Underreporting of Patient-Reported Outcomes Seen in Blood Cancer Trials

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Caleb Rans, PharmD

The incorporation of patient-reported outcomes (PROs) in clinical trials provides a means for researchers to measure health-related quality of life (HRQOL) and patient-specific outcomes. When evaluating subjective symptoms, for example, patients are usually the most reliable source of feedback. Consequently, PROs are seen as the gold standard for assessing subjective symptoms.1

According to the authors, PROs are not often collected or reported in solid tumor trials, but less is known about RCTs focusing on blood cancers.2

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Donor Type Impacts Survival in MF Cell Transplantation

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Leonardo Jaimes

Patients with myelofibrosis (MF) who receive hematopoietic cell transplantation (HCT) from a matched sibling donor appear to have better overall survival (OS) than those who receive transplants from other donor types, according to a recently published study in Blood Advances.

“Understanding the impact of donor type is crucial not only to improve the clinical outcomes with HCT but also to establish the donor pool with viable options and eventually improve access to HCT,” the authors wrote.

HCT is currently the only disease-modifying therapy available for MF, the study team noted. The outcome after transplantation is diverse and dependent on several disease- and patient-associated factors, they added. According to recent research, donor type could also influence the prognosis of patients with MF after HCT. One study showed that patients with matched sibling donors had a better OS than the rest.

However, previous research has not taken the impact of posttransplantation cyclophosphamide for graft versus host disease prophylaxis into consideration, the researchers noted. Furthermore, no patients in previous studies had received vHLA-haploidentical donor grafts, they continued.

Therefore, the authors aimed to assess the impact of donor type in OS, considering the factors above and using the Center for International Blood and Bone Marrow Transplant Research registry data for HCTs done between 2013 and 2019. The study included over 1000 patients who received HCTs for MF.

Results showed that similarly to previous findings, matched sibling transplants were associated with better overall survival and lower graft failure than the rest. However, OS was only superior to the rest in the first 90 days after transplant. There was no significant difference in OS among patients who received mismatched unrelated, matched unrelated, and haploidentical donor transplants.

Despite the findings, the authors remarked that HCTs should not be delayed in the search for fully matched donors and highlighted the need for solutions regarding graft failure.

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Prospective Study to Evaluate Fedratinib Plus Nivolumab in Myelofibrosis

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Andrea S. Blevins Primeau, PhD, MBA

A single-arm, phase 2 study of fedratinib, a selective JAK2 inhibitor, plus nivolumab is planned for patients with myelofibrosis (MF) who had a suboptimal or no response to a JAK inhibitor was initiated, according to a report published in the Annals of Hematology.

“This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives,” the researchers wrote in their report. Currently, 23 of 30 planned patients are enrolled in the study and recruitment is expected to be completed by December 2024.

The open-label FRACTION trial will treat patients with MF from 9 academic centers in Germany, who will receive 400 mg of fedratinib daily in 28-day cycles, followed by 240 mg of nivolumab every 2 weeks beginning in cycle 2. Treatment will be given until progressive disease, relapse, death, or study discontinuation.

This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The primary efficacy endpoints will be response rate within 12 treatment cycles and RCT independency. Secondary endpoints will include safety, incidence of leukemic transformation, clinical benefit, duration of response, progression-free survival, overall survival, and disease burden. Molecular analyses will also serve as exploratory endpoints for the study.

Patients with MF primary or secondary MF are eligible if they had a suboptimal or no response to a JAK inhibitor, which is defined by persistent symptoms, splenomegaly, cytopenia, or hyperproliferation. Patients who have received a prior immune checkpoint inhibitor or history of uncontrolled autoimmune disease are not eligible for the study.

Disclosures: This research was supported in part by Celgene/Bristol Myers Squibb. Please see the original reference for a full list of disclosures.

