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2019 ASCO Updates

Updates in AML, CML, ALL

Acute Myeloid Leukemia (AML)

There was a nice subanalysis of the pivotal trial of gilteritinib, the study that’s called “The ADMIRAL.” That was the study that led to the registration of gilteritinib. It was a randomized study for salvage of patients with FLT3-mutated AML, and patients were randomized to receive gilteritinib or standard chemotherapy. As we know, the results were positive, with significant improvement in overall survival. There was also an improvement in all the secondary endpoints of event-free survival response rate with a very good safety profile.

Jorge Cortes, MD
D. B. Lane Cancer Research Distinguished Professor for Leukemia Research
Deputy Department Chair, Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center Houston, TX

The analysis that was presented at ASCO was an analysis looking at two important features of these patients. One is co-mutations and the impact of co-mutations, because we know that FLT3 mutations don’t happen alone. Many times patients have other mutations in addition to FLT3. The most common in this cohort of patients were NPM1, DNMT3, WT1 – not surprising. Those are relatively common mutations, so that’s kind of expected.

What the analysis showed was that the presence of these co-mutations does not have a negative impact on the outcome of patients treated with gilteritinib. So, patients with or without mutations, and with or without co-mutations have an equally good prognosis with gilteritinib; whether they have or they don’t have co-mutations, when treated with gilteritinib, they do better than with standard therapy. So the benefit of gilteritinib over standard therapy is maintained regardless of the presence of these co-mutations.

The second part of the analysis was the value of the variant allele frequency. We know that the higher the allele frequency, the worse the prognosis for patients with FLT3 mutations, and so the question was whether the benefit applies in patients with higher and lower variant allele frequency. And sure enough, the benefit compared to standard chemotherapy is maintained in both subsets of patients: whether they have lower or higher allele frequency, they do better with gilteritinib. The patients with a high variant allele frequency have a somewhat worse prognosis, but it is improved with gilteritinib compared to standard chemotherapy. So those are two important observations because they’re very practical in the clinic. We see these patients with these additional mutations and different allele frequencies and that’s important to note.

There was also a very interesting study with a drug that’s called CX-01. This is an investigational drug and this was a Phase II study, but it’s attractive. It was a randomized Phase II – it had three arms. It was with patients with newly diagnosed disease. They received standard chemotherapy or standard chemotherapy plus one or two different doses of these experimental drugs. The drug is sort of like a derivative of heparin that has a P-selecting inhibition effect, and it was interesting because the response rate in the patients that took the higher dose of the investigation agent together with chemotherapy had a very high response rate, a survival benefit compared to standard chemotherapy. So this drug is now on a fast track review with the FDA. There’s additional studies that have to be done, but I like it, particularly because this concept of affecting the microenvironment as one of the elements of dealing with leukemia is important. I think we’ve had some experience the best agent so far, or the only agent that’s available: plerixafor. It’s not really approved for this indication, but there have been studies using plerixafor, and there’s more and more of these drugs that inhibit the selecting, in this case, P-selecting. There’s another one that inhibits E-selecting, others that are CXCR4 inhibitors, etc. So, I think we’re going to see more incorporation of these drugs that can help deal with the protective microenvironment and try to improve the outcome together with chemotherapy.

There was also a long-term follow up study of glasdegib plus low dose Ara-C compared to the low dose Ara-C. Again, that was the study that led to the approval of these drugs, and this was a longer-term follow-up. There were eighteen months of additional follow-up compared to the data that was available for the initial approval. As we know, glasdegib is a hedgehog inhibitor, and this was a randomized phase II study for patients that had newly diagnosed acute myeloid leukemia and had features that made them ineligible for standard chemotherapy, which could include an age over 75 or a high creatinine of greater than 1.3 or a performance status of 2 or greater, or cardiac conditions. The median age of these patients was 76-77.

All patients had at least one of these comorbidities, but the majority had at least two of these comorbidities. They were a high-risk population (sixty percent had cardiac features, etc.) and we have seen the survival benefit of the drug combined with low dose Ara-C compared to low dose Ara-C alone. At two years, 20% of patients were still alive compared to only 2% in the control arm. So it’s definitely a survival benefit that is sustained over at least a couple of years in this very high-risk population that we cannot really give them many other treatment options. It is important that this is a drug now commercially available.

