Acute Myeloid Leukemia

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1 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Acute Myeloid Leukemia Version.014 NCCN.g Continue Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

2 Panel Members * Margaret R. O Donnell, MD/Chair City of Hope Comprehensive Cancer Center Martin S. Tallman, MD/Vice-Chair Memial Sloan-Kettering Cancer Center Camille N. Abboud, MD Þ Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine Jessica K. Altman, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Frederick R. Appelbaum, MD Þ Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Daniel A. Arber, MD Stanfd Cancer Institute Eyal Attar, MD Massachusetts General Hospital Cancer Center Uma Bate, MD University of Alabama at Birmingham Comprehensive Cancer Center Steven E. Coutre, MD Stanfd Cancer Institute Lloyd E. Damon, MD UCSF Helen Diller Family Comprehensive Cancer Center Jeffrey Lancet, MD Moffitt Cancer Center Li J. Maness, MD Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center Guido Marcucci, MD Þ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Mary Ellen Martin, MD Þ Fox Chase Cancer Center Michael G. Martin, MD St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center Joseph O. Moe, MD Duke Cancer Institute Daniel A. Pollyea, MD, MS Þ University of Colado Cancer Center Farhad Ravandi, MD The University of Texas MD Anderson Cancer Center Paul J. Shami, MD Huntsman Cancer Institute at the University of Utah B. Douglas Smith, MD Þ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Richard M. Stone, MD Dana-Farber/Brigham and Women s Cancer Center Stephen A. Strickland, MD Vanderbilt-Ingram Cancer Center Eunice S. Wang, MD Roswell Park Cancer Institute Matthew Wieduwilt, MD, PhD UC San Diego Moes Cancer Center NCCN Kristina Gregy, RN, MSN Courtney Smith, PhD, MT(ASCP) NCCN Guidelines Panel Disclosures Continue Hematology/Hematology oncology Bone marrow transplantation Þ Internal medicine Medical oncology Pathology * Writing committee member Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

3 Table of Contents NCCN Panel Members Summary of Guidelines Updates Evaluation f Acute Leukemia and Diagnostic Studies (AML-1) APL, Treatment Induction (AML-) APL, Post-Consolidation Therapy (AML-5) APL, Therapy f Relapse (AML-6) AML, Treatment Induction Age (<60 y) (AML-7) AML, Post-Induction Therapy After Standard-Dose Cytarabine (Age <60 y) (AML-8) AML, Post-Induction Therapy After High-Dose Cytarabine (Age <60 y) (AML-9) AML, Post-Remission Therapy (AML-10) AML, Treatment Induction (Age 60 y) (AML-11) AML, Post-Induction Therapy (Age 60 y) (AML-1) AML, Post-Remission Therapy (Age 60 y) (AML-13) AML, Surveillance (After Completion of Consolidation) (AML-14) AML, Salvage Therapy (AML-14) Risk Status Based on Validated Cytogenetics and M olecular Abnmalities (AML-A) Evaluation and Treatment of CNS Leukemia (AML-B) Supptive Care (AML-C) Response Criteria f (AML-D) Moniting During Therapy (AML-E) Salvage Chemotherapy Regimen Options (AML-F) Clinical Trials: NCCN believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN Member Institutions, click here: nccn.g/clinical_trials/physician.html. NCCN Categies of Evidence and Consensus: All recommendations are categy A unless otherwise specified. See NCCN Categies of Evidence and Consensus. The NCCN Guidelines are a statement of evidence and consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk (NCCN ) makes no representations warranties of any kind regarding their content, use, application, and disclaims any responsibility f their application use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of NCCN Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

4 Updates Summary of the changes in the.014 version of the NCCN Guidelines f from the version include: AML-4 - The following regimen changed from a categy A to a categy 1: ATRA 45 mg/m in divided doses until clinical remission daily + arsenic trioxide 0.15 mg/kg IV daily until bone marrow remission. MS-1 - The discussion section was updated to reflect the changes in the algithm. Summary of the changes in the version of the NCCN Guidelines f from the.013 version include: AML-1 Evaluation f Acute Leukemia AML-4 Footnote aa modified: Lo-Coco F, Avvisati G, Vignetti G, et al. Footnote a modified with the addition of the following sentence: Multiplex gene panels and sequencing assays are available f the assessment of other molecular abnmalities that may have prognostic impact in AML (see ). AML- Footnote k modified with the addition of the following sentence: Retinoic acid and arsenic trioxide f acute promyelocytic leukemia. N Engl J Med 013;369: Prophylaxis with prednisone 0.5mg/kg day 1 through completion of induction. If patient develops differentiation syndrome, change prednisone to dexamethasone 10 mg every 1 h until acute differentiation resolves, then return to previous prednisone dose. These risk groups are combined into one categy in most treatment protocols. AML-6 Post-remission therapy AML-3 Decision points added f No pri exposure to arsenic trioxide A new regimen was added: late relapse ( 6 mo) after arsenic trioxide-containing regimen Induction: ATRA 45 mg/m (days 1 36, divided) + age-adjusted and early relapse (<6 mo) after ATRA arsenic trioxide only (no idarubicin 6 1 mg/m on days, 4, 6, 8 + arsenic trioxide 0.15 mg/kg (days 9 6 as -h IV infusion) Consolidation: ATRA 45 mg/m x 8 days + arsenic trioxide 0.15 mg/kg/day x 8 days f 5 wks x 1 cycle, then ATRA 45 mg/m x 7 d every wks x 3 + arsenic trioxide 0.15 mg/kg/day x 5 d f 5 wks x 1 anthracycline) and early relapse (<6 mo) after arsenic trioxide/anthracycline-containing regimen. F early relapse (<6 mo) after ATRA arsenic trioxide only (no anthracycline), the following treatment recommendation was added: Consider ATRA 45 mg/m PO daily + idarubicin 1 mg/m cycle The regimen is based on the following reference in footnote u : Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, on days, 4, 6, 8 + arsenic trioxide 0.15 mg/kg IV daily until count recovery with marrow confirmation of remission. Content as previously written f No pri exposure to arsenic idarubicin, and IV arsenic trioxide as initial therapy in acute trioxide late relapse ( 6 mo) after arsenic trioxide-containing promyelocytic leukemia (APML4). Blood 01;10: A regimen and Early relapse (<6 mo) after arsenic statement was added to this reference: Prophylaxis with prednisone trioxide/anthracycline-containing regimen. 1mg/kg/d f at least 10 d is needed f differentiation syndrome Second remission: Strongly consider removed befe CNS regardless of WBC at presentation. prophylaxis Footnote n modified: Premature mphologic and molecular Footnote jj added: Dose adjustment f patients >60 years: 9 assessment (day marrow) can be misleading; a nadir marrow is mg/m /day IV (ages 61-70) 6 mg/m /day IV (ages >70). Iland HJ, not recommended. Patients often remain molecularly positive at the end Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, of induction, even when the marrow shows mphologic remission. A and IV arsenic trioxide as initial therapy in acute promyelocytic marrow f assessment of mphologic remission should not be leukemia (APML4). Blood 01;10: perfmed befe day 8 until count recovery. The first assessment of molecular remission should be made after consolidation. Footnote x added: Consider 4-6 doses of IT chemotherapy (eg, doses f each consolidation cycle) as an option f CNS prophylaxis. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. UPDATES

