Observational MOST Trial Reveals Progression Trends in Low-Risk Myelofibrosis

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July 11, 2024

Author(s):Jax DiEugenio

Findings from the prospective, observational MOST trial (NCT02953704) showed that 58.5% of patients with low- or intermediate-1–risk myelofibrosis enrolled in cohort A (n = 205) met at least 1 criterion for disease progression after a median follow-up of less than 53 months, which was a higher rate than investigators expected, according to Aaron Gerds, MD.

Cohort A included patients with low-risk or intermediate-1–risk disease, where patients were considered to have intermediate-1–risk myelofibrosis based on age only. Cohort B (n = 27) featured patients with intermediate-1–risk disease with other Dynamic International Prognostic Scoring System (DIPSS) risk factors beyond age.

Findings presented at the 2024 EHA Congress showed that of the 120 patients in cohort A who experienced disease progression, 64 (53.3%) met 1 criterion for progression, 27 (22.5%) met 2 criteria, and 29 (24.2%) met at least 3 disease progression criteria. The most common progression criteria met in cohort A included a hemoglobin level of less than 10 g/dL (47.5%) and a platelet count of less than 100 x 109/L (31.7%). For Cohort B, 25 patients (92.6%) met 1 progression criterion, 1 patient (3.7%) met 2 progression criteria, and 1 patient (3.7%) met 3 progression criteria.

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Myelofibrosis management in routine clinical practice with a focus on patients with cytopenias: recommendations from a global consensus group

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Steffen Koschmieder, Prithviraj Bose, Martin H. Ellis, Vikas Gupta, Jean-Jacques Kiladjian, John Mascarenhas, Vikram Mathews, Francesco Passamonti & Claire Harrison

Leukemia (2024)

Myelofibrosis (MF) is a Philadelphia chromosome (BCR::ABL1)-negative myeloproliferative neoplasm, a hallmark of which is progressive deposition of fibrotic tissue in bone marrow [1]. Clinical manifestations of MF often include splenomegaly, cytopenias (such as severe anemia), and extramedullary hematopoiesis [1]. The Janus kinase inhibitor (JAKi) therapies ruxolitinib (RUX) and fedratinib (FED) have demonstrated significant clinical efficacy in splenic volume reduction and symptom improvement, but they may induce treatment-related anemia and thrombocytopenia [2,3,4,5,6,7,8,9]. Other JAKi options include pacritinib (PAC), which received FDA approval in 2022 for patients with MF and severe thrombocytopenia (platelet count <50 × 109/l), and momelotinib (MMB), which received FDA and EMA approval in 2023/2024, respectively, for patients with MF and anemia [10,11,12]. Clinical trials with JAKis in MF are summarized in reference [1].

National and international guidelines exist for the management of MF; however, a need remains for practical guidance applicable in everyday clinical practice, especially for patients experiencing cytopenias or potential failure of current therapy. The landscape is further complicated by the availability of multiple prognostic tools for MF; as such, clinicians may find disease prognostication challenging and confusing. Additionally, to maximize clinical applicability of trial data, inclusivity of eligibility criteria in the context of the real-world MF patient population should be considered.

Recognizing these significant challenges, an international expert consensus group was established to provide best practice recommendations for healthcare professionals, intending to supplement, but not replace, existing guidelines.

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Mascarenhas on the SENTRY Trial Design and Goals

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J

By John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial (NCT04562389) for patients with JAK inhibitor treatment-naive myelofibrosis.

SENTRY is a global, multicenter, phase 1/3 study where investigators are assessing the efficacy and safety of selinexor (Xpovio) combined with ruxolitinib (Jakafi) in this patient population.

According to Mascarenhas, the primary end points of phase 3 of the trial include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35), and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24 (TSS50), as measured by the myelofibrosis symptom assessment form V4.0.

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Ph- MPN in Adolescent and Young Adult Patients

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June 26, 2024

Elizabeth L. Courville, MD

England JT, Szuber N, Sirhan S, et al. Clinical features and long-term outcomes of a pan-Canadian cohort of adolescents and young adults with myeloproliferative neoplasms: a Canadian MPN group study. Leukemia. 2024;38(3):570-578.

