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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Acute Lymphoblastic

Leukemia

Version 1.2021 — April 6, 2021

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NCCN Guidelines for Patients

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Discussion

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NCCN Guidelines Panel Disclosures

ξ Bone marrow

transplantation

‡ Hematology/Hematology

oncology

Þ Internal medicine

† Medical oncology

≠ Pathology

€ Pediatric oncology

§ Radiotherapy/Radiation

oncology

* Discussion Section

Writing Committee

*Patrick A. Brown, MD/Chair €

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

*Bijal Shah, MD/Vice-Chair †

Moffitt Cancer Center

Anjali Advani, MD † ‡

Case Comprehensive Cancer Center/University

Hospitals Seidman Cancer Center and

Cleveland Clinic Taussig Cancer Institute

Patricia Aoun, MD, MPH ≠

City of Hope National Medical Center

Michael W. Boyer, MD ‡ ξ €

Huntsman Cancer Institute

at the University of Utah

Patrick W. Burke, MD † ‡

University of Michigan Rogel Cancer Center

Daniel J. DeAngelo, MD, PhD † ‡

Dana-Farber/Brigham and Women’s

Cancer Center

Shira Dinner, MD † ‡

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

Amir T. Fathi, MD † ‡ Þ

Massachusetts General Hospital

Cancer Center

Jordan Gauthier, MD, MSc ‡

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Nitin Jain, MD † ‡

The University of Texas

MD Anderson Cancer Center

Suzanne Kirby, MD ‡

Duke Cancer Institute

Michaela Liedtke, MD ‡

Stanford Cancer Institute

Mark Litzow, MD ‡

Mayo Clinic Cancer Center

Aaron Logan, MD, PhD ‡

UCSF Helen Diller Family

Comprehensive Cancer Center

Selina Luger, MD †

Abramson Cancer Center

at the University of Pennsylvania

Lori J Maness, MD ‡

Fred & Pamela Buffett Cancer Center

Stephanie Massaro, MD, MPH € ‡

Yale Cancer Center/Smilow Cancer Hospital

Ryan J. Mattison, MD † ‡ Þ

University of Wisconsin Carbone Cancer Center

William May, MD €

UCLA Jonsson Comprehensive Cancer Center

Olalekan Oluwole, MD ‡

Vanderbilt-Ingram Cancer Center

Jae Park, MD †

Memorial Sloan Kettering Cancer Center

Amanda Przespolewski, DO ‡

Roswell Park Comprehensive Cancer Center

Sravanti Rangaraju, MD † ‡

O'Neal Comprehensive Cancer Center at UAB

Jeffrey E. Rubnitz, MD, PhD €

St. Jude Children’s Research Hospital/The

University of Tennessee Health Science Center

Geoffrey L. Uy, MD ‡ † ξ

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Madhuri Vusirikala, MD ξ ‡

UT Southwestern Simmons

Comprehensive Cancer Center

Matthew Wieduwilt, MD, PhD ‡ ξ

UC San Diego Moores Cancer Center

NCCN

Beth Lynn, RN, BS

Ndiya Ogba, PhD

Deborah Freedman-Cass, PhD

Mallory Campbell, PhD

NCCN Guidelines Version 1.2021

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Table of Contents

Discussion

NCCN Acute Lymphoblastic Leukemia Panel Members

Summary of the Guidelines Updates

Diagnosis (ALL-1)

Workup and Risk Stratification (ALL-2)

Ph+ ALL (AYA/Adult) Treatment Induction and Consolidation Therapy (ALL-3)

Ph- ALL (AYA) Treatment Induction and Consolidation Therapy (ALL-4)

Ph- ALL (Adult) Treatment Induction and Consolidation Therapy (ALL-5)

Surveillance (ALL-6)

Relapsed/Refractory Disease, Treatment (ALL-7)

Cytogenetic Risk Groups for B-ALL (ALL-A)

Evaluation and Treatment of Extramedullary Involvement (ALL-B)

Supportive Care (ALL-C)

Principles of Systemic Therapy (ALL-D)

Response Assessment (ALL-E)

Minimal/Measurable Residual Disease Assessment (ALL-F)

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

clinical circumstances 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 NCCN

not be reproduced in any form without the express written permission of NCCN. 2021.

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

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Discussion

UPDATES

ALL-1

• Molecular Characterization

Third bullet revised: Comprehensive testing by next-generation sequencing (NGS) for gene fusions and pathogenic mutations is

recommended encouraged for gene fusions and pathogenic mutations

, particularly if known to be BCR-ABL1/Ph-negative or Ph-like.

Additional optional tests include, rst bullet revised: Assessment (array cGH)

with chromosomal microarray (CMA)/array cGH in cases of

aneuploidy or failed karyotype.

• Classication

Sentence was revised: Together, these studies allow determination of the World Health Organization (WHO) ALL subtypes and cytogenetic

and clinical risk groups.

ALL-1A

• Footnote g revised to include: In cases of hypodiploid ALL where germline

TP53

mutations are common, testing should be considered.

• Footnote i added: High WBC count (≥30 x 10

/L for B lineage or ≥100 x 10

/L for T lineage) is considered a high-risk factor based on some

studies in ALL. Data demonstrating the eect of WBC counts on prognosis are less rmly established for adults than for the pediatric

population and likely superseded by MRD quantication after treatment. (Also pages ALL-2, ALL-3A, ALL-4A, and ALL-5)

• Footnote j added: ALL arising from prior chemotherapy or underlying hematologic malignancy may be associated with adverse outcomes.

Saygin C, et al. Blood Adv 2019;3:4228-4237.

ALL-2

• Workup

Urinalysis removed.

Last bullet revised: Strongly consider human leukocyte antigen (HLA) typing and early evaluation and search for family or an alternative

donor early transplant evaluation and donor search.

• Risk Stratication, top pathway, added: and Adult.

ALL-3

• Ph+ AYA pathway was combined with the Ph+ Adult pathway.

• Risk Stratication

Top pathway, added: AYA and adult.

Bottom pathway, added: Adult.

• Consolidation Therapy was extensively revised. The following: “Allogeneic hematopoietic cell transplantation (HCT), in appropriate

candidates followed by the option to consider post-HCT TKI or Continue multiagent chemotherapy + TKI followed by the option maintenance

therapy + TKI” was replaced with:

Persistent/Rising MRD

◊ Blinatumomab

TKI (B-ALL) or Continue multiagent chemotherapy/corticosteroid + TKI or Allogeneic HCT in appropriate candidates.

MRD

◊ Continue multiagent chemotherapy/corticosteroid + TKI or Allogenic HCT in appropriate candidates.

Updates in Version 1.2021 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 2.2020 include:

Continued

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Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 2.2020 include:

Continued

ALL-3A

• Footnotes

Added:

◊ Footnote h: See Cytogenetic Risk Groups for B-ALL (ALL-A). (Also page ALL-4A)

◊ Footnote cc: Consider dose modications appropriate for patient age and performance status. See Principles of Systemic Therapy -

Treatment of Older Adults (≥65 years) or Adults with Substantial Comorbidities (ALL-D 9 of 10).

◊ Footnote dd: The prognostic signicance of MRD positivity may be regimen-, ALL subtype-, and/or ALL risk-dependent. MRD timepoints

and levels prompting allogeneic HCT should be guided by the specic treatment protocol being used. In general, MRD positivity at the

end of induction predicts high relapse rates and should prompt evaluation for allogeneic HCT. Therapy aimed at eliminating MRD prior to

allogeneic HCT is preferred when possible (See Discussion). (Also pages ALL-4A and ALL-5)

◊ Footnote ee: Consider using an alternative and more broadly acting TKI. See Principles of Systemic Therapy - Regimens for Ph-Positive

B-ALL (ALL-D 3 of 10).

◊ Footnote : TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Dasatinib and imatinib are

the preferred TKIs for induction therapy; ponatinib is also preferred for the hyper-CVAD regimen. Not all TKIs have been directly studied

within the context of each specic regimen and the panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specic TKI

should account for anticipated/prior TKI intolerance, BCR-ABL1 mutations, and disease-related features. For contraindicated mutations,

see ALL-D 3 of 10.

◊ Footnote gg: See Supportive Care: Toxicity Management (ALL-C 2 of 4). (Also page ALL-4A)

◊ Footnote hh: Although long-term remission after blinatumomab treatment is possible, allogeneic HCT should be considered as

consolidative therapy. (Also page ALL-4A)

Revised:

◊ Footnote r: All ALL treatment regimens include CNS prophylaxis. See Evaluation and Treatment of Extramedullary Involvement (ALL-B).

(Also pages ALL-4A and ALL-5)

◊ Footnote v: Optimal timing of HCT is not clear. For t patients, additional therapy is recommended to eliminate MRD prior to transplant.

Proceeding to allogeneic HCT with MRD is not optimal. (Also pages ALL-4A and ALL-5)

◊ Footnote w: Data suggest that for younger patients (aged ≤21 y), particularly for those who achieve MRD negativity, allogeneic HCT may

not oer an advantage over chemotherapy + TKI...

ALL-4A

• Footnote ii added: Consider retesting for MRD at rst available opportunity. (Also page ALL-5)

ALL-6

• Surveillance, Other General Measures, rst bullet revised: Bone marrow aspirate can be considered as clinically indicated every

at a

frequency of up to 3–6 months for at least 5 years.

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Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 2.2020 include:

ALL-7

• Relapsed/Refractory Disease

"B" added to Ph+ and Ph- ALL.

T-ALL pathway added.

• Treatment

Following ABL1 Kinase domain mutation testing, options revised: ... Blinatumomab

TKI (TKI intolerant/refractory B-ALL) or Inotuzumab

ozogamicin

bosutinib (TKI intolerant/ refractory, B-ALL)...

Cytogenetic Risk Groups for B-ALL (ALL-A)

• Poor risk

Removed: Ph-like ALL.

Added:

◊ BCR-ABL 1-like (Ph-like) ALL.

◊ JAK-STAT (CRLF2r, EPORr, JAK1/2/3r, TYK2r, mutations of SH2B3, IL7R, JAK1/2/3)

◊ ABL class (rearrangements of ABL1, ABL2, PDGFRA, PDGFRB, FGFR)

◊ Other (NTRKr, FLT3r, LYNr, PTL2Br)

◊ t(17;19): TCF3-HLF fusion

◊ Alterations of IKZF1

• Footnotes added:

Footnote c: Alternatively dened as DNA index less than protocol-dened threshold or other clear evidence of hypodiploid clone.

Hypodiploid ALL is also often associated with TP53 loss of function mutations and Li-Fraumeni syndrome.

Footnote d: Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood 2017;129:572-

581; Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activation lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med

2014;371:1005-1015.

Footnote e: Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med

2009;360:470-480; Stanulla M, Dagdan E, Zaliova M, et al. IKZF1plus denes a new minimal residual disease-dependent very-poor

prognostic prole in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin Oncol 2018;36:1240-1249.

Footnote f: Emerging evidence suggests DUX4r ALL is favorable. Additionally in cases of DUX4r, IKZF1 alterations do not confer poor

prognosis.

ALL-B

• Evaluation and Treatment of Extramedullary Involvement, third bullet, third sub-bullet revised: The panel recommends that LP be done

concurrently with initial IT therapy. IT therapy be administered with initial LP.

ALL-C (2 of 4)

• Supportive Care: Toxicity Management Inotuzumab, Blinatumomab, and Tisagenlecleucel

Blinatumomab, second bullet, last sentence revised: Consider tocilizumab for patients with refractory

severe CRS.

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UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 2.2020 include:

ALL-C (3 of 4)

• Supportive Care: Asparaginase Toxicity Management

Second bullet, added: (in patients ≤21 years).

Third bullet added: The panel recommends that the dose of PEG or Cal-PEG should be capped at 1 vial (3,750 IU).

Hypersensitivity, Allergy, and Anaphylaxis:

◊ Fourth bullet revised: For Grade 1 reactions and Grade 2 reactions (rash, ushing, urticaria, and drug fever ≥38°C) without

bronchospasm, hypotension, edema, or need for parenteral intervention, the asparaginase that caused the reaction may be

continued, with consideration for anti-allergy premedication (such as hydrocortisone, famotidine or ranitidine, diphenhydramine, and

acetaminophen).

◊ Fifth bullet added: Measures that can be considered for preventing or limiting severity of infusion reactions or hypersensitivity reactions

include slowing the infusion to ≥2 hours, infusing normal saline concurrently, and use of premedications provided above.

