Difference between revisions of "Acute myeloid leukemia, FLT3-positive"
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[[#top|Back to Top]] | [[#top|Back to Top]] | ||
</div> | </div> | ||
− | {{#lst: | + | {{#lst:Editorial board transclusions|aml}} |
<big>'''Note: these are regimens tested in biomarker-specific populations for patients with FLT3 internal tandem duplicated (FLT3-ITD) or tyrosine kinase domain mutated (FLT3-TKD) AML, please see the [[Acute myeloid leukemia|main AML page]] for other regimens.'''</big> | <big>'''Note: these are regimens tested in biomarker-specific populations for patients with FLT3 internal tandem duplicated (FLT3-ITD) or tyrosine kinase domain mutated (FLT3-TKD) AML, please see the [[Acute myeloid leukemia|main AML page]] for other regimens.'''</big> | ||
+ | <br>''For placebo or observational studies in this condition, please visit [[Acute myeloid leukemia, FLT3-positive - null regimens|this page]].'' | ||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
|- | |- | ||
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|} | |} | ||
{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
+ | =Guidelines= | ||
+ | '''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.''' | ||
+ | ==NCCN== | ||
+ | *''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411 NCCN Guidelines - Acute Myeloid Leukemia].'' | ||
=Upfront induction therapy, standard patients= | =Upfront induction therapy, standard patients= | ||
==7+3d (intermediate-dose) {{#subobject:e82156|Regimen=1}}== | ==7+3d (intermediate-dose) {{#subobject:e82156|Regimen=1}}== | ||
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{| 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%" | | + | ! style="width: 20%" |Dates 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]] | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] |
− | |2016-2019 | + | |2016-09-27 to 2019-08-14 |
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | | | + | |1a. [[#7.2B3d_.26_Quizartinib|7+3d & Quizartinib]]<br>1b. [[#7.2B3i_.26_Quizartinib|7+3i & Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 35: | Line 40: | ||
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>) | *[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>) | ||
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3 | *[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3 | ||
− | ''' | + | '''7-day course''' |
</div></div><br> | </div></div><br> | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | |||
===Regimen variant #2 {{#subobject:cf53dd|Variant=1}}=== | ===Regimen variant #2 {{#subobject:cf53dd|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 | ||
− | ! style="width: 20%" | | + | ! style="width: 20%" |Dates 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 | ||
Line 52: | Line 58: | ||
| style="background-color:#d73027" |Inferior OS | | style="background-color:#d73027" |Inferior OS | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] |
− | |2016-2019 | + | |2016-09-27 to 2019-08-14 |
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | | | + | |1a. [[#7.2B3d_.26_Quizartinib|7+3d & Quizartinib]]<br>1b. [[#7.2B3i_.26_Quizartinib|7+3i & Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 70: | Line 76: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261 | + | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114/ PubMed] [https://clinicaltrials.gov/study/NCT00651261 NCT00651261] |
− | #'''QuANTUM-First:''' Erba | + | #'''QuANTUM-First:''' Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653] |
− | #'''Q-SOC:''' NCT04676243 | + | #'''Q-SOC:''' [https://clinicaltrials.gov/study/NCT04676243 NCT04676243] |
==7+3d & Midostaurin {{#subobject:b7ea7e|Regimen=1}}== | ==7+3d & Midostaurin {{#subobject:b7ea7e|Regimen=1}}== | ||
7+3d & Midostaurin: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, Midostaurin | 7+3d & Midostaurin: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, Midostaurin | ||
Line 83: | Line 89: | ||
{| 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%" | | + | ! style="width: 20%" |Dates 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 | ||
Line 92: | Line 98: | ||
| style="background-color:#1a9851" |Phase 3 (E-RT-esc) | | style="background-color:#1a9851" |Phase 3 (E-RT-esc) | ||
|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] | |[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]] | ||
− | | style="background-color:#1a9850" |Superior OS<br>Median OS: 74.7 vs 25.6 mo<br>(HR 0.78, 95% CI 0.63-0.96) | + | | style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 74.7 vs 25.6 mo<br>(HR 0.78, 95% CI 0.63-0.96) |
|- | |- | ||
|} | |} | ||
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<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *RATIFY, patients who achieved complete remission (CR): [[#HiDAC_.26_Midostaurin|HiDAC & Midostaurin]] consolidation. Stem cell transplantation was allowed. |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261 | + | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114/ PubMed] [https://clinicaltrials.gov/study/NCT00651261 NCT00651261] |
==7+3d & Quizartinib {{#subobject:6d491a|Regimen=1}}== | ==7+3d & Quizartinib {{#subobject:6d491a|Regimen=1}}== | ||
7+3d & Quizartinib: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, Quizartinib | 7+3d & Quizartinib: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, Quizartinib | ||
Line 117: | Line 123: | ||
{| 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%" | | + | ! style="width: 20%" |Dates 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]] | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] |
− | |2016-2019 | + | |2016-09-27 to 2019-08-14 |
− | | style="background-color:#1a9851" |Phase 3 (E-esc) | + | | style="background-color:#1a9851" |Phase 3 (E-RT-esc) |
− | | | + | |1a. [[#7.2B3d_.28intermediate-dose.29|7+3d]]; intermediate-dose<br>1b. [[#7.2B3i|7+3i]] |
− | | style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98) | + | | style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98) |
|- | |- | ||
|} | |} | ||
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<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *QuANTUM-First, patients who achieved complete remission (CR): [[#HiDAC_.26_Quizartinib|HiDAC & Quizartinib]] consolidation. Stem cell transplantation was allowed. |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''QuANTUM-First:''' Erba | + | #'''QuANTUM-First:''' Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653] |
==7+3i {{#subobject:ehcll6|Regimen=1}}== | ==7+3i {{#subobject:ehcll6|Regimen=1}}== | ||
7+3i: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>i</u>'''darubicin | 7+3i: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>i</u>'''darubicin | ||
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{| 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%" | | + | ! style="width: 20%" |Dates 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]] | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] |
− | |2016-2019 | + | |2016-09-27 to 2019-08-14 |
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | | | + | |1a. [[#7.2B3d_.26_Quizartinib|7+3d & Quizartinib]]<br>1b. [[#7.2B3i_.26_Quizartinib|7+3i & Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 165: | Line 171: | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>) | *[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>) | ||
− | *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/ | + | *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | ''' | + | '''7-day course''' |
</div></div><br> | </div></div><br> | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | |||
===Regimen variant #2 {{#subobject:oboxnd|Variant=1}}=== | ===Regimen variant #2 {{#subobject:oboxnd|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 | ||
− | ! style="width: 20%" | | + | ! style="width: 20%" |Dates 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]] | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] |
− | |2016-2019 | + | |2016-09-27 to 2019-08-14 |
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | | | + | |1a. [[#7.2B3d_.26_Quizartinib|7+3d & Quizartinib]]<br>1b. [[#7.2B3i_.26_Quizartinib|7+3i & Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 188: | Line 195: | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>) | *[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>) | ||
− | *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/ | + | *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