5 Updates Summary of the changes in the version of the NCCN Guidelines f from the.013 version include: AML-8 Footnote oo deleted: ECOG repted a significant increase in complete response rates and overall survival using daunubicin 90 mg/m x 3 days versus 45 mg/m x 3 days in patients <60 years of age. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 009;361: If there is residual disease on days 1-14, the additional daunubicin dose is 45 mg/m x 3 days. AML-10 Intermediate risk HiDAC dosing changed from 1.5-3g to 1-3g. 1- cycles of HiDAC consolidation followed by HSCT removed as a treatment option. AML-11 Favable cytogenetic/molecular markers changed to Nonadverse cytogenetic/molecular markers. preferred added to idarubicin. Mitoxantrone schedule clarified as x 3 days Clofarabine removed as a treatment option. Low-intensity therapy clarified with may be me appropriate f elderly patients relatively unfit patients with combidities Therapy-related AML/pri MDS unfavable cytogenetics/molecular markers preferred added to idarubicin. Mitoxantrone schedule clarified as x 3 days Clofarabine removed as a treatment option. Low-intensity therapy clarified with may be me appropriate f fit patients who are candidates f subsequent HSCT Footnote mmm modified with the addition of Consider continuing hypomethylating agents until progression. AML-1 Residual blasts: HiDAC 1- g/m added as a treatment option. Footnote nnn is new to the page: Reduced-intensity HSCT may be appropriate f patients with a low level of residual disease post-induction (eg, patients with pri MDS who reverted back to MDS with 5%-7% blasts). It is preferred that this approach be given in the context of a clinical trial. AML-14 Footnote sss is new to the page: Studies are ongoing to evaluate the role of molecular moniting in the surveillance of early relapse in patients with AML (see ). AML-C of APL differentiation syndrome: The following sentence was added, F ATRA + arsenic trioxide regimens, prophylaxis with prednisone 0.5mg/kg day 1 through completion of induction. If patient develops differentiation syndrome, change prednisone to dexamethasone 10 mg every 1 h until acute differentiation resolves, then return to previous prednisone dose. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide f acute promyelocytic leukemia. N Engl J Med 013;369: AML-E Induction, bullet : LFTs added to chemistry profile. AML-F Clofarabine + cytarabine + GCSF changed to Clofarabine ± cytarabine + GCSF ± idarubicin. Reference added: Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combination as acute myeloid leukemia salvage therapy. Cancer 008;113: Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. UPDATES

