Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.

The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.

Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis.

PURPOSE OF REVIEW: Development of hepcidin therapeutics has been a ground-breaking discovery in restoring iron homeostasis in several haematological disorders. The hepcidin mimetic, rusfertide, is in late-stage clinical development for treating polycythemia vera patients with a global phase 3 trial [NCT05210790] currently underway. Rusfertide serves as the first possible noncytoreductive therapeutic option to maintain haematocrit control and avoid phlebotomy in polycythemia vera patients. In this comprehensive review, we discuss the pathobiology of dysregulated iron metabolism in polycythemia vera, provide the rationale for targeting the hepcidin-ferroportin axis and elaborate on the preclinical and clinical trial evidence supporting the role of hepcidin mimetics in polycythemia vera. RECENT FINDINGS: Recently, updated results from two phase 2 clinical trials [NCT04057040 & NCT04767802] of rusfertide (PTG300) demonstrate that the drug is highly effective in eliminating the need for therapeutic phlebotomies, normalizing haematological parameters, repleting iron stores and relieving constitutional symptoms in patients with polycythemia vera. In light of these findings, additional hepcidin mimetic agents are also being evaluated in polycythemia vera patients. SUMMARY: Hepcidin agonists essentially serve as a 'chemical phlebotomy' and are poised to vastly improve the quality of life for phlebotomy requiring polycythemia vera patients.

Exclusion of Acute Myeloid Leukemia Patients with Central Nervous System Involvement from Clinical Trials: An Analysis of the National Institutes of Health Clinical Trials Registry from 2012-2022.

INTRODUCTION: Central nervous system (CNS) involvement in acute myeloid leukemia (AML) can be successfully treated with intrathecal chemotherapy and carries debatable prognostic impact. However, patients with CNS involvement are commonly excluded from clinical trials at an unknown rate. We systematically evaluated exclusion criteria of AML clinical trials based on CNS involvement and determined associations with clinical trial characteristics. METHODS: The National Institutes of Health Clinical Trials Registry was searched for interventional adult AML trials between 2012-2022 that were phase I, II, or III and relevant trial characteristics were extracted. RESULTS: 1270 trials were included in the analysis with 790 trials (62.1%) explicitly excluding CNS involvement. There was no significant change in rates of CNS exclusion over the past decade. CNS exclusion was higher in trials that included the non-transplant population compared to trials exclusive to the transplant population (66.9% vs. 43.8%, p<0.01). Non-transplant trials were also more likely to exclude patients with a history of or ambiguous timing of CNS involvement (p<0.01). Phase III trials were associated with more liberal definitions of CNS exclusion (history or ambiguous timing) as compared to phase I and II trials that had higher rates of excluding patients with only active CNS involvement (P<0.01). CONCLUSION: A majority of AML clinical trials, particularly in the non-transplant setting, exclude patients with CNS involvement. Many of these trials, most notably phase 3 trials, exclude patients not only with active, but any history of CNS involvement. Further research is needed to determine optimal management of these patients in order to increase representation in large clinical trials.

Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis.

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).

Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes overactive, leading to scarring and subsequently a lack of healthy blood cells being produced. The main symptoms of MF include anemia, fatigue, weakness and pain or discomfort in the abdomen. MF is associated with a shortened life expectancy. The current go-to treatment for MF is ruxolitinib. However, ruxolitinib has shown limited efficacy in improving clinical symptoms long term; so, new safe and effective treatments are needed. Pelabresib is a novel drug currently in clinical development for treating MF. The aim of this article is to describe the design of the ongoing, global phase III MANIFEST-2 study. MANIFEST-2 is evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with MF.

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Clinical Benefit Derived from Decitabine Therapy for Advanced Phases of Myeloproliferative Neoplasms.

