New Developments in MPN Management Provide Additional Options for Patients

Posted on December 13, 2023December 13, 2023 by mpn_admin

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

McMullin MF, Anderson LA. Aetiology of myeloproliferative neoplasms. Cancers (Basel). 2020;12(7):1810. doi:10.3390/cancers12071810
FDA approves ruxolitinib. News release. FDA. Updated February 22, 2016. Accessed October 18, 2023. bit.ly/3PVXObQ
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
Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus best available 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
FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed October 18, 2023. bit.ly/3rXAt1u
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
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
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
FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed October 18, 2023. bit.ly/3s30OuX
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
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
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
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
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

Ruxolitinib Treatment Outperforms Best Available Therapy in Pooled Analysis

Posted on December 13, 2023December 13, 2023 by mpn_admin

By Patrick Daly

December 6, 2023

Patients with polycythemia vera (PV) who received ruxolitinib treatment achieved sustained hematocrit control over 80 weeks and had improved symptom control at week 16 compared with patients who received best available therapy (BAT), based on a post hoc pooled analysis of data from the RESPONSE and RESPONSE 2 trials.

The efficacy data were presented at the 65^th American Society of Hematology Annual Meeting & Exposition in San Diego, California, by lead author, Claire Harrison, MD, of the Guy’s and St. Thomas’ NHS Foundation Trust in London, United Kingdom.

“Reductions in JAK2V617F allele burden were consistently observed through Week 208 in patients treated with ruxolitinib, including those who crossed over from BAT,” Dr. Harrison and colleagues reported.

The analysis assessed 371 pooled patients from RESPONSE and RESPONSE 2, of which 184 were treated with ruxolitinib and 187 with BAT. The cohort had a median age of 61.8 ± 11 years and most patients were White (88.1%) and male (62.5%). Hematocrit control was defined as hematocrit maintained below 45% starting week 16 plus one or less phlebotomy between baseline and week four.

At week 28, the proportion of patients with hematocrit control was 62.0% (95% CI, 54.5-69.0) in the ruxolitinib group versus 18.2% (95% CI, 12.9-24.5) in the BAT group. Further, 47.3% (95% CI, 39.9-54.8) of patients in the ruxolitinib group had sustained hematocrit control through week 80; authors noted nearly all patients in the BAT group had crossed over to the ruxolitinib group by that point.

The proportion of patients who achieved a 50% or greater reduction from baseline in Myeloproliferative Neoplasms Symptoms Assessment Form Total Symptom Score at week 16 was 48.7% (95% CI, 40.7-56.8) in the ruxolitinib group compared with 18.0% (95% CI, 12.5-24.6) in the BAT group (odds ratio, 4.3; 95% CI, 2.6-7.2), and the mean change in score was -4.4 ± 10.0 and 0.6 ± 6.9, respectively.

Additionally, patients randomized to ruxolitinib had consistently decreased JAK2V617F allele burden through week 208, and mean JAK2V617F allele burden decreased from 66.1% to 41.4% at four years.

“Taken together, these results provide further evidence of the patient benefit of ruxolitinib in patients with PV with or without splenomegaly,” Dr. Harrison and colleagues concluded.

Reference

Harrison C, Kiladjian JJ, Palandri F, et al. Ruxolitinib treatment in polycythemia vera results in reduction in JAK2 allele burden in addition to improvement in hematocrit control and symptom burden. Abstract #4553. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

Blood Cancer: AOP Health Announces New Findings in Patients With Polycythemia Vera to Be Presented at the American Society of Hematology (ASH) 65th Annual Meeting

Posted on December 13, 2023December 13, 2023 by mpn_admin

December 7, 2023

SAN DIEGO–(BUSINESS WIRE)–AOP Orphan Pharmaceuticals GmbH (AOP Health), Vienna, Austria, announced the results of an analysis assessing the impact of an individually optimized dosing regimen of ropeginterferon alfa-2b on treatment response in patients with low-risk polycythaemia vera (PV)¹ These new data show that some low-risk PV patients require and can tolerate high ropeginterferon alfa-2b doses, and that the optimal dose varies substantially between patients.

“The results of this analysis expand the depth of data and add the clinically relevant and important evidence which can support health care professionals in their treatment decisions”

The first author of the abstract, Professor Heinz Gisslinger from the Medical University of Vienna/Austria, and his research team conducted the present analysis in the cohort of low-risk PV patients from the large trial PROUD-PV and its extension CONTINUATION-PV. The goal was to examine the impact of various baseline characteristics such as body mass index as well as individually optimized dose levels of ropeginterferon alfa-2b on complete hematologic response (CHR), the state when blood cell counts have returned to normal, at 12, 24, and 72 months.¹

“The results of this analysis expand the depth of data and add the clinically relevant and important evidence which can support health care professionals in their treatment decisions”, Gisslinger concludes.