◊ Sixth bullet, sub-bullets added:

– TDM for asparaginase therapy using the serum asparaginase activity (SAA) is available as a CLIA-certied test with a turnaround time

of less than one week, allowing real-time decision-making and therapeutic adjustments. Generally accepted SAA assay targets include

a minimum trough of ≥0.1 IU/mL. However, data indicate that when SAA levels fall below 0.4 IU/mL, asparagine is no longer completely

depleted, and begins to rebound, suggesting an optimal trough of ≥0.4 IU/mL.

– Routine premedication has generally been avoided in the past for fear of “masking” hypersensitivity reactions. However, given the

diculty in distinguishing hypersensitivity and non-allergic infusion reactions and the availability of TDM, universal premedication and

TDM can be considered, which can reduce the incidence and severity of adverse events and the need for substitution of pegaspargase

with Erwinia.

ALL-C (4 of 4)

• Supportive Care: Asparaginase Toxicity Management (continued); Hepatotoxicity; rst bullet revised: For direct bilirubin >5.0, either

discontinue asparaginase or hold asparaginase until <2.0 mg/dL, then resume with very

consideration for dose reduction and close

monitoring.

Principles of Systemic Therapy (ALL-D)

ALL-D (1 of 10)

• Heading revised: Induction

Regimens for Ph-Positive B-ALL.

Protocols for AYA Patients, option added: Blinatumomab ± TKI.

Adult Patients (<65 y) added: and without substantial comorbidities. (Also page ALL-D 2 of 10)

◊ Option added: Blinatumomab ± TKI.

Statement following table revised: For treatment of older adult patients ≥65 y with ALL or adult patients with substantial comorbidities, see

ALL-D 9 of 10. (Also page ALL-D 2 of 10)

Continued

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Updates in Version 1.2021 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 2.2020 include:

Continued

UPDATES

ALL-D1A

• Footnotes revised:

Footnote c: There are data to support the benet The use

of rituximab should be considered in addition to chemotherapy for CD20-positive

patients (especially in patients <60 years). (Also page ALL-D 2A)

Footnote e: These regimens are used for

The specic drugs listed are primarily used in induction. therapy and additional therapy is needed

For post-induction components, see listed references. (Also page ALL-D 2A)

Footnote g: last sentence added: For contraindicated mutations, see ALL-D 3 of 10. (Also page ALL-D 9 of 10).

Footnote i: For patients receiving 6-MP, consider testing for TPMT gene polymorphisms, particularly in patients who develop severe

neutropenia after starting 6-MP. Testing for both TPMT and NUDT15 variant status should be considered, especially for patients of East

Asian origin. Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine

dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther 2019;105:1095-1105. (Also page ALL-D 2A)

• Footnotes added:

Footnote d: An FDA-approved biosimilar is an appropriate substitute for rituximab. (Also pages ALL-D 2A and ALL-D 4 of 10)

Footnote h: For consolidation.

• Footnote removed: These regimens are used for induction therapy and additional therapy is needed.

ALL-D (2 of 10)

• AYA Patients

Preferred regimens, rst and last options, removed: (ongoing study in patients aged <40 years).

◊ Third option, removed: added to consolidation regimen.

Other Recommended Regimens

◊ Third option revised: Hyper-CVAD ± rituximab

: hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone,

alternating with high-dose methotrexate and cytarabine; with rituximab for CD20-positive disease.

◊ Fourth option revised: USC/MSKCC ALL regimen based on CCG-1882 regimen: daunorubicin, vincristine, prednisone, and methotrexate

with augmented pegaspargase (patients aged 18–60 years).

◊ Fifth option revised: Linker 4-drug regimen: daunorubicin, vincristine, pegaspargase, and prednisone; with rituximab for CD20-positive

disease.

• Adult Patients (<65 y and without substantial comorbidities)

Other Recommended Regimens

◊ Third option revised: Hyper-CVAD ± rituximab

: hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone,

alternating with high-dose methotrexate and cytarabine; with rituximab for CD20-positive disease.

◊ Fourth option added: USC/MSKCC ALL regimen based on CCG-1882 regimen: daunorubicin, vincristine, prednisone, and methotrexate

with augmented pegaspargase (patients aged <60 years).

◊ Fifth option revised: Linker 4-drug regimen ± rituximab

: daunorubicin, vincristine, prednisone, and pegaspargase; with rituximab for

CD20-positive disease (patients aged <60 years).

• Statement after table revised: For treatment of older adult patients ≥65 y with ALL or adult patients with substantial comorbidities see ALL 9

of 10.

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UPDATES

ALL-D (3 of 10)

• Heading revised: Regimens for Relapsed or Refractory Ph-Positive B-ALL.

Other Recommended Regimens

◊ Options revised:

– Blinatumomab

TKI (for B-ALL) (TKI intolerant/refracory).

– Inotuzumab ozogamicin

bosutinib (for B-ALL) (TKI intolerant/refractory).

– The regimens listed on ALL-D 4 of 10 for Ph-negative B-ALL may be considered for Ph-positive B-ALL refractory to TKIs.

◊ Option removed: MOpAD regimen (category 2B): methotrexate, vincristine, pegaspargase, dexamethasone; with rituximab for CD20

positive disease and TKI.

ALL-D (4 of 10)

• Heading revised: Regimens for Relapsed or Refractory Ph-Negative B-ALL.

Other Recommended Regimens

◊ Option removed: Nelarabine alone or in combination (eg, nelarabine, etoposide, cyclophosphamide) for T-ALL.

◊ Option revised: MOpAD regimen (for R/R Ph-negative ALL only): methotrexate, vincristine, pegaspargase, dexamethasone; with

rituximab for CD20-positive disease.

ALL-D (5 of 10)

• New section added: Principles of Systemic Therapy: Regimens for Relapsed or Refractory Ph-Negative T-ALL.

ALL-D (6 of 10) and ALL-D (7 of 10) and ALL-D (8 of 10)

• References updated.

ALL-D (9 of 10)

• Header revised: Treatment of Older Adults (≥65 years) or Adults with ALL

Substantial Comorbidities. (Also page ALL-D 10 of 10)

Induction Regimens for Ph-negative ALL header, removed: Adults Aged ≥65 y

Induction Regimens for Ph-positive B-ALL header, removed: Adults Aged ≥65 y

• Footnote f revised: TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Dasatinib and imatinib

are the preferred TKIs for induction therapy; ponatinib is also preferred for the hyper-CVAD regimen. Not all TKIs have been directly studied

within the context of each specific regimen and the panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI

should account for anticipated/prior TKI intolerance and disease-related features. For contraindicated mutations, see ALL-D 3 of 10.

ALL-F

• Minimal/Measurable Residual Disease Assessment

First bullet revised: The preferred sample for MRD assessment is the rst small volume (of up to 3 mL) pull of the bone marrow aspirate, if

feasible.

Third bullet, last sentence added: If validated MRD assessment technology with appropriate sensitivity (at least 10-4) is not available

locally, there are commercially available tests.

Sixth bullet, last sentence added: Methods not achieving these sensitivity levels are not suitable.

Updates in Version 1.2021 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 2.2020 include:

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Discussion

ALL-1

Acute

lymphoblastic

leukemia

(ALL)

a,b,c

Patients should undergo evaluation and treatment at specialized centers

The diagnosis of ALL generally requires demonstration of ≥20% bone marrow lymphoblasts

d,e

upon

hematopathology review of bone marrow aspirate and biopsy materials, which includes:

• Morphologic assessment of Wright-Giemsa–stained bone marrow aspirate smears, and H&E–stained core

biopsy and clot sections

• Comprehensive ow cytometric immunophenotyping

• Baseline ow cytometric and/or molecular characterization of leukemic clone to facilitate subsequent

minimal/measurable residual disease (MRD) analysis (see ALL-F)

• Karyotyping of G-banded metaphase chromosomes

MOLECULAR CHARACTERIZATION

Optimal risk stratication and treatment planning require testing marrow or peripheral blood lymphoblasts

for specic recurrent genetic abnormalities using:

• Interphase uorescence in situ hybridization (FISH) testing, including probes capable of detecting the

major recurrent genetic abnormalities

• Reverse transcriptase-polymerase chain reaction (RT-PCR) testing BCR-ABL1 in B-ALL (quantitative or

qualitative) including determination of transcript size (ie, p190 vs. p210)

• Comprehensive testing by next-generation sequencing (NGS) for gene fusions and pathogenic mutations

is recommended, particularly if known to be BCR-ABL1/Ph-negative or Ph-like.

Additional optional tests include:

• Assessment with chromosomal microarray (CMA)/array cGH in cases of aneuploidy or failed karyotype.

CLASSIFICATION

Together, these studies allow determination of the World Health Organization (WHO) ALL subtypes and

cytogenetic and clinical risk groups.

h,i,j

See Workup

and Risk

Stratication

(ALL-2)

DIAGNOSIS

See footnotes on ALL-1A

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Discussion

ALL-1A

Subtypes: B-cell lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities includes hyperdiploidy, hypodiploidy, and commonly occurring translocations:

t(9;22)(q34.1;q11.2)[BCR-ABL1]; t(v;11q23.3)[KMT2A rearranged]; t(12;21)(p13.2;q22.1)[ETV6-RUNX1]; t(1;19)(q23;p13.3)[TCF3-PBX1]; t(5;14)(q31.1;q32.3)[IL3-

IGH]; Ph–like; B-lymphoblastic leukemia/lymphoma with iAMP21; early T-cell precursor lymphoblastic leukemia.

Criteria for classification of mixed phenotype acute leukemia (MPAL) should be based on the WHO 2016 criteria. Note that in ALL, myeloid-associated antigens such

as CD13 and CD33 may be expressed, and the presence of these myeloid markers does not exclude the diagnosis of ALL, nor is it associated with adverse prognosis.

Burkitt leukemia/lymphoma, see the NCCN Guidelines for B-Cell Lymphomas.

While these guidelines pertain primarily to patients with leukemia, patients with lymphoblastic lymphoma (LL) (B- or T-cell) also benefit from ALL-like regimens versus

traditional lymphoma therapy. Such patients should be treated in a center that has experience with LL. See Discussion.

If there are sufficient numbers of circulating lymphoblasts (at least 1,000 per microliter as a general guideline) and clinical situation precludes bone marrow aspirate

and biopsy, then peripheral blood can be substituted for bone marrow.

The following immunophenotypic findings are particularly notable: CD10 negativity correlates with KMT2A rearrangement; ETP T-ALL (typically lacking expression

of CD5, CD8, and CD1a and expression of one or more myeloid/stem cell markers); CD20 positivity: definition not clear, most studies have used >20% of blasts

expressing CD20. See Discussion.

The Ph-like phenotype is associated with recurrent gene fusions and mutations that activate tyrosine kinase pathways and includes gene fusions involving ABL1,

ABL2, CRLF2, CSF1R, EPOR, JAK2, or PDGFRB and mutations involving FLT3, IL7R, SH2B3, JAK1, JAK3, and JAK2 (in combination with CRLF2 gene fusions).

Testing for these abnormalities at diagnosis may aid in risk stratification. The safety and efficacy of targeted agents in this population is an area of active research.

For more information regarding Ph-like ALL, please see the Discussion. In cases of hypodiploid ALL where germline

TP53

mutations are common, testing should be

considered.

See Cytogenetic Risk Groups for B-ALL (ALL-A).

High WBC count (≥30 x 10

/L for B lineage or ≥100 x 10

/L for T lineage) is considered a high-risk factor based on some studies in ALL. Data demonstrating the effect

of WBC counts on prognosis are less firmly established for adults than for the pediatric population and likely superseded by MRD quantification after treatment.

ALL arising from prior chemotherapy or underlying hematologic malignancy may be associated with adverse outcomes. Saygin C, et al. Blood Adv 2019;3:4228-4237.

FOOTNOTES

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

ALL-2

High WBC count (≥30 x 10

/L for B lineage or ≥100 x 10

/L for T lineage) is considered a high-risk factor based on some studies in ALL. Data demonstrating the effect

of WBC counts on prognosis are less firmly established for adults than for the pediatric population and likely superseded by MRD quantification after treatment.

The following list represents minimal recommendations; other testing may be warranted according to clinical symptoms and discretion of the clinician.

For patients with major neurologic signs or symptoms at diagnosis, appropriate imaging studies should be performed to detect meningeal disease, chloromas, or

central nervous system (CNS) bleeding. See Evaluation and Treatment of Extramedullary Involvement (ALL-B).

The panel recommends first LP be performed at time of initial scheduled IT therapy unless directed by symptoms to perform earlier.

The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age is not a firm reference point because some of the recommended regimens

have not been comprehensively tested across all ages.

