New Developments in MPN Management Provide Additional Options for Patients

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December 5, 2023

Kyle Doherty

Although myeloproliferative neoplasms (MPNs), which are comprised of essential thrombocythemia, polycythemia vera (PV), and myelofibrosis, remain relatively rare— with estimated annual incidence rates of 1.03, 0.84, and 0.47 per 100,000 individuals, respectively—there remains an unmet need for effective treatment options for patients with these diseases who progress on standard of care therapies.1 However, significant progress has been made in terms of understanding this group of disorders and developing treatment strategies to combat them, with Naveen Pemmaraju, MD, saying the medical field has entered a “golden era” of MPN treatment.

During a recent OncLive Peer Exchange® video series titled “Expert Insights Into the Management of MPNs,” Jamile M. Shammo, MD, explained, “MPNs represent a heterogeneous group of hematopoietic stem cell neoplasms that share common features. Myeloid proliferation is certainly something that we see [in MPNs], as well as a propensity for thrombotic events, symptoms that are related either to constitutional symptoms or splenomegaly related. All 3 entities tend to progress to higher myeloid neoplasms; essential thrombocythemia [to] PV that goes to myelofibrosis and then myelofibrosis can evolve into acute leukemia. Of course, the rate of progression varies from one entity to the other, with essential thrombocythemia having the lowest risk [of progression].”

The development of MPNs is almost always associated with mutations in JAK2, making this family of genes an attractive treatment target. JAK2 mutations are observed in approximately 95% of patients with PV and approximately 50% of both patients with essential thrombocythemia and myelofibrosis. Notably, the emergence of additional treatment targets also has sparked the development of novel agents in recent years.1

During the discussion, expert oncologists reviewed updated findings from ongoing and completed clinical trials in the field. They primarily focused on studies evaluating emerging agents in PV and myelofibrosis.

MANAGING PV

Abdulraheem Yacoub, MD, began the discussion on PV by noting that the JAK1/2 inhibitor ruxolitinib (Jakafi) has been the standard-of-care agent in PV since 2015. Prior to this, PV was historically managed with phlebotomy, hydroxyurea, and/or interferons. Ruxolitinib became the first FDA-approved drug for the treatment of patients with PV in December 2014 when it received an indication from the agency for patients who had an inadequate response to or were intolerant of hydroxyurea.2

“The introduction of ruxolitinib to the treatment landscape of patients with myelofibrosis has truly been transformative,” Shammo commented. “We all remember the patients we had in the clinic [in the past] and how we had simply nothing but supportive care to offer. Ruxolitinib was approved based on the results of 2 phase 3 studies. COMFORT-I [NCT00952289] randomly assigned patients [with myelofibrosis] to receive ruxolitinib or placebo and examined [spleen] volume reduction and reduction in total symptom score from baseline at 24 weeks. COMFORT-II [NCT00934544], which ran mostly in Europe, randomly assigned patients to be treated with ruxolitinib or best available therapy [as selected by the investigator]. This study [also evaluated] spleen volume reduction, but at week 48. In either trial, ruxolitinib was statistically significantly more active in attaining the primary end point and for that reason it was approved. Some might say that the evidence is perhaps less compelling than what you would [typically] find in a phase 3 study, but when you have multiple studies showing the same thing, that treatment with ruxolitinib improves [outcomes] compared with placebo or best available therapy, I tend to feel like it’s reasonable enough to believe that actually is the case.”

Long-term data from 2 phase 3 trials, RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036), comparing the safety and efficacy of ruxolitinib with best available therapy in different patient populations with PV recently were published in The Lancet Haematology. RESPONSE enrolled adult patients with PV who were resistant to or intolerant of hydroxyurea and randomly assigned them 1:1 to receive either ruxolitinib (n = 110) or best available therapy (n = 112; hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide (Agrylin), approved immunomodulators, or observation without pharmacological treatment). RESPONSE-2 enrolled a higher-risk patient population; eligible patients had inadequately controlled PV without splenomegaly and were intolerant of or resistant to hydroxyurea with an ECOG performance status of 2 or less. They were randomly assigned to receive ruxolitinib (n = 74) or best available therapy (n = 75).3,4

Follow-up data from RESPONSE demonstrated that the 5-year overall survival (OS) rate was 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group vs 91.0% (95% CI, 82.8%-95.4%) in the best available therapy arm. Most patients (88%) in the best available therapy arm crossed over to receive ruxolitinib, and no patients remained in this arm after week 80. There were 25 primary responders in the ruxolitinib arm, 6 of whom had progressed by the time of the final analysis. The 5-year probability of maintaining a primary composite response was 74% (95% CI, 51%-88%), the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%), and the probability of maintaining overall clinicohematological responses was 67% (range, 54%-77%).3

At a median follow-up of 67 months (IQR, 65-70), findings from RESPONSE-2 showed that the 5-year OS rate was 96% (95% CI, 87%-99%) in the ruxolitinib arm compared with 91% (95% CI, 80%-96%) in the best available therapy arm. In the ruxolitinib arm, 22% of patients (95% CI, 13%-33%) achieved durable hematocrit control with an estimated median duration of control not reached (NR) at week 260 (95% CI, 144-NR). Most patients in the best available therapy arm (77%) crossed over to ruxolitinib, no patients continued with best available therapy after week 80 per protocol, and the median duration of hematocrit control was not reported due to the small number of responders at week 80.4

In light of findings from RESPONSE and RESPONSE-2, investigators in both studies concluded that ruxolitinib is a safe and effective long-term treatment option for patients with PV for whom hydroxyurea proved ineffective.3,4

“Both studies have ong-term follow-up and have published 5-year data showing very durable responses,” Yacoub said. “There were very few late failures on ruxolitinib and no unexpected adverse effects were observed with longterm follow up. This has built a strong case for ruxolitinib as a standard treatment for patients [with PV] after hydroxyurea failure.”

