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

Posted on by

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.

Read more

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

Posted on by

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.

Read more

Defining and Treating Classic Cases of Myeloproliferative Neoplasms

Posted on by

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

Read more

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

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

Abstract

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

Introduction

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

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

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

Read more

Novel Prognostic Scoring System May Help in Patient Stratification in Myelofibrosis

Posted on by

November 22, 2023

By Johnathan Goodman

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

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

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

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

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

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

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

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

Reference

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

Read more

Diagnosis and Management of Cardiovascular Risk in Patients with Polycythemia Vera

Posted on by

November 22, 2023

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

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

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

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

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

Read more

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

Posted on by

November 21, 2023

By Jordyn  Sava

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Read more

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

Posted on by

November 21, 2023

By Ryan Scott

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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

Read more

NCCN Guidelines Update Adds Momelotinib for High-, Low-Risk Myelofibrosis

Posted on by

November 21, 2023

By Pearl Steinzor

Momelotinib has been added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the treatment of patients with high- and low-risk myelofibrosis (MF) and myelofibrosis with anemia.

MF is part of a group of heterogeneous disorders of the hematopoietic system collectively knowns as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). MPNs are considered a rare disease, with the prevalence of MF in the United States estimated to be approximately 13,000, respectively.

Furthermore, MPNs are associated with symptom burdens that result in worse quality of life, functional status, and activities of daily living. Patients with MF are more likely to report symptoms such as fever, night sweats, and weight loss compared with patients with polycythemia vera (PV) or essential thrombocythemia (ET).

Momelotinib is an oral Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with a recommended dosage of 200 mg orally once daily with or without food. Special considerations for the use of momelotinib also includes risk of major adverse cardiovascular events, thrombosis, and development of malignancies, especially in patients who currently smoke or previously smoked.

The treatment approach for MF is currently identical for primary MF (PMF), post-PV MF, or post-ET MF.

Treatment for lower-risk MF includes momelotinib as a category 2B drug in symptomatic patients. Symptomatic patients may be treated with category 2A drugs, including ruxolitinib, peginterferon alfa-2a, or hydroxyurea, or category 2B momelotinib.

The treatment pathway requires monitoring the response and signs/symptoms of disease progression every 3 to 6 months. For those who respond to the treatment, the guidelines recommend continuing treatment and monitoring. For those with no response or loss of response, the guidelines recommend an alternative option not used for initial treatment, such as momelotinib. The guidelines recommend that patients with disease progression are moved to a higher-risk and accelerated/blast phase MF status.

In patients with high-risk MF, momelotinib was given category 2A status for those with higher platelets (≥50 x 109/L) who were not a transplant candidate; other drugs include ruxolitinib (category 1), fedratinib (category 1), or pacritinib (category 2B). Similarly, the guidelines recommend monitoring patients every 3 to 6 months, continuing treatment for those with a response, recommending a clinical trial or alternative JAK inhibitor not used before for those with no response or loss of response, and accelerated/blast phase MF status for those with disease progression.

For the management of MF-associated anemia, the guideline recommends ruling out coexisting causes, such as bleeding; iron, vitamin B12, or folate deficiency; and hemolysis. After treating coexisting causes, preferred regimens in patients with higher serum erythropoietin (≤500 mU/mL) include clinical trials or momelotinib. Other drugs that may be useful in certain circumstances include danazol, lenalidomide with or without prednisone, thalidomide with or without prednisone, or luspatercept (category 3). Those with a response are recommended to continue treatment, and those with no response or loss of response are recommended to select a treatment other than the one they initially began.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2023. Accessed November 21, 2023. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf\

Read more

JAK2 Inhibition’s Role in Newly Diagnosed Myelofibrosis

Posted on by

November 20, 2023

Targeted Oncology Staff

At a live virtual event, Jeanne Palmer, MD, provided commentary on the development of myeloproliferative neoplasms in patients, particularly those with newly diagnosed aggressive myelofibrosis. She highlighted the importance of the Janus kinase (JAK)-STAT pathways and how mutations in genes such as JAK2 can change a prognosis and a physician’s approach to treatment. Furthermore, she discussed the data behind the use of JAK inhibitors in this patient population and how they benefit patients in multiple ways but present a challenge in certain subsets of patients.

