Risk factors for disease progression and treatment goals in polycythemia vera.

Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by the clonal proliferation of hematopoietic cells, leading to the overproduction of erythrocytes and the elaboration of inflammatory cytokines. Management is aimed at reducing the risk of thromboembolic events, alleviating the symptom burden, decreasing splenomegaly, and potentially mitigating the risk of disease progression. Existing treatment options include therapeutic phlebotomy and cytoreductive agents including hydroxyurea, pegylated recombinant interferon alpha 2a, ropegylated recombinant interferon alpha 2b, and ruxolitinib. We review risk factors for both thrombotic events and disease progression in patients with polycythemia vera. We discuss existing and novel therapeutic approaches to mitigate the risk of disease-related complications and progression.

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes.

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ("much" or "very much" improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.

Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced-intensity conditioning (RIC) regimen for patients with myelofibrosis (MF) undergoing transplantation in a 2-stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and nonrelapse mortality (NRM) compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study. The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or ≥6 failures occurred in the URD. A total of 21 patients were enrolled, including 7 in the RD arm and 14 in the URD arm. The RD arm did not meet the predetermined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures. In all 19 transplant recipients, ruxolitinib was tapered successfully without significant side effects, and 9 patients (47%) had a significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute graft-versus-host disease (GVHD), and chronic GVHD at 24 months were 16%, 28%, 64%, and 76%, respectively. On an intention-to-treat basis, the 2-year overall survival was 61% for the RD arm and 70% for the URD arm. Ruxolitinib can be integrated as pretransplantation treatment for patients with MF, and a tapering strategy before transplantation is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.

Impact of High-Molecular-Risk Mutations on Transplantation Outcomes in Patients with Myelofibrosis.

Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent allo-HCT and evaluated the association of mutations and clinical variables with transplantation outcomes. Overall survival (OS) at 5 years post-transplantation was 52%, and relapse-free survival (RFS) was 51.1 % for this cohort. Nonrelapse mortality (NRM) accounted for most deaths. Patient's age, donor's age, donor type, and Dynamic International Prognostic Scoring System score at diagnosis did not predict for outcomes. Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2, and TP53, did not impact OS or RFS. The presence of U2AF1 (P = .007) or DNMT3A (P = .034) mutations was associated with worse OS. A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79%), and there were no differences in outcomes between patients with high risk scores and those with intermediate and low risk scores. Collectively, these data identify mutational predictors of outcome in MF patients undergoing allo-HCT. These genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision making.

Implications of Mutation Profiling in Myeloid Malignancies-PART 2: Myeloproliferative Neoplasms and Other Myeloid Malignancies.

Myeloid malignancies arise from the acquisition of somatic mutations among various genes implicated in essential functioning of hematopoietic stem cells and progenitor cells. In this second part of our two-part review, we discuss the use of mutation profiling in the diagnosis, prognosis, and treatment of patients with myeloproliferative neoplasms and other myeloid diseases. We also discuss the entity known as clonal hematopoiesis of indeterminate potential, awareness of which is a result of the increasing availability and improved quality of mutation profiling.

Implications of Mutation Profiling in Myeloid Malignancies-PART 1: Myelodysplastic Syndromes and Acute Myeloid Leukemia.

The advent of high-throughput gene sequencing has revolutionized our understanding of the genetic mutations that drive myeloid malignancies. While these mutations are of interest pathobiologically, they are increasingly being recognized as clinically meaningful in providing diagnostic, prognostic, and therapeutic information to guide patient care. In this first part of our two-part review, we introduce mutation profiling as a relevant clinical tool for hematologists treating patients with myeloid malignancies. Next, we discuss the diagnostic and prognostic role of mutation profiling in myelodysplastic syndrome and acute myeloid leukemia. Finally, we detail the therapeutic implications of specific mutations in myelodysplastic syndrome and acute myeloid leukemia. In Part 2, we will discuss similar clinical approaches using mutation profiling in myeloproliferative neoplasms and other myeloid malignancies.

Distinguishing autoimmune myelofibrosis from primary myelofibrosis.