¹Gisslinger H et al. Individualized dosing of ropeginterferon alfa-2b ensures optimal response in patients with low-risk polycythemia vera (PV). ASH 2023, Abstract #4563 (https://ash.confex.com/ash/2023/webprogram/Paper173499.html)

About Polycythaemia Vera
Polycythaemia Vera (PV) is a rare cancer of the blood-building stem cells in the bone marrow resulting in a chronic increase of red blood cells, white blood cells and platelets. This condition increases the risk for circulatory disorders such as thrombosis and embolism, its symptoms lead to a reduced quality of life and on the long run may progress to myelofibrosis or transform to leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to blood-building stem cells in the bone marrow with a set of acquired mutations, the most important being a mutant form of JAK2 that make up the malignant clone.

Important PV treatment goals are to achieve healthy blood counts (hematocrit below 45%), improve quality of life and to slow or delay the progression of disease.

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

Posted on December 4, 2023December 4, 2023 by mpn_admin

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.

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

Posted on December 4, 2023December 4, 2023 by mpn_admin

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.

Long-Acting Interferon: Pioneering Disease Modification of Myeloproliferative Neoplasms

Posted on November 13, 2023November 13, 2023 by mpn_admin

Seug Yun Yoon, Sung-Yong Kim

Abstract

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

Validation of myeloproliferative neoplasms associated risk factor RDW as predictor of thromboembolic complications in healthy individuals: analysis on 6849 participants of the SHIP-study

Posted on June 27, 2023June 27, 2023 by mpn_admin

June 23, 2023

Kirsi Manz, Jeanette Bahr, Till Ittermann, Konstanze Döhner, Steffen Koschmieder, Tim H. Brümmendorf, Martin Griesshammer, Matthias Nauck, Henry Völzke & Florian H. Heidel

Chronic myeloproliferative neoplasms (MPN) are characterized by hyperproliferation of myeloid cells leading to erythrocytosis, thrombocytosis, leukocytosis and splenomegaly. Thromboembolic events (TE) are among the most prevalent complications in patients with different subtypes of MPN such as polycythemia vera (PV) [1, 2], with arterial and venous thromboses being among the major causes of morbidity and mortality. Pathophysiologic mechanisms that contribute to TE complications, besides increased cell counts, include functional alterations of leucocytes, red blood cells, platelets and endothelial cells [3]. The rate of thromboembolic complications in MPN patients ranges from 1.1 to 4.4% per year, while this rate is significantly lower in the normal population (0.6 and 0.9% per year in the absence or presence of cardiovascular risk factors, respectively) [4, 5]. Therefore, prediction of occurrence of thromboembolic events for risk estimation is of great importance. While the risk of these patients to experience thromboembolic complications is clearly high, prognostic parameters beyond age and past history of thrombosis are currently lacking. This leads to challenges in clinical decision making regarding the indication of cytoreductive drugs and the prophylaxis and use of anticoagulants. Therefore, in our previous work, we used a machine learning algorithm to identify risk factors for this high-risk population of patients with PV for clinical use that can predict thromboembolic events [6]. Using the publicly available OPTUM database that consists of patient data provided by US insurance companies, we could define red cell distribution width (RDW), lymphocyte and platelet counts as independent prognostic parameters for thromboembolic events: Lymphocyte ratio (LYP) and RDW predicted the risk of occurrence of TEs of patients without a history of TEs within the next 12 months. In addition, predictive factors for patients with a history of TE complications included lymphocyte ratio and platelet count. Recently, neutrophil-lymphocyte ratio (NLR) was confirmed as predictive risk factor for venous thrombosis in an independent retrospective cohort of PV patients [7]. While these analyses require prospective validation in clinical trials, the predictive value of these parameters in a normal control population without myeloproliferation or hematopoietic cancers remains to be investigated.

In order to validate these findings in a control cohort of non-MPN patients, we retrieved data of the SHIP study conducted at Greifswald University Medicine. The Study of Health in Pomerania (SHIP) is a population-based epidemiological study consisting of currently 5 independent cohorts [8]. The SHIP investigates common risk factors, subclinical disorders and manifest diseases with highly innovative non-invasive methods in the population of northeast Germany. As this study is not focused on one specific disease it aims to investigate health in all aspects and complexity involving the collection and assessment of data relevant to the prevalence and incidence of common, population-relevant diseases and their risk factors.