Ropeginterferon Takes Center Stage

A more recent breakthrough for patients with PV was the emergence of the interferon ropeginterferon alfa-2b-njft (Besremi). In November 2021, ropeginterferon became the first agent to receive FDA approval for patients with PV regardless of their treatment history.5

Ropeginterferon was compared with hydroxyurea in the phase 3 PROUD-PV trial (NCT01949805) and its extension continuation study, CONTI-PV (NCT02218047). Eligible patients were 18 years or older and had earlystage PV with no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment. Patients could opt to enter CONTI-PV after 1 year of initial treatment in PROUD-PV.6

Findings from the studies revealed that at a median follow-up of 182.1 weeks (IQR, 166.3- 201.7) patients in PROUD-PV who received ropeginterferon (n = 122) achieved complete hematological response with normal spleen size at a rate of 21% compared with 28% of patients who received hydroxyurea (n = 123). However, in CONTI-PV, 53% of patients in the ropeginterferon arm (n = 95) had a complete hematological response with improved disease burden at 36 months vs 38% of patients in the hydroxyurea arm (n = 74; P = .044). Moreover, at 36 months in CONTI-PV, the complete hematological response rate regardless of spleen criterion was 71% vs 51% in the investigative and comparator arms, respectively (P = .012); at 12 months in PROUD-PV these rates were 43% vs 46%, respectively (P = .63).6

Study authors concluded that ropeginterferon was effective in inducing hematological responses. Although noninferiority to hydroxyurea in terms of hematological response and normal spleen size was not observed at 12 months, improved responses vs hydroxyurea were present at 36 months. Thus, the authors wrote that ropeginterferon offers an effective and “safe long-term avenue for treatment with distinct features from hydroxyurea.”6

“It’s wonderful to have options because we get patients with PV [who] could not be any more different,” Yacoub said. “They have different goals of care, and at the end of the day, we are treating individual patients, not diseases. For each patient, we have to define what we are trying to achieve. There are patients who are going to live with the disease a lot longer. They have more high-risk presentations and would benefit from the maximum data that we have with the application of the effective agents. There are patients who have relatively low-risk disease, and they’re likely going to live their natural lives with some medical management from our end. We have to individualize our choices.”

Looking ahead, the phase 3 VERIFY trial (NCT05210790) is underway with the aim of adding rusfertide (PTG-300), a novel and potent hepcidin mimetic, to the PV treatment landscape. Rusfertide previously demonstrated clinical activity in early-phase studies, characterized by good tolerability and consistent and durable hematocrit control, as well as improvements in iron deficiency among patients who required higher than normal amounts of phlebotomies even after standard-of-care therapy.7

VERIFY is enrolling patients with PV who have received at least 3 phlebotomies in the previous 6 months or at least 5 in the previous 12 months as a result of inadequate hematocrit control, with or without concurrent cytoreductive therapy. Eligible patients will be randomly assigned 1:1 to receive either placebo plus ongoing therapy or rusfertide plus ongoing therapy.

Part 1a of the trial is the double-blind, placebo- controlled, add-on phase that will enroll parallel groups and last 32 weeks. During part 1b, patients who complete part 1a will receive rusfertide for 20 weeks. Patients who successfully complete part 1b will enter the long term extension phase, part 2, and will continue to be treated with rusfertide for 104 weeks. The primary end point is the proportion of patients achieving a response in from week 20 to week 32 in part 1A. The study was initiated in January 2022 and has a target enrollment of 250 patients.7

Managing Myelofibrosis

Patients with myelofibrosis have more FDA-approved treatment options than those with PV. To date, 3 Janus kinase (JAK) inhibitors have been approved for the treatment of patients with myelofibrosis: ruxolitinib, fedratinib (Inrebic), and pacritinib (Vonjo).

Similar to PV, ruxolitinib became the first FDA-approved therapy for the treatment of patients with myelofibrosis, gaining an indication for patients with intermediate- and high-risk disease in November 2011. In August 2019, patients with intermediate- 2 or high-risk primary or secondary myelofibrosis gained fedratinib as an FDA-approved option. Finally, the FDA approved pacritinib in March 2022 for the treatment of adult patients with intermediate- or high-risk primary or secondary myelofibrosis with platelet levels below 50,000/μL.8-10

“The current NCCN [National Comprehensive Cancer Network] guidelines are really agnostic of the second-line therapy, which is interesting,” Raajit K. Rampal, MD, PhD, said. “You can start a patient who [at that time] has over 50,000 platelets on ruxolitinib or fedratinib. And if there is a need to change therapy, you could use any of these 3 agents. That’s an important message for our audience to remember, that the second line is not platelet restricted. We have an abundance of options.”

After summarizing updated data from pivotal trials of the already approved agents, the panelists shifted their focus to new findings from trials evaluating investigational therapies beyond JAK inhibitors in myelofibrosis. Updates from the studies were presented during the 2023 American Society of Clinical Oncology Annual Meeting in June.

Novel Agents Seek to Augment the Armamentarium

In the phase 2 ACE-536-MF-001 trial (NCT03194542), investigators examined the erythroid maturation agent luspatercept-aamt (Reblozyl) for the management of anemia in patients with myelofibrosis; it occurs in approximately 40% of patients. Investigators noted that luspatercept demonstrated anemia improvement across all cohorts of in the study, regardless of transfusion dependency and use of ruxolitinib. For example, 26.3% (95% CI, 13.4%- 43.1%) of patients who were red blood cell transfusion dependent and received prior ruxolitinib (n = 38) achieved transfusion independence following treatment with luspatercept.11

The phase 1/2 LIMBER study (NCT04455841) evaluated the safety and efficacy of the oral ALK2 inhibitor zilurgisertib alone and in combination with ruxolitinib in adult patients with intermediate 1 or 2 primary or secondary myelofibrosis. Among patients in the monotherapy group who were not transfusion dependent (n = 6), anemia improvement (hemoglobin increase of ≥ 1.5 g/ dL relative to baseline) occurred in 1 patient; this level of improvement was observed in 3 of 9 patients in the combination group. Zilurgisertib monotherapy or combination therapy with ruxolitinib was determined to be generally well tolerated and displayed the potential for therapeutic activity, the study authors concluded.12

Another phase 1/3 trial, XPORT-MF-034 (NCT04562389) evaluated a ruxolitinibcontaining combination, this time with the selective inhibitor of nuclear export selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis. At week 24, efficacy-evaluable patients (n = 22) achieved spleen volume reduction of at least 35% (SVR35) from baseline at a rate of 64%. Investigators noted that the combination displayed encouraging activity, and updated data will be made available at a future date.13

Finally, in a single-arm phase 2b study (NCT04217993) the oral, novel JAK/ACVR1 inhibitor jaktinib showed promising activity in patients with myelofibrosis who were intolerant to ruxolitinib. Efficacy-evaluable patients who received jaktinib (n = 44) achieved an SVR35 rate of 43% at 24 weeks, and the best spleen response rate was 55%. Notably, response was maintained for a minimum of 12 weeks in 80% of patients.14

“It’s exciting to have all these non-JAK inhibitors [in the pipeline],” Rampal said in conclusion. “Ultimately, hopefully, we can figure out what the best fit is for an individual patient. We’re not there yet, but with an abundance of data, we’ll get there. It’s also important to note that there are a number of agents that are earlier on [in development] that are moving along. Even beyond this next generation of non-JAK inhibitors already in the pipeline, there is a generation beyond that that is in clinical trial development.”

