Dr Tremblay on the Identification and Prevalence of MDS/MPN Overlap Syndromes

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Douglas A. Tremblay, MD

Douglas A. Tremblay, MD, assistant professor, medicine, Icahn School of Medicine at Mount Sinai, discusses the prevalence of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes and the evolving treatment paradigm for these diseases, which he discussed in a presentation at the 41st Annual CFS®.

MDS/MPN overlap syndromes include a cluster of 4 related diseases: chronic myelomonocytic leukemia (CMML); atypical chronic myeloid leukemia; MDS/MPN with ring sideroblasts and thrombocytosis; and unclassifiable MDS/MPN, Tremblay says. These diseases are often difficult to manage because they share many characteristics that are indicative of both myeloproliferative diseases and MDS, Tremblay notes. Although these conditions are considered rare, they are likely more prevalent than initially hypothesized because of the overlapping nature of MPNs and MDS, Tremblay explains. However, treatment decisions for patients with these overlap syndromes are typically influenced by insights garnered from the MDS and MPN treatment paradigms, Tremblay emphasizes. In the future, the management of these overlap syndromes may become more specialized, Tremblay says. Tailored therapies are emerging, particularly in the CMML field, where JAK inhibitors have gained prominence, Tremblay explains.

Treatment decisions for patients with MDS/MPN overlap syndromes are largely based on the main issue patients experience, such as cytopenias, splenomegaly, or constitutional syndromes, Tremblay notes. Overall, patients with high-risk disease should be referred to autologous stem cell transplant because it is the only curative therapy for these syndromes, Tremblay says. Conversely, many of the treatment strategies for patients who are ineligible for transplant, such as hypomethylating agents (HMAs), are borrowed from the MDS/MPN treatment paradigms, Tremblay explains. However, HMAs have displayed limited efficacy in this population, Tremblay emphasizes. For instance, the phase 3 DACOTA trial (NCT02214407) showed no difference in event-free survival (EFS) or overall survival (OS) with decitabine vs hydroxyurea in patients with a myeloproliferative subtype of CMML.

Efforts to find effective therapies for patients with MDS/MPN overlap syndromes beyond HMAs have spurred research with JAK inhibitors in patients with CMML, according to Tremblay. The JAK-STAT signaling pathway is hypersensitive in CMML cells, and preclinical studies have shown the efficacy of halting that pathway, Tremblay says. Furthermore, a phase 1/2 trial (NCT03722407) showed the advantages of using ruxolitinib (Rituxan) to improve spleen and symptom responses in patients with CMML. Further research is investigating JAK inhibitors in combination with HMAs in patients with CMML and other MDS/MPN overlap syndromes, Tremblay concludes.

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Characteristics, Primary Treatment, And Survival of MDS/MPN with Neutrophilia: A Population-Based Study

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Saskia Klein (UMCG, Netherlands) Gerwin Huls (University Medical Center Groningen, Netherlands), Otto Visser (IKNL, Netherlands) Hanneke Kluin-Nelemans (University Medical Center Groningen, University og Groningen, Netherlands) Avinash Dinmohamed (Erasmus MC AND Amsterdam UMC, Netherlands)

Abstract
MDS/ MPN with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the myelodysplastic/myeloproliferative neoplasms is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/
MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged >65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (>65 years of age HR 1.85, P=0.001 and alloHSCT HR 0.51, P=0.039). As no other treatment modality, seemed to impact survival and might cause toxicity, we propose that all patients eligible for alloHSCT should whenever possible receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.

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Long-Acting Interferon: Pioneering Disease Modification of Myeloproliferative Neoplasms

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Seug Yun Yoon, Sung-Yong Kim

Abstract

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory responses and tend to transform into more aggressive clones, leading to disease progression. The progression of MPNs follows a biological sequence from the early phases of malignancy, polycythemia vera, and essential thrombocythemia, to advanced myelofibrosis and leukemic transformation. To date, the treatment of MPNs has focused on preventing thrombosis by decreasing blood cell counts and relieving disease-related symptoms. However, interferon (IFN) has been used to treat MPNs because of its ability to attack cancer cells directly and modulate the immune system. IFN also has the potential to modulate diseases by inhibiting JAK2 mutations, and recent studies have demonstrated clinical and molecular improvements. Long-acting IFN is administered less frequently and has fewer adverse effects than conventional IFN. The current state of research on long-acting IFN in patients with MPNs is discussed, along with future directions.

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MPN Subtypes May Predict Risk of Thromboembolic Events

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November 8, 2023

Johnathan Goodman, MPHiL

Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) are at an increased risk of arterial and venous thromboembolic (ATE and VTE, respectively) complications, according to research published in Hamostaseologie. Patients with polycythemia vera (PV), furthermore, appeared to be at a particularly high risk for these events.
BCR-ABL-negative MPNs, which include PV, essential thrombocythemia (ET), and myelofibrosis (MF), are each associated with an increased risk of VTE and ATE. These events, moreover, are linked with an increased risk of both morbidity and mortality.

Previous research has suggested that JAK2 mutations are linked with an increased risk of thromboembolic events, while CALR mutations in the MF setting may reduce this risk. Detailed data in these populations are lacking, necessitating further study for risk stratification.

Overall, in the enrolled cohort, 39.1% of patients were male, the median age at MPN diagnosis was 50.7 years, and 31.7%, 34.1%, and 31.1% of patients had ET, PV, and MF, respectively; 3% of patients had an unclassified MPN. Genetic analysis showed that 69.8% of patients had a JAK2 mutation, while 14.4% of patients had a CALR mutation.

The median follow-up was 6.6 years, during which 180 first thromboembolic events were noted; 105 and 75 events were VTEs and ATEs, respectively. The incidence rate for first ATE or VTE was 2.43% per patient/year; the overall probability of a vascular event was 36.2%.

The most commonly noted VTE subtype was deep vein thrombosis (incidence rate, 0.59% per patient/year); the most common ATE subtype was stroke (incidence rate, 0.32% per patient/year).

Analysis showed that PV was linked with a higher risk of ATE or VTE (hazard ratio [HR], 1.66; 95% CI, 1.206-2.286). Compared with JAK2 mutations, CALR mutations were linked with a lower risk of these events (HR, 0.346; 95% CI, 0.172-0.699).