Bone marrow fibrosis (BMF) is a histologic finding in a wide range of diseases, including malignancies, endocrine disorders, autoimmune diseases, and infections. Autoimmune myelofibrosis (AIMF) is an uncommon etiology of BMF; it can be secondary to a defined autoimmune disease, or it can be primary in the absence of a clinically diagnosed autoimmune disease but the presence of serologic evidence of autoantibodies. Distinguishing between primary myelofibrosis (PMF) and non-neoplastic AIMF is of the utmost importance because the prognosis and therapeutic options are different. This distinction, however, can be complicated by overlapping findings in the 2 disease entities. Here, using the case of a patient with BMF in the setting of idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia, we present a systematic approach to distinguishing between PMF and AIMF.

Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: Findings from the MPN Landmark survey.

BACKGROUND: This analysis of the myeloproliferative neoplasm (MPN) Landmark survey evaluated gaps between patient perceptions of their disease management and physician self-reported practices. METHODS: The survey included 813 patient respondents who had MPNs (myelofibrosis [MF], polycythemia vera [PV], or essential thrombocythemia [ET]) and 457 hematologist/oncologist respondents who treated patients with these conditions. RESULTS: Greater proportions of physician respondents reported using prognostic risk classifications (MF, 83%; PV, 59%; ET, 77%) compared with patient recollections (MF, 54%; PV, 17%; ET, 31%). Most physician respondents reported that their typical symptom assessments included asking patients about the most important symptoms or a full list of symptoms, whereas many patient respondents reported less specific assessments (eg, they were asked how they were feeling). Many patient respondents did not recognize common symptoms as MPN-related. For example, approximately one-half or more did not believe difficulty sleeping resulted from their MPN (MF, 49%; PV, 64%; ET, 76%). Physician respondents underestimated the proportion of patients who had symptomatic PV or ET at diagnosis compared with patient respondents. There was discordance regarding treatment goals: among patient respondents with MF or PV, "slow/delay progression of condition" was the most important treatment goal, whereas physician respondents reported "symptom improvement" and "prevention of vascular/thrombotic events," respectively. Finally, more than one-third of patient respondents were not "very satisfied" with their physician's overall management/communication. CONCLUSIONS: The care and satisfaction of patients with MPN may be improved with increased patient education and improved patient-physician communication. Cancer 2017;123:449-458. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis.

Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×109/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1-24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.

Myeloproliferative neoplasms (MPNs) have a significant impact on patients' overall health and productivity: the MPN Landmark survey.

BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. METHODS: The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. RESULTS: The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). CONCLUSIONS: These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.

"Irony" of managing refractory anemia with transfusional support in hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening derangement of the immune system in which host macrophages phagocytose the patient's own blood cells. Herein, we present the case of a patient with HLH and associated refractory anemia who developed rapid iron deposition in the liver after transfusion of sixteen units of packed red blood cells (RBCs). Before transfusion, neither a liver biopsy nor computed tomography scan demonstrated iron deposition in the organ parenchyma. After receiving sixteen units of packed RBCs, liver iron concentration rose to 6.7 mg/g dry weight, which is highly unusual in other diseases requiring transfusional support.

Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia.

The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the heterogeneous molecular basis of the disease. Since genetic sequencing has become a standard practice, several driver mutations have been identified. Accordingly, novel targeted therapeutic agents have been developed and are now approved for the treatment of subsets of patients that carry mutations in FLT3, IDH1, and IDH2 [1, 2]. The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.

Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy.

BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Advances in myelofibrosis: a clinical case approach.

Primary myelofibrosis is a member of the myeloproliferative neoplasms, a diverse group of bone marrow malignancies. Symptoms of myelofibrosis, particularly those associated with splenomegaly (abdominal distention and pain, early satiety, dyspnea, and diarrhea) and constitutional symptoms, represent a substantial burden to patients. Most patients eventually die from the disease, with a median survival ranging from approximately 5-7 years. Mutations in Janus kinase 2 (JAK2), a kinase that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 50% of patients with myelofibrosis. The approval of a JAK2 inhibitor in 2011 has improved the outlook of many patients with myelofibrosis and has changed the treatment landscape. This article focuses on some of the important issues in current myelofibrosis treatment management, including differentiation of myelofibrosis from essential thrombocythemia and polycythemia vera, up-dated data on the results of JAK2 inhibitor therapy, the role of epigenetic mechanisms in myelofibrosis pathogenesis, investigational therapies for myelofibrosis, and advances in hematopoietic stem cell transplant. Three myelofibrosis cases are included to underscore the issues in diagnosing and treating this complex disease.