References

  1. McMullin MF, Anderson LA. Aetiology of myeloproliferative neoplasms. Cancers (Basel). 2020;12(7):1810. doi:10.3390/cancers12071810
  2. FDA approves ruxolitinib. News release. FDA. Updated February 22, 2016. Accessed October 18, 2023. bit.ly/3PVXObQ
  3. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera
    (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
  4. Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus bestavailable therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/ S2352-3026(22)00102-8
  5. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed October 18, 2023. bit.ly/3rXAt1u
  6. Gisslinger H, Klade C, Georgiev P, et al; PROUD-PV Study Group. Ropeginterferon alfa-2b versus standard therapy for polycythaemia
    vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol.
    2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4
  7. Verstovsek S, Kuykendall A, Hoffman R, et al. Verify: a phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2022;140(suppl 1):3929-3931. doi:10.1182/ blood-2022-163755
  8. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008-3014. doi:10.1158/1078-0432.CCR-11-3145
  9. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed October 18, 2023. bit.ly/3s30OuX
  10. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed October 18, 2023. bit.ly/3S0PVVj
  11. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study. J Clin Oncol.2023;41(suppl 16):7016.doi:10.1200/JCO.2023.41.16_suppl.7016
  12. Bose P, Mohan S, Oh S, et al. Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928,
    LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF). J Clin Oncol. 2023;41(suppl 16):7017. doi:10.1200/JCO.2023.41.16_suppl.7017
  13. Ali H, Kishtagari A, Maher KR, et al. Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with
    myelofibrosis: updated results from XPORT-MF-034. J Clin Oncol. 2023;41(suppl 16):7063. doi:10.1200/JCO.2023.41.16_suppl.7063
  14. Zhang Y, Zhou H, Xiao ZJ, et al. Jaktinib in patients (pts) with myelofibrosis (MF) who were intolerant to ruxolitinib (RUX): an open-label, single-arm phase 2b study. J Clin Oncol. 2023;41(suppl 16):7061.doi:10.1200/JCO.2023.41.16_suppl.7061

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Anticoagulation for Splanchnic Vein Thrombosis in Patients with Myeloproliferative Neoplasms: A Systematic Review and Meta-Analysis

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November 28, 2023

Pavlina Chrysafi, MD; Kevin Barnum, MD, PhD; Genevieve Garhard, MD; Thita Chiasakul, MD; Arshit Narang; Megan McNichol; Nicolette Riva, MD, PhD; Walter Ageno, MD; Jeffrey Zwicker, MD; Rushad Patell, MBBS

Introduction:

Splanchnic vein thrombosis (SVT) is a common manifestation of myeloproliferative neoplasms (MPN). The optimal anticoagulation strategies in MPN-SVT remain unclear due to the challenge of balancing the concurrent prothrombotic state of MPN with the risk for SVT complications, such as gastrointestinal bleeding.

Methods:

We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of anticoagulation in patients with MPN following SVT incidence. This study protocol was registered on PROSPERO (#CRD42023414120). On April 07, 2023, we comprehensively searched multiple databases from Cochrane Library, EMBASE, and PubMed/MEDLINE. Retrospective or prospective studies in English with at least ten adult patients with MPN-SVT were included. Study screening by title/abstract, full text, and data extraction were performed in duplicate. Primary outcomes included recurrence of venous thrombosis (SVT and non-SVT), arterial thrombosis, and major bleeding. The risk of bias was assessed with MINORS scale. Pooled risk ratio (RR) of recurrent thrombosis and major bleeding events with respective 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method with random-effects model. Pooled rates of recurrent thrombosis and major bleeding events with respective 95% CI were calculated by DerSimonian and Laird method using random-effects model. Inter study heterogeneity was evaluated using the Cochran Q test and I 2 statistic.

Results:

Of a total of 4624 studies that were identified on the initial abstract screen, full texts were obtained and reviewed for 192 records. We included five retrospective and one prospective study that provided outcome rates for 387 patients with MPN treated with anticoagulation following SVT. All patients receiving anticoagulation in the six studies included in this analysis were treated with vitamin K antagonists (VKA). Of note, one additional study evaluating MPN-SVT with rivaroxaban was not included in the analysis because of short follow-up compared to the other six studies. Most studies were conducted in Europe (n=4), one was international, and one was done in the United Kingdom. The median follow-up was 3.2 years (follow-up was not reported in one study) and median age of patients at SVT diagnosis was 47.5 years old. JAK2V617F positivity was reported in 311/387 (80.3%). Regarding quality assessment and bias risk, four of the studies had moderate and two high risk of bias by the MINORS scale.

Pooled incidence rates showed that subsequent venous thrombosis was the most common complication while on anticoagulation (Pooled rate 9.6%; 95% CI 5.6 – 15.8; I 2=27%), followed by major bleeding (Pooled rate, 9%; 95% CI, 3.7 – 20.3; I 2=72%). Four of the six studies provided data comparing management with anticoagulation vs. no anticoagulation in 288 patients. The rates of venous (SVT and non-SVT) and arterial thrombosis following SVT were similar between the anticoagulation vs. no anticoagulation group (venous: RR 0.90; 95% CI, 0.412 – 1.966; I 2 = 0%, Figure 1 and arterial: RR, 1.01; 95% CI, 0.36 – 2.80; I 2=0%). Similarly, there was no significant difference in the risk of major bleeding between the two groups (RR, 0.52; 95% CI, 0.23- 1.14; I 2=0%). (Figure 2)

Conclusion:

Risk of recurrent thrombosis and bleeding in patients with MPN-SVT are considerable. Anticoagulation with VKA in MPN patients following SVT was not associated with a reduction in the risk of subsequent venous or arterial thrombosis or increased risk of major bleeding. Further studies with larger populations are warranted to elucidate the optimal medical management for MPN-SVT.