“While patients diagnosed with PV or generally JAK2 mutated MPN patients had a significantly increased risk of thromboembolic complications compared with the other MPN subtypes, this risk was significantly reduced in CALR-mutated patients,” the authors wrote in their report.

Reference

Wille K, Deventer E, Sadjadian P, et al. Arterial and venous thromboembolic complications in 832 patients with BCR-ABL-negative myeloproliferative neoplasms. Hamostaseologie. Published online October 9, 2023. doi:10.1055/a-2159-8767

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Exploring Promising New Treatments for Myeloproliferative Neoplasms

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By Catlin Nalley

With ongoing advancements, the therapeutic landscape for myeloproliferative neoplasms continues to evolve. Naveen Pemmaraju, MD, Associate Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, discussed where the field currently stands during his presentation, “Promising New Drugs for MPN Therapy,” at the International Congress on Myeloproliferative Neoplasms, held November 2-3, 2023, in New York.

When it comes to myeloproliferative neoplasms, “we have entered into a new golden era of research and potential that we have never seen before,” he noted. “Our field has been previously dominated by the first breakthrough—JAK inhibitor monotherapy—which was fantastic for our patients. However, as much of a revolution as this era was, by and large, it did not lead to cures of the disease. The only curative therapy as we close 2023 remains allogeneic stem cell transplant.”

In recent years, the field has seen breakthroughs with novel agents beyond the JAK/STAT pathway, according to Pemmaraju, who also highlighted the growing exploration of combination therapies in this patient population. “This is an important time in the MPN field,” he emphasized. “All of this is coming together, hopefully for the immediate good of our patients and then also establishing a new scientific era in myeloproliferative neoplasms,” he stated.

Main Takeaways

While discussing his presentation—and the MPN field as a whole—with Oncology Times, Pemmaraju highlighted a research study that explored life after ruxolitinib in myelofibrosis patients (Cancer 2020; doi: 10.1002/cncr.32664). Interestingly, he noted that the trial found that 40.8 percent of patients had stopped ruxolitinib at 3 years. Reasons for discontinuation included lack or loss of a spleen response, ruxolitinib-related adverse events, progression to blast phase, ruxolitinib-unrelated adverse events, and allogeneic transplantation during response.

The data also showed that the median survival after ruxolitinib was 13.2 months and the use of investigational agents was in fact associated with improved outcomes versus conventional agents, according to Pemmaraju, who noted this underscores the importance of ongoing investigation and advances.

In terms of combination treatments, Pemmaraju highlighted many different approaches, such as navitoclax, a BCL-XL/BCL-2 inhibitor. The potential of this agent has been explored in several studies, including the Phase II REFINE study (J Clin Oncol 2022; doi: 10.1200/JCO.21.02188). Data showed the addition of navitoclax to ruxolitinib among patients with persistent or progressive myelofibrosis led to durable spleen volume reduction, improved total symptom score, and hemoglobin response, reported Pemmaraju, an investigator on the trial.

Two phase III trials are currently underway to further explore the combination of navitoclax and ruxolitinib. The TRANSFORM-1 study is a frontline, upfront JAK inhibitor-naive study of ruxolitinib plus navitoclax versus ruxolitinib plus placebo. The other Phase III study, TRANSFORM-2, is looking at the efficacy and safety of this combination beyond the frontline setting.

Pemmaraju also highlighted several new novel agents that could have an impact on how we approach the treatment of MPNs. This includes but is not limited to agents that target the MDM2 pathway, telomerase inhibition, and cell cycle.

Additionally, he discussed another avenue targeting anemia in myelofibrosis. For instance, momelotinib was recently approved in September 2023 for intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythemia vera and post-essential thrombocythemia), in adults with anemia. Luspatercept is another example. This agent recently gained FDA approval for the treatment of anemia in myelodysplastic syndrome and is currently being studied in patients with myelofibrosis.

As the field evolves and advancements continue, Pemmaraju emphasized what is most important—the patient. “Everything we do is for our patients and every stakeholder has an important role to play,” he said. “Let’s continue to have awesome discoveries in the lab. Let’s pledge together to try to translate those quickly with all of our stakeholders who can help bring these findings to the clinic.

“And then, let’s make a pledge together to disseminate those findings accurately, faithfully, and rapidly through all platforms, not just academic literature, so that everyone can see these data in real time, debate, discuss, and have a say,” Pemmaraju concluded.

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Is Treatment for Cytopenic Myelofibrosis Still an Unmet Clinical Need?

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Madeline Caduc and Steffen Koschmieder

Nov 2023

Philadelphia-negative myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of clonal hematological disorders driven by mutated hematopoietic stem cells. MF, as de novo myeloid malignancy (primary MF: PMF) or secondary to an antecedent MPN (post-ET-MF or post-PV-MF), is a life-threatening condition associated with shortened survival and risk of leukemic transformation in about 20% of the patients. Clonal expansion of malignant myeloid stem- and progenitor cells and stromal changes along with increased proinflammatory cytokines production drive the remodeling of the bone marrow (BM) microenvironment and disrupt physiological hematopoiesis. Clinical manifestations of MF-associated progressive BM failure, such as cytopenia (anemia, thrombocytopenia), hepatosplenomegaly, constitutional symptoms (eg, weight loss, fever, night sweating), significantly impact patients’ quality-of-life (QoL) and correlate with poor prognosis for overall survival (OS).,

The identification of a constitutive JAK–STAT pathway activity and underlying somatic driver mutations in the janus kinase 2 (jak2), calreticulin (calr), and thrombopoietin receptor (mpl) genes has revolutionized the therapeutic landscape with the development of JAK inhibitors (JAKi).

Ruxolitinib, a dual JAK1/JAK2 inhibitor, was the first JAKi approved for treatment in patients with intermediate- or high-risk MF (U.S. Food and Drug Administration [FDA]) or MF with disease-associated splenomegaly or symptoms (European Medicines Agency [EMA]) and remains the standard of care. However, although 2 phase 3 clinical trials, COMFORT-I and –II, demonstrated that ruxolitinib induces rapid spleen volume reductions (SVR) as well as symptom improvement, treatment discontinuations are frequent (up to 60% in 3 y), because of grade of ≥3 cytopenia, and resulting in suboptimal symptom control, risk of disease relapse, and decreased survival.–

Nearly a decade later, the selective JAK2 and FMS-like tyrosine kinase 3 (FLT3) inhibitor fedratinib was approved for the treatment of intermediate and high-risk MF (FDA) or MF with disease-associated splenomegaly or symptoms (EMA). Although fedratinib was active in untreated patients but also patients with documented progression during ruxolitinib or intolerance to ruxolitinib, fedratinib induced comparable myelosuppression with anemia and thrombocytopenia as the most common causes for treatment discontinuation. Thus, although the development of JAKi has significantly improved MF treatment, cytopenic myelofibrosis still presents a significant unmet medical need.

