Progress and Challenges Mark the Myelofibrosis Landscape

Rami S. Komrokji, MD

A growing understanding about the underlying biology of myelofibrosis has helped improve the diagnosis and treatment of the disease during the past decade and is paving the way for further advancements, according to a panel of experts in the field. “We’ve learned more about the disease biology in the last 5 to 10 years than we did over the 50 years prior, and hopefully, within the next few years, we will have more effective treatments for patients,” Rami S. Komrokji, MD, said during a recent OncLive Peer Exchange^® program.

Today, approaches for treating patients are more closely matched with the characteristics of the malignancy, noted Ruben A. Mesa, MD, FACP, of UT Health San Antonio MD Anderson Cancer Center, who headed the effort to develop the first National Comprehensive Cancer Network (NCCN) Guidelines for myelofibrosis and other myeloproliferative neoplasms (MPNs) in 2017.

“I’m incredibly hopeful. Certainly during my career, I’ve witnessed a change in MPNs from largely using agents for which we did not really have a strong scientific rationale. They were empirically being used from development from other indications,” Mesa said.

MPNs are a rare group of chronic blood cancers associated with dysregulation of the JAK2-STAT5 signaling pathway.^1,2 Myelofibrosis is the least common but most aggressive of the Philadelphia chromosome—negative MPNs, a group that also includes polycythemia vera (PV) and essential thrombocythemia (ET). Individuals can develop primary myelofibrosis (PMF), which includes prefibrotic or early PMF (pre-PMF) and overt PMF,³ or myelofibrosis can result from progression of ET or PV.^1,4 Mesa said the US incidence of primary myelofibrosis is approximately 1 per 100,000 cases per year, according to a database study he and his colleagues conducted.4 Because patients with myelofibrosis frequently survive several years after diagnosis, the estimated prevalence is much higher than the incidence would suggest (4-6 per 100,000).^4,5

Pretreatment Considerations

Harry P. Erba, MD, PhD, who moderated the panel of distinguished MPN researchers, noted that although significant overlap exists between MPN subtypes, each has distinct biological characteristics that guide diagnosis and treatment decisions. Allogeneic stem cell transplant (ASCT) is the only curative treatment for myelofibrosis, but its life-threatening risks render many patients ineligible for transplant. “As we learn more about the biology, hopefully, we’re going to move more toward targeted agents directed at the biology,” he said. The identification of JAK2 as a driver mutation in myelofibrosis led to FDA approval in 2011 of ruxolitinib (Jakafi), the first targeted therapy for myelofibrosis. The panel reviewed data from clinical trials of ruxolitinib and discussed other targeted agents in the pipeline. They also talked about important considerations for incorporating ruxolitinib into practice.Accurately diagnosing myelofibrosis is essential before selecting treatment. In 2016, the World Health Organization (WHO) developed updated criteria for classifying MPNs with the goal of making it easier for clinicians to distinguish between ET, PV, and PMF.3 Srdan Verstovsek, MD, PhD, said the criteria make it clear that strong clinical suspicion is not sufficient to diagnose myelofibrosis. “A combination of tests is required to make the diagnosis,” he said, noting that 2016 WHO guidelines emphasize the necessity of a bone marrow biopsy. Biopsy results in a patient with overt PMF will show proliferation of atypical megakaryocytes accompanied by grade 2 or 3 reticulin and/ or collagen fibrosis. He said other essential tests include genetic screening for a JAK2, CALR, or MPL mutation and a complete blood cell count. Verstovsek said anemia, an elevated serum lactate dehydrogenase level, leukoerythroblastosis in the peripheral smear, leukocytosis, splenomegaly, and constitutional symptoms are all minor criteria used to make a diagnosis.³

Mesa said he often has patients referred to him with a diagnosis of myelofibrosis based on biopsy results showing fibrosis in the bone marrow. “I see this all the time…but fibrosis does not mean myelofibrosis as a disease entity. It needs to be worked up,” he said. The panel discussed how fibrosis also occurs with myelodysplastic syndromes, chronic myeloid leukemia, or other myeloid neoplasms, which must be ruled out when diagnosing PMF.