WORKUP

RISK STRATIFICATION

• History and physical (H&P)

• Complete blood count (CBC), platelets, dierential, chemistry prole, liver function tests

(LFTs)

• Disseminated intravascular coagulation (DIC) panel: d-dimer, brinogen, prothrombin time

(PT), partial thromboplastin time (PTT)

• Tumor lysis syndrome (TLS) panel: Lactate dehydrogenase (LDH), uric acid, potassium,

calcium, phosphorus (See Tumor Lysis Syndrome in the NCCN Guidelines for B-Cell

Lymphomas)

• Hepatitis B/C, HIV, CMV Ab testing

• Pregnancy testing, fertility counseling, and preservation

• CT/MRI of head with contrast, if neurologic symptoms

• Lumbar puncture (LP)

l,m

with intrathecal (IT) chemotherapy

See Evaluation and Treatment of Extramedullary Involvement (ALL-B)

• CT of neck/chest/abdomen/pelvis with IV contrast, as indicated for symptoms

Consider PET/CT if lymphomatous involvement is suspected

• Testicular exam, including scrotal ultrasound as indicated

• Infection evaluation:

Screen for opportunistic infections, as appropriate (See NCCN Guidelines for Prevention

and Treatment of Cancer-Related Infections)

• Echocardiogram or cardiac nuclear medicine scan should be considered in all patients,

since anthracyclines are important components of ALL therapy, but especially in

patients with prior cardiac history and prior anthracycline exposure or clinical symptoms

suggestive of cardiac dysfunction.

• Central venous access device of choice

• Strongly consider early transplant evaluation and donor search.

Ph+ ALL (AYA

and Adult)

Ph- ALL (AYA)

Ph- ALL (Adult)

See Treatment

(ALL-3)

See Treatment

(ALL-4)

See Treatment

(ALL-5)

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

RISK

STRATIFICATION

h,i

TREATMENT INDUCTION

,r,s

CONSOLIDATION THERAPY

,r,s

Ph+

ALL

AYA

n,p,q

and

adult patients

<65 years of

age

without

substantial

comorbidities

Adult patients

≥65 years

of age

o,bb

or with

substantial

comorbidities

Clinical trial

Tyrosine kinase

inhibitor (TKI) +

chemotherapy

TKI +

corticosteroid

Clinical trial

TKI +

corticosteroid

t,cc

TKI +

chemotherapy

t,cc

Less than CR

Monitoring for

MRD

u,v

See MRD

Assessment

(ALL-F)

Response

Assessment

(ALL-E)

Blinatumomab ± TKI

t,ee

(B-ALL)

gg,hh

Continue multiagent

chemotherapy/

corticosteroid + TKI

t,ee

Allogeneic hematopoietic

cell transplantation

(HCT), in appropriate

candidates

v,w,x

Consider

post-HCT

TKI

t,y,z,aa

See

Surveillance

(ALL-6)

Persistent/

Rising

MRD

dd,ee

Continue multiagent

chemotherapy/

corticosteroid + TKI

t,cc

Allogenic HCT in

appropriate

candidates

v,w,x

Maintenance

therapy

TKI

t,z,aa

MRD-

Allogeneic

HCT

See Relapsed/Refractory

Disease (ALL-7)

ALL-3

Consider

post-HCT

TKI

t,y,z,aa

See footnotes on ALL-3A

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

See Cytogenetic Risk Groups for B-ALL (ALL-A).

High WBC count (≥30 x 10

/L for B lineage or ≥100 x 10

/L for T lineage) is considered a high-risk factor based on some studies in ALL. Data demonstrating the effect

of WBC counts on prognosis are less firmly established for adults than for the pediatric population and likely superseded by MRD quantification after treatment.

The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age is not a firm reference point because some of the recommended regimens

have not been comprehensively tested across all ages.

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 NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology.

It is reasonable to approach the initial treatment of blast phase CML with similar strategies to Ph+ ALL, with a goal of proceeding to HCT.

All ALL treatment regimens include CNS prophylaxis. This may be particularly important when using agents without known CNS penetrance including blinatumomab

and certain TKIs. See Evaluation and Treatment of Extramedullary Involvement (ALL-B).

See Principles of Supportive Care (ALL-C).

See Principles of Systemic Therapy (ALL-D).

See Minimal/Measurable Residual Disease Assessment (ALL-F).

Optimal timing of HCT is not clear. For fit patients, additional therapy is recommended to eliminate MRD prior to transplant. Proceeding to allogeneic HCT with MRD is

not optimal.

Data suggest that for younger patients (aged ≤21 y), particularly for those who achieve MRD negativity, allogeneic HCT may not offer an advantage over

chemotherapy + TKI. Schultz KR, et al. J Clin Oncol 2009;27:5175-5181; Schultz KR, et al. Leukemia 2014;28:1467-1471.

Many variables determine eligibility for allogeneic HCT including donor availability, depth of remission, comorbidities, and social support.

See Discussion for use of different TKIs in this setting.

The recommended duration of TKI after HCT is at least one year. The recommended duration of TKI during maintenance chemotherapy is at least until completion of

maintenance chemotherapy. The optimal duration of TKI is unknown in both settings.

Consider periodic MRD monitoring (no more than every 3 months) for patients with complete molecular remission (undetectable levels). Increased frequency may be

indicated for detectable levels.

For additional considerations in the management of older adult patients with ALL, see the NCCN Guidelines for Older Adult Oncology.

Consider dose modifications appropriate for patient age and performance status. See Principles of Systemic Therapy - Treatment of Older Adults (≥65 years) or Adults

with Substantial Comorbidities (ALL-D 9 of 10).

The prognostic significance of MRD positivity may be regimen-, ALL subtype-, and/or ALL risk-dependent. MRD timepoints and levels prompting allogeneic HCT

should be guided by the specific treatment protocol being used. In general, MRD positivity at the end of induction predicts high relapse rates and should prompt

evaluation for allogeneic HCT. Therapy aimed at eliminating MRD prior to allogeneic HCT is preferred when possible (See Discussion).

Consider using an alternative and more broadly acting TKI. See Principles of Systemic Therapy - Regimens for Ph-Positive B-ALL (ALL-D 3 of 10).

TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Dasatinib and imatinib are the preferred TKIs for induction therapy;

ponatinib is also preferred for the hyper-CVAD regimen. Not all TKIs have been directly studied within the context of each specific regimen and the panel notes that

there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance,

BCR-ABL1

mutations, and disease-related

features. For contraindicated mutations, see ALL-D 3 of 10.

See Supportive Care: Toxicity Management (ALL-C 2 of 4).

Although long-term remission after blinatumomab treatment is possible, allogeneic HCT should be considered as consolidative therapy.

ALL-3A

FOOTNOTES

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Table of Contents

Discussion

Continue multiagent

chemotherapy

Consider allogeneic HCT

v,x

(especially if high-risk features)

h,i

ALL-4

RISK

STRATIFICATION

h,i

TREATMENT INDUCTION

r,s

CONSOLIDATION THERAPY

r,s

See

Surveillance

(ALL-6)

Ph- ALL

(AYA)

n,o,p

Clinical trial

Pediatric-inspired

regimens

(preferred)

Multiagent

chemotherapy

Less than CR

Monitoring

for MRD

See MRD

Assessment

(ALL-F)

Allogeneic HCT

(especially if high-risk features)

h,i

Consider continuing

multiagent

chemotherapy

Maintenance

therapy

See Relapsed/Refractory

Disease (ALL-7)

Response

Assessment

(ALL-E)

MRD-

MRD

unavailable

MRD+

Blinatumomab (B-ALL)

Consider allogeneic HCT

v,x

Maintenance

therapy

Allogeneic

HCT

See footnotes on ALL-4A

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

See Cytogenetic Risk Groups for B-ALL (ALL-A).

High WBC count (≥30 x 10

/L for B lineage or ≥100 x 10

/L for T lineage) is considered a high-risk factor based on some studies in ALL. Data demonstrating the effect

of WBC counts on prognosis are less firmly established for adults than for the pediatric population and likely superseded by MRD quantification after treatment.

The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age is not a firm reference point because some of the recommended regimens

have not been comprehensively tested across all ages.

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 NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology.

All ALL treatment regimens include CNS prophylaxis. See Evaluation and Treatment of Extramedullary Involvemnt (ALL-B).

See Principles of Supportive Care (ALL-C).

See Principles of Systemic Therapy (ALL-D).

See Minimal/Measurable Residual Disease Assessment (ALL-F).

Optimal timing of HCT is not clear. For fit patients, additional therapy is recommended to eliminate MRD prior to transplant. Proceeding to allogeneic HCT with MRD is

not optimal.

Many variables determine eligibility for allogeneic HCT including donor availability, depth of remission, comorbidities, and social support.

The prognostic significance of MRD positivity may be regimen-, ALL subtype-, and/or ALL risk-dependent. MRD timepoints and levels prompting allogeneic HCT

should be guided by the specific treatment protocol being used. In general, MRD positivity at the end of induction predicts high relapse rates and should prompt

evaluation for allogeneic HCT. Therapy aimed at eliminating MRD prior to allogeneic HCT is preferred when possible (See Discussion).

See Supportive Care: Toxicity Management (ALL-C 2 of 4).

Although long-term remission after blinatumomab treatment is possible, allogeneic HCT should be considered as consolidative therapy.

Consider retesting for MRD at first available opportunity.

FOOTNOTES

ALL-4A

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-5

See Cytogenetic Risk Groups for B-ALL (ALL-A).

High WBC count (≥30 x 109/L for B lineage or ≥100 x 109/L for T lineage) is

considered a high-risk factor based on some studies in ALL. Data demonstrating

the effect of WBC counts on prognosis are less firmly established for adults than

for the pediatric population and likely superseded by MRD quantification after

treatment.

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.

All ALL treatment regimens include CNS prophylaxis. See Evaluation and

Treatment of Extramedullary Involvemnt (ALL-B).

See Principles of Supportive Care (ALL-C).

See Principles of Systemic Therapy (ALL-D).

See Minimal/Measurable Residual Disease Assessment (ALL-F).

Optimal timing of HCT is not clear. For fit patients, additional therapy is

recommended to eliminate MRD prior to transplant. Proceeding to allogeneic HCT

with MRD is not optimal.

Many variables determine eligibility for allogeneic HCT including donor availabiltiy,

depth of remission, comorbidities, and social support.

For additional considerations in the management of older adult patients with

ALL, see the NCCN Guidelines for Older Adult Oncology.

Consider dose modifications appropriate for patient age and performance status.

See Principles of Systemic Therapy - Treatment of Older Adults (≥65 years) or

Adults with Substantial Comorbidities (ALL-D 9 of 10).

The prognostic significance of MRD positivity may be regimen-, ALL subtype-,

and/or ALL risk-dependent. MRD timepoints and levels prompting allogeneic

HCT should be guided by the specific treatment protocol being used. In general,

MRD positivity at the end of induction predicts high relapse rates and should

prompt evaluation for allogeneic HCT. Therapy aimed at eliminating MRD prior

to allogeneic HCT is preferred when possible (See Discussion).

See Supportive Care: Toxicity Management (ALL-C 2 of 4).

Although long-term remission after blinatumomab treatment is possible,

allogeneic HCT should be considered as consolidative therapy.

Consider retesting for MRD at first available opportunity.

RISK

STRATIFICATION

h,i

TREATMENT INDUCTION

r,s

CONSOLIDATION THERAPY

r,s

Ph- ALL

(Adult)

Patients

<65 years of

age

without

substantial

comorbidities

Patients

≥65 years

of age

o,bb

or with

substantial

comorbidities

Clinical trial

Multiagent

chemotherapy

Clinical trial

Multiagent

chemotherapy

t,cc

Palliative

corticosteroid

Continue multiagent

chemotherapy

Consider allogeneic HCT

v,x

(especially if high-risk features)

h,i

See

Surveillance

(ALL-6)

Less than CR

Monitoring

for MRD

See MRD

Assessment

(ALL-F)

Allogeneic HCT

(especially if high-risk features)

h,i

Consider continuing

multiagent chemotherapy

Maintenance

therapy

See Relapsed/Refractory

Disease (ALL-7)

MRD-

MRD+

Blinatumomab (B-ALL)

Consider allogeneic HCT

v,x

Maintenance

therapy

Allogeneic

HCT

Response

Assessment

(ALL-E)

MRD

unavailable

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Surveillance recommendations apply after completion of chemotherapy, including maintenance.

While there is insufficient evidence to guide MRD monitoring for Ph-negative patients following completion of maintenance therapy, the approval of blinatumomab, and

potentially future therapies for the MRD-positive relapse, may warrant testing in this regard. Alternatively, for patients showing evidence of symptomatic relapse, the

diagnostic workup should be repeated as per ALL-1.

