Leukemia - acute
Pre-B ALL
B lymphoblastic leukemia / lymphoma with BCR-ABL1-like / Ph-like


Topic Completed: 21 January 2019

Revised: 22 January 2019

Copyright: (c) 2018-2019, PathologyOutlines.com, Inc.

PubMed Search: B lymphoblastic leukemia BCR-ABL1-like

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Cite this page: Kaseb H, Hudnall SD. B lymphoblastic leukemia / lymphoma with BCR-ABL1-like / Ph-like. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/leukemiaprebbcrabl1like.html. Accessed March 23rd, 2019.
Definition / general
Essential features
ICD coding
Epidemiology
Pathophysiology
  • Harbors a large number of kinase activating gene rearrangements primarily involving the ABL class, JAK / STAT or RAS pathway associated signaling pathways
  • Common genes involved include ABL1, ABL2, CRLF2, CSF1R, EPOR, NTRK3, PDGFRB, JAK1, JAK2, JAK3, FLT3, IL7R, SH2B3 and IKZF1
    • These genes encode proteins involved in B cell development, proliferation and differentiation, cell cycle regulation and cell signaling
  • Overexpression of cytokine receptors such as cytokine receptor-like factor 2 (CRLF2) occurs in both ALL with BCR-ABL1-like / Philadelphia-like and other B ALL categories (Eur J Cancer 2017;82:203)
Clinical features
  • B ALL in general usually presents with symptoms related to bone marrow suppression by lymphoblasts
    • Patients can present with anemia, leucopenia or thrombocytopenia or a combination of these
    • Symptoms include bruising or bleeding due to thrombocytopenia, pallor or fatigue due to anemia and recurrent infections caused by neutropenia / leucopenia or bone pains
    • May also present with lymphadenopathy (> 10 mm in single dimension of the lymph node), hepatomegaly or splenomegaly
  • B ALL with BCR-ABL1-like and other B ALL with recurrent genetic abnormalities show no unique clinical presentation or microscopic findings
    • Further, similar to some other B ALL with recurrent genetic abnormalities, B ALL with BCR-ABL1-like shows no unique immunophenotypic profile (Pediatr Blood Cancer 2017;64:10.1002)
  • Essentially a diagnosis of exclusion
  • Identifying patients with B ALL with BCR-ABL1-like can influence the management of the patient
    • Those with PDGFRB translocation can benefit from tyrosine kinase inhibitors, while patients with JAK translocations may benefit from JAK inhibitors (Pediatr Blood Cancer 2017;64:10.1002)
  • Adults tend to have poor outcome even with high intensity chemotherapy regimens
Laboratory
  • B ALL with BCR-ABL1-like patients do not show a BCR-ABL1 fusion protein expressed from t(9;22)(q34;q11.2); however, they have a gene expression profile similar to ALL with BCR-ABL1
  • Almost none of the genetic alterations are detected by standard genetic diagnostic methods such as conventional karyotyping and FISH because these genetic alterations are diverse and often cryptic
  • Patients can only be diagnosed by gene expression panels (genome wide Affymetrix gene expression arrays):
    • Currently 2 gene expression signatures have been verified for diagnosis of B ALL with BCR-ABL1-like / Ph-like
  • BCR-ABL1-like gene expression array consists of 110 expression probe sets and was originally developed to classify B ALL in a population based Dutch / German cohort
    • Gene expression of a group of cases were similar to ALL with BCR-ABL1 and therefore named the category ALL with BCR-ABL1-like
    • These had an overall unfavorable outcome (Lancet Oncol 2009;10:125)
  • Philadelphia-like signature was first demonstrated in cases of B ALL with IKZF1 deletions in a high risk United States cohort (N Engl J Med 2009;360:470)
  • Differences between these 2 gene expression signatures can be explained by their different origins and discovery cohorts
Prognosis
  • Prognostic factors include age, white blood cell count, immunophenotype, genetics and detection of measurable residual disease
    • Numerous stratification schemes to assess risk in B ALL
    • NCI risk group:
      • NCI standard risk group: WBC < 50,000/microL and age 1 to < 10 years
      • NCI high risk group: WBC ≥ 50,000/microL or age ≥ 10 years (up to 13 years if treated on a COG protocol)
    • One scheme stratifies patients into standard risk and high risk based on age (< 10 years = standard, > 10 years = high) and WBC count (< 50,000/mm3 = standard, > 50,000/mm3 = high)
  • Recurrent genetic abnormalities are identified in the majority of B ALL cases
  • Prognosis of B ALL with BCR-ABL1-like is generally unfavorable
Case reports
Treatment
  • B ALL with BCR-ABL1-like is managed by standard combination chemotherapy
    • Effective treatment modality for B ALL since the 1950s
    • Usually administered in 3 distinct phases (induction, consolidation and maintenance) and should include intrathecal treatment, which is directed to the central nervous system
  • Addition of tyrosine kinase inhibitors in B ALL with BCR-ABL1-like depends on the specific genetic alteration and has been shown to improve patient's outcome
  • Both imatinib and dasatinib specifically inhibit ABL1, ABL2, PDGFRB and CSF1R kinases; ruxolitinib inhibits JAK / CRLF2 / EPOR alterations (Eur J Cancer 2017;82:203)
  • Sensitivity to ruxolitinib in patients with JAK class aberrations is promising and has been successful in 2 JAK class fusion positive patients and 1 JAK2 mutated ALL (Eur J Cancer 2017;82:203)
  • Adults tend to have poor outcome even with high intensity chemotherapy regimens; therefore, bone marrow transplantation becomes an important treatment option
Microscopic (histologic) description
  • Blasts have scant agranular cytoplasm, coarse to fine chromatin, often with indistinct nucleoli
  • No Auer rods and no dysplastic myeloid cells
Peripheral smear images