Treatment options are limited for patients with advanced forms of myeloproliferative neoplasms (MPN) including blast-phase disease (MPN-BP). Decitabine has frequently been deployed but its efficacy and safety profile are not well described in this population. We retrospectively reviewed 42 patients treated with decitabine either alone or in combination with ruxolitinib at our institution: 16 with MPN-BP, 14 with MPN accelerated-phase (MPN-AP), and 12 with myelofibrosis with high-risk features (MF-HR). The median overall survival (OS) for the MPN-BP patients was 2.6 months, and for those who received ≥2 cycles of decitabine therapy, it was 6.7 months (3.8-29.8). MPN-BP patients with a poor performance status and who required hospitalization at the time of the initiation of decitabine had a dismal prognosis. After a median follow-up of 12.4 months for MPN-AP patients, and 38.7 months for MF-HR patients, the median OS was not reached for either cohort, with 1 and 2 patients alive at 60 months, respectively. The probability of spleen length reduction and transfusion independence within 12 months of initiating decitabine was 28.6 and 23.5%, respectively. The combination of decitabine and ruxolitinib appeared to improve overall survival versus single-agent decitabine (21 and 12.9 months, respectively). Decitabine, alone or in combination with ruxolitinib, appears to have clinical benefit for patients with advanced phases of MPN when initiated early in the disease course prior to the development of MPN-BP.

Modern management of splenomegaly in patients with myelofibrosis.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly secondary to extramedullary hematopoiesis. Patients frequently exhibit debilitating symptoms including pain and early satiety, in addition to cellular sequestration causing severe cytopenias. JAK 1/2 inhibitors, such as ruxolitinib and fedratinib, are the mainstay of therapy and produce significant and durable reductions in spleen volume. However, many patients are not eligible for JAK 2 inhibitor therapy or become refractory to treatment over time. Novel therapies are in development that can reduce the degree of splenomegaly for some of these patients. However, splenectomy, splenic irradiation, and partial splenic artery embolization remain valuable therapeutic options in select patients. In this review, we will discuss currently available pharmacologic therapies and describe promising drugs currently in development. We will also delve into the efficacy and safety concerns of splenectomy, splenic irradiation, and partial splenic artery embolization. Finally, we will propose a treatment algorithm to help guide clinicians in the management of symptomatic splenomegaly in patients with MF.

Associations of Physical and Psychologic Symptom Burden in Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms.

BACKGROUND: The physical symptom burden of patients with myeloproliferative neoplasms (MPNs) may last for extended periods during their disease trajectories and lead to psychologic distress, anxiety, or depression or all of these. OBJECTIVE: This study evaluated the relationship between physical symptom burden captured by the Physical Problem List (PPL) on the Distress Thermometer and Problem List and psychologic outcomes (distress, anxiety, and depression) in the MPN setting. METHODS: Patients (N = 117) with MPNs completed questionnaires containing the Distress Thermometer and Problem List and the Hospital Anxiety and Depression Scale in a dedicated MPN clinic within an academic medical center. They reported symptoms from any of 22 physical problems on the PPL. Items endorsed by more than 10% of participants were assessed for their associations with distress (Distress Thermometer and Problem List), anxiety (Hospital Anxiety and Depression Scale-Anxiety), and depression (Hospital Anxiety and Depression Scale-Depression). The total number of endorsed PPL items per participant was also evaluated. RESULTS: Nine of 22 PPL items (fatigue, sleep, pain, dry skin/pruritus, memory/concentration, feeling swollen, breathing, and sexual) were reported by >10% of participants. In univariate analyses, all PPL items but one were associated with distress and depression, and all but 2 were associated with anxiety. In multivariate analyses, the total number of PPL items was associated with depression only (p < 0.001) when controlling for covariates. CONCLUSION: Physical symptom burden in MPN patients was clearly associated with psychologic symptoms. Depression was uniquely associated with overall physical symptom burden. As such, the endorsement of multiple PPL items on the Distress Thermometer and Problem List should prompt an evaluation for psychologic symptoms to improve MPN patients' overall morbidity and quality of life.

Prevalence of Physical Problems Detected by the Distress Thermometer and Problem List in Patients With Myeloproliferative Disorders.

