Elsevier

The Lancet Haematology

Volume 2, Issue 9, September 2015, Pages e376-e383
The Lancet Haematology

Articles
Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study

https://doi.org/10.1016/S2352-3026(15)00127-1Get rights and content

Summary

Background

Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML.

Methods

We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868.

Findings

We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9–25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3–4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib.

Interpretation

Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting.

Funding

MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.

Introduction

Imatinib1, 2, 3 and second-generation tyrosine kinase inhibitors (TKIs) such as dasatinib4, 5 or nilotinib6, 7 result in many patients responding to therapy and have excellent long-term outcomes as first-line treatment in patients with chronic-phase chronic myeloid leukaemia (CML). However, up to 25–30% of patients are resistant to first-line TKI therapy8, 9 through various mechanisms, most often mutations of ABL kinase domain.10, 11 Thus, outcomes could be improved by treatments that circumvent or prevent TKI resistance.

Ponatinib is a third-generation TKI that is highly active in patients with CML with resistance to multiple TKIs or with a Thr315Ile mutation.12, 13, 14, 15, 16 In mutagenesis assays, ponatinib also prevents the emergence of resistant clones.12 Ponatinib is a multikinase inhibitor that inhibits kinases other than non-BCR-ABL1 kinase such as FLT3, FGFR, PDGFR, KIT, RET, SRC, and VEGFR.17, 18, 19 In a phase 2 trial of patients with CML resistant to multiple TKIs,14 a major cytogenetic response (MCyR) occurred in 60% of 267 patients treated. Complete cytogenetic response (CCyR) occurred in 53%, major molecular response (MMR) in 59%, and MR4·5 in 20% of patients. 2 year progression-free survival was 67% and 2 year overall survival was 86%.20

Based on these results, in May, 2012, we started a phase 2 trial to assess whether ponatinib was safe and active as initial therapy for patients with CML in chronic phase.

Section snippets

Study design and participants

We did a single-arm, phase 2 study. The protocol is available in the appendix. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with CML in early chronic phase from MD Anderson Cancer Center, Houston, TX, USA. Eligibility criteria for patients included diagnosis of chronic-phase CML within 6 months; no previous therapy for CML other than hydroxycarbamide or 1 month or less of therapy with approved TKIs; age 18 years and older; Eastern Cooperative Oncology Group performance status

Results

We enrolled 51 patients with a median age of 48 years (range 21–75) and median time from diagnosis to treatment of 0·7 months (0–2; table 1, figure 1). Sokal risk score was low for most patients (table 1) and EUTOS score was low risk in 41 (91%) of 45 patients evaluated and high risk in four (9%). Median follow-up was 20·9 months (IQR 14·9–25·2). Only one of six patients who had previously received a TKI had achieved complete haematological response (receiving dasatinib for 30 days) and 73%

Discussion

We show that ponatinib induces deep and early responses when used as first-line treatment in patients with chronic-phase CML. Use of ponatinib in this setting was associated with frequent elevation of pancreatic enzymes and the occurrence of some arteriothrombotic events.

Imatinib has considerably improved outcomes for patients with chronic-phase CML. Dasatinib and nilotinib further improved the rate, depth, and time to response when used as a first-line therapy. However, second-generation TKIs

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