Jamile M. Shammo, MD, FASCP, FACP, said the opposite is also possible: A patient with PMF may have no evidence of fibrosis in the bone marrow. These patients have pre-PMF, a new classification of PMF under 2016 WHO criteria. Patients with pre-PMF have grade 0 to 1 reticulin fibrosis, which can lead to misdiagnosis as ET.⁶ However, ET and pre-PMF have different clinical presentations. For example, one study found that 52% of patients with ET met none of the minor criteria for a pre-PMF diagnosis, whereas 91% of patients with pre-PMF met at least 1 minor criteria.⁷ The WHO guidelines also describe morphological characteristics that distinguish pre-PMF from ET (eg, megakaryocytes in ET have less atypia).^3,7 Median overall survival (OS) is significantly longer for patients with ET than for patients with pre-PMF (22.2 vs 11.9 years; P <.001), underscoring the importance of making the correct diagnosis.⁷

“Therapy for myelofibrosis is fundamentally going to fall to observation, medical therapies, or transplant,” Mesa said, noting that the goal of transplant is to cure, whereas the goal of medication is to reduce morbidity. “Decreasing morbidity is in and of itself disease modification, because many patients die from progressive morbidity,” he said.

Treatment selection is based on risk. Observation is common for asymptomatic patients with lower-risk disease, but medication or transplant may be appropriate if severe symptoms, splenomegaly, transfusion-dependent anemia, or adverse cytogenetic factors are present.5,6,8 “The majority of patients we see in the clinic have intermediate- to highrisk disease,” Erba said, adding that the life expectancy for these patients is limited. The approach for patients with higher-risk disease is similar for primary and secondary myelofibrosis and is generally ASCT or ruxolitinib, a JAK1/ JAK2 inhibitor.⁵

To assess risk, “there are more prognostic scores than we can keep track of,” Mesa said. The panel discussed risk-stratification tools available for myelofibrosis and concluded they were useful but imperfect. “It’s always important to use good clinical common sense,” said Mesa, whose primary concern when making treatment decisions is evidence of progression, such as an enlarging spleen or increasing debilitation.

When Transplant is Not an Option

“There is prognostic information from the models…but we are also using them as therapeutic tools to decide who we are taking to transplant,” Komrokji said. He considers age and disease-related risk when deciding whether to refer someone for transplant but acknowledged the emerging importance of the presence or absence of somatic mutations such as ASXL1 and SRSFS2. “We are starting to learn about the effect of transplant in patients with those mutations,” he said.Verstovsek and Mesa were investigators for the phase III, randomized, controlled COMFORT-I and COMFORT-II trials of ruxolitinib, which enrolled patients with intermediate-2 or highrisk myelofibrosis.⁹ “These were patients with advanced features, with an enlarged spleen and bad symptoms,” Verstovsek said. The control arms of COMFORT-I and COMFORT-II received placebo or best available care, respectively, and were permitted to cross over to ruxolitinib if splenomegaly worsened. “Now we have more than 5 years of follow-up from these studies. We found that people with good control of signs and symptoms lived an average of about 3 years longer in both studies,” he said.

“The starting dose of ruxolitinib is usually based on the platelet level,” Verstovsek said. He recommended that clinicians follow dosing recommendations in the new guidelines on MPNs released by NCCN.5 He said because ruxolitinib can aggravate anemia, many clinicians start patients at a suboptimal dose. “My goal is to start with the suggested dose and modify if necessary,” he said. “Receiving a higher dose of ruxolitinib in the beginning has the potential to provide the greatest reduction in spleen size, which correlates directly with survival.” If a patient has anemia or develops anemia during treatment, Verstovsek said, he addresses it with transfusions or an antianemia medication such as danazol.

Erba said he uses a starting ruxolitinib dose of 5 mg twice daily in older patients who have impaired hepatic or renal function or low platelet counts and increases the dose within a month if the drug is tolerated well. His experience shows that starting ruxolitinib in patients with anemia at 10 mg twice daily is effective “as long as you go to 15 mg [twice daily] the next month and then 20 mg [twice daily] the month after and do not wait 3 months,” he said.

“Dosing and familiarity with the treatment are the keys to success,” Komrokji said. He and his colleagues conducted a study of 145 patients with myelofibrosis treated at their institution with ruxolitinib.¹⁰ They concluded that the clinical benefits of ruxolitinib were even more pronounced in the real-world setting than in the clinical trials but that starting patients at too low of a dose compromised outcomes, he said.

