Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
</div>
 
</div>
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{{#lst:Section editor transclusions|giei}}
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{| class="wikitable" style="text-align:center; width:50%;"
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''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Pancreatic NET - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
+
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#4a1486" |'''Section editor'''
−
<big>Note: for more general neuroendocrine regimens, please visit the '''[[neuroendocrine tumors]]''' page.</big>
+
|-
 +
| style="background-color:#F0F0F0" |[[File:Hilal.jpg|frameless|upright=0.3|center]]
 +
|<big>Talal Hilal, MD<br>University of Mississippi<br>Jackson, MS</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/THilalMD THilalMD]
 +
|-
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|}
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
|}
 
|}
 +
<big>'''Note: most of these regimens include complex dose adjustments based on therapeutic troughs, concomitant medications, and other factors. Therefore, the focus on this page will be inclusion of drug names and references, but not necessarily drug dosages.'''</big>
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
=Guidelines=
 
=Guidelines=
−
==[http://www.esmo.org/ ESMO]==
+
==ASBMT==
−
*'''2020:''' Pavel et al. [https://doi.org/10.1016/j.annonc.2020.03.304 Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*'''2012:''' Martin et al. [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3404151/ First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation]
−
===Older===
+
==EBMT/ELN==
−
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Gastroenteropancreatic-Tumours Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*'''2013:''' Ruutu et al. [https://doi.org/10.1038/bmt.2013.107 Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice]
−
==NANETS==
+
==ESBMT==
−
*'''2020:''' Halfdanarson et al. [https://doi.org/10.1097/mpa.0000000000001597 The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors]
+
*'''2020:''' Penack et al. [https://doi.org/10.1016/s2352-3026(19)30256-x Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation]
−
*'''2020:''' Howe et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7029300/ The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors]
+
=="How I Treat"==
−
==[https://www.nccn.org/ NCCN]==
+
*'''2020:''' Martin PJ. How I treat steroid-refractory acute graft-versus-host disease. Blood. 2020 May 7;135(19):1630-1638. [https://doi.org/10.1182/blood.2019000960 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32202630 PubMed]
−
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]
+
*'''2019:''' Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133(11):1191-1200. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6418480/ link to PMC article]
−
=All lines of therapy=
+
*'''2014:''' Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015 Jan 22;125(4):606-15 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304105/ link to PMC article]
−
==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}==
+
=Prevention=
 +
''This is very basic for now, to expand in the future. Information can also be found under individual regimens on the [[Allogeneic_HSCT|allogeneic HSCT]] page.''
 +
==Cyclophosphamide, Mycophenolate mofetil, Tacrolimus==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:fc2dd9|Variant=1}}===
+
===Regimen {{#subobject:8ajb82|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 50%" |Study
 
! style="width: 50%" |Study
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633246/ Luznik et al. 2008]
−
| style="background-color:#ffffbe" |Retrospective
+
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[https://doi.org/10.1016/j.bbmt.2012.06.019 Solomon et al. 2012]
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+
*[[Cyclophosphamide (Cytoxan)]]
−
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day at bedtime on days 10 to 14
+
*[[Mycophenolate mofetil (CellCept)]]
−
====Supportive therapy====
+
*[[Tacrolimus (Prograf)]]
−
*[[Ondansetron (Zofran)]] 8 mg (route not specified) once per day on days 1 to 14, prior to [[Temozolomide (Temodar)]]
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. [https://doi.org/10.1002/cncr.25425 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20824724 PubMed]
+
#Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. [https://doi.org/10.1016/j.bbmt.2008.03.005 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633246/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18489989 PubMed]
−
==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}==
+
#Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012 Dec;18(12):1859-66. Epub 2012 Aug 1. [https://doi.org/10.1016/j.bbmt.2012.06.019 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22863841 PubMed]
 +
==Cyclophosphamide & Cyclosporine==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a9c7ed|Variant=1}}===
+
===Regimen {{#subobject:9134yg|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: 20%"|Study
Line 54: Line 63:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
| rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992]
+
|[https://doi.org/10.1182/bloodadvances.2021005847 Broers et al. 2022 (HOVON-96)]
−
|rowspan=2|1978-1985
+
|2013-2018
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|1. [[#Chlorozotocin_monotherapy_88|Chlorozotocin]]
+
|[[#Cyclosporine_.26_Mycophenolic_acid_88|CsA & MPA]]
−
| style="background-color:#1a9850" |Superior OS
+
| style="background-color:#1a9850" |Superior GRFS
 
|-
 
|-
−
|2. [[#Fluorouracil_.26_Streptozocin|5-FU & Streptozocin]]
+
|}
−
| style="background-color:#1a9850" |Superior OS
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunosuppressive therapy====
 +
*[[Cyclophosphamide (Cytoxan)]]
 +
*[[Cyclosporine]]
 +
</div></div>
 +
===References===
 +
#'''HOVON-96:''' Broers AEC, de Jong CN, Bakunina K, Hazenberg MD, van Marwijk Kooy M, de Groot MR, van Gelder M, Kuball J, van der Holt B, Meijer E, Cornelissen JJ. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv. 2022 Jun 14;6(11):3378-3385. [https://doi.org/10.1182/bloodadvances.2021005847 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35143644/ PubMed] NL2128
 +
==Cyclosporine & Methotrexate==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[http://www.bloodjournal.org/content/92/7/2303.long Ratanatharathorn et al. 1998]
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Methotrexate_.26_Tacrolimus|Methotrexate & Tacrolimus]]
 +
| style="background-color:#d73027" |Inferior aGVHD rate
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(09)70225-6 Finke et al. 2009 (AP-AS-21-DE)]
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclosporine.2C_Methotrexate.2C_ATG|Cyclosporine, MTX, ATG]]
 +
| style="background-color:#ffffbf" |Seems not superior
 +
| style="background-color:#eeee01" |Similar NRM
 +
|-
 +
|[https://doi.org/10.1182/blood.2020009050 Kennedy et al. 2021]
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclosporine.2C_MTX.2C_Tocilizumab_99|Cyclosporine, MTX, Tocilizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint
 +
|style="background-color:#ffffbf" |Similar NRM
 
