Category Archives: Blood Cancer

Allogeneic HSCT Improves Overall Survival in MDS/MPN With Neutrophilia

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Lauren Dembeck, PhD
A large, nationwide, population-based study of patients with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) with neutrophilia found that, to date, only allogeneic hematopoietic stem cell transplantation (alloHSCT) significantly improves overall survival (OS), according to research published in Blood Advances.

“MDS/MPN with neutrophilia is a very rare disease. It carries a poor median overall survival of 15 months (with a reported range of 12.4 to 37 months),” the study authors explained in their report. “Without treatment, 30-40% of patients progress to acute myeloid leukemia.”

Researchers retrospectively analyzed a cohort of 347 adult patients diagnosed with MDS/MPN with neutrophilia, previously known as atypical chronic myeloid leukemia, who were registered in the Netherlands Cancer Registry between 2001 and 2019. The aim of the study was to validate known prognostic markers, identify novel prognostic markers, and provide evidence-based treatment recommendations.

The demographic baseline data of the cohort was consistent with those of cohorts from other studies. Most patients were male (65%) and >65 years old (71%). The median age at diagnosis was 72 years (range, 22-95 years). Only 5 patients (1.4%) were known to have a prior hematological malignancy (MDS, n=2; lymphoma, n=3). The median OS for the overall cohort was 15.8 months (95% CI, 13.8-17.2 months), and no significant difference in OS was observed between the sexes.

Among 110 patients diagnosed between 2014-2019, cytogenetic testing data was available for 89% of patients. Of those, 15% had cytogenetic abnormalities, which were all in patients aged >65 years. The most common cytogenetic abnormality was trisomy 8 (6/15 patients).

Within the same subgroup, molecular analysis was available for 92% of patients. Of those, 49 patient harbored a total of 16 distinct molecular mutations, with some patients (16/101) having up to 3 different mutations. The most frequent mutations were in ASXL1 (22%), SETBP1 (18%), SRSF2 (12%), and CSFR3 (12%).

In the overall cohort, a multivariable Cox regression analysis adjusted for primary therapy revealed that age (>65 years of age hazard ratio [HR], 1.85; 95% CI, 1.34-2.55; P =.001) and alloHSCT (HR, 0.51; 95% CI, 0.26-0.97; P =.039) were associated with OS.

“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,” the study authors concluded in their report.

Reference

Klein SK, Huls GA, Visser O, Kluin-Nelemans HC, Dinmohamed AG. Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study. Blood Adv. Published online November 7, 2023. doi:10.1182/bloodadvances.2023011181

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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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CHA2DS2-VASC Predicted Thrombotic Risk in Patients With MPNs and Atrial Fibrillation

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November 16, 2023

Andrea S. Blevins Primeau, PhD, MBA

Although CHA2DS2-VASC does not account for myeloproliferative neoplasms (MPNs), it accurately predicted thrombotic risk in this patient population with atrial fibrillation (AF). However, HAS-BLED did not predict bleeding risk, according to the results of a retrospective study.

“Further investigation is needed to refine risk scores in MPN,” the authors wrote in their report. The study, which was published in the Journal of Thrombosis and Thrombolysis, analyzed data from 1617 patients with and 24,185 matched patients without MPNs from the National Readmission Database. All patients had AF. The primary outcomes were in-hospital or 30-day readmission for bleeding or thrombosis.

Characteristics were balanced between the cohorts. Overall, 29% of patients were on long-term anticoagulation, 25% were on long-term antiplatelet therapy. Comorbidities were common, with 76% of patients with hypertension, 42% with congestive heart failure, 35% with anemia, 33% with coronary artery disease, 24% with chronic lung disease, and 22% with diabetes.

However, patients with MPN were not at an increased risk of bleeding, with 2.60% experiencing a bleed compared with 2.98% of patients without MPNs (OR, 0.87; 95% CI, 0.63-1.19). Risk of bleeding was not accurately predicted by HAS-BLED, with a c-statistic of 0.55 (95% CI, 0.46-0.64) among patients with MPNs. For patients without MPN, the HAS-BLED was moderately predictive (c-statistic, 0.56; 95% CI, 0.54-0.58).

