ASH 2014 Report #2: New data on Ponatinib – most potent, but overdosed?

EPIC-Bestresponse[Translations: German]

Ponatinib, the first 3rd generation Tyrosine Kinase Inhibitor and potentially one of the most potent CML drugs on the market, has gone through a roller coaster ride over the past two years.

The patient community has been following the development of ponatinib since it the first data of a phase I study with the so-called AP24534, today called ponatinib/Iclusig, was presented at ASH 2009. Given it is the only drug effective against T315I and some other multi-resistant mutations, and seems to work very effectively in many patients even after failure of imatinib, dasatinib and nilotinib, the drug has deserved a lot of attention. Based on a rough regulatory ride due to new concerns on the side effect profile, the CML community was now curious to hear the new data on ponatinib presented at ASH 2014. Of special interest were updates on side effects and risk factors, and whether those trial participants who had to reduce their ponatinib doses were still responding well to the drug, but with better tolerability.


In December 2012, ponatinib (Iclusig), which is the only drug that works on CML with a multi-resistant T315I mutation, was approved in the USA. On 31 October 2013, the Food and Drug Administration (FDA) suggested to ponatinib’s manufacturer ARIAD to voluntarily suspend marketing of ponatinib, and to suspend all ongoing clinical trials. This request resulted from the observation of a steady increase in the number of events of life-threatening blood clots and severe narrowing of blood vessels, which was observed through continued safety monitoring on ongoing clinical trials. In January 2014, after further assessment of the data, marketing of ponatinib was resumed in the USA in January 2014 alongside with a more restricted approval, an updated safety information for doctors, and the requirement that ARIAD conducts new trials evaluating lower doses, treatment response and toxicity of ponatinib.

In parallel, the European Medicines Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) carried out a review of available data and concluded that the risk of blood vessel blockage with ponatinib is likely to be dose-related, however at the same time the data was insufficient to formally recommend the use of lower doses, which on the other hand might not be as effective in all patients and in long-term treatment. In contrast to the FDA, potentially also because the European EMA approval only allowed the use of ponatinib as a third line drug after failure or intolerance of dasatinib or nilotinib, ponatinib continued to be approved in Europe on the same dose (45mg/day), however also requiring additional clinical trials.

New data on Ponatinib presented at ASH 2014

Six presentations and posters covered ponatinib at this year’s ASH congress.

PACE-landmarkThe first presentation by Dr Martin Müller from Mannheim provided an update on the PACE phase II study, analysing the achievement of responses of CML to the drug at early time points. Of note, participants of this study had experienced a failure of dasatinib, nilotinib, or developed a T315I mutation, before they enrolled in this study. 60% of the patients had at least three other TKI treatments before getting ponatinib. 80% of patients were resistant to nilotinib or dasatinib, and only 15% were intolerant to both drugs. The median time since diagnosis was 7 years, and the median follow-up of patients on this study was 38 months. After 12 months of ponatinib therapy, 56% of patients achieved a complete cytogenetic response, and 39% a major molecular response (BCR-ABL <0,1%). The two-year overall survival was 90% of those that achieved <1% BCR-ABL within 3 months after start of ponatinib, and 84% of those whose BCR-ABL was still above 1% after 3 months. Achieving an major molecular response (MMR) early in treatment with ponatinib, even for those heavily pre-treated patients, seemed to improve outcomes. This means that even after failing other 2nd generation TKIs, a significant proportion of patients achieves good responses on ponatinib. Early monitoring of response on ponatinib treatment might help to decide whether continuing with the therapy, or switching to bone marrow transplant, might be the preferred option for the individual patient. Benefits and risks, also taking into account comorbidities) when using ponatinib would need to be assessed within the context of each individual patient.

EPIC-Vascular2A second presentation by Dr Jeff Lipton described the Phase III EPIC trial which investigated ponatinib as a first line treatment after CML diagnosis, and compared this to Imatinib. Even though the study was suspended in October 2013 due to aforementioned regulatory safety concerns, the safety and efficacy data up to the point of study termination, by which patients received on median 5 months of ponatinib, has now been presented. 36% of patients on ponatinib had to reduce the dose (initially 45mg/day) due to side effects and 57% had to interrupt treatment. However 94% of ponatinib patients, in comparison to 68% of patients on imatinib, achieved <10% BCR-ABL at 3 months, and 15% of ponatinib patients, as opposed to none of the Imatinib patients, achieved even an MR4.5 within that short time frame. However, there was clearly a higher incidence of severe adverse events with ponatinib. Most critical were serious blood clotting events, which 7% of the ponatinib and less than 1% of the imatinib patients experienced. However, of those 12 patients that developed these vascular events, 11 had at least one cardiovascular risk factor or relevant medical event in the past.