We utilized data from different independent cohorts of the SHIP study: the baseline examination of SHIP-START (SHIP-START-0) between 1997 and 2001 (n = 4308), and the baseline examination of SHIP-TREND (SHIP-TREND-0) between 2008 and 2011 (n = 4420). After excluding missing datapoints, a total of 2491 datasets (derived from individual participants) from the SHIP-START-0 and 4358 from the SHIP-TREND-0 were included in the analyses. Data on all probands with baseline data on RDW, lymphocyte percentage, platelet count, body mass index (BMI), prior TE, neutrophil percentage, leukocytes and hematocrit was used for the study. Also, all documented medication was recorded and included for analysis. Of note, SHIP-START-0 data does not include differential blood counts, including lymphocyte and neutrophil percentage. Occurrence of TE in SHIP-START was defined as thrombosis, stroke or myocardial infarction or use of an antithrombotic agent while SHIP-TREND also included evidence of thrombophlebitis. Antithrombotic agents were defined as agents belonging to the Anatomical Therapeutic Chemical (ATC) classification system section B01 “antithrombotic agents”. This section includes oral anticoagulants such as vitamin K antagonists, platelet inhibitors (ASA and P2Y-antagonists) and direct oral anticoagulants (DOACs) among others. Single use of antithrombotic agents e.g. for in-flight prophylaxis was not considered. Cardiovascular risk factors included were elevated blood lipids, hypertension, diabetes mellitus, current smoking, BMI, and subjects’ age. Subjects with missing diabetes mellitus status and HbA1c > = 6.5% were counted as diabetic. In the absence of elevated blood lipid status, subjects with cholesterol > = 6 mmol/l and/or triglyceride > 1.9 mmol/l were assigned to elevated blood lipids. Descriptive statistics are provided as median and minimum – maximum, or as frequency and percentage, as appropriate. The non-parametric Mann Whitney U test was used to assess differences of continuous variables between two groups. Categorical variables were compared using the Fisher’s exact test. First, all candidate variables were adjusted for age and sex. Then, all significant age- and sex-adjusted variables were included in the backward variable selection procedure. Variable selection was performed 1000 times using bootstrapping methods. To report the most relevant variables, the final model consists of those selected in at least 80% of the bootstrapping runs. In both cohorts, 70% of the data were used to build and 30% were used to validate the model. To assess the predictive value of both models, accuracy and receiver operating characteristic (ROC) curve were calculated. Statistical significance was claimed at 5% (p < 0.05) and no correction for multiple testing was performed. The data was prepared using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and analyzed using R Version 4.2.2 [9].

Regarding baseline characteristics, TE events had occurred in 321 (12.9%) of the 2491 individuals of the SHIP-START cohort while the prevalence of TE events was 21.4% (932 events in 4358 individuals) in the SHIP-TREND cohort. Overall, established risk factors for TE such as male sex, higher age, higher body-mass-index (BMI), arterial hypertension, hypercholesterolemia, and diabetes mellitus were associated with significantly higher rate of TE events (Table 1). Of note, TE events were more frequently reported in non-smokers compared to smokers in both cohorts. In regard to laboratory parameters, higher RDW and lower platelet counts showed significant association with TE complications. In contrast, higher leukocyte counts, lower hematocrit and lower lymphocyte ratio showed exclusively significance in the SHIP-TREND cohort analysis.

Table 1 Baseline characteristics of both cohorts.

To assess for effects of the above risk factors on TE events, we used multivariable logistic regression models. When investigating the SHIP-START cohort of 2491 individuals, male sex (p < 0.0001), presence of hypertension (p = 0.0042), hypercholesterolemia (p < 0.0001) or diabetes mellitus (p = 0.0008), and higher age (p < 0.0001) were validated as TE risk factors. Regarding laboratory parameters, higher RDW (p = 0.0006) was the only predictor for TE complications.

Analysis of the SHIP-TREND cohort of 4358 individuals confirmed independent predictive value of higher age (p < 0.0001) and hypercholesterolemia (p < 0.0001) while elevated body mass index (BMI; p = 0.0003) scored as an additional predictive factor due to availability of the respective data points in this cohort. In contrast, male sex and hypertension were not confirmed as independent risk factors. Consistent with the SHIP-START cohort, higher RDW (p < 0.0001) was identified as predictive for TE events, along with lower platelet counts (p < 0.0028). Taken together, alterations of laboratory parameters such as red cell distribution width and platelet count at study entry were associated with occurrence of thromboembolic events in this retrospective assessment of individuals without evidence for hematologic malignancies.