6 EVALUATION FOR ACUTE LEUKEMIA Histy and physical (H&P) Complete blood count (CBC), platelets, differential, chemistry profile Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen Bone marrow with cytogenetics (karyotype ± FISH) Cryopreserve samples f evaluation of c-kit, FLT3-ITD, NPM1, and CEBPA mutationsa Immunophenotyping and cytochemistry Human leukocyte antigen (HLA) typing f sibling unrelated don (except f patients with a maj contraindication to hematopoietic stem cell transplantation [HSCT]) CT/MRI if neurologic symptoms b Lumbar puncture (LP), if symptomaticb (categy B f asymptomatic) Evaluate myocardial function (echocardiogram MUGA scan) in patients with a histy symptoms of cardiac disease pri exposure to cardiotoxic drugs radiation to thax Central venous access device of choice DIAGNOSTIC STUDIES (WHO 008) Multidisciplinary diagnostic studies c,d DIAGNOSIS c,d,e,f Acute promyelocytic leukemia (APL) Acute myeloid leukemia (AML) Myelodysplastic syndromes (MDS) B T lymphoblastic leukemia/lymphoma d See Treatment Induction (AML-) See Treatment Induction (AML-7) See NCCN Guidelines f Myelodysplastic Syndromes See NCCN Guidelines f Acute Lymphoblastic Leukemia athese molecular abnmalities are imptant f prognostication in a subset of patients (categy A) and may guide therapeutic intervention (categy B) ( See AML-A). These are useful f patients with nmal karyotype (especially FLT3-ITD, NPM1 mutations) ce binding fact leukemia (especially c-kit mutation). Multiplex gene panels and sequencing assays are available f the assessment of other molecular abnmalities that may have prognostic impact in AML (see ). If a test is not available at your institution, consult pathology about preserving material from the iginal diagnostic sample f future use at an outside reference lab after full cytogenetic data are available. bf patients with maj neurologic signs symptoms at diagnosis, appropriate imaging studies should be perfmed to detect meningeal disease, chlomas, CNS bleeding. LP should be perfmed if no mass/lesion is detected on the imaging study. Screening LP should be considered at first remission f patients with M5 M4 mphology WBC count >100,000/mcL at diagnosis. See Evaluation and Treatment of CNS Leukemia (AML-B). cthe WHO classification defines acute leukemia as 0% blasts in the marrow blood. A diagnosis of AML may be made with less than 0% blasts in patients with recurrent cytogenetic abnmalities (eg, t(15;17), t(8;1), t(16;16), inv(16)). AML evolving from MDS (AML-MDS) is often me resistant to cytotoxic chemotherapy than AML that arises without antecedent hematologic disder and may have a me indolent course. Some clinical trials designed f high-grade MDS may allow enrollment of patients with AML-MDS. dwhen presented with rare cases such as acute leukemias of ambiguous lineage, including mixed phenotype acute leukemias (accding to 008 WHO classification), consultation with an experienced hematopathologist is strongly recommended. eyoung adults may be eligible f pediatric trials with me intensive induction regimens and transplant options. AML patients should preferably be managed at experienced leukemia centers where clinical trials may be me available. fpatients who present with isolated extramedullary disease (myeloid sarcoma) should be treated with systemic therapy. Local therapy (surgery/radiation therapy [RT]) may be used f residual disease. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-1

7 Acute Promyelocytic Leukemia APL CLASSIFICATION TREATMENT INDUCTION g,j CONSOLIDATION THERAPY j Able to tolerate anthracyclines See Treatment Induction (AML-3) APL g,h,i APL mphology and (+) f t(15;17) by either cytogenetics molecular testing; consider possibility of APL variant High risk (WBC count >10,000/mcL) Low/intermediate risk (WBC count 10,000/mcL) k Not able to tolerate anthracyclines All-trans retinoic acid (ATRA) 45 mg/m in divided doses daily + arsenic trioxide 0.15 mg/kg IV dailyl,m until bone marrow remission See Treatment Induction (AML-4) At count recovery, proceed with consolidation n,o Arsenic trioxide 0.15 mg/kg/day IV 5 days/week f 4 weeks every 8 weeks f a total of 4 cycles, and ATRA 45 mg/m /day PO f weeks every 4 weeks f a total of 7 cyclesl,m See Post- Consolidation Therapy (AML-5) g Several groups have published large trials with excellent outcomes. However, to achieve the expected results, one needs to use the regimen consistently through all components and not mix induction from one trial with consolidation from another. htherapy-related APL is treated the same as de novo APL. iin patients with clinical and pathologic features of APL, start ATRA upon first suspicion of APL without waiting f genetic confirmation of the diagnosis. Early initiation of ATRA may prevent the lethal complication of bleeding. If cytogenetic and molecular testing do not confirm APL, discontinue ATRA and continue treatment as f AML. jmonit f APL differentiation syndrome and coagulopathy; see Supptive Care (AML-C of ). k New data suggest similar outcomes in patients with low intermediate risk. These risk groups are combined into one categy in most treatment protocols. lshen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/aso3combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 004;101(15): Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 009;7: msee Arsenic trioxide moniting, Supptive Care (AML-C of ). npremature mphologic and molecular assessment (day marrow) can be misleading; a nadir marrow is not recommended. Patients often remain molecularly positive at the end of induction, even when the marrow shows mphologic remission. The first assessment of molecular remission should be made after consolidation. oearly mtality is related to bleeding, differentiation syndrome, infection. Persistent disease is rare. See first relapse on AML-6. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-

