AMP case report: Adult B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like

In the absence of gene expression profiling, diagnosis of BCR-ABL1-like ALL may be time-consuming and costly due to the wide number of translocations and mutations seen in this entity. However, identification is of the utmost importance for prognostic and therapeutic purposes. Common strategies include testing with a limited FISH panel, often starting with probes to identify CRLF2 rearrangements and reflexing negative cases to analysis with additional FISH probes.⁹ Flow cytometry assays to assess for high CRLF2 expression are also available. These approaches are specific but not sensitive, as they do not identify the wide range of genetic alterations associated with this disease. Additionally, large next-generation sequencing panels to evaluate for a broad range of possible mutations and RNA fusions are available, though these large panels are costly and can have a turnaround time upward of three weeks.

 

Quantitative reverse transcriptase-PCR–based low-density array (LDA) provides a sensitive and rapid approach to identify cases of BCR-ABL1-like ALL including those with abnormalities outside of the commonly used FISH panels. The LDA assay was developed by the Children’s Oncology Group and evaluates the expression levels of 15 previously described genes (and a control gene) shown to be associated with the diagnosis BCR-ABL1-like ALL.^10-13 A score is generated based on a composite of the individual amplification curves to determine if the case shows expression levels at or above the validated threshold of positivity.¹⁰ A coefficient of 0.5–1 is considered positive for expression of a Ph-like profile.¹⁰ The assay also screens for multiple fusions such as BCR-ABL1 and ETV6-RUNX1 that would preclude the diagnosis of BCR-ABL1-like ALL and those that are commonly associated with BCR-ABL1-like ALL such as P2RY8-CRLF2.^10-13 Cases with positive LDA screens can be reflexed to further testing, as specific mutations and less common fusion rearrangements cannot be identified using this technology. Importantly, this screening method allows clinicians to risk stratify appropriately, develop a treatment plan, and possibly enroll patients into clinical trials as additional tests (FISH and/or sequencing) are completed.

 

BCR-ABL1-like B-ALL is a recently described entity, and thus significant studies describing treatment effects in adult patients are lacking. Patients often receive more intensive treatment, which may be linked to development of t-MN.¹⁴ Development of a secondary hematologic malignancy following treatment underscores the prognostic implications of BCR-ABL1-like B-ALL, including the hope that therapy targeting the aberrant genes or pathways may effect better outcomes.

1. Wu B, Jug R, Luedke C, et al. Lineage switch between B-lymphoblastic leukemia and acute myeloid leukemia intermediated by “occult” myelodysplastic neoplasm: two cases of adult patients with evidence of genomic instability and clonal selection by chemotherapy. Am J Clin Pathol. 2017;148(2):136–147.
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.
3. Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572–581.
4. Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults. J Clin Oncol. 2017;35(4):394–401.
5. Borowitz MJ, Chan JKC, Downing JR, et al. B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Rev. 4th ed. IARC Press; 2017:208.
6. Conant JL, Czuchlewski DR. BCR-ABL1-like B-lymphoblastic leukemia/lymphoma: review of the entity and detection methodologies. Int J Lab Hematol. 2019;41(Suppl 1):126–130.
7. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–1015.
8. Maese L, Tasian SK, Raetz EA. How is the Ph-like signature being incorporated into ALL therapy? Best Pract Res Clin Haematol. 2017;30(3):222–228.
9. Jain S, Abraham A. BCR-ABL1-like B-acute lymphoblastic leukemia/lymphoma: a comprehensive review. Arch Pathol Lab Med. 2020;144(2):150–155.
10. Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults. J Clin Oncol. 2017;35(4):394–401.
11. Harvey RC, Kang H, Roberts KG, et al. Development and validation of a highly sensitive and specific gene expression classifier to prospectively screen and identify B-precursor acute lymphoblastic leukemia (ALL) patients with a Philadelphia chromosome-like (“Ph-like” or “BCR-ABL1–like”) signature for therapeutic targeting and clinical intervention. Blood. 2013;122(21):826.
12. Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group. Blood. 2017;129(25):3352–3361.
13. Willman CL, Harvey R, Davidson GS, et al., inventors; STC.UNM, Sandia Corp., assignees. Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia, outcome correlations and diagnostic and therapeutic methods related to same. U.S. patent 8,568,974 (B2). Oct. 29, 2013.
14. Verma D, O’Brien S, Thomas D, et al. Therapy-related acute myelogenous leukemia and myelodysplastic syndrome in patients with acute lymphoblastic leukemia treated with the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimens. Cancer. 2009;115(1):101–106.

Dr. Kerwin is a hematopathology fellow, Dr. Chabot-Richards is associate professor, and Dr. Toth is visiting assistant professor, Department of Pathology, University of New Mexico, Albuquerque.

Test yourself answers

Answers are also online now at www.amp.org/casereports.

1. Which of these patients with B-lymphoblastic leukemia (B-ALL) should be screened for a Philadelphia-like (Ph) expression profile?
a. Pediatric patient with new diagnosis and karyotype showing hyperdiploidy.
b. Pediatric patient with new diagnosis and karyotype showing KMT2A rearrangement.
c. Pediatric patient with morphologic remission at end of induction chemotherapy.
d. Adult patient with new diagnosis and karyotype negative for t(9;22) BCR-ABL1.

2. What is the prognostic and therapeutic significance of Ph-like B-ALL?
a. Favorable prognosis; may respond to inotuzumab.
b. Favorable prognosis; may respond to immunotherapy.
c. Worse prognosis; may respond to tyrosine kinase inhibitors.
d. Worse prognosis; may respond to immunotherapy.

3. What is the most common molecular abnormality associated with Ph-like B-ALL?
a. CRLF2 gene rearrangements.
b. EPOR gene rearrangements.
c. Activating JAK1 or JAK2 point mutations.
d. KMT2A rearrangement; t(4;11) or KMT2A/AF4 fusion.