Patients with MPN were more likely to experience bleeding if their MPN type was essential thrombocythemia (P =.009), if they had anemia (P <.001), peripheral vascular disease (P =.024), or chronic kidney disease (P =.047). However, after multivariate analysis only ET remained independently associated with bleeding (adjusted OR, 3.08; 95% CI, 1.04-9.16).

Any hospital readmission within 30 days occurred among 18.6% of patients with MPN compared with 11.9% of patients without MPNs (P <.001). Within 90 days, 26.4% and 20.4% of patients with and without MPNs had a hospital readmission (P <.001).

Cardiovascular (CV)-related hospital readmission, which included arterial thrombosis, heart failure, and arrythmia, was also more common among patients with MPNs, occurring among 6.2% compared with 5.0% without MPN within 30 days (P =.046). However, there was no significant difference in CV readmission rates during the 90-day period.

Reference
Leiva O, How J, Grevet J, et al. In-hospital and readmission outcomes of patients with myeloproliferative neoplasms and atrial fibrillation: insights from the National Readmissions Database. J Thromb Thrombolysis. Published online October 15, 2023. doi: 10.1007/s11239-023-02900-z

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Allogeneic HCT Provides OS Benefit Independent of TP53 Allelic Status in MDS

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November 18, 2023

By Kyle Doherty

Patients with myelodysplastic syndrome (MDS) harboring a TP53 mutation experienced a survival benefit with allogeneic hematopoietic cell transplantation (HCT) compared with non-HCT treatment regardless of TP53 allelic status, according to findings from an analysis of the phase 2 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 study (NCT02016781) published in the Journal of Clinical Oncology.1

Findings from a univariate analysis showed that, irrespective of treatment strategy, patients with a TP53 mutation (n = 87) experienced a 3-year overall survival (OS) rate of 21% (standard error [SE] ± 5%) compared with 52% (SE ± 4%) among patients who were TP53 wild-type (n = 222; HR, 2.55; 95% CI, 1.86-3.50; P < .001). Additionally, the 3-year OS rate among patients with a single TP53 mutation (n = 39) was comparable with that of patients with a TP53 multi-hit mutation (n = 48), at 22% (SE ± 8%) vs 20% (SE ± 6%), respectively (HR, 1.29; 95% CI, 0.79-2.11; P = .31).

When HCT was used as a time-dependent covariate, patients with a TP53 mutation who received HCT (n = 48) experienced a 3-year OS rate of 23% (SE ± 7%) vs 11% (SE ± 7%) in patients who were treated with non-HCT therapy (n = 32; HR, 1.76; 95% CI, 1.02-3.06; P = .04). Moreover, the 3-year OS rate among patients with very high-risk MDS per the Molecular International Prognostic Scoring System per molecular International Prostate Symptom Score (IPSS-M) without a TP53 mutation who received HCT (n = 22) was significantly improved compared with those with the same risk profile and mutational status who received non-HCT therapy (n = 8), at 68% (SE ± 10%) vs 0% (SE ± 12%), respectively (P = .001).

“The absence of a non-HCT control group in [other] retrospective analyses has called into question whether the long-term survival observed in these studies was reasonably attributable to the transplantation intervention,” investigators wrote. “In this study, we directly addressed this question and now conclude definitively that reduced intensity transplantation mediates long-term survival for patients with TP53-mutated MDS compared with non-HCT treatment. Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53-mutated MDS.”

Previously published findings from the primary analysis of BMT CTN 1102 showed that patients who received reduced intensity conditioning HCT (n = 260) achieved a 3-year OS rate of 47.9% (95% CI, 41.3%-54.1%) compared with 26.6% (95% CI, 18.4%-35.6%) among those who were treated with non-HCT therapy or best supportive care (n = 124), for an absolute difference of 21.3% (95% CI, 10.2%-31.8%; P = .0001). The 3-year leukemia-free survival rates were 35.8% (95% CI, 29.8%-41.8%) vs 20.6% (95% CI, 13.3%-29.1%), respectively (absolute difference, 15.2%; 95% CI, 13.3%-29.1%; P = .003).2