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MPN Word of the Month: Hematocrit

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Hematocrit is a key measurement in hematology that represents the proportion of blood volume occupied by red blood cells (RBCs). Expressed as a percentage, it provides crucial insights into an individual’s red blood cell mass and overall blood health. Typically, hematocrit levels are assessed through a routine blood test, often as part of a complete blood count (CBC).

In the context of myeloproliferative neoplasms (MPNs)—hematocrit plays a significant role in diagnosis and management. Polycythemia vera, essential thrombocythemia, and myelofibrosis each affect blood cell production but in different ways.

  1. Polycythemia Vera (PV): One of the indicators of PV is an elevated hematocrit level. In PV, the bone marrow produces an excess of red blood cells, leading to a high hematocrit. This can increase how thick the blood is (viscosity), potentially causing complications such as blood clots, strokes, or heart attacks. Regular monitoring of one’s hematocrit is essential for managing PV and assessing the effectiveness of treatments aimed at reducing the risk of these complications.
  2. Essential Thrombocythemia (ET): While ET primarily involves elevated platelet counts, a high hematocrit may also be observed due to secondary effects or overlapping features with other MPNs. Management focuses on controlling platelet levels to prevent thrombotic events, but monitoring hematocrit remains important for comprehensive disease management.
  3. Primary Myelofibrosis (PMF): In PMF, hematocrit levels may be low due to the replacement of bone marrow with fibrous tissue, leading to anemia. The disease’s progression can cause varying hematocrit levels, which are crucial for tracking disease progression and response to treatment.

In summary, hematocrit is more than just a routine blood test value; it is a vital indicator in the diagnosis, treatment, and management of myeloproliferative neoplasms.

High Neutrophil Ratio as a Thrombosis Predictor in Myeloproliferative Neoplasms

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July 24, 2024

The following is a summary of “Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis,” published in the July 2024 issue of Hematology by Nagaharu et al.

A nationwide study was conducted to identify clinical features of thrombosis in patients with myeloproliferative neoplasms to inform risk-based treatment strategies.

Researchers conducted a retrospective study to determine which complete blood count (CBC) parameters predicted thrombosis in patients with myeloproliferative neoplasms.

They investigated patients from JSH-MPN-R18, focusing on essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456). Using Welch’s T-test, the CBC parameters were compared with those with or without thrombotic events. Statistical analyses were conducted with R software.

The results showed that 74 patients with ET experienced thrombotic events. In multivariate analysis, patients with ET and thrombosis had a slightly but significantly higher neutrophil ratio compared to those without thrombosis (P<0.05). The absolute neutrophil count (aNeu) emerged as a valuable predictor for thrombosis in patients with low-risk according to the revised International Prognostic Score of Thrombosis for ET. Among patients with PV, those with thrombosis had notably higher hematocrit and aNeu levels than those without thrombosis. Additionally, the neutrophil ratio was slightly but significantly higher in patients with ET with thrombosis, potentially reflecting a greater JAK2 V617F allelic frequency, though was not detailed in JSH-MPN-R18.

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Dr Watts on the Investigation of INCB057643 in Advanced Myelofibrosis and MPN

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July 24, 2024

Author(s): Justin M. Watts, MD

Justin M. Watts, MD, associate professor of medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, discusses the design of a phase 1 trial (NCT04279847) investigating INCB057643 in patients with advanced myelofibrosis and other myeloid neoplasms, and highlights how this agent could address unmet needs in patients with relapsed/refractory myeloproliferative neoplasms (MPNs).

INCB057643 is an oral small molecule BET inhibitor that most selectively targets BRD-4, he begins. The agent is being evaluated in a phase 1 dose-escalation and -expansion study of patients with advanced myelofibrosis, including those with relapsed/refractory myelofibrosis and patients who are suboptimal responders to ruxolitinib (Jakafi), Watts details. Patients in the former group received the BET inhibitor as a monotherapy; those in the latter cohort received the agent as an add-on therapy, he explains.

