Ponatinib superior to imatinib in combination with reduced-intensity chemotherapy in newly diagnosed Ph positive ALL

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Published: 15 Jun 2023
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Dr Elias Jabbour - MD Anderson Cancer Center, Houston, USA

Dr Elias Jabbour speaks to ecancer at EHA 2023 about the PhALLCON study which evaluated ponatinib versus imatinib in newly diagnosed Ph positive ALL.

He explains that patients were randomised between low-dose chemotherapy and ponatinib and low-dose chemotherapy and imatinib.

Dr Jabbour reports that patients in the ponatinib arm showed a two-fold increase in the rate of MRD-negative CR.

Hello, my name is Elias Jabbour. Today I’ll be sharing with you the data from the PhALLCON which is a randomised phase III trial, randomising patients with Philadelphia positive ALL into two arms, 2:1, low dose chemotherapy and ponatinib or low dose chemotherapy and imatinib. The ponatinib dose was 30mg/day reduced to 15mg/day once the CMR was obtained; the standard of care arm was imatinib 600mg/day all along. The design was 2:1, again, induction, consolidation and maintenance on single drug alone. 

The primary endpoint of the study was quite original, it is what you call MRD negative CR, meaning patients had to have two criteria – CR for four weeks or longer and MRD by the end of induction, which is week 12, so a composite endpoint. The secondary endpoints, the relevant ones, were event free survival and other endpoints were survival, safety, duration of response and others. 

Why the study was designed to start with, we know that TKI and chemotherapy or steroid followed by transplant are standard of care in Ph positive ALL. There are no optimal TKIs to be used up front. We know that when we use first or second generation TKIs responses are high, mainly in CR, but CMR, or complete molecular remission, is around 20%. Then in the long run only 40% make it in the long run. Why is this? It’s because of two things, one, we don’t have deep molecular responses, and, two, because we have the emergence of certain mutations, 359, that can cause resistance to ponatinib or certain TKIs. Therefore the aim of the study was to compare ponatinib plus chemotherapy to imatinib and chemotherapy.

So, this is the design of the study, this is how it is. Patients were enrolled and when you look at the patient disposition we have a follow-up of 18-20 months. On the study more patients on ponatinib stayed on treatment compared to imatinib, there was a high drop-out, mainly due to resistance which is not the case for ponatinib. From safety there was no difference between the two arms. Characteristics of the patients were similar, the median age was in the 60s – around 40% are 60s and older. Then it’s important to note that 50% had one cardiovascular risk factor, 30% had two risk factors which is what we see in this patient population. 

The primary endpoint was met, in fact, ponatinib shows a twofold increase in the rate of MRD negative CR. This was around 36% for ponatinib and 17% for imatinib therapy. However, when we look at real-life practice we assess only for MRD, we don’t care about CR, whether full CR or not. If we focus on such a scenario the rate of MRD negativity with ponatinib was 40% compared to 20% with imatinib. Not only have we seen at 12 weeks the MRD improving, at different timepoints there were deeper responses with ponatinib sustained all along at three, six, nine, twelve months. Then we have seen a deeper response with ponatinib, what we call MR4.5 and deeper. When it comes to duration of response, we have seen more durable responses on ponatinib compared to imatinib and less patients requiring subsequent therapeutic treatment at treatment failure.

With the follow-up we have today, it’s important to note that there are more patients on imatinib who discontinued treatment to receive subsequent care, mainly ponatinib or blinatumomab. This is very important because when you move from imatinib to get second line better therapy, this is crossover. We have seen more patients on the imatinib arm receiving ponatinib and blinatumomab. The impact of that is when it comes to event free survival, so that’s what brings me to the event free survival. The follow-up is short for the study and, despite crossover, meaning patients on imatinib receiving ponatinib and blinatumomab, we see a trend for better EFS in favour of ponatinib which was not hugely significant. 

So what is EFS? EFS is defined by death, loss of response, CR, and this is it. So event or loss of response and death. Essentially when we look at what we call PFS where it is, in addition to loss of response and not responding and death, loss of molecular response or patients who did not achieve MRD negativity, then we see an even better advantage in favour of ponatinib which is parallel to what we do in our lives. So an EFS trend and PFS by far better with ponatinib compared to imatinib therapy.

For survival it’s still a short follow-up and there was no difference in survival between the two arms. It’s important to note, however, that we know historically with imatinib the survival at three years is only 40%. In this trial the survival is at 85% and even higher and that reflects the importance of subsequent therapy or what we call crossover.

Finally, when it comes to safety, the treatment was well tolerated – grade 1 and 2 mainly, grade 3 and 4 were rare and there was no difference between the two arms. We’ve seen some hypertension, LFTs increase but nothing significant. Now, people will ask me about what about the vascular events. Grade 3 and 4 emergent adverse events were similar between the two arms; when we look at the vascular activity adverse events, it was 2% with ponatinib, 1% with imatinib and imatinib is a very tolerable regimen. Therefore we did not see an increase in toxicities with ponatinib compared to imatinib therapy. The discontinuation rate was equivalent between the two; the venous thrombotic events were equivalent between the two. That affects the safety of ponatinib, mainly due to two factors. One, we started at 31mg and we reduced the dose and the patients enrolled were not really sick from the cardiovascular point of view. 

So based on the safety and efficacy data today of ponatinib, I can say the study met its endpoint, it is significant improvement of MRD CR which is quite relevant. The drug has been shown to be safe compared to imatinib therapy. Based, therefore, on efficacy and safety, ponatinib should be considered standard of care in combination with chemotherapy in the management of Philadelphia positive ALL in the front line.