Pacritinib, a potent JAK2 and interleukin-1 receptor associated kinase 1 (IRAK1) inhibitor, received FDA-approval for use in MF patients with platelet counts of ≤50 × 109/L, based on the results of the PERSIST-1 and PERSIST-2 studies. The efficacy and safety of pacritinib compared with physician’s choice of therapy (including ruxolitinib) is currently being further investigated in MF patients with severe thrombocytopenia in the phase 3 study PACIFICA (NCT03165734). Interestingly, a post hoc analysis of the PERSIST-2 study showed an anemia benefit in patients treated with pacritinib, which was attributed to activin A receptor type 1 (ACVR1) inhibition. However, further investigations are needed to unravel the detailed biological mechanisms involved, including the role of IRAK1 inhibition.

The pathophysiology of MF-related anemia has not been fully deciphered. In addition to progressive reticulin deposition, dysregulation of iron homeostasis has emerged as a pivotal process for disruption of normal erythropoiesis. Hepcidin, a key regulator of iron metabolism, was discovered to be elevated in MF patients, and this upregulation proved to be unresponsive to ruxolitinib treatment. Interestingly, the combined JAK1/2 inhibitor, Momelotinib (MMB), also inhibits ACVR1 and thereby decreases hepcidin, emerging as a promising therapeutic alternative for patients with MF-related anemia. MMB was assessed as treatment of intermediate- or high-risk MF patients in 2 phase 3 trials, SIMPLIFY-1 and SIMPLIFY-2. Although MMB met the primary endpoint in the SIMPLIFY-1 trial (noninferiority to ruxolitinib regarding spleen volume response), the key secondary endpoint was not met (noninferiority to ruxolitinib regarding symptom response). However, MMB activity demonstrated consistent anemia benefits including conversion to transfusion-independence (TI), SVR, and QoL improvement, when compared with baseline. The SIMPLIFY-2 trial evaluated the superiority of MMB over the best available therapy (BAT) in MF patients who had previously received ruxolitinib treatment. The defectiveness of currently available therapies for cytopenic MF was emphasized by the fact that 89% of the BAT patients continued treatment with ruxolitinib. However, the primary endpoint (superiority of MMB versus BAT regarding spleen volume reduction at week 24 [SVR24]) was not met, although the MMB group demonstrated a higher rate of conversion to TI, emphasizing its anemia-alleviating potential when compared with BAT. Of note, the lack of JAKi washout period before MMB-treatment start might have influenced the results.

Recently, MMB-induced anemia benefit was further investigated in the double-blind, (2:1) randomized clinical trial of MMB versus danazol, the MOMENTUM trial. This trial enrolled MF patients with failure to JAKi treatment, moderate-to-severe anemia (hemoglobin <10 g/dL), and a total symptom score (TSS) ≥10. The primary endpoint, a ≥50% reduction in the mean TSS at week 24, was met, as well as key secondary endpoints, including TI rate at week 24 and SVR24. Importantly, several of the symptoms were not directly correlated with anemia (eg, early satiety, abdominal discomfort, bone pain, and night sweats). Thus, inferiority of danazol might not be surprising. However, at the time of the study, danazol treatment was in alignment with the guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology for the management of MF-associated anemia.

In the present HemaSphere issue, Mesa et al present novel data from the MOMENTUM trial, bridging the knowledge gap of how MMB impacts MF-associated symptoms. In line with the results of SIMPLIFY-1 and -2, MMB improved anemia and led to a higher proportion of patients achieving TI compared to the danazol group. Interestingly, some patients experienced fatigue relief without attaining TI. Although some anemia benefits might have not been captured by the strict TI endpoint of the study, these findings underscore the multifactorial pathogenesis of fatigue. Thus, MMB treatment–associated benefits may well extend beyond its proerythrogenic activity with the reduction of cytokines production as a possible mechanism for the reported TSS improvement. However, as pointed out by the investigators, although patient-reported fatigue was a secondary endpoint of MOMENTUM, the trial was not designed to explore the relationship between anemia and symptoms. Further investigations will be needed.

In addition to anemia and RBC transfusion–dependency, recent surveys emphasized severe thrombocytopenia (platelet count ≤50 × 109/L) as a critical negative prognostic factor, with higher rates of both hemorrhagic and thrombotic complications, as well as a higher risk for leukemic transformation. Furthermore, fatigue as a multifactorial and burdensome MF-symptom with significant repercussion on patients’ cognitive, physical, and social functioning was shown to be significantly increased in thrombocytopenic MF patients.

In a second publication in this HemaSphere issue, Kiladjian et al present data from their post hoc combined analysis of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials on the efficacy and safety of MMB in patients with thrombocytopenia. All patients with baseline platelet counts of <100 × 109/L were included and defined as the “sub-100 group.” Of note, patients with severe thrombopenia (<50 × 109/L) were not analyzed separately because of low patient numbers but were integrated within the sub-100 group. Overall, platelet counts were stable or increased in the MMB treated sub-100 group, enabling continuous adequate dosing beyond the initial 24-week-treatment period. Interestingly, this retrospective analysis of the SIMPLIFY trials indicates a reduced ruxolitinib effectiveness in patients with platelet counts below 100 × 109/L. The numerically higher TSS reduction, SVR, and conversation rate to TI in the MMB group may be because of a higher myelosuppressive activity of ruxolitinib, leading to more frequent dose reductions and treatment discontinuations. Thus, this post hoc analysis suggests that MMB may be superior to ruxolitinib, BAT, and danazol in patients with low platelet counts, without altering the safety profile. However, because of the descriptive nature of this analysis, prospective real world data will be required to confirm these results.