Findings from the study were reported at the 2024 ASCO Annual Meeting, and demonstrated that INCB057643 when used as a monotherapy (n = 28) or in combination with ruxolitinib (n = 16), was generally well tolerated at doses ranging from 4 mg to 10 mg.

The maximum tolerated dose of the agent was established at 10 mg per day, Watts continues. INCB057643 monotherapy is currently being evaluated in a dose-expansion phase, with the combination regimen being assessed in the dose escalation phase at 8 mg, he reports. Watts notes that 8 mg is likely to be the optimal dose of INCB057643 when administered alongside ruxolitinib. During the dose expansion phases, different dosing of the BET inhibitor is permitted based on a patient’s platelet count, Watts says. This cohort includes both patients with myelofibrosis and those with essential thrombocythemia who have progressed on standard therapy, he states.

Initially, the dose escalation phase of the trial included a cohort of patients with myelodysplastic syndromes (MDS) and MDS/MPN overlap syndrome, Watts expands. However, the study’s focus has since shifted exclusively to patients with advanced myelofibrosis due to the significant unmet needs present in this patient population, Watts says. Many patients with advanced myelofibrosis have progressed on multiple lines of therapy or are completely intolerant or refractory to JAK inhibition, he explains. Accordingly, enhancing their response to therapy, reducing toxicities, decreasing spleen size beyond what can be achieved with ruxolitinib alone, and concurrently addressing anemia could benefit these patients, Watts concludes.

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Pelabresib/Ruxolitinib Data Underscore Need for Novel End Points in Myelofibrosis Trials

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July 15, 2024

Author(s): Jax DiEugenio

Although a 35% reduction in spleen volume (SVR35) and a 50% reduction in total symptom score (TSS50) have been established as key end points in clinical trials evaluating therapies for the treatment of patients with myelofibrosis, integrating end points such as overall survival (OS) and progression-free survival (PFS) as key objectives in future studies could help guide drug development and measure any disease-modifying properties of treatments, according to Aaron Gerds, MD.

“[Findings] from [the phase 3] MANIFEST-2 [NCT04603495] and TRANSFORM-1 [NCT04472598] trials are a wakeup call for the field that we need to move beyond SVR35 and TSS50 [as clinical trial end points in myelofibrosis]. We have drugs that are good at making patients’ symptoms better; however, we need are drugs that truly modify the disease course in a meaningful way,” Gerds explained.

Updated data from the MANIFEST-2 presented at the 2024 ASCO Annual Meeting showed that patients with myelofibrosis who received frontline pelabresib (CPI-0610) plus ruxolitinib (Jakafi; n = 214) experienced an SVR35 rate of 65.9% at week 24 compared with 35.2% for those given ruxolitinib plus placebo (n = 216). Notably, updated data showed that in patients who experienced an SVR35 at any time, 13.4% of patients in the experimental arm lost that response vs 27.8% of patients in the placebo arm.1

Additionally, the TSS50 rates at week 24 were 52.3% for pelabresib plus ruxolitinib vs 46.3% for placebo plus ruxolitinib, translating to a numerical improvement that was not statistically significant (difference, 6.0%; 95% CI, –3.5% to 15.5%; nominal P = .216).

Notably, 40.2% of patients in the pelabresib arm experienced both SVR35 and TSS50 at week 24 compared with 18.5% of patients in the placebo arm.

In an interview with OncLive®, Gerds an assistant professor of medicine, Hematology, and Medical Oncology at Cleveland Clinic Taussig Cancer Institute in Ohio, detailed prior data from MANIFEST-2 presented at the 2023 ASH Annual Meeting;2 expanded on updated data presented at the 2024 ASCO Annual Meeting; and emphasized the need to look beyond current end points in clinical trials evaluating treatments for patients with myelofibrosis.