'''7-day course''' | '''7-day course''' | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''QuANTUM-First:''' Erba | + | #'''QuANTUM-First:''' Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653] |
==7+3i & Quizartinib {{#subobject:6d4gac|Regimen=1}}== | ==7+3i & Quizartinib {{#subobject:6d4gac|Regimen=1}}== | ||
7+3i & Quizartinib: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>i</u>'''darubicin, Quizartinib | 7+3i & Quizartinib: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>i</u>'''darubicin, Quizartinib | ||
Line 199: | Line 206: | ||
{| 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%" | | + | ! style="width: 20%" |Dates 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]] | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] |
− | |2016-2019 | + | |2016-09-27 to 2019-08-14 |
− | | style="background-color:#1a9851" |Phase 3 (E-esc) | + | | style="background-color:#1a9851" |Phase 3 (E-RT-esc) |
− | | | + | |1a. [[#7.2B3d_.28intermediate-dose.29|7+3d]]; intermediate-dose<br>1b. [[#7.2B3i|7+3i]] |
− | | style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98) | + | | style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98) |
|- | |- | ||
|} | |} | ||
Line 214: | Line 221: | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day or 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m<sup>2</sup>) | *[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day or 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m<sup>2</sup>) | ||
− | *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/ | + | *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
====Targeted therapy==== | ====Targeted therapy==== | ||
*[[Quizartinib (Vanflyta)]] 40 mg PO once per day on days 8 to 21 | *[[Quizartinib (Vanflyta)]] 40 mg PO once per day on days 8 to 21 | ||
Line 221: | Line 228: | ||
<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *QuANTUM-First, patients who achieved complete remission (CR): [[#HiDAC_.26_Quizartinib|HiDAC & Quizartinib]] consolidation. Stem cell transplantation was allowed. |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''QuANTUM-First:''' Erba | + | #'''QuANTUM-First:''' Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653] |
==DA 3 + 10 {{#subobject:5c0062|Regimen=1}}== | ==DA 3 + 10 {{#subobject:5c0062|Regimen=1}}== | ||
− | DA 3 + 10: '''<u>D</u>''' | + | DA 3 + 10: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine |
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:211741|Variant=1}}=== | ===Regimen {{#subobject:211741|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 | ||
− | ! style="width: 20%" | | + | ! style="width: 20%" |Dates 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 | ||
Line 237: | Line 244: | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ Burnett et al. 2015 (UK NCRI AML17)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ Burnett et al. 2015 (UK NCRI AML17)] | ||
− | | | + | |2009-2014 |
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
|[[#DA_3_.2B_10|DA 3 + 10]]; high-dose | |[[#DA_3_.2B_10|DA 3 + 10]]; high-dose | ||
Line 252: | Line 259: | ||
<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *[[#DA_3. | + | *[[#DA_3.2B8_888|DA 3+8]] versus [[#DA_3.2B8_.26_Lestaurtinib_777|DA 3+8 & Lestaurtinib]] re-induction |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m<sup>2</sup> vs 60 mg/m<sup>2</sup> in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. [https://doi.org/10.1182/blood-2015-01-623447 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25833957 PubMed] ISRCTN55675535 | + | #'''UK NCRI AML17:''' Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m<sup>2</sup> vs 60 mg/m<sup>2</sup> in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. [https://doi.org/10.1182/blood-2015-01-623447 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25833957/ PubMed] ISRCTN55675535 |
− | ##'''Update:''' Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. [https://doi.org/10.3324/haematol.2018.189514 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165825/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29976746 PubMed] | + | ##'''Update:''' Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. [https://doi.org/10.3324/haematol.2018.189514 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165825/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29976746/ PubMed] |
+ | |||
=First-line induction therapy, older patients or "unfit" patients= | =First-line induction therapy, older patients or "unfit" patients= | ||
==Azacitidine monotherapy {{#subobject:5ujvv0|Regimen=1}}== | ==Azacitidine monotherapy {{#subobject:5ujvv0|Regimen=1}}== | ||
Line 263: | Line 271: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 271: | Line 279: | ||
|2016-NR | |2016-NR | ||
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | |[[#Azacitidine_. | + | |[[#Azacitidine_.26_Gilteritinib_999|Azacitidine & Gilteritinib]] |
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS | | style="background-color:#ffffbf" |Did not meet primary endpoint of OS | ||
|- | |- | ||
Line 281: | Line 289: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''LACEWING:''' Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, Chou WC, Laribi K, Esteve J, Altman JK, Havelange V, Watson AM, Gambacorti-Passerini C, Patkowska E, Liu S, Wu R, Philipose N, Hill JE, Gill SC, Rich ES, Tiu RV. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022 Oct 27;140(17):1845-1857. Epub 2022 Aug 2. [https://doi.org/10.1182/blood.2021014586 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35917453/ PubMed] NCT02752035 | + | #'''LACEWING:''' Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, Chou WC, Laribi K, Esteve J, Altman JK, Havelange V, Watson AM, Gambacorti-Passerini C, Patkowska E, Liu S, Wu R, Philipose N, Hill JE, Gill SC, Rich ES, Tiu RV. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022 Oct 27;140(17):1845-1857. Epub 2022 Aug 2. [https://doi.org/10.1182/blood.2021014586 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35917453/ PubMed] [https://clinicaltrials.gov/study/NCT02752035 NCT02752035] |
==7+3d & Sorafenib {{#subobject:6ad412|Regimen=1}}== | ==7+3d & Sorafenib {{#subobject:6ad412|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 287: | Line 295: | ||
{| class="wikitable sortable" style="width: 60%; text-align:center;" | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
!style="width: 33%"|Study | !style="width: 33%"|Study | ||
− | !style="width: 33%"| | + | !style="width: 33%"|Dates of enrollment |
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
Line 305: | Line 313: | ||
<div class="toccolours" style="background-color:#cbd5e7"> | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | * | + | *CALGB 11001, patients not achieving a hypoplastic marrow on day 14: [[#5.2Bd_.26_Sorafenib_888|5+2d & sorafenib]] re-induction |
− | * | + | *CALGB 11001, patients achieving a CR or CRi: [[#IDAC_.26_Sorafenib|IDAC & sorafenib]] consolidation |
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''CALGB 11001:''' Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366 PubMed] NCT01253070 | + | #'''CALGB 11001:''' Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366/ PubMed] [https://clinicaltrials.gov/study/NCT01253070 NCT01253070] |
=Consolidation after upfront therapy= | =Consolidation after upfront therapy= | ||
Line 322: | Line 330: | ||
{| class="wikitable sortable" style="width: 60%; text-align:center;" | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
!style="width: 33%"|Study | !style="width: 33%"|Study | ||
− | !style="width: 33%"| | + | !style="width: 33%"|Dates of enrollment |
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ Stone et al. 2017 (RATIFY)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ Stone et al. 2017 (RATIFY)] | ||
|2008-2011 | |2008-2011 | ||
− | | style="background-color:#91cf61" |Non-randomized | + | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT |
|- | |- | ||
|} | |} | ||
Line 336: | Line 344: | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 ( | + | *[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle) |
====Targeted therapy==== | ====Targeted therapy==== | ||
*[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 8 to 21 | *[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 8 to 21 | ||
Line 346: | Line 354: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261 | + | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114/ PubMed] [https://clinicaltrials.gov/study/NCT00651261 NCT00651261] |
