Second- and Third-Generation TKI Combo Therapies Are at the Forefront of Frontline Ph+ ALL Investigations

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Ponatinib (Iclusig) plus blinatumomab (Blincyto) and dasatinib (Sprycel) plus inotuzumab ozogamicin (Besponsa) represent notable combination therapy approaches with TKIs under evaluation in the frontline Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL) setting, according to Gregory Roloff, MD.

Later-generation TKIs such as ponatinib have already solidified a place in the treatment landscape. In the phase 3 PhALLCON trial (NCT03589326), which was the first phase 3 randomized clinical trial to compare 2 TKIs for the frontline treatment of Ph-positive ALL, ponatinib bested imatinib (Gleevec).1 Now, the combination of ponatinib and blinatumomab is being evaluated in a phase 2 study (NCT03263572). The regimen yielded a complete molecular response rate of 83% in patients with newly diagnosed Ph-positive ALL (n = 60).2 Notably, the combination reduced the need for intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) for most patients in first remission; only 2 patients underwent HSCT.

Additionally, interim analysis data from an ongoing phase 2 study (NCT04747912) examining the combination of dasatinib plus inotuzumab ozogamicin in the same patient population showed that 100% of patients (n = 18) achieved a complete molecular response and/or minimal residual disease negativity by next-generation sequencing within 3 courses of treatment.3

In an interview with OncLive®, Roloff highlighted ongoing frontline TKI research in Ph-positive ALL and why he uses a newer-generation TKI over imatinib. Roloff is an assistant professor of medicine and hematologist at UChicago Medicine in Illinois.

OncLive: What is important to highlight with imatinib vs ponatinib in Ph-positive ALL?

Roloff: By and large, most doctors who are treating [patients with] Ph-positive ALL are likely not reaching for imatinib anymore as their drug of choice as a TKI. Most of us will choose a second-generation or [later] TKI. But, in the spirit of doing systematic, randomized clinical research, it’s perfectly reasonable to ask: Do the [later]-generation kinase inhibitors lead to a noticeable difference in clinical outcome? The answer is probably yes, but not strikingly so. The reason that was is because although we were able to appreciate that the third-generation TKI ponatinib was not just well tolerated but able to get patients into a molecular remission at a higher rate and faster—which was important for patients’ clinical outcomes—overall survival was not [significantly] different at the end of the day. I’m not sure that can be placed solely at the feet of imatinib or ponatinib, but it’s probably likely due to the fact that we have other tricks up our sleeve if patients [experience] relapse, and they can be salvaged in certain ways.

I don’t think this is a knock against using a [later]-generation TKI, which we know are generally more potent, well tolerated, and can get patients into molecular remission faster, allowing them to, for example, proceed to allogeneic transplant or [achieve] some other clinical end point in a more expeditious manner. But there wasn’t a [significant] difference in overall survival [with ponatinib] vs the cheap, easily available, and relatively minimally toxic imatinib. It’s not a wrong choice, but when I’m treating patients with Ph-positive ALL, I will reach for a second- or [later-] generation TKI and that is commensurate with what most academic doctors in the field would do as well.

If a T315I mutation drives most relapses beyond second-generation TKIs, what is the role of ponatinib for patients with newly diagnosed Ph-positive ALL given that it may be effective in this context?

That’s being actively investigated. A different study in Ph-positive ALL used ponatinib in combination with blinatumomab in an upfront setting. The combination of blinatumomab, which is an immune-based therapy, and ponatinib, which is a TKI, has very high response rates. Investigators can take solace in knowing that more often than not their patient is going to get into a first remission with this combination. This is a chemotherapy-free approach that does not have a particularly bothersome or worrisome adverse effect [AE] profile. Ponatinib, at the very highest dose levels, can put patients at risk of arterial occlusive events and some vascular AEs, but this has been something that we’ve been able to fine-tune in our practice with ponatinib over the years. You can use a de-escalation strategy to use a somewhat higher dose of ponatinib upfront and then de-escalate and get patients to a much lower maintenance dose that they’ll stay on for a prolonged period.

In this study, the [investigators] saw some later relapses into the central nervous system. Therefore, they’ve modified the protocol a bit to make sure that patients still get generous intrathecal chemotherapy to prevent these relapses. I believe that those relapses have largely only occurred in patients who had a very high white blood cell count at presentation, so you’re able to identify who those patients may be.

How could ongoing studies looking at combination regimens with dasatinib affect the Ph-positive ALL space?

That’s a good question, and it allows me to highlight the work that a friend and colleague of mine, Anand A. Patel, MD, is doing here at the University of Chicago. In the same vein that we were talking about a chemotherapy-free regimen for newly diagnosed Ph-positive ALL upfront, which combines immunotherapy and a TKI—in [the prior case it] was ponatinib and blinatumomab—we have other TKIs and immunotherapies for ALL. It’s a very reasonable question to test other combinations.

Dr Patel and others have all enrolled patients in this study we’re doing at the University of Chicago which tests dasatinib and inotuzumab ozogamicin, a different immune-based therapy, for ALL. This [was also] typically developed for relapsed settings but is being investigated as an upfront combination. Dr Patel presented a preliminary first look at the data at the 2024 ASH Annual Meeting, and we’re seeing response rates of approximately 80% [within 2 courses of therapy].

We know that patients tolerate dasatinib pretty well. The thing that’s nice about inotuzumab is that it’s a relatively feasible drug to give in the outpatient [setting]. It’s 3 days a month that the drug is dosed, so that’s hopefully not too cumbersome on patients. We’re excited to finish enrollment on this study. We’re almost there in terms of our target enrollment.

References

1. Jabbour E, Kantarjian HM, Aldoss I, et al. Ponatinib vs imatinib in frontline Philadelphia chromosome–positive acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2024;331(21):1814-1823. doi:10.1001/jama.2024.4783
2. Kantarjian H, Short NJ, Haddad FG, et al. Results of the simultaneous combination of ponatinib and blinatumomab in Philadelphia chromosome–positive ALL. J Clin Oncol. 2024;42(36):4246-4251. doi:10.1200/JCO.24.00272
3. Patel AA, Duvall AS, Saygin C, et al. Interim results of a phase II study investigating dasatinib and inotuzumab ozogamicin-based induction for newly-diagnosed Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2024;144(suppl 1):1432. doi:10.1182/blood-2024-193442