Background: Patients with myeloproliferative neoplasms (MPNs) can have a severe physical symptom burden over an extended disease trajectory that contributes to decreased quality of life. Few studies, however, have characterized which patients most frequently consider physical symptoms a problem. This study describes the physical symptoms of patients with MPNs and the relationship of these symptoms to patient characteristics. Methods: Patients with MPNs (N=117) completed questionnaires in a dedicated academic medical center MPN clinic. Patients reported demographics (age, race/ethnicity, sex, marital status, employment status), disease characteristics (MPN type, time with MPN), and whether they were bothered by any of 22 variables in the "Physical Problems" list in the Distress Thermometer and Problem List (DT&PL). Results: The median number of physical problems endorsed by patients was 2 (median, 2.26; SD, 3.18), with a range from 0 to 20. Two-fifths endorsed no physical problems, one-fifth endorsed 1 problem, and two-fifths endorsed ≥2 problems, with fatigue (35.5%), sleep (27.1%), pain (21.5%), dry skin/pruritus (18.7%), and memory/concentration (16.8%) being the most commonly reported. Non-Caucasian participants reported more problems with sleep (P=.050), pain (P=.016), and tingling (P=.026). Patients with polycythemia vera (PV) reported more issues with tingling (P=.046) and sexual problems (P=.032). Conclusions: Patients with MPNs are more likely to report physical symptom bother than to report no bother with multiple physical problems on the DT&PL. Patients of minority race/ethnicity and those with PV, however, showed heightened prevalence of physical problems-characteristics which may be used to triage patients for more intensive symptom management.

Psychological Manifestations of Early Childhood Adversity in the Context of Chronic Hematologic Malignancy.

BACKGROUND: Myeloproliferative neoplasms (MPNs), a group of chronic hematologic malignancies, carry significant physical and psychological symptom burdens that significantly affect patients' quality of life. OBJECTIVES: We sought to identify the relationship between early childhood adversity (ECA) and psychological distress in patients with MPNs, as ECA may compound symptom burden. METHODS: Patients with MPNs were assessed for ECA (i.e., the Risky Families Questionnaire-subscales include abuse/neglect/chaotic home environment), distress (i.e., Distress Thermometer and Problem List), anxiety (i.e., Hospital Anxiety and Depression Scale-Anxiety [HADS-A]), depression (i.e., Hospital Anxiety and Depression Scale-Depression [HADS-D]), meeting standardized cutoff thresholds for distress (i.e., Distress Thermometer and Problem List≥ 4 or ≥ 7)/anxiety (HADS-A ≥8)/depression (HADS-D ≥ 8), and demographic factors. RESULTS: A total of 117 participants completed the study (78% response rate). ECA was associated with depression (p < 0.000), anxiety (p < 0.000), and distress (p < 0.000) and problem list variables emotional (p < 0.000), physical (p = 0.004), family (p = 0.01), and spiritual (p = 0.01) by bivariate analysis and only with distress (HADS) (p = 0.038) on multivariate analysis. ECA was associated with meeting cutoff threshold criteria for distress (p = 0.007), anxiety (p = 0.001), and depression (p = 0.02). ECA subscale variables abuse and chaotic home environment were associated with psychological outcomes. ECA was higher based on disease subtypes with greater symptom burden (other > polycythemia vera > myelofibrosis > essential thrombocythemia) (p = 0.047) and taking an antidepressant (p = 0.011). CONCLUSION: ECA is associated with psychological distress and meets screening criteria for anxiety and depression in patients with MPNs. ECA may help to explain individual patient trajectories, and further understanding may enhance patient-centered care among patients with MPNs.

Preferences of Patients With Myeloproliferative Neoplasms for Accepting Anxiety or Depression Treatment.

BACKGROUND: Patients with chronic hematologic malignancies such as myeloproliferative neoplasms suffer from significant physical and psychological symptom burden. This study examined their willingness to accept an antidepressant and their preferences for which provider (mental health professional or hematologist/oncologist) prescribes an antidepressant for the management of anxiety and depression. METHODS: Anxiety and depression treatment preferences were measured with 3 questions assessing: (1) willingness to accept an antidepressant, (2) willingness to have their hematologist/oncologist prescribe the antidepressant, and (3) preference for treatment by a psychiatrist or mental health professional. Additionally, the Distress Thermometer and Problem List, Hospital Anxiety and Depression Scale, Risky Families Questionnaire, and demographic information were assessed to assess levels of distress, anxiety, and depression. RESULTS: Of the 117 participants, 69 (63.0%) were willing to accept an antidepressant in general and 61 (58.1%) were willing to accept an antidepressant from their hematologist/oncologist (p < 0.000). Although 41(39.0%) preferred to be treated by a mental health provider, this preference was not significantly associated with their respective preference for accepting an antidepressant (p = 0.057). Participants already taking antidepressants and those with elevated chronic stress levels were more willing to receive an antidepressant from their hematologist/oncologist (p = 0.035, p = 0.03, respectively). Treatment preferences did not vary based on myeloproliferative neoplasm type, length of time with myeloproliferative neoplasm, race/ethnicity, marital or working status, or by meeting distress/anxiety/depression criteria. A significant minority (n = 28, 26.7%) would not accept any treatment. CONCLUSION: Most patients with myeloproliferative neoplasm accepted an antidepressant and readily accepted the prescription from their hematologist/oncologist. The hematologists/oncologist׳s psychopharmacologic knowledge and their willingness to prescribe antidepressants should be assessed.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic and Advanced Phase Myelofibrosis.