+ | ==HiDAC & Quizartinib {{#subobject:aquf1b|Regimen=1}}== | ||
+ | HiDAC & Quizartinib: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Quizartinib | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:c3eqc2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] | ||
+ | |2016-09-27 to 2019-08-14 | ||
+ | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT | ||
+ | |- | ||
+ | |} | ||
+ | ''Note: Patients undergoing allogeneic HSCT after consolidation proceeded to maintenance anytime between day +30 and day +180.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *[[#7.2B3d_.26_Quizartinib|7+3d & Quizartinib]] or [[#7.2B3i_.26_Quizartinib|7+3i & Quizartinib]] induction, with CR | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Cytarabine (Ara-C)]] by the following age-based criteria: | ||
+ | **Younger than 60 years old: 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle) | ||
+ | **60 years old or older: 1500 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle) | ||
+ | ====Targeted therapy==== | ||
+ | *[[Quizartinib (Vanflyta)]] 40 mg PO once per day on days 6 to 19 | ||
+ | '''Up to 4 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *[[#Quizartinib_monotherapy|Quizartinib]] maintenance (see note) | ||
+ | </div></div> | ||
+ | |||
+ | ===References=== | ||
+ | #'''QuANTUM-First:''' Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653] | ||
+ | |||
==IDAC & Sorafenib {{#subobject:c2cc06|Regimen=1}}== | ==IDAC & Sorafenib {{#subobject:c2cc06|Regimen=1}}== | ||
IDAC & Sorafenib: '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Sorafenib | IDAC & Sorafenib: '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Sorafenib | ||
Line 353: | Line 397: | ||
{| class="wikitable sortable" style="width: 60%; text-align:center;" | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
!style="width: 33%"|Study | !style="width: 33%"|Study | ||
− | !style="width: 33%"| | + | !style="width: 33%"|Dates of enrollment |
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
Line 377: | Line 421: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''CALGB 11001:''' Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366 PubMed] NCT01253070 | + | #'''CALGB 11001:''' Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366/ PubMed] [https://clinicaltrials.gov/study/NCT01253070 NCT01253070] |
=Maintenance after upfront therapy, including allogeneic HSCT= | =Maintenance after upfront therapy, including allogeneic HSCT= | ||
==Midostaurin monotherapy {{#subobject:e0bb17|Regimen=1}}== | ==Midostaurin monotherapy {{#subobject:e0bb17|Regimen=1}}== | ||
Line 384: | Line 428: | ||
{| class="wikitable sortable" style="width: 80%; text-align:center;" | {| class="wikitable sortable" style="width: 80%; text-align:center;" | ||
!style="width: 25%"|Study | !style="width: 25%"|Study | ||
− | !style="width: 25%"| | + | !style="width: 25%"|Dates of enrollment |
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
Line 390: | Line 434: | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ Stone et al. 2017 (RATIFY)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ Stone et al. 2017 (RATIFY)] | ||
|2008-2011 | |2008-2011 | ||
− | | style="background-color:#91cf61" |Non-randomized | + | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT |
|CR rate: 59% after induction | |CR rate: 59% after induction | ||
|- | |- | ||
Line 400: | Line 444: | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Midostaurin (Rydapt)]] 50 mg PO twice per day | + | *[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 1 to 28 |
'''28-day cycle for up to 13 cycles (1 year)''' | '''28-day cycle for up to 13 cycles (1 year)''' | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261 | + | #'''RATIFY:''' Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114/ PubMed] [https://clinicaltrials.gov/study/NCT00651261 NCT00651261] |
− | #'''ARO-021:''' NCT03258931 | + | #'''ARO-021:''' [https://clinicaltrials.gov/study/NCT03258931 NCT03258931] |
− | #'''HOVON 156 AML:''' NCT04027309 | + | #'''HOVON 156 AML:''' [https://clinicaltrials.gov/study/NCT04027309 NCT04027309] |
+ | ==Quizartinib monotherapy {{#subobject:anmo4b|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:q3fqc2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)] | ||
+ | |2016-09-27 to 2019-08-14 | ||
+ | | style="background-color:#91cf61" |Non-randomized part of phase 3 RCT | ||
+ | |- | ||
+ | |} | ||
+ | ''Note: Patients undergoing allogeneic HSCT after consolidation began maintenance anytime between day +30 and day +180. The dose of quizartinib was increased only if the mean QT interval corrected with Fridericia's formula [QTcF] was less than or equal to 450 ms on C1D15.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *[[#HiDAC_.26_Quizartinib|HiDAC & Quizartinib]] consolidation, +/- allogeneic HSCT | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Quizartinib (Vanflyta)]] as follows: | ||
+ | **Cycle 1: 30 mg PO once per day on days 1 to 14, then 60 mg PO once per day on days 15 to 28 | ||
+ | **Cycles 2 to 36: 60 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycle for up to 36 cycles (3 years)''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | #'''QuANTUM-First:''' Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653] | ||
+ | |||
==Sorafenib monotherapy {{#subobject:23822e|Regimen=1}}== | ==Sorafenib monotherapy {{#subobject:23822e|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 412: | Line 484: | ||
{| 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%" | | + | ! style="width: 20%" |Dates 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 | ||
Line 418: | Line 490: | ||
|- | |- | ||
|[https://doi.org/10.1016/s1470-2045(20)30455-1 Xuan et al. 2020 (Sorafenib-Flt3 AML-2015)] | |[https://doi.org/10.1016/s1470-2045(20)30455-1 Xuan et al. 2020 (Sorafenib-Flt3 AML-2015)] | ||
− | |2015-2018 | + | |2015-06-20 to 2018-07-21 |
| style="background-color:#1a9851" |Phase 3 (E-esc) | | style="background-color:#1a9851" |Phase 3 (E-esc) | ||
− | |[[# | + | |[[Acute_myeloid_leukemia,_FLT3-positive_-_null_regimens#Observation|Observation]] |
− | | style="background-color:#1a9850" |Superior 1-year cumulative incidence of relapse | + | | style="background-color:#1a9850" |Superior 1-year cumulative incidence of relapse (primary endpoint)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 72% vs 55.9%<br>(HR 0.55, 95% CI 0.34-0.88) |
|- | |- | ||
|} | |} | ||
+ | ''<sup>1</sup>Reported efficacy is based on the 2023 update.'' | ||
<div class="toccolours" style="background-color:#cbd5e8"> | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[Allogeneic stem cells|Allogeneic stem cell transplant]] | + | *[[Allogeneic stem cells|Allogeneic stem cell transplant]] consolidation |
</div> | </div> | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
Line 437: | Line 510: | ||
{| class="wikitable sortable" style="width: 60%; text-align:center;" | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
!style="width: 33%"|Study | !style="width: 33%"|Study | ||
− | !style="width: 33%"| | + | !style="width: 33%"|Dates of enrollment |
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
Line 451: | Line 524: | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Sorafenib (Nexavar)]] 400 mg PO twice per day | + | *[[Sorafenib (Nexavar)]] 400 mg PO twice per day on days 1 to 28 |
'''28-day cycle for up to 12 cycles''' | '''28-day cycle for up to 12 cycles''' | ||
</div></div><br> | </div></div><br> | ||
Line 458: | Line 531: | ||
{| 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%" | | + | ! style="width: 20%" |Dates 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 | ||
Line 466: | Line 539: | ||
|2010-2016 | |2010-2016 | ||
| style="background-color:#1a9851" |Phase 3 (E-esc) | | style="background-color:#1a9851" |Phase 3 (E-esc) | ||
− | |[[# | + | |[[Acute_myeloid_leukemia,_FLT3-positive_-_null_regimens#Placebo|Placebo]] |
− | | style="background-color:#1a9850" |Superior RFS<br>RFS24: 85% vs 53.3%<br>(HR 0.39, 95% CI 0.18-0.85) | + | | style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS24: 85% vs 53.3%<br>(HR 0.39, 95% CI 0.18-0.85) |
|} | |} | ||
+ | ''Note: dose was escalated only if tolerated.'' | ||
<div class="toccolours" style="background-color:#cbd5e8"> | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[Allogeneic stem cells|Allogeneic stem cell transplant]] | + | *[[Allogeneic stem cells|Allogeneic stem cell transplant]] consolidation |
