Sequential High-Dose Chemotherapy Reinduction Followed By Haploidentical Transplantation in Acute Leukemias

Introduction: Outcomes after T-cell replete haploidentical stem cell transplantation (Haplo HSCT) with post- transplant Cyclophosphamide have been encouraging. As previously published (Schmid C. et al, JCO 2005; Ringdén O. et al, Br J Haematol. 2017), the sequential use of intensive chemotherapy and allogeneic transplantation represents a possible approach for the treatment of high-risk / relapsed-refractory Acute Myeloid Leukemia (AML).

Patients and Methods: At our Center, 22 high-risk patients were transplanted during chemo-induced neutropenia after high-dose salvage chemotherapy. Median age at transplant was 49 years (range 21-62); 6/22 (27%) had received a previous allograft. All patients but 2, who presented with blast crisis of chronic myeloid leukemia, suffered from refractory (no. 12) or secondary AML (no. 8). All patients had active disease at the time of Sequential Therapy and median marrow blast count before reinduction was 25% (range 6-88%). All patients received high-dose Cytarabine (≥1g/sqm) containing regimens as reinduction therapy. Conditioning, myeloablative, in 14/22 (64%) and non-myeloablative in 8/22 (36%), was started at a median of 9 days (range 4-15) after the last day of chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cyclophosphamide with calcineurine inhibitors and mycophenolic acid. Bone marrow was used as stem cell source in 18/22 (82%) patients.

Results: One/22 patient (4%) experienced primary graft failure and was successfully rescued with a second haploidentical transplant from the same donor. Median day of neutrophil recovery was day +18 (range 14-24). Median follow-up of survivors was 4.1 years (range 5-69 months); 1-year Overall and Event-Free Survivals were 34.5% and 30.3%, while 1-year Relapse Incidence and Non Relapse Mortality were 41.9% and 28%, respectively. Overall cumulative incidences of acute and chronic GVHD were 41% and 33.6% at day +100 and + 400. Among patients who developed GVHD, 3 grade III-IV acute GVHD and 2 moderate-severe chronic GVHD were observed. At 4.1 years post Haplo-HSCT, 5/22 (23%) patients are alive and disease free.

Conclusions: To our knowledge, we report the first experience of a sequential approach including Haplo HSCT. Though small the patient cohort, which also includes second transplants, our findings suggest that transplant-related toxicity was acceptable and early relapse was the major treatment-failure. However, long-term survival and disease-free rates in these very poor prognosis patients are rather encouraging. Only the prompt availability of a haploidentical donor allowed to implement this treatment modality.