DEVELOPMENT AND INHIBITION TARGETS OF MYELOPROLIFERATIVE NEOPLASMS

The pathogenesis of the myeloproliferative neoplasms [MPNs], particularly the ones that are BCR-ABL1 negative, [occurs] primarily through the JAK-STAT pathway.1 This is where we find what we call the driver mutations, which are the mutations that are critical in making the disease progress. There are 3 different mutations that we more commonly see, with the first being JAK2 V617F.2 So JAK1 and JAK2…are right below the cell membrane, [and with this mutation], JAK2 is the one that is mutated, and when it is mutated, it keeps the 2 receptors it’s attached to on, which keeps it constitutively activated. Therefore, it goes on and continues to signal throughout the cell to make the cell grow disproportionally to what it should be.

In polycythemia vera [PV], most mutations are JAK2 V617F; however, there is a small percentage [of mutations in patients with PV] that are JAK2 exon 12, which is a mutation in another part of the JAK2 gene.2 The [other 2] driver mutations, which are less common, are MPL and calreticulin.1

The MPL mutation is in the thrombo-poietin receptor…and the CALR mutation is in calreticulin, and what happens is the calreticulin sits outside of the cell membrane.1 The CALR mutation is interesting because it is extracellular. There are currently different therapeutics that target that because it is outside of the cell. The calreticulin is divided into type 1 or type 2. The type 1 is associated with a good prognosis, [whereas] type 2 isn’t necessarily [tied to a good prognosis].2

There are many factors that influence the production of MPNs, and this is an area of a lot of research, but there are a couple of [factors] that are prominent. First, the JAK2 mutant clone provides a survival advantage, and any of the mutations that are present in these myeloproliferative cells make them grow a lot.3 They’re extremely tough, they’re difficult to kill, and they try to predominate. There’s also evidence that some of the inflammation can drive these so that you have the cells that create inflammation because of the mutations and then that further drives for the replication and reproduction of the cells.3

There are also higher incidences of prior autoimmune conditions in patients with MPNs, and there’s a genetic predisposition to some of the MPNs as well as to the JAK2 mutation. Disruption of the JAK-STAT pathway can also affect NF-κB signaling, and there’s defective negative feedback regulation, hence what I talked about before about the signal being constitutively on.3

PATHWAYS INVOLVED IN MYELOFIBROSIS

One of the things that we’re learning with myelofibrosis is that there are a number of different pathways involved. We all know about the JAK-STAT pathway, but there are a couple of other pathways that we think are probably important and help us differentiate the [use] of different JAK inhibitors. One of them is IRAK1 and the other one is ACVR1.4 IRAK1 primarily involves a lot of the inflammatory cytokines…whereas ACVR1 [affects] the hepcidin pathway. We all remember hepcidin…from medical school when we learned about that iron metabolism pathway that you thought you’d never have to learn again. Well, hepcidin has made a resurgence not only in anemia of chronic disease but also in myelofibrosis and PV. However, one of the problems in myelofibrosis is that patients’ hepcidin [levels] can be too high, so if you can suppress it, they may benefit [from that kind of treatment]. The ACVR1 pathway reduces hepcidin transcription, which is thought to help anemia…and [researchers] found that this also appears to be a target of pacritinib [Vonjo].4

PERSIST-2 FINDINGS DEMONSTRATE PACRITINIB’S ROLE IN TREATMENT

[The baseline characteristics of the PERSIST-2 (NCT02055781) study] showed that there were fairly equivalent patient populations [between the study arms].5 One thing to note about the baseline demographics…is that in the control arm, almost half the patients had ruxolitinib [Jakafi] as their best available therapy and were allowed to continue it at the dosing level appropriate [for them]… depending on their platelet level. Again, [for those with] 50 × 109/L to less than 100 × 109/L platelet count, the dose recommended was 5 mg twice a day, which is what most patients were on [in the control arm].5

When we look at the spleen volume reduction rate in PERSIST-2 [findings]…it is a 35% decrease, and this spleen volume reduction is not as impressive in this [study]. The [spleen volume reduction] percentage is less [with] pacritinib as we would see [with] ruxolitinib.5 I also want to point out that these patients [in this study] have lower platelet [count], have a lower JAK2 allele burden, and maybe are less likely to respond well to JAK inhibitors. However, it is important to note that in PERSIST-2 [findings], the spleen volume reduction was greater in the patients who received treatment compared with those who did not.5

People have looked at JAK2 burden and response to JAK inhibitors, but they were more compiled data rather than split. You need a lot more patients to be able to note that difference. I would not use JAK2 allele burden as a decision point of whether to give somebody a JAK inhibitor or not. But there are some circumstantial data that [suggest] if somebody has a higher JAK2 allele burden then they’re more likely to respond to treatment.6

But that’s more likely because [the patient] probably has a proliferative variant, they have the hyperproliferative disease rather than cytopenic disease, and those patients tend to be more likely to respond to therapy because you can dose them adequately because their counts are high enough.