|-
 
|-
 
|}
 
|}
 +
''Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22
+
*[[Cyclosporine]]
−
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
*[[Methotrexate (MTX)]]
−
'''42-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://doi.org/10.1056/NEJM199202203260804 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1310159 PubMed]
+
#Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. [http://www.bloodjournal.org/content/92/7/2303.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/9746768 PubMed]
−
==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}==
+
#'''AP-AS-21-DE:''' Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. [https://doi.org/10.1016/S1470-2045(09)70225-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19695955 PubMed] NCT00655343
 +
##'''Update:''' Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. [http://www.bloodjournal.org/content/117/23/6375.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21467544 PubMed]
 +
##'''Update:''' Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. [https://doi.org/10.1016/s2352-3026(17)30081-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28583289/ PubMed]
 +
# Kennedy GA, Tey SK, Buizen L, Varelias A, Gartlan KH, Curley C, Olver SD, Chang K, Butler JP, Misra A, Subramoniapillai E, Morton AJ, Durrant S, Henden AS, Moore J, Ritchie D, Gottlieb D, Cooney J, Paul SK, Hill GR. A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis. Blood. 2021 Apr 8;137(14):1970-1979. [https://doi.org/10.1182/blood.2020009050 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33512442/ PubMed]
 +
==Cyclosporine, Methotrexate, ATG==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:5ea369|Variant=1}}===
+
===Regimen===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)]
+
|[https://doi.org/10.1016/S1470-2045(09)70225-6 Finke et al. 2009 (AP-AS-21-DE)]
−
|2006-2007
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#91cf61" |Phase 2
+
|[[#Cyclosporine_.26_Methotrexate|Cyclosporine & MTX]]
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#ffffbf" |Seems not superior
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#eeee01" |Similar NRM
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]
+
|[https://doi.org/10.1016/S2352-3026(19)30220-0 Walker et al. 2020 (CBMTG 0801)]
−
|2007-2009
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+
|[[#Cyclosporine_.26_Methotrexate|Cyclosporine & MTX]]
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
+
| style="background-color:#91cf60" |Seems to have superior OS
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 11 vs 4.6 mo<br>(HR 0.35, 95% CI 0.27-0.45)
+
| style="background-color:#ffffbf" |Similar NRM
 
|-
 
|-
 
|}
 
|}
 +
''Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Immunosuppressive therapy====
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
+
*[[Cyclosporine|Cyclosporine]]
−
'''Continued indefinitely'''
+
*[[Methotrexate (MTX)]]
 +
*[[Antithymocyte globulin, rabbit ATG (Grafalon)|Antithymocyte globulin, rabbit ATG (ATG-Fresenius)]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''RADIANT-1:''' Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [https://doi.org/10.1200/jco.2009.24.2669 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933912 PubMed] NCT00363051
+
#'''AP-AS-21-DE:''' Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. [https://doi.org/10.1016/S1470-2045(09)70225-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19695955 PubMed] NCT00655343
−
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://doi.org/10.1056/NEJMoa1009290 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21306238 PubMed] NCT00510068
+
##'''Update:''' Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. [http://www.bloodjournal.org/content/117/23/6375.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21467544 PubMed]
−
## '''Update:''' Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Öberg K. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. Epub 2016 Sep 30. [https://doi.org/10.1200/JCO.2016.68.0702 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791842/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27621394 PubMed]
+
##'''Update:''' Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. [https://doi.org/10.1016/s2352-3026(17)30081-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28583289/ PubMed]
−
# '''Review:''' Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. [http://cancerres.aacrjournals.org/content/73/5/1449.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23436795 PubMed]
+
#'''CBMTG 0801:''' Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Cell Therapy Transplant Canada. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2020 Feb;7(2):e100-e111. Epub 2020 Jan 17. [https://doi.org/10.1016/S2352-3026(19)30220-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31958417 PubMed] NCT01217723
−
#'''COMPETE:''' NCT03049189
+
==Cyclosporine, Methotrexate, Methylprednisolone==
−
#'''COMPOSE:''' NCT04919226
 
−
==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:b0f62f|Variant=1}}===
+
===Regimen {{#subobject:9126b2|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#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
+
|[http://www.bloodjournal.org/content/96/7/2391.long Ruutu et al. 2000]
−
|2005-2006
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#91cf61" |Phase 2
+
|[[#Cyclosporine_.26_Methotrexate|Cyclosporine & MTX]]
 +
| style="background-color:#1a9850" |Lower rate of aGVHD
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Immunosuppressive therapy====
−
*[[Everolimus (Afinitor)]] 5 mg PO once per day
+
*[[Cyclosporine]]
−
====Endocrine therapy====
+
*[[Methotrexate (MTX)]]
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
+
*[[Methylprednisolone (Solumedrol)]]
−
'''28-day cycles'''
+
</div></div>
−
</div></div><br>
+
===References===
 +
#Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood. 2000 Oct 1;96(7):2391-8. [http://www.bloodjournal.org/content/96/7/2391.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11001889 PubMed]
 +
##'''Update:''' Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018 Feb 15;124(4):727-733. Epub 2017 Nov 7. [https://doi.org/10.1002/cncr.31100 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29112242 PubMed]
 +
==Cyclosporine, Methotrexate, Prednisone==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2 {{#subobject:f82bb5|Variant=1}}===
+
===Regimen {{#subobject:81a6b2|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#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
+
|[https://doi.org/10.1056/NEJM199310213291703 Chao et al. 1993]
−
|2005-2006
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
| style="background-color:#91cf61" |Phase 2
+
|[[#Cyclosporine_.26_Prednisone_88|Cyclosporine & Prednisone]]
−
|-
+
| style="background-color:#91cf60" |Seems to have lower rate of grade II to IV aGVHD
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010 (RADIANT-1)]
 
−
|2006-2007
 
−
| style="background-color:#91cf61" |Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
''Note: In Yao et al. 2008, everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory." Patients in RADIANT-1 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study; they were continued on their prestudy dose up to 30 mg.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Immunosuppressive therapy====
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
+
*[[Cyclosporine]]
−
====Endocrine therapy====
+
*[[Methotrexate (MTX)]]
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
+
*[[Prednisone (Sterapred)]]
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618 PubMed]
+
#Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nademanee AP, Negrin RS, O'Donnell MR, Parker PM, Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman SJ. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med. 1993 Oct 21;329(17):1225-30. [https://doi.org/10.1056/NEJM199310213291703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8413388 PubMed]
−
# '''RADIANT-1:''' Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [https://doi.org/10.1200/jco.2009.24.2669 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19933912 PubMed] NCT00363051
+
==Cyclosporine & Mycophenolate mofetil==
−
==FAS {{#subobject:66b05e|Regimen=1}}==
 
