Schiller Talks TKIs, Treatment Discontinuation, and Transplant in CML

First-in-class STAMP inhibitors, escalated dosing strategies, and parameters for treatment discontinuation have become prominent areas of research in chronic phase chronic myeloid leukemia (CML), unlike sequencing strategies, which have remained relatively unexplored, according to Gary J. Schiller, MD.

“A lot of people are starting with second-generation TKIs, and when the patient achieves a complete cytogenetic or major molecular response [MMR], [they switch] to imatinib [Gleevec]. Others start with imatinib, and if it fails to produce a deep molecular response in the patient, they switch to a second-generation TKI. We don’t know what the right strategy is,” said Schiller.

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Schiller, director of the Bone Marrow/Stem Cell Transplantation and professor of hematology/oncology at the David Geffen School of Medicine, University of California, Los Angeles, discussed data from the 2020 ASH Annual Meeting and Exposition and the role of transplant in CML.

OncLive: The STAMP inhibitor asciminib showed significant improvements in MMR versus bosutinib (Bosulif) in the ASCEMBL trial. What is unique about this drug, and what caught your attention from the study? 

Schiller: This is a very interesting new drug that blocks a different part of the novel BCR-ABL transgene product, a myristoyl-ABL pocket. Acting at a different site, the drug is not sensitive to mechanisms of resistance within the active ATP binding site the phosphorylation of downstream proteins, which all the other TKIs work on.

[ASCEMBL] was a randomized study that led to some criticism regarding the choice of bosutinib, and the particular dose of bosutinib. Patients were eligible if they had received prior therapy with two or more TKIs. Patients were stratified for disease variables, and there was a 2:1 randomization and [crossover] was allowed.

Despite the randomization, more patients were intolerant [to their prior] TKI in the asciminib arm, but both groups had a large number of patients whose disease had demonstrated resistance to TKIs. A total of 22 patients, nearly 9% of patients assigned to 500-mg bosutinib arm were switched to asciminib. A little more than one-quarter of the patients on the asciminib arm achieved an MMR. That end point was achieved by only 13.2% of those on bosutinib. The MMR at 24 weeks was significantly better for asciminib, at 25% versus 11.9% for bosutinib. The rate of cytogenetic complete remission at 24 weeks was 40.8% for asciminib versus 24.2% for bosutinib. 

Adverse effects [AEs] were seen in both populations; the rate was 89.7% in the asciminib arm versus 96% in the bosutinib arm. Treatment discontinuations were rare. Cardiovascular events were not so common, but they occurred in 3.2% of patients assigned to asciminib versus 1.3% of those assigned to bosutinib. The study was very interesting, because it demonstrated statistically significant efficacy for asciminib compared with bosutinib, but there was some imbalance in randomization, which will need to be figured out when one interprets the trial.

What is the significance of these data, and what’s the hope for this drug in the space?

There’s a lot of hope for this drug. There still is a need for novel agents that operate through a mechanism that’s a little bit different from the ATP binding site of the transgene product. The big question is: How would this drug compete with ponatinib? A lot of these patients have had ponatinib, so that’s a problem.

How has the concern for cardiovascular toxicity with ponatinib in the PACE and OPTIC trials affected dosing strategies? 

[PACE and OPTIC] are old, phase 2 trials that now have a lot of follow up. The PACE trial [enrolled] 270 patients with chronic phase CML who were resistant or intolerant to prior TKIs. Patients received a fixed dose of 45 mg a day of ponatinib. In the OPTIC trial, a variety of doses [were evaluated]. Patients were randomized to 30, 45, or 50 mg [of treatment] a day. The treatment duration was long in this patient population.

In both studies, the response rate was quite high, but there was cardiovascular toxicity. In the PACE trial, the cardiovascular toxicity was quite significant. Treatment-emergent adverse vascular or arterial occlusive events [occurred in] 7.8% [of patients] and 7% after more than 1 year of therapy. After 1 to less than 2 years of therapy, 15% of patients on PACE had some arterial vascular event; 30% of those events were serious. For patients who had received 2 to less than 3 years of treatment, more than 11% of patients experienced these events with ponatinib, and 10.3% had serious AEs.

As a guy with a history of an arterial occlusive vascular event, I take this very seriously. It’s an important end point. In the OPTIC trial, the AE rate in terms of arterial occlusion was much lower. I don’t know if that was related to the fact that different doses were used. The ultimate conclusion was one should start at 45 mg a day for a rapid response and then taper thereafter. 

How do these agents compare with one another? 

Two drugs came out as winners here: asciminib and ponatinib, so that’s your choice when patients have a disease that is resistant to or in the rare instance, they are intolerant to second-generation TKIs. The alternative for this population is allogeneic transplant. What we’re comparing is a third-line or even potentially fourth-line drug with asciminib versus allogeneic transplant.

Allogeneic transplant has the potential to be curative, but even in patients with disease that’s highly resistant, there is a credible relapse rate, plus all the non-relapse related AEs of allogeneic transplant that limits its use in such a disease. You have to always contextualize drugs in the advanced disease setting against allogeneic transplant.

Are TKIs easily sequenced?

A lot of things are being done in practice that are not well analyzed from study. A lot of people are starting with second-generation TKIs, and when the patient achieves a complete cytogenetic or MMR, switching to imatinib. Others do it the other way around. They start with imatinib, and if it fails to produce in the patient, a deep molecular response, then they switch to a second-generation TKI. We don’t know what the right strategy is. 

For patients who are interested in discontinuing treatment, how is the feasibility of treatment-free remission typically evaluated? 

There are milestones of response. Historically, these have included time to complete hematologic response, time to complete cytogenetic remission, and time to MMR. There now is another end point: time to deep molecular response, an MMR of 4 or 4.5 logarithmic reduction that could permit patients time off TKIs. It may not be a milestone that we can demonstrate to be associated with survival, but it is a milestone to achieve if you want to get off drug.

Do you believe TKI discontinuation is possible?

TKI discontinuation is possible, but most patients at some time or another will have progression by molecular tests and have to go back on a TKI, so it is not for every patient. Patients who are uncomfortable with the idea that their disease might relapse, even though everyone is closely followed with quarterly assessments by quantitative PCR, will not go off [drug]. But for patients who like the idea [of going] off therapy for a period of time, at least have the opportunity to do so, particularly if they are in first chronic phase, and only if they’ve achieved a very deep MMR.

Will we see a similar step toward TKI discontinuation for patients with accelerated or blast phase CML?

Discontinuation has been adequately explored, but there’s a lot of research potential there. The studies of alternative agents in the third-line setting or beyond, typically are for [patients with] chronic phase [disease], so there’s not quite enough experience in the way of publication for [patients with] accelerated or blast phase [disease], where the goal is generally to get to transplant. I understand why there are not a lot of studies in that area. If you look at survival statistics, even if you had some miracle drug that got everybody with blast phase into a second chronic phase and to allogeneic transplant, it’s really the effect of the transplant that will predict for survival—maybe more than the effect of the way you got patient into second chronic phase. However, how you manage patients with accelerated or blast phase is an abiding question.