Recent Approvals Across Hematologic Malignancies Usher in a New Era

Mikkael A. Sekeres, MD, MS

The introduction of momelotinib (Ojjaara) into the treatment paradigm for patients with anemic myelofibrosis is one example of how the evolving hematologic therapeutic landscape is allowing oncologists to consider approaches beyond long-standing standard of care therapies, providing more choices, potentially less toxicity, and overall better outcomes for patients, according to Mikkael A. Sekeres, MD, MS.

“We are seeing an explosion of new therapies and combinations of therapies that we can offer our patients with hematologic malignancies. We’re also trying to be systematic in how we apply these new regimens and are thinking about the [optimal] ordering of regimens,” Sekeres said in an interview with OncLive^® regarding a recent OncLive State of the Science Summit on hematologic malignancies, which he chaired. “[Additionally], in the past decade or decade and a half, we have [developed] treatments to offer to patients who have myelofibrosis, whereas before they had none—now there’s a real conversation with somebody as opposed to a conversation right out of the gates about going to a bone marrow transplant.”

In the interview, Sekeres expanded on key topics in hematologic malignancies that were discussed by his colleagues at the event, including the role of momelotinib in anemic myelofibrosis, the potential impact of emerging BTK inhibitor based–regimens for patients with chronic lymphocytic leukemia (CLL), and other key updates in large B-cell lymphoma (LBCL).

Sekeres is a professor of medicine and the chief of the Division of Hematology, Leukemia Section, at the University of Miami Health System and Sylvester Comprehensive Cancer Center in Florida.

OncLive: Regarding the presentation by Terrence J. Bradley, MD, what clinical benefit has been seen with momelotinib in anemic myelofibrosis, and where might it have a role in the current treatment paradigm based on its recent FDA approval?

Sekeres: Originally, the [phase 3 SIMPLIFY 1 (NCT01969838) and SIMPLIFY 2 (NCT02101268) trials] looked at momelotinib vs ruxolitinib [and momelotinib vs best available therapy, respectively]. In [SIMPLIFY 2] those who received momelotinib did not experience a significant improvement in spleen response, but they did have a significant improvement in symptom score, which is very important for patients with myelofibrosis. This led to the phase 3 MOMENTUM trial (NCT04173494)], which randomly assigned patients 2:1 to receive momelotinib vs danazol. In that study, we saw improvement in patients’ symptom score that was significant with momelotinib, as 25% of patients achieved at least a 50% reduction in symptoms by week 24 vs [9%] in the danazol group, and we saw significant improvement in shrinkage of the spleen size. That was the basis for the FDA approval of momelotinib. There seemed to be a trend towards patients also having improvement in their red blood cell transfusion independence rates.

What we saw more recently at the 2023 ASH Annual Meeting was a couple of phase 3 trials reporting results with combination therapy. [In the MANIFEST-2 (NCT04603495) trial] of [pelabresib] plus ruxolitinib vs placebo plus ruxolitinib, there was a significant improvement in shrinkage of the spleen, and there was a borderline significant improvement in symptom score. The phase 3 TRANSFORM-1 trial [NCT04472598] adding navitoclax to ruxolitinib vs ruxolitinib alone showed a significant improvement in spleen size, but not a significant improvement in the total symptom score. [Overall, there is] more to come on the treatment of myelofibrosis as we’re now about to enter the era of combination therapy.

How has the management of CLL recently shifted with the incorporation of BTK inhibitors into the armamentarium, based on the presentation by Alvaro Alencar, MD?

I don’t personally treat patients who have CLL, but I certainly have moderated sessions at ASH where we’ve seen some of these advances in how these patients are treated. Without a doubt, we can now comfortably say that we are in an era of treating CLL where we don’t have to use chemotherapy. There was yet another presentation [at the ASH Annual Meeting] comparing a BTK inhibitor based–therapy with traditional fludarabine, cyclophosphamide and rituximab [Rituxan; FCR] for lymphoid malignancies including CLL. [In this presentation], we saw a survival advantage for patients who received BTK inhibitor based–therapy without the downstream consequences of patients receiving chemotherapy.

I specialize in myelodysplastic syndrome [MDS], and the composition in my clinic of patients who also have CLL has changed over the years. I used to see a lot of patients with CLL who had a therapy-related MDS from getting chemotherapy to treat their CLL. I’m not seeing those patients as much anymore because they’re now getting non-traditional cytotoxic chemotherapy-based approaches that are sculpted around BTK inhibitors. That’s great for patients. The latest in those BTK inhibitors is pirtobrutinib [Jaypirca], which has been looked at in patients who received previous BTK inhibitors and has been shown to be very effective. Now we’re seeing movement of that drug into the up-front setting and into combinations.

What were major updates in LBCL according to the presentation by Juan Alderuccio, MD?

In lymphoma, we’ve certainly seen some advances in large cell lymphomas [which] some people would argue [is] for the first time in decades. For patients who have lymphomas, we recently saw the incorporation of polatuzumab vedotin-piiq [Polivy] into what was traditionally an R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] regimen for LBCL. This was demonstrated in a large, randomized trial. One important caveat is that the addition of polatuzumab vedotin did not show a clear benefit compared with R-CHOP alone in patients who were 60 years of age or younger, had the germinal center B-cell-like subtype of diffuse LBCL, had bulky disease, and in those who had lower International Prognostic Index scores. There does appear to be a role [for the polatuzumab vedotin regimen] in a small subset of patients with LBCL, but we can’t fault people who turn back to the old standard of R-CHOP for the remainder of the population.