Tyrosine Kinase Inhibitors with or without Donor Lymphocyte Infusion Continue to Provide Long-Term Survival after Relapse of Chronic Myeloid Leukemia Following Hematopoietic Cell Transplantation
Authors: Schmidt Sarah Ann , Holter Chakrabarty Jennifer , Liu Ying , Hu Zhen-Huan , Williams Kirsten M. , Alyea Edwin P. , Popat Uday , Sobecks Ronald , Scott Bart L , Saber Wael 
Published: October 2019

Abstract
Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) has expanded to include tyrosine kinase inhibitors (TKI) in addition to the prior standard of care, donor lymphocyte infusions (DLI). In the post-imatinib era of CML, pre-transplant therapy with TKI as well as maintenance with TKI after HCT has become common practice. We hypothesized TKI salvage therapy for relapse after HCT would continue to confer survival advantage compared to patients who received DLI alone, and would enhance therapy when combined with donor lymphocyte infusion. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database.
Methods: We retrospectively reviewed all patients reported to the CIBMTR registry from 2002-2014 who underwent HCT for CML and then subsequently relapsed post HCT. All the patients had received TKI pre-transplantation. Patients were included if: age was greater than 18 years, underwent first allogeneic transplantation (reduced or myeloablative), received marrow or peripheral blood from sibling/other related or unrelated donor and relapsed following HCT. One month post-relapse was used as a landmark to avoid selection bias due to early death post-relapse. The Cox proportional hazards model was used for multivariate analysis. Variables evaluated in the multivariate analysis included patient-related (age, gender, Karnofsky's performance status (KPS)), disease-related (disease status prior to HCT), and HCT-related (year of HCT, in-vivo T-cell depletion, time from transplant to relapse, conditioning intensity, post HCT TKI maintenance, recipient CMV status, donor type, graft source, GVHD Prophylaxis and pre-relapse GVHD).
Results: A total of 215 HCT recipients relapsed and were analyzed in the following groups 1) TKI alone n=128, 2) TKI with DLI n=48, and 3) DLI without TKI n=39 (Table 1). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). As compared to those in CP1, recipients that went to transplant in blast phase (BP) had a hazard ratio (HR) of 5.5 (95% confidence intervals [CI] 2.92-10.36; p<0.001) and patients in CP2 or higher had a HR 2.65 (95% CI 1.46-4.81; p = 0.001). Patients that received a DLI alone compared to a TKI with DLI had inferior survival HR 2.28 (95% CI 1.23-4.24; p = 0.009). Those who received TKI alone had similar survival compared to those who received TKI with DLI (p=0.81). In a sensitivity multivariate analysis, after controlling for how relapse was detected [clinical/hematologic vs. subclinical [molecular or cytogenetic]), TKI with or without DLI remained significantly associated with superior survival compared to DLI alone (p=0.003). Recipients who did not receive post-HCT maintenance had inferior survival with HR 2.0 (95% CI 1.21-3.31), p = 0.007. The presence of acute GVHD prior to relapse was not significantly associated with post-relapse OS (p= 0.775). Adjusted survival shows OS survival advantage of TKI use, both with or without DLI compared to DLI alone (p=0.013) (Fig 1).
Conclusion: Our study showed that disease status prior to HCT continues to confer poor prognosis. Interestingly, the presence of GVHD prior to relapse shows no impact on survival in this population of patients that had relapsed following HCT. Additionally, maintenance TKI post-HCT was associated with superior post-relapse survival and this was independent of time from HCT to relapse. Post relapse overall survival was highest in HCT recipients who received a salvage TKI containing regimen compared to DLI only salvage therapy. This data supports that despite use of TKI pre-transplantation and in maintenance therapy, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. This data does not suggest that adding a DLI to TKI adds an improvement in OS, although the sample size is small.

Disclosures
No relevant conflicts of interest to declare.