Outcomes of patients with relapsed refractory Philadelphia chromosome positive ALL are very poor even in the modern TKI era. So we have ponatinib which is a very highly potent TKI but even in the relapsed refractory setting you can get response rates of maybe 40% but in the large PACE study the one year progression free survival was only 8%. So these are not durable remissions.
There is some preclinical evidence that Philadelphia chromosome positive ALL is very dependent on BCL2 for survival and so this raised the potential therapeutic role of venetoclax for this disease. There are also some preclinical studies suggesting potential synergy between ponatinib and venetoclax. This was thought to potentially be mediated by the ability of ponatinib to also target the Lyn tyrosine kinase. So inhibition of the Lyn tyrosine kinase prevents upregulation of MCL-1 which is also a known mechanism of resistance to venetoclax-based regimens. So together this was the rationale for this particular combination in Philadelphia chromosome positive ALL.
What methods were used to investigate the efficacy of ponatinib, venetoclax and dexamethasone for patients with R/R Philadelphia chromosome positive ALL?
We conducted a phase I/II study and we’re reporting the phase I results at ASH this year. Of this combination of ponatinib, venetoclax and dexamethasone, for patients with relapsed refractory Philadelphia chromosome positive ALL, or we did allow patients with CML in lymphoid blast phase, patients had to have received at least one BCR-ABL TKI. Because of the potential toxicity of ponatinib patients could not have any uncontrolled cardiovascular disease and also because we were particularly interested in the role of venetoclax in this setting they couldn’t have had any prior venetoclax.
The way that the study was designed is initially in cycle 1 we gave patients 45mg of ponatinib daily. There was an initial seven day lead-in of ponatinib monotherapy and then followed on day 8 with the combination of venetoclax, which we did a ramp up to either 400mg or 800mg depending on the dose level, and then also beginning on day 8 four days of dexamethasone 40mg daily. Then in cycles 2 and beyond the dose of ponatinib was adjusted, as we’ve done in other studies, so the ponatinib dose either got dropped to 30mg for patients who had achieved a remission or for patients who had achieved a complete molecular remission, which is absence of detectable BCR-ABL by PCR, those patients were decreased to 15mg of ponatinib. Then they continued on the same dose of venetoclax, it was given continuously, either 400mg daily or 800mg daily, and then four days of dexamethasone each cycle. We also gave CNS prophylaxis to all patients and then rituximab was added for patients who were CD20 positive.
What were the results?
We treated nine patients in the phase I portion of the study. Of course for a phase I study the main endpoint was to determine the maximum tolerated dose of venetoclax in the combination. So we treated three patients at the 400mg daily dose and then six patients at the 800mg daily dose. We actually had no DLTs observed. 800mg of venetoclax was the highest dose that we were looking to explore so that is what we’re considering the recommended phase II dose for future study.
Overall the adverse events are similar to what you would expect with this combination. There was some myelosuppression, particularly at the 800mg dose but this was easily addressed, generally speaking, by interrupting the dose of venetoclax and in some patients reducing the dose.
Even though we were talking about the phase I portion of the study, we of course wanted to look at response rates and durability of response. So we were very encouraged that the overall response rate, the combination of CR and CRi, was 56%, so five out of the nine patients. All five also achieved a complete molecular response and we saw these responses across different groups. So we saw ranging in the 50-60% range of response in patients with prior ponatinib or even prior blinatumomab or prior transplant. One particularly interesting thing that we saw was that, although the numbers were small, of the three patients who were treated with 400mg daily dose of venetoclax none responded. However, five of the six treated with the 800mg daily dose responded so the response rate is 83% in the group who received the venetoclax 800mg daily. Of all the responses, with a median follow-up of nearly a year, none of them have relapsed so that’s very encouraging, potentially durable responses that we’re seeing.
What is the future impact of these results in the treatment of R/R Philadelphia chromosome positive ALL?
So this is a population that we really have very limited options. As I said, we know ponatinib is an effective drug but the potential implications of what we’re seeing in terms of what appear to be higher response rates, higher rates of deep response as indicated by the complete molecular remission rates, and also some initial evidence of very durable responses, that this is an excellent alternative to ponatinib single agent, certainly in the relapsed refractory setting.
Importantly, this is an entirely oral regimen, oral and chemotherapy-free regimen. So this is a very easy regimen to give to patients in this setting and with a high complete molecular response rate the goal is that these patients could potentially be bridged to transplant.
So I think this opens up the potential role of venetoclax in this disease in the relapsed refractory setting and then if we see continued very encouraging data for durability of responses this is something that could also potentially be evaluated in the frontline setting and integrating venetoclax into regimens for the treatment of Philadelphia chromosome positive ALL.
I would again emphasise that this is an entirely chemotherapy-free, entirely oral regimen that we are seeing durable responses and no patients have relapsed to date with a median follow-up of 10-12 months or so. This compares very favourably to the historical data with ponatinib alone where the one year progression free survival was only 8%. So I do think these responses are much more durable that we see with ponatinib single agent so it emphasises the potential role of venetoclax in this disease.