Bone marrow neoplastic

Bone marrow - plasma cell and lymphoid neoplasms

B lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities

Therapy related B ALL

Last author update: 8 August 2022
Last staff update: 8 August 2022

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PubMed Search: Therapy related B ALL

Sharon Koorse Germans, M.D.
Jesse Manuel Jaso, M.D.
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Cite this page: Germans SK, Jaso JM. Therapy related B ALL. website. Accessed February 26th, 2024.
Definition / general
  • B lymphoblastic leukemia / lymphoma arising after cytotoxic or radiation therapy for a prior malignancy

  • Therapy related T lymphoblastic leukemia is not discussed in this topic; rare reports of such cases have been published but understanding of this entity remains limited
  • Secondary B lymphoblastic leukemia / lymphoma is not discussed in this topic
    • The term secondary B lymphoblastic leukemia / lymphoma is preferred when the patient has a history of prior malignancy but has not received cytotoxic or radiation therapy
Essential features
  • B lymphoblastic leukemia / lymphoma arising after cytotoxic or radiation therapy for a prior malignancy
  • Most common prior malignancy is breast cancer, followed by multiple myeloma and lymphoma
  • No distinct morphologic or immunophenotypic features but is commonly associated with KMT2A rearrangement, del(5 / 5q), del(7 / 7q), hypodiploidy, TP53 mutation and BCR::ABL1 rearrangement
  • Therapy related B lymphoblastic leukemia / lymphoma (t-B ALL)
ICD coding
  • ICD-10: C91.00 - acute lymphoblastic leukemia not having achieved remission
Clinical features
  • History of cytotoxic or radiation for prior malignancy
  • Older age at diagnosis (fifth - sixth decade)
  • Patients may present with cytopenia(s), fatigue, weight loss and fever or may be asymptomatic
  • Examination of blood or bone marrow
  • Complete blood cell count (CBC):
    • Patients present with lower white blood cell (WBC) counts than patients with de novo disease (Br J Haematol 2022;196:963)
      • WBC count ranges widely (may be decreased, normal or increased)
      • Anemia, thrombocytopenia or pancytopenia are frequently encountered
Prognostic factors
  • Previously mentioned cytogenetic abnormalities, as well as prior exposure to mutagenic agents, confer a worse prognosis when compared to de novo disease
  • KMT2A rearrangement is associated with faster time to development of t-B ALL, as well as worse prognosis
  • Autologous hematopoietic stem cell transplant may improve survival (Blood Rev 2019;37:100584, Br J Haematol 2022;196:963)
Case reports
  • 43 and 64 year old men with B ALL arising during lenalidomide maintenance (Am J Clin Pathol 2020;154:816)
  • 53 and 69 year old women with B ALL arising in the context of lenalidomide maintenance (Case Rep Hematol 2018;2018:9052314)
  • 60 year old woman with B ALL, 3 years after treatment for multiple myeloma with cytotoxic agents and autologous stem cell transplant with high dose melphalan conditioning (Leukemia 2005;19:299)
  • 68 year old Caucasian man and 83 year old woman, the first case series to report development of t-B ALL during lenalidomide therapy for myelodysplastic syndrome with isolated del(5q) (Int J Clin Exp Pathol 2011;4:322)
  • 69 year old man with B ALL with mutated EZH2, arising 27 months after initiation of lenalidomide therapy for myelodysplastic syndrome with isolated del(5q) (Medicine (Baltimore) 2019;98:e14011)
  • 72 year old man with B ALL, 6 years after treatment with cytotoxic agents and lenalidomide maintenance therapy for multiple myeloma (Ann Clin Lab Sci 2013;43:176)
  • 74 year old woman with B ALL, 56 months after treatment for AL amyloidosis with lenalidomide (Int J Clin Exp Pathol 2014;7:2683)
  • 80 year old man with B ALL, > 20 years after treatment with alkylating agent (chlorambucil) for Waldenström macroglobulinemia (Leukemia 2004;18:1433)
  • Early case series of B ALL arising in the context of lenalidomide maintenance (Hematol Oncol 2017;35:130)
  • Intensive chemotherapy induction regimens, such as R hyper CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin and dexamethasone)
  • Allogeneic hematopoietic stem cell transplant
Microscopic (histologic) description
  • Peripheral blood:
    • Circulating blasts are present and can range from rare to numerous
    • Blasts have irregular nuclei, variably dispersed chromatin, inconspicuous nucleoli and basophilic vacuolated cytoplasm
  • Bone marrow:
    • Aspirate smears and touch preparations contain a variable percentage of blasts (rare to numerous)
    • Core biopsy and clot sections show variable cellularity (hypocellular, normocellular or hypercellular)
    • Blasts are increased and are present in sheets / clusters or as heterogeneously distributed, clusters of immature cells in the interstitium (Am J Clin Pathol 2020;154:816)
    • Background trilineage hematopoiesis is variably diminished
  • References: Am J Clin Pathol 2020;154:816, Jaffe: Hematopathology, 2nd Edition, 2016
Microscopic (histologic) images

Contributed by Jesse Manuel Jaso, M.D.