In summary, the new results of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials underline the potential of MMB to expand our treatment options for MF patients, particularly those with symptomatic and/or RBC transfusion–dependent anemia. MMB has recently been approved by the FDA for the treatment of intermediate- or high-risk MF in adults with anemia.

In addition, several new therapeutic agents are presently under clinical investigation, either as monotherapy or as add-on therapies to JAK inhibitor. Much of their success will depend on their ability to target the underlying disease pathophysiology, to lead to clinically meaningful long-term eradication of the malignant clone and cure of the patients from MF. Thus, the unmet clinical need for the treatment of cytopenic MF is lessened, but it still exists.

Calreticulin and JAK2V617F Driver Mutations Induce Distinct Mitotic Defects in Myeloproliferative Neoplasms

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Kristin Holl, Nicolas Chatain, Susanne Krapp, Anja Scheufen, Nathalie Brock, Steffen Koschmieder, Daniel Moreno-Andrés

Abstract
Myeloproliferative neoplasms (MPNs) encompass a diverse group of hematologic disorders driven by mutations in JAK2, CALR, or MPL. The prevailing working model explaining how these driver mutations induce different disease phenotypes is based on the decisive influence of the cellular microenvironment and the acquisition of additional mutations. Here, we report increased levels of chromatin segregation errors in hematopoietic cells stably expressing CALRdel52 or JAK2V617F mutations. Our investigations employing murine 32D MPL and human erythroleukemic TF-1MPL cells demonstrate a link between CALRdel52 or JAK2V617F expression and a compromised spindle assembly checkpoint (SAC), a phenomenon contributing to error-prone mitosis. This defective SAC is associated with imbalances in the recruitment of SAC factors to mitotic kinetochores upon CALRdel52 or JAK2V617F expression. We show that JAK2 mutant CD34 + MPN patient-derived cells exhibit reduced expression of the master mitotic regulators PLK1, aurora kinase B and PP2A catalytic subunit. Furthermore, the expression profile of mitotic regulators in CD34 + patient-derived cells allows to faithfully distinguish patients from healthy controls, as well as to differentiate primary and secondary myelofibrosis from essential thrombocythemia and polycythemia vera. Altogether, our data suggest alterations in mitotic regulation as a potential driver in the pathogenesis in MPN.

Introduction
Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg. MPNs) are a heterogeneous group of clonal hematopoietic disorders clinically subdivided into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1]. The mutations in the genes of the Janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (TPOR/MPL) are driver mutations of these diseases [2, 3]. Their occurrence and variant allele frequency, together with specific bystander mutations, determine the clinical features, disease severity, and whether these disease evolve with dismal prognosis and decreased survival[3–6], towards secondary myelofibrosis (SMF), secondary acute myeloid leukemia and/or secondary solid tumors [7, 8]. The main pathogenic molecular signaling event of Ph-neg. MPNs is the constitutive activation of JAK2- STAT-dependent signaling pathways by mutations in CALR, JAK2 or the MPL receptor [2, 3]. Yet, noncanonical mechanisms of mutant JAK2[9], and CALR[10] have been recently linked to aspects of the disease pathology. However, the molecular mechanisms of the phase transition towards acute disease states are poorly defined [2, 5].

In contrast to other myeloid neoplasms such as primary acute myeloid leukemia (AML) [11, 12], myelodysplastic syndromes [13, 14] or chronic myeloid leukemia [15, 16], the cytology and molecular status of mitosis in Ph-neg. MPNs has not been studied in detail. However, karyotype abnormalities likely caused by chromatin segregation defects due to defective mitosis are present in up to 5% of ET, 20% of
PV, and 57% of PMF cases at the time of diagnosis [4, 17, 18] and accumulate over time, especially at blast-phase transformation[19–22] and frequently are associated with unfavorable prognosis and decreased survival[23–25]. Therefore, mitotic defects induced by driver Ph-neg. MPN mutations could play a role in the pathological mechanisms and contribute to the phase transition. Mitosis is tightly regulated by the crosstalk between the kinases Aurora B, CDK1 (cyclic dependent kinase 1)-Cyclin B1, and Polo-Like Kinase 1 (PLK1), and the protein phosphatase PP2A, as well as by the spindle assembly checkpoint (SAC) [26, 27]. The latter constitutes a protein network recruited to chromosome kinetochores to ensure proper chromosome-spindle attachments and accurate chromatin segregation. It includes several evolutionarily conserved proteins, like BubR1, Aurora B, MAD1, MAD2, MPS1, CDC20 and kinesin motor proteins, such as CENP-E, which are required for precise SAC function [26, 28]. Precise maintenance of the molecular equilibrium in gene expression and accurate subcellular positioning of these mitotic regulators play a critical role in preserving chromosome integrity and ensuring the stability of the karyotype [16, 28–30]. Consequently, defects in mitotic regulation promote chromosome instability (CIN), acquisition and evolution of heterogeneous karyotypes, inflammation, and epigenetic dysregulation. All these pathological mechanisms are linked to the malignant transformation in many solid cancers [31–33]. Similarly, hematological malignancies [16] such as AML [11, 12] and myelodysplastic syndromes [13, 14], show defects or dysregulation in crucial mitotic factors linked to CIN and heterogeneous karyotypes. Here, we have analyzed the mitotic cytology in murine and human cells stably expressing CALRdel52 or JAK2V617F and found error-prone mitosis. The examination of the molecular status of key mitotic regulators suggests defective SAC function. Also, CD34 + Ph-neg. MPN patient cells display differential expression profiles of a subset of important mitotic regulators, including the SAC components BUB1, MAD2L1, INCENP, CDC20, CDK1, PLK1 and Aurora A/B.