BMT CTN 1102 was a multicenter prospective trial that evaluated the efficacy of reduced intensity conditioning HCT (donor arm) vs that of hypomethylating therapy or best supportive care (no donor arm) in patients with IPSS intermediate-2 or high-risk de novo MDS who were 50 to 75 years old. To perform their genetic analysis of BMT CTN 1102, study authors performed targeted DNA sequencing on frozen whole blood samples collected at the time of enrollment, which were available for 229 patients in the donor arm and 80 patients in the no donor arm. Baseline patient characteristics did not differ significantly between those in the donor and no donor arms.1

Patients included in the genetic analysis (n = 309) had a median age of 66.9 years (range, 50.1-75.3), with most patients being over 65 years old (61.8%). Most patients were female (62.1%), had IPSS intermediate-2 disease (66.7%), and complex karyotype (65.0%). At baseline, the median hemoglobin was 9.3 g/dL (range, 8.1-10.7) and the median platelet count was 70 x 109/L (range, 34-132).

In addition to a univariate analysis, investigators constructed 2 multivariable models adjusted for age at enrollment, performance status, IPSS risk status, MDS disease duration, and clinical and genetic variables. One model was based on random assignment on the basis of donor availability and the other compared HCT vs non-HCT treatment with HCT representing a time-dependent covariate.

Additional findings from the univariate analysis showed that, outside of TP53 mutations, the presence of KMT2Apartial tandem duplications was associated with a decrease in 3-year OS rate compared with those who did not have these duplications (HR, 2.21; 95% CI, 1.22-3.99; P = .009). However, patients with a germline DDX41 mutation (HR, 0.39; 95% CI, 0.17-0.87; P = .022) and somatic mutations in STAG2 (HR, 0.57; 95% CI, 0.34-0.96; P = .034) displayed superior OS compared with those who did not have these mutations.

Results from the donor vs no donor analysis revealed that patients in the donor arm experienced an OS improvement compared with those assigned to the no donor arm (HR, 1.60; 95% CI, 1.10-2.32; P = .013). Among patients with a TP53 mutation, assignment to the donor arm did not significantly improve OS compared with the no donor arm (HR, 1.76; 95% CI, 0.95-3.26; P = .073).

In the model that compared HCT with non-HCT treatment, patients who received HCT (n = 197) experienced a significantly lower risk of death compared with those treated with non-HCT therapies (n = 78; HR, 2.31; 95% CI, 1.53-3.49; P < .001). Findings from this model showed that patients with a TP53 mutation had a much greater risk of dying if they did not receive HCT vs those who did (HR, 3.89; 95% CI, 1.87-8.12; P < .001), which study authors noted could signify that, “…HCT might improve long-term survival in patients with mutated TP53, independent of other risk factors.” Investigators also found molecular clearance of TP53 mutation before HCT not to be predictive of long-term survival.

“Together, these data indicate that no patient with TP53-mutated MDS should be excluded from consideration for HCT a priori on the basis of TP53 status alone. Despite the relative benefit of HCT over non-HCT treatment, however, the absolute survival benefit remains modest, meriting value-based discussions between physicians and patients on the appropriateness of transplantation,” study authors concluded.

Reference

  1. Versluis J, Saber W, Tsai HK, et al. Allogeneic hematopoietic cell transplantation improves outcome in myelodysplastic syndrome across high-risk genetic subgroups: genetic analysis of the blood and marrow transplant clinical trials network 1102 study. J Clin Oncol. 2023;41(28):4497-4510. doi:10.1200/JCO.23.00866
  2. Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39(30):3328-3339. doi:10.1200/JCO.20.03380

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MPN Linked to Lower Death and Cardiac Arrest, Higher Bleeding in Patients Hospitalized With AMI

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Among patients hospitalized with acute myocardial infarction (AMI), those with myeloproliferative neoplasms (MPN) have an increased risk of in-hospital bleeding but a decreased risk of in-hospital death or cardiac arrest compared with patients without MPNs. This is according to a study published in JACC: CardioOncology.

“MPN poses a clinical conundrum. They are a heterogenous group of clonal hematopoietic neoplasms that portend a prognosis measured in years in some cases,” said Orly Leiva, MD, of the New York University Grossman School of Medicine. “The association between MPN and thrombosis has been well described. However, outcomes among patients with MPN who have had AMI have not been well studied.

