AL-01. Factors of relapse-free survival in the context of prophylactic tyrosine kinase inhibitors administration after allogeneic hematopoietic stem cell transplantation in adults with Ph-positive acute lymphoblastic leukemia

Summary

The landscape of Ph-positive ALL therapy outcomes has changed favorably since the incorporation of tyrosine kinase inhibitors (TKIs) with subsequent allo-HSCT into treatment protocols compared to historical cohorts. Although this therapy can offer a curative option, relatively high rate of relapse still limits the benefit of an allo-HSCT in a significant proportion of patients. To address whether posttransplant TKIs is a valid therapeutic approach to decrease the relapse rate, we conducted the study to assess its efficacy in multivariate analysis with disease- and allo-HSCT-specific factors.

Materials and methods

Patient characteristics and features of the disease are presented in Table 1. Cox proportional hazards model was used to assess the relation between covariates and RFS. As independent covariates were used: the year of allo-HSCT, donor type, the fact of prophylactic TKIs after transplant and the status of the disease at transplant, which included minimal residual disease (MRD) and complete remission (CR) status in two manners. To assess the effect of chronic GvHD on RFS in the context of posttransplant TKIs, a landmark analysis was performed for day+180, +270, +360. By day+ 360, almost all of the patients with active disease have died due to disease progression and this factor was excluded from the model.

Results and discussion

5-year OS and RFS were 54.4% (95% CI 43.6-65.2) and 40.2% (95% CI 29.8-50.6), respectively, whereas there is a trend to higher relapse rates for MRD-positive prior to allo-HSCT patients (52.2% (95% CI 34.6-69.8) vs 34.5% (95% CI 17.5-51.5)), (р=0.067) in the univariate analysis. Nonetheless, in a multivariate analysis for RFS, performed to assess the impact of MRD and relapsed/refractory (r/r) disease before allo-HSCT in the context of posttransplant TKIs application, the following factors were associated with reduced risk of relapse/death: allo-HSCT after 2012 (HR=0.49, 95% CI 0.27-0.89, p=0.019), any status of the disease before allo-HSCT except active disease with relatively the same HR (0.16-0.21), posttransplant TKIs prophylaxis (HR=0.26, 95% CI 0.14-0.48, p<0.001). With another distribution of statuses and TKIs we confirmed the data of favorable impact of later year of transplant (HR=0.46, 95% CI 0.26-0.83, p=0.009) and the ability of posttransplant TKIs to reduce negative effect of MRD-positive status. In addition, allo-HSCT from haploidentical donor increased the risks in both models (HR=2.49, 95% CI 1.08-5.75, p=0.032 and HR=2.71, 95% CI 1.20-6.13, p=0.016, respectively). There is no significance for cGvHD when performing landmark analysis on day+180 and day+270 on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32, p=0.161, respectively). Moreover, for those who survived by day+360, all remaining factors lose their significance on RFS.

Conclusions

This study confirms that TKIs are a critical posttransplant prophylactic component for adult patients with Ph-positive ALL. We found a significant benefit of prophylactic TKIs, thus the MRD-positive status and r/r disease prior to transplant did not decrease RFS. Moreover, the improvement of the transplant strategy since 2013 (first of all due to the widespread introduction of posttransplant cyclophosphamide into clinical practice) helps to improve outcomes. In the era of prophylactic TKIs a larger group of patients is needed to assess the effect of cGVHD on RFS at the time-dependent manner.

Keywords

Acute lymphoblastic leukemia, Ph-positive, BCR/ABL, tyrosine kinase inhibitors, allogeneic stem cell transplantation, relapse, chronic graft-versus-host disease.