A Phase 2 Study of Ponatinib for Prevention of Relapse after Allotransplantation in FLT3-ITD + AML Patients : The Ponallo Trial

Background : For acute myeloid leukemia (AML) patients relapse remains a major issue after allogeneic stem cell transplantation (allo-SCT). In those with a FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD+), survivals have been improved with the use of small molecule Flt3 receptor protein-tyrosine kinase inhibitors in maintenance due to a significant decrease of relapse after allo-SCT. Ponatinib (pona) is a multikinase inhibitor that is approved for the treatment of Philadelphia chromosome-positive acute lymphoblastic and chronic myelogenous leukemias. It has also activity against FLT3-mutants including ITD and ITD691L but not D835 within the Flt3 activation segment. Pona may then represent an alternative drug for maintenance after allo-SCT in FLT3-ITD+ AML patients.

Methods : This was a multicenter phase 2 non-randomized prospective study testing the efficacy and tolerability of pona after allo-SCT in FLT3-ITD+ AML patients (ClinicalTrial.gov ID : NCT03690115). The main objective was the incidence of relapse at 2 years post-transplant with the hypothesis that this incidence at 2 years will be reduced at 15% instead of 30%. Seventy-seven patients had to be included. Inclusion criteria were all patients, aged between 18 and 70 yo, with a FLT-3 ITD+ AML in cytologic complete remission (<5% of bone marrow blasts) and a documented engraftment at the time of starting pona after an allo-SCT using any type of conditioning regimen and donor. The control of a GVHD (if present) was mandatory as well as a platelets count ≥70 Giga/l and a neutrophils count ≥ 1 Giga/l at time of inclusion. The study was supported by Incyte.

Initially, pona administration had to start between day +60 and +90/100 at the dose of 30 mg/day for 1-year. However, because of excesssive hematopoietic toxicity, an amendment was made after the 14th patient to start pona between day 100 and day 120 post-allo. During the study, It was allowed to restart pona at 15 mg/day after resolution of 30 mg dose related toxicities. After 1 year of pona it was not allowed to start a new FLT3 inhibitor or pursue pona.

Results : Twenty-three patients were included between December 2019 and April 2022. Among them, 22 were effectively treated. Indeed, the last patient included did not receive pona due to hepatic abnormalities incompatible with the start of pona. Also, because of a very low rate of enrollment, the trial was closed prematurely in accordance with the sponsor in December 2022. Results for the 22 treated patients are reported here. Patient characteristics are given in Table 1. With a median follow-up of 740 days (range : 374-930), 1-y and 2-y overall survival were 81.3% (66.3-99.6) and 63.9% (45.4-90.0), and 1-y and 2-y leukemia-free survival were 54.5% (37.2-79.8) and 49% (31.8-75.7), respectively. Ten relapses occured at a median of 186 days (range=69-481) after allo-SCT with a CI of relapse of 45.5% at 2 years.

Pona was started at a median of 69 days post-allo-SCT (range : 60-130). The median duration of treatment was 75.5 days (range : 4-369). Only 3 patients received one year of treatment and all at 30 mg/day as required by the protocol. The reasons for stopping pona were toxicity in 11 patients, relapse in 6, toxicity then relapse in 1, GVHD then relapse in 1. Among the 13 patients who stopped pona for toxicity or GVHD, 6 restarted pona (15 mg n=5, 30 mg n=1) then stoppped again for toxicity (n=4) or progression (n=2).

A total of 36 adverse events related to pona were documented in 17 patients. The majority was grade 1 or 2 (n=27, 75%) while 6 grade 3 (17%) and 3 grade 4 (8%) occured. ( Table 2)

Conclusion : Ponatinib administration after allo-SCT is associated with toxicity and do not reduce relapse or improve survival in this small cohort of FLT3+ AML patients. Other FLT3 inhibitors have to be considered in FLT3+ AML patients for maintenance after allo-SCT.