8 Acute Promyelocytic Leukemia TREATMENT INDUCTION (HIGH RISK) g,j,p ATRA 45 mg/m in divided doses until clinical remission + daunubicin 50 mg/m x 4 days + cytarabine 00 mg/m x 7 days ATRAq 45 mg/m in divided doses until clinical remission + daunubicin 60 mg/m x 3 days + cytarabine 00 mg/m x 7 days g Several groups have published large trials with excellent outcomes. However, to achieve the expected results, one needs to use the regimen consistently through all components and not mix induction from one trial with consolidation from another. j m n q ATRAq 45 mg/m in divided doses until clinical remission + idarubicin 1 mg/m on days, 4, 6, 8t ATRA 45 mg/m (days 1-36, divided) + age-adjusted idarubicin 6-1 mg/m on days, 4, 6, 8 + arsenic trioxide 0.15 mg/kg (days 9-6 as h IV infusion) u Clinical trial r s At count recovery, LP and proceed with consolidationo Monit f APL differentiation syndrome and coagulopathy; see AML-C of. See Arsenic trioxide moniting, see Supptive Care (AML-C of ). Premature mphologic and molecular assessment (day marrow) can be misleading; a nadir marrow is not recommended. Patients often remain molecularly positive at the end of induction, even when the marrow shows mphologic remission. A marrow f assessment of mphologic remission should not be perfmed befe day 8 until count recovery. The first assessment of molecular remission should be made after consolidation. oearly mtality is related to bleeding, differentiation syndrome, infection. Persistent disease is rare. See first relapse on AML-6. pf patients with ( who develop) a high WBC count (>10,000), consider prophylactic dexamethasone to prevent differentiation syndrome. q Data suggest that lower doses of ATRA (5 mg/m ) in divided doses until clinical remission may be used in children and adolescents. rpowell BL, et al. Arsenic trioxide improves event-free and overall survival f adults with acute promyelocytic leukemia: Nth American Leukemia Intergroup Study C9710. Blood 010;116: n,v n,v At count recovery, LP and proceed with consolidationo n,v At count recovery, LP and proceed with consolidationo n,v At count recovery, LP and proceed with consolidationo z CONSOLIDATION THERAPY w Arsenic trioxide 0.15 mg/kg/day x 5 days f 5 wks x cycles, then ATRA 45 mg/m x 7 days + daunubicin 50 mg/m x 3 days f cycles sades LA, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): A comparison of French-Belgian-Swiss and PETHEMA results. Blood 008;111: tsanz MA, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy f high u v risk patients: further improvements in treatment outcomes. Blood 010;115: Iland HJ, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 01;10: Prophylaxis with prednisone 1mg/kg/d f at least 10 d is needed f differentiation syndrome regardless of WBC at presentation. Breccia M, et al. Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count. Br J Haematol 003;10: All regimens include high cumulative doses of cardiotoxic agents. Cardiac function should be assessed pri to each anthracycline/mitoxantrone-containing course. Consider 4-6 doses of IT chemotherapy (eg, doses f each consolidation cycle) as an option f CNS prophylaxis. Although the iginal regimen included high-dose cytarabine as second consolidation, some investigats recommend using high-dose cytarabine early f CNS prophylaxis, especially f patients not receiving IT chemotherapy. w x y m Daunubicin 60 mg/m x 3 days + cytarabine 00 mg/m x 7 days x 1 cycle, then cytarabine g/m (age <50) 1.5 g/m (age 50-60) every 1 h x 5 days y,z + daunubicin 45 mg/m x 3 days x 1 cycle 5 doses of IT chemotherapy s (categy 1) ATRA 45 mg/m x 15 days + idarubicin 5 mg/m and cytarabine 1 g/m x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone 10 mg/m /day x 5 days x 1 cycle, then ATRA x 15 days + idarubicin 1 mg/m x 1 dose + cytarabine 150 mg/m /8 h x 4 days x 1 cyclet, x ATRA 45 mg/m x 8 days + arsenic trioxidem 0.15 mg/kg/day x 8 days f 5 wks x 1 cycle, then ATRA 45 mg/m x 7 d every wks x 3 + arsenic trioxide 0.15 mg/kg/day x 5 d f 5 wks x 1 cycle Dose adjustment of cytarabine may be needed f older patients patients with renal dysfunction. r,x u See Post- Consolidation Therapy (AML-5) See Post- Consolidation Therapy (AML-5) See Post- Consolidation Therapy (AML-5) See Post- Consolidation Therapy (AML-5) Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-3

9 Acute Promyelocytic Leukemia TREATMENT INDUCTION (LOW/INTERMEDIATE RISK) g,j,p CONSOLIDATION THERAPY w ATRA 45 mg/m in divided doses until clinical remission daily + arsenic trioxidem 0.15 mg/kg IV daily until bone marrow remission aa (categy 1) ATRAq 45 mg/m in divided doses until clinical remission + daunubicin 50 mg/m x 4 days + cytarabine 00 mg/m x 7 days ATRAq 45 mg/m in divided doses until clinical remission + daunubicin 60 mg/m x 3 days + cytarabine 00 mg/m x 7 days s,bb (categy 1) q ATRA 45 mg/m in divided doses until clinical remission + idarubicin 1 mg/m on days, 4, 6, 8t,bb (categy 1) r,bb At count recovery, n,o proceed with consolidation At count recovery, n,o proceed with consolidation At count recovery, n,o proceed with consolidation At count recovery, n,o proceed with consolidation Arsenic trioxide m 0.15 mg/kg/day IV 5 days/week f 4 weeks every 8 weeks f a total of 4 cycles, and ATRA 45 mg/m /day f weeks every 4 weeks f a total of 7 cycles aa (categy 1) m Arsenic trioxide 0.15 mg/kg/day x 5 days f 5 wks x cycles, then ATRA 45 mg/m x 7 days + daunubicin 50 mg/m x 3 days f cyclesr Daunubicin 60 mg/m x 3 days + cytarabine 00 mg/m x 7 days x 1 cycle, then cytarabine 1 g/m every 1 h x 4 days + daunubicin 45 mg/m x 3 days x 1 cycle s (categy 1) ATRA 45 mg/m x 15 days + idarubicin 5 mg/m x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone 10 mg/m /day x 5 days x 1 cycle, then ATRA x 15 days + idarubicin 1 mg/m x 1 dose x 1 cycle (categy 1) cc See Post- Consolidation Therapy (AML-5) See Post- Consolidation Therapy (AML-5) See Post- Consolidation Therapy (AML-5) See Post- Consolidation Therapy (AML-5) Clinical trial g Several groups have published large trials with excellent outcomes. However, to achieve the expected results, one needs to use the regimen consistently through all components and not mix induction from one trial with consolidation from another. Monit f APL differentiation syndrome and coagulopathy; see Supptive Care (AML-C j of ). See Arsenic trioxide moniting, Supptive Care (AML-C of ). Premature mphologic and molecular assessment (day marrow) can be misleading; a nadir marrow is not recommended. Patients often remain molecularly positive at the end of induction, even when the marrow shows mphologic remission. The first assessment of molecular remission should be made after consolidation. Early mtality is related to bleeding, differentiation syndrome, infection. Persistent disease is rare. See first relapse on AML-6. F patients with ( who develop) a high WBC count (>10,000), consider prophylactic dexamethasone to prevent differentiation syndrome. Data suggest that lower doses of ATRA (5 mg/m ) in divided doses until clinical remission may be used in adolescents. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival f adults with acute promyelocytic leukemia: Nth American Leukemia Intergroup Study C9710. Blood 010;116: m n o p q r s Ades LA, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): A comparison of French-Belgian-Swiss and PETHEMA results. Blood 008;111: Sanz MA, Montesinos P, Rayon C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy f high risk patients: further improvements in treatment outcomes. Blood 010;115: All regimens include high cumulative doses of cardiotoxic agents. Cardiac function should be assessed pri to each anthracycline/mitoxantrone-containing course. Lo-Coco F, Avvisati G, Vignetti G, et al. Retinoic acid and arsenic trioxide f acute promyelocytic leukemia. N Engl J Med 013;369: Prophylaxis with prednisone 0.5mg/kg day 1 through completion of induction. If patient develops differentiation syndrome, change prednisone to dexamethasone 10 mg every 1 h until acute differentiation resolves, then return to previous prednisone dose. F patients who have rapidly escalating WBC counts other high-risk features during course of induction therapy, see Consolidation Therapy on AML-3. Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation f adult patients younger than 61 years: results of the AIDA-000 trial of the GIMEMA Group. Blood 010;116: t w aa bb cc Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-4