The classical BCR:: ABL1-negative myeloproliferative neoplasms (Ph- MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are typically diseases of older adults, with a median age at diagnosis within the sixth decade of life. In two large case series from cancer centers in the United States, adolescent and young adult (AYA) patients were reported to account for 11 to 12% of the Ph- MPNs evaluated.1,2  The data on AYA patients with Ph- MPNs is less robust than that available for their older counterparts, and this patient population may not be represented in cohorts used to develop prognostic scoring systems.

Recently, James T. England, MD, MSc, and colleagues investigated the clinical features and long-term outcomes of a cohort of 609 patients (17 pediatric patients aged <18 years and 592 patients aged 18-45 years) with Ph- MPNs from across eight participating centers in Canada. Initial diagnoses are shown in Figure 1. Clinical features from the current study cohort are compared with those of a 2018 Mayo Clinic AYA cohort1  (Table). The patients were diagnosed between 2000 and 2022, with MPN driver mutation analysis performed in 89% and next-generation sequencing (NGS) of clinically relevant myeloid genes performed in 48%. More than one-third of patients (211) had NGS testing first performed during initial disease phase, with a median time from diagnosis of 3.9 years (range, 0-29 years). Sixty-four patients had NGS first performed during the post-ET/post-PV secondary myelofibrosis (SMF) phase, while 19 had NGS first performed during the accelerated phase (AP)/blast phase (BP) of disease. Non-MPN driver mutations were detected in a higher proportion of patients evaluated during disease progression (secondary myelofibrosis or elevated blasts) than during initial disease phase, including more frequent high molecular risk (HMR) mutations (Figure 2). Mutations defined as HMR included pathogenic and likely pathogenic variants in ASXL1, EZH2, IDH1/2, SRSF2, TP53, and U2AF1Q157. Among those patients with NGS testing performed during the initial disease phase, additional mutations were most frequently detected in those with overt PMF (26%).

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Allogeneic HSCT for Myelofibrosis: What to Know as More Patients Receive Treatment

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June 25, 2024

Due to new transplant approaches, allogeneic hematopoietic stem cell transplant (HSCT) is now perceived as a safer therapeutic option in patients with myelofibrosis, even among older patients. Authors of a review published in the American Journal of Hematology emphasized the crucial role of early consideration and implementation of HSCT in improving clinical outcomes in this patient population.

Despite the approval of new therapies and “various other exciting non-transplant treatments in development, allogeneic HSCT remains at present the only curative therapy for patients with myelofibrosis,” wrote coauthors Haris Ali, MD, and Andrea Bacigalupo, MD.

The challenges associated with treating myelofibrosis include transplant-related mortality and the risk for relapse after HSCT. The authors aimed to provide a comprehensive review of current clinical data, new transplant platforms, and clinical updates, which can enhance patient outcomes.

“The number of patients undergoing an allogeneic HSCT annually is steadily increasing,” Dr. Ali and Dr. Bacigalupo wrote. “This reflects the fact that HSCT has become safer with the reduction in non-relapse mortality over the years, making the choice of an HSCT more attractive among hematologists caring for [patients with myeloproliferative neoplasms].”

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PharmaEssentia Completes Patient Enrollment for Phase 2b EXCEED-ET Trial in Essential Thrombocythemia and Phase 3b ECLIPSE-PV Trial in Polycythemia Vera

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June 25, 2024

PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TWSE: 6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology, oncology and immunology, today announced completion of enrollment for two clinical trials evaluating its ropeginterferon alfa-2b-njft (BESREMi ® ).

The Phase 2b EXCEED-ET trial (NCT05482971), which is evaluating the effectiveness and safety of ropeginterferon alfa-2b-njft in adult patients with essential thrombocythemia (ET), has exceeded the enrollment goal of 64 patients to include 91 patients. EXCEED-ET is evaluating people diagnosed with ET who are either treatment naïve or have received previous ET treatment with hydroxyurea or anagrelide but require a treatment change due to intolerance or because the previous treatment is no longer effective. This trial is being conducted in the United States and Canada and will use the accelerated dosing schedule (250, 350, 500 mcg). This accelerated dosing schedule has been previously assessed in Asian clinical trials.