After Ruxolitinib Failure

The NCCN guidelines recommend evaluating symptom burden at baseline and periodically during treatment.⁵ The guidelines define a ruxolitinib response as ≥50% reduction in symptoms but note that lesser reductions may still be clinically meaningful for some patients. Patients with PV and myelofibrosis “should be monitored just like anybody else with a hematologic malignancy, and they should have their symptoms evaluated,” Shammo said.“We are starting to see the challenge of what we call ruxo failure and what happens to those patients,” Komrokji said, describing it as an unmet need in myelofibrosis. He said his realworld study found that OS after ruxolitinib failure ranged from 14 to 17 months,10 which was consistent with findings from a phase I/II trial that the University of Texas MD Anderson Cancer Center in Houston conducted that showed median OS after discontinuation was 14 months.¹¹

“Life after ruxolitinib is not good, and it’s short,” Verstovsek said. He discussed results from JAKARTA-2, a phase II trial of the investigational drug fedratinib in 97 patients resistant to or intolerant of ruxolitinib.¹² Fedratinib is more selective for JAK2 than JAK1 but also affects FLT3, he said: “Fedratinib was very active; more than half the patients had a significant decrease in spleen volume ≥35%.” A clinical hold was placed on fedratinib because of central nervous system toxicity, but just 8 of 800 patients were affected, Verstovsek said, and the hold was lifted. “We are looking forward to further testing and perhaps, in the near future, approval of this drug in either frontline or second-line,” he said.

Mesa discussed data from a phase III trial he was involved in that compared the novel agent pacritinib with best available therapy, including ruxolitinib, in 311 patients with myelofibrosis.¹³ Pacritinib primarily inhibits JAK2. Significantly more patients in the pacritinib arm than in the best available therapy arm achieved a spleen volume reduction ≥35% (18% vs 3%, respectively; P = .001).13 It was placed under a clinical hold because of an increased risk of cardiac events and hemorrhage, which Mesa attributed to patient selection and poorly optimized dosing. The hold was released, and another trial is under way to determine the optimal dose. The hope is that pacritinib will become an option for patients with marked thrombocytopenia who cannot take ruxolitinib.

Other studies are evaluating 2 novel recombinant fusion proteins that act as a ligand trap for transforming growth factor—β. Luspatercept and sotatercept have shown promising efficacy at improving anemia in patients with myelodysplastic syndromes, Komrokji said, and luspatercept is now being evaluated in a phase III trial as an add-on in patients with anemia who are taking ruxolitinib for an MPN, including patients with myelofibrosis. “Anemia is an unmet need in myelofibrosis, and this drug is promising and definitely worth testing,” he said. “It’s used every 3 weeks as a subcutaneous injection. No major [adverse] effects have been reported so far.”

Shammo emphasized the importance of having more treatment options for myelofibrosis, saying his patients find it “anxiety-inducing” to start ruxolitinib: “They feel like they’re sort of getting to the end of the line.”

References

1. Spivak JL. Myeloproliferative neoplasms. N Engl J Med. 2017;376(22):2168-2181. doi: 10.1056/NEJMra1406186.
2. Shantzer L, Berger K, Pu JJ. Primary myelofibrosis and its targeted therapy. Ann Hematol. 2017;96(4):531-535. doi: 10.1007/s00277- 016-2785-9.
3. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi: 10.1038/s41408-018-0054-y.
4. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595-600. doi: 10.3109/10428194.2013.813500.
5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Myeloproliferative neoplasms, version 2.2019. nccn.org/professionals/ physician_gls/pdf/mpn.pdf. Published October 29, 2018. Accessed November 1, 2018.
6. Palandri F, Sabattini E, Maffioli M. Treating early-stage myelofibrosis [published online October 20, 2018]. Ann Hematol. doi: 10.1007/s00277-018-3526-z.
7. Jeryczynski G, Thiele J, Gisslinger B, et al. Pre-fibrotic/early primary myelofibrosis vs. WHO-defined essential thrombocythemia: the impact of minor clinical diagnostic criteria on the outcome of the disease. Am J Hematol. 2017;92(9):885-891. doi: 10.1002/ ajh.24788.
8. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome- negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069. doi: 10.1038/s41375-018-0077-1.
9. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi: 10.1186/ s13045-017-0527-7.
10. Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435-441. doi: 10.1007/s00277-017-3194-4.
11. Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017;130(9):1125-1131. doi: 10.1182/blood-2017-05-783225.
12. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-e324. doi: 10.1016/S2352-3026(17)30088-1.
13. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi: 10.1001/ jamaoncol.2017.5818.