In Myelofibrosis, New Possibilities for Minimizing Symptoms and Drug Side Effects

New research is offering hope for symptomatic relief in patients with myelofibrosis (MF), one of the less-common but more deadly of the myoproliferative neoplasms (MPNs).

Primary MF, characterized by clonal hematopoietic stem cell expansion in the bone marrow and reactive nonclonal fibroblastic proliferation and marrow fibrosis, affects roughly 18,000 to 20,000 people in the U.S. Median survival is just 3.5 to 5.5 years.

Common symptoms include anemia, shortness of breath and fatigue. Thrombocytopenia and neutropenia are typical and can lead to hemorrhage and infection, respectively. Patients also frequently experience anorexia, weight loss, night sweats and the characteristic splenic and hepatic enlargement.

Only one drug, the selective janus kinase (JAK)1/JAK2 inhibitor ruxolitinib is currently approved by the U.S. Food and Drug Administration for the treatment of myelofibrosis. It doesn’t work for all patients, and even when it does the disease typically progresses after about three years, some to acute leukemia. Moreover, its use is often hampered by side effects, including both anemia and thrombocytopenia.

Cleveland Clinic is involved in trials looking at several new approaches, including other agents that inhibit various points in the Janus kinase and other pathways that underlie the condition, as well as potential concomitant agents that can help minimize anemia and/or thrombocytopenia to enable more effective dosing of primary treatments.

Cleveland Clinic hematologist/oncologist Aaron T. Gerds, MD, MS, sees promise along several fronts. “A short-term focus for the field is how can we make ruxolitinib work better and avoid the negative consequences, both side effects and non-efficacy.”

And in the longer term, “We want to address the underpinnings of the disease. We can’t cure the disease outside of transplantation, but if we can reverse the fibrosis and improve hematopoiesis, it will certainly go a long way in helping patients to live better and longer,” says Dr. Gerds, who recently became chair of the National Comprehensive Cancer Network (NCCN) guidelines panel for MPNs.

Inhibiting the hedgehog: a stumble, but perhaps not a wipeout

At ASH 2017, Dr. Gerds will present the results of Phase I/II Trial of Glasdegib in Heavily Pre-Treated Patients with Primary or Secondary Myelofibrosis. Glasdegib is a selective inhibitor of the Hedgehog (Hh) pathway, via inhibition of Smoothened. While the JAK pathway is the “main highway” underlying all of the MPNs, Hh acts as a “side road” in promoting MF, Dr. Gerds explains.

In animal models, blockage of Hh inhibited growth and self-renewal of bone marrow stem/progenitor cells that differentiate into cells of the myeloid lineage, and reduced splenic fibrosis.

In the single-arm, open-label trial, 21 patients in whom ruxolitinib had failed received glasdegib100 mg orally once daily until there was no further benefit.

Five patients had reductions in spleen volume, ranging from 2.3 to 32.9 percent, with none achieving the standard primary efficacy measure of a 35 percent or greater reduction from baseline by week 24. One patient had an improvement in anemia from grade 3 to 2 and became transfusion independent, while another patient had an improvement in absolute neurophil counts from grade 2 to 0.

There were toxicities, however, including dysgeusia in 13 patients (62 percent), muscle spasms in 12 (57 percent), alopecia in eight (38 percent), decreased appetite and fatigue in seven patients each (33 percent), and increased lipase and decreased weight in five patients each (24 percent). Other side effects occurring in 10 percent or more of patients included nausea, pyrexia, hyperuricemia, anemia, asthenia, constipation, cough, dehydration, prolonged electrocardiogram QT, decreased lymphocyte count, myalgia, extremity pain, thrombocytopenia and upper respiratory tract infection.

Based on these results, Pfizer decided to stop pursuing glasdegib for myelofibrosis, although the company continues to pursue the drug for treating myelodysplastic syndrome and acute leukemia.

