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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Hematology

      Acute Lymphoblastic Leukemia (ALL) Guidelines

      Updated: Jul 02, 2021
      • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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      Guidelines

      Guidelines Summary

      The National Comprehensive Cancer Network (NCCN) provides frequently updated recommendations for the diagnosis and management of acute lymphoblastic leukemia (ALL), along with surveillance milestones or algorithms to monitor response to treatment. The guidelines are further delineated to address differences in the management of adolescent and young adults (AYA), ages 15 to 39 years, from adults 40 years and older. However, the guidelines caution that regardless of chronological age, patients need to be evaluated individually to determine fitness for treatment. [20]

      In 2017, the College of American Pathologists and the American Society of Hematology (CAP/ASH) issued guidelines on the initial diagnostic workup of acute leukemia (AL). [94]

      In 2016, the European Society for Medical Oncology (ESMO) released updated guidelines for the management of ALL. [95]

      Diagnosis and Risk Stratification

      CAP/ASH guidelines on the workup of AL include the following recommendations [94] :

      • A complete diagnosis of AL requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping and karyotype analysis, and, often, molecular genetic testing.
      • The treating clinician should provide relevant clinical data, including physical examination and imaging findings, or ensure that those data are readily accessible by the pathologist.
      • The pathologist should review recent or concurrent complete blood cell (CBC) counts and leukocyte differentials and evaluate a peripheral blood (PB) smear.
      • Obtain a fresh bone marrow (BM) aspirate for all patients suspected of AL, a portion of which should be used to make BM aspirate specimens for morphologic evaluation. If performed, the pathologist should evaluate an adequate BM trephine core biopsy, BM trephine touch preparations, and/or marrow clots, in conjunction with the BM aspirates.
      • In addition to morphologic assessment (blood and BM), obtain sufficient samples and perform conventional cytogenetic analysis (ie, karyotype), appropriate molecular-genetic and/or fluorescence in situ hybridization (FISH) testing, and flow cytometry immunophenotyping (FCIp). The flow cytometry panel should be sufficient to distinguish acute myeloid leukemia (including acute promyelocytic leukemia), T-ALL (including early T-cell precursor leukemias), B-cell precursor ALL (BCP-ALL), and AL of ambiguous lineage for all patients diagnosed with AL. Molecular genetic and/or FISH testing does not, however, replace conventional cytogenetic analysis.
      • For patients with suspected or confirmed AL, cytochemical studies to assist in the diagnosis and classification of acute myeloid leukemia (AML) may be requested and evaluated.
      • The treating clinician or pathologist may use cryopreserved cells or nucleic acid, nondecalcified formalin fixed paraffin-embedded (FFPE) tissue, or unstained marrow aspirate or PB specimens obtained and prepared from PB, BM aspirate, or other involved tissues for molecular or genetic studies in which the use of such material has been validated.
      • For patients with ALL receiving intrathecal therapy, a cerebrospinal fluid (CSF) sample should be obtained. The treating clinician or pathologist should ensure that a cell count is performed and that examination/enumeration of blasts on a cytocentrifuge preparation is performed and is reviewed by the pathologist.
      • For patients with suspected or confirmed AL, the pathologist may use flow cytometry in the evaluation of CSF.
      • For patients who present with extramedullary disease without BM or blood involvement, a tissue biopsy should be evaluated and processed for morphologic, immunophenotypic, cytogenetic, and molecular genetic studies, as recommended for the BM.
      • For pediatric patients with suspected or confirmed B-ALL, ensure testing for t(12;21)(p13.2;q22.1); ETV6-RUNX1, t(9;22)(q34.1;q11.2); BCR-ABL1, KMT2A (previously MLL) translocation; iAMP21; and trisomy 4 and 10 is performed.
      • For adult patients with suspected or confirmed B-ALL, ensure testing for t(9;22)(q34.1;q11.2) and BCR-ABL1. In addition, testing for KMT2A (previously MLL) translocations may be performed.

      NCCN guidelines note that diagnosis of ALL generally requires the following [20] :

      • Demonstration of ≥20% bone marrow lymphoblasts
      • Morphologic assessment of Wright/Giemsa–stained bone marrow aspirate smears
      • Hematoxylin and eosin (H&E)–stained bone marrow core biopsy and clot sections
      • Comprehensive flow cytometric immunophenotyping

      For optimal risk stratification and treatment planning in patients with ALL, the NCCN advises that bone marrow or peripheral blood lymphoblasts must be tested for specific recurrent genetic abnormalities, as follows [20] :

      • Cytogenetics – Karyotyping of G-banded metaphase chromosomes
      • Interphase FISH
      • Reverse transcriptase polymerase chain reaction (RT-PCR) for fusion genes (eg,  BCR-ABL)

      The NCCN considers tests for hyperdiploidy and hypodiploidy to be optional.

