Management Strategies Set for Varying Patterns of Ruxolitinib Progression in Myelofibrosis

Vikas Gupta, MD

Vikas Gupta, MD

A report from the Canadian Myeloproliferative Neoplasm (MPN) Group has outlined different patterns of treatment failure from JAK inhibitor therapy in patients with myelofibrosis. The report, published inJCO Oncology Practice,suggests management practices for each pattern of response.¹

Ruxolitinib (Jakafi), a JAK1/2 inhibitor, is a standard of care for patients with myelofibrosis that has shown significant improvement in symptoms. Although the experience with ruxolitinib is well known, the criteria for failure have been less well defined and are heterogeneous. Vikas Gupta, MD, and the study co-authors pointed out the variability of discontinuation rates from ruxolitinib treatment and eligibility criteria for clinical trials of second-line agents as examples of the different definitions of ruxolitinib failure.

Gupta et al stressed that an understanding of the cause of a patient’s resistance or intolerance to treatment and the pattern of failure are necessary to know how to treat these patients next. They defined 7 potential patterns of JAK inhibitor therapy failure and offered a potential management strategy for each.

One such pattern is a suboptimal spleen response, which was considered to be a less than 25% reduction in palpable splenomegaly or persistent symptomatic splenomegaly after at least 3 months of receiving the optimal dose of JAK inhibitor therapy. A loss of spleen response was determined to be a more than 50% increase in spleen length from the patient’s best response.

In this case, the authors suggested reviewing dosing, compliance, and drug-drug interactions and potentially increasing the dose of ruxolitinib if possible. They noted that the reintroduction of ruxolitinib after a period of time could result in new spleen responses in a small group of patients.

Additionally, hematopoietic stem cell transplantation (HCT) should be considered for eligible patients to overcome the modest survival rates of patients with suboptimal or loss of spleen response, amounting to 14 to 18 months. Other options include switching to fedratinib (Inrebic), clinical trials, salvage therapies, and splenectomy.

A third pattern is the development of anemia that requires transfusions. Although anemia is a known adverse event associated with ruxolitinib—with 96.1% of patients treated with ruxolitinib in the COMFORT-1 trial²developing anemia of any grade—and a known feature of progressive myelofibrosis, transfusion-requiring anemia after 24 weeks of treatment could be due to ruxolitinib failure. The Canadian MPN Group defined transfusion-dependent anemia as requiring at least 4 units of red blood cell transfusions in 8 weeks occurring within 6 months of ruxolitinib treatment. Those with transfusion-dependent anemia and myelofibrosis receiving JAK inhibition have a median survival of 8 months, according to a study from the Princess Margaret Cancer Centre.³

Erythropoiesis-stimulating agents were suggested to treat the anemia as long as the patient was otherwise responding well to treatment with ruxolitinib and had a serum erythropoietin level below 500 IU/L. The dose of ruxolitinib could also be reduced in patients who did not have a low erythropoietin level.

Momelotinib, a second-generation JAK inhibitor in development, demonstrated efficacy in reducing transfusions among patients with myelofibrosis in the SIMPLIFY 2 trial.⁴At week 24, 43% of patients receiving momelotinib were transfusion independent compared with 21% receiving best available therapy (nominalP= .0012). Forty percent of patients in the momelotinib arm were transfusion independent for the complete treatment phase. However, the primary end point of the trial, reduction in spleen volume, was not met in the trial.

Severe thrombocytopenia is another pattern of progression and a dose-limiting toxicity for ruxolitinib. The MPN Group defined severe thrombocytopenia as the inability to maintain a platelet count greater than 35-50 x 10⁹/L in those on anticoagulation medication and greater than 25 x 10⁹/L in those not receiving anticoagulants. Patients with myelofibrosis and severe thrombocytopenia had a median survival of 2.2 years and a survival range of 6 to 9 months while on ruxolitinib. The study authors recommended lowering the dose of ruxolitinib or switching to an alternate therapy.

Another form of disease progression on ruxolitinib is the transformation to accelerated or blast phase, which the authors suggested both be treated similarly. These patients demonstrate a median survival of 4 to 6 months and not all are able to receive HCT.

Gupta et al recommended these patients participate in clinical trials with targeted agents as other treatments, such as intensive chemotherapy or hypomethylating agents, have only demonstrated limited and temporary control of disease.

A small proportion of patients on ruxolitinib may develop a secondary malignancy, possibly due to the immunosuppressive effects of the JAK inhibitor. An increase in the development of lymphoma following treatment with ruxolitinib in patients with MPNs has been reported in some studies, and nonmelanoma skin cancers have been reported in patients receiving ruxolitinib as well.

The treatment for patients who develop a secondary malignancy should be approached on a case-by-case basis, but in patients who develop localized nonmelanoma skin cancer, ruxolitinib can usually be continued unless the disease is aggressive or recurrent.

Ruxolitinib treatment is associated with a risk of infection, especially herpes zoster infection. The most common infections found with ruxolitinib treatment in the JUMP study were herpes zoster, bronchitis, and urinary tract infections at a rate of 8%, 6.1%, and 6%, respectively.⁵

Although many centers administer the Shingrix vaccine before starting ruxolitinib, no guidelines exist for the use of prophylactic strategies to prevent infection in patients with myelofibrosis receiving ruxolitinib. Common infections typically do not require terminating ruxolitinib treatment, but management should be evaluated individually if the infection is life-threatening.

When discontinuation of ruxolitinib is required to deal with progression, the study authors recommended a slow taper of treatment and potentially adding in a short course of steroids. In the case of moving on to transplantation, the taper should be over 5 days with a 1-day waiting period before receiving conditioning therapy.

Even earlier switch to HCT should be considered in patients with high-risk prognostic system scores, transfusion-dependent anemia prior to initiating ruxolitinib, and those with high-risk mutations.

References

1. Gupta V, Cerquozzi S, Foltz L, et al. Patterns of Ruxolitinib Therapy Failure and Its Management in Myelofibrosis: Perspectives of the Canadian Myeloproliferative Neoplasm Group [published online March 5, 2020].JCO Oncol Pract. doi: 10.1200/JOP.19.00506.
2. Verstovsek S, Mesa RA, Gotlib J, et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis.N Engl J Med. 2012;366(9):799-807. doi: 10.1056/NEJMoa1110557.
3. Bartoszko J, Panzarella T, Lau A, et al. Effect of red blood cell transfusion dependence on the natural history of myeloproliferative neoplasm-associated myelofibrosis.Clin Lymphoma Myeloma Leuk. 2015;15(1:e151-e156. doi: 10.1016/j.clml.2015.09.001.
4. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial.Lancet Haematol.2018;5(2):e73-e81. doi: 10.1016/S2352-3026(17)30237-5.
5. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety And Efficacy Of Ruxolitinib In An Open-Label, Multicenter, Single-Arm Phase 3b Expanded-Access Study In Patients With Myelofibrosis: A Snapshot Of 1144 Patients In The JUMP Trial.Haematologica.2016;101:1065-1073. doi: 10.3324/haematol.2016.143677.