But Dr. Gerds holds out hope for targeting this pathway in MF. “The clinical responses were not overwhelmingly exciting, but there were some people who got better,” he said. “It may be better to take aim at targets downstream in the pathway such as Gli1 as opposed to Smoothened.”

He’d like to see a study combining Hh inhibition with ruxolitinib, although that’s not likely to happen in the near future. In addition, he believes that the standard outcome measures of 35 percent reduction in spleen volume, or 50 percent reduction in symptom burden may not be appropriate for this group of refractory patients.

“Perhaps for patients in whom ruxolitinib has failed, the goalposts need to be a little bit different…Maybe if they have even a 10 percent reduction in spleen volume, they might actually feel better.”

Attacking JAK: other agents on the horizon

Meanwhile, Cleveland Clinic is participating in two newly-launched clinical trials for other agents that block the JAK pathway.

One is pacritinib, a JAK2/Fms-like tyrosine kinase 3 (FLT3) inhibitor that CTI BioPharma was developing for MF when the FDA halted the phase 3 studies in February 2016 following reports of patient deaths. The hold was lifted in January 2017 after the company provided additional safety data.

The new dose-finding study will enroll approximately 105 patients who have primary or secondary MF with thrombocytopenia and who were previously treated with ruxolitinib. Evaluation of the dose-response relationship will include the percentage of patients achieving the 35 percent or greater spleen volume reduction.

This study is particularly important because ruxolitinib is contraindicated in patients with very low platelet counts (although it’s often used off-label). “These patients are certainly a population in need and there’s an efficacy signal. It makes a lot of sense,” Dr. Gerds says.

Another phase 2 trial soon launching will investigate the pure JAK1 inhibitor itacitinib (Incyte Corporation) either alone or in combination with ruxolitinib in about 42 patients with MF. Because it only blocks JAK1 and not JAK2, itacitinib could reduce spleen volume and other symptoms with less risk for thrombocytopenia or anemia.

Results for both of those trials are expected by March 2019.

Addressing anemia

Anemia is among the major adverse manifestations of MF, and can worsen with ruxolitinib treatment. A newly-launched phase 2, multicenter, international open-label study is investigating the use of luspatercept (Celgene) in 70 patients with MF and anemia.

Luspatercept is a novel fusion protein that blocks transforming growth factor beta, which inhibits erythropoiesis. The FDA awarded the drug orphan drug status in 2013 and fast-track designation in 2015 for both myelodysplastic syndromes and beta thalassemia.

“We really struggle with anemia in MF,” says Dr. Gerds, noting that multiple weekly transfusions represent a huge burden to patients’ quality of life, while erythropoietin-stimulating agents (ESAs) only work for about a third of patients.

“It’s a different drug altogether, and seems to work well in patients for whom ESA’s aren’t working. So that’s a really exciting thing. It’s only treating one specific MF symptom, anemia, but has the possibility of making a huge impact on patients’ quality of life,” Dr. Gerds says.

Moreover, he notes, reducing the anemia can allow for up-titration of the ruxolitinib dose, increasing the chances for efficacy in some patients. “We’re still trying to treat the underlying disease, but this could be an easy win for the field, treating one of the most troublesome symptoms.”

Cleveland Clinic: a leader in MPN management

Cleveland Clinic is also involved in several other MF-related research projects, including a study of Incyte’s phosphoinositide-3 kinase (PI3K)-delta inhibitor INCB050465 in combination with ruxolitinib in MF patients, and a planned in-house investigation of the role of the angiotensin-renin system in the development of fibrosis.

Clinically, Dr. Gerds and his colleagues in the Leukemia and Myeloid Disorders Program at Cleveland Clinic Cancer Center see approximately 130 new MPN patients per year (including polycythemia vera and essential thrombocythemia in addition to MF), out of roughly 300,00 total such patients living with these diagnoses in the U.S.

“Our MPN program is actively growing. We’re delivering specialized care for this rare set of diseases, and playing key roles in developing new therapies, both in partnership with industry as well as our own internal efforts to better understand the biology and bring treatment from that understanding to the patient.”