10 Acute Promyelocytic Leukemia APL POST-CONSOLIDATION THERAPY MONITORING Document molecular remission after consolidation dd,ee Polymerase chain reaction (PCR) negative PCR positive dd,ee Maintenance therapy as per the initial treatment protocol ff Monit by PCR f up to y Repeat PCR f confirmation within 4 wks PCR negative PCR positive dd,ee PCR negative PCR positive dd,ee Repeat PCR f confirmation within 4 wks PCR negative PCR positive dd,ee First relapse See Therapy f Relapse (AML-6) ddpcr should be perfmed on a marrow sample at completion of consolidation to document molecular remission. Subsequent moniting by PCR can be done with peripheral blood, although marrow is a me sensitive moniting technique and may give earlier signs of relapse. Pri practice guidelines have recommended moniting marrow by PCR every 3 mo f y to detect molecular relapse. We continue to endse this f high-risk patients, those >age 60 y who had long interruptions during consolidation, patients not able to tolerate maintenance. Clinical experience indicates that risk of relapse in patients with low-risk disease who are in molecular remission at completion of consolidation is low and moniting may not be necessary outside the setting of a clinical trial. eeto confirm PCR positivity, a second marrow sample should be done in -4 weeks in a reliable labaty. If molecular relapse is confirmed by a second positive test, treat as first relapse ( AML-6 ). If the second test was negative, frequent moniting (every 3 mo f y) is strongly recommended to confirm that the patient remains negative. The PCR testing lab should indicate level of sensitivity of assay f positivity (most clinical labs have a sensitivity level of 10-4), and testing should be done in the same lab to maintain the same level of sensitivity. Consider consultation with a physician experienced in molecular diagnostics if results are equivocal. ffthe majity of studies showing benefit with maintenance occurred pri to the use of ATRA and/ arsenic trioxide and/ cytarabine f consolidation. The role of maintenance chemotherapy remains unclear, particularly f patients with low-risk disease who achieve a molecular remission at the end of consolidation. Avvisati G, Lo-Coco F, Paoloni FP, et al. AIDA 0493 protocol f newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 011;117: Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-5

11 APL Acute Promyelocytic Leukemia THERAPY FOR RELAPSE ADDITIONAL THERAPY First relapse No pri exposure to arsenic trioxide late relapse ( 6 mo) after arsenictrioxide-containing regimen Early relapse (<6 mo) after ATRA arsenic trioxide only (no anthracycline) Early relapse (<6 mo) after arsenic trioxide/ anthracyclinecontaining regimen Arsenic trioxide 0.15 mg/kg IV daily m,gg,hh ± ATRA 45 mg/m in divided doses dailyii until count recovery with marrow confirmation of remission Consider ATRA 45 mg/m PO daily + idarubicinjj 1 mg/m on days, 4, 6, 8 + arsenic trioxide 0.15 mg/kg IV dailym,gg,hh until count recovery with marrow confirmation of remission Arsenic trioxide 0.15 mg/kg IV daily m,gg,hh ± ATRA 45 mg/m in divided doses dailyii until count recovery with marrow confirmation of remission Second remission (mphologic) No remission CNS prophylaxis PCR negative PCR positive Transplant candidate Not transplant candidate Transplant candidate Not transplant candidate Autologous HSCT Arsenic trioxidem consolidation (total of 6 cycles) Matched sibling alternative don HSCT Clinical trial Clinical trial Matched sibling alternative don HSCT m gg See Arsenic trioxide moniting, Supptive Care (AML-C of ). At the end of cycles, if the patient is not in molecular remission, consider matched sibling alternative don HSCT clinical trial. Testing is recommended at least -3 weeks after the completion of arsenic to avoid false positives. hhoutcomes are uncertain in patients who received arsenic trioxide during initial induction/consolidation therapy. iithere is a small randomized trial that suggests that the addition of ATRA does not confer any benefit over arsenic alone. Raffoux E, Rousselot P, Poupon J, et al. Combined treatment with arsenic trioxide and all-trans-retinoic-acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 003;1: jj Dose adjustment f patients >60: 9 mg/m /day IV (ages 61-70) 6 mg/m /day IV (ages >70). Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 01;10: Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-6

