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VJVirtual | Dasatinib-blinatumomab for adult Ph+ ALL

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Robin Foà

Robin Foà, MD, Sapienza University of Rome, Rome, Italy, outlines the results of a Phase II study recently published in the New England Journal of Medicine, evaluating dasatinib-blinatumomab in adult patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In this study, dasatinib was administered to adult patients as induction therapy for 85 days, followed by consolidation therapy using blinatumomab, a bi-specific CD19-targeting monoclonal antibody. At the end of induction, 29% of patients obtained a molecular response; this increased to 60% following two cycles of post-inductive blinatumomab. In addition, after more cycles of blinatumomab, the percentage of patients achieving a molecular response increased. Prof. Foà highlights the ease of administration of dasatinib and blinatumomab, which is highly relevant during the era of COVID-19. Within the Ph+ cohort of patients, variations in the IKZF1 gene were observed and were reflected as differences in the frequency of molecular response achieved. Prof. Foà also highlights the potential for resistance to dasatinib via changes in ABL gene expression and discusses that incidences of resistance were shown to be mediated by consolidation blinatumomab. This interview was recorded via an online conference call with The Video Journal of Hematological Oncology (VJHemOnc).

Transcript (edited for clarity)

Well, the idea here was to stay with an induction that was without systemic chemotherapy, through treatment with a tyrosine kinase inhibitor. We chose dasatinib, second-generation TKI, based on previous data that we published with dasatinib. Also, it was the fact that dasatinib has a role in activating lymphocytes, so that could help for the second part of the protocol I’ll mention in a minute...

Well, the idea here was to stay with an induction that was without systemic chemotherapy, through treatment with a tyrosine kinase inhibitor. We chose dasatinib, second-generation TKI, based on previous data that we published with dasatinib. Also, it was the fact that dasatinib has a role in activating lymphocytes, so that could help for the second part of the protocol I’ll mention in a minute. And third, also, the dasatinib passes the CNS barrier, so that could be a help in the absence of systemic chemotherapy. Plus induction based on dasatinib for 84 days. So that is similar to, exactly the same, in fact, to previous studies. But here, what we did, we added the consolidation.

So, while in other GIMEMA studies, we showed that you can induce into remission between 94 and 100% of adults Philadelphia positive ALL, only with a tyrosine kinase inhibitor, whichever this may be, plus steroids. And I must say that we have CNX prophylaxis. So the cerebral nervous system prophylaxis is underway so that the only chemo they get in a central nervous system, that’s all. But here we add into the induction and consolidation and what was the consolidation? It was a form of immunotherapy based on this bi-specific monoclonal antibody, which is called blinatumomab, which targets CD19, which is present on B-lineage, ALL cell in all cases. But the activity is mediated by the patient’s T-cells. So it’s a bi-specific monoclonal antibody targeting two antigens CD19 on the leukemic cells and CD3 on a patient’s T-cells. So they are activated to target leukemic, residual B-cells, especially in CD19.

So it’s a form of immunotherapy. Now, a couple of words on blinatumomab, which has been around for some years, very active drug approved by, first by FDA then by EMA, for relapse refractory B-lineage ALL. And more recently, this drug has also been approved for the treatment in b-lineage ALL, Philadelphia negative patients so far, for the treatment of minimal residual disease. So in the history of medicine, this is the first drug indeed that has been approved for the management of mineral residual disease. Now bi-specific, it’s a technology, so all antibodies have been developed. This’ll be the first one to reach the clinical arena and with these very important results. So we decided years ago to start this study, putting together an induction I mentioned, and adding in consolidation blinatumomab. So the design was induction with dasatinib, 84 days. After that all patients, unless they were non-responsive to the induction, but this almost never happens. In fact, it didn’t happen in our study in this last study, too, all patients of that got at least two cycles of blinatumomab, which are given by continuous infusion.

But after the two cycles up to three more cycles were permitted. So you could go up to five cycles. The primary endpoint of the study was the rate of patients who obtain the molecular response after two cycles of blinatumomab. So after induction with a TKI and two cycles of immunotherapy. Treatment after that was left open, and we are accumulating the data in an ancillary study. But this study and the data on the New England paper that came out yesterday, 22 October, is in fact at the primary end point. So what we found was to try to summarize at the end of induction dasatinib we have 29% of patients who’d already obtained a molecular response, which was good and in line with what we served in the previous published paper.

After the two cycles of blinatumomab, this percentage of molecular response increased to 60%. So the significant increase in patient with becoming MRD negative after two cycles of blinatumomab. So we met the primary end point of the study. What we also served, and this is of interest, and maybe something we did not expect that after further cycles of blinatumomab, you got further increase in MRD response. So reaching 80%, 80.5% after the fourth cycle of blina, as reported in the study. So this was obviously very rewarding and the data of disease-free survival and overall survival at 18 months are extremely good. I would say the best so far seen. With very limited toxicity, very limited. And one thing I did not mention, and I must underlie, this protocol for all adult patients, again, with no up age limit, go from 18 up until whatever it just this may be.

So this is obviously doable protocol, limited toxicity. And I will add another point that I think is extremely relevant. That dasatinib is given like all TKIs, orally. So it’s not intravenous treatment, and most of the time you can be at home even, so you don’t need to be hospitalized. And even blinatumomab, apart from the few days in hospital, then they can continue the continuous infusion, which goes up to 28 days at home, partly, or even all of this at home. So this I think is relevant. Something we did not put in the paper, but I’ve made this point other times, that this can be extremely relevant at this very difficult time we are living in, the pandemic. This means that we are reducing the hospital days, which makes obviously a big value at this very difficult moment.

And in fact, all patient during the protocol, even at the peak of the pandemic, as we had already back in March of this year, all patient continued treatment. So that was a key point and I think it was worth underlining. And the point that came out from the study, were of interest, I can say that we monitor MRD very closely, obviously. These all been done centrally. It came to our lab, both from diagnosis and all the MRD has been done centrally in order to test all patients in the same way with standardized technology, all been done by quantitative PCR. And so that obviously reduces the risk of different from one lab to another. What else I can say is that we do an extended biological workup at diagnosis on patients. And we could demonstrate that the patients have a genetic profile, which is based on the presence of the Ikaros mutation, plus additional genetic abnormalities.

These patients do less well. So they’re not all the same within the Philadelphia-positive. And we’ve defined a sub group, which in line with other study, I must say, do less well. And this is going to be important for the next question you would probably put, where is the future. Another important point is that under TKI treatment, and in particularly dasatinib, you may develop mutations of the ABL gene, which can confer resistance to the TKI. And so we monitor that carefully, particularly patient having an increase in MRD. And we found that a few patients in fact had the presence of mutations for which they were resistant to dasatinib, and of interest they disappeared with blinatumomab. So blinatumomab may be active even on a mutation that confers resistance to the TKI. There’s an additional piece of information. Now, as I said, that protocol was manageable, and we didn’t have many severe toxicity, so much less than we would see with chemotherapy combined to TKI.

Final point, and then I’ll go back to, is a transplant, there’s not part of the study where we put it in the paper. The 24 patients were allo- transplanted after induction consolidation. And without going into detail, because I said, this will not an endpoint of this study, it will be in a subsequent ancillary study, but these patients had a very, very low transplant related mortality down to 4.1%, which is lowest I think that you can ever see. And the reason for that is most likely the fact that many patients went to transplant not having had systemic chemotherapy. So the toxicity of chemotherapy was not there. So they’re going in much better conditions. And this is probably the main reason for the reduced transplant rate of toxicity.


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