−
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:de76a2|Variant=1}}===
+
===Regimen {{#subobject:81a8h4|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
! style="width: 50%" |Study
+
! style="width: 25%" |Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2004.04.024 Kouvaraki et al. 2004]
+
|[https://doi.org/10.1016/S2352-3026(19)30088-2 Sandmaier et al. 2019 (FH 2448.00)]
−
| style="background-color:#ffffbe" |Retrospective
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclosporine.2C_Mycophenolate_mofetil.2C_Sirolimus|Cyclosporine, MMF, Sirolimus]]
 +
| style="background-color:#d73027" |Higher rate of grade II to IV aGVHD
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+
*[[Cyclosporine]] 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
−
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1
+
*[[Mycophenolate mofetil (CellCept)]] 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD
−
*[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. [https://doi.org/10.1200/jco.2004.04.024 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15570077 PubMed]
+
#'''FH 2448.00:''' Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. [https://doi.org/10.1016/S2352-3026(19)30088-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31248843 PubMed] NCT01231412
−
==Fluorouracil & Streptozocin {{#subobject:6f7b84|Regimen=1}}==
+
==Cyclosporine, Mycophenolate mofetil, Sirolimus==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:e45011|Variant=1}}===
+
===Regimen {{#subobject:8ajb82|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#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198011203032101 Moertel et al. 1980]
+
|[https://doi.org/10.1016/S2352-3026(19)30088-2 Sandmaier et al. 2019 (FH 2448.00)]
−
|1972-1978
 
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|[[#Fluorouracil_monotherapy_88|Fluorouracil]]
+
|[[#Cyclosporine_.26_Mycophenolate_mofetil|Cyclosporine & MMF]]
−
| style="background-color:#d9ef8b" |Might have superior OS
+
| style="background-color:#1a9850" |Lower rate of grade II to IV aGVHD
 
|-
 
|-
−
| rowspan="2" |[https://doi.org/10.1056/NEJM199202203260804 Moertel et al. 1992]
+
|}
−
|rowspan=2|1978-1985
+
<div class="toccolours" style="background-color:#b3e2cd">
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+
====Immunosuppressive therapy====
−
|1. [[#Chlorozotocin_monotherapy_88|Chlorozotocin]]
+
*[[Cyclosporine]] 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
−
| style="background-color:#ffffbf" |Did not meet endpoint of OS
+
*[[Mycophenolate mofetil (CellCept)]] 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD
 +
*[[Sirolimus (Rapamune)]] 2 mg PO once per day from day -3 to day +150 (adjusted to maintain trough level of 3 to 12 ng/mL), then tapered off by day +180 in the absence of GVHD
 +
</div></div>
 +
===References===
 +
#'''FH 2448.00:''' Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. [https://doi.org/10.1016/S2352-3026(19)30088-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31248843 PubMed] NCT01231412
 +
==Methotrexate & Tacrolimus==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen===
 +
{| 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#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]]
+
|[http://www.bloodjournal.org/content/92/7/2303.long Ratanatharathorn et al. 1998]
−
| style="background-color:#d73027" |Inferior OS
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclosporine_.26_Methotrexate|Cyclosporine & Methotrexate]]
 +
| style="background-color:#1a9850" |Superior aGVHD rate
 
|-
 
|-
 
|}
 
|}
−
''Note: treatment details are from Moertel et al. 1992.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
*[[Methotrexate (MTX)]]
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+
*[[Tacrolimus (Prograf)]]
−
'''42-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. [https://doi.org/10.1056/NEJM198011203032101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6252466 PubMed]
+
#Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. [http://www.bloodjournal.org/content/92/7/2303.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/9746768 PubMed]
−
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://doi.org/10.1056/NEJM199202203260804 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1310159 PubMed]
+
==Methotrexate, Tacrolimus, Tocilizumab {{#subobject:fe1c2e|Regimen=1}}==
−
==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a9ee08|Variant=1}}===
+
===Regimen {{#subobject:2d492b|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: 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: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865423/ Drobyski et al. 2018]
−
|2006-2013
+
| style="background-color:#91cf61" |Phase 2
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 18 mo<br>(HR 0.47, 95% CI 0.30-0.73)
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ Caplin et al. 2016 (CLARINET OLE)]
 