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Cardiovascular Risk Factors Are Common in Myeloproliferative Neoplasms and Portend Worse Survival and Thrombotic Outcomes

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November 28, 2023

Joan How, MD; Orly Leiva, BS; Anna Marneth, PhD; Baransel Kamaz, MD; Chulwoo Kim; Lachelle Weeks, MD, PhD; Mohammed Wazir; Maximilian Stahl, MD; Daniel DeAngelo; R. Coleman, Lindsley, Marlise Luskin, MD; Gabriela Hobbs, MD

BACKGROUND

Myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) are characterized by increased risk of arterial and venous thrombosis. Cardiovascular risk factors (CV RFs) including hypertension, hyperlipidemia, diabetes, smoking, and obesity likely contribute to thrombotic risk, but the exact incidence of these risk factors and the impact of CV RF modification in MPNs is less clear. The purpose of this study was to determine the prevalence of baseline CV RFs in MPN patients, investigate their association with genomic profiles, and evaluate their effect on long-term outcomes.

METHODS

We retrospectively analyzed patients who received targeted gene sequencing at Massachusetts General Brigham / Dana Farber Cancer Institute (N=977) from 2014-2023, and met WHO 2016 criteria for PV, ET, MF, or pre-fibrotic MF. CV RFs were identified through ICD-9 or 10 codes present prior to MPN diagnosis, and defined as hypertension, hyperlipidemia, diabetes, current smoking status, or BMI>30. Patient and treatment characteristics were described with summary statistics. Genomic profiles were compared between ET, PV, and MF patients with vs without a CV RF. Primary outcome was overall death. Secondary outcomes were venous thromboembolism, arterial thrombosis (including myocardial infarction and stroke), and transformation to MF or acute myeloid leukemia (AML). We calculated cumulative incidence functions of arterial/venous thrombosis as well as overall survival in patients with or without a CV RF. Hazard ratios (HR) were estimated for outcomes using Cox proportional hazards regression.

RESULTS

Our cohort contained 399 (39.6%) ET, 312 (31.0%) PV, and 237 (23.5%) MF or pre-fibrotic MF patients. The median age at diagnosis was 58.5 years, and 47.9% of patients were male. The overall prevalence of hyperlipidemia, hypertension, and diabetes at MPN diagnosis was 16%, 20%, and 8%. The average BMI at diagnosis in all MPNs was 27.28, with 64% and 23% of patients having a BMI of >25 and >30. Six percent of MPN patients were current smokers at time of diagnosis, compared to 39% former smokers and 56% never smokers.

ET and PV patients with ≥1 CV RF at MPN (N = 234, 32.9%) diagnosis were older (mean age 61.1 vs 52.1 years, p<0.001), and more likely to be male (50.9% vs 41.3%, p=0.02), non-White (12.4% vs 7.6%, p=0.015), and have a prior history of atherosclerotic disease (16.2% vs 4.4%, p<0.001), thrombosis (13.7% vs 5.0%, p<0.001), and heart failure (2.1% vs 0.4%, p=0.042). MF patients with ≥1 CV RF (N = 120, 50.6%) were also more likely to be older (mean age 67.5 vs 60.4 years, p<0.001), male (66.7% vs 53.9%, p=0.047), and have a prior history of atherosclerotic disease (19.2% vs 6.0%, p=0.003) (Table).

Results of targeted gene sequencing closest to MPN diagnosis were analyzed. A similar proportion of driver ( JAK2, CALR, MPL) and concomitant ( TET2, ASXL1, DNMT3A, SRSF2, SF3B1, U2AF1, ZRSR2) mutations were seen in MPN patients with or without a CV RF. However, patients with ET or PV with ≥1 CV RF had a lower variant allele fraction (VAF) of their driver mutation (mean 41.0% vs 48.1%, p = 0.004), which was primarily driven by JAK2 (mean 43.5% vs 52.0%, p=0.003).

In ET and PV, after adjusting for variables significant on univariate analysis, the presence of ≥1 CV RF was associated with higher risk of death from any cause (HR 1.73, 95% CI 1.08-2.76) and arterial thrombosis (HR 2.33, 95% CI 1.22-4.42). Among patients with MF, the presence of ≥1 CV RF was not associated with increased risk of death when adjusted for age, sex, and prior thrombosis (HR 1.36, 95% CI 0.84 – 2.20). MPN patients with ≥1 CV RF did not have increased rates of MF or leukemia progression (Fig).

DISCUSSION

In our study, CV RFs are common among patients with MPN. CV RFs were associated with adverse outcomes, including death and thrombosis among patients with ET or PV. We found no differences in the molecular profiles in MPN patients with or without CV RFs, although a lower JAK2 VAF was seen in patients without CV RFs, which will need to be explored further. MPN patients with a CV RF had significantly worse overall survival and cumulative arterial thrombosis rates, although the presence of CV RFs does not impact MF or leukemia progression. However, our results highlight the importance of addressing CV RFs in MPN care to improve morbidity and mortality.

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TP53 mutations and Their Impact on Survival in Patients with Myeloproliferative Neoplasms

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November 28, 2023

Benjamin Rolles, MD; Cilomar Martins De Oliveira Filho, MD; Julia Keating, MS; Marlise Luskin. MD, MSCE; Daniel DeAngelo; Coleman Lindsley, MD, PhD; Annette Kim, MD, PhD; Jessica Hem; Chulwoo Kim; Lachelle Week, MD, PhD; Mohammad Wazir; Joan How, MD; Anne Marneth, PhD; Yiwen Liu; Martin Aryee, PhD; Harrison Tsai, MD, PhD; Maximilian Stahl, MD; Ann Mullaly, MD

Introduction: TP53 mutations in patients with myeloproliferative neoplasms (MPN) are associated with poor prognosis, including progression to blast phase MPN. However, low variant allele fraction (VAF) TP53 mutations have been reported to remain stable over years in chronic phase MPN. A major unmet clinical need in MPN is the ability to discriminate patients with TP53-mutant MPN who are at high-risk of secondary AML (sAML) and warrant immediate intervention from those who are at lower risk of sAML in whom active surveillance can be employed. Therefore, we sought to identify parameters associated with leukemic transformation and overall survival in the context of MPN with genetic aberrations in TP53.