“There are no current guidelines on specific treatment of AMI among patients with MPN. As such, current treatment of patients with MPN, including revascularization strategy and choice and duration of antithrombotic therapies, is usually made per current guidelines of the general population and on an individual basis based on the patient’s perceived thrombotic and bleeding risks,” Dr. Leiva said. “Our study aimed to shed some light on describing the characteristics of patients with MPN admitted for AMI and outcomes compared to the general population and to encourage further study that may lead to a more refined and personalized approach to the management of AMI among patients with MPN.”

Between January 2006 and December 2018, 1,644,304 patients (mean age = 67.2 years; 61.1% male) admitted for AMI were identified using the National Inpatient Sample, which captures around 20% of hospitalizations in the U.S. Among the 5,374 patients (0.3%) with MPN, 48.8% had polycythemia vera (PV), 47.8% had essential thrombocythemia (ET), and 5.8% had primary myelofibrosis (MF). The procedures captured included left heart catheterization, percutaneous coronary intervention (PCI), mechanical circulatory support (MCS), and coronary artery bypass grafting (CABG). The researchers compared the in-hospital outcomes between patients with and without MPN. The primary outcome was in-hospital death or cardiac arrest, and the secondary outcome was major bleeding.

Baseline patient characteristics were adequately balanced between patients with and without MPN after propensity score weighting. Compared with patients without MPN, those with MPN had a lower risk of in-hospital death or cardiac arrest (odds ratio [OR] = 0.83; 95% CI 0.82-0.84) but a higher risk of major bleeding (OR=1.29; 95% CI 1.28-1.30). Patients without MPN had a decreasing temporal rate of in-hospital death or cardiac arrest and bleeding (ptrend<0.001 for both). However, patients with MPN had an increasing temporal rate of in-hospital death or cardiac arrest (ptrend<0.001) and a stable rate of major bleeding (ptrend=0.48). This was despite a similar reduction in ST-segment elevation myocardial infarction (STEMI) presentations between patients with and without MPN over time (ptrend for both < 0.001). The risk factors associated with an increased likelihood of death, cardiac arrest, or bleeding included peripheral vascular disease, anemia, STEMI presentation, and an ET and primary MF MPN phenotype.

Invasive management (left heart catheterization, PCI, or CABG) was lower, although not significantly so, in patients with MPN than in those without (68.8% vs. 71.6%; SMD = 0.06). Patients with MPN were less likely than those without MPN to undergo PCI (38.3% vs. 43.2%; standardized mean difference [SMD] = 0.10) but not CABG (8.9% vs. 8.8%; SMD = 0.002). For patients with and without MPN, use of MCS (5.5% vs. 5.0%; SMD = 0.018) and prevalence of cardiogenic shock (3.6% vs. 3.9%; SMD = 0.02) were similar.

“Our study suggested no increase in in-hospital mortality among patients with MPN compared with the general population. However, patients with MPN had increased rates of bleeding events, including gastrointestinal and procedure-related bleeding,” said Dr. Leiva. “Additionally, patients with MPN were less likely to be treated with PCI.”

Limitations to the study include its retrospective design. Further, the data in the National Inpatient Sample are abstracted from billing codes, which are prone to errors. Data on the treatment of MPN, blood counts, disease duration, and genetic testing (JAK2 mutation) are not reported and may affect cardiovascular outcomes.

“My hope is that our study spurs further research on the management of AMI among patients with MPN and other cancers to better understand bleeding and thrombotic risk and to develop therapeutic paradigms that better balance these competing risks,” Dr. Leiva said.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Leiva O, Xia Y, Siddiqui E, et al. Outcomes of patients with myeloproliferative neoplasms admitted with myocardial infarction: insights from National Inpatient Sample. JACC CardioOncol. 2023;5(4):457-468.

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GSK and Queer Eye’s Thom Filicia Partner on Blood Cancer Awareness Initiative

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• GSK launches Mapping Myelofibrosis to help chart course for those affected by the disease.
• Myelofibrosis is a complex blood cancer that impacts nearly 25,000 people in the U.S.

