New Data May Significantly Improve Options for Myelofibrosis Therapy Following Ruxolitinib Failure

Ruben Mesa, MD

Ruben Mesa, MD

The first-generation JAK1/2 inhibitor ruxolitinib (Jakafi) has been largely unrivaled for the better part of a decade as treatment of primary or secondary myelofibrosis (MF), but newly approved agents and those under investigation may introduce options for patients who lose their response or become intolerant of frontline therapy.

At the24th AnnualInternational Congress on Hematologic Malignancies, host by Physicians’ Education Resource^â, 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

Another finding at 2019 ASH revealed that the small molecule inhibitor navitoclax added to ruxolitinib induced clinically meaningful spleen responses and symptom improvement in patients with primary or secondary myelofibrosis and developed resistance to ruxolitinib in the frontline setting. At 24 weeks, SVR35 was achieved by 30% of patients, with an additional 53% having resolution of palpable splenomegaly. Additionally, navitoclax was successful in reducing the total symptom score (TSS) in most patient at 24 weeks compared with the baseline (7 TSS vs 12 TSS).⁹

Concomitant Therapy for Anemia

Due to high rates of anemia requiring red blood cell transfusions in both primary and secondary MF, therapeutic strategies to get patients to be TI are needed.

Results of a phase II trial of luspatercept in patients with MF and anemia were reported at 2019 ASH, with clinically significant activity of luspatercept seen in patients regardless of ruxolitinib therapy. The primary end point in patients not receiving transfusions was a hemoglobin increase ≥1.5 g/L at every assessment from baseline for ≥12 consecutive weeks within the first 24 weeks. In patients receiving transfusions, the primary end point was TI for ≥12 consecutive weeks within the first 24 weeks. Patients who received ruxolitinib and did not require transfusions achieved the primary end point at a rate of 21% versus 32% of patients who did require transfusions. Those not receiving ruxolitinib achieved the primary end point at rates of 14% and 10%, respectively.¹⁰

Mesa concluded by reviewing clinical scenarios for which each agent may find its niche. Based on National Comprehensive Cancer Network guidelines, fedratinib is the only officially recommended therapy following ruxolitinib failure.¹¹However, based on promising data, other JAK inhibitors, combination therapy with ruxolitinib, concomitant therapy, and investigational single agents may join the paradigm.

References

1. Mesa RA. Treatment after first-generation JAK inhibitors in myelofibrosis. Presented at24th AnnualInternational Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma; February 27-March 1, 2020; Miami, Florida.
2. FDA approves fedratinib for myelofibrosis. FDA website. bit.ly/2vqcgDB. Published August 16, 2019. Accessed February 28, 2020.
3. Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation.Blood. 2017;130(9):1125-113 doi: 10.1182/blood-2017-05-783225.
4. Gerds A, Su D, Martynova A, et al. Ruxolitinib rechallenge can improve constitutional symptoms and splenomegaly in patients with myelofibrosis: a case series.Clin Lymphoma Myeloma Leuk. 2018;18(11):e463-e468. doi: 10.1016/j.clml.2018.06.02.
5. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib induces spleen responses and reduces symptom burden in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) and low platelet counts, who were either ruxolitinib-naïve or were previously treated with ruxolitinib.Blood. 2019;134(suppl 1; abstr 668). doi: 10.1182/blood-2019-129288.
6. Harrison C, Schaap N, Vannucchi A, et al. Fedratinib in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) previously treated with ruxolitinib (RUX): a reanalysis of the phase 2 JAKARTA-2 study. Presented at: 24th Congress of the European Hematology Association; June 13-16, 2019; Amsterdam, Netherlands. Abstract PS1459. bit.ly/2VzFjzz.
7. Pettit K, Curtin N, Tartaczuch M, et al. A phase 2a study of the LSD1 inhibitor IMG-7289 for the treatment of myelofibrosis. Presented at: 24th Congress of the European Hematology Association; June 13-16, 2019; Amsterdam, Netherlands. Abstract S832. bit.ly/2wgR3MM.
8. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a phase 2 study of CPI-0610, a Bromodomain and extraterminal domain inhibitor (BETi), as monotherapy or “add-on” to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis.Blood. 2019;134(suppl 1; abstr 670). doi: 10.1182/blood-2019-127119.
9. Harrison CN, Garcia JS, Mesa JA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis.Blood. 2019;134(suppl 1; abstr 671). doi: 10.1182/blood-2019-130158.
10. Gerds AT, Vannucchi AM, Passamonti F, et al. A phase 2 study of Luspatercept in patients with myelofibrosis-associated anemia.Blood. 2019;134(suppl 1; abstr 557). doi: 10.1182/blood-2019-122546.
11. NCCN clinical practice guidelines in oncology (NCCN guidelines): Myeloproliferative Neoplasms, version 3.2019. National Comprehensive Cancer Network website. bit.ly/2wYLNOd. Published September 4, 2019. Accessed February 28, 2020.