</div> | </div> | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
*[[Sorafenib (Nexavar)]] as follows: | *[[Sorafenib (Nexavar)]] as follows: | ||
− | **Cycle 1: 200 mg PO twice per day on days 1 to 14, then 400 mg PO twice per day | + | **Cycle 1: 200 mg PO twice per day on days 1 to 14, then 400 mg PO twice per day on days 15 to 28 |
− | **Cycles 2 to 26: 400 mg PO twice per day | + | **Cycles 2 to 26: 400 mg PO twice per day on days 1 to 28 |
'''28-day cycle for up to 26 cycles (2 years)''' | '''28-day cycle for up to 26 cycles (2 years)''' | ||
</div></div> | </div></div> | ||
+ | |||
===References=== | ===References=== | ||
− | #'''CALGB 11001:''' Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366 PubMed] NCT01253070 | + | #'''CALGB 11001:''' Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366/ PubMed] [https://clinicaltrials.gov/study/NCT01253070 NCT01253070] |
− | #'''SORMAIN:''' Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, Wollmer E, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner EM, Kröger N, Wolschke C, Schleuning M, Götze KS, Schmid C, Crysandt M, Eßeling E, Wolf D, Wang Y, Böhm A, Thiede C, Haferlach T, Michel C, Bethge W, Wündisch T, Brandts C, Harnisch S, Wittenberg M, Hoeffkes HG, Rospleszcz S, Burchardt A, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With ''FLT3''-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol. 2020 Sep 10;38(26):2993-3002. Epub 2020 Jul 16. [https://doi.org/10.1200/jco.19.03345 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32673171 PubMed] [https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-018539-16/AT Link to clinical trial registration] DRKS00000591 | + | #'''SORMAIN:''' Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, Wollmer E, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner EM, Kröger N, Wolschke C, Schleuning M, Götze KS, Schmid C, Crysandt M, Eßeling E, Wolf D, Wang Y, Böhm A, Thiede C, Haferlach T, Michel C, Bethge W, Wündisch T, Brandts C, Harnisch S, Wittenberg M, Hoeffkes HG, Rospleszcz S, Burchardt A, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With ''FLT3''-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol. 2020 Sep 10;38(26):2993-3002. Epub 2020 Jul 16. [https://doi.org/10.1200/jco.19.03345 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32673171/ PubMed] [https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-018539-16/AT Link to clinical trial registration] DRKS00000591 |
− | #'''Sorafenib-Flt3 AML-2015:''' Xuan L, Wang Y, Huang F, Fan Z, Xu Y, Sun J, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Yu C, Zhou X, Lin R, Chen Y, Tu S, Huang X, Liu Q. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1201-1212. Epub 2020 Aug 10. [https://doi.org/10.1016/s1470-2045(20)30455-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32791048 PubMed] NCT02474290 | + | #'''Sorafenib-Flt3 AML-2015:''' Xuan L, Wang Y, Huang F, Fan Z, Xu Y, Sun J, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Yu C, Zhou X, Lin R, Chen Y, Tu S, Huang X, Liu Q. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1201-1212. Epub 2020 Aug 10. [https://doi.org/10.1016/s1470-2045(20)30455-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32791048/ PubMed] [https://clinicaltrials.gov/study/NCT02474290 NCT02474290] |
+ | ##'''Update:''' Xuan L, Wang Y, Yang K, Shao R, Huang F, Fan Z, Chi P, Xu Y, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Lin R, Chen Y, Tu S, Zhang Y, Sun J, Huang X, Liu Q. Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023 Aug;10(8):e600-e611. Epub 2023 Jul 3. [https://doi.org/10.1016/s2352-3026(23)00117-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37414062/ PubMed] | ||
+ | |||
=Relapsed or refractory, salvage therapy= | =Relapsed or refractory, salvage therapy= | ||
==Midostaurin monotherapy {{#subobject:badb27|Regimen=1}}== | ==Midostaurin monotherapy {{#subobject:badb27|Regimen=1}}== | ||
Line 490: | Line 567: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 497: | Line 574: | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ Fischer et al. 2010 (CPKC412A2104)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ Fischer et al. 2010 (CPKC412A2104)] | ||
|2002-NR | |2002-NR | ||
− | | style="background-color:#1a9851" |Randomized | + | | style="background-color:#1a9851" |Randomized phase 2b (E-de-esc) |
|[[#Midostaurin_monotherapy_2|Midostaurin]]; 100 mg twice per day | |[[#Midostaurin_monotherapy_2|Midostaurin]]; 100 mg twice per day | ||
| style="background-color:#d3d3d3" |Not reported | | style="background-color:#d3d3d3" |Not reported | ||
Line 504: | Line 581: | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Midostaurin (Rydapt)]] 50 mg PO twice per day | + | *[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 1 to 28 |
− | ''' | + | '''28-day cycles''' |
</div></div><br> | </div></div><br> | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 511: | Line 588: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 518: | Line 595: | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ Fischer et al. 2010 (CPKC412A2104)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ Fischer et al. 2010 (CPKC412A2104)] | ||
|2002-NR | |2002-NR | ||
− | | style="background-color:#1a9851" |Randomized | + | | style="background-color:#1a9851" |Randomized phase 2b (E-esc) |
|[[#Midostaurin_monotherapy_2|Midostaurin]]; 50 mg twice per day | |[[#Midostaurin_monotherapy_2|Midostaurin]]; 50 mg twice per day | ||
| style="background-color:#d3d3d3" |Not reported | | style="background-color:#d3d3d3" |Not reported | ||
Line 525: | Line 602: | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Midostaurin (Rydapt)]] 100 mg PO twice per day | + | *[[Midostaurin (Rydapt)]] 100 mg PO twice per day on days 1 to 28 |
− | ''' | + | '''28-day cycles''' |
</div></div><br> | </div></div><br> | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 532: | Line 609: | ||
{| class="wikitable sortable" style="width: 60%; text-align:center;" | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
!style="width: 33%"|Study | !style="width: 33%"|Study | ||
− | !style="width: 33%"| | + | !style="width: 33%"|Dates of enrollment |
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
Line 546: | Line 623: | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Midostaurin (Rydapt)]] 75 mg PO three times per day | + | *[[Midostaurin (Rydapt)]] 75 mg PO three times per day on days 1 to 28 |
'''28-day cycles''' | '''28-day cycles''' | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005 Jan 1;105(1):54-60. Epub 2004 Sep 2. [https://doi.org/10.1182/blood-2004-03-0891 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15345597 PubMed] | + | #Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005 Jan 1;105(1):54-60. Epub 2004 Sep 2. [https://doi.org/10.1182/blood-2004-03-0891 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15345597/ PubMed] |
− | #'''CPKC412A2104:''' Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. [https://doi.org/10.1200/jco.2010.28.9678 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20733134 PubMed] NCT00045942 | + | #'''CPKC412A2104:''' Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. [https://doi.org/10.1200/jco.2010.28.9678 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20733134/ PubMed] [https://clinicaltrials.gov/study/NCT00045942 NCT00045942] |
=Relapsed or refractory, further lines of therapy= | =Relapsed or refractory, further lines of therapy= | ||
==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}== | ==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}== | ||
Line 558: | Line 635: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 577: | Line 654: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] NCT02421939 | + | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] [https://clinicaltrials.gov/study/NCT02421939 NCT02421939] |
##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ||
==Azacitidine & Sorafenib {{#subobject:e3a8ee|Regimen=1}}== | ==Azacitidine & Sorafenib {{#subobject:e3a8ee|Regimen=1}}== | ||
Line 584: | Line 661: | ||
{| class="wikitable sortable" style="width: 60%; text-align:center;" | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
!style="width: 33%"|Study | !style="width: 33%"|Study | ||
− | !style="width: 33%"| | + | !style="width: 33%"|Dates of enrollment |
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