SURVEILLANCE

• Year 1 (every 1–2 months):

Physical exam

CBC with dierential

LFTs until normal

• Year 2 (every 3–6 months):

Physical exam

CBC with dierential

• Year 3+ (every 6–12 months or as indicated):

Physical exam

CBC with dierential

Other General Measures

• Bone marrow aspirate can be considered as clinically indicated at a frequency of

up to 3–6 months for at least 5 years

If bone marrow aspirate is done: Flow cytometry with additional studies that

may include comprehensive cytogenetics, FISH, molecular testing, and MRD

assessment

• Periodic BCR-ABL1 transcript-specic quantication (Ph+ ALL)

• Refer to Survivorship recommendations in the NCCN Guidelines for Survivorship

• Refer to the ALL Long-term Follow-up Guidelines from the Children’s Oncology

Group (COG): http://www.survivorshipguidelines.org/

See Relapsed/Refractory

Disease (ALL-7)

ALL-6

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-7

RELAPSED/REFRACTORY DISEASE TREATMENT

Relapsed/

refractory

ll,mm

Ph+

B-ALL

(AYA

adult)

Ph-

B-ALL

(AYA

adult)

Clinical trial

TKI

± chemotherapy

or TKI

± corticosteroid

Blinatumomab

± TKI

Inotuzumab ozogamicin

± bosutinib (TKI intolerant/

refractory, B-ALL)

Tisagenlecleucel

(patients <26 y and with refractory

B-ALL disease or ≥2 relapses and failure of 2 TKIs)

ABL1 kinase

domain

mutation

testing

Clinical trial

Blinatumomab

(B-ALL) (category 1)

Inotuzumab ozogamicin

(B-ALL) (category 1)

Tisagenlecleucel

(patients <26 y and with refractory

B-ALL disease or ≥2 relapses)

Chemotherapy

Consider

HCT

pp,qq

Consider

HCT

pp,qq

Molecular

characterization

and MRD

assessment, if not

previously done

(see ALL-1)

T-ALL

Consider

HCT

pp,qq

See footnotes on ALL-7A

Clinical trial

See relapsed/refractory

regimens on ALL-D 5 of 10

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age is not a firm reference point because some of the recommended regimens

have not been comprehensively tested across all ages.

See Supportive Care: Toxicity Management (ALL-C 2 of 4).

Isolated extramedullary relapse (both CNS and testicular) requires systemic therapy to prevent relapse in marrow.

See NCCN Guidelines for Palliative Care.

See Treatment Options Based on BCR-ABL1 Mutation Profile (ALL-D 3 of 10).

See Principles of Systemic Therapy (ALL-D 3 of 10, ALL-D 4 of 10, and ALL-D 5 of 10).

If second remission is achieved prior to transplant and patient has not had a prior HCT, consolidative HCT is recommended.

For patients with relapsed disease after allogeneic HCT, a second allogeneic HCT and/or donor lymphocyte infusion (DLI) can be considered.

The role of allogeneic HCT following tisagenlecleucel is unclear. Persistence of tisagenlecleucel in peripheral blood and persistent B-cell aplasia has been associated

with durable clinical responses without subsequent HCT. In the global registration trial, relapse-free survival was 59% at 12 months, with only 9% of patients

proceeding to HCT.

For patients in late relapse (>3 years from initial diagnosis), consider treatment with the same induction regimen (See ALL-D 2 of 10).

FOOTNOTES

ALL-7A

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

RISK GROUPS CYTOGENETICS

Good risk

• Hyperdiploidy (51–65 chromosomes)

Cases with trisomy of chromosomes 4, 10, and 17 appear to have the

most favorable outcome

• t(12;21)(p13;q22): ETV6-RUNX1

Poor risk

• Hypodiploidy

b,c

(<44 chromosomes)

• KMT2A rearranged (t[4;11] or others)

• t(v;14q32)/IgH

• t(9;22)(q34;q11.2): BCR-ABL1 (dened as high risk in the pre-TKI era)

• Complex karyotype (5 or more chromosomal abnormalities)

• BCR-ABL1-like (Ph-like) ALL

JAK-STAT (

CRLF2r,

EPORr

JAK1/2/3r

TYK2r

, mutations of

SH2B3

IL7R

JAK1/2/3

)

ABL class (rearrangements of

ABL1

ABL2

PDGFRA

PDGFRB

FGFR

)

Other (

NTRKr

FLT3r

LYNr

PTL2Br

)

• Intrachromosomal amplication of chromosome 21 (iAMP21)

• t(17;19):

TCF3-HLF

fusion

• Alterations of

IKZF1

e,f

ALL-A

CYTOGENETIC RISK GROUPS FOR B-ALL

The translocation t(12;21)(p13;q22) is typically cryptic by karyotyping and requires FISH or PCR to identify.

There are other results that are not less than 44 chromosomes that may be equivalent to hypodiploidy and have the same implications. It is important to distinguish

true hypodiploidy from masked hypodiploidy, which results from the doubling of hypodiploid clones. Carroll AJ, Shago M, Mikhail FM, et al. Masked hypodiploidy:

Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group. Cancer Genet 2019;238:62-68.

Alternatively defined as DNA index less than protocol-defined threshold or other clear evidence of hypodiploid clone. Hypodiploid ALL is also often associated with

TP53

loss of function mutations and Li-Fraumeni syndrome.

Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood 2017;129:572-581; Roberts KG, Li Y, Payne-Turner D,

et al. Targetable kinase-activation lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014;371:1005-1015.

Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-480; Stanulla M, Dagdan E, Zaliova

M, et al. IKZF1plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin

Oncol 2018;36:1240-1249.

Emerging evidence suggests DUX4r ALL is favorable. Additionally in cases of DUX4r, IKZF1 alterations do not confer poor prognosis.

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Acute Lymphoblastic Leukemia

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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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-B

Lazarus HM, Richards SM, Chopra R, et al. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL

trial MRC UKALL XII/ECOG E2993. Blood 2006;108:465-472.

EVALUATION AND TREATMENT OF EXTRAMEDULLARY INVOLVEMENT

• The aim of CNS prophylaxis and/or treatment is to clear leukemic cells within sites that cannot be readily accessed by systemic

chemotherapy due to the blood-brain barrier, with the overall goal of preventing CNS disease or relapse.

• Factors associated with increased risks for CNS leukemia in adults include mature B-cell immunophenotype, T-cell immunophenotype, high

presenting white blood cell (WBC) counts, and elevated serum LDH levels.

• CNS involvement should be evaluated (by LP) at the appropriate timing:

Timing of LP should be consistent with the chosen treatment regimen.

Pediatric-inspired regimens typically include LP at the time of diagnostic workup.

The panel recommends that IT therapy be administered with initial LP.

• Classication of CNS status:

CNS-1: No lymphoblasts in cerebrospinal uid (CSF) regardless of WBC count.

CNS-2: WBC <5/mcL in CSF with presence of lymphoblasts.

CNS-3: WBC ≥5/mcL in CSF with presence of lymphoblasts.

If the patient has leukemic cells in the peripheral blood and the LP is traumatic and WBC ≥5/mcL in CSF with blasts, then compare the

CSF WBC/red blood cell (RBC) ratio to the blood WBC/RBC ratio. If the CSF ratio is at least two-fold greater than the blood ratio, then the

classication is CNS-3; if not, then it is CNS-2.

• All patients with ALL should receive CNS prophylaxis. Although the presence of CNS involvement at the time of diagnosis is uncommon

(about 3%–7%), a substantial proportion of patients (>50%) will eventually develop CNS leukemia in the absence of CNS-directed therapy.

• CNS-directed therapy may include cranial irradiation, IT chemotherapy (eg, methotrexate, cytarabine, corticosteroid), and/or systemic

chemotherapy (eg, high-dose methotrexate, intermediate or high-dose cytarabine, pegaspargase). Generally, IT therapy should start during

the induction phase.

• CNS leukemia (CNS-3 and/or cranial nerve involvement) at diagnosis, or persisting after induction, may warrant treatment with cranial

irradiation of 18 Gy in 1.8 to 2.0 Gy/fraction. The recommended dose of radiation, where given, is highly dependent on the intensity of

systemic chemotherapy; thus, it is critical to adhere to a given treatment protocol in its entirety. The entire brain and posterior half of the

globe should be included. The inferior border should include C2.

• Note that areas of the brain targeted by the radiation eld in the management of ALL are dierent from areas targeted for brain metastases of

solid tumors.

• With the incorporation of adequate systemic chemotherapy (eg, high-dose methotrexate, intermediate or high-dose cytarabine) and IT

chemotherapy regimens (eg, methotrexate alone or with cytarabine and a corticosteroid, which constitutes the triple IT regimen), it may be

possible to avoid the use of upfront prophylactic cranial irradiation except in cases of overt CNS leukemia at diagnosis, and to reserve the

use of irradiation for relapsed/refractory therapy settings.

• Adequate systemic therapy should be given in the management of isolated CNS relapse.

• Patients with clinical evidence of testicular disease at diagnosis that is not fully resolved by the end of the induction therapy should

be considered for radiation to the testes in the scrotal sac, which is typically done concurrently with the rst cycle of maintenance

chemotherapy. Testicular total dose should be 24 Gy in 2.0 Gy/fraction.

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Acute Lymphoblastic Leukemia

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

ALL-C

1 OF 4

SUPPORTIVE CARE

Best Supportive Care

• Infection control (See NCCN Guidelines for Prevention and

Treatment of Cancer-Related Infections)

For infection risk, monitoring, and prophylaxis recommendations

for immune-targeted therapies, see INF-A in the NCCN Guidelines

for Prevention and Treatment of Cancer-Related Infections

• Acute TLS (See Tumor Lysis Syndrome on NHODG-B in the NCCN

Guidelines for B-Cell Lymphomas)

• Toxicity Management for Inotuzumab ozogamicin, Blinatumomab,

and Tisagenlecleucel (ALL-C 2 of 4)

• Pegaspargase Toxicity Management (ALL-C 3 of 4 and ALL-C 4 of 4)

• Methotrexate and Glucarpidase

Trimethoprim/Sulfamethoxazole may be held when high-dose

methotrexate is administered and re-started when methotrexate

clearance is achieved per protocol or institutional guidelines.

Consider use of glucarpidase in patients with signicant renal

dysfunction and toxic plasma methotrexate concentrations

with delayed methotrexate clearance (plasma methotrexate

concentrations >2 standard deviations of the mean methotrexate

excretion curve specic for the dose of methotrexate

administered). Leucovorin remains a component in the treatment

of methotrexate toxicity and should be continued for at least 2

days following glucarpidase administration. However, be aware

that leucovorin is a substrate for glucarpidase, and therefore

should not be administered within two hours prior to or following

glucarpidase.

• Consider debrotide for patients who develop veno-occlusive

disease (VOD) related to inotuzumab ozogamicin toxicity.

• Steroid management

Acute side eects

◊ Steroid-induced diabetes mellitus

– Tight glucose control using insulin to decrease infection

complications

◊ Steroid-induced psychosis and mood alteration

– Consider anti-psychotics. If no response, consider dose

reduction.

– Use of a histamine-2 antagonist or proton pump inhibitor (PPI)

should be considered during steroid therapy.

– There may be important drug interactions between PPIs and

methotrexate that need to be considered prior to initiation of

methotrexate-based therapy.

– There are signicant interactions between PPIs and TKIs

regarding the bioavailability of certain BCR-ABL1 TKIs with

gastric acid suppression that should be considered.

Long-term side eects of corticosteroids

◊ Osteonecrosis/avascular necrosis (also see Discussion)

– Obtain vitamin D and calcium status and replete as needed.

– Consider radiographic evaluation with plain lms or MRI or

bone density study.

– Consider withholding steroid in patients with severe avascular

necrosis.

• Transfusions

Products should be leukoreduced/irradiated.

• Use of granulocyte colony-stimulating factor (G-CSF)

Recommended for myelosuppressive blocks of therapy or as

directed by treatment protocol

• Hyperleukocytosis

Although uncommon in patients with ALL, symptomatic

hyperleukocytosis may require emergent treatment (See

Symptomatic Leukocytosis in the NCCN Guidelines for Acute

Myeloid Leukemia).

• Antiemetics (See NCCN Guidelines for Antiemesis)

Given as needed prior to chemotherapy and post chemotherapy

Routine use of corticosteroids as antiemetics are avoided

• Gastroenterology

Consider starting a bowel regimen to avoid constipation if

receiving vincristine.