When adjusting for age and sex (Fig. 1A, B), BMI, hypercholesterolemia, hypertension, diabetes mellitus and RDW consistently showed elevated odds ratios in both cohorts, using the basic model. Assessment for TE risk factors in the final model confirmed age, hypercholesterolemia and RDW as predictors of thromboembolic events in both cohorts. Here, RDW showed an OR of 1.28 (95% CI: 1.11–1.47) for SHIP-START and 1.25 (95% CI 1.12–1.38) for SHIP TREND (Fig. 1C, D). Of note, the SHIP-TREND model could also be validated using SHIP-START data. In order to select an optimal model, receiver operating characteristic (ROC) analysis was performed showing an AUC of 0.846 (95% CI: 0.805–0.886) for SHIP-START and an AUC of 0.847 (95% CI: 0.827–0.866) for SHIP-TREND (Fig. 1E, F). Accuracy of the SHIP-START model was 89.2% and of the SHIP-Trend model 86.8%.

**Fig. 1: Effects of risk factors on TE events.**

Red cell distribution width is a marker for the variation of erythrocyte size (anisocytosis) and used in combination with other laboratory markers for differential diagnosis of hematological diseases such as anemia and bone marrow dysfunction. Changes in RDW have been reported for a variety of chronic inflammatory conditions such as diabetes, cardiovascular disease, infections and cancer and its predictive and prognostic value has been reported for cardiovascular disease as well as for overall mortality of the general population [10]. Likewise, differential blood counts have been described as biomarkers of inflammatory processes and cancers. Identification of RDW, platelet counts and lymphocyte ratio as biomarkers for thromboembolic events in PV patients is therefore not surprising, as JAK2-mutated cancers are associated with broad activation of cell signaling [11] and increase of pro-inflammatory cytokines [3, 12]. Recently, exome-analysis studies have shown age-related clonal hematopoiesis (CH) in healthy individuals, driven by mutations of genes recurrently mutated in myeloid neoplasms and associated with an increased risk of hematologic cancer and cardiovascular disease. Critically, both SHIP-cohorts reported in this analysis have not been investigated for the presence of clonal hematopoiesis. Therefore, we cannot exclude the influence of CH on the predictive value of RDW and occurrence of TE events. Moreover, cutoffs for RDW may vary and have not been generally defined in previous analyses. Critical limit values of these potential biomarkers may depend on the underlying condition, comorbidities (e.g. previous TE complications) or concomitant medication. Finally, in SHIP-TREND, we used a broad definition of TE events (including peripheral thrombosis and thrombophlebitis) and predictive biomarker values may vary with a definition restricted to deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke. Of note, the allocation of individuals into the “TE-event” cohort based on the use of anticoagulants may result in inclusion of individual participants using ASA and P2Y-antagonists as primary rather than secondary prophylaxis.

Taken together, we could confirm RDW as an independent predictive parameter for thromboembolic events in the general population. Development and prospective validation of predictive scoring systems combining predictive laboratory parameters are clearly warranted but are beyond the scope of this report.

Fedratinib and Ruxolitinib: Advice for Deciding Which Agent to Give and When

Posted on October 16, 2019October 16, 2019 by mpn_admin

The introduction of fedratinib (Inrebic) to the treatment landscape of myelofibrosis (MF) and the challenges that have arisen over deciding between administering fedratinib or ruxolitinib (Jakafi) means more community oncologists should consult specialists when treating these patients, said Andrew Kuykendall, MD.

Research shows that fedratinib and the earlier JAK inhibitor, ruxolitinib have similar efficacy in patients with MF. However, their toxicity profiles differ, and the potential for encephalopathy with fedratinib is an ongoing concern, resulting in a black box warning on the label. Now that the agent is FDA approved for the treatment of MF, oncologists are left with a decision of which JAK inhibitor to give to which patients and when to prescribe them.

How to continue using ruxolitinib now that fedratinib is available remains an unanswered question, said Kuykendall, assistant member, Moffitt Cancer Center; however, experts in treating myeloproliferative neoplasms (MPNs) can be a helpful resource for other oncologists.

Another resource for treatment decision-making is clinical data from the JAKARTA-2 trial, which studied fedratinib in patients with MF who were previously treated with ruxolitinib. Findings from a re-analysis of the study were presented at the 2019 ASCO Annual Meeting and showed that 46 of the 83 assessable patients achieved a spleen response (55%; 95% CI, 44%-66%), meeting the primary endpoint of the study.

The most common adverse events included diarrhea (n = 60), nausea (n = 54), vomiting (n = 40), constipation (n = 20), and others. Additionally, hematologic abnormalities including, grade 3/4 anemia (n = 96), thrombocytopenia (n = 68), and neutropenia (n = 23) were seen. Eighteen patients (19%) discontinued treatment due to adverse events.

These data suggest that fedratinib may be a second-line option for patients who are resistant or sensitive to ruxolitinib. The management of the gastrointestinal (GI)-related toxicities and checking of thymine levels to prevent encephalopathy, however, are newer management concerns that physicians must be aware of when administering fedratinib to patients with MF and is another point when consulting an MPN specialist may come in handy.

Read Targeted Oncology’s interview with Dr. Kuykendall.