−
|2009-NR
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Immunosuppressive therapy====
−
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1
+
*[[Methotrexate (MTX)]]
−
'''28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET OLE)'''
+
*[[Tacrolimus (Prograf)]]
 +
*[[Tocilizumab (Actemra)]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://doi.org/10.1056/NEJMoa1316158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25014687 PubMed] NCT00353496
+
#Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, Hebert KM, Dunn R, Yim S, Johnson B, D'Souza A, Eapen M, Fenske TS, Hari P, Hamadani M, Horowitz MM, Rizzo JD, Saber W, Shah N, Shaw B, Pasquini M. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica. 2018 Apr;103(4):717-727. Epub 2018 Jan 19. [http://www.haematologica.org/content/103/4/717 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865423/ linkt o PMC article] [https://pubmed.ncbi.nlm.nih.gov/29351985 PubMed]
−
# '''CLARINET OLE:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. [https://doi.org/10.1530/erc-15-0490 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26743120 PubMed] NCT00842348
+
==Methotrexate, Tacrolimus, Vorinostat {{#subobject:ca16a7|Regimen=1}}==
−
==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:652f4d|Variant=1}}===
+
===Regimen {{#subobject:191ac5|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
! style="width: 50%" |Study
+
! style="width: 25%" |Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]
+
|[http://www.bloodjournal.org/content/130/15/1760.long Choi et al. 2017]
−
| style="background-color:#ffffbe" |Pilot, <20 pts
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
''Note: Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Immunosuppressive therapy====
−
*[[Lanreotide (Somatuline)]] 3 mg SC twice per day
+
*[[Methotrexate (MTX)]] 5 mg/m<sup>2</sup> IV once per day on days +1, +3, +6, +11
−
====Immunotherapy====
+
*[[Tacrolimus (Prograf)]] by one of the following routes, starting on day -3:
−
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
+
**IV: 0.03 mg/kg/day
 +
**PO: 0.045 mg/kg/day
 +
**Goal trough level of 8 to 12 ng/mL
 +
**In absence of GVHD, tapering begins on day +100 and completes on day +180
 +
*[[Vorinostat (Zolinza)]] 100 mg PO twice per day on days -10 to +100
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889 PubMed]
+
#Choi SW, Braun T, Henig I, Gatza E, Magenau J, Parkin B, Pawarode A, Riwes M, Yanik G, Dinarello CA, Reddy P. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood. 2017 Oct 12;130(15):1760-1767. Epub 2017 Aug 7. [http://www.bloodjournal.org/content/130/15/1760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28784598 PubMed]
−
==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}==
+
==Rabbit ATG==
 +
====Immunosuppressive therapy====
 +
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]]
 +
</div></div>
 +
===References===
 +
#Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Canadian Blood and Marrow Transplant Group. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016 Feb;17(2):164-173. Epub 2015 Dec 24. [https://doi.org/10.1016/s1470-2045(15)00462-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26723083 PubMed] ISRCTN29899028
 +
#'''ATGFamilyStudy:''' Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, Nagler A, Selleri C, Risitano A, Messina G, Bethge W, Pérez de Oteiza J, Duarte R, Carella AM, Cimminiello M, Guidi S, Finke J, Mordini N, Ferra C, Sierra J, Russo D, Petrini M, Milone G, Benedetti F, Heinzelmann M, Pastore D, Jurado M, Terruzzi E, Narni F, Völp A, Ayuk F, Ruutu T, Bonifazi F. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016 Jan 7;374(1):43-53. [https://doi.org/10.1056/NEJMoa1506002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26735993 PubMed] NCT00678275
 +
#'''ProfGVHD1:''' Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A, Pession A, Fagioli F, Favre C, Lanino E, Giorgiani G, Merli P, Pagliara D, Prete A, Zecca M. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1126-1136. Epub 2017 Jul 10. [https://doi.org/10.1016/s1470-2045(17)30417-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28705454 PubMed] NCT00934557
 +
==Sitagliptin, Sirolimus, Tacrolimus==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cd8cf6|Variant=1}}===
+
===Regimen {{#subobject:9134b2|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 33%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1093/annonc/mdh216 Oberg et al. 2004]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7845486/ Farag et al. 2021 (IUSCC-0522)]
−
| style="background-color:#ffffbe" |Consensus guideline
+
|2016-2018
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Immunosuppressive therapy====
−
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given two to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
+
*[[Sitagliptin (Januvia)]]
−
**"A reasonable starting dose is" 0.15 mg SC three times per day
+
*[[Sirolimus (Rapamune)]]
−
'''Continued indefinitely'''
+
*[[Tacrolimus (Prograf)]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Review:''' Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [https://doi.org/10.1016/s0039-6109(05)70141-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11459269 PubMed]
+
#'''IUSCC-0522:''' Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, Blakley AJ, Abonour R, Robertson MJ, Broxmeyer HE, Zhang S. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N Engl J Med. 2021 Jan 7;384(1):11-19. [https://doi.org/10.1056/nejmoa2027372 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7845486/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33406328 PubMed] NCT02683525
−
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956 PubMed]
+
=Treatment, aGVHD, all lines of therapy=
−
==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}==
+
==Ruxolitinib monotherapy {{#subobject:05e2b6|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:f0bc1b|Variant=1}}===
+
===Regimen {{#subobject:bhy62c|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: 20%"|Study
Line 292: Line 349:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7229262/ Jagasia et al. 2020 (REACH1)]
−
|2001-2008
+
|2016-2018
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
+
| style="background-color:#d3d3d3" |
−
| style="background-color:#1a9850" |Superior TTP<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)
+
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1056/nejmoa1917635 Zeiser et al. 2020 (REACH2)]
 +
|2017-2019
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|Investigator's choice
 +
| style="background-color:#1a9850" |Superior ORR
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Immunosuppressive therapy====
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
+
*[[Ruxolitinib (Jakafi)]] 10 mg PO twice per day
−
'''28-day cycles'''
+
'''Continued for at least 56 days, tapered thereafter'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956 PubMed]
+
#'''REACH2:''' Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. Epub 2020 Apr 22. [https://doi.org/10.1056/nejmoa1917635 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32320566 PubMed] NCT02913261
−
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057 PubMed] NCT00171873
+
#'''REACH1:''' Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. [https://doi.org/10.1182/blood.2020004823 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7229262/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32160294/ PubMed] NCT02953678
−
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
+
=Treatment, cGVHD, all lines of therapy=
−
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
+
==Cyclosporine & Prednisone {{#subobject:7a7c79|Regimen=1}}==
−
#'''NETTER-2:''' NCT03972488
 
−
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cbf5c4|Variant=1}}===
+
===Regimen {{#subobject:c940ce|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 50%" |Study
+
! style="width: 25%" |Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]
+
|[http://www.bbmt.org/article/S1083-8791(01)50043-9 Arora et al. 2001]
−
| style="background-color:#ffffbe" |Pilot, <20 pts
+
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#Cyclosporine.2C_Prednisone.2C_Thalidomide_99|Cyclosporine, Prednisone, Thalidomide]]
 +
| style="background-color:#ffffbf" |Seems not superior
 
|-
 
|-
 
|}
 
|}
−
''Note: Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Immunosuppressive therapy====
−
*[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given two to three times per day
+
*[[Cyclosporine|Cyclosporine]]
−
====Immunotherapy====
+
*[[Prednisone (Sterapred)]]
−
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 to 5,000,000 units SC once per day, 3 to 7 days per week (total of 9,000,000 to 25,000,000 units per week)
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765 PubMed]
+
#Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, Miller WJ, Weisdorf DF. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7(5):265-73. [http://www.bbmt.org/article/S1083-8791(01)50043-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11400948 PubMed]
−
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12025889 PubMed]
+
==Cyclosporine, Corticosteroids, Rituximab {{#subobject:9fffb0|Regimen=1}}==
−
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:ee13c4|Regimen=1}} ==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:33d0ef|Variant=1}}===
+
===Regimen {{#subobject:0de254|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
!style="width: 17%"|Study
+
! style="width: 33%" |Study
−
!style="width: 15%"|Years of enrollment
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!style="width: 17%"|Comparator
 
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]
+
|[http://www.bloodjournal.org/content/130/20/2186.long Malard et al. 2017]
−
|2012-2016
+
| style="background-color:#91cf61" |Phase 2
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+
| style="background-color:#d4d4d4" |ORR at 12 mo: 83%
−
| [[#Octreotide_LAR_monotherapy|Octreotide LAR]]; high-dose
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)
 
