Dr Gangat on JAK Inhibitor Selection in Treatment-Naive Myelofibrosis

Naseema Gangat, MBBS, hematologist, oncologist, education chair and program director, Division of Hematology, Department of Medicine, Mayo Clinic Rochester, provides insight into the clinical utility of momelotinib (Ojjaara) and expands on JAK inhibitor selection for patients with treatment-naive myelofibrosis.

Gangat highlights the functionality of momelotinib in addressing both spleen symptoms and total symptom score. She notes that the agent can also have activity against anemia, which presents a significant advantage over other previously favored JAK inhibitors, such as ruxolitinib (Jakafi). In September 2023, 

 for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.

When choosing a JAK inhibitor in the frontline setting for patients with myelofibrosis, momelotinib could be the preferred option for those with borderline hemoglobin levels—such as approximately 10 to11 g/dL—prominent spleen enlargement, and symptoms, according to Gangat. In a patient with borderline hemoglobin, starting with ruxolitinib could exacerbate anemia, which could adversely affect the patient's quality of life, she adds.

Although the approval of momelotinib was a significant development in myelofibrosis treatment, unmet needs still exist for this patient population, Gangat continues. For the subset of patients who do not experience an improvement in anemia when treated with momelotinib, improved treatment options are needed, she says.

Additionally, retrospective comparisons between patient outcomes on ruxolitinib and momelotinib in clinical trials conducted at the Mayo Clinic revealed superior drug retention rates with momelotinib. Specifically, drug survival data indicate that at the 10-year mark, approximately 7% of patients treated with momelotinib were still on therapy, whereas a higher discontinuation rate was observed with ruxolitinib, primarily attributed to anemia-related adverse effects, she says.

Gangat suggests that while momelotinib offers a valuable treatment alternative over with benefits in symptom control and anemia management, further exploration and development of treatments that can fully address the spectrum of myelofibrosis symptoms and complications are still required.

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Naseema Gangat, MBBS discusses the clinical utility of momelotinib and JAK inhibitor selection in treatment-naive myelofibrosis.

Dr Gangat on the Evolution of JAK Inhibitors in Myelofibrosis

Naseema Gangat, MBBS, hematologist/oncologist, education chair and program director, Division of Hematology, Department of Medicine, Mayo Clinic Rochester, discusses the evolution of JAK inhibitors within the treatment landscape for patients with myelofibrosis.

 mutation in 2005 catalyzed intensive efforts toward developing inhibitors targeting the JAK/STAT pathway, Gangat begins. Ruxolitinib (Jakafi) emerged as the pioneering medication in this domain, becoming the first JAK inhibitor approved in this space in 2011. Subsequent years led to the introduction of three additional JAK inhibitors: 

Aiming to build on the efficacy displayed by these JAK inhibitors as single-agent treatment, numerous ongoing clinical trials are investigating the activity and safety of combining JAK inhibitors with other agents with different mechanisms of action, Gangat explains. One noteworthy endeavor includes assessing the combination of ruxolitinib with the BCL-xL inhibitor navitoclax

in the phase 3 TRANSFORM-1 trial (NCT04472598), where the combination elicited an improvement in spleen volume reduction of 35% or more (SVR35) compared with ruxolitinib plus placebo. Additionally, the phase 3 MANIFEST-2 trial (NCT04603495) is evaluating pelabresib (CPI-0610) in combination with ruxolitinib vs ruxolitinib plus placebo, and data from this study also demonstrated an improvement in SVR35 with the combination vs the placebo regimen.

Although these novel combinations show promise in enhancing spleen response, their potential disease-modifying activity and impact on survival remain under scrutiny, Gangat explains. Additionally, concerns regarding heightened toxicity with the combination regimens underscore the necessity for continued evaluation.

The current landscape of treatment for patients with myelofibrosis delineates 3 primary domains: single-agent utilization of approved JAK inhibitors, ongoing exploration of combination therapies in clinical trials, and investigation into agents with novel mechanisms of action, she continues Notable among the latter are interventions targeting anemia, including luspatercept-aamt (Reblozyl) and therapies such as the anti-hemoglobin antibodies and ALK inhibitors.

Collectively, these advancements signify a critical juncture in myelofibrosis therapeutics, marked by a burgeoning array of treatment modalities, Gangat explains. However, the translation of experimental combinations into tangible clinical benefits, particularly in terms of disease modification and survival enhancement, necessitates continued scrutiny and rigorous evaluation, she adds.

Gangat concludes that the multifaceted landscape of treatment for patients with myelofibrosis underscores the imperative for tailored therapeutic strategies informed by evolving evidence and patient-specific considerations.

Naseema Gangat, MBBS, on evolution of JAK inhibitors for the treatment of patients with myelofibrosis.

Naseema Gangat, MD

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Dr Gangat on JAK Inhibitor Selection in Treatment-Naive Myelofibrosis

Dr Gangat on the Evolution of JAK Inhibitors in Myelofibrosis