Line 602: | Line 679: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''MDACC 2010-0511:''' Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62. Epub 2013 Apr 23. [https://doi.org/10.1182/blood-2013-01-480228 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674666/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23613521 PubMed] NCT01254890 | + | #'''MDACC 2010-0511:''' Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62. Epub 2013 Apr 23. [https://doi.org/10.1182/blood-2013-01-480228 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674666/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23613521/ PubMed] [https://clinicaltrials.gov/study/NCT01254890 NCT01254890] |
==FLAG-Ida {{#subobject:d8c75b|Regimen=1}}== | ==FLAG-Ida {{#subobject:d8c75b|Regimen=1}}== | ||
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Filgrastim), '''<u>Ida</u>'''rubicin | FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Filgrastim), '''<u>Ida</u>'''rubicin | ||
Line 609: | Line 686: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 617: | Line 694: | ||
|2014-2017 | |2014-2017 | ||
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | |[[# | + | |[[#Quizartinib_monotherapy_2|Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 637: | Line 714: | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31175001 PubMed] NCT02039726 | + | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726] |
− | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] NCT02421939 | + | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] [https://clinicaltrials.gov/study/NCT02421939 NCT02421939] |
##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ||
− | #'''ARO-013:''' NCT03250338 | + | #'''ARO-013:''' [https://clinicaltrials.gov/study/NCT03250338 NCT03250338] |
+ | |||
==Gilteritinib monotherapy {{#subobject:0384e2|Regimen=1}}== | ==Gilteritinib monotherapy {{#subobject:0384e2|Regimen=1}}== | ||
<div class="toccolours" style="background-color:#eeeeee"> | <div class="toccolours" style="background-color:#eeeeee"> | ||
Line 650: | Line 728: | ||
{| 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%" | | + | ! style="width: 20%" |Dates 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]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5572576/ Perl et al. 2017 (2215-CL-0101)] |
|2013-2015 | |2013-2015 | ||
| style="background-color:#91cf61" |Phase 1/2 | | style="background-color:#91cf61" |Phase 1/2 | ||
Line 664: | Line 742: | ||
|2015-2018 | |2015-2018 | ||
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc) | | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc) | ||
− | |Investigator's choice of:<br>1a. [[#MEC|MEC]]<br>1b. [[#FLAG-Ida|FLAG-Ida]]<br>1c. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]<br>1d. [[# | + | |Investigator's choice of:<br>1a. [[#MEC|MEC]]<br>1b. [[#FLAG-Ida|FLAG-Ida]]<br>1c. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]<br>1d. [[#Azacitidine_monotherapy_2|Azacitidine]] |
− | | style="background-color:#1a9851" |Superior OS<sup>1</sup><br>Median OS: 9.3 | + | | style="background-color:#1a9851" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 9.3 vs 5.6 mo<br>(HR 0.665, 95% CI 0.52-0.85) |
+ | |- | ||
+ | |[https://clinicaltrials.gov/study/NCT03182244 Awaiting publication (2215-CL-0303)] | ||
+ | |2018-2023 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | ||
+ | |1a. [[#MEC|MEC]]<br>1b. [[#FLAG|FLAG]]<br>1c. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]] | ||
+ | | style="background-color:#d3d3d3" |TBD if different primary endpoint of OS | ||
+ | |||
|} | |} | ||
''<sup>1</sup>Reported efficacy is based on the 2022 update.'' | ''<sup>1</sup>Reported efficacy is based on the 2022 update.'' | ||
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Gilteritinib (Xospata)]] 120 mg PO once per day | + | *[[Gilteritinib (Xospata)]] 120 mg PO once per day on days 1 to 28 |
'''28-day cycles''' | '''28-day cycles''' | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | #'''2215-CL-0101:''' Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. Epub 2017 Jun 20. [https://doi.org/10.1016/s1470-2045(17)30416-3 link to original article] [ | + | #'''2215-CL-0101:''' Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. Epub 2017 Jun 20. [https://doi.org/10.1016/s1470-2045(17)30416-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5572576/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28645776/ PubMed] [https://clinicaltrials.gov/study/NCT02014558 NCT02014558] |
− | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] NCT02421939 | + | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] [https://clinicaltrials.gov/study/NCT02421939 NCT02421939] |
##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ||
− | #'''2215-CL-0303:''' NCT03182244 | + | #'''2215-CL-0303:''' [https://clinicaltrials.gov/study/NCT03182244 NCT03182244] |
+ | |||
==Low-dose Cytarabine monotherapy (LoDAC) {{#subobject:48ba18|Regimen=1}}== | ==Low-dose Cytarabine monotherapy (LoDAC) {{#subobject:48ba18|Regimen=1}}== | ||
LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine) | LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine) | ||
Line 685: | Line 771: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 693: | Line 779: | ||
|2014-2017 | |2014-2017 | ||
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | |[[# | + | |[[#Quizartinib_monotherapy_2|Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 708: | Line 794: | ||
'''28-day cycles''' | '''28-day cycles''' | ||
</div></div> | </div></div> | ||
+ | |||
===References=== | ===References=== | ||
− | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001 PubMed] NCT02039726 | + | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726] |
− | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] NCT02421939 | + | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] [https://clinicaltrials.gov/study/NCT02421939 NCT02421939] |
##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ||
==MEC {{#subobject:48e49b|Regimen=1}}== | ==MEC {{#subobject:48e49b|Regimen=1}}== | ||
Line 718: | Line 805: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 726: | Line 813: | ||
|2014-2017 | |2014-2017 | ||
| style="background-color:#1a9851" |Phase 3 (C) | | style="background-color:#1a9851" |Phase 3 (C) | ||
− | |[[# | + | |[[#Quizartinib_monotherapy_2|Quizartinib]] |
| style="background-color:#fc8d59" |Seems to have inferior OS | | style="background-color:#fc8d59" |Seems to have inferior OS | ||
|- | |- | ||
Line 741: | Line 828: | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first''' | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first''' | ||
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second''' | *[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second''' | ||
− | '''28-day cycle for | + | '''28-day cycle for 1 to 2 cycles''' |
</div></div> | </div></div> | ||
+ | |||
===References=== | ===References=== | ||
− | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001 PubMed] NCT02039726 | + | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726] |
− | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] NCT02421939 | + | #'''ADMIRAL:''' Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] [https://clinicaltrials.gov/study/NCT02421939 NCT02421939] |
##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ##'''Update:''' Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed] | ||
==Quizartinib monotherapy {{#subobject:1684ae|Regimen=1}}== | ==Quizartinib monotherapy {{#subobject:1684ae|Regimen=1}}== | ||
Line 752: | Line 840: | ||
{| 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%"| | + | !style="width: 20%"|Dates 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 | ||
Line 761: | Line 849: | ||
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | ||
|Investigator's choice of:<br>1a. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]<br>1b. [[#MEC|MEC]]<br>1c. [[#FLAG-Ida|FLAG-Ida]] | |Investigator's choice of:<br>1a. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]<br>1b. [[#MEC|MEC]]<br>1c. [[#FLAG-Ida|FLAG-Ida]] | ||
− | | style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 6.2 vs 4.7 mo<br>(HR 0.76, 95% CI 0.58-0.98) | + | | style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 6.2 vs 4.7 mo<br>(HR 0.76, 95% CI 0.58-0.98) |
|} | |} | ||
− | ''Note: Quizartinib is only | + | ''Note: Quizartinib was studied at a variety of doses; references are provided below for historic context; the dose here is from QuANTUM-R, and was only increased if certain QTc parameters were met; see the paper for details.'' |