Results
CALRdel52 and JAK2V617F 32D MPL cells have a stresssensitive and error-prone mitosis To investigate chromatin segregation and the duration of mitosis, we performed long term live-cell imaging of murine 32D MPL cells (Fig. 1A) for a duration of 20 h followed by image analysis. In comparison with control 32D MPL (EV) cells, 32D MPL cells transduced with CALRdel52 or JAK2V617F showed a slight and non-significant increase in the numbers of chromatin bridges and lagging chromosomes (Fig. 1B). In contrast, the percentage of telophase micronuclei is significantly increased in the JAK2V617F mutant cell (p < 0.008, Fisher´s exact test). The occurrence of all three kinds of chromatin segregation errors further increases significantly in comparison to EV when DNA damage is induced with the chemotherapeutic agent doxorubicin [34] (p < 0.05, Fisher´s exact test), or SAC malfunction with the antimitotic drug NMS-P715 [35] (p < 0.02, Fisher´s exact test), which inhibits the checkpoint kinase MPS1 (Fig. 1B). The average mitotic timing in untreated cells or upon treatment with doxorubicin or MPS1 inhibitor is similar between mutants and control (EV) transfected cells (Supplementary Fig. S1). As expected, treatment the SAC inhibitor NMS-P715 reduced the mitotic timing with respect to untreated samples (Supplementary Fig. S1). These data suggest that mitosis in CALRdel52 and JAK2V617F mutant 32D MPL cells is stress sensitive. A weakened SAC contributes to error-prone mitosis in murine 32D
MPL CALRdel52 and JAK2V617F cells JAK2V617F [9, 36] and CALRdel52 [37] mutations have been linked to increased ROS production. In
addition, JAK2V617F is also linked to replication stress[38], and to lower p53 levels, a factor which is critical for the DNA damage response[39]. Replication stress and DNA damage signalling pathways, together with mitotic dysregulation, are well-known sources of karyotype aberrations such as aneuploidy, CIN, and genomic instability [40]. Therefore, we investigated whether the observed error-prone mitosis in CALRdel52 and JAK2V617F cells after doxorubicin treatment could be due to an altered response to DNA damage or replication stress.

First, we tested whether CALRdel52 or JAK2V617F transduced 32D MPL cells show increased levels of double-strand breaks during entry into mitosis as compared to control (EV) cells by immunofluorescence staining of γ-H2AX (H2AX S139ph) a well-described marker for DNA damage [41]. Visual inspection of γH2AX foci in untreated prometaphase EV and mutant cells revealed similar low levels of DNA damage. As
expected, the number of γ-H2AX foci increased to a similar extent in control (EV) and mutant cells after doxorubicin treatment (Supplementary Fig. S2A). In agreement with the literature [39], p53 basal levels in untreated JAK2V617F cells were much lower than in control EV cells or CALRdel52 (Supplementary Fig. S2B, Supplementary Figure S8). After doxorubicin treatment, p53 levels increased more than four-fold in all the cell lines. These results indicate that DNA damage is similarly induced by doxorubicin in control (EV) and mutant cells during mitotic entry and all cells showed a comparable functional stabilization of p53 after genotoxic stress. To test whether defects in SAC could contribute to the observed increase of chromatin segregation errors in CALRdel52 and JAK2V617F mutant cells, we challenged them with the spindle poison nocodazole. Cells with a weakened or defective SAC escape faster from the nocodazole induced mitotic arrest [29, 42]. Nocodazole treatment induced mitotic arrest in all three cell lines, but compared to control (EV) cells (257 ± 45 min), CALRdel52 (210 ± 36 min, p < 0.02 one-way ANOVA) or JAK2V617F (186 ± 35 min, p < 0.0001) transduced 32D MPL cells showed significantly shorter mitotic arrest and faster mitotic exit (Fig. 2A, B). The outcomes of mitotic arrest induced with microtubule inhibitors are diverse among cancer and normal cell lines due to the different pathways they induce [43, 44]. The current ‘competing networks-threshold’ model proposes that cell fate determination of – either cell death or extended survival – hinges on which of the two thresholds is reached first: either the activation of pro-apoptotic caspases or the degradation of cyclin B1 leading to mitotic slippage [43, 45]. To discriminate between these two options, we directly analyzed the fate of individual cells under mitotic arrest. The fraction of cells with mitotic death after mitotic arrest upon nocodazole treatment is very low (< 10%) and without significant differences between control (EV), CALRdel52, and JAK2V617F cells (two-way ANOVA with Dunnet post test) (Fig. 2C). In all conditions the arrested cells mostly escaped mitotic arrest by mitotic slippage without significant differences between the different cell types (two-way ANOVA with Dunnet post test) (Fig. 2C).

It has been proposed that murine cells are naturally more resistant than human cells to mitotic poisons due to the presence of clearance systems [46]. Therefore, we determined whether cyclin B1 accumulation was different between control (EV) and CALRdel52 or JAK2V617F cells after 3 hours of nocodazole treatment, which is the lower average time the cells (JAK2V617F cells, Fig. 2A) spend in mitotic arrest
before they undergo slippage. Cyclin B1 accumulated similarly in all three cell lines (Fig. 3A). Once accumulated, cyclin B1 was degraded faster in cells expressing CALRdel52 and JAK2V617F mutations (Fig. 3B; Supplementary Fig. S3; Supplementary Fig. S6) suggesting that a weakened SAC contributes to the error-prone mitosis in these cells.

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Incyte To Spotlight More Than 40 Hematology And Oncology Abstracts Including A Plenary Presentation At The ASH Annual Meeting

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November 2, 2023

– Sixteen oral presentations, as well as a plenary session and poster presentations, highlight new advances across eight of the Company’s medicines

– Plenary Scientific Session will feature the full data from AGAVE-201 evaluating axatilimab, an anti-CSFR-1R monoclonal antibody, in patients with chronic graft-versus-host disease (GVHD)

– Incyte to host an in-person analyst and investor event on Monday, December 11, 2023 from 12:00-1:30 p.m. PT to discuss key data presentations at ASH

WILMINGTON, Del.–(BUSINESS WIRE)–Nov. 2, 2023– Incyte (Nasdaq:INCY) today announced that more than 40 abstracts highlighting data from eight of its hematology and oncology products will be presented at the upcoming 65th American Society of Hematology Annual Meeting 2023 (ASH 2023), held December 9-12, 2023, in San Diego and virtually.

“We have continued to make significant progress in advancing our hematology and oncology pipeline with the goal to deliver better medicines for a range of diseases that have limited treatment options, including myeloproliferative neoplasms (MPNs) and chronic graft-versus-host disease (GVHD),” said Pablo J. Cagnoni, M.D., President and Head of Research and Development, Incyte. “We are excited to showcase the depth of our portfolio and clinical progress at this year’s ASH congress. In particular, we look forward to the presentation of the axatilimab AGAVE-201 trial results in patients with chronic GVHD at the Plenary Scientific Session, as well as the numerous oral and poster presentations including new data for our mutant CALR, BET, ALK2 and CK0804 programs in MPNs. Additionally, we are proud that the first presentation of data for INCB160058, our new potentially disease modifying JAK2V617F therapy for patients with MPNs, will be at this year’s meeting.”

