Tyrosine kinase inhibitor-related factors pre-disposing to post-transplant thrombotic microangiopathy in patients with CML and Ph+ acute leukemias.

Abstract

Introduction: We have previously reported that pre-transplant use of tyrosine kinase inhibitors (TKIs) is independently associated with the occurrence of transplant-associated thrombotic microangiopathy (TA-TMA). However, the precise TKI-related factors which predispose to TA-TMA are unknown. In this retrospective analysis, we identify the TKI-related factors that are associated with TA-TMA.

Methods: This was a single center retrospective analysis of all patients with Philadelphia chromosome-positive (Ph+) malignancies who received BCR-ABL TKIs prior to transplant and underwent allogeneic hematopoietic stem cell transplantation (HSCT) between January 2008 and March 2019. Definite TA-TMA was defined as per Blood & Marrow Transplant Clinical Trials Network (BMT CTN) criteria and probable TMA as per Cho criteria. Details about the timing of the start and stop of TKI pre-transplant, the dose of TKIs used, and the number of TKIs exposed to pre-transplant were obtained. Imatinib > 400 mg/day, dasatinib > 100 mg/day, or nilotinib > 800 mg/day were considered as high dose TKI.

Results: Seventy-two patients with chronic myeloid leukemia (CML)/Ph+ acute leukemias underwent transplant in the above period. Patient, donor, and transplant characteristics are shown in Table 1 and were well-matched between those with and without TMA. Overall, 13 (18%) had TA-TMA (median day +128), with 9 definite and 4 probable. The only TKI-related factor significantly associated with TA-TMA was the use of high-dose TKI (p=0.04). Among non-TKI-related factors, acute graft versus host disease (GVHD) was associated with TA-TMA (p=0.01). On multivariate analysis, high dose TKI did not remain statistically significant (Odds Ratio (OR) 4.6, p=0.16). TA-TMA was associated with significantly worse long-term survival (6-year survival was 30% with TMA versus 62% without TMA, p=0.026).

Conclusions: Pre-transplant use of TKI was associated with risk of TMA in about one-fifth of patients. High-dose TKI and acute GVHD increased the risk of TA-TMA. Prospective studies are warranted to confirm these findings. TA-TMA was associated with significantly worse long-term survival.