12 CLASSIFICATION TREATMENT INDUCTION mm,nn AML kk,ll Age <60 y Age 60 y See Treatment Induction (AML-11) Clinical trial (preferred) Standard-dose cytarabine mg/m continuous infusion x 7 days with idarubicin 1 mg/m daunubicin 90 mg/m x 3 days oo,pp (categy 1) Standard-dose cytarabine 00 mg/m continuous infusion x 7 days with daunubicin 60 mg/m x 3 days and cladribine 5 mg/m x 5 days (categy 1) qq High-dose cytarabine (HiDAC) pp,rr g/m every 1 hours x 6 daysss 3 g/m every 1 h x 4 daystt with idarubicin 1 mg/m daunubicin 60 mg/m x 3 days (1 cycle) (categy B) See Post- Induction Therapy (AML-8) See Post- Induction Therapy (AML-9) kkpatients with blast counts >50,000/mcL are at higher risk f tum lysis and gan dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC count include apheresis hydroxyurea. Prompt institution of definitive therapy is essential. llpo perfmance status and combid medical condition, in addition to age, are facts that influence ability to tolerate standard induction therapy. mmsee Supptive Care (AML-C 1 of ). nnsee Moniting During Therapy (AML-E). ooecog repted a significant increase in complete response rates and overall survival using daunubicin 90 mg/m x 3 days versus 45 mg/m x 3 days in patients <60 years of age. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 009;361: If there is residual disease on days 1-14, the additional daunubicin dose is 45 mg/m x 3 days. ppf patients with impaired cardiac function, other regimens that combine a nonanthracycline (such as fludarabine topotecan) with cytarabine have been published. qqholowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added to daunubicin and cytarabine during induction prolongs survival of patients with acute myeloid rr leukemia: a multicenter, randomized phase III study. J Clin Oncol 01;30: The use of high-dose cytarabine f induction outside the setting of a clinical trial is still controversial. While the remission rates are the same f standard- and high-dose cytarabine, two studies have shown me rapid marrow blast clearance after one cycle of high-dose therapy and a disease-free survival advantage f patients age 50 who received the high-dose therapy (categy B). Kern W and Estey EH. High-dose cytarabine arabinoside in the treatment of acute myeloid leukemia: review of three randomized trials. Cancer 006;107: There are no data using me than 60 mg of daunubicin 1 mg of idarubicin with high-dose cytarabine. ss Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996;88: tt Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996;87: Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-7

13 AML POST-INDUCTION THERAPY AFTER STANDARD-DOSE CYTARABINE Age <60 y Follow-up bone marrow nn 7-10 d after induction completed Significant residual blasts vv Significant cyteductionww with low % residual blasts Hypoplasia xx HiDAC alone (HiDAC g/m every 1 hours x 6 days) yy Standard-dose cytarabine with idarubicin daunubicinzz See treatment f induction failure Standard-dose cytarabine with idarubicin daunubicin zz Await recovery Marrow to document remission status upon hematologic recovery, including cytogenetics and molecular studies as appropriate aaa Complete response uu,bbb Induction failure uu Consolidation See Post- Remission Therapy (AML-10) Clinical trial Matched sibling alternative don HSCT HiDAC ( if not previously used as treatment f persistent disease at day 15) ± anthracycline (daunubicin idarubicin), if a clinical trial is not available while awaiting identification of a don See AML-F f other salvage regimens Best supptive care nn See Moniting During Therapy (AML-E). See Response Criteria f (AML-D). Begin alternate don search (unrelated don cd blood) if no appropriate sibling don is available and the patient is a candidate f an allogeneic HSCT. If ambiguous, consider repeat bone marrow biopsy in 5-7 days befe proceeding with therapy. Hypoplasia is defined as cellularity <10%-0% and residual blasts <5%-10%. F re-induction, no data are available to show superiity with intermediate high-dose cytarabine. F patients with residual blasts after induction with standard-dose cytarabine with daunubicin and cladribine, a second cycle of the same induction regimen can be given. Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added to daunubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 01;30: The role of immunophenotyping in detecting minimal residual disease is being evaluated. Patients with an increased risk of meningeal involvement (initial WBC count >100,000/mcL monocytic histology) should be considered f CNS evaluation with a LP upon achieving complete response. See Evaluation and Treatment of CNS Leukemia (AML-B). uu vv ww xx yy zz aaa bbb Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-8

14 AML POST-INDUCTION THERAPY AFTER HIGH-DOSE CYTARABINE Age <60 y Follow-up bone marrow nn 7-14 d after induction completed Significant residual blasts vv Significant cyteduction with low % residual blasts Hypoplasia xx Clinical trial Matched sibling alternative don HSCT See AML-F f salvage regimens Best supptive care Await recovery vv Await recovery Marrow to document remission status upon hematologic recovery, including cytogenetics and molecular studies as appropriate aaa Complete response uu,bbb Induction failure uu Consolidation See Post- Remission Therapy (AML-10) Clinical trial Matched sibling alternative don HSCT Best supptive care See AML-F f salvage regimens nn See Moniting During Therapy (AML-E). uusee Response Criteria f (AML-D). vvbegin alternate don search (unrelated don cd blood) if no appropriate sibling don is available and the patient is a candidate f an allogeneic HSCT. xxhypoplasia is defined as cellularity <10%-0% and residual blasts <5%-10%. aaathe role of immunophenotyping in detecting minimal residual disease is being evaluated. bbbpatients with an increased risk of meningeal involvement (initial WBC count >100,000/mcL monocytic histology) should be considered f CNS evaluation with a LP upon achieving complete response. See Evaluation and Treatment of CNS Leukemia (AML-B). Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-9

