Cytogenetic Evolution and Its Effect on Survival of Patients with Relapse Myeloid Neoplasms after Allogeneic Hematopoietic Cell Transplantation

Abstract

Survival of patients with myeloid neoplasms that relapsed after allogeneic hematopoietic cell transplantation (HCT) is poor. It is generally presumed that acquisition of increasing cytogenetic complexity may contribute to poor outcomes, but cytogenetic changes that accompany relapse are not well characterized. The role of cytotoxic chemotherapy in promoting mutagenic events has been proposed, however, the specific correlation between type and dose of chemotherapy with cytogenetic evolution has not been studied. A single institution, retrospective case cohort analysis of patients with myeloid malignancies who relapsed after an allogeneic HCT. Cytogenetic (CG) data at diagnosis and at relapse were compared with special emphasis on gain in abnormalities resulting in increasing cytogenetic complexity, known as cytogenetic evolution (CGE). Transplant-related characteristics were compared between patients who developed CGE and those who did not. Overall survival expressed in Kaplan-Meier curve, compared by log-rank test between the two groups. Of 506 patients undergoing allogeneic HCT transplanted for a myeloid malignancy at Mayo Clinic Arizona between 2006-2014, 92 patients relapsed post-transplantation, 49 cases met inclusion criteria; CGE was observed in 25, while 24 cases demonstrated unchanged cytogenetic results at relapse. Age was similar between groups (mean=49.4). Male to female ratio was equal in the CGE cohort (48% vs 52%), and a slight female predominance was observed in the non-CGE cohort (67% vs 33%). Patient disease spectrum included 27 de-novo AML, 19 MDS-MPN, and 3 CML. The ratio of MDS-MPN to de-novo AML was 12/11 in CGE cohort versus 7/16 in non-CGE cohort. High risk to intermediate disease risk ratio in CGE was 64.0/36.0 versus non-CGE 45.8/54.2. Both cohorts had similar median days from BMT to relapse and comparable induction and conditioning regimen exposures. Median OS was 1.35 months (95% CI: 0.69-2.76) in CGE cohort versus 5.65 (95% CI: 2.14-8.48) in the unchanged cohort, p<0.001. CG evolution, defined as gains in cytogenetic abnormalities resulting in increasing CG complexity, is common at relapse of myeloid malignancies after allogeneic HCT. CGE is associated with a significantly shorter survival after relapse compared to patients without CGE. The CGE cohort exhibits two major trends when compared to the non-CGE group: 1. a greater proportion of high-risk disease than intermediate-risk and 2. a larger proportion of MDS/MPN disease spectrum than de-novo AML. There was no association with myeloablative versus reduced intensity conditioning regimen or lines of salvage therapy received. The clear association of CGE and shorter survival suggests that new markers would be useful to identify patients with risk of cytogenetic instability at transplant, to enable more individualized therapy in this patient group.