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

Lymphoblasts

Positive stains
Negative stains
Molecular / cytogenetics description
  • Gene expression profiling is the gold standard for diagnosis of B ALL with BCR-ABL1-like / Ph-like (Lancet Oncol 2009;10:125, N Engl J Med 2009;360:470)
  • Genetic alterations in B ALL with BCR-ABL1-like are harder to detect by standard genetic diagnostic approaches (Eur J Cancer 2017;82:203)
  • Common gene rearrangements include CRLF2, EPOR and IGH
  • Down syndrome patients uniquely show CRLF2 translocation
  • ABL1 oncogene translocation with ABL2, PDGFRB, NTRK3, TYK2, CSF1R and JAK2 have all been reported
  • Many cases of B ALL with BCR-ABL1-like may additionally show other deletions or mutations that have a clear role in leukemogenesis such as IKZFA and CDKN2A / B
  • FISH and karyotyping are helpful in ruling out other B ALL entities, especially ALL with recurrent genetic abnormalities
  • Multiplex FISH testing can be useful in ruling out B ALL with recurrent genetic abnormalities
  • Identifying patients with B ALL with BCR-ABL1-like can influence patients' prognosis and management of the patient
    • PDGFRB translocation: may benefit from tyrosine kinase inhibitors
    • JAK translocations: may benefit from JAK inhibitors
Differential diagnosis
Board review question #1
What is the most sensitive test in diagnosing B lymphoblastic leukemia / lymphoma with BCR-ABL1-like / Ph-like?

  1. Flow cytometry
  2. Gene expression profiling
  3. Karyotyping
  4. Multiplex FISH
Board review answer #1
B. Only gene expression profiling can diagnose the entity B ALL with BCR-ABL1-like / Ph-like

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Board review question #2
Which of the following is a characteristic of B lymphoblastic leukemia / lymphoma with BCR-ABL1-like / Ph-like?

  1. NCI high risk features
  2. NCI intermediate risk features
  3. NCI low risk features
  4. NCI risk features is not applicable
Board review answer #2
A. ALL with BCR-ABL1-like shows the following characteristics: NCI high risk features, persistent postinduction minimal residual disease (MRD), genetic alterations that activate kinase signaling (Pediatr Blood Cancer 2017;64:10.1002). NCI risk stratifications include NCI standard risk group: WBC < 50,000/microL and age 1 to < 10 years; NCI high risk group: WBC ≥ 50,000/microL or age ≥ 10 years (up to 13 years if treated on a COG protocol).

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