Therapy-related B-cell acute lymphoblastic leukemia in adults has unique genetic profile with frequent loss of TP53 and inferior outcome

It has been recognized that patients treated with cytotoxic agents for a primary malignancy, autoimmune disorder, or after solid organ transplant are at increased risk of developing

therapy-related hematopoietic neoplasms. These neoplasms include therapy-related myeloid neoplasms (MNs) and less commonly, acute lymphoblastic leukemia (ALL). While therapy-related MNs have

been well characterized and gained recognition as a distinctive high-risk entity by World Health Organization classification of hematopoietic neoplasms [1], attention has turned to

therapy-related ALL relatively recently and more studies are needed to reveal genetic markers of prognostic and therapeutic significance. Diagnostic criteria for t-ALL cases have not been

clearly defined and previous studies often grouped therapy-related B-cell ALL (t-B-ALL) with T-cell ALL and secondary ALL (defined as ALL with a prior history of other malignancy, regardless

of treatment). To the best of our knowledge, only two studies with strict inclusive criteria focused on t-B-ALL [2, 3], with other two [4, 5] combining B-cell and T-cell ALL cases together.

Confirming previously reported findings [2,3,4,5], our cohort of t-B-ALL patients showed significantly higher frequency of high-risk lymphoid cytogenetic abnormalities, including KMT2A

translocations, hypodiploid, or complex karyotype. Although t(9;22)/BCR-ABL1 fusion was identified in both cohorts, CRLF2 rearrangement, frequent in de novo BCR-ABL1-like B-ALL, was not

noted in our t-B-ALL cohort. Some specific genetic markers associated with dismal outcome in B-ALL, i.e., haploinsufficiency of IKZF1 and TP53, and biallelic loss of CDKN2A/CDKN2B are highly

overrepresented in t-B-ALL compared to de novo B-ALL. Thus, t-B-ALL should be considered as a high-risk lymphoid neoplasm based on these genetic features.

The authors would like to thank the staff of the cytogenetics and molecular diagnostics laboratories for their technical expertise.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Liron Barnea Slonim, Juehua Gao, Xinyan Lu, Firas Wehbe, Lawrence Jennings, Yi-Hua Chen & Madina Sukhanova

Department of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Madelyn Burkart, Shira N. Dinner, Firas Wehbe & Jessica K. Altman

Department of Pathology and Laboratory Medicine and Medical Education, Loyola University Chicago Stritch School of Medicine, Chicago, IL, USA

Department of Preventive Medicine (Health and Biomedical Informatics), Northwestern University Feinberg School of Medicine, Chicago, IL, USA

MS undertook concept and design; LBS, JG, Y-HC, OEO, KMM, MB, SND, JKA, FW provided study materials; MS and LBS collected and assembled data; MS, LBS, JG, and MK undertook data analysis and

clinical interpretation; MS, LBS, and JG wrote the manuscript; LJ and XL reviewed the manuscript and provided constructive critics, and MS edited the article and provided final approval.

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