Hematologists Dive into the Current Treatment Landscape

Ehab L. Atallah, MD

When considering updates to the treatment landscape for patients with chronic lymphocytic leukemia (CLL), the phase 2 CAPTIVATE study (NCT02910583) and the phase 3 GLOW study (NCT03462719) stand out due to their notable overall results demonstrating the efficacy of the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta). In addition to this, over the course of 2023, various trials and data reported helped shift the treatment paradigm for patients across hematologic malignancies, according to faculty who presented at an OncLive® State of the Science Summit™ on hematologic malignancies.

Ehab L. Atallah, MD, a professor of medicine and Section Head of hematological malignancies in the Division of Hematology and Oncology at the Medical College of Wisconsin, in Milwaukee, chaired the event and highlighted updates in CLL, emphasizing the importance of understanding the plethora of options that are present for oncologists treating patients within this population.

Atallah was joined by his colleagues:

• Laura Michaelis, MD, chief, professor, Hematology, Medical Oncology, Froedtert Hospital and Medical College of Wisconsin
• Sameem Abedin, MD, associate professor, Hematology, Medical Oncology, Froedtert Hospital and Medical College of Wisconsin
• Lyndsey Runaas, MD, assistant professor, Hematology, Medical Oncology, Froedtert Hospital and Medical College of Wisconsin
• Timothy Fenske, MD, MS, professor, Hematology, Medical Oncology, Froedtert Hospital and Medical College of Wisconsin
• Guru Subramanian Guru Murthy, MD, MS, assistant professor, Hematology, Medical Oncology, Froedtert Hospital and Medical College of Wisconsin

Below, Atallah, Michaelis, Abedin, Runaas, Fenske, and Murthy summarize the main messages from their presentations.

Updates in CLL

Atallah: We talked about ibrutinib and venetoclax—[specifically] the CAPTIVATE study [which evaluated the] combination and included patients with or without a 17p deletion. Of patients who had undetectable minimal residual disease, impressive results [were seen] with the pill/pill [combination].¹

Moreover, the randomized [GLOW] study was just published [which evaluated] 3 cycles of ibrutinib and 12 cycles of ibrutinib plus venetoclax. The control arm was obinutuzumab [Gazyva] and chlorambucil [Leukeran]. The 30-month progression-free survival [PFS] with ibrutinib and venetoclax was 80.5% [vs 35.8% with the control arm].² Again, for a pill/pill [combination], no infusion, these results were impressive in a randomized trial.

Based on this, ibrutinib and venetoclax is in guidelines—it is not FDA approved as a combination, but it is in the NCCN guidelines. What’s the next step from this? The phase 3 CLL 17 trial [NCT04608318] is randomizing patients to ibrutinib monotherapy vs venetoclax/binutuzumab vs ibrutinib/venetoclax, and we’ll see the results of that study. It’s asking the question, what is the best choice here?

In my practice, and I’m told that not a lot of practices do [this] in frontline CLL, I use a BTK [inhibitor] and venetoclax—we have enough safety data, multiple trials, and multiple randomized trials. If the insurance approves it, I use a BTK inhibitor and venetoclax upfront.

Management of Myelofibrosis

Michaelis: I want to mention that an anti-anemia agent [pelabresib (CPI-0610)], which should be coming along, is a BET inhibitor. The phase 2 MANIFEST study [NCT02158858], and we were part of this trial, used the BET inhibitor with or without ruxolitinib [Jakafi]. We saw a slow but steady increase in hemoglobin levels. When I think about anemia in myelofibrosis, you will of course want to rule out other causes.

I tend to measure the serum erythropoietin level. In an individual with decreased serum erythropoietin, maybe because they have a renal insufficiency or otherwise, it’s reasonable to try an erythropoietin stimulating agent, but certainly in those with higher than 250 or 500 mU/mL, you would look towards either luspatercept-aamt [Reblozyl] or a clinical trial. It is very reasonable to think about momelotinib [Ojjaara] or even pacritinib [Vonjo] in that setting.

