Ponatinib in the leukemia world: why a reevaluation is necessary for Philadelphia chromosome-positive patients with T315I mutation

Abstract

Strategic drug design is used to meet the needs of numerous diseases for which there is no other recourse. Take the T315I mutation, for example, which occurs in Philadelphia chromosome-positive leukemias and renders all currently available tissue kinase inhibitors useless. The US FDA therefore saw it fit to avail ponatinib, the therapeutic result of careful drug design, to patients based on early data. However, its sales and marketing were later suspended due to emerging safety concerns. This drug has now returned to market albeit with tighter labeling. While the lesson for early approvals may be to restrict the drug to as narrow a patient population as possible, the potential benefits of this drug for the target population must not be lost amidst the controversy.

Keywords::

• leukemia
• Philadelphia chromosome
• ponatinib
• T315I mutation
• tyrosine kinase inhibitor

Ponatinib (Ariad Pharmaceuticals, Cambridge, MA, USA) underwent fast-track approval on December 14, 2012, based on data from an ongoing Phase II study of 449 patients with a 10-month median follow-up [1]. At this early stage, the efficacy data were highly favorable, with approximately one out of two patients in the chronic phase of chronic myelogenous leukemia (CML) demonstrating cytogenic response, and approximately one out of two patients with accelerated phase CML showing major hematologic response. However, safety data became an issue in subsequent months, and on October 31, 2013, the US FDA asked the manufacturer to suspend sales and marketing. Just 7 weeks later, this decision was partially reversed for a select group of patients who could be treated under single-patient emergency investigational new drug application. Potential ponatinib patients under investigational new drug included those previously on the drug who were responding, and new patients who had no other treatment option and for whom all other available therapies had failed. In January 2014, Ariad Pharmaceuticals resumed marketing ponatinib with indications for use limited to treatment of adult patients with T315I mutation in the setting of CML or acute lymphoblastic leukemia.

Among CML patients, 95% are Philadelphia chromosome-positive (Ph+), and among acute lymphoblastic leukemia patients, 25–30% of adult cases and 2–10% of pediatric cases are Ph+ [2]. The majority of Ph+ CML and Ph+ acute lymphoblastic leukemia patients express the 210 kDa form of the BCR-ABL protein [2]. Ponatinib belongs to the tyrosine kinase inhibitor (TKI) class of small molecule drugs engineered to target the BCR-ABL oncogene product which is the cause of leukemic transformation in Ph+ hematopoietic stem cells [3]. Imatinib, the first-in-class among TKIs, remains as the first-line therapy for many patients, but fails in approximately 40% of cases due to disease resistance or unacceptable side effects [4]. Several genetic mutations have been identified in the TKI-binding domain of imatinib-resistant patients, which disrupt the drug binding site or create steric hindrance. While patients respond favorably to second-generation TKIs, the T315I mutation in the BCR-ABL gene present in 37.4% of imatinib-resistant patients creates steric hindrance which renders all second-generation TKIs ineffective [5]. Ponatinib is a third-generation TKI specifically engineered to overcome steric hindrance imposed by the T315I mutation [6]. Moreover, ponatinib inhibits native BCR-ABL, in addition to all mutations including T315I [3]. The efficacy of ponatinib in the T315I mutation is evident from the Phase II clinical trial as well as from structure–function studies [3,7].

Whereas the efficacy of ponatinib was clear early on during Phase I as well as Phase II trials, there are questions about why there was a lag in the awareness of the severity of adverse events or whether there was too much haste in its fast-track approval. On October 11, 2013, the FDA reported that while the clinical trials conducted before approval had serious arterial blood clots in 8% of ponatinib-treated patients and blood clots in the veins in 3% of patients, new data showed that at least 20% of all participants treated with ponatinib had developed blood clots or narrowing of blood vessels. It must be noted that these were severe adverse events, which included death. So, was there a lag in public awareness regarding adverse events? Clinical trials by design do involve risks, including death as a direct result or as an indirect result of participating in the use of untested drugs. Individuals and their families must always be applauded for their decision to enter a drug trial at the risk of shortening their lives beyond the limit imposed by disease, while providing benefit to society. Therefore, adverse events in a clinical trial are to be expected, within reason, and these conform to strict reporting guidelines. However, there is the question of fast-track approval of ponatinib. Wisdom comes in hindsight, and perhaps the labeling of ponatinib could have been more restrictive. It is a fine balancing act to fast-track approve an orphan drug which could make the difference between life and death, and at the same time slow down to acquire long-term safety data.

In spite of the controversy, by far the most compelling evidence for the acceptance of ponatinib in the clinical setting comes from the FDA report of 200 patients who accessed ponatinib through filing single-patient investigational new drug applications between October and December 2013, at a time when ponatinib was taken off the market due to highly publicized adverse events, including fatal adverse events [8]. This fact alone makes it imperative that a case be made to address availing this drug to those who have no other recourse and for whom there is clinical benefit. In the Phase I clinical trial dose escalation study, ponatinib was administered once daily at seven doses ranging from 2 to 60 mg, and 45 mg was determined to be the maximum tolerated dose [7]. This dose was selected as the recommended dose for all further clinical studies, including the Phase II trial [9]. In preclinical experimentation, 40 nM concentrations suppressed the emergence of any single mutation [6]. Pharmacokinetics data from the Phase I study illustrate that a daily dose of 30 mg achieved concentrations above 40 nM, whereas a lower dose at 15 mg fell short. Pharmacodynamics data indicated that 30 mg daily dose achieved ≥50% reduction in phospho-CRKL in all patients, and in two out of three patients, it was achieved at 15 mg. The in vivo BCR-ABL kinase inhibition measurement by phospho-CRKL monitoring is recognized as a prognostic parameter.

Strategies to maximize benefits while reducing the adverse events could include proactive risk management, such as introducing anticoagulants during treatment. Another approach would be to create a dosing regimen that reduces toxicity, such as dose interruptions, dose reductions and/or sequential step-up and step-down regimen. It is highly likely that a daily dose of ponatinib below 45 mg and above 15 mg would meet the pharmacokinetic and pharmacodynamic targets of 40 nM and ≥50% phospho-CRKL reduction, respectively. A new recommended dose is necessary to provide the balance between safety, efficacy and toxicity that is acceptable. While the side effects deemed intolerable by patients have often times justified switching treatment therapies, the safety profile of ponatinib does not merit adoption of this treatment regimen so lightly. More importantly, the dispensing of this drug under unnecessary circumstances must not compromise its availability to patients with the T315I mutation in the BCR-ABL gene for whom all second-generation TKIs are ineffective. That dose levels can be reduced and still produce desired outcomes is supported by recent data presented at the American Society of Clinical Oncology meeting in June, 2014 [10]. Furthermore, the addition of another TKI can only pave the path to individualized medicine through patient genome matching with each TKI’s binding site to predict therapeutic success [11].

Financial & competing interest disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.