• Nutritional support

Consider enteral or parenteral support for >10% weight loss.

• Palliative treatment for pain (See NCCN Guidelines for Adult Cancer

Pain)

Continued

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SUPPORTIVE CARE

Toxicity Management for Inotuzumab, Blinatumomab, and Tisagenlecleucel

ALL-C

2 OF 4

Continued

Inotuzumab Ozogamicin:

• Cytoreduction should be considered for those with WBC >10,000 cells per microliter. On clinical trial, hydroxyurea or a combination of

steroids and vincristine was used.

• Myelosuppression is common, and prophylactic antimicrobial strategies in accordance with institutional practice should be employed.

• Liver enzymes, and particularly bilirubin, should be closely monitored, as sinusoidal obstruction syndrome (SOS) (or VOD) may occur,

particularly among patients at higher risk (including those who are status-post allogeneic HCT, those whose treatment extends beyond

two cycles, and/or those who previously received or will receive double alkylator conditioning prior to allogeneic HCT. For those patients

receiving inotuzumab as a bridge to allogeneic transplant, double alkylator conditioning is strongly discouraged. Ursodiol may be

considered for VOD prophylaxis.

Blinatumomab:

• Cytoreduction should be considered for those with WBC >15,000 cells per microliter, as high tumor burden may increase the risks of toxicity.

On clinical trial, steroids were most commonly used.

• Patients should be monitored for cytokine release syndrome (CRS), a systemic inammatory condition characterized by fever or

hypothermia, that may progress to hypotension, hypoxia, and/or end organ damage. Infusion should be held with consideration for steroids

and/or vasopressors for those with severe symptoms in accordance with manufacturer guidelines and prescriber information. Consider

tocilizumab for patients with severe CRS.

• Because concurrent severe infection may mimic CRS, an evaluation for underlying infection and consideration of empiric antimicrobial

therapy in accordance with institutional practice should be performed.

• Patients should be monitored for neurologic toxicity, which may include confusion, word-nding diculty, somnolence, ataxia, tremor,

seizure, or syncope. Infusion should be held with consideration of steroids for those with severe symptoms in accordance with

manufacturer guidelines and prescribing information, and re-started (once symptoms have suciently improved) with dosing adjustments

as per manufacturer guidelines and prescribing information.

Tisagenlecleucel:

• Severe CRS and/or neurologic toxicity may accompany therapy, and should be managed in accordance with the manufacturer Risk

Evaluation and Mitigation Strategies (REMS) program, to include tocilizumab (preferred for CRS) and steroids (preferred for tocilizumab-

refractory CRS and/or neurologic toxicity).

• Prophylaxis with anti-seizure medication may be considered during the rst month after tisagenlecleucel infusion.

• Severe neutropenia, T-cell depletion, and B-cell aplasia can occur, for which growth factor, prophylactic antimicrobial therapy, and

intravenous immunoglobulin administration should be considered, in accordance with institutional practice.

• See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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ALL-C

3 OF 4

Continued

SUPPORTIVE CARE

Asparaginase Toxicity Management

Bleyer A, Asselin BL, Koontz SE, Hunger S. Clinical application of asparaginase activity levels following treatment with pegaspargase. Pediatr Blood Cancer

2015;62:1102-1105.

• Asparaginase should only be used in specialized centers and patients should be closely monitored in the period during and after infusion for allergic

response.

• There are three formulations of asparaginase in clinical use: 1) pegaspargase (PEG), 2) calaspargase pegol-mknl (Cal-PEG) (in patients ≤21 years), and

3) asparaginase Erwinia chrysanthemi (Erwinia). PEG is a common component of therapy for children, adolescents, and young adults with ALL. The

preferred route for administration for both PEG and Cal-PEG is intravenous (IV). The toxicity prole of these asparaginase products presents signicant

challenges in clinical management. The following guidelines are intended to help providers address these challenges.

• The panel recommends that the dose of PEG or Cal-PEG should be capped at 1 vial (3,750 IU).

• For more detailed information, refer to Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated

toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011:52:2237-2253. All toxicity grades refer to CTCAE

v4.03. National Cancer Institute; National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 2010. Available at:

https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.

Hypersensitivity, Allergy, and Anaphylaxis

• There is a signicant incidence of hypersensitivity reactions with asparaginase products in some regimens. Of particular concern are Grade 2 or higher

systemic allergic reactions, urticaria, or anaphylaxis, because these episodes can be (but are not necessarily) associated with neutralizing antibodies and

lack of ecacy.

• Erwinia is commonly used as a second-line agent in patients who have developed a systemic allergic reaction or anaphylaxis due to PEG hypersensitivity.

• Anaphylaxis or other allergic reactions of Grade 3–4 severity (CTCAE 4.0) merit permanent discontinuation of the type of asparaginase that caused the

reaction.

• For Grade 1 reactions and Grade 2 reactions (rash, ushing, urticaria, and drug fever ≥38°C) without bronchospasm, hypotension, edema, or need

for parenteral intervention, the asparaginase that caused the reaction may be continued, with consideration for anti-allergy premedication (such as

hydrocortisone, famotidine or ranitidine, diphenhydramine, and acetaminophen).

• Measures that can be considered for preventing or limiting severity of infusion reactions or hypersensitivity reactions include slowing the infusion to ≥2

hours, infusing normal saline concurrently, and use of premedications provided above.

• If anti-allergy premedication is used prior to PEG or Erwinia administration, consideration should be given to therapeutic drug monitoring (TDM) using

commercially available asparaginase activity assays, since premedication may “mask” the systemic allergic reactions that can indicate the development of

neutralizing antibodies.

TDM for asparaginase therapy using the serum asparaginase activity (SAA) is available as a CLIA-certied test with a turnaround time of less than one

week, allowing real-time decision-making and therapeutic adjustments. Generally accepted SAA assay targets include a minimum trough of ≥0.1 IU/mL.

However, data indicate that when SAA levels fall below 0.4 IU/mL, asparagine is no longer completely depleted, and begins to rebound, suggesting an

optimal trough of ≥0.4 IU/mL.

Routine premedication has generally been avoided in the past for fear of “masking” hypersensitivity reactions. However, given the diculty in

distinguishing hypersensitivity and non-allergic infusion reactions and the availability of TDM, universal premedication and TDM can be considered,

which can reduce the incidence and severity of adverse events and the need for substitution of pegaspargase with Erwinia.

NCCN Guidelines Version 1.2021

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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ALL-C

4 OF 4

SUPPORTIVE CARE

Asparaginase Toxicity Managment (continued)

Pancreatitis

• Permanently discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the case of Grade 2 pancreatitis (enzyme elevation or

radiologic ndings only), asparaginase should be held until these ndings normalize and then resume.

Non-CNS Hemorrhage

• For Grade 2 or greater hemorrhage, hold asparaginase until Grade 1, then resume. Consider coagulation factor replacement. Do not hold for

asymptomatic abnormal laboratory ndings.

Non-CNS Thromboembolism

• For Grade 2 or greater thromboembolic event, hold asparaginase until resolved and treat with appropriate antithrombotic therapy. Upon

resolution of symptoms and antithrombotic therapy stable or completed, consider resuming asparaginase.

• Consider checking ATIII levels if administering heparin.

Intracranial Hemorrhage

• Discontinue asparaginase. Consider coagulation factor replacement. For Grade 3 or less, if symptoms/signs fully resolve, consider resuming

asparaginase at lower doses and/or longer intervals between doses. For Grade 4, permanently discontinue asparaginase.

• Magnetic resonance angiography (MRA)/magnetic resonance venography (MRV) to rule out bleeding associated with sinus venous

thrombosis.

Cerebral Thrombosis, Ischemia, or Stroke

• Discontinue asparaginase. Consider antithrombotic therapy. For Grade 3 or less, if symptoms/signs fully resolve, consider resuming

asparaginase at lower doses and/or longer intervals between doses. For Grade 4, permanently discontinue asparaginase.

Hyperglycemia

• Treat hyperglycemia with insulin as indicated. For Grade 3 or higher, hold asparaginase and steroids until blood glucose has been regulated

with insulin, then resume.

Hypertriglyceridemia

• Treat hypertriglyceridemia as indicated. For Grade 4, hold asparaginase until normalized, then resume.

Hepatotoxicity (elevation in bilirubin, AST, ALT)

• For direct bilirubin ≤3.0 mg/dL, continue asparaginase. For direct bilirubin 3.1–5.0 mg/dL, hold asparaginase until <2.0 mg/dL, then resume.

For direct bilirubin >5.0, either discontinue asparaginase or hold asparaginase until <2.0 mg/dL, then resume with consideration for dose

reduction and close monitoring.

• For Grade 3 AST or ALT elevation, hold until Grade 1, then resume. For Grade 4 AST or ALT elevation, hold until Grade 1. If resolution to

Grade 1 takes 1 week or less, then resume. Otherwise, either discontinue or resume with very close monitoring.

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-D

1 OF 10

PRINCIPLES OF SYSTEMIC THERAPY

Induction Regimens for Ph-Negative ALL

References

REGIMENS FOR Ph-POSITIVE B-ALL

b,c,d,e

Protocols for AYA

Patients:

Other Recommended Regimens

• EsPhALL regimen: TKI

+ backbone of the Berlin-Frankfurt-Münster regimen (cyclophosphamide, vincristine, daunorubicin,

dexamethasone, cytarabine, methotrexate, pegaspargase, and prednisone)

1-3

• TKI

+ hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating with high-dose

methotrexate, and cytarabine

4-8

• TKI

+ multiagent chemotherapy (daunorubicin, vincristine, prednisone, and cyclophosphamide)

9-13

• TKI

g,14,15

+ corticosteroid

• TKI

+ vincristine + dexamethasone

• CALGB 10701 regimen: TKI

+ multiagent chemotherapy (dexamethasone, vincristine, daunorubicin, methotrexate, etoposide, and cytarabine)

• Blinatumomab ± TKI

h,18

Adult Patients (<65 y and without substantial comorbidities):

Other Recommended Regimens

• TKI

+ hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating with high-dose

methotrexate, and cytarabine

4–8

• TKI

+ multiagent chemotherapy (daunorubicin, vincristine, prednisone, and cyclophosphamide)

9-13

• TKI

g,14,15

+ corticosteroid

• TKI

+ vincristine + dexamethasone

16,19

• CALGB 10701 regimen: TKI

+ multiagent chemotherapy (dexamethasone, vincristine, daunorubicin, methotrexate, etoposide, and cytarabine)

• Blinatumomab ± TKI

h,18

For treatment of older adult patients ≥65 y with ALL or adult patients with substantial comorbidities, see ALL-D 9 of 10.

Maintenance Regimens:

• Add TKI

to maintenance regimen; optimal duration is unknown.

• Monthly vincristine/prednisone pulses (for 2–3 years). May include weekly methotrexate + daily 6-mercaptopurine (6-MP) as tolerated.

i,j

See footnotes on ALL-D1A

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Acute Lymphoblastic Leukemia

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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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

For infection risk, monitoring, and prophylaxis recommendations for immune targeted therapies, see INF-A in the NCCN Guidelines for Prevention and

Treatment of Cancer-Related Infections.

All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple

IT therapy with methotrexate, cytarabine, corticosteroid).

There are data to support the benefit of rituximab in addition to chemotherapy for CD20-positive patients (especially in patients <60 years).

An FDA-approved biosimilar is an appropriate substitute for rituximab.

The specific drugs listed are primarily used in induction. For post-induction components, see listed references.

The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age is not a firm reference point because some of the recommended regimens

have not been comprehensively tested across all ages.

TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Dasatinib and imatinib are the preferred TKIs for

induction therapy; ponatinib is also preferred for the hyper-CVAD regimen. Not all TKIs have been directly studied within the context of each specific

regimen and the panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI

intolerance and disease-related features. For contraindicated mutations, see ALL-D 3 of 10.

For consolidation.

For patients receiving 6-MP, consider testing for TPMT gene polymorphisms, particularly in patients who develop severe neutropenia after starting 6-MP.

Testing for both TPMT and NUDT15 variant status should be considered, especially for patients of East Asian origin. Relling MV, Schwab M, Whirl-

Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018

update. Clin Pharmacol Ther 2019;105:1095-1105.

Dose modifications for antimetabolites in maintenance should be consistent with the chosen treatment regimen. It may be necessary to reduce dose/

eliminate antimetabolite in the setting of myelosuppression and/or hepatotoxicity.

ALL-D

1 A

FOOTNOTES

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Acute Lymphoblastic Leukemia

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-D

2 OF 10

Induction Regimens for Ph-Positive ALL

References

REGIMENS FOR Ph-NEGATIVE ALL

b,c,d,e

AYA

Patients:

Preferred Regimens

• CALGB 10403 regimen: daunorubicin, vincristine, prednisone, and

pegaspargase.