Bone marrow with increased blasts

CD34 highlighting clusters of blasts

Positive stains
Flow cytometry description
Molecular / cytogenetics description
  • Shows several genetic abnormalities that are also seen in therapy related myeloid neoplasms, suggesting a similar pathogenesis (Blood Rev 2019;37:100584)
  • KMT2A (formerly MLL) rearrangement:
    • Most frequently identified genetic abnormality
    • Associated with patients treated for early stage breast cancer with alkylating agents or topoisomerase inhibitors
    • Shorter latency interval than other forms of t-B ALL (Blood Rev 2019;37:100584)
  • Hypodiploidy:
    • Hypodiploidy is a common finding, often with deletion of chromosomes 5 / 5q, 7 / 7q, 13 / 13q, 17 and others
  • Low hypodiploid, near triploid karyotype may be seen in t-B ALL (Br J Haematol 2022;196:963)
    • Previously described in pediatric patients and associated with aggressive disease (Genes Chromosomes Cancer 2014;53:524)
    • Subset of B ALL with low hypodiploidy (31 - 39 chromosomes) may undergo aberrant endoduplication, resulting in a seemingly high hyperdiploid (51 - 65) or near triploid (66 - 79) karyotype on conventional cytogenetic analysis
    • Copy number analysis (CNA) can identify this masked hypodiploidy, which is also associated with P53 mutation and loss of chromosome (7p12) (IKZF1 locus), often concurrently (Genes Chromosomes Cancer 2014;53:524)
      • IKZF1 encodes Ikaros, a transcription factor involved in B cell development, among other functions
    • Relationship between these cytogenetic and molecular findings and t-B ALL pathogenesis remains incompletely understood
    • Pediatric patients with this karyotype should also be screened for Li-Fraumeni and other inherited disorders
  • BCR::ABL1 rearrangement:
    • Seen in a subset of cases
    • Incidence and role in t-B ALL pathogenesis is incompletely understood
Sample pathology report
  • Bone marrow, aspirate, clot, core biopsy and peripheral blood:
    • Therapy related B lymphoblastic leukemia / lymphoma (see comment)
    • Comment: The bone marrow shows increased blasts (***% by manual differential; *** by immunohistochemistry for CD34 / TdT) with atypical morphology and an aberrant B lymphoblast immunophenotype by flow cytometry.
    • The findings, in combination with the history of cytotoxic / radiation therapy for prior malignancy (list malignancy) are consistent with therapy related B lymphoblastic leukemia / lymphoma. Correlation with cytogenetic studies is recommended. If clinically indicated, molecular testing for germline mutations should be considered.
Differential diagnosis
Additional references
Board review style question #1
A 65 year old woman presents with a new diagnosis of B lymphoblastic leukemia / lymphoma. She has a history of breast cancer 10 years prior, which was treated with alkylating agents and topoisomerase inhibitors. Which of the following genetic abnormalities is most likely to be identified?

  1. BCR::ABL1 rearrangement
  2. CREBBP mutation
  3. ETV6::RUNX1 mutation
  4. IKZF1 mutation
  5. KMT2A rearrangement
Board review style answer #1
E. KMT2A rearrangement. Therapy related B lymphoblastic leukemia with KMT2A rearrangement is frequently associated with exposure to alkylating agents and topoisomerase inhibitors as treatment for prior breast cancer.

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Reference: Therapy related B ALL
Board review style question #2

A 20 month old patient presents with lethargy and fever. CBC shows pancytopenia. A bone marrow examination is performed (see image 1 for bone marrow aspirate and image 2 for bone marrow core biopsy with CD34 immunostain). Flow cytometry shows an aberrant B lymphoblast population (15% of total events). Molecular genetic studies identify a mutation in TP53. Which of the following statements is the most correct?

  1. A concurrent mutation in KMT2A is likely to be identified
  2. Conventional karyotype and copy number analysis studies are not indicated in these cases
  3. Germline molecular testing and geneticist consultation should be considered
  4. The disease is associated with in utero exposure to alkylating agents
  5. The molecular findings imply a good prognosis
Board review style answer #2
C. Germline molecular testing and geneticist consultation should be considered. Hypodiploidy with concurrent TP53 mutation may be seen in children and young patients with B lymphoblastic leukemia / lymphoma and a masked hypodiploid karyotype; however, testing for germline mutation of TP53 and other genes should be considered to rule out the presence of an inherited disorder (e.g., Li-Fraumeni) that predisposes to multiple cancers.

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