Materials and Methods: We retrospectively analyzed a cohort of 947 MPN patients from the Dana-Farber Cancer Institute Hematologic Malignancies Data Repository (HMDR) with at least one clinical next-generation sequencing (NGS) panel performed. Patient characteristics such as age at MPN diagnosis, gender, MPN subtype and driver mutations were recorded. Furthermore, information about the course of disease was extracted including occurrence of sAML and overall survival (Figure 1). We also analyzed type and number of additional mutations as well as cytogenetics. With respect to TP53-specific parameters, we evaluated the number of TP53 mutations, TP53 VAF, loss of heterozygosity (LOH) at the TP53 locus, phenotypic annotations of TP53 (i.e. PHANTM score) and 17p deletion. We defined “multi-hit” TP53 as the presence of two or more TP53 mutations, TP53 VAF higher than 50%, TP53 mutation plus 17p deletionor TP53 mutation and documented LOH.

Results: A total of 947 patients were analyzed, of which 40 harbored at least one detectable TP53 mutation. A total of 13 patients were found to have a multi-hit TP53 mutations defined by > 50% VAF in 6 patients, two or more TP53 mutations in 5 patients and TP53 mutation + 17p deletion in 5 patients. The MPN diagnosis at time of TP53 mutation detection was post ET/PV myelofibrosis (secondary MF) (n=23, 58%), primary myelofibrosis (MF) (n=7, 18%), pre-fibrotic MF (n=2, 5%), essential thrombocythemia (ET) (n=6, 15%) and polycythemia vera (PV) (n=2, 5%). Two patients with ET and one patient with PV did not have a concurrent in-house bone marrow biopsy performed at the time the TP53 mutation was detected. Two patients with ET developed sAML within 12 months of TP53 mutation detection, without prior mention of fibrosis. Age at first MPN diagnosis was not significantly different between patients with or without TP53 mutation. The average time from initial MPN diagnosis to detection of the first TP53 mutation was 9 years (range: 0-33 years). The most common MPN driver mutation among patients with TP53 mutations was JAK2 (75%), followed by CALR (13%)and MPL (5%). Out of all TP53-mutated patients, 8% showed a triple negative status. The most frequent additional mutations among patients with TP53 mutations were TET2 (25%), U2AF1 (15%), ASXL1 (13%), and DNMT3A (10%). There was no significant difference between single-hit and multi-hit TP53 status regarding MPN subtype, driver mutations and co-mutations (Table 1). Seven patients (single-hit: 15%, multi-hit: 23%) with a TP53 mutation developed sAML during the course of their disease, compared with only 3% of all patients without a TP53 mutation and 50% (single-hit: 41%, multi-hit: 69%) were deceased at the time of the last follow-up compared to 18% of all patients without a TP53 mutation.

We focused on overall survival from the initial MPN diagnosis and considered whether patients developed bone marrow fibrosis during their disease course (Figure 1). Survival did not differ significantly between single-hit TP53 and patients with multi-hit TP53 (p=0.2), but survival did differ significantly between multi-hit TP53 patients and TP53 wildtype patients with MF/prefibrotic MF/Secondary MF (p=0.02) as well as compared to all MPN patients without a TP53 mutation (p<0.001). Survival was not significantly different between single-hit TP53 and TP53 wildtype MF/prefibrotic MF/Secondary MF patients (p=0.4).

Conclusions: In a large cohort of 947 molecularly characterized MPN patients, 4% of the cohort developed a TP53 mutation during their course of disease. 18% of all TP53-mutant patients developed sAML with an adverse effect on overall survival for patients with multi-hit but not single-hit TP53 mutations.

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Defining and Treating Classic Cases of Myeloproliferative Neoplasms

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Targeted Oncology Staff

In the first article of a 2-part series, Pankit Vachhani, MD, discusses what makes classical cases of myeloproliferative neoplasms unique and how ruxolitinib impacts their reduction of spleen volume.

CASE

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue.
  • Her spleen was palpable 6-7 cm below the left costal margin​.
  • Medical History: No known comorbidities
  • Next-generation sequence testing: JAK2 V617F mutation​
  • Karyotype: 46XX​
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​
  • Blood smear: leukoerythroblastosis​
  • Diagnosis: Primary myelofibrosis​
  • Dynamic International Prognostic Scoring System: intermediate-1​
  • Mutation-enhanced International Prognostic Score System 70: intermediate risk
  • The patient was not interested in transplant​.
  • A decision was made to initiate ruxolitinib (Jakafi).

Targeted Oncology: What makes myeloproliferative neoplasms (MPNs) unique among blood cancers?

PANKIT VACHHANI, MD: Every time I have a patient with chronic myeloid neoplasms, meaning a myeloid neoplasm that’s not an acute leukemia, I like to think of it under the framework of World Health Organization 2022 classification schemes….1 It’s important because there are a few different subcategories of chronic myeloid neoplasms, one of which is MPNs. This [disease] used to be called myeloproliferative disorders, but around 2008 the name was formally changed to neoplasms…putting it into perspective, the fact that it is a blood cancer.1

When looking at the category of MPNs, there are many of these…including the classic chronic myeloid leukemia, Philadelphia chromosome–positive MPN, and [more]. These also include polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis, pre-fibrotic and overt myelofibrosis, chronic neutrophilic leukemia, eosinophilic leukemia, and the MPN unclassifiable. Now, when we think of MPNs, the 3 classical Philadelphia chromosome–negative MPNs [specifically], include PV, ET, and myelofibrosis, which are the most common of the MPNs.

How do MPNs present in patients?

What connects all these MPNs is that they present somewhat similarly. They present with high white blood counts, or high blood counts in general, and they present [in patients] with symptoms, an enlarged spleen, for example. But if you’ve looked just at PV, ET, and myelofibrosis, what you will see is that there is a Janus Kinase [JAK]-STAT signaling pathway that is over activated.2

If you want to take a step back and think about it, we all know that there are cells and cells have receptors, receptors need lichens to be active, and one such receptor would be the erythropoietin [EPO] receptor. You need the EPO ligand to bind to the EPO receptor, and then the JAK would get activated and they would make the STATs activated and the activated STATs would go inside the nucleus and lead to transcription of different proteins.