−
| style="background-color:#d73027" |More cytopenias (neutropenia, thrombocytopenia and lymphopenia)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Endocrine therapy====
+
====Immunosuppressive therapy====
−
* [[Octreotide LAR (Sandostatin LAR)]] 30 mg SC once on day 1, '''given 2 hours after each lutetium Lu 177 dotatate infusion'''
+
*[[Cyclosporine|Cyclosporine]] 6 mg/kg PO twice per day
−
'''4-week cycles'''
+
**Or, continued at the dose at time of study entry
−
====Radioconjugate therapy====
+
**Goal level 200 to 400 ng/mL
−
* [[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV once on day 1
+
*[[:Category:Steroids|Corticosteroids]] equivalent to 1 mg/kg/day of [[Prednisone (Sterapred)]]
−
====Supportive therapy====
+
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
* For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes prior to drug infusion.
+
''Rituximab given as a 4-week course, repeated one month later if PR or better. Corticosteroids and CsA tapered per standard of care.''
−
'''8-week cycle for 4 cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709 PubMed] NCT01578239
+
#Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, Tabrizi R, Magro L, Vanhove B, Blancho G, Moreau P, Gaugler B, Chevallier P, Mohty M. Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017 Nov 16;130(20):2186-2195. Epub 2017 Sep 1. [http://www.bloodjournal.org/content/130/20/2186.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28864814 PubMed]
−
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
+
==Cyclosporine, Sirolimus, Prednisone {{#subobject:1ffc79|Regimen=1}}==
−
==Sunitinib monotherapy {{#subobject:ee13d2|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:80d0ef|Variant=1}}===
+
===Regimen {{#subobject:cc1bce|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 17%"|Study
+
! style="width: 25%" |Study
−
!style="width: 15%"|Years of enrollment
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Comparator
−
!style="width: 17%"|Comparator
+
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]
+
|[http://www.haematologica.org/content/103/11/1915 Carpenter et al. 2018 (BMT CTN 0801)]
−
|2007-2009
+
| style="background-color:#1a9851" |Phase 2/3 (C)
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+
|[[#Sirolimus_.26_Prednisone_99|Sirolimus & Prednisone]]
−
|[[Pancreatic_NET_-_null_regimens#Placebo|Placebo]]
+
| style="background-color:#ffffbf" |Seems not superior
−
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 12.6 vs 5.8 mo<br>(HR 0.32, 95% CI 0.18-0.55)
 
−
| style="background-color:#d73027" |More diarrhea; seems to have worse insomnia
 
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy is based on the 2017 update.''<br>
 
−
''Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Immunosuppressive therapy====
−
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day
+
*[[Cyclosporine|Cyclosporine]]
−
'''Continued indefinitely'''
+
*[[Sirolimus (Rapamune)]]
 +
*[[Prednisone (Sterapred)]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://doi.org/10.1056/NEJMoa1003825 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21306237 PubMed] NCT00428597
+
#'''BMT CTN 0801:''' Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. [http://www.haematologica.org/content/103/11/1915 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29954931 PubMed]
−
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://doi.org/10.1007/s11523-016-0462-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27924459 PubMed]
+
==Ibrutinib monotherapy {{#subobject:5d9394|Regimen=1}}==
−
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://doi.org/10.1093/annonc/mdw561 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27836885 PubMed]
 
−
==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:6aac4c|Variant=1}}===
+
===Regimen {{#subobject:7f34b4|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable" style="color:white; background-color:#404040"
−
! style="width: 50%" |Study
+
|<small>'''FDA-recommended dose'''</small>
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
|-
 +
|}
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]
+
|[http://www.bloodjournal.org/content/130/21/2243.long Miklos et al. 2017 (PCYC-1129-CA)]
−
| style="background-color:#ffffbe" |Retrospective
+
| style="background-color:#91cf61" |Phase 1b/2 (RT)
 +
| style="background-color:#bfd3e6" |Best ORR: 67%
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Temozolomide (Temodar)]] as follows:
+
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
−
**Cycle 1: 100 or 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000 PubMed]
+
#'''PCYC-1129-CA:''' Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, Li Y, Chang S, Lal I, Dubovsky J, James DF, Styles L, Jaglowski S. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017 Nov 23;130(21):2243-2250. Epub 2017 Sep 18. [http://www.bloodjournal.org/content/130/21/2243.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28924018 PubMed] NCT02195869
−
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}==
+
==Ruxolitinib monotherapy {{#subobject:05e2b6|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:be3718|Variant=1}}===
+
===Regimen {{#subobject:bhy62c|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable" style="color:white; background-color:#404040"
−
!style="width: 33%"|Study
+
|<small>'''FDA-recommended dose'''</small>
−
!style="width: 33%"|Years of enrollment
+
|-
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
|}
 +
{| 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012 (DFCI 04-272)]
+
|[https://doi.org/10.1056/nejmoa2033122 Zeiser et al. 2021 (REACH3)]
−
|2004-2005
+
|2017-2019
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|Best available therapy
 +
| style="background-color:#1a9850" |Superior ORR at week 24
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21
+
*[[Ruxolitinib (Jakafi)]] 10 mg PO twice per day
−
====Targeted therapy====
+
'''28-day cycle for at least 6 cycles'''
−
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
 
