PONATINIB EXPERIENCE IN A PEDIATRIC CHRONIC MYELOID LEUKEMIA PATIENT

Abstract

Objective: Chronic myeloid leukemia (CML) is rarely seen in children. The development of myelofibrosis in CML is not uncommon and is associated with a poor prognosis. In cases unresponsive to treatment, tyrosine kinase mutation should be checked for drug resistance, second generation tyrosine kinase inhibitor (TKI) drugs (dasatinib/nilotinib) should be switched to and a suitable donor for bone marrow transplantation should be sought. Third-choice TKI can be used in children who are unresponsive to treatment and do not have a suitable donor. Materials and Methods: Experience of third-choice TKI(ponatinib) in a child with CML diagnosis due to unresponsiveness to treatment. Results: A 5.5-year-old female patient with no known disease was referred to us because of hepatosplenomegaly (liver 5 cm, spleen 10 cm). There was no laboratory disorder except for anemia (hgb 8.9 g/dL) and high LDH (1104 U/L). WBC was 11.1 × 103/µL neu 6.92 × 103/ µL plt 304000/µL. Peripheral smear showed leukoerythroblastosis. Bone marrow biopsy result was evaluated as compatible with myelofibrosis and an increase in blast rate from 8% to 18% in the bone marrow. The patient was diagnosed CML accelerated phase with cytogenetic (46,XX,t(9:22)(q34;q11))and translocation (t(9:22)- p210,BCR/ABL positive) results and. Imatinib treatment was started at 400 mg/m2.The copy number of BCR-ABL p210 checked before treatment was 72% IS. However, the patient developed febrile neutropenia, and imatinib dose reduction (< 200 mg/m2) and interruption were required in the follow-up.Under imatinib treatment, BCR-ABL copy number was 16%IS at 1 month, 11%IS at 3 months, and 95%IS at 5 months. Due to the increase in the BCR-ABL copy number, nilotinib was switched to as a second-choice TKI(230 g/m2/dose, in 2 doses).No mutation could be detected in the c-ABL gene, which was examined for tyrosine kinase resistance. HLA groups were sent from the family and compatible donors were not found. Due to severe neutropenia in the follow-up, nilotinib could be continued at 50% dose. Under nilotinib treatment, the BCR-ABL copy number was 13% IS at 1 month, 10% IS at 2 months, and 31% IS at 3 months. The patient was started on ponatinib (18 mg/m2/day) as a third choice TKI. However, due to the deep neutropenia of the patient, it was possible to continue with a dose of 10 mg/m2 from the 2nd week. With this dose, the neutrophil is around 0.8-1 × 103/µL. Under ponatinib treatment, BCR-ABL copy number was 6.6% IS at 1 month, 0.8% IS at 3 months, 0.09% at 5 months, and 0.05% at 6 months. No significant side effects were observed except neutropenia. Conclusion: There is no approved treatment in pediatric CML cases where the second choice TKI fails and there is no donor for transplantation. FDA approval for ponatinib in adult patients was obtained in December 2020. Ponatinib is a natural or mutant pan-BCR-ABL mutation inhibitor. It also inhibits VEGFR, FGFR,PDGFR,EPH and SRC kinases as well as KIT,RET,TIE2 and FLT3. The use of ponatinib should be evaluated by monitoring side effects/tolerance in pediatric cases where there is no other treatment option, and there is a need for studies on this subject.