<div class="toccolours" style="background-color:#b3e2cd"> | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Targeted therapy==== | ====Targeted therapy==== | ||
− | *[[Quizartinib (Vanflyta)]] 60 mg PO once per day | + | *[[Quizartinib (Vanflyta)]] as follows: |
− | ''' | + | **Cycle 1: 30 mg PO once per day on days 1 to 15, then 60 mg PO once per day on days 16 to 28 |
+ | **Cycle 2 onwards: 60 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
</div></div> | </div></div> | ||
===References=== | ===References=== | ||
− | # '''CP0001:''' Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. Epub 2013 Sep 3. [https://doi.org/10.1200/jco.2013.48.8783 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3804291/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24002496 PubMed] NCT00462761 | + | # '''CP0001:''' Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. Epub 2013 Sep 3. [https://doi.org/10.1200/jco.2013.48.8783 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3804291/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24002496/ PubMed] [https://clinicaltrials.gov/study/NCT00462761 NCT00462761] |
<!-- | <!-- | ||
# '''Abstract:''' Jorge E. Cortes, Alexander E Perl, Hervé Dombret, Sabine Kayser, Björn Steffen, Philippe Rousselot, Giovanni Martinelli, Elihu H. Estey, Alan K Burnett, Guy Gammon, Denise Trone, Eugen Leo, and Mark J. Levis Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients ≥ 60 Years of Age with FLT3 ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 48. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/48 link to abstract] --> | # '''Abstract:''' Jorge E. Cortes, Alexander E Perl, Hervé Dombret, Sabine Kayser, Björn Steffen, Philippe Rousselot, Giovanni Martinelli, Elihu H. Estey, Alan K Burnett, Guy Gammon, Denise Trone, Eugen Leo, and Mark J. Levis Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients ≥ 60 Years of Age with FLT3 ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 48. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/48 link to abstract] --> | ||
− | # '''ACE:''' Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. Epub 2018 May 31. [https://doi.org/10.1016/s1470-2045(18)30240-7 link to original article] [ | + | # '''ACE<sub>AML</sub>:''' Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. Epub 2018 May 31. [https://doi.org/10.1016/s1470-2045(18)30240-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8152787/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29859851/ PubMed] [https://clinicaltrials.gov/study/NCT00989261 NCT00989261] |
− | # '''2689-CL-2004:''' Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, Levis MJ. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018 Aug 9;132(6):598-607. Epub 2018 Jun 6. [https://doi.org/10.1182/blood-2018-01-821629 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6085992/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29875101 PubMed] NCT01565668 | + | # '''2689-CL-2004:''' Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, Levis MJ. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018 Aug 9;132(6):598-607. Epub 2018 Jun 6. [https://doi.org/10.1182/blood-2018-01-821629 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6085992/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29875101/ PubMed] [https://clinicaltrials.gov/study/NCT01565668 NCT01565668] |
− | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31175001 PubMed] [https://clinicaltrials.gov/ | + | #'''QuANTUM-R:''' Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726] |
+ | |||
=Prognosis= | =Prognosis= | ||
==Prognosis in cytogenetically normal AML== | ==Prognosis in cytogenetically normal AML== | ||
− | #''Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome:'' Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. [https://doi.org/10.1056/NEJMoa074306 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18450602 PubMed | + | #''Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome:'' Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. [https://doi.org/10.1056/NEJMoa074306 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18450602/ PubMed] |
− | |||
− | |||
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[[Category:Acute myeloid leukemia regimens]] | [[Category:Acute myeloid leukemia regimens]] | ||
[[Category:Biomarker-specific pages]] | [[Category:Biomarker-specific pages]] | ||
[[Category:Acute leukemias]] | [[Category:Acute leukemias]] |
Latest revision as of 12:12, 23 June 2024
Section editor | |
---|---|
Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA |
Note: these are regimens tested in biomarker-specific populations for patients with FLT3 internal tandem duplicated (FLT3-ITD) or tyrosine kinase domain mutated (FLT3-TKD) AML, please see the main AML page for other regimens.
For placebo or observational studies in this condition, please visit this page.
22 regimens on this page
26 variants on this page
|
Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
NCCN
- NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Myeloid Leukemia.
Upfront induction therapy, standard patients
7+3d (intermediate-dose)
7+3d: 7 days of cytarabine + 3 days of daunorubicin
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Phase 3 (C) | 1a. 7+3d & Quizartinib 1b. 7+3i & Quizartinib |
Seems to have inferior OS |
Note: this was the lower bound of cytarabine dosing in QuANTUM-First.
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
- Daunorubicin (Cerubidine) 60 mg/m2 IV over 5 minutes once per day on days 1 to 3
7-day course
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Stone et al. 2017 (RATIFY) | 2008-2011 | Phase 3 (C) | 7+3d & Midostaurin | Inferior OS |
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Phase 3 (C) | 1a. 7+3d & Quizartinib 1b. 7+3i & Quizartinib |
Seems to have inferior OS |
Note: this was the upper bound of cytarabine dosing in QuANTUM-First.
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
- Daunorubicin (Cerubidine) 60 mg/m2 IV over 5 minutes once per day on days 1 to 3
Supportive therapy
- "According to commonly accepted guidelines with no prophylactic IV antibiotics"
- Granulocyte colony-stimulating factor recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression
7-day course
References
- RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00651261
- QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653
- Q-SOC: NCT04676243
7+3d & Midostaurin
7+3d & Midostaurin: 7 days of cytarabine, 3 days of daunorubicin, Midostaurin
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Stone et al. 2017 (RATIFY) | 2008-2011 | Phase 3 (E-RT-esc) | 7+3d (intermediate-dose) | Superior OS (primary endpoint) Median OS: 74.7 vs 25.6 mo (HR 0.78, 95% CI 0.63-0.96) |
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Midostaurin (Rydapt) 50 mg PO twice per day on days 8 to 21
Supportive therapy
- Hydroxyurea (Hydrea) (no dosage specified) was allowed to be used for up to 5 days before the start of therapy while waiting for results of FLT3 mutation testing
21-day course; retreatment with a second course was allowed if day 21 bone marrow biopsy showed residual AML.
Subsequent treatment
- RATIFY, patients who achieved complete remission (CR): HiDAC & Midostaurin consolidation. Stem cell transplantation was allowed.
References
- RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00651261
7+3d & Quizartinib
7+3d & Quizartinib: 7 days of cytarabine, 3 days of daunorubicin, Quizartinib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Phase 3 (E-RT-esc) | 1a. 7+3d; intermediate-dose 1b. 7+3i |
Seems to have superior OS (primary endpoint) Median OS: 31.9 vs 15.1 mo (HR 0.78, 95% CI 0.62-0.98) |
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2/day or 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m2)
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Quizartinib (Vanflyta) 40 mg PO once per day on days 8 to 21
21-day course; retreatment with a second course was allowed if day 21 bone marrow biopsy showed residual AML.
Subsequent treatment
- QuANTUM-First, patients who achieved complete remission (CR): HiDAC & Quizartinib consolidation. Stem cell transplantation was allowed.
References
- QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653
7+3i
7+3i: 7 days of cytarabine + 3 days of idarubicin
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Phase 3 (C) | 1a. 7+3d & Quizartinib 1b. 7+3i & Quizartinib |
Seems to have inferior OS |
Note: this was the lower bound of cytarabine dosing in QuANTUM-First.
