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NCCN.org
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) ®
Acute LymphoblasticLeukemiaVersion 1.2012
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Joseph C. Alvarnas, MD/Co-Chair ‡
† ‡
‡
‡
‡
† Þ
City of Hope ComprehensiveCancer Center
Patrick A. Brown, MD/Co-Chair €The Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins
Patricia Aoun, MD, MPHUNMC Eppley Cancer Center atThe Nebraska Medical Center
Karen Kuhn Ballen, MDMassachusetts General HospitalCancer Center
Naresh Bellam, MD, MPHUniversity of Alabama at Birmingham
Comprehensive Cancer Center William Blum, MDThe Ohio State University ComprehensiveCancer Center - James Cancer Hospitaland Solove Research Institute
Michael W. Boyer, MDHuntsman Cancer Instituteat the University of Utah
Hetty E. Carraway, MDThe Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins
Peter F. Coccia, MD €
UNMC Eppley Cancer Center atThe Nebraska Medical Center
Steven E. Coutre, MDStanford Comprehensive Cancer Center
Jennifer Cultrera, MDH. Lee Moffitt Cancer Center &Research Institute
Lloyd E. Damon, MDUCSF Helen Diller FamilyComprehensive Cancer Center
Daniel J. DeAngelo, MD, PhDDana-Farber Cancer Institute
Dan Douer, MDMemorial Sloan-Kettering Cancer Center
Haydar Frangoul, MD € Vanderbilt-Ingram Cancer Center
Olga Frankfurt, MDRobert H. Lurie Comprehensive Cancer Center of Northwestern University
Salil Goorha, MDUniversity of Tennessee Cancer Institute
‡
‡
† ‡
†
‡
†
Michael M. Millenson, MD
Fox Chase Cancer Center
Susan O’Brien, MDThe University of TexasMD Anderson Cancer Center
Stephen H. Petersdorf, MDFred Hutchinson Cancer ResearchCenter/Seattle Cancer Care Alliance
Arati V. Rao, MDDuke Cancer Institute
Stephanie Terezakis, MD §
‡ Þ
†
† ‡
† Þ
† Þ
† Þ
The Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins
Geoffrey Uy, MDSiteman Cancer Center at Barnes-Jewish Hospital and WashingtonUniversity School of Medicine
Meir Wetzler, MDRoswell Park Cancer Institute
Andrew Zelenetz, MD, PhDMemorial Sloan-Kettering Cancer Center
‡ Hematology/Hematology oncology € Pediatric oncology
Pathology
† Medical oncologyÞ Internal medicine
§ Radiotherapy/Radiation oncology* Writing Committee
Bone marrow transplantation
Continue
NCCN Guidelines Panel Disclosures
NCCN Guidelines Version 1.2012 Panel MembersAcute Lymphoblastic Leukemia
NCCNKristina Gregory, RN, MSNMaoko Naganuma, MSc
*
*
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NCCN Acute Lymphoblastic Leukemia Panel Members
Diagnosis (ALL-1)Workup and Risk Stratification (ALL-2)Ph+ ALL (AYA) Treatment Induction and Consolidation Therapy (ALL-3)Ph+ ALL (Adult) Treatment Induction and Consolidation Therapy (ALL-4)Ph- ALL (AYA) Treatment Induction and Consolidation Therapy (ALL-5)
Ph- ALL (Adult) Treatment Induction and Consolidation Therapy (ALL-6)Surveillance (ALL-7)Relapse/Refractory Disease, Treatment (ALL-7)Typical Immunophenotype by Major ALL Subtypes (ALL-A)Supportive Care (ALL-B)Evaluation and Treatment of Extramedullary Involvement (ALL-C)
Principles of Chemotherapy (ALL-D)Response Criteria (ALL-E)Minimal Residual Disease Assessment (ALL-F)Treatment Options Based on Kinase Domain Mutation Sta tus (ALL-G)BCR-ABL
Clinical Trials:
Categories of Evidence andConsensus:NCCN
believes thatthe best management for any cancer patient is in a clinical trial.Participation in clinical trials isespecially encouraged.
To find clinical trials online at NCCNMember Institutions,
All recommendationsare Category 2A unless otherwisespecified.See
NCCN
click here:nccn.org/clinical_trials/physician.html.
NCCN Categories of Evidenceand Consensus.
The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinicalcircumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network (NCCN ) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCNGuidelines are copyrighted by National Comprehensive Cancer Network . All rights reserved. The NCCN Guidelines and the illustrations herein may notbe reproduced in any form without the express written permission of NCCN. ©2012.
®
® ®
®
NCCN Guidelines Version 1.2012 Table of ContentsAcute Lymphoblastic Leukemia
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Version 1.2012, 03/12/12 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .® ®
Note: All recommendations are category 2A 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.