The Phase 3b ECLIPSE-PV trial (NCT05481151), assessing the effectiveness and safety of two dosing regimens of ropeginterferon alfa-2b-njft in adult patients with polycythemia vera (PV), has also exceeded the enrollment goal of 100 patients to include 111 patients. ECLIPSE-PV is evaluating two ropeginterferon alfa-2b-njft doses, including the accelerated dosing schedule (as described above) in comparison to the current recommended dosing regimen. The ECLIPSE-PV study is being performed in the United States and Canada.

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Are thrombosis, progression, and survival in ET predictable?

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June 25, 2024

Ghaith Abu-Zeinah, Katie Erdos, Neville Lee, Ahamed Lebbe, Imane Bouhali, Mohammed Khalid, Richard T. Silver & Joseph M. Scandura

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) that originates from a hematopoietic stem cell harboring a mutated JAK2, CALR, or MPL gene, or none of these three mutations (10–15% are “triple negative”). Although considered the most indolent MPN, ET is linked to burdensome vasomotor symptoms, and potentially fatal complications that include thrombosis, hemorrhage, and disease progression to myelofibrosis and aggressive myeloid neoplasms. Prognostic measures to identify those at greatest risk for thrombosis, progression, and death in ET (events) are important for timely risk-adapted intervention with available treatments, and for development of interventional trials to improve event-free survival (EFS). But predicting risks of events in ET has been difficult because ET is an uncommon and clinically heterogenous chronic disease. Predicting progression and excess mortality is even more challenging because these events typically occur decades after ET diagnosis [1]. Thus, retrospective analysis of large cohorts with sufficiently long follow-up is required to identify prognostic measures to stratify risk in patients with ET.

Prognostic models have been developed to assess the risk of thrombosis (IPSET-thrombosis [2]) or overall survival (OS) in ET (IPSET-survival [3], MIPSS-ET [4], and triple A [AAA] [5]). This journal recently published two large retrospective ET cohorts: Gangat et al. at the Mayo Clinic (Mayo) [6] and Loscocco et al. at the Florence Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM) [7]. Both studies confirmed previously identified risk factors for thrombosis, progression and/or death in ET that include older age (Age ≥ 60), male sex, elevated white blood cell count (WBC > 11 × 109/L), elevated absolute neutrophil count (ANC ≥ 8 × 109/L), and low absolute lymphocyte count (ALC < 1.7 × 109/L) at the time of presentation. We evaluated these parameters and current risk models in our cohort of 328 adult patients with ET treated at the Weill Cornell Medicine (WCM) Silver MPN Center over a median follow-up of 6 years [8]. This cohort was rigorously defined according to the 2022 World Health Organization diagnostic criteria and therefore all patients had a diagnostic bone marrow biopsy and had alternative diagnoses scrupulously ruled out. The methods of data collection, retrieval, and analysis used were previously described [9], and cohort characteristics are included in Supplementary Table 1.

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Outcomes of the Myelofibrosis Symptom Tracking Survey

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We would like to thank the 147 patients who responded to a survey that targeted how people with
Myelofibrosis tracked their symptoms and then how they used the information they gleaned from
their tracking. You’ll never guess what we found.

Nearly 65 percent of respondents said they had never tracked their symptoms. When asked why,
a piece of the MF story unfolded. Some people acknowledged that the variability of both the
symptoms and their occurrence made it difficult to track, while others felt that bringing a focus to
their MF and symptoms each day undermined their mental health. A few mentioned that they
made mental notes of their symptoms, had their various doctors tracking symptoms, or just knew
innately when something changed. Several felt that there was no reason to track their symptoms,
this may be due in part to responses to another question that revealed only around 20 percent of
individuals were encouraged by their physician to keep track of their symptoms. Of those that
did track their symptoms, most did so with their own personal pen-and-paper accounting and
used a variety of approaches using numerical scales, happy and sad faces, or a more journaling
style.