Myelofibrosis (MF) is a chronic progressive hematologic malignancy with a median overall survival (OS) of approximately 6 years. Allogeneic hematopoietic stem cell transplantation (HSCT) is the sole treatment approach that offers curative potential. The use of reduced-intensity conditioning regimens has expanded the application of HSCT to patients with MF up to age 70 years. Recent retrospective and prospective reports have suggested worse HSCT outcomes for patients with MF receiving an unrelated donor graft compared with those receiving a related donor graft. To identify patient- and HSCT-specific variables influencing outcomes, we conducted a retrospective analysis of 42 patients with chronic and advanced-phase MF who underwent HSCT at our institution. For this cohort, at a median follow-up of 43 months, progression-free survival (PFS) was 15 months and OS was 25 months. In multivariable analysis, the sole clinical variable that negatively influenced outcome was the use of an unrelated donor, with a median PFS and OS both of 11 months versus not yet reached in patients receiving a related donor graft. At 2 years, OS was 38% (95% confidence interval [CI], 20%-56%) and nonrelapse mortality (NRM) was 53% (95% CI, 36%-78%) in the unrelated donor graft group, compared with 75% (95% CI, 46%-90%) and 21% (95% CI, 9%-47%) in the related donor graft group. There was no difference in the rates of grade III-IV acute graft-versus-host disease between the unrelated and related donor groups (38% versus 38%). Despite a more aggressive disease state, 2-year PFS and OS were both 42% (95% CI, 15%-67%) in patients with myeloproliferative neoplasm-blast phase undergoing HSCT. Graft failure rate was higher in patients receiving a mismatched donor graft compared with those receiving a matched donor graft (60% versus 13%; P = .0398). Retransplantation of patients with graft failure resulted in long-term survival. Baseline splenomegaly did not affect transplantation outcomes. Given the particularly poor outcomes seen in the unrelated donor cohort here and elsewhere, a formal exploration of alternative hematopoietic stem cell sources is warranted.

Psychological Symptoms Among Patients With BCR-ABL-Negative Myeloproliferative Neoplasms.

BACKGROUND: BCR-ABL-negative myeloproliferative neoplasms (MPNs) represent a heterogeneous group of diseases, including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Psychological manifestations among these diseases have not been adequately described. METHODS: Cross-sectional surveys measuring distress, anxiety, and depression were collected from patients with BCR-ABL-negative MPNs from May 2015 to October 2015. Participants provided demographic information and completed the Distress Thermometer and Problem List (DT&PL) to assess distress and the Hospital Anxiety and Depression Scale (HADS) to assess distress, anxiety, and depression. They provided information on how their MPN affected their lives. RESULTS: Of the 117 participants, 31.2% had PV, 28.4% had ET, 28.4% had MF, and 11.9% had another type of MPN. Time with MPN varied from less than 1 year (7.5%), 1 to 3 years (19.8%), 3 to 5 years (23.6%), 5 to 10 years (19.8%), and more than 10 years (29.2%). Distress averaged 3.14 (SD, 2.83; DT&PL), with 40.4% meeting NCCN criteria for distress, and averaged 8.97 (SD, 7.44; HADS), with 38.5% meeting HADS criteria for distress. Anxiety averaged 5.54 (SD, 4.37), with 31.3% meeting HADS criteria for anxiety. Depression averaged 3.4 (SD, 3.4), with 12.5% meeting HADS criteria for depression. Distress was higher for PV (3.86), MF (3.12), and "other" MPN (4.33) than it was for ET (1.81; P=.016). Distress was more common in non-white patients (P=.015) and those with either PV or MF but not ET (DT&PL ≥4; P=.038). Patients' comments described coping strategies or symptom burden. CONCLUSIONS: Distress and anxiety are highly prevalent with BCR-ABL-negative MPNs and may correspond to disease-related symptom burden. These findings deserve further study.

Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-α 2a specifically targets JAK2V617F-positive polycythemia vera cells.

Interferon (IFN-α) is effective therapy for polycythemia vera (PV) patients, but it is frequently interrupted because of adverse events. To permit the long-term use of IFN, we propose combining low doses of IFN with Nutlin-3, an antagonist of MDM2, which is also capable of promoting PV CD34(+) cell apoptosis. Combination treatment with subtherapeutic doses of Peg IFN-α 2a and Nutlin-3 inhibited PV CD34(+) cell proliferation by 50% while inhibiting normal CD34(+) cells by 30%. Combination treatment with Nutlin-3 and Peg IFN-α 2a inhibited PV colony formation by 55%-90% while inhibiting normal colony formation by 22%-30%. The combination of these agents also decreased the proportion of JAK2V617F-positive hematopoietic progenitor cells in 6 PV patients studied. Treatment with low doses of Peg IFN-α 2a combined with Nutlin-3 increased phospho-p53 and p21 protein levels in PV CD34(+) cells and increased the degree of apoptosis. These 2 reagents affect the tumor suppressor p53 through different pathways with Peg IFN-α 2a activating p38 MAP kinase and STAT1, leading to increased p53 transcription, whereas Nutlin-3 prevents the degradation of p53. These data suggest that treatment with low doses of both Nutlin-3 combined with Peg IFN-α 2a can target PV hematopoietic progenitor cells, eliminating the numbers of malignant hematopoietic progenitor cells.

Recent advances in JAK2 inhibition for the treatment of myelofibrosis.

INTRODUCTION: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, cytopenias, a potential for leukemic transformation, and increased mortality. Patients who are ineligible for stem cell transplant rely on pharmacologic therapies of noncurative intent, whose cornerstone consists of JAK inhibitors (JAKi). While current JAKi are efficacious in controlling symptoms and splenic volume, none meaningfully reduce clonal burden nor halt disease progression, and patients oftentimes develop JAKi intolerant, relapsed, or refractory MF. As such, there remains an urgent necessity for second-line options and novel therapies with disease-modifying properties. AREAS COVERED: In this review, we delineate the mechanistic rationale, along with the latest safety and efficacy data, of investigational JAKi-based MF treatment strategies, with a focus on JAKi monotherapies and combinations of novel agents with approved JAKi. Our literature search consisted of extensive review of PubMed and clinicaltrials.gov. EXPERT OPINION: A myriad of promising MF-directed therapies are in late-phase studies. Following their approval, treatment selection should be tailored to patient-specific treatment goals and disease characteristics, with an emphasis on combination therapies of JAKi with novel agents of differing mechanistic targets that possess anti-clonal properties, in attempt to alter disease course and concurrently limit dose-dependent JAKi toxicities.

Contemporary Challenges in Polycythemia Vera Management From the Perspective of Patients and Physicians.

Although polycythemia vera (PV) is a chronic and incurable disease, effective management can allow most patients to maintain functional lives with near-normal life expectancy. However, there remain several inter-related factors that contribute to many ongoing challenges associated with the management of PV, which this review aims to explore. First, as a disease hallmarked by constitutive activation of the JAK/STAT pathway, PV is often accompanied by inflammatory symptoms that negatively impact quality of life. Next, patients often require recurrent therapeutic phlebotomies to maintain their hematocrit below the 45% threshold that has been associated with a decreased risk of thrombotic events. The need to closely monitor hematocrit and perform conditional therapeutic phlebotomies ties patients to the healthcare system, thereby limiting their autonomy. Furthermore, many patients describe therapeutic phlebotomies as burdensome and the procedure is often poorly tolerated, further contributing to quality-of-life decline. Phlebotomy needs can be reduced by utilizing cytoreductive therapy; however, standard first-line cytoreductive options (i.e., hydroxyurea and interferon) have not been shown to significantly improve symptom burden. Collectively, current PV management, while reducing thrombotic risk, often has a negative impact on patient quality of life. As researchers continue to advance towards the goal of developing a disease-modifying therapy for patients with PV, pursuit of nearer-term opportunities to shift the current treatment paradigm towards improving symptoms without compromising quality of life is also warranted, for example, by reducing or eliminating the frequent use of phlebotomy.