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Ropeginterferon alfa-2b shows anti-polycythaemia vera activity without causing clinically significant anaemia

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Keita Kirito, Albert Qin, Shanshan Suo, Rongfeng Fu, Daoxiang Wu, Toshiaki Sato, Oleh Zagrijtschuk, Kazuya Shimoda, Norio Komatsu & Jie Jin

July 11, 2o24

Polycythaemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) that, in most cases, harbour the Janus kinase 2 gene (JAK2) driver mutation JAK2V617F [1]. PV is characterised by an over-production of blood cells with increased haematocrit levels, which is a risk factor for thrombotic events (TEs) and cardiovascular mortality [1, 2]. Low-dose aspirin and phlebotomy are usually recommended for patients with low-risk PV (i.e., no history of thrombosis and age ≤60 years). The National Comprehensive Cancer Network (NCCN) recommends ropeginterferon alfa-2b (BESREMi®) as a preferred cytoreductive treatment for patients with low- or high-risk PV [3].

Ropeginterferon alfa-2b is a novel polyethylene glycol (PEG)-conjugated recombinant proline-interferon alpha (IFN-a) with a favourable in vivo pharmacokinetic (PK) profile [4, 5]. Ropeginterferon alfa-2b has demonstrated substantial anti-PV clinical activity, including complete haematologic response (CHR; defined as a haematocrit <45% without phlebotomy, a platelet count ≤ 400 × 109/L, and a white blood cell count ≤10 × 109/L) and a reduction in the JAK2V617F allele burden [6,7,8,9]. Ropeginterferon alfa-2b injection is approved for adult patients with PV at an initial dose of 100 µg (or 50 µg for patients already receiving cytoreductive therapy) with 50 µg incremental intrapatient increases in the dose up to a maximum recommended dose of 500 µg every two weeks. It can take several months to reach the plateau dose level [6]. An alternative dosing regimen with a higher starting dose of 250 µg and simpler intrapatient dose escalation to 500 µg every two weeks with flexible dose adjustment according to tolerability was explored as a treatment option. This regimen controlled PV effectively, as defined by the CHR, and was associated with a shorter time to achieve a CHR [8, 9]. In this report, we aimed to examine the data from the approved slow-dose titration and exploratory higher starting dose regimens focusing on the dynamics of haemoglobin (Hgb) and the occurrence of anaemia. Anaemia is important in the context of PV treatment for several reasons. First, patients who undergo frequent phlebotomy may suffer from symptomatic iron deficiency, leading to anaemia [10]. Anaemia and symptoms can negatively affect the patient well-being and should be avoided in patients with PV and MPNs. The symptoms include headache, insomnia, concentration difficulties, dizziness, restless legs and may coincide and potentiate the disease-related symptoms of the underlying MPN [11,12,13]. Commonly used agents in the PV treatment cause anaemia in substantial numbers of cases ranging from 18% with hydroxyurea (HU) [14] to 72% with ruxolitinib [11, 15]. Anaemia is symptomatic in many cases and may limit the treatment dose or lead to treatment interruption if uncontrolled or severe cases are present. Association between venous thromboembolism and iron-deficiency anaemia has also been shown [16]. Thus, having an agent that can effectively control the elevated haematocrit without excessively suppressing the normal erythropoiesis is a major therapeutic advantage.

An important question regarding ropeginterferon alfa-2b in this context is whether the control of haematocrit is commonly accompanied by clinically significant anaemia, i.e., at the ≥grade 3 level or at the moderate, grade 2 level, but the anaemia is persistent and unmanageable. We therefore performed a retrospective analysis of the effect of ropeginterferon alfa-2b on Hgb levels at various time points or on the occurrence of anaemia with the data available from our two prospective clinical studies in patients with PV.