So was the 45mg/day as a starting dose in all studies probably set too high? Fixed starting doses of 45mg/day of ponatinib were used in all recent ponatinib studies, but the option of treatment interruptions and dose reductions in those trials, coupled with multiple assessments of molecular responses of patients, enabled now to explore dose-response relationships. An analysis presented on poster #4546 showed that the average number of days required to decrease initial BCR-ABL levels by 10-fold was 47.5 days for ponatinib, while it took patients on imatinib the double number of days. In newly diagnosed patients, even ponatinib doses as low as 15 mg per day induced more rapid decreases in BCR-ABL levels than 400 mg imatinib per day.

With regards to the association of doses and side effects, an analysis of 671 ponatinib patients of different studies, presented on poster #4546, demonstrated that ponatinib dosing level is associated with many side effects including blood clotting and narrowing of blood vessels.

The data supports investigating approaches to reduce the average dose level, such as starting at lower doses and/or reducing dose when response is achieved, to reduce toxicity while keeping high efficacy of the treatment. Dose-ranging trials of ponatinib are currently in preparation to evaluate benefit/risk of different dosing schemes.

Some thoughts

Much of the data presented at ASH 2014 reflected the importance of ponatinib in terms of efficacy, even in a third line setting. However it also underlined the concerns in terms of toxicity which seems to be much stronger at the currently approved dose of 45mg ponatinib per day than on any other TKI on its standard dosing. For patients with resistance or intolerance on imatinib, dasatinib and nilotinib, and for patients harbouring the T315I mutation, ponatinib is an important treatment, maybe even the only option.

EPIC-SEIt however seems that the trials that led to approval of ponatinib have aimed too high in terms of dosing, focusing too much on best efficacy against CML while taking not enough time to investigate toxicity well enough. This led to this unfortunate regulatory rollercoaster ride for patients, authorities and the manufacturer, when it occurred that a significant proportion of patients were suffering from severe side effects. The mechanisms that cause these side effects are still poorly understood (which is not only in the case of ponatinib, but also for rarer but still existent cardiovascular challenges of some patients on nilotinib, dasatinib and imatinib). However, many abstracts at ASH2014 demonstrate that the community is doing a lot of research on this and on all drugs – which again is one advantage of patients who participate in trials in comparison to those getting new drugs outside of trials, given that many studies and study clinics included cardiovascular monitoring of at-risk patients once the concerns started to arise.

At ASH, it became clear that physicians will be watching cardiovascular risk factors of each patient more closely now, for example high blood pressure, diabetes and previous cardiovascular events. The data on ponatinib presented at ASH 2014 reflects those benefit-risk discussions very well. It provides a good basis for dose-ranging trials which might investigate dynamic dosing schemes for still effective treatment with reduced side effects.

For example, the upcoming SPIRIT3 trial in the UK, coordinated by Dr Stephen O’Brien, will evaluate the selective use of dose-optimized ponatinib in patient who are not responding optimally to first-line treatment, and will also use the QRISK2 score to evaluate the cardiovascular risk of CML patients. The emphasis will be on finding the right balance between efficacy and risk for each individual patient.

Innovative trial designs (like SPIRIT3), and patients that decide to join clinical studies, will surely help the community to understand these issues much better in the future.

Additional information

Related ASH Abstracts

See the ASH-Abstracts database

  • 4546 Impact of Dose Intensity of Ponatinib on Selected Adverse Events: Multivariate Analyses from a Pooled Population of Clinical Trial Patients
  • 3135 Long-Term Follow-up of Ponatinib Efficacy and Safety in the Phase 2 PACE Trial
  • 3153 High-Resolution Analysis of the Relationship Between Dose and Molecular Response in CP-CML Patients Treated with Ponatinib or Imatinib
  • 4558 Long-Term Follow-up of a Phase 1 Study of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)
  • 4552 Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials
  • 4535 Ponatinib As Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

See our other detailed reports from ASH 2014:


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