Select key abstract presentations from Incyte-developed and partnered programs include:

Plenary Scientific Session

Axatilimab

Safety and Efficacy of Axatilimab at 3 Different Doses in Patients with Chronic Graft-Versus-Host Disease (AGAVE-201)1 (Abstract #1. Plenary Scientific Session. Sunday, December 10, 5:00 p.m. – 7:00 p.m. ET)

Oral Presentations

Ruxolitinib (MPN)

A Real-World Evaluation of Risk Factors for Disease Progression in Patients with Polycythemia Vera (PV) Enrolled in REVEAL (Abstract #385. Session: 906. Outcomes Research – Myeloid Malignancies: Risk Factors and Health Disparities. Saturday, December 9, 7:00 p.m. ET)

Phase 1/2 Study of the Activin Receptor-Like Kinase-2 Inhibitor Zilurgisertib (INCB000928, LIMBER-104) as Monotherapy or with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (Abstract #624. Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Charting The Future Of MPN Therapies. Sunday, December 10, 8:45 p.m. ET)

Bromodomain and Extra-Terminal (BET) Inhibitor INCB057643 (LIMBER-103) in Patients with Relapsed or Refractory Myelofibrosis (R/R MF) and Other Advanced Myeloid Neoplasms: A Phase 1 Study (Abstract #750. Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Treatment and Outcomes in MPNs. Monday, December 11, 2:45 p.m. ET)

Ruxolitinib (GVHD)

Ruxolitinib in Patients with Chronic Graft-Versus-Host Disease: Three-Year Final Analysis of Efficacy and Safety of the Phase 3 REACH3 Study2 (Abstract #654. Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Innovative Approaches to GVHD Prevention and Treatment. Sunday, December 10, 8:45 p.m. ET)

Tafasitamab

Tafasitamab for the Treatment of Relapsed/Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) in the U.S. Real-World Setting (Abstract #265. Session: 905. Outcomes Research – Lymphoid Malignancies: Outcomes Research in Lymphoma/CLL: Biomarkers, Dosing Strategies, and Big-Data. Saturday, December 9, 5:00 p.m. ET)

Itacitinib

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 INCB 39110-211 Placebo-Controlled, Randomized Cohort (Abstract #356. Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Prediction and Management of CAR-T Cell Related Toxicity. Saturday, December 9, 7:15 p.m. ET)

INCB160058

Preclinical Evaluation of INCB160058 – A Novel and Potentially Disease-Modifying Therapy for JAK2V617F Mutant Myeloproliferative Neoplasms (Abstract #860. Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Lineage Tracing and Novel Target Discovery. Monday, December 11, 6:00 p.m. ET)

Poster Presentations

Ruxolitinib (MPN)

Effect of New or Worsening Anemia on Clinical Outcomes in 2,233 Patients with Myelofibrosis (MF) Treated with Ruxolitinib in the Expanded-Access JUMP Study (Abstract #5174. Session: 906. Outcomes Research—Myeloid Malignancies: Poster III. Monday, December 11, 9:00 p.m. – 11:00 p.m. ET)

Ruxolitinib Treatment in Polycythemia Vera Results in Reduction in JAK2 Allele Burden in Addition to Improvement in Hematocrit Control and Symptom Burden (Abstract #4553. Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster III. Monday, December 11, 9:00 p.m. – 11:00 p.m. ET)

High Rate of Disease Progression in Patients with Low-Risk Myelofibrosis (MF) Enrolled in the Prospective, Real-World, MOST Study Abstract #3803. Session: 906. Outcomes Research—Myeloid Malignancies: Poster II. Sunday, December 10, 9:00 p.m. – 11:00 p.m. ET)

Progression to Myelofibrosis in Patients with Essential Thrombocythemia: A Real-World Analysis from the Prospective MOST Study (Abstract #2433. Session: 906. Outcomes Research—Myeloid Malignancies: Poster I. Saturday, December 9, 8:30 p.m. – 10:30 p.m. ET)

Clinical and Disease Characteristics of Patients With Myelofibrosis and Essential Thrombocythemia that Harbor a Calreticulin (CALR) Gene Mutation: Subanalysis of the MOST Study (Abstract #3812. Session: 906. Outcomes Research—Myeloid Malignancies: Poster II. Sunday, December 10, 9:00 p.m. – 11:00 p.m. ET)

Comparison of the Enzymatic and Cellular Profiles of Clinical JAK2 Inhibitors for the Treatment of Myelofibrosis (Abstract #4532. Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster III. Monday, December 11, 9:00 p.m. – 11:00 p.m. ET)

ALK2 and JAK2 Inhibition for Improved Treatment of Anemia in Myelofibrosis Patients: Preclinical Profile of an ALK2 Inhibitor Zilurgisertib in Combination with Ruxolitinib (Abstract #1789. Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster I. Saturday, December 9, 8:30 p.m. – 10:30 p.m. ET)

The Association between Blood Cell Counts and Thrombotic Events in Japanese Patients with Polycythemia Vera: A Retrospective Database Study2 (Abstract #3191. Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster II. Sunday, December 10, 9:00 p.m. – 11:00 p.m. ET)

Tafasitamab

Real-World Use of Tafasitamab (tafa) for Relapsed or Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) Among Racial and Ethnic Minorities in the United States (Abstract #2415. Session: 905. Outcomes Research – Lymphoid Malignancies: Poster I. Saturday, December 9, 8:30 – 10:30 p.m. ET)

Tafasitamab in Combination with a CD20xCD3 Bispecific T-cell Engager Significantly Prolongs Survival in Preclinical Lymphoma Models3 (Abstract #2813. Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II. Sunday, December 10, 9:00 – 11:00 p.m. ET)

Pemigatinib

Deep and Durable Cytogenetic and Molecular Responses with Pemigatinib in Myeloid/Lymphoid Neoplasms with Fibroblast Growth Factor Receptor 1 Rearrangement: The FIGHT-203 Study (Abstract #4551. Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster III. Monday, December 11, 9:00 p.m. – 11:00 p.m. ET)