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Issued: Philadelphia, PA

GSK plc (LSE/NYSE: GSK) has partnered with former Queer Eye star and interior designer Thom Filicia to launch Mapping Myelofibrosis, a new health education initiative aiming to help those impacted by myelofibrosis (MF) better navigate the disease. This year marks the 10-year anniversary of Filicia donating bone marrow to his brother, who was diagnosed with MF a few months prior to the transplant. Filicia now looks to use his voice to help raise awareness of this blood cancer, which can be difficult to diagnose and manage.1

MF impacts nearly 25,000 people in the U.S. and is part of a larger group of blood cancers that affect the bone marrow, called myeloproliferative neoplasms (MPNs).2,3 Each person experiences MF differently, presenting significant challenges in identifying symptoms and mapping out treatment paths.1

“After my brother’s diagnosis, we didn’t understand the magnitude of what he was up against,” said Filicia. “The reality of MF presents unique challenges for each individual, and as my brother overcame this disease, I realized the need to ensure more accessible information and resources. This experience led me to team up with GSK on Mapping Myelofibrosis to continue raising awareness of this complex blood cancer.”

Mapping Myelofibrosis includes the launch of a website featuring educational resources about MF, community stories, and messages from Filicia. In developing the initiative, GSK sought input from the MF community through collaborations with organizations including the MPN Research Foundation (MPNRF) and MPN Advocacy & Education International (MPN A&E).

Faris El Refaie, Head of Oncology, US of GSK said: “At GSK, we are committed to advancing the standard of care in oncology and supporting communities impacted by hematologic cancers. Recognizing an unmet need in myelofibrosis, we developed Mapping Myelofibrosis to cultivate awareness and provide a platform to foster support and education.”

Kapila Viges, CEO of MPN Research Foundation said: “This initiative by GSK represents a meaningful step forward in ensuring those living with MF and their families have access to tailored resources to help guide them through the complexities of this disease. Hearing Filicia tell his story reinforces the importance of enhancing our understanding of MF, and all MPNs.”

Ann Brazeau, CEO and Founder of MPN A&E said: “Ensuring that patients with MF and their loved ones feel seen and heard while navigating a rare disease is so important. Educational resources like GSK’s Mapping Myelofibrosis initiative are critical for patients and their families when it comes to making informed decisions around their care.”

In early stages, approximately one third of individuals with MF will not exhibit symptoms.1 However, key signs and symptoms of the disease may include, but are not limited to low blood counts (anemia), low platelet counts (thrombocytopenia) or enlarged spleen (splenomegaly).1 For those who have not been diagnosed, early detection of the disease may be beneficial. For those who have been diagnosed, understanding your symptoms is key to making informed decisions regarding treatment and care with your healthcare providers.1

Explore MappingMF.com to find resources and learn more.

About Mapping Myelofibrosis
GSK created Mapping Myelofibrosis to increase awareness of myelofibrosis, seeking to connect the community with educational tools, resources and stories to help navigate all aspects of the disease.

Explore MappingMF.com to find resources and learn more about myelofibrosis. You can also follow the initiative on Facebook.

About myelofibrosis (MF)
Myelofibrosis is a complex blood cancer affecting approximately 25,000 people in the U.S.2 MF is part of a larger group of blood cancers that affect the blood and bone marrow, known as myeloproliferative neoplasms, or MPNs.3 In people with MF, blood cells may not be produced in a typical way, causing inflammation and scarring of the bone marrow, which is called fibrosis.3 The signs and symptoms of MF may include severe low blood counts or anemia, enlarged spleen (splenomegaly), low blood platelets (thrombocytopenia), and other symptoms.1

GSK in oncology
GSK is focused on maximizing patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, tumor cell targeting therapies and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilizing modalities such as small molecules, antibodies and antibody-drug conjugates, either alone or in combination.

About GSK
GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com.

References:
1. Cleveland Clinic. Myelofibrosis. Available at: https://my.clevelandclinic.org/health/diseases/15672-myelofibrosis. Accessed October 2023
2. Data on file. Sierra Oncology. 2021.
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