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Risk of myeloproliferative neoplasms among U.S. Veterans from Korean, Vietnam, and Persian Gulf War eras

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July 18, 2024

Andrew Tiu, Zoe McKinnell, Shanshan Liu, Puneet Gill, Martha Antonio, Zoe Shancer, Nandan Srinivasa, Guoqing Diao, Ramesh Subrahmanyam, Craig M. Kessler, Maneesh Jain

Abstract

The Promise to Address Comprehensive Toxics (PACT) Act expanded U.S. Veterans’ health care and benefits for conditions linked to service-connected exposures (e.g., Burn Pits, Agent Orange). However, myeloproliferative neoplasms (MPN) are not recognized as presumptive conditions for Veterans exposed to these toxic substances. This study evaluated the development of MPN among U.S. Veterans from the Korean, Vietnam, and Persian Gulf War eras. This retrospective cohort study included 65 425 Korean War era Veterans; 211 927 Vietnam War era Veterans; and 214 007 Persian Gulf War era Veterans from January 1, 2006, to January 26, 2023. Veterans with MPN, thrombosis, bleeding, and cardiovascular risk factors were identified through ICD-9 and -10 codes. Veterans from the Persian Gulf War era had the highest risk of developing MPN compared with Veterans from the Korean and Vietnam War eras, hazard ratio (HR) 4.92, 95% confidence interval (CI) 4.20–5.75 and HR 2.49, 95% CI 2.20–2.82, both p < .0001, respectively. Vietnam War era Veterans also had a higher risk of MPN development compared with Korean War era Veterans, HR 1.97, 95% CI 1.77–2.21, p < .0001. Persian Gulf War era Veterans were diagnosed with MPN at an earlier age, had higher risks of thrombosis and bleeding, and had lower survival rates compared with Korean War and Vietnam War era Veterans. This study reinforces evidence that environmental and occupational hazards increase the risk of clonal myeloid disorders and related complications, impacting overall survival with MPN. Limitations include the inability to confirm clonality and fully verify deployment and exposure status.

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Immunofluorescence microscopy on the blood smear identifies patients with myeloproliferative neoplasms

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July 17, 2024

Carlo Zaninetti, Leonard Vater, Lars Kaderali, Carl C. Crodel, Tina M. Schnöder, Jessica Fuhrmann, Leonard Swensson, Jan Wesche, Carmen Freyer, Andreas Greinacher & Florian H. Heidel

Myeloproliferative neoplasms (MPN) are a group of clonal stem cell disorders with heterogeneous clinical presentation [1]. Due to the risk of severe thromboembolic complications and disease progression, the early recognition of an MPN prior to the appearance of clinical complications is clearly warranted to facilitate early pharmacologic intervention [2,3,4]. Detection of the somatic mutations by genotyping has become an essential part of the diagnostic work-up of suspected subjects, as well as of the risk stratification after the diagnosis of MPN has been confirmed [5]. However, in many parts of the world molecular testing is barely affordable.

We have established an immunofluorescence microscopy (IF)-based method for platelet phenotyping on the peripheral blood smear [6]. This method has been proven to be highly efficient in the diagnosis of diverse hereditary platelet disorders by recognizing disease-specific changes of cell structures, including alterations of leukocytes and red blood cells (RBC) [7, 8]. Major advantages of this approach are the need of small amounts of blood (<100 μL) and the possibility to send the blood films by regular mail even long distances.

It is well-known that morphology of peripheral blood cells is also often altered in MPN [9, 10]. However, due to different methods and the heterogeneity of the patients’ populations, results are difficult to compare.

In the present study, we aimed at assessing platelet phenotype using our IF method in a cohort of patients diagnosed with MPN. The study has been registered in the German Clinical Trials Register (DRKS-ID: DRKS00032588). Three German reference centers for diagnosis and treatment of MPN took part in the study: Internal Medicine C, University Medicine Greifswald; Internal Medicine 2, University Hospital Jena; and Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany. The study protocol was approved by the institutional review boards of all centers. Patients or their legal guardians signed written informed consent to the investigation, which was conducted according to the Declaration of Helsinki. Healthy controls were enrolled among blood donors at the Institute for Transfusion Medicine, University Medicine Greifswald, Germany.

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