Ponatinib

Long-term Results From the OPTIC Trial: A Dose-Optimization Study of 3 Starting Doses of Ponatinib4 (Abstract #3164. Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II. Sunday, December 10, 9:00 – 11:00 p.m. ET)

Ponatinib Versus Imatinib in Patients with Newly Diagnosed Ph+ ALL: Subgroup Analysis of the Phase 3 PhALLCON Study4 (Abstract #2871. 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II. Sunday, December 10, 9:00 – 11:00 p.m. ET)

Itacitinib

Janus Kinase (JAK) 1 Inhibition Results in Significant Changes in Serum Proteins and Peripheral T-Cell Populations that Correlated with Clinical Scores in Chronic Graft-Versus-Host Disease (GVHD) Patients (an Analysis from GRAVITAS-309) (Abstract #2197. Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster I. Saturday, December 9, 8:30 – 10:30 p.m. ET)

Axatilimab

Axatilimab Ameliorates Inflammation and Fibrosis by Targeting the Macrophages in a Preclinical Model of Chronic GVHD (Abstract #2540. Session: 201. Granulocytes, Monocytes, and Macrophages: Poster II. Sunday, December 10, 9:00 – 11:00 p.m. ET)

CK0804

A Phase 1b, Open-Label Study of Add on Therapy with CK0804 in Participants with Myelofibrosis and Suboptimal Response to Ruxolitinib5 (Abstract #1813. Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I. Saturday, December 9, 8:30 – 10:30 p.m. ET)

More information regarding the congress is available on the ASH website: https://www.hematology.org/meetings/annual-meeting. This in-person event will be broadcast virtually and access to the meeting’s virtual platform is included with registration.

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FDA Approval of Momelotinib May Establish New SOC for Myelofibrosis With Anemia

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November 2, 2023

Courtney Flaherty

The JAK1/JAK2 and ACVR1 inhibitor momelotinib (Ojjaara) not only provides spleen volume and constitutional symptom benefits in patients with anemic symptomatic myelofibrosis that is noninferior to that achieved with available JAK inhibitors, but may meaningfully reduce disease-related anemia symptoms that standard-of-care agents or danazol do not address, according to Andrew T. Kuykendall, MD. He added that the agent’s recent approval in this population requires re-evaluation of current approaches for managing these aspects of the disease.

On September 15, 2023, the FDA approved momelotinib for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary or secondary myelofibrosis, and disease-related anemia.1,2 Findings from the phase 3 MOMENTUM trial (NCT04173494), as well as data from a subpopulation of adult patients with anemia from the phase 3 SIMPLIFY-1 trial (NCT01969838), supported the regulatory decision.

Twenty-five percent of patients with symptomatic and anemic myelofibrosis who were previously exposed to a JAK inhibitor experienced at least a 50% reduction in tumor symptom score (TSS) with momelotinib vs 9% of patients treated with danazol, which translated to a treatment difference of 16% (95% CI, 6%-26%; P < .01). Additionally, 30% of patients in the momelotinib arm achieved transfusion independence (TI) vs 20% of those in the danazol arm, which translated to a noninferiority treatment difference of 14% (95% CI, 2%-25%; P = .023). Spleen volume reduction and a decrease in anemia-related symptoms were also observed with momelotinib.3

“[With momelotinib], we’re extending the benefits of JAK inhibition to more people and we’re potentially helping [to ameliorate] anemia, which has been an area of unmet need for a long time for patients with myelofibrosis,” said Kuykendall, who is an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

In an interview with OncLive®, Kuykendall discussed the importance of this approval for treating patients with anemic symptomatic myelofibrosis in clinical practice, key efficacy and safety data from the MOMENTUM trial that supported the decision, and unanswered questions regarding the agent’s potential role in other subsets within this population.

OncLive: What is the significance of the recent FDA approval of momelotinib for patients with myelofibrosis and anemia?

Kuykendall: This decision represents our further advancement in the perpetual story of [managing patients with] myelofibrosis [over] the past decade. On one hand, [we’re] trying to bring JAK inhibition to as many patients with myelofibrosis as possible. Ruxolitinib [Jakafi] really changed the game in myelofibrosis by allowing patients to [experience] profound improvement of splenomegaly and disease-related symptoms; it is also associated with a modest survival benefit. However, we continue to run into issues with patients who have anemia, which is most patients with myelofibrosis. [These patients, as well as those] who have low platelets, can’t experience the full benefit of JAK inhibition. The accelerated approval of pacritinib [Vonjo] helped with some aspects of that.

Now, momelotinib [provides] a full dose of a potent JAK inhibitor for patients who are anemic and may even be able to help with that anemia, as well. On the flip side, it looks like it can help with patients [who have] low platelets, as well. [The MOMENTUM trial] enrolled [patients] [with a] platelet count [of more than 25 x 109 cells/L].

What is unique about the mechanism of action of momelotinib compared with other JAK inhibitors?

All of the main approved agents in myelofibrosis are JAK2 inhibitors. However, their kinase inhibition profiles serve as differentiating factors. Momelotinib is a bit different in the sense that, like ruxolitinib, it [targets] JAK1 and JAK2. Pacritinib, and to a lesser extent, fedratinib [Inrebic], are more selective for JAK2. [Momelotinib] also inhibits ACVR1, which we believe plays a key role in modulating hepcidin and improving anemia. This potentially distinguishes momelotinib from ruxolitinib.

Now, instead of worsening anemia, which we often see happen with ruxolitinib or fedratinib, we’re able to get those symptom and spleen benefits [that come with] JAK1/JAK2 inhibition, and at the very least, mitigate some of the anemia we saw with ruxolitinib. [Momelotinib could] potentially lead to an overall improvement in anemia and fewer transfusions for patients.

Could you expand on the design of the MOMENTUM trial, and the patient population enrolled?

The MOMENTUM trial was the third phase 3 trial of momelotinib. Ultimately, the trial enrolled patients who had previously been exposed to ruxolitinib, were anemic, had some degree of myelofibrosis-related symptoms, and had splenomegaly. Patients didn’t have to be [treated with] ruxolitinib for a long time. They could have been on it for just about a month, [during which] they had some anemia. Those patients were randomly assigned 2:1 to either momelotinib or danazol, which we know is a control. This means that we use the agent for patients who are anemic.

What key efficacy findings were reported?