20,l,m

• COG AALL0232 regimen: daunorubicin, vincristine, prednisone,

and pegaspargase

(patients aged ≤21 years).

21,m

• COG AALL0434 regimen with nelarabine (for T-ALL): daunorubicin,

vincristine, prednisone, pegaspargase;

and nelarabine.

22,m

• DFCI ALL regimen based on DFCI Protocol 00-01: doxorubicin,

vincristine, prednisone, high-dose methotrexate, and

pegaspargase.

23,l,m

Other Recommended Regimens

• GRAALL-2005 regimen: daunorubicin, vincristine, prednisone,

pegaspargase,

and cyclophosphamide (patients aged <60 years),

with rituximab for CD20-positive disease.

24,m

• PETHEMA ALL-96 regimen: daunorubicin, vincristine, prednisone,

pegaspargase,

and cyclophosphamide (patients aged <30

years).

25,m

• Hyper-CVAD: hyperfractionated cyclophosphamide, vincristine,

doxorubicin, and dexamethasone, alternating with high-dose

methotrexate and cytarabine; with rituximab for CD20-positive

disease.

• USC/MSKCC ALL regimen based on CCG-1882 regimen:

daunorubicin, vincristine, prednisone, and methotrexate with

augmented pegaspargase

(patients aged 18–60 years).

27,28,m

• Linker 4-drug regimen: daunorubicin, vincristine, pegaspargase,

and prednisone;

with rituximab for CD20-positive diseae.

Adult Patients (<65 y and without substantial comorbidities):

Other Recommended Regimens

• CALGB 8811 Larson regimen: daunorubicin, vincristine,

prednisone, pegaspargase,

and cyclophosphamide; for

patients aged ≥60 years, reduced doses for cyclophosphamide,

daunorubicin, and prednisone.

30,31

• GRAALL-2005 regimen: daunorubicin, vincristine, prednisone,

pegaspargase,

and cyclophosphamide (patients aged <60 years)

with rituximab for CD20-positive disease.

• Hyper-CVAD: hyperfractionated cyclophosphamide, vincristine,

doxorubicin, and dexamethasone, alternating with high-dose

methotrexate and cytarabine; with rituximab for CD20-positive

disease.

26,32

• USC/MSKCC ALL regimen based on CCG-1882 regimen:

daunorubicin, vincristine, prednisone, and methotrexate with

augmented pegaspargase

(patients aged <60 years).

27,28,m

• Linker 4-drug regimen: daunorubicin, vincristine, prednisone, and

pegaspargase;

with rituximab for CD20-positive disease (patients

aged <60 years).

29,33

• MRC UKALLXII/ECOG2993 regimen: daunorubicin, vincristine,

prednisone, and pegaspargase

(induction phase I); and

cyclophosphamide, cytarabine, and 6-MP

(induction phase II).

For treatment of older adult patients ≥65 y with ALL or adult patients

with substantial comorbidities, see ALL 9 of 10.

Maintenance Regimen:

• Weekly methotrexate + daily 6-MP

j,k

+ monthly vincristine/

prednisone pulses (duration based on regimen)

PRINCIPLES OF SYSTEMIC THERAPY

See footnotes on ALL-D2A

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Table of Contents

Discussion

For infection risk, monitoring, and prophylaxis recommendations for immune targeted therapies, see INF-A in the NCCN Guidelines for Prevention and

Treatment of Cancer-Related Infections.

All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple

IT therapy with methotrexate, cytarabine, corticosteroid).

There are data to support the benefit of rituximab in addition to chemotherapy for CD20-positive patients (especially in patients <60 years).

An FDA-approved biosimilar is an appropriate substitute for rituximab.

The specific drugs listed are primarily used in induction. For post-induction components, see listed references.

The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age is not a firm reference point because some of the recommended regimens

have not been comprehensively tested across all ages.

For patients receiving 6-MP, consider testing for TPMT gene polymorphisms, particularly in patients who develop severe neutropenia after starting 6-MP.

Testing for both TPMT and NUDT15 variant status should be considered, especially for patients of East Asian origin. Relling MV, Schwab M, Whirl-

Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018

update. Clin Pharmacol Ther 2019;105:1095-1105.

Dose modifications for antimetabolites in maintenance should be consistent with the chosen treatment regimen. It may be necessary to reduce dose/

eliminate antimetabolite in the setting of myelosuppression and/or hepatotoxicity.

Pegaspargase may be substituted with calaspargase pegol-mknl, an asparagine-specific enzyme, in patients ≤21 years for more sustained

asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.

Pediatric-inspired regimen.

FOOTNOTES

ALL-D

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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ALL-D

3 OF 10

For infection risk, monitoring, and prophylaxis recommendations for immune targeted therapies, see INF-A in the NCCN Guidelines for Prevention and Treatment of

Cancer-Related Infections.

All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with

methotrexate, cytarabine, corticosteroid).

The safety of relapsed/refractory regimens in older adults (≥65 years) has not been established. Please see ALL-D 9 of 10 for additional information.

Ponatinib has activity against T315I mutations and is effective in treating patients with resistant or progressive disease on multiple TKIs. However, it is associated with

a high frequency of serious vascular events (eg, strokes, heart attacks, tissue ischemia). The FDA indications are for the treatment of adult patients with T315I -positive,

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and for the treatment of adult patients with Ph+ ALL for whom no other TKI therapy is

indicated. For details, see http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203469s034lbl.pdf.

See Supportive Care: Toxicity Management (ALL-C 2 of 4).

Mutations contraindicated for imatinib are too numerous to include. There are compound mutations that can cause resistance to ponatinib, but those are uncommon

following treatment with bosutinib, dasatinib, or nilotinib.

Bosutinib has minimal activity against F317L mutation. Nilotinib may be preferred over bosutinib in patients with F317L mutation.

Ponatinib is a treatment option for patients with a T315I mutation and/or for patients for whom no other TKI is indicated.

References

REGIMENS FOR RELAPSED OR REFRACTORY Ph-POSITIVE B-ALL

b,l

Other Recommended Regimens

• TKI (dasatinib,

35,36

imatinib,

ponatinib,

nilotinib,

or bosutinib

)

The TKIs noted above may also be used in combination with any of the induction regimens noted on ALL-D 1 of 10 that were not

previously given.

• Blinatumomab ± TKI (for B-ALL)

18,41,n

• Inotuzumab ozogamicin ± bosutinib (for B-ALL) (TKI intolerant/refractory)

42,n

• Tisagenlecleucel (for B-ALL) (patients <26 y and with refractory disease or ≥2 relapses and failure of 2 TKIs)

43,n

• The regimens listed on ALL-D 4 of 10 for Ph-negative B-ALL may be considered for Ph-positive B-ALL refractory to TKIs.

TREATMENT OPTIONS BASED ON BCR-ABL1 MUTATION PROFILE

Therapy Contraindicated Mutations

Bosutinib T315I, V299L, G250E, or F317L

Dasatinib

T315I/A, F317L/V/I/C, or V299L

Nilotinib T315I, Y253H, E255K/V, or F359V/C/I or G250E

Ponatinib

None

Regimens for Relapsed/Refractory Ph-Negative B-ALL

PRINCIPLES OF SYSTEMIC THERAPY

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-D

4 OF 10

For infection risk, monitoring, and prophylaxis recommendations for immune targeted therapies, see INF-A in the NCCN Guidelines for Prevention and Treatment of

Cancer-Related Infections.

All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with

methotrexate, cytarabine, corticosteroid).

An FDA-approved biosimilar is an appropriate substitute for rituximab.

The safety of relapsed/refractory regimens in older adults (≥65 years) has not been established. Please see ALL-D 9 of 10 for additional information.

See Supportive Care: Toxicity Management (ALL-C 2 of 4).

For patients in late relapse (>3 years from initial diagnosis), consider treatment with the same induction regimen (See ALL-D 2 of 10).

References

REGIMENS FOR RELAPSED OR REFRACTORY Ph-NEGATIVE B-ALL

b,l,r

Preferred Regimens

• Blinatumomab (for B-ALL) (category 1)

44,n

• Inotuzumab ozogamicin (for B-ALL) (category 1)

42,n

• Tisagenlecleucel (for B-ALL) (patients <26 y and with refractory disease or ≥2 relapses)

43,n

Other Recommended Regimens

• Inotuzumab ozogamicin

+ mini-hyperCVD for B-ALL (cyclophosphamide, dexamethasone, vincristine, methotrexate, cytarabine)

• Augmented hyper-CVAD: hyperfractionated cyclophosphamide, intensied vincristine, doxorubicin, intensied dexamethasone, and

pegaspargase; alternating with high-dose methotrexate and cytarabine

• Vincristine sulfate liposome injection (VSLI)

47,48

• Clofarabine alone

49-52

or in combination (eg, clofarabine, cyclophosphamide, etoposide

50,53,54

)

• MOpAD regimen (for R/R Ph-negative ALL only): methotrexate, vincristine, pegaspargase, dexamethasone; with rituximab

for CD20-

positive disease

• Fludarabine-based regimens

FLAG-IDA: udarabine, cytarabine, granulocyte colony-stimulating factor, ± idarubicin

FLAM: udarabine, cytarabine, and mitoxantrone

• Cytarabine-containing regimens: eg, high-dose cytarabine, idarubicin, IT methotrexate

• Alkylator combination regimens: eg, etoposide, ifosfamide, mitoxantrone

Regimens for Relapsed/Refractory Ph-Positive B-ALL

PRINCIPLES OF SYSTEMIC THERAPY

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF SYSTEMIC THERAPY

ALL-D

5 OF 10

References

For infection risk, monitoring, and prophylaxis recommendations for immune targeted therapies, see INF-A in the NCCN Guidelines for Prevention and Treatment of

Cancer-Related Infections.

All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with

methotrexate, cytarabine, corticosteroid).

The safety of relapsed/refractory regimens in older adults (≥65 years) has not been established. Please see ALL-D 9 of 10 for additional information.

For patients in late relapse (>3 years from initial diagnosis), consider treatment with the same induction regimen (See ALL-D 2 of 10).

REGIMENS FOR RELAPSED OR REFRACTORY Ph-NEGATIVE T-ALL

b,l,r

Preferred Regimens

• Nelarabine

60-63

± etoposide and cyclophosphamide

64-66

Other Recommended Regimens

• Bortezomib

+ chemotherapy

• Daratumumab (Category 2B)

68-72

• HiDAC: high-dose cytarabine

• Mitoxantrone, etoposide, and cytarabine

• Venetoclax + chemotherapy (eg decitabine, hyper-CVAD, nelarabine, mini-hyper-CVD) (Category 2B)

74-77

• The regimens listed on ALL-D 4 of 10 for relapsed/refractory Ph-negative B-ALL may be appropriate/considered for R/R T-ALL.

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

ALL-D

6 OF 10

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.

Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and

adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL):

a randomised, open-label, intergroup study. Lancet Oncol 2012;13:936-945.

Slayton WB, Schultz KR, Kairalla JA, et al. Dasatinib plus intensive chemotherapy in children,

adolescents, and young adults with Philadelphia chromosome-positive acute lymphoblastic

leukemia: Results of Children's Oncology Group Trial AALL0622. J Clin Oncol 2018;36:2306-

2314.

Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-

CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute

lymphoblastic leukemia. Blood 2010;116:2070-2077.

Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute

lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004;103:4396-4407.

Thomas DA, Kantarjian HM, Cortes J, et al. Outcome after frontline therapy with the

hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated

Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) [abstract]. Blood

2008;112(Supple 11):Abstract 2931.

Thomas DA, O'Brien SM, Faderl S, et al. Long-term outcome after hyper-CVAD and imatinib (IM)

for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia

(Ph-ALL) [abstract]. J Clin Oncol 2010;28:Abstract 6506.

Jabbour EJ, Kantarjian H, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-

line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia:

a single-centre, phase 2 study. Lancet Oncol 2015;16(15):1547-1555.

Mizuta S, Matsuo K, Yagasaki F, et al. Pre-transplant imatinib-based therapy improves the

outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute

lymphoblastic leukemia. Leukemia 2011;25:41-47.

Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome

by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute

lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin

Oncol 2006;24:460-466.

Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multiagent chemotherapy for newly

diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood 2015;126:746-756.

Slayton W, Schultz KR, Kairalla JA, et al. Dasatinib plus intensive chemotherapy in children,

adolescents, and young adults with Philadelphia chromosome-positive acute lymphoblastic

leukemia: results of Children’s Oncology Group Trial AALL0622. J Clin Oncol 2018;36:2306-

2314.