−
====Supportive therapy====
 
−
*PCP prophylaxis: [[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday
 
−
**Allergic patients received alternate prophylaxis
 
−
*VZV prophylaxis: [[Acyclovir (Zovirax)]] 400 mg PO three times per day
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''DFCI 04-272:''' Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. [https://doi.org/10.1200/jco.2011.40.3147 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22778320 PubMed] NCT00137774
+
#'''REACH3:''' Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F; REACH3 Investigators. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021 Jul 15;385(3):228-238. [https://doi.org/10.1056/nejmoa2033122 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34260836/ PubMed] NCT03112603
−
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}==
+
==Sirolimus, Tacrolimus, Prednisone {{#subobject:05e07b|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:ceca5a|Variant=1}}===
+
===Regimen {{#subobject:bc128c|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 50%" |Study
+
! style="width: 25%" |Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2005.03.6046 Kulke et al. 2006]
+
|[http://www.haematologica.org/content/103/11/1915 Carpenter et al. 2018 (BMT CTN 0801)]
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 2/3 (C)
 +
|[[#Sirolimus_.26_Prednisone_99|Sirolimus & Prednisone]]
 +
| style="background-color:#ffffbf" |Seems not superior
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunosuppressive therapy====
−
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21
+
*[[Sirolimus (Rapamune)]]
−
====Targeted therapy====
+
*[[Tacrolimus (Prograf)]]
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day
+
*[[Prednisone (Sterapred)]]
−
'''28-day cycles'''
+
</div></div>
 +
===References===
 +
#'''BMT CTN 0801:''' Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. [http://www.haematologica.org/content/103/11/1915 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29954931 PubMed]
 +
=Response criteria=
 +
==2005 NIH cGVHD Consensus Panel==
 +
</div></div>
 +
===References===
 +
#Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, Turner ML, Akpek G, Gilman A, McDonald G, Schubert M, Berger A, Bross P, Chien JW, Couriel D, Dunn JP, Fall-Dickson J, Farrell A, Flowers ME, Greinix H, Hirschfeld S, Gerber L, Kim S, Knobler R, Lachenbruch PA, Miller FW, Mittleman B, Papadopoulos E, Parsons SK, Przepiorka D, Robinson M, Ward M, Reeve B, Rider LG, Shulman H, Schultz KR, Weisdorf D, Vogelsang GB; Response Criteria Working Group. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006 Mar;12(3):252-66. [http://www.bbmt.org/article/S1083-8791(06)00070-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/16503494 PubMed]
 +
==2014 NIH Response Criteria==
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. [https://doi.org/10.1200/jco.2005.03.6046 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16421420 PubMed]
+
#Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, Pidala J, Olivieri A, Martin PJ, Przepiorka D, Pusic I, Dignan F, Mitchell SA, Lawitschka A, Jacobsohn D, Hall AM, Flowers ME, Schultz KR, Vogelsang G, Pavletic S. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015 Jun;21(6):984-99. Epub 2015 Mar 19. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744804/ link to PMC article]
−
[[Category:Pancreatic NET regimens]]
+
=Scoring=
 +
==Glucksberg acute graft versus host (GVHD) scores==
 +
===Skin===
 +
*Stage 0: No rash
 +
*Stage 1: Maculopapular rash <25% of body surface area
 +
*Stage 2: Maculopapular rash on 25-50% of body surface area
 +
*Stage 3: Generalized erythroderma
 +
*Stage 4: Generalized erythroderma with bullous formation and desquamation
 +
===Liver===
 +
*Stage 0: Bilirubin <2 mg/dL
 +
*Stage 1: Bilirubin 2-3 mg/dL
 +
*Stage 2: Bilirubin 3.01-6 mg/dL
 +
*Stage 3: Bilirubin 6.01-15 mg/dL
 +
*Stage 4: Bilirubin >15 mg/dL
 +
===GI===
 +
*Stage 0: No diarrhea, or diarrhea less than 500 mL/day
 +
*Stage 1: Diarrhea 500-999 mL/day
 +
*Stage 2: Diarrhea 1000-1499 mL/day
 +
*Stage 3: Diarrhea >1500 mL/day
 +
*Stage 4: Severe abdominal pain, with or without ileus
 +
===Glucksberg grade===
 +
{| class="wikitable" style="text-align:center;"
 +
! align="left" |Overall grade
 +
!I
 +
!II
 +
!III
 +
!IV
 +
|-
 +
| align="left" |Skin
 +
|1-2
 +
|1-3
 +
|2-3
 +
|2-4
 +
|-
 +
| align="left" |GI
 +
|0
 +
|1
 +
|2-3
 +
|2-4
 +
|-
 +
| align="left" |Liver
 +
|0
 +
|1
 +
|2-4
 +
|2-4
 +
|-
 +
|Karnofsky performance scale
 +
|90-100%
 +
|70-80%
 +
|50-60%
 +
|30-40%
 +
|-
 +
|}
 +
===IBMTR severity index===
 +
The severity is the highest level which the patient reaches based on separate skin, liver, and GI staging.
 +
{| class="wikitable" style="text-align:center;"
 +
! align="left" |Overall grade
 +
!A
 +
!B
 +
!C
 +
!D
 +
|-
 +
| align="left" |Skin
 +
|1
 +
|2
 +
|3
 +
|4
 +
|-
 +
| align="left" |GI
 +
|0
 +
|1-2
 +
|3
 +
|4
 +
|-
 +
| align="left" |Liver
 +
|0
 +
|1-2
 +
|3
 +
|4
 +
|-
 +
|}
 +
==Chronic GVHD==
 +
===Localized===
 +
*Localized skin and/or liver dysfunction due to chronic GVHD
 +
===Extensive===
 +
*Generalized skin involvement or localized skin and/or liver dysfunction due to chronic GVHD '''plus at least one of the following''':
 +
**Liver biopsy showing cirrhosis, chronic aggressive hepatitis, bridging necrosis
 +
**Eye involvement, defined as [http://en.wikipedia.org/wiki/Schirmer's_test Schirmer's test] with less than 5 mm wetting
 +
**Involvement of oral mucosa on lip biopsy or minor salivary glands
 +
**Other organ involvement
 +
*Overall severity categories: mild/moderate/severe
 +
==References==
 +
#Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (first of two parts). N Engl J Med. 1975 Apr 17;292(16):832-43 [https://doi.org/10.1056/NEJM197504172921605 link to original article] [https://pubmed.ncbi.nlm.nih.gov/234595 PubMed]
 +
#Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975 Apr 24;292(17):895-902 [https://doi.org/10.1056/NEJM197504242921706 link to original article] '''(contains staging scale)''' [https://pubmed.ncbi.nlm.nih.gov/235092 PubMed]
 +
#Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, Cahn JY, Calderwood S, Gratwohl A, Socié G, Abecasis MM, Sobocinski KA, Zhang MJ, Horowitz MM. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997 Jun;97(4):855-64. [https://doi.org/10.1046/j.1365-2141.1997.1112925.x/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/9217189 PubMed]
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[[Category:Graft versus host disease regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
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[[Category:Endocrine cancers]]
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[[Category:Alloimmune hematologic conditions]]
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[[Category:Gastrointestinal cancers]]
 

Revision as of 13:00, 17 October 2022

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Section editor
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 Talal Hilal, MD
University of Mississippi
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Note: most of these regimens include complex dose adjustments based on therapeutic troughs, concomitant medications, and other factors. Therefore, the focus on this page will be inclusion of drug names and references, but not necessarily drug dosages.


Guidelines

ASBMT

EBMT/ELN

ESBMT

"How I Treat"

  • 2020: Martin PJ. How I treat steroid-refractory acute graft-versus-host disease. Blood. 2020 May 7;135(19):1630-1638. link to original article PubMed
  • 2019: Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133(11):1191-1200. link to PMC article
  • 2014: Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015 Jan 22;125(4):606-15 link to PMC article

Prevention

This is very basic for now, to expand in the future. Information can also be found under individual regimens on the allogeneic HSCT page.

Cyclophosphamide, Mycophenolate mofetil, Tacrolimus

Regimen

Study Evidence
Luznik et al. 2008 Non-randomized
Solomon et al. 2012 Phase 2

Immunosuppressive therapy

References

  1. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. link to original article link to PMC article PubMed
  2. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012 Dec;18(12):1859-66. Epub 2012 Aug 1. link to original article PubMed

Cyclophosphamide & Cyclosporine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Broers et al. 2022 (HOVON-96) 2013-2018 Phase 3 (E-switch-ic) CsA & MPA Superior GRFS

Immunosuppressive therapy

References

  1. HOVON-96: Broers AEC, de Jong CN, Bakunina K, Hazenberg MD, van Marwijk Kooy M, de Groot MR, van Gelder M, Kuball J, van der Holt B, Meijer E, Cornelissen JJ. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv. 2022 Jun 14;6(11):3378-3385. link to original article PubMed NL2128

Cyclosporine & Methotrexate

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Ratanatharathorn et al. 1998 Phase 3 (C) Methotrexate & Tacrolimus Inferior aGVHD rate
Finke et al. 2009 (AP-AS-21-DE) Phase 3 (C) Cyclosporine, MTX, ATG Seems not superior Similar NRM
Kennedy et al. 2021 Phase 3 (C) Cyclosporine, MTX, Tocilizumab Did not meet primary endpoint Similar NRM

Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.