What mutations are there in this disease?

The JAK-STAT pathway is involved in transmitting the signal from outside of the cell to inside of the nucleus, therefore making the changes.2 What happens in PV, ET, and myelofibrosis is that this pathway is hyperactive; it doesn’t even need a signal frequently to be over activated. In the case of PV, for example, most of the cases have a classic JAK2 V617F mutation, then a very small fraction [of the patients without this mutation have] either the JAK2 exon 12 mutation, or some very unusual [and rare] mutations….3 The same JAK2 V617F [mutation can] also be found in ET and myelofibrosis. In fact, that JAK2 mutation constitutes about 60% of myelofibrosis and ET cases.3

If you look at the [patients with] myelofibrosis, what happens to those remaining 40% of patients who don’t have the JAK2 mutation? They have a CALR mutation or committal mutation, with CALR being the more common of those 2.3 About 10% of patients don’t have a mutation in either of these 3 driver gene mutations and that’s when we call it triple-negative myelofibrosis. Largely speaking, you are not going to find more than 1 of these mutations in the same case, so they’re more or less mutually exclusive. What’s common, however, between all 3 [disease types] is that the all 3 leads to this JAK-STAT pathway being over activated.2 So that’s the commonality that connects MPNs.

What were the spleen reduction outcomes in the COMFORT-I study (NCT00952289)?

Data from COMFORT-1 showed that the 35% spleen volume reduction [SVR], which was a primary end point at 24 weeks, was met in about 42% of patients [given ruxolitinib] vs less than 1% of patients on placebo [P < .001].4 The SVR results were comparable with COMFORT-II [NCT00934544] with 28% of patients on jak[having a SVR compared with no one on the best available therapy].5

So, there was a massive difference [in these results] with ruxolitinib and the comparator…. If you look at the change in spleen response for individual patients…most patients who got ruxolitinib in COMFORT-I had a spleen volume that decreased. On the other hand, the patients who got placebo had an increase of spleen volume, and there were very similar data from the COMFORT-II study [showing SVR in individuals who got ruxolitinib].4,5 Further, these results support ruxolitinib across the different subgroups, be that male vs female, primary or secondary myelofibrosis, or patients positive for the JAK2 mutation.

References

1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1

2. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-90. doi:10.1056/NEJMoa1311347

3. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. doi:10.1056/NEJMoa1312542

4. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

5. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi:10.1056/NEJMoa1110556

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Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis

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Zijian Fang, Giuditta Corbizi Fattori, Thomas McKerrell, Rebecca H. Boucher, Aimee Jackson, Rachel S. Fletcher, Dorian Forte, Jose-Ezequiel Martin, Sonia Fox, James Roberts, Rachel Glover, Erica Harris, Hannah R. Bridges, Luigi Grassi, Alba Rodriguez-Meira, Adam J. Mead, Steven Knapper, Joanne Ewing, Nauman M. Butt, Manish Jain, Sebastian Francis, Fiona J. Clark, Jason Coppell, Mary F. McMullin, et al.

Abstract

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

Introduction

Myeloproliferative neoplasms (MPN) arise from mutations acquired by HSPCs, most frequently affecting the genes encoding the kinase JAK21,2,3,4 or the multi-functional protein CALR5,6. Currently JAK1/2 inhibitors can improve disease-related symptoms and overall survival but have a limited impact on clone size7,8, likely because they cannot discriminate between mutant and wild-type JAK2 or due to the acquisition of pharmacological resistance9,10,11. Allogeneic HSC transplantation remains the only curative treatment for MPN but can only be performed in a minority of patients due to its toxicity12, warranting investigation of new therapies.

Men exhibit a higher prevalence of myeloid neoplasia compared with women13,14. Furthermore, MPN subtypes with poorer prognosis (primary myelofibrosis and polycythemia vera, compared with essential thrombocythemia) have a higher prevalence in males than in females15,16,17. Additionally, the risk of secondary myelofibrosis, which worsens the outcomes of PV/ET, is higher for men than for women, regardless of their age17,18,19. However, the reasons underlying this gender difference are unclear. It is possible that sex-chromosome genes and gender-dependent differences in epigenetic regulation, metabolism or immune response partly account for sexual dimorphism in cancer20. Another explanation might be the loss of sex chromosomes with age, which preferentially occurs in males, perhaps suggesting a higher genomic instability in men21.

However, one key determinant of gender disparities in cancer might be the effect of sex hormones20. Estrogens regulate the self-renewal, proliferation, and apoptosis of mouse hematopoietic stem and progenitor cells (HSPCs)22,23. Estrogen receptors (ERs) are differentially expressed in mouse HSPC subsets22. ERα activation induces proliferation of mouse long-term HSCs22,23 and protects them from proteotoxic stress through the modulation of UPR24. The selective ER modulator (SERM) tamoxifen induces apoptosis of multipotent hematopoietic progenitors but spares normal HSCs22. In MPN mouse models, tamoxifen restores the physiological apoptosis levels in mutant HSCs and selectively eliminates these cells, but not their non-mutated counterparts22. Based on these preclinical studies, we conducted a Phase II, multicenter, single-arm A’herns design clinical trial assessing tamoxifen’s safety and activity in reducing molecular markers of disease burden in MPN (TAMARIN). Here we report the results of the TAMARIN study. In addition, we describe an exploratory analysis of HSPCs from study patients and associated laboratory research investigating the mechanism of action of tamoxifen in human MPN.

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Novel Prognostic Scoring System May Help in Patient Stratification in Myelofibrosis

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November 22, 2023

By Johnathan Goodman

A novel prognostic tool may help in stratifying vulnerable patients with myelofibrosis (MF) based on the presence of comorbidities, according to research published in Cancers. However, the authors of the study noted that the tool — the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) — requires further validation in larger cohorts.

Although clinicians used an established prognostic system for MF that includes blast presence in peripheral blood and genomic abnormalities, comorbidities are also known to affect overall survival (OS) outcomes.

