Page 266 - Haematologica - Vol. 105 n. 6 - June 2020

K. Halaburda et al.
scripts represent molecular attributes of CBF AML and are driver mutations for leukemogenesis. They disrupt normal hematopoiesis dependent on core binding factor subunit α (RUNX1) and β (CBFB) by silencing tumor suppressor genes leading to neoplastic transformation.2 Accompanying secondary gene mutations (mutations of NRAS, KIT, NF1, FLT3, KRAS, ASXL1&2), additional cyto- genetic abnormalities, and clinical features at diagnosis (age, white blood cell and blast counts, extramedullary involvement) affect treatment outcomes, but general prog- nosis in CBF AML remains favorable.3,4 Indeed, current induction chemotherapy standards lead to a complete remission (CR) rate of 87-89%, involving a high propor- tion of younger patients.5,6 Repeated high or intermediate- dose cytarabine consolidation provides long-term disease control in a large proportion of patients. Conventional chemotherapy results in long-term survival in 53-64% of patients. The major reason for treatment failure in CBF AML is relapse, reported in 30-50% of patients.7,8 Given the relatively favorable results of chemotherapy, patients with CBF leukemia are not usually candidates for allo- geneic hematopoietic stem cell transplantation (HSCT) in first CR (CR1). However, CBF AML is a heterogeneous group of malignancies. Several variables, including type of CBF subunit involved, age, additional molecular or cytoge- netic abnormalities, and dynamics of measurable residual disease (MRD) are known to influence the outcomes and contribute to disease recurrence.7-11 HSCT is recognized as a standard procedure in patients who relapse and subse- quently achieve CR2.4,12 To evaluate the results of HSCT in CBF AML patients in CR2, we decided to perform a retro- spective study using registry data from 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 transplant centers, mainly in Europe. Member centers are required to report all consecutive stem cell transplantations and follow ups 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 deter- mine accuracy of data. Before transplantation, patients or legal guardians provide informed consent authorizing the use of their anonymized personal information for research purposes.
Methods
Patients and data selection
The study was approved by the ALWP Institutional Review Board and included all adult patients undergoing HSCT in the peri- od from the year 2000 to 2014 reported to the EBMT. The centers were asked by survey to provide data on all patients with t(8;21) or inv(16) to verify the cytogenetic aberrations and to update the transplantation outcomes using designated clinical forms. The patients had to have de novo CBF AML, with classical cytogenetics confirmation of t(8;21) or inv(16) at initial diagnosis, undergoing HSCT in hematologic CR2, defined as less than 5% blasts in the bone marrow (BM) and absence of extramedullary involvement, and regardless of current peripheral blood (PB) counts (i.e. bona fide CR or CR with incomplete hematologic recovery). All patients received BM or PB transplantation (BMT, PBSCT) from matched sibling (MSD) or unrelated donors (UD) after myeloablative (MAC) or reduced intensity (RIC) conditioning, as defined by the
EBMT criteria.13 The variables selected to assess outcomes were: age, type of AML, white blood cell count, presence of extramedullary involvement at diagnosis, additional cytogenetic abnormalities, time from diagnosis to CR1, duration of CR1, time from diagnosis and from CR2 to transplantation, molecular remis- sion status at transplantation, Karnofsky performance score (KPS) at transplantation, sex matching of patients and donors, cytomegalovirus (CMV) serological status of patients and donors, year of transplantation, type of the donor, source of stem cells, conditioning intensity, and in vivo T-cell depletion.
End points and statistical analysis
The primary end point was leukemia-free survival (LFS). Secondary end points were: overall survival (OS), relapse inci- dence (RI), non-relapse mortality (NRM), graft-versus-host disease- free and leukemia-free survival (GRFS), as well as acute and chron- ic graft-versus-host disease (aGvHD and cGvHD). LFS was defined as survival without any symptoms of disease recurrence. OS was defined as probability of survival from transplantation to the last follow up. Relapse was defined as presence of >5% blasts in the BM or extramedullary disease after transplantation. NRM was defined as mortality from any cause not related to disease recur- rence and GRFS was defined as survival without leukemia, aGvHD grade III-IV or extensive cGvHD.14 Minimal residual dis- ease (MRD) was measured in the BM during the interval between last chemotherapy and transplantation. Real-time quantitative polymerase chain reaction (RT-qPCR) was used for RUNX1- RUNX1T1 and CBFB-MYH11 quantification. MRD results were reported by the centers as absent (MRDneg) or present (MRDpos) in line with their local guidelines. Acute GvHD was graded according to Glucksberg criteria.15 Surviving patients were cen- sored at last follow up. Probabilities of LFS, OS, and GRFS were calculated using Kaplan-Meier estimates. Cumulative incidence functions (CIF) were used to determine RI and NRM in a compet- ing risk setting with each other. Univariate analyses were per- formed using Gray’s test for CIF and the log-rank test for LFS and OS. For all univariate analyses, continuous variables were catego- rized and the median was used as cut-off point. Associations of patient and transplantation characteristics with outcomes were evaluated in multivariate analysis using Cox proportional hazards model. Multivariate models were built by using stepwise selection procedure. Results were expressed as the hazard ratio (HR) with 95% Confidence Interval (CI). All tests were two-sided. The type- 1 error rate was fixed at 0.05 for determination of factors associat- ed with time to event outcomes. Statistical analyses were per- formed with SPSS 24 (SPSS Inc. /IBM, Armonk, NY, USA) and R 1.3.0 (R Development Core Team, Vienna, Austria) software pack- ages.
Results
The detailed characteristics of the 631 patients from 181 transplant centers who met the study inclusion criteria are shown in Table 1. Three hundred and sixty-six patients (58%) harbored inv(16) and 265 (42%) t(8;21). The two groups were compared for essential patient and transplant characteristics (Online Supplementary Table S1). The differ- ences included: sex of the patients [with more males in the t(8;21) group], time from diagnosis to transplantation [which was longer in the t(8;21) group], and time from diagnosis to CR1 [which was also longer in the t(8;21) group]. Altogether there were 361 (57%) males and 270 (43%) females. Median age at transplantation was 41.7 years [range 18-73, interquartile range (IQR) 31.3-51.2],
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