Examining Two Approaches for Improving the Care of Myelofibrosis

While the only potentially curative therapy for patients with advanced myelofibrosis is an allogenic stem cell transplant, an option unavailable for many patients, the treatment landscape for the disease is rapidly changing. Efforts such as the COMFORT-I and -II studies are proving which agents may or may not be effective for myelofibrosis, while other studies are looking at the aspects that make for a successful for stem cell transplant.

CURE sat down with John O. Mascarenhas, assistant professor of Medicine, Hematology and Medical Oncology, Mount Sinai School of Medicine, to gain insight into these advancements.

What are the objectives of the COMFORT studies, and what kind of impact do they have?

The COMFORT studies were pivotal studies. There was COMFORT-I in the U.S. and COMFORT-II in nine countries in Europe. These were randomized phase 3 studies that compared Jakafi (ruxolitinib), a JAK 1 and 2 inhibitor, with placebo in the U.S. and best available therapy in Europe.

What these studies showed was that Jakafi was superior in reducing splenomegaly and improving symptoms mostly by down-modulating inflammatory cytokine signaling. The deficits of this drug have been mild suppression, so the dose-limiting toxicity of Jakafi is thrombocytopenia, and a certain proportion of patients will concur anemia. If an oncologist is treating a patient with advanced myelofibrosis that has thrombocytopenia and/or significant transfusion-dependent anemia, Jakafi is not necessarily the most desirable drug to use, which kind of opened the door for second-generation TKIs against JAK 2, namely pacritinib and momelotinib.

Unfortunately, pacritinib was put on a full clinical hold by the FDA due to concerns regarding thrombocytopenia and bleeding, as well as cardiovascular events. I personally think that it is still premature to discount the potential benefit and opportunity for pacritinib to move forward. I’m hopeful that with more investigation, the benefits of the drug will become clear and we can better understand the potential downsides of the drug, whatever they may be. So I think there is still more to be learned about pacritinib and I’d like to think that it is not yet a dead drug.

What are some new approaches to treat myelofibrosis?

There are many new approaches, many of which are combination therapy approaches, using Jakafi as a backbone and then adding novel therapies that might target different types of pathways to Jakafi to improve response.

Beyond that, there are a number of different novel therapeutic approaches that are being evaluated that are non-JAK 2 inhibitor therapies, like the telomerase inhibitor imetelstat, which is a Geron drug. Along with Janssen, they’re running a large, multi-center, randomized phase 2 study evaluating two different doses of the intravenous drug that targets telomerase. This is a novel approach that has a lot of attention, mainly because the Mayo Clinic ran a pilot study in approximately 33 patients with advanced myelofibrosis and had some very exciting responses in terms of complete responses: resolution of bone marrow, histopathologic abnormalities, regression of bone marrow fibrosis and even complete molecular responses in a handful of patients. This is not something we would normally see, particularly in a pilot study. It would suggest that there is really a signal of clinical activity. That will be evaluated in a more robust fashion in a multi-center randomized setting. And I think that’s a drug and an approach to be keeping an eye out on.

The other drug that has really received attention as an innovative approach is PRM-151. This is also an infusion agent. The main concept here is that by improving the hematopoietic niche and reducing fibrosis, which we believe would obstruct that, you would prove normal hematopoiesis. The phase 2, stage 1 results were encouraging in that there were decreases in degree of fibrosis within the treated patients and even a trend toward improvement in anemia and thrombocytopenia in some of the patients. This will be evaluated in a larger, stage 2 aspect of the phase 2 study, which is now enrolling patients.

What are some of the improvements in stem cell transplants?

Transplant is the only potentially curative modality for patients with advanced myelofibrosis, patients with intermediate and high risk by the DIPSS scoring. The problem that often plagues the use of transplant is our patient population is often advanced in age. Often there are not viable donor options, whether it's siblings or unrelated donors. So there's an unmet need to optimize transplantation.

The use of Jakafi prior to transplant has been an attractive approach that's been evaluated and is currently being evaluated in perspective studies. The MPD-RC 114 study is a trial of using Jakafi intensively for two months prior to reduced intensity conditioning hematopoietic stem cell transplantation with fludarabine and busulfan in patients with intermediate or worse myelofibrosis. The concept is by improving their disease-related symptoms you would improve, hopefully, their transplant-related mortality or reduce it. By reducing their splenomegaly, you would hopefully improve rates of engraftment. You would favorably improve the instance of graft-versus-host-disease (GVHD), which is a major issue for many patients that undergo transplantation.

Again, patients with myelofibrosis tend to be advanced in age. Many may not be considered viable candidates obviously for fully myeloablative transplants and many of them do not have siblings who are viable candidates. This is particularly important for myelofibrosis.

The MPD-RC 101 study was a phase 2 trial that clearly showed a difference in outcomes of patients who underwent reduced-intensity transplant with a sibling-related donor versus an unrelated donor. The sibling arm did far better. At a median follow-up of two years, 75 percent of patients in the sibling arm were alive and engrafted, as opposed to 32 percent in the unrelated arm. There was a clear difference in outcomes between unrelated and related arms. So for patients with unrelated donor options only or who don't have any donor options, the search for alternative donors has become an area of clinical interest.