TO THE EDITOR:
A 16-year-old male patient was diagnosed with B lymphoid blast phase (BP) CML, and received initial treatment with prednisolone combined with imatinib at 600 mg/day for 4 weeks. A follow-up bone marrow (BM) study showed complete hematologic response (CHR) with major cytogenetic response. While maintaining imatinib with the aim of undergoing allogeneic HSCT, the patient relapsed to accelerated phase (AP) 4 months after achieving initial CHR. Complete blood count at the time of AP relapse showed a white blood cell count of 11.77×109/L (8% blasts), hemoglobin 8.6 g/dL and platelet count of 82×109/L, while the BM showed 18% blasts (Fig. 1). The patient progressed to B lymphoid BP again one month later. Molecular studies for
The patient proceeded to matched sibling donor peripheral blood stem cell transplantation, with myeloablative conditioning consisting of busulfan and cyclophosphamide. The immediate post-transplant course was complicated by veno-occlusive disease and hemorrhagic cystitis. Although the patient continued to show a PB RQ-RT-PCR value of 0 after HSCT, a surveillance study obtained 9 months after transplant showed an increased value of 4×10-5. The patient was restarted on ponatinib at the previous dose of 45 mg/day, resulting in conversion to molecularly undetectable status again 2 months later. Six months after restarting ponatinib, the dose was decreased to 15 mg/day as the
Several studies have reported on the use of ponatinib in pediatric Philadelphia chromosome-positive (Ph+) leukemias [2-7], including 22 patients in total with CML [2, 5-7]. Six of these CML patients had the T315I mutation and ponatinib therapy resulted in decreased leukemic burden in 4 patients (Table 1) [2, 6, 7]. Our case study adds to the literature on T315I mutation (+) pediatric CML patients who showed a rapid and favorable response to ponatinib therapy.
Although ponatinib is effective in CML patients resistant to first-line TKI therapy, the drug also has the potential for serious side effects. A phase 2 study of ponatinib in adult patients with Ph+ leukemias with long-term follow-up reported that the most common adverse events in chronic phase CML patients were rash, abdominal pain and thrombocytopenia, while serious adverse events included pancreatitis, atrial fibrillation, pneumonia and angina pectoris . The majority of these side effects occurred within 3 months of starting ponatinib . Perhaps the most distinct complication of ponatinib therapy is arterial occlusive events (AOEs), and the landmark phase 2 study reported a 25% cumulative incidence of AOEs at 5 years, with a median time to onset of 13.4 months . The risk for AOEs is likely related to the dose of ponatinib, underscoring the need to treat with the minimum effective dose . Our patient showed skin complications, including facial rash and peripheral limb erythema, on restarting ponatinib after post-HSCT molecular relapse. We subsequently decreased the ponatinib dose once the
The optimum duration of prophylactic TKI therapy for CML patients post-allogeneic HSCT remains unclear. One recent study on adult patients with Ph+ leukemias reported a median duration of post-HSCT TKI therapy of 16 months . Specifically regarding ponatinib, one study on an adult patient with T315I mutation (+) BP CML described prophylactic therapy for more than 1 year after HSCT . Studies on the duration of TKI therapy necessary for patients who show molecular relapse post-HSCT are also few. One adult study showed that 4 out of 10 CML patients continued to show complete molecular response after stopping imatinib therapy initiated for molecular or cytogenetic relapse after HSCT; the median duration of TKI therapy was 269 days in the 4 patients . Maintaining deep molecular remission for at least 2 years was a criterion used in studies on imatinib cessation in both adult and pediatric CML patients [14,15]. A similar prerequisite may be considered for stopping TKI therapy administered for post-HSCT relapse, although patients who have received allogeneic HSCT, unlike transplant-naïve patients treated with TKI only, may be aided by the immunologic effects of the graft.
In summary, our case study adds to the limited literature on children and adolescents with T315I mutation (+) CML treated with ponatinib. The TKI was able to significantly decrease the
No potential conflicts of interest relevant to this article were reported.