Ponatinib Plus Chemo: A New Way to Treat Ph-positive ALL

Ponatinib is effective against the T315I mutation, which is a leading cuase of resistance, and has shown sustainable responses in patients with Ph+ acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), which accounts for 25% of diagnoses, has traditionally been associated with a very poor prognosis.

Before the onset of tyrosine kinase inhibitors (TKIs), intensive chemotherapy was the only option. Of late, the combination of TKIs with or without chemotherapy for induction therapy for Ph+ ALL has been used. First-generation agents, such as imatinib, with chemotherapy have shown a response rate of greater than 90%. The second-generation agent dasatinib alone with steroids has also been shown to have very good response rates.1

Even though there have been good initial responses, eventually most patients relapse and have poor long term survival, at around 60% at 3 years. The most common reason for the disease to become refractory or relapse is the T315I mutation.2

Ponatinib, a third-generation TKI, is known to be effective against the T315I mutation.3 A study was done by Jabbour et al at MD Anderson using ponatinib along with chemotherapy, such as hyper-CVAD, as first-line therapy for patients with Ph+ ALL.4 In this study, 37 patients received 8 cycles of hyper-CVAD with ponatinib at 45 mg from days 1 to 14 of cycle 1 and continuously thereafter.

Major molecular response was seen is 100% of the patients and complete molecular response was seen in 78% of patients treated with the combination. There were just 2 relapses. The complete response (CR) rate at 2 years was 97%.

The event-free and overall survival rates were 81% and 80% at 2 years, which is better than what has been seen with any of the first- or second-generation TKIs. The adverse events with ponatinib consist mainly of myocardial infarction and thrombotic events, and are higher than earlier generation TKIs.

Given the significant improvement over the previous agents, ponatinib plus chemotherapy should be the first-line standard of care for patients with Ph+ ALL who don't have contraindications for ponatinib.

Whether these patients should still receive allogeneic transplants as soon as a CR is achieved or left on maintenance ponatinib indefinitely until there is evidence of minimal residual disease or relapse still needs to be studied. A randomized study to answer this question should be completed soon.

References

  1. Foà R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome—positive acute lymphoblastic leukemia. Blood. 2011;118(25): 6521-6528.
  2. Ravandi F, O’Brien S, Thomas D, et al. First report of phase II study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116:2070—2077.
  3. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401—412
  4. Jabbour E, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015;16(15):1547-1555.