15 RISK STATUS ( See AML-A) Better-risk cytogenetics and/ molecular abnmalities POST-REMISSION THERAPY Clinical trial HiDAC 3 g/m over 3 h every 1 h on days 1, 3, cycles (categy 1) ddd,eee 1 to cycles of HiDAC-based consolidation followed by autologous HSCT fff (categy B) See Surveillance (AML-14) Age <60 Intermediate-risk cytogenetics and/ molecular abnmalities Clinical trial Matched sibling alternative don HSCT HiDACggg 1-3 g/m over 3 h every 1 h on days 1, 3, 5 x 3-4 cycles See Surveillance (AML-14) Treatment-related disease po-risk cytogenetics and/ molecular abnmalities vv,ccc Clinical trial Matched sibling alternative don HSCT hhh See Surveillance (AML-14) vvbegin alternate don search (unrelated don cd blood) if no appropriate sibling don is available and the patient is a candidate f an allogeneic HSCT. cccflt3-itd mutations are also emerging as a po-risk feature in the setting of otherwise nmal karyotype, and these patients should be considered f clinical trials where available. There is controversy regarding allogeneic transplant f FLT3-ITD-only mutations in the absence of other po prognostic features. dddmayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331: eeealternate dosing of cytarabine f postremission therapy has been repted ( see ). Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose f acute myeloid leukemia. N Engl J Med 011;364: fff While both options--multiple cycles of dose-intensive consolidation and one cycle of dose-intensive consolidation followed by autologous HSCT--can produce good survival f patients with favable cytogenetics, there are significant differences in toxicity. Patient age, combid conditions, and issues such as fertility and salvage options should be considered when choosing consolidation. gggthere is no evidence that HiDAC is superi to lower doses of cytarabine in intermediate-risk patient subgroup. hhhpatients may require at least one cycle of high-dose cytarabine consolidation while don search is in progress to maintain remission. Patients may proceed directly to transplant following achievement of remission if a don (sibling alternative) is available. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-10

16 AML PS 0- kk,iii 60y Non-adverse cytogenetic/ molecular markers without pri MDS/therapy-related AML Therapy-related AML/pri MDS unfavable cytogenetic/ molecular markers TREATMENT INDUCTION mm,jjj Clinical trial Standard-dose cytarabine ( mg/m continuous infusion x 7 days) with idarubicinkkk 1 mg/m (preferred) daunubicinlll mg/m x 3 days mitoxantrone 1 mg/m x 3 days Low-intensity therapy (subcutaneous cytarabine, 5-azacytidine, decitabine) mmm (may be me appropriate f elderly patients relatively unfit patients with combidities) Clinical trial Low-intensity therapy (5-azacytidine, decitabine) mmm Standard-dose cytarabine ( mg/m continuous infusion x 7 days) with idarubicinkkk 1 mg/m (preferred) daunubicin mg/m x 3 days mitoxantrone 1 mg/m x 3 days (may be me appropriate f fit patients who are candidates f subsequent HSCT) See Post-Induction Therapy (AML-1) See Post- Remission Therapy (AML-13) See Post- Remission Therapy (AML-13) See Post-Induction Therapy (AML-1) PS > PS 0-3 with significant combidities Clinical trial Low-intensity therapy ([ 5-azacytidine, decitabine], mmm subcutaneous cytarabine) Best supptive care (hydroxyurea, transfusion suppt) See Post- Remission Therapy (AML-13) kk Idarubicin treatment compared to high doses of daunubicin up to 80 mg/m yields a higher complete response rate and me complete responses after one course. (Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses f induction and recombinant interleukin- f maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 010;8: ). lllthe complete response rates and -yr overall survival in patients between 60 and 65 years of age treated with daunubicin 90 mg/m is also comparable to the outcome f idarubicin 1 mg/m ; the higher dose daunubicin did not benefit patients > age 65 (Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunubicin in older patients with acute myeloid leukemia. N Engl J Med. 009;361: ). mmm Response may not be evident befe 3-4 cycles of treatment with hypomethylating agents (5- azacytidine, decitabine). Similar delays in response are likely with novel agents on a clinical trial, but endpoints will be defined by the protocol. Consider continuing hypomethylating agents until progression. Patients with blast counts >50,000/mcL are at risk f tum lysis and gan dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC count include apheresis hydroxyurea. Prompt institution of definitive therapy is essential. See Supptive Care (AML-C 1 of ). There is a web-based scing tool available to evaluate the probability of complete response and early death after standard induction therapy in elderly patients with AML: Krug U, Rollig C, Koschmieder A, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years older with acute myeloid leukaemia: a web-based application f prediction of outcomes. Lancet 010;376: Patients >75 years old with significant combidities usually do not benefit from conventional chemotherapy treatment. However, the rare patient with good nmal karyotype and no significant combidities may benefit from chemotherapy. mm iii jjj kkk Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-11

17 AML POST-INDUCTION THERAPY AFTER STANDARD-DOSE CYTARABINE Age 60 y Follow-up bone marrow nn 7-10 d after induction completed Residual blasts vv Clinical trial Additional standard-dose cytarabine with anthracycline (idarubicinkkk daunubicin lll) mitoxantrone HiDAC (1- g/m ) containing regimens Reduced-intensity matched sibling alternative don HSCT, if patient meets critieria f HSCTnnn Await recovery Best supptive care See Post-Remission Therapy (AML-13) Hypoplasia xx Await recovery nnsee Moniting During Therapy (AML-E). vvbegin alternate don search (unrelated don cd blood) if no appropriate sibling don is available and the patient is a candidate f an allogeneic HSCT. xxhypoplasia is defined as cellularity <10%-0% and residual blasts <5%-10%. kkk Idarubicin treatment compared to high doses of daunubicin up to 80 mg/m yields higher complete response rate and me complete responses after one course. (Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses f induction and recombinant interleukin- f maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 010;8: ). lll The complete response rates and -yr overall survival in patients between 60 and 65 years of age treated with daunubicin 90 mg/m is also comparable to the outcome f idarubicin 1 mg/m ; the higher dose daunubicin did not benefit patients > age 65 (Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunubicin in older patients with acute myeloid leukemia. N Engl J Med 009;361: ). nnnreduced-intensity HSCT may be appropriate f patients with a low level of residual disease post-induction (eg, patients with pri MDS who reverted back to MDS with 5%-7% blasts). It is preferred that this approach be given in the context of a clinical trial. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-1