Yoon JH, Yhim HY, Kwak JY, et al. Minimal residual disease-based effect and long-term

outcome of first-line dasatinib combined with chemotherapy for adult Philadelphia chromosome-

positive acute lymphoblastic leukemia. Ann Oncol 2016;27:1081-1088.

Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions

and prolonged survival in elderly Philadelphia chromosome-positive patients with acute

lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie

Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood 2007;109:3676-3678.

Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with

Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2011;118:6521-6528.

Chalandon Y, Thomas X, Hayette S, et al. Randomized study of reduced-intensity

chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.

Blood 2015;125:3711-3719.

Wieduwilt MJ, Yin J, Wetzler M, et al. A phase II dtudy of dasatinib and dexamethasone as

primary therapy followed by transplantation for adults with newly diagnosed Ph/BCR-ABL1-

positive acute lymphoblastic leukemia (Ph+ ALL): Final results of Alliance/CALGB Study 10701.

Blood 2018;132:309.

Foa R, Bassan R, Vitale A, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic

leukemia in adults. N Engl J Med 2020;383:1613-1623.

Rousselot P, Coude MM, Gokbuget N, et al. Dasatinib and low-intensity chemotherapy in elderly

patients with Philadelphia chromosome-positive ALL. Blood 2016;128:774-782.

Stock W, Luger SM, Advani AS, et al: Favorable outcomes for older adolescents and young

adults (AYA) with acute lymphoblastic leukemia (ALL): Early results of U.S. Intergroup Trial

C10403. 2014 ASH Annual Meeting. Abstract 796. Presented December 9, 2014.

Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual

disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood

2015;126:964-971.

Winter SS, Dunsmore KP, Devidas M, et al. Safe integration of nelarabine into intensive

chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children’s Oncology

Group Study AALL0434.

DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired

regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.

Leukemia 2015;29:526-534.

Maury S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute lymphoblastic

leukemia. N Engl J Med 2016;375:1044-1053.

Ribera JM, Oriol A, Sanz MA, et al. Comparison of the results of the treatment of adolescents

and young adults with standard-risk acute lymphoblastic leukemia with the Programa Espanol

de Tratamiento en Hematologia pediatric-based protocol ALL-96. J Clin Oncol 2008;26:1843-

1849.

Thomas DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and

rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor

B-lineage acute lymphoblastic leukemia. J Clin Oncol 2010;28:3880-3889.

Douer D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based integration of multiple doses

of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute

lymphoblastic leukemia. J Clin Oncol 2014;32:905-911

Geyer MB, Ritchie EK, Rao AV, et al. Pediatric-inspired chemotherapy incorporating

pegaspargase is safe and results in high rates of minimal residual disease negativity in

adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Haematologica 2020; Online ahead of print.

Linker C, Damon L, Ries C, Navarro W. Intensified and shortened cyclical chemotherapy for

adult acute lymphoblastic leukemia. J Clin Oncol 2002;20:2464-2471.

Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive

consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study

8811. Blood 1995;85:2025-2037.

Stock W, Johnson JL, Stone RM, et al. Dose intensification of daunorubicin and cytarabine

during treatment of adult acute lymphoblastic leukemia: results of Cancer and Leukemia Group

B Study 19802. Cancer 2013;119:90-98.

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Table of Contents

Discussion

ALL-D

7 OF 10

Kantarjian H, Thomas D, O'Brien S, et al. Long-term follow-up results of hyperfractionated

cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-

intensive regimen, in adult acute lymphocytic leukemia. Cancer 2004;101:2788-2801.

Wieduwilt MJ, Jones BA, Schiller GJ, et al. A phase II study of pegylated asparaginase,

cyclophosphamide, rituximab, and dasatinib added to the UCSF 8707 (Linker 4-drug) regimen

with liposomal cytarabine CNS prophylaxis for adults with newly diagnosed acute lymphoblastic

leukemia (ALL) or lymphoblastic lymphoma (LBL): University of California Hematologic

Malignancies Consortium Study (UCHMC) 1401. Blood 2018:132:4018.

Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic

leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/

ECOG E2993. Blood 2005;106:3760-3767.

Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily

in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a

phase 3 study. Am J Hematol 2010;85:164-170.

Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic

responses in adult patients with Philadelphia chromosome positive acute lymphoblastic

leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood

2007;110:2309-2315.

Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with

relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood

2002;100:1965-71.

Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia

chromosome-positive leukemias. N Engl J Med 2013;369:1783-1796.

Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia

chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.

Gambacorti-Passerini C, Kantarjian HM, Kim DW, et al. Long-term efficacy and safety of

bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and

other tyrosine kinase inhibitors. Am J Hematol 2015;90:755-768:

Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in

adult patients with relapsed/refractory Philadelphia Chromosome-positive B-Precursor acute

lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-

arm, multicenter study. J Clin Oncol 2017;35:1795-1802.

Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy

for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-753.

Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with

b-cell lymphoblastic leukemia. N Engl J Med 2018;378:439-448.

Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced

acute lymphoblastic leukemia. N Engl J Med 2017;376: 836-847.

Jabbour E, Ravandi F, Kebriaei P, et al. Salvage chemoimmunotherapy with inotuzumab

ozogamicin combined with mini-Hyper-CVD for patients with relapsed or refractory Philadelphia

chromosome-negative acute lymphoblastic leukemia: A phase 2 clinical trial. JAMA Oncol

2018;4:230-234.

Faderl S, Thomas DA, O'Brien S, et al. Augmented hyper-CVAD based on dose-intensified

vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage

therapy. Clin Lymphoma Myeloma Leuk 2011;11:54-59.

Deitcher OR, O'Brien S, Deitcher SR, et al. Single-agent vincristine sulfate liposomes injection

compared to historical single-agent therapy for adults with advanced, relapsed and/or

refractory Philadelphia chromosome negative acute lymphoblastic leukemia [abstract]. Blood

2011;118:Abstract 2592.

O'Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection

for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute

lymphoblastic leukemia. J Clin Oncol 2012;31:676-683.

Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with

refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006;24:1917-1923.

Alkhateeb HB, Damlaj M, Lin T, et al. Clofarabine based chemotherapy in adult relapsed/

refractory acute leukemia/lymphoma: a single institution. Blood 2015;126:4910.

51 Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine

in patients with refractory or relapsed acute leukemia. Blood 2003;102:2379-2386.

52 Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of

clofarabine in patients with solid and hematologic cancers. J Clin Oncol 2003;21:1167-1173.

Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide and etoposide for the

treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk Lymphoma

2012;53:1693-1698.

Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with

etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute

lymphoblastic leukemia. Blood 2011;118:6043-6049.

Kadia TM, Kantarjian HM, Thomas DA, et al. Phase II study of methotrexate, vincristine,

pegylated-asparaginase, and dexamethasone (MOpAD) in patients with relapsed/refractory

acute lymphoblastic leukemia. Am J Hematol 2015;90:120-124.

Specchia G, Pastore D, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed

adult acute lymphoblastic leukemia. Ann Hematol 2005;84:792-795.

Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M, et al. Fludarabine, cytarabine, and

mitoxantrone (FLAM) for the treatment of relapsed and refractory adult acute lymphoblastic

leukemia. A phase study by the Polish Adult Leukemia Group (PALG). Ann Hematol

2006;85:717-722.

Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of idarubicin combined with

cytarabine as induction therapy for adult patients with recurrent or refractory acute

lymphoblastic leukemia. Cancer 2002;95:581-587.

Schiller G, Lee M, Territo M, Gajewski J, Nimer S. Phase II study of etoposide, ifosfamide, and

mitoxantrone for the treatment of resistant adult acute lymphoblastic leukemia. Am J Hematol

1993;43:195-199.

DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with

relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma:

Cancer and Leukemia Group B study 19801. Blood 2007;109:5136-5142.

Zwaan CM, Kowalczyk J, Schmitt C, et al. Safety amd efficacy of nelarabine in children and

young adults with relapsed/refractory T-lineage acute lymphoblastic leukaemia or T-lineage

lymphoblastic lymphoma: results of phase 4 study. Br J Haematol 2017;179:284-293.

Gokbuget N, Basara N, Baumann H, et al. High single-drug activity of nelarabine in relapsed

T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell

transpantation. Blood 2011;118:3504-3511.

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Candoni A, Lazzarotto D, Ferrara F, et al. Nelarabine as salvage therapy and bridge to

allogenic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute

lymphoblastic leukemia/lymphoma. A CAMPUS ALL study. Am J Hematol 2020;95:1466-1472.

Luskin MR, Ganetsky A, Landsburg DJ, et al. Nelarabine, cyclosphosphamide and etoposide

for adults with relapsed T-cell acute lymphoblastic leukemai and lymphoma. BR J Haematol

2016;174:332-334.

Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with nelarabine,

etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic

leukaemia and lymphoma. Br J Haematol 2010;150:345-351.

Whitlock J, dalla Pozza L, Goldberg JM, et al. Nelarabine in combination with etoposide and

cyclophosphamide is active in first relapse of childhood T-acute lymphocytic leukemia (T-ALL)

and T-lymphoblastic lymphoma (T-LL). Blood 2014;124:795.

Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction chemotherapy in high-risk ALL in

first relapse: a report from the Children's Oncology Group. Br J Haematol 2019;186:274-285.

Ofran Y, Ringerstein-Harlev S, Slouzkey I, et al. Daratumumab for eradication of minimal

residual disease in high-risk advanced relapse of T-cell/CD19/CD22-negative acute

lymphoblastic leukemia. Leukemia 2020;34:293-295.

Ruhayel SD, Valvi S. Daratumumab in T-cell acute lymphoblastic leukemia: A case report and

review of the literature. Pediatr Blood Cancer 2020;e28829.

Cerrano M, Castella B, Lia G, et al. Immunomodulatory and clinical effects of daratumumab in

T-cell acute lymphoblastic leukemia. Br J Haematol 2020;191:e28-e32.

Mirgh S, Ahmed R, Agrawal N, et al. Will daratumumab be the next game changer in early

thymic precursor-acute lymphoblastic leukemia? Br J Haematol 2019;187:e33-e35.

Bonda A, Punatar S, Gokarn A, et al. Daratumumab at the frontiers of post-transplant refractory

T-acute lymphoblastic leukemia-a worthwhile strategy? Bone Marrow Transplant 2018;53:1487-

1489.

Liedtke M, Dunn T, Dinner S, et al. Salvage therapy with mitoxantrone, etoposide and

cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leuk Res 2014;38:1441-

1445.

Richard-Carpentier G, Jabbour E, Short NJ, et al. Clinical experience with venetoclax

combined with chemotherapy for relapsed or refractory T-Cell acute lymphoblastic leukemia.

Clin Lymphoma Myeloma Leuk 2020;20:212-218.

Parovichnikova E, Gavrilina O, Troitskaya V, et al. Veneotoclax plus decitabine in the

treatment of MRD-persistent and relapsed/refractory T-cell acute lymphoblastic leukemia.

European Hematology Association Congress 2020;EP427.

Rubnitz J, Alexander TB, Laetsch TW, et al. Venetoclax and navitoclax in pediatric patients

with acute lymphoblastic leukemia and lymphoblastic lymphoma. ASH Annual Meeting

Abstracts 2020;Abstract #466.

Jain N, Stevenson KE, Winer ES, et al. A multicenter phase I study combining venetoclax with

mini-hyper-CVD in older adults with untreated and relapsed/refractory acute lymphoblastic

leukemia. Blood 2019;134:3867.