Immunosuppressive therapy

References

  1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. link to original article PubMed
  2. AP-AS-21-DE: Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. link to original article PubMed NCT00655343
    1. Update: Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. link to original article PubMed
    2. Update: Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. link to original article PubMed
  3. Kennedy GA, Tey SK, Buizen L, Varelias A, Gartlan KH, Curley C, Olver SD, Chang K, Butler JP, Misra A, Subramoniapillai E, Morton AJ, Durrant S, Henden AS, Moore J, Ritchie D, Gottlieb D, Cooney J, Paul SK, Hill GR. A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis. Blood. 2021 Apr 8;137(14):1970-1979. link to original article PubMed

Cyclosporine, Methotrexate, ATG

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Finke et al. 2009 (AP-AS-21-DE) Phase 3 (E-esc) Cyclosporine & MTX Seems not superior Similar NRM
Walker et al. 2020 (CBMTG 0801) Phase 3 (E-esc) Cyclosporine & MTX Seems to have superior OS Similar NRM

Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.

Immunosuppressive therapy

References

  1. AP-AS-21-DE: Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. link to original article PubMed NCT00655343
    1. Update: Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. link to original article PubMed
    2. Update: Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. link to original article PubMed
  2. CBMTG 0801: Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Cell Therapy Transplant Canada. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2020 Feb;7(2):e100-e111. Epub 2020 Jan 17. link to original article PubMed NCT01217723

Cyclosporine, Methotrexate, Methylprednisolone

Regimen

Study Evidence Comparator Comparative Efficacy
Ruutu et al. 2000 Phase 3 (E-esc) Cyclosporine & MTX Lower rate of aGVHD

Immunosuppressive therapy

References

  1. Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood. 2000 Oct 1;96(7):2391-8. link to original article PubMed
    1. Update: Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018 Feb 15;124(4):727-733. Epub 2017 Nov 7. link to original article PubMed

Cyclosporine, Methotrexate, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Chao et al. 1993 Phase 3 (E-esc) Cyclosporine & Prednisone Seems to have lower rate of grade II to IV aGVHD

Immunosuppressive therapy

References

  1. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nademanee AP, Negrin RS, O'Donnell MR, Parker PM, Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman SJ. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med. 1993 Oct 21;329(17):1225-30. link to original article PubMed

Cyclosporine & Mycophenolate mofetil

Regimen

Study Evidence Comparator Comparative Efficacy
Sandmaier et al. 2019 (FH 2448.00) Phase 3 (C) Cyclosporine, MMF, Sirolimus Higher rate of grade II to IV aGVHD

Immunosuppressive therapy

  • Cyclosporine 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
  • Mycophenolate mofetil (CellCept) 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD

References

  1. FH 2448.00: Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. link to original article contains dosing details in abstract PubMed NCT01231412

Cyclosporine, Mycophenolate mofetil, Sirolimus

Regimen

Study Evidence Comparator Comparative Efficacy
Sandmaier et al. 2019 (FH 2448.00) Phase 3 (E-esc) Cyclosporine & MMF Lower rate of grade II to IV aGVHD

Immunosuppressive therapy

  • Cyclosporine 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
  • Mycophenolate mofetil (CellCept) 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD
  • Sirolimus (Rapamune) 2 mg PO once per day from day -3 to day +150 (adjusted to maintain trough level of 3 to 12 ng/mL), then tapered off by day +180 in the absence of GVHD

References

  1. FH 2448.00: Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. link to original article contains dosing details in abstract PubMed NCT01231412

Methotrexate & Tacrolimus

Regimen

Study Evidence Comparator Comparative Efficacy
Ratanatharathorn et al. 1998 Phase 3 (C) Cyclosporine & Methotrexate Superior aGVHD rate

Immunosuppressive therapy

References

  1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. link to original article PubMed

Methotrexate, Tacrolimus, Tocilizumab

Regimen

Study Evidence
Drobyski et al. 2018 Phase 2

Immunosuppressive therapy

References

  1. Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, Hebert KM, Dunn R, Yim S, Johnson B, D'Souza A, Eapen M, Fenske TS, Hari P, Hamadani M, Horowitz MM, Rizzo JD, Saber W, Shah N, Shaw B, Pasquini M. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica. 2018 Apr;103(4):717-727. Epub 2018 Jan 19. link to original article linkt o PMC article PubMed

Methotrexate, Tacrolimus, Vorinostat

Regimen

Study Evidence
Choi et al. 2017 Phase 2

Immunosuppressive therapy

  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6, +11
  • Tacrolimus (Prograf) by one of the following routes, starting on day -3:
    • IV: 0.03 mg/kg/day
    • PO: 0.045 mg/kg/day
    • Goal trough level of 8 to 12 ng/mL
    • In absence of GVHD, tapering begins on day +100 and completes on day +180
  • Vorinostat (Zolinza) 100 mg PO twice per day on days -10 to +100

References

  1. Choi SW, Braun T, Henig I, Gatza E, Magenau J, Parkin B, Pawarode A, Riwes M, Yanik G, Dinarello CA, Reddy P. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood. 2017 Oct 12;130(15):1760-1767. Epub 2017 Aug 7. link to original article contains dosing details in manuscript PubMed

Rabbit ATG

Immunosuppressive therapy

References

  1. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Canadian Blood and Marrow Transplant Group. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016 Feb;17(2):164-173. Epub 2015 Dec 24. link to original article PubMed ISRCTN29899028
  2. ATGFamilyStudy: Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, Nagler A, Selleri C, Risitano A, Messina G, Bethge W, Pérez de Oteiza J, Duarte R, Carella AM, Cimminiello M, Guidi S, Finke J, Mordini N, Ferra C, Sierra J, Russo D, Petrini M, Milone G, Benedetti F, Heinzelmann M, Pastore D, Jurado M, Terruzzi E, Narni F, Völp A, Ayuk F, Ruutu T, Bonifazi F. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016 Jan 7;374(1):43-53. link to original article PubMed NCT00678275
  3. ProfGVHD1: Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A, Pession A, Fagioli F, Favre C, Lanino E, Giorgiani G, Merli P, Pagliara D, Prete A, Zecca M. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1126-1136. Epub 2017 Jul 10. link to original article PubMed NCT00934557

Sitagliptin, Sirolimus, Tacrolimus

Regimen

Study Years of enrollment Evidence
Farag et al. 2021 (IUSCC-0522) 2016-2018 Phase 2

