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Allogeneic transplantation for -5/5q- AML
Introduction
Allogeneic stem cell transplantation (SCT) is a standard of care in patients with intermediate and high-risk acute myeloid leukemia (AML).1,2 High-risk AML is mainly defined by the presence of determined poor-risk cytoge- netic abnormalities at diagnosis together with specific mutational events.3-6 In general, conventional post-remis- sion high-dose chemotherapy is not capable of eradicating the leukemic-initiating stem-cell population of high-risk AML, harboring strong chemoresistance mechanisms,7 and only the potent graft-versus-leukemia (GvL) effect mediated by SCT may provide the capability to eradicate this cell population and overcome the poor prognosis of these high-risk AML subtypes, as previously demonstrat- ed.2,8-10 Among the heterogeneous group of high-risk AML, prognosis can be further stratified based on specific genet- ic abnormalities, and the potential benefit of SCT differs among these diverse AML subtypes.11 Monosomy 5 or deletion of the long arm of chromosome 5 (-5/5q) has been part of the definition of high-risk AML for many years.12 Furthermore, monosomal karyotype (MK) described ten years ago referred to a cytogenetic risk cate- gory constantly associated with a very poor outcome.13,14 Within this subgroup, patients harboring a single mono- somy, including monosomy 5, have a relatively better out- come than patients with two or more monosomies.15 We recently reported the outcome of SCT in 125 patients with AML and abnormalities of the short arm of chromosome 17 [abn(17p)] transplanted in first remission. The addition of -5/5q- to abn(17p) translated into a very bad outcome with a 2-year leukemia-free survival (LFS) of about 12%.16 The benefit of SCT in this subgroup appears very limited, which raises the question of the role of SCT in these patients. However, this observation was based on a limit- ed number of patients and it was difficult to draw any conclusions as to whether the dismal outcomes were driv- en by -5/5q- itself or by the combination of -5/5q- with abn(17p) or TP53 mutations. In addition, the frequent association of -5/5q- with abn(17p) suggests co-operation between TP53 deletion/mutations and loss of putative tumor suppressor genes localized in the commonly delet- ed 5q region.17-19 However, -5/5q- is also well-represent- ed in patients with MK and complex karyotype (CK) without abn(17p). The interaction observed between -5/5q- and abn(17p) in our previous dataset raised the question of the impact of other additional adverse cytoge- netic abnormalities such as monosomy 7 or deletion 7q (-7/7q-), abn(17p), CK and MK on the outcomes of AML with -5/5q- after SCT, and this formed the rationale for our current retrospective study.
Methods
Patient selection and data collection
This is a retrospective registry-based analysis on behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). The EBMT is a non-profit, scientific society representing more than 600 trans- plant centers, mainly in Europe, that are required to report all consecutive stem cell transplantations and their follow up once a year. Data are entered, managed and maintained in a central database with internet access; each EBMT center is represented in this database. Audits are routinely performed to determine
the accuracy of the data. Patients or legal guardians provide informed consent authorizing the use of their personal informa- tion for research purposes. The study was approved by the ALWP review board.
Eligibility criteria for the study included all patients >18 years with de novo or secondary AML transplanted between 1st January 2000 and 31st December 2015 from an HLA-matched sibling or a fully-matched (10/10) unrelated donor. Patients undergoing sec- ond transplantation, as well as patients receiving a haplo-identi- cal or cord-blood transplantation, were excluded. We further selected patients harboring -5/5q- and having a full karyotype report within the database in order to study the prognostic effect of additional cytogenetic features. A total of 501 patients from 148 centers met the study inclusion criteria and have been selected for further analysis. Myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) have been defined elsewhere.20
The following variables were selected and included in the analysis: year of transplantation, age, gender, white blood cell count (WBC) at diagnosis, number of induction courses to achieve complete remission (CR), status at transplantation, time from diagnosis to SCT, type of conditioning regimen, use of total body irradiation (TBI), in vivo T-cell depletion (including both anti-thymocyte globulins and alemtuzumab), cytomegalovirus (CMV) status of donor and recipient, donor type, source of stem cells, Karnofsky performance status (KPS) at transplantation, engraftment, presence of acute and chronic graft-versus-host disease (GvHD), and grade of acute GvHD. For the analysis of additional cytogenetic abnormalities, we includ- ed in our analysis the presence of abn(17p), -7/7q-, MK and CK classified according to cytogenetic status according to Medical Research Council UK criteria.5 MK has been defined according to Breems et al.,13 and CK was defined by the presence of >3 chromosomal abnormalities.
Statistical analysis and end point definitions
The primary end point was LFS. Secondary end points included relapse incidence (RI), non-relapse mortality (NRM), overall sur- vival (OS), acute and chronic GvHD, and refined GvHD- free/relapse-free survival (GRFS). All outcomes were measured from the time of transplant. LFS was defined as survival without relapse; patients alive without relapse were censored at the time of last contact. OS was based on death from any cause. NRM was defined as death without previous relapse. GRFS was defined as survival without grade 3-4 acute GvHD, extensive chronic GvHD, relapse or death.21 Surviving patients were censored at the time of last contact. The probabilities of OS, LFS, and GRFS were calculat- ed by the Kaplan-Meier test, and those of acute and chronic GvHD, NRM, and relapse by the cumulative incidence estimator to accommodate competing risks. For NRM, relapse was the com- peting risk, and for relapse, the competing risk was NRM. For acute and chronic GvHD, death without the event and relapse were the competing risks.
For all univariate analyses, continuous variables were catego- rized and the median value was used as a cut-off point. A Cox pro- portional hazards model was used for multivariate regression including factors associated with LFS in univariate analysis and individual cytogenetic abnormalities. Finally, we defined four groups according to the presence of CK, MK and the presence or not of individual cytogenetic abnormalities significantly associat- ed with the outcome. Patients', disease and transplant-related characteristics for the four groups were compared by using χ2 sta- tistics for categorical variables and the Kruskall-Wallis test for con- tinuous variables. Factors differing in distribution between the groups or conceptually important were included in the final Cox
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