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
- Idarubicin 12 mg/m2 IV once per day on days 1 to 3
7-day course
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Phase 3 (C) | 1a. 7+3d & Quizartinib 1b. 7+3i & Quizartinib |
Seems to have inferior OS |
Note: this was the upper bound of cytarabine dosing in QuANTUM-First.
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
- Idarubicin 12 mg/m2 IV once per day on days 1 to 3
7-day course
References
- QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653
7+3i & Quizartinib
7+3i & Quizartinib: 7 days of cytarabine, 3 days of idarubicin, Quizartinib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Phase 3 (E-RT-esc) | 1a. 7+3d; intermediate-dose 1b. 7+3i |
Seems to have superior OS (primary endpoint) Median OS: 31.9 vs 15.1 mo (HR 0.78, 95% CI 0.62-0.98) |
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2/day or 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m2)
- Idarubicin 12 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Quizartinib (Vanflyta) 40 mg PO once per day on days 8 to 21
21-day course; retreatment with a second course was allowed if day 21 bone marrow biopsy showed residual AML.
Subsequent treatment
- QuANTUM-First, patients who achieved complete remission (CR): HiDAC & Quizartinib consolidation. Stem cell transplantation was allowed.
References
- QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653
DA 3 + 10
DA 3 + 10: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Burnett et al. 2015 (UK NCRI AML17) | 2009-2014 | Phase 3 (C) | DA 3 + 10; high-dose | Did not meet primary endpoint of OS |
Note: this regimen is very similar to 7+3d (intermediate-dose); however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3.
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2 IV every 12 hours on days 1 to 10
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 3, 5
10-day course
Subsequent treatment
- DA 3+8 versus DA 3+8 & Lestaurtinib re-induction
References
- UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN55675535
- Update: Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. link to original article link to PMC article PubMed
First-line induction therapy, older patients or "unfit" patients
Azacitidine monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2022 (LACEWING) | 2016-NR | Phase 3 (C) | Azacitidine & Gilteritinib | Did not meet primary endpoint of OS |
References
- LACEWING: Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, Chou WC, Laribi K, Esteve J, Altman JK, Havelange V, Watson AM, Gambacorti-Passerini C, Patkowska E, Liu S, Wu R, Philipose N, Hill JE, Gill SC, Rich ES, Tiu RV. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022 Oct 27;140(17):1845-1857. Epub 2022 Aug 2. link to original article PubMed NCT02752035
7+3d & Sorafenib
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Uy et al. 2017 (CALGB 11001) | 2011-NR | Phase 2 |
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 7
7-day course
Subsequent treatment
- CALGB 11001, patients not achieving a hypoplastic marrow on day 14: 5+2d & sorafenib re-induction
- CALGB 11001, patients achieving a CR or CRi: IDAC & sorafenib consolidation
References
- CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01253070
Consolidation after upfront therapy
HiDAC & Midostaurin
HiDAC & Midostaurin: High Dose Ara-C (Cytarabine) & Midostaurin
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence |
---|---|---|
Stone et al. 2017 (RATIFY) | 2008-2011 | Non-randomized part of phase 3 RCT |
Preceding treatment
- 7+3d & midostaurin induction, with CR
Chemotherapy
- Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
Targeted therapy
- Midostaurin (Rydapt) 50 mg PO twice per day on days 8 to 21
28-day cycle for 4 cycles
Subsequent treatment
- Stem cell transplantation "was allowed" for eligible patients; others proceeded to midostaurin maintenance
References
- RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00651261
HiDAC & Quizartinib
HiDAC & Quizartinib: High Dose Ara-C (Cytarabine) & Quizartinib
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Non-randomized part of phase 3 RCT |
Note: Patients undergoing allogeneic HSCT after consolidation proceeded to maintenance anytime between day +30 and day +180.
Preceding treatment
- 7+3d & Quizartinib or 7+3i & Quizartinib induction, with CR
Chemotherapy
- Cytarabine (Ara-C) by the following age-based criteria:
- Younger than 60 years old: 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
- 60 years old or older: 1500 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
Targeted therapy
- Quizartinib (Vanflyta) 40 mg PO once per day on days 6 to 19
Up to 4 cycles
Subsequent treatment
- Quizartinib maintenance (see note)
References
- QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in manuscript PubMed NCT02668653
IDAC & Sorafenib
IDAC & Sorafenib: Intermediate Dose Ara-C (Cytarabine) & Sorafenib
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Uy et al. 2017 (CALGB 11001) | 2011-NR | Phase 2 |
Preceding treatment
- 7+3d & sorafenib induction
Chemotherapy
- Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours once per day on days 1 to 5
Targeted therapy
- Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 28
4- to 6-week cycle for 2 cycles
Subsequent treatment
- Sorafenib maintenance
References
- CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01253070
Maintenance after upfront therapy, including allogeneic HSCT
Midostaurin monotherapy
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Stone et al. 2017 (RATIFY) | 2008-2011 | Non-randomized part of phase 3 RCT | CR rate: 59% after induction |
Preceding treatment
- HiDAC & Midostaurin consolidation
Targeted therapy
- Midostaurin (Rydapt) 50 mg PO twice per day on days 1 to 28
28-day cycle for up to 13 cycles (1 year)
References
- RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00651261
- ARO-021: NCT03258931
- HOVON 156 AML: NCT04027309
Quizartinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Erba et al. 2023 (QuANTUM-First) | 2016-09-27 to 2019-08-14 | Non-randomized part of phase 3 RCT |
Note: Patients undergoing allogeneic HSCT after consolidation began maintenance anytime between day +30 and day +180. The dose of quizartinib was increased only if the mean QT interval corrected with Fridericia's formula [QTcF] was less than or equal to 450 ms on C1D15.
Preceding treatment
- HiDAC & Quizartinib consolidation, +/- allogeneic HSCT
Targeted therapy
- Quizartinib (Vanflyta) as follows:
- Cycle 1: 30 mg PO once per day on days 1 to 14, then 60 mg PO once per day on days 15 to 28
- Cycles 2 to 36: 60 mg PO once per day on days 1 to 28
28-day cycle for up to 36 cycles (3 years)
References
- QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in manuscript PubMed NCT02668653
Sorafenib monotherapy
Regimen variant #1, 6 months
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Xuan et al. 2020 (Sorafenib-Flt3 AML-2015) | 2015-06-20 to 2018-07-21 | Phase 3 (E-esc) | Observation | Superior 1-year cumulative incidence of relapse (primary endpoint) Superior OS1 (secondary endpoint) OS60: 72% vs 55.9% (HR 0.55, 95% CI 0.34-0.88) |
1Reported efficacy is based on the 2023 update.
Preceding treatment
- Allogeneic stem cell transplant consolidation
Regimen variant #2, 12 mos
Study | Dates of enrollment | Evidence |
---|---|---|
Uy et al. 2017 (CALGB 11001) | 2011-NR | Phase 2 |
Preceding treatment
- IDAC & Sorafenib consolidation
Targeted therapy
- Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 28
28-day cycle for up to 12 cycles
Regimen variant #3, 2 years
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Burchert et al. 2020 (SORMAIN) | 2010-2016 | Phase 3 (E-esc) | Placebo | Superior RFS (primary endpoint) RFS24: 85% vs 53.3% (HR 0.39, 95% CI 0.18-0.85) |
Note: dose was escalated only if tolerated.