When using pacritinib, it’s important to remember that we don’t expect to see platelet [count] improvement, but sometimes we [see it] because the spleen shrinks, and when the spleen shrinks, you have less sequestration. But in general, I’ve seen platelet [count] go down a lot, so it’s very important not to give this drug [while] thinking, “Oh, my patients’ platelet [levels] are going to go up.” And then [you see the platelet levels go down and think] the drugs [are] not working, because what you hope for is that this will flatline.

When we look at the hematologic response [to pacritinib in the PERSIST-2 study findings], you do see that change in platelet count.5 Although 400 mg daily is not the prescribing dose, [their platelet counts went up]. Although those 400-mg data are not included in a lot of analyses because the dosing that’s found to be the best is 200 mg twice a day, you’ll see that the platelet [count] for those who were on 200 mg of pacritinib twice a day is flat. I don’t have a good explanation why the platelet [count] went up in the 400-mg once-a-day [group], because the responses weren’t that great, so [it] wasn’t the dose that was chosen to move forward. In terms of the red blood cell transfusions over time, they went down in patients, so the lower the red blood cell transfusion, the better it is in patients who are on 200 mg of pacritinib twice a day.5

When you look at patients with low platelet [count], the impressive thing about pacritinib is that you can maximize the dose and maximize the spleen volume reduction. If you took patients [with low platelet count] who got ruxolitinib at 5 mg twice a day, about 10% of them will have a spleen volume reduction of greater than 35%, so this is an extremely low rate of spleen volume reduction.5 One of the things that’s important to remember about this is pacritinib allows maximal JAK inhibition for patients with low platelet [count]. If you have somebody with normal platelet [count] and give them pacritinib, you’re not going to see the same benefit as you would with ruxolitinib, but a big part of that is [due to] the limitations with the cytopenias. For patients who have thrombocytopenia, pacritinib provides a significant advantage because you can maximize the dose.

TOXICITIES TO CONSIDER WITH JAK INHIBITION

[In the PERSIST-2 trial findings], all the adverse events [AEs] were expected, but I want to point out diarrhea is a major AE with pacritinib [Figure5]. Whenever using pacritinib, it’s extremely important to give [the patient] antidiarrhea and antinausea [medicine] when you start this medication. The majority of patients will have diarrhea, and it can be a significant AE.5

[Researchers in this study also looked at]…viral infections [and saw that] zoster can be activated in these patients through fungal infection.7 That’s something of interest to me, especially because I live in Arizona, where we have a lot of valley fever, which is a fungal infection.

What they had found…was that [in] these infections, especially if you look at pacritinib vs best available therapy or when best available therapy is ruxolitinib, we don’t see as [many cases], and in…[other] secondary [malignant tumors], it was even [fewer with] pacritinib compared with best available therapy with ruxolitinib.7

Frankly, there’s a lot of focus on these numbers that…when you look at the absolute numbers of these events, [they] are extremely low, but this is one area that they are trying to highlight where there is less of an infection risk [with pacritinib].7

References

1. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390. doi:10.1056/NEJMoa1311347

2. 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

3. Mendez Luque LF, Blackmon AL, Ramanathan G, Fleischman AG. Key role of inflammation in myeloproliferative neoplasms: instigator of disease initiation, progression. and symptoms. Curr Hematol Malig Rep. 2019;14(3):145-153. doi:10.1007/s11899-019-00508-w

4. Chifotides HT, Verstovsek S, Bose P. Association of myelofibrosis phenotypes with clinical manifestations, molecular profiles, and treatments. Cancers (Basel). 2023;15(13):3331. doi:10.3390/cancers15133331

5. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

6. Vannucchi A, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2(1):21-32. doi:10.1177/2040620710394474

7. Pemmaraju N, Harrison C, Gupta V, et al. Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis. EJHaem. 2022;3(4):1346-1351. doi:10.1002/jha2.591

Read more