Ponatinib, High-Dose Chemo Combo Likely to Benefit High-risk BP-CML

Survival rates for patients with blast-phase chronic myeloid leukemia (BP-CML) are notoriously poor, necessitating effective treatments to fill the care gap for this group who often survive less than 1 year.

Survival rates for patients with blast-phase chronic myeloid leukemia (BP-CML) are notoriously poor, necessitating effective treatments to fill the care gap for this group who often survive less than 1 year.1-3

However, final results from the dose-finding, seamless phase 1/2 MATCHPOINT trial4 presented at this year’s 63rd American Society of Hematology Annual Meeting & Exposition show a novel combination treatment holds great promise to address the treatment and care gaps for individuals with this rare type of leukemia.

The abstract, “Ponatinib in Combination with FLAG-IDA Chemotherapy for Blast-Phase Chronic Myeloid Leukemia: Final Results of the Seamless Phase I/II Dose-Finding UK Trials Acceleration Programme (TAP) Matchpoint Trial,”5 presented on Saturday, December 11, showed that the tyrosine kinase inhibitor (TKI) ponatinib, administered daily, can be safely combined with high-dose salvage chemotherapy comprising fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) for use in patients with BP-CML. The combination is meant to enable patients to achieve long-term survival, or remission, with a return to chronic phase disease.

After the 17 patients were recruited for participation between March 2015 and April 2018, from the UK Trials Acceleration Programme, the investigators used the EffTox method6 to uncover both treatment efficacy and dose-limiting toxicity (DLT) to reach their goal of optimal ponatinib dose when combined with chemotherapy. Second chronic phase and DLT were the primary outcomes, while combination therapy toxicity, allogeneic stem cell transplantation (ASCT), and survival were secondary outcomes.

“Crucially, long-term survival post transplant depends on first attaining a return to chronic phase though salvage treatment,” the authors wrote. “Novel strategies that improve response and can optimize transplant outcomes are therefore required.”

The median follow-up was 41 months, after which these results were seen post treatment:

  • Median overall survival (OS) was 12 months (95% CI, 6 months-not calculable)
  • Median OS was not reached in those who underwent ASCT
  • 30-mg daily ponatinib was seen as the optimal dose
  • Chronic phase was achieved by 11 patients
  • DLTs were experienced by just 4 patients
  • All patients in the study completed at least 1 treatment cycle of ponatinib and FLAG-IDA, with 8 completing both planned cycles

When ponatinib and FLAG-IDA were administered as salvage therapy, complete cytogenetic response was seen in 8 patients and major molecular response (MMR) was seen in 5 patients.

Three patients died during the study, and their deaths were attributed to treatment. The most common grade 3/4 nonhematologic toxicity was febrile neutropenia, seen in 29%, followed by lung infection in 24%, fever in 18%, and hypocalcemia in 18%. In addition, 12 patients were able to undergo ASCT, and 58% remain alive a median 3 years after follow-up. There was 1 disease relapse of a patient who had achieved MMR following ASCT.

The investigators stressed that their findings show great benefits of the ponatinib/FLAG-IDA, because of the combination treatment’s safety and that it enables patients with BP-CML, a known high-risk group, to once more achieve chronic-phase disease.

“Responding patients subsequently undergoing alloSCT can benefit from long-term disease-free survival,” they concluded. “The EffTox method enabled very efficient data usage from this high-risk patient population, and is a model for investigating novel therapies in other ultra-orphan cancers.”


1. Harrison C. Understanding blast phase chronic myeloid leukemia. Cancer Therapy Advisor. September 7, 2017. Accessed December 21, 2021. https://www.cancertherapyadvisor.com/home/cancer-topics/chronic-myeloid-leukemia/understanding-blast-phase-chronic-myeloid-leukemia/

2. Hehlmann R. How I treat CML blast crisis. Blood. 2012;120(4):737-47. doi:10.1182/blood-2012-03-380147

3. Lauseker M, Bachl K, Turkina A, et al. Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin. Am J Hematol. 2019;94(11):1236-1243. doi:10.1002/ajh.25628

4. University of Birmingham/Cancer Research UK Clinical Trials Unit. MAnagement of Transformed CHronic myeloid leukaemia: POnatinib and INTensive chemotherapy: a dose-finding study. Posted September 23, 2016. Accessed December 21, 2021. https://www.birmingham.ac.uk/Documents/college-mds/trials/crctu/haematology/matchpoint/Matchpoint-Trial-Summary-v5.0-23Sep2016-Clean-Copy.pdf

5. Copland M, Slade D, McIlroy G, et al. Ponatinib in combination with FLAG-IDA chemotherapy for blast-Phase chronic myeloid leukemia: final results of the seamless phase I/II dose-finding UK Trials Acceleration Programme (TAP) Matchpoint trial. Presented at: 63rd American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 312. Accessed December 17, 2021. https://ash.confex.com/ash/2021/webprogram/Paper147972.html

6. Brock K, Billingham L, Copland M, Siddique S, Sirovica M, Yap C.Implementing the EffTox dose-finding design in the Matchpoint trial. BMC Med Res Methodol. 2017;17(1):112. doi:10.1186/s12874-017-0381-x