Placebo

Regimen

Study Evidence Comparator Efficacy
Kuter et al. 2008 (Amgen 20030105) Phase 3 (C) Romiplostim Inferior durable platelet response
Kuter et al. 2008 (Amgen 20030212) Phase 3 (C) Romiplostim Inferior durable platelet response
Bussel et al. 2009 (TRA100773) Phase 3 (C) Eltrombopag Inferior RR
Cheng et al. 2010 (RAISE-ITP) Phase 3 (C) Eltrombopag Inferior RR
Ghanima et al. 2015 (RITP) Phase 3 (C) Rituximab Did not meet primary endpoint of rate of treatment failure within 78 weeks
Grainger et al. 2015 (PETIT2) Phase 3 (C) Eltrombopag Inferior durable platelet response
Tarantino et al. 2016 (Amgen 20080279) Phase 3 (C) Romiplostim Inferior durable platelet response

No active treatment; used as a comparator arm and here for reference purposes only. Note that RAISE should not be confused with the trial by the same name in colorectal cancer.

References

  1. Amgen 20030105: Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. link to original article PubMed NCT00102323
  2. Amgen 20030212: Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. link to original article contains dosing details in manuscript PubMed NCT00102336
  3. TRA100773: Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Feb 21;373(9664):641-8. link to original article contains dosing details in manuscript PubMed NCT00102739
  4. RAISE: Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011 Jan 29;377(9763):393-402. Epub 2010 Aug 23. Erratum in: Lancet. 2011 Jan 29;377(9763):382. link to original article contains dosing details in manuscript PubMed NCT00370331
  5. RITP: Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4. link to original article contains dosing details in abstract PubMed NCT00344149
  6. PETIT2: Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, Drelichman G, Sirachainan N, Holzhauer S, Lebedev V, Lemons R, Pospisilova D, Ramenghi U, Bussel JB, Bakshi KK, Iyengar M, Chan GW, Chagin KD, Theodore D, Marcello LM, Bailey CK. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015 Oct 24;386(10004):1649-58. Epub 2015 Jul 28. link to original article contains dosing details in manuscript PubMed NCT01520909
  7. Amgen 20080279: Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. link to original article contains dosing details in manuscript PubMed NCT01444417
  8. Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. link to original article PubMed

Rituximab monotherapy

Regimen

Study Evidence Comparator Efficacy
Godeau et al. 2008 Phase 2
Ghanima et al. 2015 (RITP) Phase 3 (E-esc) Placebo Did not meet primary endpoint of rate of treatment failure within 78 weeks

Patients in Godeau et al. 2008 had "ITP lasting 6 or more months before inclusion; at least 1 previous treatment for ITP; and platelet count less than 30 × 109/L at inclusion" and were candidates for splenectomy."

Immunosuppressive therapy

Supportive therapy

4-week course

References

  1. Godeau B, Porcher R, Fain O, Lefrère F, Fenaux P, Cheze S, Vekhoff A, Chauveheid MP, Stirnemann J, Galicier L, Bourgeois E, Haiat S, Varet B, Leporrier M, Papo T, Khellaf M, Michel M, Bierling P. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008 Aug 15;112(4):999-1004. link to original article contains dosing details in manuscript PubMed
  2. Prospective cohort: Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, Kanter J, Neufeld E, Taube T, Ramenghi U, Shenoy S, Ward MJ, Mihatov N, Patel VL, Bierling P, Lesser M, Cooper N, Bussel JB. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012 Jun 21;119(25):5989-95. link to original article contains dosing details in manuscript link to PMC article PubMed
  3. RITP: Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, Kahrs J, Darne B, Holme PA; RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Apr 25;385(9978):1653-61. Epub 2015 Feb 4.link to original article contains dosing details in abstract PubMed NCT00344149

Romiplostim monotherapy

Regimen

Study Evidence Comparator Efficacy
Kuter et al. 2008 (Amgen 20030105) Phase 3 (E-esc) Placebo Superior durable platelet response
Kuter et al. 2008 (Amgen 20030212) Phase 3 (E-esc) Placebo Superior durable platelet response
Tarantino et al. 2016 (Amgen 20080279) Phase 3 (E-esc) Placebo Superior durable platelet response

Patients in Amgen 20030105 had undergone splenectomy. Patients in Amgen 20080279 were younger than 18 years old at time of study entry; see paper for details on dose titration.

Growth factor therapy

28-day cycles

References

  1. Amgen 20030105: Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. link to original article contains dosing details in manuscript PubMed NCT00102323
  2. Amgen 20030212: Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. link to original article contains dosing details in manuscript PubMed NCT00102336
  3. Amgen 20080279: Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, Williams B, Beam D, Morales J, Rose MJ, Carpenter N, Nie K, Eisen M. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Jul 2;388(10039):45-54. Epub 2016 Apr 18. link to original article contains dosing details in manuscript PubMed NCT01444417

Vinblastine-loaded platelets

Regimen

Study Evidence Efficacy
Ahn et al. 1978 Phase 1 CR in 6 of 11 patients

Reference

  1. Phase 1: Ahn YS, Byrnes JJ, Harrington WJ, Cayer ML, Smith DS, Brunskill DE, Pall LM. New England Journal of Medicine. 1978; 298:1101-1107. link to original article PubMed
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