Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission

Abstract

The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5-6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2-63) after Allo-SCT (p = 0.01). The median starting dose of PONA was 30 mg/day (range 15-45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7-118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2-100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank p = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE.

Keywords: TKI; acute lymphoblastic leukemia; allogeneic stem cell transplantation; ponatinib.

Figure 1

Patients (pts) who discontinued PONA therapy after Allo-SCT. Pts 1a–3a, artery disease. Pts 4b–5b, intolerance. Pt 6c, second Allo-SCT. Pts 7d–12d, leukemia relapse. Pts 13e–16e, stop PONA for long-lasting cytologic remission with MRD negativity. Legend: (1) PONA prophylaxis (pts MRD neg); (2) PONA pre-emptive (pts MRD pos).

Figure 2

(A) Overall survival after Allo-SCT (92% at 60 months) (0 deaths in prophylaxis group and 2 deaths in the pre-emptive group). (B) Relapse-free survival (RFS) from the start of PONA—all 48 cases (71% at 60 months). (C) RFS according to the strategy (1 prophylaxis vs. 2 pre-emptive = dot line). Median RFS = NR in prophylaxis group and 81 months in pre-emptive group; log-rank, p = 0.02. (D) RFS according to the pre-Allo-SCT MRD status (pos or neg) and to the post-Allo-SCT PONA strategy (prophylaxis or pre-emptive). For RFS evaluation, the event was death or morphologic relapse. Only in the pre-emptive group, DLI + PONA in 10/22 cases (45%).

Figure 2

(A) Overall survival after Allo-SCT (92% at 60 months) (0 deaths in prophylaxis group and 2 deaths in the pre-emptive group). (B) Relapse-free survival (RFS) from the start of PONA—all 48 cases (71% at 60 months). (C) RFS according to the strategy (1 prophylaxis vs. 2 pre-emptive = dot line). Median RFS = NR in prophylaxis group and 81 months in pre-emptive group; log-rank, p = 0.02. (D) RFS according to the pre-Allo-SCT MRD status (pos or neg) and to the post-Allo-SCT PONA strategy (prophylaxis or pre-emptive). For RFS evaluation, the event was death or morphologic relapse. Only in the pre-emptive group, DLI + PONA in 10/22 cases (45%).