The primary end point of the trial was symptom improvement and aimed for a 50% reduction in TSS. Overall, we expected to see improvement with momelotinib over danazol, [However], we know that symptoms can be related not just to inflammatory cytokines or to splenomegaly but can also occur due to anemia. We expected danazol to help with some of those [symptoms]. Some key secondary end points [included] some improvement in splenomegaly reduction compared with danazol. Although the results didn’t meet the criteria for superiority, TI rate [with momelotinib] was nominally better than the rate [observed with danazol]. More patients on the momelotinib arm were TI after 24 weeks vs [those in] the danazol arm with essentially an equal number [transfusion dependent between groups] at baseline.

Spleen response rates [with momelotinib] are similar to what you might expect to see with ruxolitinib or another JAK inhibitor. However, momelotinib has been directly compared with ruxolitinib in the SIMPLIFY-1 trial, where treatment-naive patients were randomly assigned to momelotinib or ruxolitinib. In that trial, momelotinib was noninferior to ruxolitinib in terms of spleen responses. Therefore, we know it is a potent JAK inhibitor in terms of inducing spleen responses. It was exciting to see results play out like that in this pivotal trial.

What should be known about the safety profile of momelotinib?

[The toxicities associated with momelotinib] are relatively benign. When we think about JAK inhibitors, we consider the safety profiles. In general, these are palliative medications that we’re using to make people feel better and improve quality of life and functionality. If our ultimate goal is for people to feel better, we need these agents to be well tolerated. When one of our key findings is symptoms improving, you can see that these are well-tolerated medications. In the short term, patients are reporting that they feel better than they did previously after going on these medications.

In terms of things to watch out for, there’s a mild increase in gastrointestinal [GI] toxicity vs what was seen with danazol. Still, these rates are relatively low for those experiencing nausea, which is also usually low grade. This is probably lower than what we have seen in other trials with pacritinib and fedratinib that inhibit FLT3, as anything that inhibits FLT3 is associated with some degree of GI toxicity.

In previous trials, there was some concern for peripheral neuropathy, which wasn’t really seen in the MOMENTUM study. There were relatively low rates of anemia and thrombocytopenia. In fact, this agent is likely to improve, or at least stabilize, anemia and was leveraged safely in patients with a quite low platelet count. Overall, there’s not too much to be concerned about [regarding] hematologic adverse effects. [Additionally,] momelotinib actually had fewer adverse effects on the kidneys than danazol did.

With this approval, where do you see momelotinib fitting into the treatment paradigm in myelofibrosis?

The clearest answer is [that it will be used for] patients who are quite anemic and have struggled to continue treatment with ruxolitinib at adequate doses without needing transfusions or developing symptomatic anemia. That’s the ideal population. Certainly, you could think about using it outside of those bounds, as well. Anyone with anemia and some degree of splenomegaly symptoms could be afforded momelotinib as an option, given the concern that ruxolitinib or fedratinib treatment might drop hemoglobin [levels], pushing people into transfusion dependency.

In that anemic population, there are outstanding questions: What about patients who don’t have symptomatic splenomegaly and don’t have a ton of disease-related symptoms, but are anemic? Is this now going to be our treatment of choice for this cytopenic population? Momelotinib was nominally better than danazol [at reducing transfusion dependence], so are we going to now choose this over danazol in a patient without too many splenic symptoms? That’s tough to say right now, but you could make an argument for momelotinib in that space.

In patients who are not anemic and are being treated with ruxolitinib but need to move to a second-line agent, is [momelotinib an option] that you’re going to leverage, knowing that anemia is part of the natural history of this disease over time and that it may be reasonable to start this type of an agent earlier rather than later? There are many different areas where this could be a beneficial agent, but [its potential role in] the anemic population is very clear.

What is your main message for colleagues regarding this approval?

Momelotinib is another tool in the toolbox. [It’s approval] is another reason to differentiate and understand when and why you would use different JAK inhibitors since we now have 4 [available]. You have to understand why and when to use one agent over the other, when you’re going to switch from one to the other, when you’re going to dose modify, and which agents are best [for each case]. This is a good time to think about those questions and have a clear plan in mind. It’s great to have different options for patients, but knowing when to use them is going to ensure that we’re using them in the right way.

References

  1. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed October 4, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia
  2. Momelotinib (Ojjaara) Prescribing information. GlaxoSmithKline; 2023. Accessed November 2, 2023. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Ojjaara/pdf/OJJAARA-PI-PIL.PDF
  3. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0

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EXCEED-ET Study Evaluates Ropeginterferon alfa-2b-njf in ET

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November 2, 2023

Lucia Masarova, MD

Lucia Masarova, MD, PhD, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale of the EXCEED-ET study (NCT05482971) of ropeginterferon alfa-2b-njf (Besremi) for patients with essential thrombocytopenia (ET).

Transcription:

0:10 | The EXCEED-ET study is getting the ropeginterferon, which is the novel interferon into the space of ET. It is phase 1/2 study that gets the novel ropeginterferon in patients in North America. The patients are hydroxyurea-refractory or hydroxyurea-naive. Patients that have ET platelets over 450,000 need the therapy with some symptoms, and do not have a contraindication for interferons, which also had to be mentioned that the drugs could not be used in patients that have previous autoimmune disease, psychiatric diseases, or neurological because it could aggravate their symptoms.

0:51 | But those patients, if they would be eligible, they could be getting the full access to the drug. Also, with patients with ET, the escalation is going to be a lot faster to 250 micrograms, every other week, 350, and then 500 is the maximum dose that has been explored. However, I have to say the approval of ropeginterferon for PV had even higher dose, and the maximum-tolerated dose was not reached. This is a perfectly safe dose that we have patients on. We’re going to see how it’s going to do in ET patients.

1:25 | There is a core treatment period, which continues after the 4 weeks of escalation of up to 56 weeks. The patients will be dosed every other week with a tolerable dose. We will be monitoring the primary end points of durability of control, hematologic control, platelets less than 450, white cells less than 10. That will basically sustain 80% of 36 consecutive weeks. Then, the key secondary end points are going to include all important end points in ET patients, such as complete hematologic response, composite hematologic response, that includes control of spleen, control of symptoms, absence of disease progression, and absence of thromboembolic events. Then, it’s going to also have this exciting end point, which is basically a decline or allele burden. We’ll be checking the allo burden, what we call the molecular response, and then bone marrow morphology response.

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