The authors of the present paper designed the MDS-CI, which is based on the Hematopoietic Cell Transplant Comorbidity Index (HCT-CI), to gauge the influence of comorbidities in 4 major organ systems: heart, lung, liver, and kidneys. For this retrospective study, researchers aimed to determine the prognostic potential of the MDS-CI in addition to 2 other scoring systems among patients with MF. They utilized the Dynamic International Prognostic Scoring System (DIPSS) and the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70.

Overall, data from 70 patients with MF were included, all of whom had not received stem cell transplantation. In the cohort, 51 patients had primary MF whereas 19 had secondary disease. The median follow-up was 40 months.

Initial analysis showed that cardiac disease (23 of 70 patients) and solid tumors (12 of 70) were the most common comorbidities noted at diagnosis.

The MDS-CI effectively predicted survival: a low score (38 patients) was linked with a median OS of 101 months, an intermediate score (25 patients) with a median OS of 50 months, and a high score (7 patients) with a median OS of 8 months (P <.001).

When the authors included the MDS-CI as a categorical variable in a multivariate model with the dichotomized DIPSS or the MIPSS-70, the MDS-CI added prognostic information. This inclusion affected hazard ratios (HRs): a high score was linked with an HR for OS of 14.64 compared with a low-risk score (P = .0002) when included with the DIPSS; a high score was also linked with an HR for OS of 19.65 compared with a low-risk score (P < .001) when included with the MIPSS-70.

“Our observations on the prognostic impact of comorbidities as determined by the MDS-CI in MF confirmed the importance of comorbidities, especially cardiac disease and solid tumors, for the course of the disease and overall survival in MF,” the authors wrote in their report.

Reference

Koster KL, Messerich NM, Volken T, et al. Prognostic significance of the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) in patients with myelofibrosis: a retrospective study. Cancers (Basel). 2023;15(19):4698. doi:10.3390/cancers15194698

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Diagnosis and Management of Cardiovascular Risk in Patients with Polycythemia Vera

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November 22, 2023

Giulia Benevolo,1 Monia Marchetti,2 Remo Melchio,3 Eloise Beggiato,1 Chiara Sartori,4 Carlo Alberto Biolé,5 Davide Rapezzi,6 Benedetto Bruno,1,7 Alberto Milan8

1University Hematology Division, Città della Salute e della Scienza di Torino, Turin, Italy; 2Hematology and Transplant Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; 3Division of Internal Medicine, A.O. S. Croce E Carle, Cuneo, Italy; 4Cardiology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; 5SCDO Cardiology, AOU San Luigi Gonzaga Orbassano, Turin, Italy; 6Hematology Division A.O. S. Croce e Carle, Cuneo, Italy; 7Department of Molecular Biotechnolgies and Medical Sciences, University of Turin, Turin, Italy; 8Department of Medical Sciences, University of Turin, Città della Salute e della Scienza di Torino, Turin, Italy

Correspondence: Giulia Benevolo, University Hematology Division, Città della Salute e della Scienza di Torino, via Genova 3, Turin, 10126, Italy, Tel +39 011 633 4301, Fax +39 011 633 4187, Email gbenevolo@cittadellasalute.to.it

Abstract: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.

Plain Language Summary: Patients with the myeloproliferative neoplasm (MPN) polycythemia vera (PV) are at increased risk of cardiovascular (CV) events, including stroke, heart attacks, and peripheral arterial disease. High blood pressure, smoking, and dyslipidemia are common in MPN and contribute to the increased cardiovascular risk. Effectively controlling cardiovascular risk factors in PV, along with appropriate hematological therapy such as direct-acting oral anticoagulants alone or in combination with aspirin, may improve the outcomes of patients with PV, but further research is needed.

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MANIFEST-2 Meets Primary End Point With Pelabresib Plus Ruxolitinib in MF

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November 21, 2023

By Jordyn  Sava

The combination of pelabresib (CPI-0610), an investigational BET inhibitor, with the ruxolitinib (Jakafi), a JAK inhibitor, demonstrated a statistically significant and clinically meaningful improvement in the proportion of JAK inhibitor-naive patients with myelofibrosis (MF) achieving at least a 35% reduction in spleen volume (SVR35) at week 24 compared with placebo plus ruxolitinib, according to topline results from the phase 3 MANIFEST-2 study (NCT04603495).1

A total of 66% of patients treated with pelabresib plus ruxolitinib achieved SVR35 at week 24 vs 35% of patients given placebo plus ruxolitinib (95% CI, 21.6-39.3; P <.001), meeting the primary end point of the study.

Further, the key secondary end points of symptom improvement in patients achieving at least a 50% reduction in total symptom score (TSS50) and absolute change in total symptom score (TSS) from baseline at week 24 were also promising with a strong positive trend favoring pelabresib plus ruxolitinib combination with TSS reduced by 15.99 points at week 24 at baseline vs 14.05 points at week 24 in the placebo plus ruxolitinib arm (Δ -1.94; 95% CI, -3.92-0.04, P =.0545), using least square mean estimate.

“Pelabresib is a first-in-class oral inhibitor of BET proteins, primarily those containing the BD1 and BD2 domains. It’s being developed currently in myelofibrosis. It has been tested in other diseases, but it has shown significant activity in myelofibrosis,” said Joseph M. Scandura, MD, PhD, Weill Cornell Medicine,in an interview with Targeted OncologyTM.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” said John Mascarenhas, MD, director of the adult leukemia program at The Tisch Cancer Institute at Mount Sinai, New York, in a press release.1 “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term myelofibrosis patient outcomes. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

MANIFEST-2 is an ongoing, randomized, double-blind, phase 3 trial where 430 patients with JAK inhibitor-naive MF were randomly assigned in a 1:1 ratio to receive upfront pelabresib plus ruxolitinib vs ruxolitinib alone.2

Patients aged ≥ 18 years with a confirmed diagnosis of MF, adequate hematologic, renal, and hepatic function, and an ECOG performance status of ≤ 2 were eligible for inclusion in the trial. Enrollment was also open to patients who had at least 2 symptoms with an average score ≥ 3 or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0, a prognostic risk-factor score of intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system, and a spleen volume of ≥ 450 cm3.

If patients had splenectomy or splenic irradiation in the previous 6 months, chronic or active conditions and/or concomitant medication use that would prevent them from receiving treatment, or had previously been treated with any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm, they were excluded from the study.

