Success is built on failures: tackling the challenge of ponatinib failure

Long-term follow up of clinical trials using imatinib, dasatinib, and nilotinib shows that 60–75% of patients with chronic phase chronic myeloid leukemia (CML-CP) can achieve major molecular response (MMR) [1–3] and the life expectancy of CML-CP patients treated with TKI therapy is now comparable to that of the normal population [4]. However, treatment discontinuation due to lack of response or intolerance is high, and 10–15% of CML-CP patients are likely to fail multiple sequential TKIs. Ponatinib, a third generation BCR-ABL1 TKI, potently inhibits BCR-ABL1 as well as all single mutants associated with resistance to imatinib and second generation TKIs including T315I. The phase 2 PACE trial enrolled patients with Philadelphia chromosome-positive (Phþ) leukemia, including all phases of CML as well as Phþ acute lymphoblastic leukemia. The patients were heavily pretreated: 93% and 60% patients had received two and three prior TKIs, respectively. Ponatinib therapy resulted in a complete cytogenetic response (CCyR) and MMR in 46% and 34% of patients, respectively [5]. Estimated five-year progression free survival (PFS) and overall survival (OS) in CML-CP were 49% and 77%, respectively [6]. Despite these promising results, 64% of patients in the PACE trial discontinued ponatinib either due to toxicity or disease progression [6] and the outcome of patients failing ponatinib is not known. In this issue, Boddu et al. from the MD Anderson Cancer Center report on the outcome of 36 CML patients after ponatinib discontinuation. Most of the patients who started ponatinib in CML-CP (13/19) and accelerated phase (AP; 15/17) stopped due to unsatisfactory response [7]. Very few patients treated with non-SCT approaches responded to subsequent therapy. The median OS for all patients was 16.6 months after discontinuing ponatinib therapy, but was higher in CML-CP patients (31 months) compared to CML-AP and BC (9 and 13 months, respectively) [7]. Thus, the management of patients failing ponatinib therapy remains an important challenge. As might be expected in a heavily treated population, 81% of patients who discontinued ponatinib did so due to resistance. The mechanism of ponatinib resistance is an active area of research. In contrast to first and second generation TKIs, no specific individual BCR-ABL1 kinase domain mutations were associated with ponatinib failure in CML-CP [8,9]. Compound mutations (variants containing 2 mutations within the same BCR-ABL1 allele) have emerged as a cause of ponatinib resistance in mutagenesis screens in vitro, but are not commonly identified in clinical samples. The incidence of new mutations emerging during ponatinib treatment is lower than in earlier studies of secondor third-line treatment with nilotinib, dasatinib, or bosutinib. Thus BCR-ABL1 kinase domain mutations do not appear to be the major driver of ponatinib resistance in CML-CP patients [7–9]. Treatment choices for patients after ponatinib failure are limited, and may include hematopoietic stem cell transplantation (HSCT), omacetaxine, supportive care, and clinical trials. Allogeneic HSCT remains the only curative option for heavily pretreated CML patients, and is recommended by the European Leukemia Net as third line therapy for CML-CP patients failing two TKIs, and in advanced phase CML and Phþ ALL patients. The optimal timing of HSCT for CML-CP patients remains unclear. Due to the availability of multiple TKIs, the tendency is to exhaust TKI options before referring the patient for transplant.