JAK Inhibitors Remain the Gold Standard in Myelofibrosis

Daniel DeAngelo MD, PhD

As the standard approach to myelofibrosis management has evolved to include JAK inhibitors, which offer tailored options based on patient-specific factors such as the presence of anemia and thrombocytopenia, recent trials seek to leverage these agents in various combination regimens, according to Daniel DeAngelo MD, PhD. Although these combinations have generated benefit in terms of spleen reduction, DeAngelo noted that symptom improvement remains a challenge.

“My take is that ruxolitinib [Jakafi] and JAK inhibition in general is [effective] in terms of reducing the total symptom score [TSS]. It’s hard to get better [outcomes] with either a different JAK inhibitor, or, in this case, [an agent] that’s added to the JAK inhibition,” DeAngelo said in an interview with OncLive^® regarding a recent State of the Science Summit™ on hematologic malignancies, which he chaired. “[However], there are still some unmet needs, [including] patients who have lackluster responses and spleen reduction.”

In the interview, DeAngelo outlined the selection of JAK inhibitors for patients with myelofibrosis according to risk stratification and symptoms, discussed findings from recent JAK inhibitor–based combination trials, and shed light on the likelihood of developing anemia following treatment with ruxolitinib.

DeAngelo, a professor of medicine at Harvard Medical School, as well as a physician and chief of the Division of Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts, also discussed the potential disease-modifying role of a novel monoclonal antibody, INCA033989, for patients with CALR type 1 mutated–myelofibrosis in another interview.

OncLive: What is the current standard-of-care (SOC) approach to myelofibrosis management?

DeAngelo:The current SOC for patients with myelofibrosis is stratified based on risk. For patients with higher risk, or patients with symptomatic disease, symptomatic splenomegaly or just symptoms in general, we initiate JAK inhibition. Ruxolitinib is the old standard, but 3 other drugs are now approved. [One such agent is] fedratinib [Inrebic], which is very similar to ruxolitinib. The problem with both of those agents is that they cause anemia. Momelotinib [Ojjaara] is the new [kid] in town, and was approved [by the FDA] this past year for patients with primary myelofibrosis or secondary myelofibrosis who have anemia or are red blood cell [RBC] transfusion dependent. [Lastly], pacritinib [Vonjo] was approved a couple years ago for a group of patients with severe thrombocytopenia, defined as less than 50,000 [platelets per mL].

What recent studies have contributed to the development of ruxolitinib-containing regimens in myelofibrosis? Do such strategies adequately improve upon JAK inhibition alone?

There were 2 combination trials that were conducted and recently presented. There was the phase 3 TRANSFORM-1 study [NCT04472598], which combined ruxolitinib with navitoclax, which is a BCL-XL inhibitor, and the combination was…thought to be more effective than ruxolitinib alone. This was a placebo-controlled trial, and what the study showed is that there is a marked, statistically significant improvement in spleen reduction, but there was no change in the symptom score. Although [the addition of navitoclax] significantly improved spleen reduction, navitoclax plus ruxolitinib didn’t change the TSS.

There was a second combination study called the phase 3 MANIFEST-2 study [NCT04603495], which was a randomized study combining pelabresib [CPI-0610], a BET inhibitor, with ruxolitinib vs placebo. Essentially, similar results were found. The combination strategy improved the reduction in spleen size, which is good; however, there was no significant improvement in TSS. In my opinion, it’s hard to beat ruxolitinib in terms of improving those strategies.

What advice would you give to your colleagues regarding the integration of JAK inhibitors into their own clinical practice?

The phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies, which were the initial foray into this field, were designed for symptom improvement and spleen reduction, which was very modest thinking in terms of the outcomes. Surprisingly, even though all patients ended up crossing over [to the investigational arm], there was an improvement in overall survival [with ruxolitinib vs placebo]. [Notably], these were patients with intermediate-2 or high-risk [disease according to] the Dynamic International Prognostic Scoring System, or symptomatic splenomegaly with intermediate-1 [disease]. These were not all patients, but higher risk or symptomatic patients. [These studies established ruxolitinib as] the SOC. Transplantation is a cure, but transplantation is not for everybody, so the standard [approach is to get eligible] patients onto a JAK inhibitor.

The problem is that there is a 2-point drop in hemoglobin [levels], on average, during the first 2 months [of treatment] with ruxolitinib. It’s an on-target effect. JAK2 is important in erythropoiesis, and when you inhibit normal JAK2, it results in a drop in the hemoglobin [levels]. Now this can be ameliorated with momelotinib and pacritinib, and that’s how they got FDA approved for patients who are anemic. However, it’s important to be cognizant of the fact that you can take a patient with a marginal hemoglobin [level] and, [through treatment with ruxolitinib], dramatically cause anemia. That doesn’t mean the drug is not working, and very often I see patients being taken off an appropriate dose of ruxolitinib because of the anemia, when that’s an expectation.

My guidance to clinicians is to manage expectations. I always talk to the patient, [and tell them to] expect that their hemoglobin is going to go down. It doesn’t mean that their disease is progressing. There’s lots of ways to abrogate that, either with RBC transfusions, growth factors, or switching to different agents if it becomes an issue. [However], most patients [experience a] drop [in hemoglobin levels] for the first 2 months, and then it gradually improves after months 3 and 4.