Immunosuppressive therapy

References

  1. IUSCC-0522: Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, Blakley AJ, Abonour R, Robertson MJ, Broxmeyer HE, Zhang S. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N Engl J Med. 2021 Jan 7;384(1):11-19. link to original article link to PMC article PubMed NCT02683525

Treatment, aGVHD, all lines of therapy

Ruxolitinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Jagasia et al. 2020 (REACH1) 2016-2018 Phase 2 (RT)
Zeiser et al. 2020 (REACH2) 2017-2019 Phase 3 (E-switch-ooc) Investigator's choice Superior ORR

Immunosuppressive therapy

Continued for at least 56 days, tapered thereafter

References

  1. REACH2: Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. Epub 2020 Apr 22. link to original article PubMed NCT02913261
  2. REACH1: Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. link to original article link to PMC article PubMed NCT02953678

Treatment, cGVHD, all lines of therapy

Cyclosporine & Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Arora et al. 2001 Randomized (C) Cyclosporine, Prednisone, Thalidomide Seems not superior

Immunosuppressive therapy

References

  1. Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, Miller WJ, Weisdorf DF. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7(5):265-73. link to original article PubMed

Cyclosporine, Corticosteroids, Rituximab

Regimen

Study Evidence Efficacy
Malard et al. 2017 Phase 2 ORR at 12 mo: 83%

Immunosuppressive therapy

Rituximab given as a 4-week course, repeated one month later if PR or better. Corticosteroids and CsA tapered per standard of care.

References

  1. Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, Tabrizi R, Magro L, Vanhove B, Blancho G, Moreau P, Gaugler B, Chevallier P, Mohty M. Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017 Nov 16;130(20):2186-2195. Epub 2017 Sep 1. link to original article contains dosing details in manuscript PubMed

Cyclosporine, Sirolimus, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Carpenter et al. 2018 (BMT CTN 0801) Phase 2/3 (C) Sirolimus & Prednisone Seems not superior

Immunosuppressive therapy

References

  1. BMT CTN 0801: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. link to original article PubMed

Ibrutinib monotherapy

Regimen

FDA-recommended dose
Study Evidence Efficacy
Miklos et al. 2017 (PCYC-1129-CA) Phase 1b/2 (RT) Best ORR: 67%

Immunosuppressive therapy

References

  1. PCYC-1129-CA: Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, Li Y, Chang S, Lal I, Dubovsky J, James DF, Styles L, Jaglowski S. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017 Nov 23;130(21):2243-2250. Epub 2017 Sep 18. link to original article contains dosing details in manuscript PubMed NCT02195869

Ruxolitinib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Zeiser et al. 2021 (REACH3) 2017-2019 Phase 3 (E-RT-switch-ooc) Best available therapy Superior ORR at week 24

Immunosuppressive therapy

28-day cycle for at least 6 cycles

References

  1. REACH3: Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F; REACH3 Investigators. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021 Jul 15;385(3):228-238. link to original article contains dosing details in manuscript PubMed NCT03112603

Sirolimus, Tacrolimus, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Carpenter et al. 2018 (BMT CTN 0801) Phase 2/3 (C) Sirolimus & Prednisone Seems not superior

Immunosuppressive therapy

References

  1. BMT CTN 0801: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. link to original article PubMed

Response criteria

2005 NIH cGVHD Consensus Panel

References

  1. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, Turner ML, Akpek G, Gilman A, McDonald G, Schubert M, Berger A, Bross P, Chien JW, Couriel D, Dunn JP, Fall-Dickson J, Farrell A, Flowers ME, Greinix H, Hirschfeld S, Gerber L, Kim S, Knobler R, Lachenbruch PA, Miller FW, Mittleman B, Papadopoulos E, Parsons SK, Przepiorka D, Robinson M, Ward M, Reeve B, Rider LG, Shulman H, Schultz KR, Weisdorf D, Vogelsang GB; Response Criteria Working Group. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006 Mar;12(3):252-66. link to original article PubMed

2014 NIH Response Criteria

References

  1. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, Pidala J, Olivieri A, Martin PJ, Przepiorka D, Pusic I, Dignan F, Mitchell SA, Lawitschka A, Jacobsohn D, Hall AM, Flowers ME, Schultz KR, Vogelsang G, Pavletic S. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015 Jun;21(6):984-99. Epub 2015 Mar 19. link to PMC article

Scoring

Glucksberg acute graft versus host (GVHD) scores

Skin

  • Stage 0: No rash
  • Stage 1: Maculopapular rash <25% of body surface area
  • Stage 2: Maculopapular rash on 25-50% of body surface area
  • Stage 3: Generalized erythroderma
  • Stage 4: Generalized erythroderma with bullous formation and desquamation

Liver

  • Stage 0: Bilirubin <2 mg/dL
  • Stage 1: Bilirubin 2-3 mg/dL
  • Stage 2: Bilirubin 3.01-6 mg/dL
  • Stage 3: Bilirubin 6.01-15 mg/dL
  • Stage 4: Bilirubin >15 mg/dL

GI

  • Stage 0: No diarrhea, or diarrhea less than 500 mL/day
  • Stage 1: Diarrhea 500-999 mL/day
  • Stage 2: Diarrhea 1000-1499 mL/day
  • Stage 3: Diarrhea >1500 mL/day
  • Stage 4: Severe abdominal pain, with or without ileus

Glucksberg grade

Overall grade I II III IV
Skin 1-2 1-3 2-3 2-4
GI 0 1 2-3 2-4
Liver 0 1 2-4 2-4
Karnofsky performance scale 90-100% 70-80% 50-60% 30-40%

IBMTR severity index

The severity is the highest level which the patient reaches based on separate skin, liver, and GI staging.

Overall grade A B C D
Skin 1 2 3 4
GI 0 1-2 3 4
Liver 0 1-2 3 4

Chronic GVHD

Localized

  • Localized skin and/or liver dysfunction due to chronic GVHD

Extensive

  • Generalized skin involvement or localized skin and/or liver dysfunction due to chronic GVHD plus at least one of the following:
    • Liver biopsy showing cirrhosis, chronic aggressive hepatitis, bridging necrosis
    • Eye involvement, defined as Schirmer's test with less than 5 mm wetting
    • Involvement of oral mucosa on lip biopsy or minor salivary glands
    • Other organ involvement
  • Overall severity categories: mild/moderate/severe

References

  1. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (first of two parts). N Engl J Med. 1975 Apr 17;292(16):832-43 link to original article PubMed
  2. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975 Apr 24;292(17):895-902 link to original article (contains staging scale) PubMed
  3. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, Cahn JY, Calderwood S, Gratwohl A, Socié G, Abecasis MM, Sobocinski KA, Zhang MJ, Horowitz MM. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997 Jun;97(4):855-64. link to original article PubMed
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