[Regarding] future studies to watch, I want to point out that the navitoclax story is just unfolding in myelofibrosis, [although] the phase 3 TRANSFORM-1 study [NCT04472598], I do not believe has reported results yet. However, that will be in patients who are naive, which will be [evaluating] ruxolitinib plus navitoclax vs ruxolitinib alone in patients. That’s based on favorable data from the phase 2 REFINE study [NCT03222609], where they not only saw spleen reduction, but also saw a reduction in bone marrow fibrosis, and a reduction in driver mutation VAF.

Now we can think about pacritinib and momelotinib [in the] first-line for splenomegaly, for symptoms, especially in individuals with anemia. When you have somebody with just anemia, think about choosing your JAK inhibitors with that in mind. Hopefully we can get some combination data, as well.

Overall, JAK inhibition is becoming more nuanced. You have to think about symptoms, know patients’ adverse effects, understand the cytopenias, and understand what’s going to happen once you put somebody on the drug. It’s always important to look at treatment goals too, because sometimes you’re choosing among those. The off-target effects may play a role, and it’s interesting that what we’re seeing is additional benefits from something that the drug may not have been initially defined for. So far there is no definitive effect on survival, but that [data] may be coming.

Updates in Graft-Vs-Host Disease (GVHD)

Abedin: Recently, the phase 1/2 [NCT03604692] study results using axatilimab [SNDX-6352] in patients with refractory chronic GVHD was published in the Journal of Clinical Oncology.³ What we found in these patients that had seen ruxolitinib, and in some cases had seen belumosudil [Rezurock] as well, was responses, particularly improvements in terms of fibrosis. This medicine, as opposed to those, is given intravenously, but with a different sort of targeting.

Perhaps targeting of the macrophage will result in some sort of resolution of fibrosis and may offer an option in patients who have resistant chronic GVHD. This is another option that we potentially may have to improve quality of life [QOL] in these post-transplant patients.

Chronic GVHD is an immune mediated complication that occurs after an allogeneic transplant. Certainly, the development of chronic GVHD significantly impairs QOL. After corticosteroid therapy, approximately 50% of patients will require additional interventions, and this is an area of significant proliferation in terms of clinical trials, as well as FDA approved options for treatment.

In terms of first-line, the best data compared with existing therapies exists with ruxolitinib. This is even compared with some patients who received ibrutinib on that study, so I would consider ruxolitinib as first-line [treatment] for steroid refractory, chronic GVHD. After that, then belumosudil is now an option and certainly in patients who have impaired QOL after ruxolitinib, is something to consider.

There is investigation in chronic GVHD right now, so hopefully we can continue to chip away at chronic GVHD, improve QOL, and there may be things to continue to help these patients who have been transplanted.

Updates in Acute Myeloid Leukemia (AML)

Runaas: When we’re looking at drugs that have similar response rates, especially in a relapsed/refractory patient population, looking at adverse effects is critically important. Overall olutasidenib [Rezlidhia] was fairly well tolerated [according to data from a phase 1 study (NCT02719574). IDH inhibitors and FLT3 inhibitors have both been shown to cause differentiation syndrome at times. In this study, the rate was approximately 14%. In the phase 1 study, they did have 1 death with complications related to differentiation syndrome. The death was some time after the initial presentation of differentiation syndrome, but it was ultimately attributable to it.

There was some liver function test [LFT] abnormalities seen in approximately 15% of patients, and 7 patients discontinued because of these. None of the LFT abnormalities lead to liver failure. There was some QT prolongation seen in approximately 8% of patients, but overall, it was transient. There was a response rate in the mid-30% range, with that favorable duration of response seen with olutasidenib. The pros and cons of this drug is that it’s once daily dosing vs twice daily dosing of ivosidenib [Tibsovo]; we’re kind of splitting hairs here. However, it needs to be taken on a completely empty stomach, which can sometimes be difficult for our patients. There was not a clinically significant increase in QTC prolongation and that is definitely a pro of this drug vs ivosidenib. Take what you will from cross trial comparisons, [but] the duration of response for those who do respond does seem to compare favorably to ivosidenib.