      NCCN recommendations for the initial workup include the following:

      • History and physical
      • CBC, platelets, differential
      • Chemistry profile
      • Disseminated intravascular coagulation (DIC) panel
      • Tumor lysis syndrome panel
      • Computed tomography/magnetic resonance imaging (CT/MRI) of head with contrast, if neurologic symptoms
      • Lumbar puncture
      • CT of chest with contrast (for patients with T-ALL), plus baseline positron emission tomography (PET) imaging for patients with a mediastinal mass
      • Testicular exam
      • Infection evaluation: Screen for active infections if febrile or for symptomatic opportunistic infections
      • Consider echocardiogram or cardiac scan, especially in patients with prior cardiac history and prior anthracycline exposure or clinical symptoms suggestive of cardiac dysfunction.
      • Central venous access device of choice
      • Human leukocyte antigen (HLA) typing (except for patients with a major contraindication to hematopoietic cell transplant)

      The ESMO recommendations concur with those of NCCN while noting that the initial diagnostic workup should be completed quickly and before any chemotherapy is administered in order to accomplish the following [95] :

      • Confirm diagnosis and shorten time to onset of treatment

      • Distinguish BCP-ALL from T-ALL

      • Distinguish Burkitt leukemia (B-ALL) from BCP-ALL 

      • Distinguish Philadelphia (Ph) chromosome-positive (Ph+) ALL from Ph-negative (Ph−) ALL 

      Treatment strategies

      As a general rule, the NCCN recommends enrolling patients with ALL in a clinical trial, if possible. Otherwise, NCCN recommendations for first-line treatment are based on risk stratification and age, as follows [20]

      • Philadelphia chromosome–positive (Ph+) ALL (in AYA): Chemotherapy and tyrosine kinase inhibitor (TKI), followed by allogeneic stem cell transplantation (SCT) if an appropriate donor is available; if transplantation is not feasible, continue multiagent chemotherapy and a TKI

      • Ph+ ALL (adults < 65 y): Chemotherapy and tyrosine kinase inhibitor (TKI); consider allogeneic SCT if an appropriate donor is available and the patient has good performance status and no or limited comorbidities; if transplantation is not feasible, continue multiagent chemotherapy and a TKI

      • Ph+ ALL (adults ≥65 y or with substantial comorbidities): TKI and corticosteroids or TKI and chemotherapy (evaluate end-organ reserve, end-organ dysfunction, and performance status)

      • Ph- ALL (AYA): Pediatric-style multiagent chemotherapy

      • Ph- ALL (Adults < 65 y): Multiagent chemotherapy

      • Ph- ALL (Adults ≥ 65 or with substantial comorbidities): Multiagent chemotherapy or corticosteroids (evaluate end-organ reserve, end-organ dysfunction)

      NCCN strongly recommends central nervous system (CNS) prophylaxis for all ALL treatment groups.

      Stem cell transplantation

      In 2012, the American Society for Blood and Marrow Transplantation (ASBMT) updated its treatment recommendations for SCT in adults with ALL, based on new evidence. The updated recommendations include the following [96] :

      • Myeloblative allogeneic SCT is an appropriate treatment for adults younger than 35 years, in all risk groups during the first complete remission

      • Allogeneic SCT is recommended over chemotherapy for all adults with ALL during the second or subsequent complete remission

      • Allogeneic SCT is preferred over autologous SCT, with similar outcomes for related and unrelated allogeneic SCT

      • Imatinib therapy before and/or after SCT for Ph+ ALL results in higher survival rates

      The 2016 ESMO guidelines include the following recommendations [95] :

      • Autologous SCT is not recommended outside of clinical trials
      • Allogeneic SCT is recommended after first complete remission in all patients with poor minimal residual disease, but not recommended for standard-risk patients with a sustained molecular response
      • After the second complete remission, allogeneic SCT was found superior to non-transplantation
      • Cord blood transplantation may be considered if no HLA-well-matched donor is found or the patient needs urgent SCT
      • Total body irradiation regimens are recommended for myeloablative SCT; reduced-intencity conditioning regimens should be used only in adults in remission unfit for myeloablative conditioning and elderly fit patients
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