Ponatinib and blinatumomab shows complete molecular response for patients with Philadelphia chromosome-positive ALL

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Published: 13 Jun 2022
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Dr Nicholas Short - MD Anderson Cancer Center, Houston, USA

Dr Nicholas Short speaks to ecancer at the EHA 2022 congress about a study looking at ponatinib and blinatumomab for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL).

He explains that 55 patients were treated with the patients seeing high rates of complete molecular response and durability.

Prof Short believes that if the data can be confirmed with longer follow up then this could be a potential paradigm shift for the treatment of Philadelphia chromosome-positive ALL.

Historically, Philadelphia chromosome positive ALL has been treated with intensive chemotherapy
plus a BCR-ABL tyrosine kinase inhibitor. With that combination we can generally achieve long-term
survival of up to about 50% in patients. However, one major problem with that combination is that
many patients still relapse and they often relapse with a specific mutation in the ABL gene called
T315I. So ponatinib is a specific BCR-ABL TKI that is able to overcome those mutations. It has been
shown to have significant activity in combination with intensive chemotherapy. We have shown very
high molecular response rates when given with hyper-CVAD plus ponatinib with many patients having
very long-term survival without need for transplant in first remission.

Blinatumomab is also a very effective drug in relapsed/refractory Philadelphia chromosome positive
ALL and it is associated with very high rates of MRD response. So this trial was specifically to look at
two of these very potent agents that we have, so ponatinib, a very potent TKI, and blinatumomab, a
very effective immune-based therapy, with the intent that we can develop this chemotherapy-free
combination.

 

What was the design of the study?

The design of the study is we give ponatinib 30mg daily in combination with blinatumomab.
Importantly, we start them both at the same time, this is in contrast, for example, to the D-ALBA study
which was done by the Italian group that did sequential dasatinib for a period of time and then
introduced the blinatumomab. So we introduced both the TKI, ponatinib, and blinatumomab at the
same time, beginning with cycle 1. We start ponatinib, again, at 30mg daily and then we decrease the
dose to 15mg daily once patients achieve a complete molecular response, meaning we can’t detect
BCR-ABL transcripts by PCR anymore. We give up to five cycles of blinatumomab and then patients
just receive maintenance ponatinib for at least five years and indefinitely if they’re tolerating it well.
We also give twelve doses of intrathecal chemotherapy which is important to prevent CNS relapses.

 

What were the key findings?

We’ve treated 55 patients so far; 35 patients with newly diagnosed Philadelphia chromosome positive
ALL, 14 patients with relapsed/refractory Ph+ ALL and six patients with CML in lymphoid blast phase.
We’ve seen very high rates of response and particularly complete molecular response, so essentially
MRD negativity. In the front line cohort, for example, 85% of patients achieved a complete molecular
response; in the relapsed/refractory cohort 79% of patients achieved a complete molecular response.
The responses are lower in the patients with CML in lymphoid blast phase because it’s really a
different biology.

Importantly, when we look at the durability of these responses, in the front line cohort in particular
what we have seen is none of the patients have relapsed and we’ve only transplanted one patient. So
this is in sharp contrast to what the dogma has been for a long time in Philadelphia chromosome
positive ALL where the thought was that we need to get everybody into remission and then transplant
them in first remission. So we’ve only transplanted one out of the 35 patients.

Despite the fact that most of these patients are not transplanted with the chemotherapy free regimen,
we have a two-year overall survival rate of 93%, again with no relapses. Outcomes also look very
good in the relapsed/refractory group – we have a two year survival of 61% – so it looks encouraging
also in patients with relapsed/refractory Ph+ ALL.

 

What did you see in terms of safety?

The safety is really consistent with the known toxicity profiles of ponatinib and blinatumomab when
given separately. Certainly ponatinib can be associated with particular toxicities – cardiovascular
toxicities, pancreatitis, blood clots. But by starting at a 30mg dose and then going down to 15mg for patients who achieve a complete molecular response, which is, again, the vast majority of patients,
we have seen some grade 3 toxicities but we have not seen any serious grade 4 or 5 toxicities with
the ponatinib regimen. Blinatumomab, again, is a very safe drug in Ph+ ALL; the main toxicities that
we see are cytokine release syndrome and neurotoxicity. We had one patient with grade 3 cytokine
release syndrome, the rest of the toxicities were grade 1 and 2. Only one patient had to discontinue
blinatumomab therapy and that was a patient who had just a recurrent grade 2 neurotoxicity. So,
overall very consistent with the known side effect profiles of those drugs given individually.

 

What impact did these results have on the treatment of ALL and what is next for the study?

We really need to confirm the durability of these responses. We were very encouraged by the idea
that we have had very high rates of complete molecular response and, so far, very good, durable
remissions without transplant. But we want to confirm the durability and make sure that there are no
later relapses with this different regimen.

Going forward, if these data are confirmed with longer follow up this is really a potential paradigm shift
in the treatment of Ph+ ALL. We’ve already seen that with, again, the study with dasatinib and
blinatumomab, seen very good results with the chemotherapy free regimen. Our study is somewhat
unique in the fact that we haven’t transplanted patients so we’ve really shown the proof of principle of
giving these chemotherapy free regimens without routine transplant and first remission.

So if these data are confirmed I think that the standard will change and we really won’t be giving
chemotherapy or transplant for the vast majority of patients with Ph+ ALL, regardless of age.