18 AML POST-REMISSION THERAPY Age 60 y Marrow to document remission status upon hematologic recovery (4-6 weeks) Complete response uu,ooo,ppp Clinical trial Reduced-intensity HSCTqqq Standard-dose cytarabine ( mg/m /day x 5-7 d x 1- cycles) ± anthracycline (idarubicin daunubicin) rrr Consider cytarabine g/m /day x 4-6 doses x 1- cycles f patients with good perfmance status, nmal renal function, better-risk nmal karyotype with favable molecular markers Continue low-intensity regimens (5-azacytidine, decitabine) every 4-6 weeks until progression See Surveillance (AML-14) Induction failure uu Clinical trial Reduced-intensity HSCT in context of clinical trial Best supptive care uusee Response Criteria f (AML-D). ooo Patients in remission may be screened with LP if initial WBC count >100,000/mcL monocytic histology. See Evaluation and Treatment of CNS Leukemia (AML-B). ppphla-typing f patients considered strong candidates f allogeneic transplantation. qqqpatients who are deemed as strong candidates f stem cell transplant and who have an available don should be transplanted in first remission. rrran excellent outcome was repted f outpatient consolidation that provides another option f elderly patients. Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood 007;109(1): Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-13

19 SURVEILLANCEsss SALVAGE THERAPY (AFTER COMPLETION OF CONSOLIDATION) Clinical trial (strongly preferred) Early (<1 mo) Salvage chemotherapyttt followed by matched sibling alternative don HSCT Age <60 Clinical trial (strongly preferred) CBC, platelets every 1-3 mo f y, then every 3-6 mo up to 5 y Bone marrow aspirate only if peripheral smear is abnmal cytopenias develop Late (>1 mo) Salvage chemotherapyttt followed by matched sibling alternative don HSCT Repeat initial successful induction regimenuuu Alternative don search Relapse uu (including cd blood) should be initiated at first relapse in appropriate patients Early Clinical trial (strongly preferred) Best supptive care concomitant with institution (<1 mo) Salvage chemotherapyttt of other therapy if no sibling followed by matched sibling alternative don HSCTvvv don has been identified Age 60 Clinical trial (strongly preferred) Repeat initial successful induction regimenuuu Late (>1 mo) Salvage chemotherapyttt followed by matched sibling alternative don HSCTvvv uusee Response Criteria f (AML-D). Best supptive care sss Studies are ongoing to evaluate the role of molecular moniting in the surveillance f early relapse in patients with AML ( see ). tttsee Salvage Chemotherapy Regimen Options (AML-F). uuureinduction therapy may be appropriate in certain circumstances, such as in patients with long first remission. If a second complete response is achieved, then consolidation with allogeneic HSCT should be considered. vvvtransplant should only be considered in the context of a clinical trial if a remission is achieved. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-14

20 mutation Printed by Eliot Williams on 6/11/014 11:10:33 AM. F personal use only. Not approved f distribution. Copyright 014 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. RISK STATUS BASED ON VALIDATED CYTOGENETICS AND MOLECULAR ABNORMALITIES 1 RISK STATUS Better-risk Intermediate-risk Po-risk CYTOGENETICS inv(16) t(8;1) t(15;17),3 t(16;16) Nmal cytogenetics +8 alone t(9;11) Other non-defined Complex ( 3 clonal chromosomal abnmalities) Monosomal karyotype -5, 5q-, -7, 7q- 11q3 - non t(9;11) inv(3), t(3;3) t(6;9) t(9;) 4 MOLECULAR ABNORMALITIES Nmal cytogenetics: NPM1 mutation in the absence of FLT3-ITD isolated biallelic CEBPA mutation t(8;1), inv(16), t(16;16): with c-kit5 mutation Nmal cytogenetics: with FLT3-ITD mutation 6 1 The molecular abnmalities included in this table reflect those f which validated assays are available in standardized commercial labaties. Given the rapidly evolving field, risk stratification should be modified based on continuous evaluation of research data. Other novel genetic mutations have been identified that may have prognostic significance. Other cytogenetic abnmalities in addition to these findings do not alter better risk status. 3Paschka P, Du J, Schlenk RF, et al. Secondary genetic lesions in acute myeloid leukemia with inv(16) t(16;16): a study of the German-Austrian AML study group (AMLSG). Blood 013;11: F Philadelphia+ AML t(9;), manage as myeloid blast crisis in CML, with addition of tyrosine kinase inhibits. 5Emerging data indicate that the presence of c-kit mutations in patients with t(8;1), and to a lesser extent inv(16), confers a higher risk of relapse. These patients should be considered f clinical trials, if available. 6FLT3-ITD mutations are considered to confer a significantly poer outcome in patients with nmal karyotype, and these patients should be considered f clinical trials where available. There is controversy as to whether FLT3-TKD mutations carry an equally po prognosis. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.014, 03/8/14 National Comprehensive Cancer Netwk, Inc. 014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. AML-A

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