Expanded Choices Emerge for Myelofibrosis Following Ruxolitinib Therapy

Audrey Sternberg
Published: Friday, Feb 28, 2020

Ruben Mesa, MD, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center
Ruben Mesa, MD
Newly approved and investigational agents are joining ruxolitinib (Jakafi) for the treatment of myelofibrosis (MF) and may provide options for patients who progress or become intolerant to frontline JAK inhibitors.

At the 24th Annual International Congress on Hematologic Malignancies, hosted by Physicians’ Education Resource®, LLC, Ruben Mesa, MD, who is director of the UT San Antonio MD Anderson Cancer Center, presented available and emerging therapy options for patients who require additional MF therapy following ruxolitinib.

The JAK inhibitor landscape includes 2 agents that are approved for use in patients with MF in the first-line setting, with fedratinib (Inrebic) receiving the designation in 2019 for patients with intermediate-2 or high-risk primary or secondary MF.2

Other agents that may become available include pacritinib, which is being evaluated in the phase II/III PACIFICA trial for patients with primary or secondary MF (NCT03165734); and momelotinib, under evaluation in the phase III MOMENTUM trial of patients with previously JAK-inhibitor treated primary or secondary MF (NCT04173494).

Continued Care With Ruxolitinib

A retrospective chart review of patients with MF who had received ruxolitinib at a single institution indicated that clinical characteristics of patients at the end of therapy showed significantly lower platelet counts, lower hemoglobin levels, and smaller spleen size. In addition, patients were more likely to be transfusion dependent and were more prone to abnormal cytogenetics such as a complex karyotype. However, platelet counts were the only clinical variable that could be tied to survival rates after discontinuation.3

Re-challenging patients with ruxolitinib therapy may be a viable treatment option for some who initially lose or have an inadequate response to the JAK2 inhibitor. In a cohort of 13 patients, first re-challenge led to 9 (69%) experiencing spleen size reduction and all but 1 (92%) having improvement in constitutional symptoms. Four patients went on to receive a second re-challenge with ruxolitinib. According to Mesa, this analysis potentiates the idea of using a treatment “holiday” to re-induce responses in these patients.4

Single-Agents After Ruxolitinib

Data reported at the latest American Society of Hematology (ASH) Annual Meeting revealed patient subsets for whom fedratinib may be the most suitable option in treating MF.

An analysis of patients treated with fedratinib in the frontline setting in the pivotal phase III JAKARTA trial and those treated post-ruxolitinib in the phase II JAKARTA2 trial demonstrated that platelet counts at baseline did not significantly affect treatment, and all treated patients achieved similar spleen volume and symptom response rates. These results indicate that fedratinib may offer promise to patients with low platelet counts who would have otherwise suffered with disappointing responses.5

Upon a reanalysis of JAKARTA2, baseline disease characteristic data indicate that fedratinib was associated with clinically meaningful and statistically significant reductions in splenomegaly and symptom burden in patients with MF who met stringent criteria for being ruxolitinib refractory or intolerant.6

The investigational agent IMG-7289—an inhibitor of the lysine-specific histone demethylase 1A (LSD1), which is an epigenetic regulator critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors—was examined in a phase I/II trial of patients with high- or intermediate-2 risk MF that is resistant or intolerant to available therapies. In 9 evaluable patients, 66% patients had spleen reduction and 56% had ≥50% total symptoms scores (TSS).7

Combination Therapy Treatment strategies that combine ruxolitinib with other agents have also shown promise in the setting of intolerance or relapse.

At 2019 ASH, the small molecule BET inhibitor CPI-0610 demonstrated a favorable safety profile and clinical benefit when combined with ruxolitinib for the treatment of patients who had inadequate or no response to or who were refractory to ruxolitinib. Additionally, bone marrow fibrosis improvement and anemia response indicate that this strategy has the potential to result in meaningful disease modification in certain patients. In patients who were transfusion dependent (TD) and relapsed/refractory or intolerant to ruxolitinib, 25% had spleen reduction ≥35% (SVR35) with a median change of -24.9%. Six out of 14 patients converted from TD to transfusion independent (TI).8

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