TREATMENT INDUCTION k CONSOLIDATION THERAPY
ALL-3
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
RISK
STRATIFICATION
Ph+ ALL (AYA)(aged 15-39 y) i,j
Clinical trialor Chemotherapy +tyrosine kinaseinhibitor (TKI)
l
m
Complete
response (CR)n
Less than CR n
Consider monitoring for
minimal residualdisease (MRD) o
Allogeneic HSCT, p if adonor is availableor If allogeneic HSCT is not
available, continuemultiagent chemotherapy+ TKI
lm
Consider post-HSCT TKI m
i
jklmno
Chronological age is a poor surrogate for fitness for therapy. Patients should be evaluated on an individual basis, including for the following factors: end-organ reserve,end-organ dysfunction, and performance status.
For additional considerations in the management of AYA patients with ALL, see the . All ALL treatment regimens include CNS prophylaxis.
.See for use of different TKIs in front-line therapy.
NCCN Guidelines for Adolescent and Young Adult Oncology
See Principles of Chemotherapy (ALL-D)
See Response Criteria (ALL-E).See Minimal Residual Disease Assessment (ALL-F).
Discussion section
p Emerging data suggest that for younger patient (aged 21 y), allogeneic HSCT may not offer an advantage over chemotherapy + TKIs; Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin
Oncol 2009;27:5175-5181.
See Relapse/RefractoryDisease (ALL-7)
Maintenancetherapy + TKIl m
SeeSurveillance(ALL-7)
SeeSurveillance(ALL-7)
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Discussion
Version 1.2012, 03/12/12 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .® ®
Note: All recommendations are category 2A 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.
ALL-4
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
Ph+ ALL(Adult)(aged 40 y)
RISK
STRATIFICATION
Patients < 65years of ageor with nosubstantialcomorbidities
i
Patients 65years of age or withsubstantialcomorbidities
≥
i,q
Clinical trialor TKI +corticosteroidsor
m
ml,r
l
TKI +chemotherapy
CR n
Continue TKI ±corticosteroids
ml
or ml
Continue TKI ±chemotherapy
i
n
o
r
Chronological age is a poor surrogate for fitness for therapy. Patients should be evaluated on an individual basis, including for the following factors: end-organ reserve,end-organ dysfunction, and performance status.
Consider dose modifications appropriate for patient age and performance status.
klm
q
All ALL treatment regimens include CNS prophylaxis..
See for use of different TKIs in front-line therapy.
For additional considerations in the management of senior adult patients with ALL, see the .
See Principles of Chemotherapy (ALL-D)Discussion section
NCCN Guidelines for Senior Adult Oncology
See Response Criteria (ALL-E).See Minimal Residual Disease Assessment (ALL-F).
TREATMENT INDUCTION k CONSOLIDATION THERAPY
Clinical trialor Chemotherapy+ TKI
lm
CR n
Lessthan CR n
Consider monitoringfor MRD o
Allogeneic HSCT, if adonor is availableor If an allogeneic HSCTdonor is not available,continue multiagentchemotherapy + TKIl,r m
Consider post-HSCT TKI m
See Relapse/RefractoryDisease ALL-7
Maintenancetherapy l m+ TKI
SeeSurveillance(ALL-7)
SeeSurveillance(ALL-7)
Maintenancetherapy l m+ TKI
Lessthan CR n
See Relapse/RefractoryDisease (ALL-7)
See
Surveillance(ALL-7)
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Discussion
Version 1.2012, 03/12/12 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .® ®
Note: All recommendations are category 2A 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.
ALL-5
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
Ph- ALL (AYA)(aged 15-39) i,j
TREATMENT INDUCTION k
Clinical trialor Pediatric-inspiredmultiagentchemotherapy s
RISK
STRATIFICATION
CONSOLIDATION THERA PY
CR n
Lessthan CR n
Consider monitoringfor MRD o
Continue multiagentchemotherapy (especially MRD-)or
l
Consider allogeneic HSCT if a donor is available (especially MRD+, WBCcount 30 x 10 /L [B lineage] or
50 x 10 /L [T lineage], hypodiploidy,or MLL rearrangement)
t
u
≥
≥
9
9
i
n
o
Chronological age is a poor surrogate for fitness for therapy. Patients should be evaluated on an individual basis, including for the following factors: end-organ reserve,end-organ dysfunction, and performance status.
j
k
l
s
t
For additional considerations in the management of AYA patients with ALL, see the All ALL treatment regimens include CNS prophylaxis.
.
. All regimens include induction/delayed intensification (especially for pediatric-inspired regimens) and maintenance therapy.Benefit with allogeneic HSCT is unclear in this setting.