Preceding treatment
- Allogeneic stem cell transplant consolidation
Targeted therapy
- Sorafenib (Nexavar) as follows:
- Cycle 1: 200 mg PO twice per day on days 1 to 14, then 400 mg PO twice per day on days 15 to 28
- Cycles 2 to 26: 400 mg PO twice per day on days 1 to 28
28-day cycle for up to 26 cycles (2 years)
References
- CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01253070
- SORMAIN: Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, Wollmer E, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner EM, Kröger N, Wolschke C, Schleuning M, Götze KS, Schmid C, Crysandt M, Eßeling E, Wolf D, Wang Y, Böhm A, Thiede C, Haferlach T, Michel C, Bethge W, Wündisch T, Brandts C, Harnisch S, Wittenberg M, Hoeffkes HG, Rospleszcz S, Burchardt A, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol. 2020 Sep 10;38(26):2993-3002. Epub 2020 Jul 16. link to original article contains dosing details in manuscript PubMed Link to clinical trial registration DRKS00000591
- Sorafenib-Flt3 AML-2015: Xuan L, Wang Y, Huang F, Fan Z, Xu Y, Sun J, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Yu C, Zhou X, Lin R, Chen Y, Tu S, Huang X, Liu Q. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1201-1212. Epub 2020 Aug 10. link to original article PubMed NCT02474290
- Update: Xuan L, Wang Y, Yang K, Shao R, Huang F, Fan Z, Chi P, Xu Y, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Lin R, Chen Y, Tu S, Zhang Y, Sun J, Huang X, Liu Q. Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023 Aug;10(8):e600-e611. Epub 2023 Jul 3. link to original article PubMed
Relapsed or refractory, salvage therapy
Midostaurin monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2010 (CPKC412A2104) | 2002-NR | Randomized phase 2b (E-de-esc) | Midostaurin; 100 mg twice per day | Not reported |
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2010 (CPKC412A2104) | 2002-NR | Randomized phase 2b (E-esc) | Midostaurin; 50 mg twice per day | Not reported |
Regimen variant #3
Study | Dates of enrollment | Evidence |
---|---|---|
Stone et al. 2004 | NR | Phase 2 |
Biomarker eligibility criteria
- FLT3 ITD or FLT3 p.D835Y mutation
References
- Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005 Jan 1;105(1):54-60. Epub 2004 Sep 2. link to original article contains dosing details in manuscript PubMed
- CPKC412A2104: Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00045942
Relapsed or refractory, further lines of therapy
Azacitidine monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perl et al. 2019 (ADMIRAL) | 2015-2018 | Phase 3 (C) | Gilteritinib | Inferior OS |
Note: Perl et al. 2019 does not contain dosing information for the control arm regimens; the dosing here is from other AML regimens.
Chemotherapy
- Azacitidine (Vidaza) 75 mg/m2 SC once per day on days 1 to 7
28-day cycle for at least 4 cycles
References
- ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
- Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
Azacitidine & Sorafenib
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Ravandi et al. 2013 (MDACC 2010-0511) | 2011-2012 | Phase 2 |
Chemotherapy
- Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
Targeted therapy
- Sorafenib (Nexavar) 400 mg PO twice per day
Supportive therapy
- "All patients received antimicrobials, supportive care, and transfusions of blood products according to the institutional guidelines."
4- to 8-week cycles
References
- MDACC 2010-0511: Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62. Epub 2013 Apr 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01254890
FLAG-Ida
FLAG-Ida: FLudarabine, Ara-C (Cytarabine), G-CSF (Filgrastim), Idarubicin
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cortes et al. 2019 (QuANTUM-R) | 2014-2017 | Phase 3 (C) | Quizartinib | Seems to have inferior OS |
Perl et al. 2019 (ADMIRAL) | 2015-2018 | Phase 3 (C) | Gilteritinib | Inferior OS |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 2 to 6
- Cytarabine (Ara-C) 2000 mg/m2 IV once per day on days 2 to 6
- Idarubicin (Idamycin) 10 mg/m2 IV once per day on days 2 to 4
Growth factor therapy
- Filgrastim (Neupogen) 5 mcg/kg or 300 mcg/m2 SC once per day on days 1 to 5
28-day cycle for up to 2 cycles
References
- QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains dosing details in abstract PubMed NCT02039726
- ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
- Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
- ARO-013: NCT03250338
Gilteritinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perl et al. 2017 (2215-CL-0101) | 2013-2015 | Phase 1/2 | ||
Perl et al. 2019 (ADMIRAL) | 2015-2018 | Phase 3 (E-RT-switch-ooc) | Investigator's choice of: 1a. MEC 1b. FLAG-Ida 1c. LoDAC 1d. Azacitidine |
Superior OS1 (co-primary endpoint) Median OS: 9.3 vs 5.6 mo (HR 0.665, 95% CI 0.52-0.85) |
Awaiting publication (2215-CL-0303) | 2018-2023 | Phase 3 (E-switch-ooc) | 1a. MEC 1b. FLAG 1c. LoDAC |
TBD if different primary endpoint of OS |
1Reported efficacy is based on the 2022 update.
References
- 2215-CL-0101: Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. Epub 2017 Jun 20. link to original article link to PMC article PubMed NCT02014558
- ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article contains dosing details in manuscript PubMed NCT02421939
- Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
- 2215-CL-0303: NCT03182244
Low-dose Cytarabine monotherapy (LoDAC)
LoDAC: Low Dose Ara-C (cytarabine)
LDAC: Low Dose Ara-C (cytarabine)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cortes et al. 2019 (QuANTUM-R) | 2014-2017 | Phase 3 (C) | Quizartinib | Seems to have inferior OS |
Perl et al. 2019 (ADMIRAL) | 2015-2018 | Phase 3 (C) | Gilteritinib | Inferior OS |
References
- QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains dosing details in abstract PubMed NCT02039726
- ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
- Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
MEC
MEC: Mitoxantrone, Etoposide, Cytarabine
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cortes et al. 2019 (QuANTUM-R) | 2014-2017 | Phase 3 (C) | Quizartinib | Seems to have inferior OS |
Perl et al. 2019 (ADMIRAL) | 2015-2018 | Phase 3 (C) | Gilteritinib | Inferior OS |
Chemotherapy
- Mitoxantrone (Novantrone) 8 mg/m2 IV push once per day on days 1 to 5, given third
- Etoposide (Vepesid) 100 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
- Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 to 5, given second
28-day cycle for 1 to 2 cycles
References
- QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains dosing details in abstract PubMed NCT02039726
- ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
- Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
Quizartinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cortes et al. 2019 (QuANTUM-R) | 2014-2017 | Phase 3 (E-switch-ooc) | Investigator's choice of: 1a. LoDAC 1b. MEC 1c. FLAG-Ida |
Seems to have superior OS (primary endpoint) Median OS: 6.2 vs 4.7 mo (HR 0.76, 95% CI 0.58-0.98) |
Note: Quizartinib was studied at a variety of doses; references are provided below for historic context; the dose here is from QuANTUM-R, and was only increased if certain QTc parameters were met; see the paper for details.
Targeted therapy
- Quizartinib (Vanflyta) as follows:
- Cycle 1: 30 mg PO once per day on days 1 to 15, then 60 mg PO once per day on days 16 to 28
- Cycle 2 onwards: 60 mg PO once per day on days 1 to 28
28-day cycles
References
- CP0001: Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. Epub 2013 Sep 3. link to original article link to PMC article PubMed NCT00462761
- ACEAML: Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. Epub 2018 May 31. link to original article link to PMC article PubMed NCT00989261
- 2689-CL-2004: Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, Levis MJ. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018 Aug 9;132(6):598-607. Epub 2018 Jun 6. link to original article link to PMC article PubMed NCT01565668
- QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains dosing details in manuscript PubMed NCT02039726
Prognosis
Prognosis in cytogenetically normal AML
- Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome: Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. link to original article PubMed