An Important Moment in the Treatment of MPNs

  • MPNRF | May 19, 2023
    Raajit Rampal, MD, PhD, MPNRF Medical Advisor

    An Important Time for MPNs

    “This is a profoundly important moment in the treatment of MPNs,” according to Raajit Rampal, MD, PhD, a hematology/oncology specialist at Memorial Sloan Kettering, and MPNRF’s medical advisor.

    We now have three FDA-approved JAK inhibitors – ruxolitinib, pacritinib, and fedratinib. We have combinations to offer, including a number of new drugs in late stages of clinical trials. And we may be able to sequence from one combination to the other. “Compared to just a few years ago, this is huge,” he explains.

    Are we coming to the moment for MPNs where, like in breast cancer, a patient with advanced disease can be stable for several years because they can go from one treatment regimen to the next? Dr. Rampal and other MPN specialists are very optimistic. “I think that it is not an unreasonable thing to say that how we treat MPNs will be completely different in the next three to five years.”

    What is the basis of this optimism?


    There were many exciting advances in MPN research and treatment reported at the American Society of Hematology (ASH) Annual Meeting and Exhibition in December 2022. Among these, came news of the anticipated 2023 approval of momelotinib for myelofibrosis (MF). While it is similar to ruxolitinib in that it inhibits both JAK1 and JAK2, it has potential additional benefits.

    “With momelotinib, it appears we have a drug that can do the things that we expect the JAK inhibitors to do, i.e., shrinking spleens and improving symptoms, without the common side effect of reducing hemoglobin,” according to Dr. Rampal. “Potentially increasing a patient’s hemoglobin, and maybe more importantly, converting transfusion-dependent patients to no longer require blood transfusions, that is an important development.”

    New Drugs Combined with Established Therapies

    Many large phase 3 trials are looking at combination drug therapies, most often combining new drugs with JAK inhibitors. Among the primary questions is how we know if positive results are related to the JAK inhibitor, like ruxolitinb, or the added drug.

    This is where some of these studies are now – determining whether or not a combination of drugs or a single drug works best.

    A randomized study, such as with pelabresib, now in a phase 3 trial with ruxolitinib, is a good example. Two arms of patients will be directly compared. In this case, one group of patients gets only ruxolitinib and the other gets ruxolitinib plus pelabresib. The implication would be that if there is a difference, it would be attributable to the second drug. “So far, this is one of the very encouraging drug combination trials for myelofibrosis,” reports Dr. Rampal.

    Next, the question becomes: How do the drugs get used, and do they get used in a sequential manner? For example, are patients started on ruxolitinib alone, then a drug like pelabresib gets added to the regimen if it’s not working well enough? “The answer is that we still don’t know, and that’s where we have to go next,” Dr. Rampal says.

    The Potential of Interferon in Combination Therapy

    Multiple forms of interferon have shown high rates of hematological and molecular responses in most patients with ET, PV, and some patients in the early phase of primary MF. But why it works for some people and not others, or why it stops working is poorly understood. That was the impetus for the MPN Research Foundation’s 2017 creation of a global, multi-institutional collaboration to learn more about how interferon works.

    At ASH 2022, Jean-Jacques Kiladjian, MD, PhD, Paris Diderot University, presented work from his studies of interferon over several years. Specifically, he reported on pegylated interferon (peginterferon alfa-2a) and as a combination therapy.

    The high-level takeaway is that the combination is reportedly safe to combine. There isn’t randomized data yet, where half of patients get pegylated interferon alone and half get it with ruxolitinib.

    “Most interesting here is data reported that the level of mutation in some patients seems to be driven down more than we would expect with either drug on its own,” according to Dr. Rampal. “That may indicate that the two are working together in certain patients. There’s more to be learned there, but we now know it seems to be safe.”

    Cytopenia and Anemia – Potentially Reducing Transfusion Dependence

    With primary MF, patients can present with anemia and/or with very low platelets. Cytopenia refers to either or both together. These people may require red cell transfusions, and sometimes platelet transfusions. Research on pacritinib – just approved for MF early in 2022 – was re-analyzed and the findings offer potentially exciting news for this population. Pacritinib is approved for first-line therapy in patients with very low platelet counts – less than 50,000.

    “We had nothing to treat these patients before,” according to Dr. Rampal. “As it turns out, pacritinib can do the same thing as momelotinib, inhibiting the same pathway (the ACVR1 pathway), leading to an increase in hemoglobin in some patients. And a proportion of patients taking pacritinib who were requiring red cell transfusions no longer needed them.”

    A CALR Antibody

    As the MPN treatment landscape expands, there is also news about a calreticulin (CALR) antibody, for people with MPNs who have a CALR mutation.

    A new drug, an antibody identified by Incyte researchers, can target the mutated calreticulin while avoiding normal cells. In mouse models, and some human cell lines, they saw that this drug was able to selectively deplete cells that had this calreticulin mutation. An immunotherapy approach, it is being called “very promising” by MPN specialists.

    “This is a complete departure from how we have generally pursued MPNs, using an immunotherapy approach instead of an inhibitor,” explains Dr. Ramapal, who reminds us that the research is still in an early stage, with all data presented (as of December 2022) from mice and cells.

    “The next step is testing in humans, where we will get a real readout about what’s going to happen. It’s potentially a big leap forward,” he adds. “First, we need to study its safety, then if determined safe, it could move onto a phase 2 clinical trial.

    Several studies reported at ASH 2022 are related to projects funded by MPNRF. Some of these are highlighted here.