Bone marrow neoplastic
Bone marrow - plasma cell and lymphoid neoplasms
B lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities
Therapy related B ALL
Editorial Board Members: Anamarija M. Perry, M.D., Alexa J. Siddon, M.D.
Last author update: 8 August 2022
Last staff update: 8 August 2022
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PubMed Search: Therapy related B ALL
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Germans SK, Jaso JM. Therapy related B ALL. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/boneneoplastictBALL.html. Accessed June 1st, 2023.
Definition / general
- B lymphoblastic leukemia / lymphoma arising after cytotoxic or radiation therapy for a prior malignancy
Notes:
- 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
Terminology
- Therapy related B lymphoblastic leukemia / lymphoma (t-B ALL)
ICD coding
- ICD-10: C91.00 - acute lymphoblastic leukemia not having achieved remission
Epidemiology
- Estimated to occur in 1 - 10% of patients who receive cytotoxic / radiation therapy (alkylating agents or topoisomerase inhibitors) as primary therapy or in preparation for hematopoietic stem cell transplant (e.g., melphalan)
- Recently discovered association with use of immunomodulatory agents (e.g., lenalidomide, thalidomide) for primary therapy or maintenance therapy (Blood Rev 2019;37:100584, Int J Clin Exp Pathol 2011;4:322, Medicine (Baltimore) 2019;98:e14011)
- More common in older patients; incidence increases with age
- Median age at presentation: fifth and sixth decade (Blood Rev 2019;37:100584, Br J Haematol 2022;196:963)
- Occasionally seen in young adults (second to third decade) and rarely in pediatric patients
- Germline mutations (e.g., TP53 mutation) are frequently present in this age group and should be excluded before a diagnosis of t-B ALL is considered (Leuk Lymphoma 2001;41:255, Blood Rev 2019;37:100584)
- Most common prior malignancy is breast cancer, treated by alkylating agents and topoisomerase inhibitors (Leuk Lymphoma 2001;41:255, Blood Rev 2019;37:100584, Br J Haematol 2022;196:963)
- Second most common are multiple myeloma and lymphoma
- Other prior malignancies include myelodysplastic syndrome with isolated del(5q) (treated with lenalidomide) and a variety of carcinomas and sarcomas
- Interval between diagnosis of primary malignancy and development of t-B ALL is approximately 2 - 7 years but can range from a few months to several decades (Blood Rev 2019;37:100584, Case Rep Hematol 2018;2018:9052314)
Sites
- Bone marrow and peripheral blood
- Central nervous system (CNS) involvement can be seen, especially in KMT2A rearranged disease (Curr Hematol Malig Rep 2020;15:83)
Pathophysiology
- Shows overlapping pathophysiology with WHO defined therapy related myeloid neoplasms (therapy related myelodysplastic syndrome and therapy related acute myeloid leukemia) and may represent a morphologic variant of those diseases (Blood Rev 2019;37:100584)
- Underlying mechanism is exposure to mutagenic agents as treatment for a prior malignancy (Leuk Lymphoma 2001;41:255, Blood Rev 2019;37:100584, Br J Haematol 2022;196:963)
- Accumulating exposure results in DNA damage, likely inducing mitotic instability (Br J Haematol 2022;196:963)
- DNA instability may result in hypodiploidy, including monosomy of chromosomes (5 / 5q), (7 / 7q), (17) and others
- Primarily associated with exposure to alkylating agents, topoisomerase inhibitors and radiation
- Recently associated with use of immunomodulatory agents (e.g., lenalidomide) as maintenance therapy after autologous stem cell transplant for plasma cell myeloma (Lancet Oncol 2014;15:333, Ann Oncol 2017;28:228, Case Rep Hematol 2018;2018:9052314, Am J Clin Pathol 2020;154:816)
- Cases of t-B ALL arising after lenalidomide therapy for myelodysplastic syndrome with isolated del(5q) have been reported (Int J Clin Exp Pathol 2011;4:322, Medicine (Baltimore) 2019;98:e14011)
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
Diagnosis
- Examination of blood or bone marrow
Laboratory
- 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
- Patients present with lower white blood cell (WBC) counts than patients with de novo disease (Br J Haematol 2022;196:963)
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)
Treatment
- 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
- CD34, TdT, CD79a, PAX5
- Assist with identification of clusters of blasts in cases with low level involvement
- References: Am J Clin Pathol 2020;154:816, Jaffe: Hematopathology, 2nd Edition, 2016
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
- Secondary B lymphoblastic leukemia / lymphoma:
- Diagnosed when patient has a prior malignancy but has not received cytotoxic or radiotherapy
- Inherited disorder (e.g., Li-Fraumeni) predisposing to multiple malignancies:
- Testing for germline mutations should be considered, especially in younger patients
- Hematogone hyperplasia:
- Potential for presentation with low blast percentages may prompt consideration of hematogone hyperplasia / bone marrow regeneration
- Flow cytometry with immunohistochemistry as needed will assist with identification (Leuk Lymphoma 2010;51:10, Am J Clin Pathol 2020;154:816)
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?
- BCR::ABL1 rearrangement
- CREBBP mutation
- ETV6::RUNX1 mutation
- IKZF1 mutation
- 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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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?
- A concurrent mutation in KMT2A is likely to be identified
- Conventional karyotype and copy number analysis studies are not indicated in these cases
- Germline molecular testing and geneticist consultation should be considered
- The disease is associated with in utero exposure to alkylating agents
- 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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