Does Post-Transplant Maintenance Therapy With Tyrosine Kinase Inhibitors Improve Outcomes of Patients With High-Risk Philadelphia Chromosome-Positive Leukemia?

Abstract

Introduction

The effect of post-transplant maintenance tyrosine kinase inhibitors (TKIs) on the outcomes of allogeneic hematopoietic stem cell transplantation in high-risk Philadelphia chromosome-positive (Ph⁺) leukemia remains unknown.

Patients and Methods

A retrospective analysis that included allograft recipients with accelerated phase and blast phase chronic myeloid leukemia or Ph⁺ acute lymphoblastic leukemia who had received post-transplant maintenance TKI therapy from 2004 to 2014.

Results

A total of 26 patients, 9 with accelerated phase/blast phase CML and 17 with Ph⁺ acute lymphoblastic leukemia, received maintenance post-transplant therapy with imatinib, dasatinib, nilotinib, or ponatinib. The TKI was selected according to the pretransplantation TKI response, anticipated toxicities, and ABL1 domain mutations, when present. Newer generation TKIs were initiated at a ≥ 50% dose reduction from the standard pretransplantation dosing to limit the toxicities and avoid therapy interruptions. TKIs were started a median of 100 days (range, 28-238 days) after transplantation and were administered for a median of 16 months (range, 8 days to 105 months). Eight patients discontinued therapy because of adverse events. With a median follow-up of 3.6 years (range, 4 months to 8.7 years), the 5-year relapse-free survival rate was 61%. All 3 patients who developed a relapse underwent successful salvage treatment and remained disease-free. The 5-year overall survival rate was 78%.

Conclusion

Maintenance TKI therapy after transplantation is feasible and might reduce the incidence of relapses and improve outcomes after allogeneic hematopoietic stem cell transplantation for patients with high-risk Ph⁺ leukemia.

Introduction

Understanding the role of the fusion oncoprotein BCR-ABL1 in the pathogenesis of Philadelphia chromosome-positive (Ph⁺) leukemia led to the development of targeted therapy with tyrosine kinase inhibitors (TKIs) and dramatic improvements in the outcomes. For chronic phase (CP) chronic myeloid leukemia (CML), the 8-year overall survival (OS) increased from < 20% to 80% to 90%, and the outcomes of TKI-responsive accelerated phase (AP) have been increasingly comparable with those for CP-CML.1, 2, 3 In Ph⁺ acute lymphoblastic leukemia (ALL), remission rates of 90% to 95% are commonly achievable when TKIs are combined with chemotherapy, and these remissions can be sustained.4, 5 Allogeneic hematopoietic stem cell transplantation (HSCT) remains the upfront standard-of-care treatment of Ph⁺ ALL in first complete remission (CR1) and blast phase (BP) CML and is reserved for TKI failure in CP- and AP-CML. However, the transplant outcomes have not improved, despite greater remissions with the use of pretransplantation TKIs,⁶ largely owing to the high incidence of post-transplant relapse.7, 8

Prophylactic or therapeutic TKIs can be safely administered after transplantation.⁹ The administration of post-transplant TKIs as prophylactic maintenance is feasible using imatinib.10, 11, 12 However, given that allografting is increasingly being performed in patients in whom first-line and later TKI therapy has failed, data on the safety and efficacy of newer generation TKIs administered after transplantation would be of great interest, especially if activity is demonstrated before transplantation. We report our single-institution outcomes of allograft recipients transplanted for advanced-phase CML and Ph⁺ ALL who received post-transplant maintenance TKI therapy.