Myeloablative conditioning with thiotepa-busulfan-fludarabine does not improve the outcome of patients transplanted with active leukemia: final results of the GITMO prospective trial GANDALF-01

Abstract

The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population.

Fig. 1. Consort diagram.

IBMDR Italian Bone Marrow Donor Registry, HSCT allogeneic hematopoietic stem cell transplantation, CR complete remission.

Fig. 2. Overall survival and progression-free survival of the entire study population.

Overall survival of the overall population (a); Simon–Makuch survival curves comparing the transplant vs not transplant cohorts (b). Progression-free survival of the overall population (c); Simon-Makuch progression-free survival curves comparing the transplant vs not transplant cohorts (d). OS overall survival, PFS progression-free survival.

Fig. 3. Overall survival and progression-free survival of the transplant cohort.

Overall survival of the transplant cohort (a); overall survival according to disease: ALL vs AML (b), to donor type (c), to disease history: relapsed vs refractory (d), and to cIBMTR score (e); overall survival, in the refractory cohort, according to the number of pre-transplant cycles of chemotherapy (f). OS overall survival, ALL acute lymphoblastic leukemia, AML acute Myeloid Leukemia, cIBMTR center of International Bone Marrow Transplantation Registry.

Fig. 4. Cumulative incidence of relapse and non-relapse mortality of the transplant cohort.

A The cumulative incidence of relapse in the transplant cohort; B the non-relapse mortality of the transplant cohort. CIR cumulative incidence of relapse, NRM non-relapse mortality.