Data demonstrating the effect of WBC counts on prognosis is less firmly established for adults than for the pediatric population.u
NCCN Guidelines for Adolescent and Young Adult Oncology
See Principles of Chemotherapy (ALL-D)
See Principles of Chemotherapy (ALL-D)
See Response Criteria (ALL-E).See Minimal Residual Disease Assessment (ALL-F).
See Relapse/RefractoryDisease (ALL-7)
Maintenancetherapy l
SeeSurveillance
(ALL-7)
SeeSurveillance(ALL-7)
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Version 1.2012, 03/12/12 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .® ®
Note: All recommendations are category 2A 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.
ALL-6
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
RISK
STRATIFICATION
Patients <65years of ageor with nosubstantialcomorbidities
i
Patients 65years of ageor withsubstantialcomorbidities
≥
i,qClinical trialor
or Corticosteroids
Multiagentchemotherapy l
CR n Chemotherapy l
TREATMENT INDUCTION k CONSOLIDATION THERAPY
Maintenancetherapy l
Lessthan CR n
Clinical trialor Multiagent
chemotherapys
CR n
Lessthan CR n
Consider monitoringfor MRD o
See Relapse/RefractoryDisease (ALL-7)
Maintenancetherapy l
SeeSurveillance(ALL-7)
Ph- ALL(Adult)(aged 40 y)
i
n
o
Chronological age is a poor surrogate for fitness for therapy. Patients should be evaluated on an individual basis, including for the following factors: end-organ reserve,end-organ dysfunction, and performance status.
k
l
q
s
t
All ALL treatment regimens include CNS prophylaxis..
For additional considerations in the management of senior adult patients with ALL, see the .. All regimens include induction/delayed intensification (especially for pediatric-inspired regimens) and maintenance therapy.
Benefit with allogeneic HSCT is unclear in this setting.
Data demonstrating the effect of WBC counts on prognosis is less firmly established for adults than for the pediatric population.u
See Principles of Chemotherapy (ALL-D)
NCCN Guidelines for Senior Adult OncologySee Principles of Chemotherapy (ALL-D)
See Response Criteria (ALL-E).See Minimal Residual Disease Assessment (ALL-F).
See Relapse/RefractoryDisease (ALL-7)
Continue multiagentchemotherapy (especially MRD-)or
l
Consider allogeneic HSCT if a donor is available (especially MRD+, WBCcount 30 x 10 /L [B lineage] or
50 x 10 /L [T lineage], hypodiploidy,or MLL rearrangement)
t
u
≥
≥
9
9
y p y pp py g p , , g
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PRINCIPLES OF CHEMOTHERAPY (1 of 4)
ALL-D1 of 4
Note: All recommendations are category 2A 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.
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
*All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine, 6-mercaptopurine) and/or IT therapy (eg, IT methotrexate, IT cytarabine;triple IT therapy with methotrexate, cytarabine, corticosteroid).
**For patients receiving 6-MP, consider testing for TPMT gene polymorphisms, particularly in patients that develop severe neutropenia after starting 6-MP.
Induction Regimens* for Ph-Positive ALLAdult patients aged 40 years:
Pediatric-inspired protocols for AYA patients aged 15-39 years:
Maintenance regimens:
≥
TKIs + hyper-CVAD: imatinib or dasatinib; and hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone,alternating with high-dose methotrexate, and cytarabineTKIs + multiagent chemotherapy: imatinib; and daunorubicin, vincristine, prednisone, and cyclophosphamideTKIs + corticosteroids: imatinib and prednisone (for this study, patients were aged >60 years)Dasatinib
COG AALL-0031 regimen: vincristine, prednisone (or dexamethasone), and asparaginase, with or without daunomycin; or prednisone (or dexamethasone) and asparaginase with or without daunomycin; imatinib added during consolidation blocks
Weekly methotrexate + daily 6-mercaptopurine (6-MP)** + monthly vincristine/prednisone pulses (for 2-3 years)Add TKIs (imatinib or dasatinib) to the above maintenance regimen
1-45,6
78,9
10
References ALL-D 4 of 4
Induction Regimens for Ph-Negative (ALL ALL-D 2 of 4)
Salvage Regimens for Relapsed/Refractory ALL ALL-D 3 of 4
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Salvage Regimens* for Relapsed/Refractory ALL
Ph-positive ALL:
Ph-negative ALL:
DasatinibNilotinib
Clofarabine
Cytarabine-containing regimensAlkylator combination regimensNelarabine (for T-ALL)
22,2324
252627
28
Augmented hyper-CVAD: hyper-fractionated cyclophosphamide, intensified vincristine, doxorubicin, intensified dexamethasone, andasparaginase; alternating with high-dose methotrexate and cytarabine 29
PRINCIPLES OF CHEMOTHERAPY (3 of 4)
ALL-D3 of 4
Note: All recommendations are category 2A 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.