After opening this little window into the MF experience. It was hard not to have additional
questions. For example, could symptom tracking be used as both a self-care practice and a tool of
empowerment? Ultimately, the tools and techniques that are most helpful come from the insight
and strength of those who experience MF every day. If symptom tracking is not the best way to
track symptoms to possibly share with your personal health care team, or the team you work with
during a clinical trial, what does work for you? We would love to learn more, and share what we
learn to benefit others. If you have a response to these questions or anything more you would like
to say on this topic, please email us at ngiocondo@mpnadvocacy.com.

Prospective Analysis Highlights Patterns of Progression to Myelofibrosis Following Essential Thrombocythemia Diagnosis

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June 17, 2024

Author(s): Caroline Seymour

Most patients with essential thrombocythemia (95.7%; 1184/1237) included in an analysis of the prospective, observational MOST study (NCT02953704) did not experience disease progression to myelofibrosis, but those who did were found to have had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment, according to findings presented at the 2024 EHA Congress.1

Of the 4.3% (n = 53) of patients who progressed to myelofibrosis, a pathologic diagnosis of the disease or grade 2 or greater fibrosis was the most common indicator (49.1%; n = 26) of disease progression, followed by new or worsening splenomegaly coupled with a combination of high white blood cell counts and low hemoglobin levels and platelet counts (22.6%; n = 12). Additional indicators were death from myelofibrosis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML; 11.3%; n = 6) and circulating blasts above 1% with new or worsening splenomegaly (5.7%; n = 3); patients also met at least 2 progression criteria (11.3%; n = 6).

“These findings and further analyses of MOST data will add insight into disease progression in patients with essential thrombocythemia and facilitate clinical management of this patient population,” lead study author Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and vice dean of cancer programs at Wake Forest University School of Medicine in Charlotte, North Carolina, and coauthors wrote in the poster.

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Disease Duration, Elevated WBC Count, and VAF Predict Disease Progression in Polycythemia Vera

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June 14, 2024

Author(s): Megan Hollasch

Time from diagnosis to enrollment, elevated white blood cell (WBC) count, and variant allele frequency (VAF) were significantly associated with an increased risk of disease progression among patients with polycythemia vera (PV), according to data from the phase 4 prospective, observational REVEAL study (NCT02252159) presented at the 2024 EHA Congress by Michael R. Grunwald, MD.

“Five predictors of PV progression were identified: disease duration, thrombotic event [TE] history, WBC count of greater than 11 × 109/L, hematocrit [HCT] level of 0.45 L/L or lower, and VAF. However, HCT [level] of 0.45 L/L or lower may be confounded by disease duration and cytoreductive treatment covariates. These results provide additional support for the use of disease duration and elevated WBC and VAF as risk factors for disease progression, and identify history of TEs as a potential novel risk factor,” Grunwald and coauthors wrote in a poster presentation of the findings. Grunwald is chief of the Leukemia Division at Atrium Health’s Levine Cancer Institute and director of the Transplantation and Cellular Therapy Program at Levine Cancer Institute in Charlotte, North Carolina.

At a median follow-up of 3.7 years, findings from REVEAL, the largest prospective, observational clinical study in patients with PV to date (n = 2023), showed that 6.7% of patients progressed to myelofibrosis (MF). Results from a univariate analysis of patients with vs without progression revealed that significant covariates consisted of time from PV diagnosis to enrollment (OR, 1.065; 95% CI, 1.040-1.090; P < .0001), history of TEs (yes vs no; OR, 1.722; 95% CI, 1.170-2.534; P = .0059), HCT levels of 0.45 L/L or lower (>0.45 vs ≤0.45 L/L; OR, 0.593; 95% CI, 0.410-0.858; P = .0056), and white blood cell (WBC) count of greater than 11 × 109/L at enrollment (>11 vs ≤11 × 109/L; OR, 2.053; 95% CI, 1.445-2.918; P < .0001).

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