Additional findings showed that treatment with the combination also showed significant improvements in both key secondary end points within an analysis of patients classified as intermediate risk who made up over 90% of patients in MANIFEST-2. DIPSS Int-1 and Int-2 was a predefined stratification factor in the protocol for the MANIFEST-2 trial. Here, TSS was reduced by 15.18 points at week 24 with pelabresib plus ruxolitinib vs 12.74 points at week 24 in the placebo plus ruxolitinib arm (Δ -2.44; 95% CI, -4.48- -0.40; P <.02).1

Another key secondary end point, TSS50, was met among 52% of patients treated with pelabresib and ruxolitinib at week 24 vs 46% treated with placebo plus ruxolitinib (95% CI, -3.5-15.5; P =.216).1 Among patients at intermediate-risk, 55% of patients achieved TSS50 in the pelabresib and ruxolitinib treatment arm at week 24 compared with 45% in the placebo plus ruxolitinib arm (95% CI, 0.35-19.76; P <.05).

Following a Type C meeting with the FDA in September 2023, absolute change in TSS was included as a key secondary end point in the study. Per clinical protocol, this continuous end point was created to directly measure change in the average TSS from baseline to week 24 to help accurately estimate the magnitude of symptom burden reduction among patients with MF.

Findings from MANIFEST-2 also demonstrated that more patients achieved hemoglobin response (≥ 1.5 g/dL from baseline)in the pelabresib and ruxolitinib arm vs the placebo and ruxolitinib arm. For safety, the safety profile of pelabresib and ruxolitinib was consistent with what was previously observed with the combination and no new safety signals were observed. Adverse events of anemia were seen less frequently among patients in the pelabresib and ruxolitinib arm than those in the placebo and ruxolitinib arm.

Findings from the phase 3 MANIFEST-2 study will be further presented during an oral presentation at the 65th American Society for Hematology Annual Meeting and Exposition. Based on this encouraging data, continued conversations with regulatory agencies will occur with hopes of submitting a new drug application for combination of pelabresib and ruxolitinib in MF to the FDA in the middle of 2024.

“Myelofibrosis patients experience a severely diminished quality-of-life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” said Ruben A. Mesa, MD, FACP, president and executive director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, in a press release.1 “Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis.”

REFERENCES:
  1. MorphoSys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. MorphoSys AG. November 20, 2023. Accessed November 21, 2023. https://tinyurl.com/2n9swrer
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023. https://www.clinicaltrials.gov/study/NCT04603495

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Pelabresib Plus Ruxolitinib Improves Spleen Volume Reduction in JAK Inhibitor-Naive Myelofibrosis

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November 21, 2023

By Ryan Scott

Treatment with the combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) led to a statistically significant and clinically meaningful improvement in spleen volume reduction vs placebo plus ruxolitinib in patients with JAK inhibitor-naive myelofibrosis, meeting the primary end point of the phase 3 MANIFEST-2 trial (NCT04603495).1

Findings showed that 66% of patients treated with the combination of pelabresib and ruxolitinib experienced a spleen volume reduction of at least 35% (SVR35) at week 24 vs 35% of patients treated with placebo plus ruxolitinib (31% difference; 95% CI, 21.6%- 39.3%; P < .001).

Furthermore, patients in the pelabresib and ruxolitinib group experienced a median reduction in total symptom score (TSS) of 15.99 points at week 24, reduced from 28.26 at baseline, compared with a reduction of 14.05 points, reduced from 27.36, in those treated with placebo plus ruxolitinib (delta, –1.94; 95% CI, –3.92 to 0.04; P = .0545).

Notably, findings revealed that a higher percentage of patients experienced a hemoglobin response of an increase of at least 1.5 g/dL from baseline when treated with the combination of pelabresib and ruxolitinib compared with those given placebo and ruxolitinib.

Detailed findings from MANIFEST-2 will be presented at the 2023 ASH Annual Meeting in December. MorphoSys, the developer of pelabresib, will continue to review data and plans to submit a new drug application to the FDA and a marketing authorization application to the European Medicines Agency for pelabresib in combination with ruxolitinib in myelofibrosis by the middle of 2024.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” John Mascarenhas, MD, director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai in New York, New York, said in a news release. “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term outcomes [for patients with myelofibrosis]. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

The randomized, double-blind, placebo-controlled MANIFEST-2 trial enrolled patients at least 18 years of with a confirmed diagnosis of myelofibrosis with adequate hematologic, renal, and hepatic function. Furthermore, patients must have a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System; a spleen volume of 450 cm3 or more; and an ECOG performance status 2 or less. Exclusion criteria include splenectomy or splenic irradiation in the previous 6 months; medication use that would prohibit treatment; or prior administration of any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm.2

Eligible patients were randomly assigned 1:1 to receive pelabresib in combination with ruxolitinib or placebo plus ruxolitinib.

TSS response from baseline at week 24 and the proportion of patients with at least a 50% reduction in TSS (TSS50) were key secondary end points.1

Patients with intermediate-risk disease comprised more than 90% of patients in the study population, and in this population, pelabresib plus ruxolitinib reduced by a median TSS by 15.18 points at week 24 from the baseline median TSS of 28.20, compared with a median reduction of 12.74 points at week 24 from a baseline TSS of 27.53 in the placebo plus ruxolitinib arm (delta, –2.44; 95% CI, –4.48 to –0.40; P < .02). This difference was statistically significant.

At week 24, 52% of patients in the pelabresib arm achieved at least a 50% reduction in TSS (TSS50) vs 46% in the placebo arm (6% difference; 95% CI, –3.5% to 15.5%; P = .216). In intermediate-risk patients, TSS50 was achieved by 55% of those in the pelabresib arm compared with 45% in the placebo arm (10% difference; 95% CI, 0.35%-19.76%; P < .05).

Regarding safety, pelabresib and ruxolitinib remained in line with the previously observed safety profile, and no new safety signals were reported. Notably, instances of anemia as an adverse effect were less frequent in patients treated with pelabresib plus ruxolitinib compared with those treated with placebo plus ruxolitinib.

“[Patients with] myelofibrosis experience a severely diminished quality of life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, said in a news release.

References

  1. Morphosys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. Morphosys. November 20, 2023. Accessed November 21, 2023.
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023.

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