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
*All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine, 6-mercaptopurine) and/or IT therapy (eg, IT methotrexate, IT cytarabine;triple IT therapy with methotrexate, cytarabine, corticosteroid).
References (ALL-D 4 of 4 )
Induction Regimens for Ph-Positive (ALL ALL-D 1 of 4)
Induction Regimens for Ph-Negative (ALL ALL-D 2 of 4)
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Version 1.2012, 03/12/12 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .® ® ALL-E
Note: All recommendations are category 2A 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.
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
RESPONSE CRITERIA
Response Criteria for Blood and Bone Marrow:
Response Criteria for CNS Disease:
Response Criteria for Mediastinal Disease:
CRNo circulating blasts or extramedullary disease
No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvementTrilineage hematopoiesis (TLH) and <5% blasts
CR with incomplete blood count recovery (CRi)Recovery of platelets but <100,000 or ANC is <1000/microL
Overall response rate (ORR=CR + CRi)
Failure to achieve CR at the end of inductionProgressive disease (PR)
Increase of at least 25% in the absolute number of circulating or bone marrow blasts or development of extramedullary diseaseRelapsed disease
Reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary site after a CR
CNS remission: Achievement of CNS-1 status ( ) in a patient with CNS-2 or CNS-3 status at diagnosis.CNS relapse: New development of CNS-3 status or clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome.
CR: Complete resolution of mediastinal enlargement by CT.CR Unconfirmed (CRu): Residual mediastinal enlargement that has regressed by >75% in the sum of the product of the greatestperpendicular diameters (SPD).PR: >50% decrease in the SPD of the mediastinal enlargement.PD: >25% increase in the SPD of the mediastinal enlargement.No Response (NR): Failure to qualify for PR or PD.Relapse: Recurrence of mediastinal enlargement after achieving CR or CRu.
Absolute neutrophil count (ANC) >1000/microLPlatelets >100,000/microLNo recurrence for 4 weeks
Refractory disease
see ALL-C
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TREATMENT OPTIONS BASED ON KINASE DOMAIN MUTATION STATUSBCR-ABL 1
Mutation Treatment Recommendation
T315I HSCT or clinical trial
V299L, T315A, F317L/V/I/C Consider nilotinib rather thandasatinib
Y253H, E255K/V, F359V/C/I Consider dasatinib rather thannilotinib
Any other mutation Consider high-dose imatinib or dasatinib or nilotinib
2
1
2
This research was originally published in Blood. Soverini S, Hochhaus A, Nicolini FE, et al. Bcr-Abl kinase domain mutation analysis in chronic myeloid leukemiapatients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. .© the American Society of Hematology.There are no sufficient data on dose escalation available to indicate if mutations with lower IC values are sensitive to high-dose imatinib.
Blood 2011;118:1208-1215
50
ALL-G
Note: All recommendations are category 2A 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.
NCCN Guidelines Version 1.2012Acute Lymphoblastic Leukemia
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NCCN Guidelines Index ALL Table of Contents
Discussion
NCCN Guidelines Version 1.2012 Acute Lymphoblastic Leukemia
glycol conjugated asparaginase for treatment of children with newlydiagnosed standard risk acute lymphoblastic leukemia: a Children's
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Version 1.2012, 03/12/12 © National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines ® and this illus tration may not be reproduced in any form witho ut the express written permission of NCCN®. REF-16
diagnosed standard-risk acute lymphoblastic leukemia: a Children'sCancer Group study. Blood 2002;99:1986-1994. Available at:http://www.ncbi.nlm.nih.gov/pubmed/11877270 .
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199. Zalewska-Szewczyk B, Gach A, Wyka K, et al. The cross-reactivityof anti-asparaginase antibodies against different L-asparaginasepreparations. Clin Exp Med 2009;9:113-116. Available at:http://www.ncbi.nlm.nih.gov/pubmed/19184328 .
200. Willer A, Gerss J, Konig T, et al. Anti-Escherichia coliasparaginase antibody levels determine the activity of second-linetreatment with pegylated E coli asparaginase: a retrospective analysiswithin the ALL-BFM trials. Blood 2011;118:5774-5782. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21940824 .201. Vrooman LM, Supko JG, Neuberg DS, et al. Erwinia asparaginaseafter allergy to E. coli asparaginase in children with acute lymphoblasticleukemia. Pediatr Blood Cancer 2010;54:199-205. Available at:http://www.ncbi.nlm.nih.gov/pubmed/19672973 .
202. EUSA Pharma (USA), Inc. Prescribing Information. AsparaginaseErwinia chrysanthemi ERWINAZE™ For Injection, Intramuscular Use.
2011. Available at: http://www.erwinaze.com/pdf/PI_18-Nov2011.pdf . Accessed February 2012.