I’m not entirely sure [what] the role of quizartinib [Vanflyta] is, [but] I will consider olutasidenib for my newly IDH1-mutated, relapsed/refractory patients with AML. This drug is also being looked at in combination with azacitidine [Vidaza]. It’s also being looked at in that very small group of patients with myelodysplastic syndrome [MDS]. Some of that data was reported, but the number of patients with MDS included in that paper was only 13 so I did not think that that was reasonable to comment on.

BTK Inhibitors for Managing Mantle Cell Lymphoma (MCL)

Fenske: [Regarding] FDA approved options for relapsed/refractory MCL, bortezomib [Velcade] was approved in 2006, lenalidomide [Revlimid] as a single agent in 2013, ibrutinib [Imbruvica] in 2013, acalabrutinib [Calquence] in 2017, zanubrutinib [Brukinsa] is 2019, and now pirtobrutinib [Jaypirca].

It is not fair to compare pirtobrutinib [with those agents] because those agents were [around] prior [to when patients were] BTK treated. However, the overall response rate and the complete response [CR] rate has progressively gone up. The median progression-free survival that we can get now for patients who relapse has progressively improved. Particularly, if patients have CR, they can stay on these BTK inhibitors sometimes for 5 years or longer. [For] many patients, it doesn’t interfere with their life, they just have a pill they need to take.

[Overall], real-world data was presented at the 2023 ASCO Annual Meeting [from] an electronic medical record [EMR] study where they looked at patients with MCL who had started a BTK inhibitor between 2019 and 2021. They looked at treatment duration using the EMR, claims, discontinuation rates, and other outcomes.

They had 402 patients they were able to pull out this way and the majority were either [treated with] ibrutinib or acalabrutinib, but a little more than 10% of patients received zanubrutinib. The average age interestingly, at the time they started a BTK inhibitor was 75 for zanubrutinib, 76 for acalabrutinib, and 72 for ibrutinib. There may be a little trend towards using the newer BTK inhibitors in the older patients.

There was a little shorter follow-up with the zanubrutinib patients because the drug was available later. If you look at the treatment duration, they concluded that patients were able to stay on therapy with the second-generation BTK inhibitors considerably longer than ibrutinib. The 90-day adherence was numerically best in the zanubrutinib patients and clearly zanubrutinib and acalabrutinib looked to be better than ibrutinib [based on the data].

This confirmed what a lot of us have experienced in our own practices, that ibrutinib was a breakthrough for sure, but it is a hard drug to keep—approximately 30% of patients would have to come off [treatment] for one reason or another. There were also significant rates of atrial fibrillation and other issues. Things have continued to move along here within the BTK space for MCL.

CAR T-Cell Therapy

Murthy: To conclude, CD-19–directed CAR T-cell therapies are safe and efficacious, even in some of these rarer lymphoid leukemias, such as B-cell acute lymphoblastic leukemia and CLL. We do have 2 FDA-approved CD-19 CAR T cells for relapsed/refractory B-cell ALL. There are still ongoing unanswered questions about what the impact of prior CD-19–directed therapy is, and whether somebody does need an allogenic transplant down the road or not.

However, the consensus opinion points to the minimization of the prior CD-19 exposure. Do follow up these patients with an allogenic transplant, if an ideal situation permits for them to have one. Ongoing studies that are targeting multiple different tumor antigens, such as CD-20, or CD-22 are also ongoing. There are some larger confirmatory studies that are also planned. This landscape is hopefully going to be changing more and more in the future.

References

1. Weirda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865. doi:10.1200/JCO.21.00807.
2. Kater AP, Owen C, Monero C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. Published May 13, 2022. N Eng J Med Evid. 2022;1(7). doi:10.1056/EVIDoa2200006.
3. Kitko CL, Arora M, DeFilipp Z, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a phase I/II study.J Clin Oncol. 2023;41(10):1864-1875. doi:10.1200/JCO.22.00958
4. Shah BD, Xue M, Yang K, et al. Real-world treatment patterns of Bruton tyrosine kinase inhibitors (BTKi) in patients with mantle cell lymphoma (MCL) in community oncology practices in the United States (US). J Clin Oncol. 2023 41:16_suppl, e19525. doi:10.1200/JCO.2023.41.16