A Retrospective Analysis of Ponatinib-Based Therapy in Patients with Myeloid Blast Phase Chronic Myeloid Leukemia: Responses Rates, Outcomes and Patterns of Relapse

Background: Ponatinib, a potent third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI), is effective in chronic myeloid leukemia (CML) with resistance mutations, including the T315I mutation, although response rates as monotherapy are modest in patients (pts) with blast phase disease. Given the aggressive nature of CML in myeloid blast phase (MBP), acute myeloid leukemia-like chemotherapy in combination with a potent TKI is recommended by consensus guidelines. However, the outcomes of ponatinib-based combination regimens in CML-MBP remain largely unknown.

Methods: We retrospectively evaluated the response rates and survival outcomes of pts who received a ponatinib-based regimen at our institution for CML-MBP. Pts could have received ponatinib as any line of therapy for CML-MBP and could have received ponatinib alone or in combination with any chemotherapy backbone. The outcomes of CML-MBP after ponatinib failure were also analyzed.

Results: 76 pts received a ponatinib-based regimen for CML-MBP between 1/2008 and 8/2023. The median age was 50 years (range, 20-90 years). 50 pts (66%) received ponatinib as their first therapy for CML-MBP (4 for de novo CML-MBP and 46 for CML-MBP transformed from previously treated earlier-phase CML); the other 26 pts (34%) received ponatinib as salvage for CML-MBP. 47% of tested pts had at least 1 ABL1 kinase domain (KD) mutation, including 8 pts with T315I, 7 with E255K and 3 with F317L mutations. Ponatinib was given with intensive chemotherapy (IC) in 28 pts (37%), with IC + venetoclax in 7 pts (9%), with hypomethylating agents (HMA) + venetoclax in 18 pts (23%), with HMA (without venetoclax) in 6 pts (8%), and as monotherapy in 17 pts (22%).

The overall response rate (ORR: including CR/CRi/MLFS/PR) with ponatinib-based therapy was 50%, including CR in 26% and CRi in 13% (CR/CRi rate: 40%). The ORR was 62% for pts receiving ponatinib as first therapy for CML-MBP vs. 27% for pts who received ponatinib for relapsed/refractory CML-MBP (P=0.003). The ORR was 56% for ponatinib combination therapy vs. 29% for ponatinib monotherapy (P=0.06). Overall, 28% of pts achieved CCyR and 20% achieved MMR or better.

Among responders, 15 pts were bridged to allogeneic stem cell transplant (ASCT) (20% overall; 40% of responders). 10 pts (67%) received a post-ASCT TKI (ponatinib in 8 and dasatinib and bosutinib in 1 each) for a median duration of 20.1 months. Overall, 8 pts died in remission (3 after ASCT and 5 in the absence of ASCT), none of which were due to ponatinib-related toxicity.

With a median follow-up of 46.3 months, the median RFS was 10.3 months (2-year RFS 32%), and the median OS was 8.5 months (2-year OS 27%). Pts who received ponatinib as first therapy for CML-MBP had better outcomes than those who received it as salvage therapy (2-year OS: 38% vs. 14%, respectively; P=0.005). Among pts who achieved CR/CRi, the median OS was 29.4 months (2-year OS 55%). In a landmark analysis, responding pts who proceeded directly to ASCT had superior outcomes to those who did not (2-year OS 71% vs. 38%, respectively; P=0.06).

49 pts experienced ponatinib failure (30 pts who were refractory to ponatinib and 19 pts who relapsed). Among the 19 relapsed pts, the median duration of response was 4.2 months (range, 1-19 months). Relapse was bone marrow (BM)-only in 13 pts (68%), extramedullary (EM)-only in 4 pts (21%), and BM + EM in 2 pts (11%). Overall, 4/19 relapses (21%) involved the CNS. Among 40 pts who received salvage therapy after ponatinib failure, the ORR to first salvage was 27% and the CR/CRi rate was 20%. 5 pts were bridged directly to ASCT (10% overall; 46% of responders). Following ponatinib failure, outcomes were poor, with a median OS of 3.9 months and 1-year OS rate of 21%.

Conclusion: Ponatinib-based therapies result in high rates of response in CML-MBP, particularly when given as first therapy for CML-MBP and when used in combination with chemotherapy. Pts who are bridged to ASCT have the best outcomes (2-year OS 71%). However, outcomes are dismal after failure of ponatinib, highlighting the need for more effective treatment strategies of CML-MBP.