Chronic Myelogenous Leukemia (CML)

In CML, there were two long-term follow-up studies that I want to mention. These were studies on treatment discontinuation. One of them is called “ENESTfreedom” and the other one is called “ENESTstop.” Very similar studies,with the main difference being that ENESTstop is a study where patients who have been receiving therapy with imatinib who had a good response but not a deep molecular response were then switched to nilotinib. If they had a sustained deep molecular response for these two years, then they were able to get offered treatment discontinuation. The ENESTfreedom study had patients who start with nilotinib as initial therapy. The criteria for treatment discontinuation between both studies were very similar. The ENESTstop had a follow-up median of 3.7 years, and at 3.7 years the estimated treatment pre-survival was 50%, so approximately half of the patients can remain treatment-free long term; very few relapses after the first couple of years. The great majority of patients who relapsed were able to regain their major molecular response and even their MR4 upon restarting therapy.

Importantly, there are some withdrawal syndromes. They can be common. Up to 50% of patients had them in the first year, but it went down in subsequent years and is grade 3 or 4 in only 2-3% of the patients. So not a very serious problem, but is something to be aware of. The ENESTfreedom had very similar results, with approximately 50% of patients with treatment-free survival and regaining the response. This shows that treatment-free remission is a reality. The important thing is that it has to be done right. If it’s not done properly, then you put the patients at risk unnecessarily.

 Acute Lymphoblastic Leukemia (ALL)

This is the last study I would like to highlight. There was a report of the end of phase I of the ZUMA-3 study, which is the CAR-T cell study. These are the Kite CAR-T cells. As we know, there are different varieties of CAR-T cells available for non-Hodgkin’s lymphomas and ALL – different vectors, different constructs, and this one, for example, uses a retrovirus, compared to the others that use all anti-virus. In this study, they reported on 54 patients that were enrolled; forty-five were dosed. Not everybody can be dosed, and that’s important, so they lost almost 20% of patients. These were patients that were heavily treated. About two-thirds of the patients had received at least three prior regimens. About 30% had received a prior transplant. About 30% were primarily refractory. So they were a very heavily pretreated population and they looked at different doses. Again, this is a phase 1 study, 0.51 and 2 million cells per kilogram. The one that’s kind of leading the way is the 1 million cells per kilogram, and the response rate was very high; 84% of patients responded. Most of these responses were CRs, with a few CRIs.

Importantly, every patient that responded became negative for measurable residual disease. Of course, there was cytokine release syndrome. They treated the prophylaxis and management a little bit, and with that, the incidence and the severity decreased some. It’s important that we are learning as we use these cells more and more, and although this is always a concern, I think little by little the management is improving without the prognosis. For patients who develop these syndromes, it’s also improving. These CAR-T cells, the Kite plus others, are really good therapies for patients with acute lymphoblastic leukemia in relapse or refractory. So it’s very important the T-cells are starting to be approved and are becoming available. Of course, this is something that not every center can do, but because there’s more and more centers, patients can be referred to different places to receive these when it’s appropriate.

Understanding Co-mutations

Co-mutations are important to consider, because we frequently talk about mutations in isolation. We talk about C3. We talk about IVH. You see these papers about prognostic significance of this mutation and that mutation, but again, a lot of patients have multiple mutations, and the effect of one mutation may be different when it’s in isolation versus with something else. For example, MPM1 has a good prognosis when there’s no FLT3 mutation, but when there is an FLT3 mutation, it doesn’t have a good prognosis. It is important to recognize that one mutation may impact another.

Another important thing to recognize is that when we are starting to use these selective therapies, like FLT3 inhibitors and IVH inhibitors, we are starting to see that there are clones that emerge with different mutations. For example, we treat patients with an FLT3 inhibitor, and we can see the emergence of clones that have Ras. These clones may not be detectable at all at the start, and then when the patient relapses, you see much less or even no FLT3 mutation, but you can see Ras. It is important any time the patient progresses or is going to change therapy to reassess, because the profile may change. In the example I gave, if you don’t realize that the FLT3 mutation clone has decreased and is more prominently a Ras mutative clone, and if you just treat it with a FLT3 inhibitor, you may not get any benefit, and you may need to consider some alternative therapy. So I think we need to be increasingly aware of these co-mutations and evolving mutations during the therapy.

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