Page 177 - Haematologica May 2020

Ph– ALL cytogenetics and allogeneic HCT outcomes
with IGH-MYC) and CRLF2 have also been reported to yield poor outcomes.24-26
Our study confirmed the previously established unfa- vorable risk associated with a complex karyotype6,27 after allogeneic HCT. Notably, we observed substantial overlap between complex karyotype, monosomal karyotype, and other common abnormalities, mandating careful data analysis and interpretation of complex cytogenetics in future studies.
Monosomy 7 was consistently associated with worse post-transplant outcomes in this and prior studies.8 Multiple mechanisms have been proposed to explain the effects of monosomy 7 on leukemogenesis including, but not limited to, loss of tumor suppressor genes, haploinsuf- ficiency, or monoallelic loss of IKZF1, an important adverse prognostic marker in B-cell ALL which is localized to chromosome 7p.28,29 Haploinsufficient deletions of IKZF1 are enriched among Ph– ALL cases and associated with inferior survival.30
Our observed higher risk of relapse among allogeneic HCT recipients with t(11;19) was also consistent with the previously reported poor survival of ALL patients with t(11;19)(q23;p13.3).31
We propose an allogeneic HCT-specific cytogenetic risk classification for Ph– ALL separating patients into three prognostic risk categories based on the presence of mono- somy 7, del(7q), t(8;14), t(11;19), del(11q), complex, tetraploid/near triploid, and high hyperdiploid karyotypes (Table 5). This novel CIBMTR ALL risk classification of Ph– patients treated with allogeneic HCT is directly rele- vant to pre-HCT decision-making and might help in strat- ifying clinical trial candidates undergoing allogeneic HCT for Ph– ALL.
Unfortunately we could not account in our analysis for pre-transplant minimal residual disease (MRD), defined by flow cytometry or FISH/molecular testing. Pre-trans- plant MRD has been important in predicting ALL relapse and future research should combine cytogenetic classifica- tions with pre-transplant MRD status. Pretreatment com- plex karyotype and low hypodiploidy/near-triploidy por- tended poor survival after adjustment for MRD in a recent single-institution study.27 Our analysis validated other established patient- and transplant-related prognostic fac- tors and thereby confirmed the additional importance of the cytogenetic groupings. As most patients in this cohort received allografts with myeloablative conditioning, future validation of the CIBMTR ALL risk scheme among recipients treated with reduced intensity conditioning will test this prognostic tool in older and/or less fit ALL patients.
Our study focused on the transplant period preceding Food and Drug Administration approvals and broader use of liposomal vincristine, blinatumomab, inotuzumab ozogamycin, or tisagenlecleucel, and it thereby focused on a more homogeneous patient population with no differen-
tial effect on treatment outcomes found according to quin- quennial transplant periods from 1995 to 2011.
While many patients with previously established high- risk Ph– cytogenetic abnormalities can benefit from allo- geneic HCT, those with monosomy 7, complex kary- otype, and t(8;14) remain at high risk for treatment failure after transplantation. Selective targeting of these and other clinically-defined high-risk cohorts will be necessary to improve post-transplant survival of patients with Ph– ALL.
Acknowledgments
The CIBMTR is supported primarily by a public health serv- ice grant/cooperative agreement U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement U24HL138660 from the NHLBI and NCI; grant U24CA233032 from the NCI; grants OT3HL147741, R21HL140314 and U01HL128568 from the NHLBI; a con- tract HHSH250201700006C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-18- 1-2888 and N00014-17-1-2850 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; *Anthem, Inc.; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; Boston Children’s Hospital; *Bristol Myers Squibb Co.; *Celgene Corp.; Children’s Hospital of Los Angeles; *Chimerix, Inc.; *CSL Behring; *CytoSen Therapeutics, Inc.; Dana Farber Cancer Institute; *Daiichi Sankyo Co., Ltd.; Fred Hutchinson Cancer Research Center; *Gamida-Cell, Ltd.; Gilead Sciences, Inc.; *GlaxoSmithKline (GSK); HistoGenetics, Inc.; Immucor; Incyte Corporation; Janssen Biotech, Inc.; *Janssen Pharmaceuticals, Inc.; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; *Kite, a Gilead Company; *Magenta Therapeutics; Medac GmbH; The Medical College of Wisconsin; Mediware; Merck & Company, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Oncology; Novartis Pharmaceuticals Corporation; *Omeros Corporation; *Oncoimmune, Inc.; PCORI; *Pfizer, Inc.; *Phamacyclics, LLC; PIRCHE AG; *Regeneron Pharmaceuticals, Inc.; REGiMMUNE Corp.; *Sanofi Genzyme; *Seattle Genetics; *Shire; Sobi, Inc.; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; Swedish Orphan Biovitrum, Inc.; *Takeda Oncology; University of Minnesota; University of Pittsburgh; University of Texas-MD Anderson; University of Wisconsin – Madison and Viracor Eurofins. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. *Corporate Members.
References
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