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

ALL-D

8 OF 10

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

ALL-D

9 OF 10

INDUCTION REGIMENS for Ph-negative ALL

• Low intensity

Vincristine + prednisone

Prednisone, vincristine, methotrexate, and 6-mercaptopurine

(POMP)

• Moderate intensity

GMALL: idarubicin + dexamethasone + vincristine +

cyclophosphamide + cytarabine ± rituximab

PETHEMA-based regimen

◊ ALLOLD07 regimen: vincristine, dexamethasone, idarubicin,

cyclophosphamide, cytarabine, methotrexate, and

L-asparaginase

GRAALL: doxorubicin + vincristine + dexamethasone + cytarabine

+ cyclophosphamide

Modied DFCI 91-01 protocol: dexamethasone, doxorubicin,

vincristine, methotrexate, cytarabine, L-asparaginase, and IT

chemotherapy

Inotuzumab ozogamicin + mini-hyperCVD for B-ALL

(cyclophosphamide, dexamethasone, vincristine, methotrexate,

cytarabine)

• High intensity

Hyper-CVAD

with dose-reduced cytarabine to 1 g/m

CALGB 9111

(cyclophosphamide, daunorubicin, vincristine,

prednisone, and pegaspargase)

INDUCTION REGIMENS for Ph-positive B-ALL

• Low intensity

TKI

± corticosteroid

10-13,14

TKI

+ vincristine + dexamethasone

15-17

• Moderate intensity

EWALL: TKI

with multiagent chemotherapy (vincristine,

dexamethasone, methotrexate, cytarabine, asparaginase)

CALGB 10701: TKI

+ multiagent chemotherapy (dexamethasone,

vincristine, daunorubicin, methotrexate, etoposide, cytarabine)

• High intensity

20,21

TKI

+ HyperCVAD with dose-reduced cytarabine to 1 g/m

PRINCIPLES OF SYSTEMIC THERAPY

Treatment of Older Adults (≥65 years) or Adults with Substantial Comorbidities

References

• Older adults (dened as those aged 65 years and older) benet from therapy, in spite of higher treatment-related morbidity and mortality.

• Careful assessment of comorbid conditions, performance status, and ability to attend to activities of daily living (ADLs) and instrumental

ADLs (IADLs) is important when deciding treatment intensity.

For tools to aid optimal assessment and management of older adults with cancer, see the NCCN Guidelines for Older Adult Oncology.

• Dose reduction of pegylated asparaginase (1000 IU/m

), anthracycline (50% dose), and/or other myelosuppressive agents may be warranted.

• The categorization of regimens as low, moderate, or high intensity is based on two factors: 1) the presence or absence of myelosuppressive

cytotoxic agents; and 2) the relative dose intensity of the included agents.

• All regimens should include CNS prophylaxis, antimicrobial prophylaxis, and growth factor support.

• For appropriate t individuals achieving remission, consideration of autologous or reduced-intensity allogeneic SCT may be appropriate.

For infection risk, monitoring, and prophylaxis recommendations for immune

targeted therapies, see INF-A in the NCCN Guidelines for Prevention and

Treatment of Cancer-Related Infections.

TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib,

or ponatinib. Dasatinib and imatinib are the preferred TKIs for induction therapy;

ponatinib is also preferred for the hyper-CVAD regimen. Not all TKIs have been

directly studied within the context of each specific regimen and the panel notes

that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should

account for anticipated/prior TKI intolerance and disease-related features. For

contraindicated mutations, see ALL-D 3 of 10.

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

ALL-D

10 OF 10

Hardisty RM, McElwain TJ, and Darby CW. Vincristine and prednisone for the

induction of remissions in acute childhood leukaemia. Br Med J 1969;2:662-665.

Berry DH, Pullen J, George S, et al. Comparison of prednisolone, vincristine,

mehtotrexate, and 6-mercaptopurine vs. vincristine and prednisone induction

therapy in childhood acute leukemia. Cancer 1975;36:98-102.

Gokbuget N, Beck J, Bruggemann M et al. Moderate intensive chemotherapy

including CNS prophylaxis with liposomal cytarabine is feasible and effective in

older patients with Ph-negative acute lymphoblastic leukemia (ALL): results of a

prospective trial from the German multicenter study group for adult ALL (GMALL).

Blood 2012;120:1493.

Ribera JM, Garcia O, Oriol A et al. PETHEMA group: Feasibility and results

of subtype-oriented protocols in older adults and fit patients with acute

lymphoblastic leukemia: results of three prospective parallel trials from the

PETHEMA group. Leuk Res 2016;41:12-20.

Hunault-Berger M, Leguay T, Thomas X, et al. A randomized study of pegylated

liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients

with acute lymphoblastic leukemia: the GRAALL-SA1 study. Haematologica

2011;96(2):245-252.

Martell MP, Atenafu EG, Minden MD, et al. Treatment of elderly patients with

acute lymphoblastic leukaemia using a paediatric-based protocol. Br J Haematol

2013;163:458-464.

Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination

with low-intensity chemotherapy for older patients with Philadelphia chromosome-

negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet

Oncol 2018;19:240-248.

O’Brien S, Thomas DA, Ravand F et al. Results of the hyperfractionated

cyclophosphamide, vincristine, doxorubicin and dexamethasone in elderly

patients with acute lymphocytic leukemia. Cancer 2008;113:2097-2101.

Larson RA, Dodge RK, Linker CA et al. A randomized control trial of filgrastim

during remission induction and consolidation chemotherapy for adults with acute

lymphoblastic leukemia: CALGB 9111. Blood 1998;92:1556-1564.

Ottmann OG, Wassmann B, Pfeiffer H et al. Imatinib compared with

chemotherapy as front-line treatment of elderly patients with Ph-chromosome

positive acute lymphoblastic leukemia. Cancer 2007;109:2068-2076.

Foa R, Vitale A, Vignetti M, et al Dasatinib as first-line treatment for adult

patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

Blood 2011;118:6521-6528.

Vignetti M, Fazi P, Cimino G et al. Imatinib plus steroids induces complete

remissions and prolonged survival in elderly Philadelphia chromosome positive

patients with acute lymphoblastic leukemia without additional chemotherapy:

results of the Gruppo Italiano Malattie Ematologiche dell Adulto (GIMEMA)

LAL0201-B protocol. Blood 2007;109:3676-3678.

Papayannidis C, Fazi P, Piciocchi A, et al. Treating Ph+ acute lymphoblastic

leukemia (ALL) in the elderly: the sequence of two tyrosine kinase inhibitors

(TKI) (nilotinib and imatinib) does not prevent mutations and relapse. Blood

2012;120:Abstract 2601.

Martinelli G, Piciocchi A, Papayannidis C, et al. First report of the GIMEMA LAL

1811 prospective study of the combination of steroids with ponatinib as frontline

therapy of elderly or unfit patients with Philadelphia chromosome-positive acute

lymphoblastic leukemia. Blood 2017;139:99.

Rousselot P, Coude MM, Gokbuget N et al. Dasatinib and low-intensity

chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.

Blood 2016;128:774-82.

Rousselot P, Coude MM, Huguet F, et al. Dasatinib and low intensity

chemotherapy for first-line treatment in patients with de novo Philadelphia

Positive ALL aged 55 and over: final results of the EWALL-Ph-01 study

[abstract]. Blood 2012;120:Abstract 666.

Rea D, Legros L, Raffoux E, et al. High-dose imatinib mesylate combined with

vincristine and dexamethasone (DIV regimen) as induction therapy in patients

with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid

blast crisis of chronic myeloid leukemia. Leukemia 2006;20:400-403.

Ottmann OG, Pfeifer H, Cayuela JM, et al. Nilotinib (Tasigna®) and low intensity

chemotherapy for first-line treatment of elderly patients with BCR-ABL1-positive

acute lymphoblastic leukemia: Final results of a prospective multicenter trial

(EWALL-PH02). Blood 2018;132:Abstract 31.

Wieduwilt MJ, Jones BA, Schiller GJ, et al. A phase II study of pegylated

asparaginase, cyclophosphamide, rituximab, and dasatinib added to

the UCSF 8707 (linker 4-drug) regimen with liposomal cytarabine CNS

prophylaxis for adults with newly diagnosed acute lymphoblastic leukemia

(ALL) or lymphoblastic lymphoma (LBL): University of California Hematologic

Malignancies Consortium Study (UCHMC) 1401. Blood 2018:132:4018.

Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of

dasatinib with hyper-CVAD for the frontline treatment of patients with

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood

2010;116:2070-2077.

Jabbour E, Kantarjian H, Ravandi F, et al. Combination of hyper-CVAD with

ponatinib as first-line therapy for patients with Philadelphia chromosome-positive

acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol

2015;16:1547-1555.

PRINCIPLES OF SYSTEMIC THERAPY - Treatment of Older Adults (≥65 years) or Adults with Substantial Comorbidities

References

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

ALL-E

RESPONSE ASSESSMENT

Response Criteria for Blood and Bone Marrow:

• CR

No circulating lymphoblasts or extramedullary disease

◊ No lymphadenopathy, splenomegaly, skin/gum inltration/

testicular mass/CNS involvement

Trilineage hematopoiesis (TLH) and <5% blasts

Absolute neutrophil count (ANC) >1000/microL

Platelets >100,000/microL

No recurrence for 4 weeks

• CR with incomplete blood count recovery (CRi)

Meets all criteria for CR except platelet count or ANC

• Overall response rate (ORR = CR + CRi)

• NOTE: MRD assessment is not included in morphologic assessment

and should be obtained (see ALL-F)

• Refractory disease

Failure to achieve CR at the end of induction

• Progressive disease (PD)

Increase of at least 25% in the absolute number of circulating or

bone marrow blasts or development of extramedullary disease

• Relapsed disease

Reappearance of blasts in the blood or bone marrow (>5%) or in

any extramedullary site after a CR

Response Criteria for CNS Disease:

• CNS remission: Achievement of CNS-1 status (see ALL-B) 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 without another explanation.

Response Criteria for Lymphomatous Extramedullary Disease:

• CT of neck/chest/abdomen/pelvis with IV contrast and PET/

CT should be performed to assess response for extramedullary

disease.

• CR: Complete resolution of lymphomatous enlargement by CT.

For patients with a previous positive PET scan, a post-treatment

residual mass of any size is considered a CR as long as it is PET

negative.

• PR: >50% decrease in the sum of the product of the greatest

perpendicular diameters (SPD) of the mediastinal enlargement. For

patients with a previous positive PET scan, post-treatment PET must

be positive in at least one previously involved site.

• PD: >25% increase in the SPD of the mediastinal enlargement. For

patients with a previous positive PET scan, post-treatment PET must

be positive in at least one previously involved site.

• No Response (NR): Failure to qualify for PR or PD.

• Relapse: Recurrence of mediastinal enlargement after achieving CR.

For patients with a previous positive PET scan, post-treatment PET

must be positive in at least one previously involved site.

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

ALL-F

Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult lymphoblastic leukemia. JAMA Oncol

2017;3:e170580.

Gaipa G, Cazzaniga G, Valsecchi MG, et al. Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal

residual disease detection in childhood acute lymphoblastic leukemia. Haematologica 2012;97(10):1582-1593.

Denys B, van der Sluijs-Gelling AJ, Homburg C, et al. Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia.

Leukemia 2013;27:635-641.

Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD

assessment in Kiel, Germany, 18-20 September 2008. Leukemia 2010;24:521-535.

Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2010;2010:7-12.

MINIMAL/MEASURABLE RESIDUAL DISEASE ASSESSMENT

• The preferred sample for MRD assessment is the rst small volume (of up to 3 mL) pull of the bone marrow aspirate, if feasible.

• MRD in ALL refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods. Patients who

achieved a CR by morphologic assessment alone can potentially harbor a large number of leukemic cells in the bone marrow.

• MRD is an essential component of patient evaluation over the course of sequential therapy. If validated MRD assessment technology with

appropriate sensitivity (at least 10

-4

) is not available locally, there are commercially available tests.

• Studies in both children and adults with ALL have demonstrated the strong correlation between MRD and risks for relapse, as well as the

prognostic signicance of MRD measurements during and after initial induction therapy.

• The most frequently employed methods for MRD assessment include at least 6-color ow cytometry assays

2,3

specically designed to

detect abnormal MRD immunophenotypes, real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect fusion genes (eg,

BCR-ABL1), and NGS-based assays, to detect clonal rearrangements in immunoglobulin (Ig) heavy chain genes and/or T-cell receptor (TCR)

genes.

• Current 6-color ow cytometry can detect leukemic cells at a sensitivity threshold of <1 × 10

-4

(<0.01%) bone marrow mononuclear cells

(MNCs).

2,3

PCR/NGS methods can detect leukemic cells at a sensitivity threshold of <1 x 10

-6

(<0.0001%) bone MNCs.

4,5

The concordance

rate for detecting MRD between these methods is generally high. Methods not achieving these sensitivity levels are not suitable.

For ow cytometric analysis of MRD, notify lab performing the MRD assessment if immunotherapy (such as rituximab, blinatumomab,

inotuzumab ozogamicin, or tisagenlecleucel) has been used.

Timing of MRD assessment:

◊ Upon completion of initial induction.

◊ Additional time points should be guided by the regimen used.

◊ Serial monitoring frequency may be increased in patients with molecular relapse or persistent low-level disease burden.

◊ For some techniques, a baseline sample may be needed or helpful for the MRD assessment to be valid.

NCCN Guidelines Version 1.2021

Acute Lymphoblastic Leukemia

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1