Clarifying the use of ruxolitinib in patients with myelofibrosis.

Myelofibrosis (MF) is a hematopoietic stem cell malignancy classified as a myeloproliferative neoplasm (MPN). The clinical course of individuals with MF is heterogeneous and characterized by constitutional symptoms, bone marrow myeloproliferation and fibrosis, progressive cytopenias, and symptomatic splenomegaly. Historically, patients with this debilitating disease have had limited treatment options, and disease-modifying agents were not available. Hematopoietic stem cell transplantation is the only potentially curative therapy, but it is only an option for select patients. The discovery of an activating point mutation in the Janus kinase 2 gene (JAK2V617F) in a significant portion of patients with MPNs led to improved understanding of the pathobiology of these disorders and prompted rapid development of JAK inhibitors. Ruxolitinib (Jakafi) is the first-in-class and only JAK inhibitor currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with MF; approval was based on the results of the COMFORT (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment) I and II studies. While not a curative option, ruxolitinib offers great palliative potential and results in significant reduction in splenomegaly and improvement in constitutional symptoms in the majority of treated patients, thus improving their quality of life and performance status. Additionally, ruxolitinib is the only agent that has demonstrated a survival benefit in patients with MF. The optimal use of ruxolitinib for MF patients is challenging and complex. In this article, we provide updated data on ruxolitinib therapy for patients with MF and offer expert opinion on the appropriate use of this agent in the community practice.

Treating accelerated and blast phase myeloproliferative neoplasms: progress and challenges.

Myeloproliferative neoplasms (MPNs) are a group of clonal hematologic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). MPNs are characterized by activating mutations in the JAK/STAT pathway and an increased risk of transformation to an aggressive form of acute leukemia, termed MPN-blast phase (MPN-BP). MPN-BP is characterized by the presence of ⩾20% blasts in the blood or bone marrow and is almost always preceded by an accelerated phase (MPN-AP) defined as ⩾10-19% blasts in the blood or bone marrow. These advanced forms of disease are associated with poor prognosis with a median overall survival (mOS) of 3-5 months in MPN-BP and 13 months in MPN-AP. MPN-AP/BP has a unique molecular landscape characterized by increased intratumoral complexity. Standard therapies used in de novo acute myeloid leukemia (AML) have not demonstrated improvement in OS. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy but is associated with significant morbidity and mortality and infrequently utilized in clinical practice. Therefore, an urgent unmet need persists for effective therapies in this advanced phase patient population. Here, we review the current management and future directions of therapy in MPN-AP/BP.

Telomerase-targeted therapies in myeloid malignancies.

Human telomeres are tandem arrays that are predominantly composed of 5'-TTAGGG-3' nucleotide sequences at the terminal ends of chromosomes. These sequences serve 2 primary functions: they preserve genomic integrity by protecting the ends of chromosomes, preventing inappropriate degradation by DNA repair mechanisms, and they prevent loss of genetic information during cellular division. When telomeres shorten to reach a critical length, termed the Hayflick limit, cell senescence or death is triggered. Telomerase is a key enzyme involved in synthesizing and maintaining the length of telomeres within rapidly dividing cells and is upregulated across nearly all malignant cells. Accordingly, targeting telomerase to inhibit uncontrolled cell growth has been an area of great interest for decades. In this review, we summarize telomere and telomerase biology because it relates to both physiologic and malignant cells. We discuss the development of telomere- and telomerase-targeted therapeutic candidates within the realm of myeloid malignancies. We overview all mechanisms of targeting telomerase that are currently in development, with a particular focus on imetelstat, an oligonucleotide with direct telomerase inhibitory properties that has advanced the furthest in clinical development and has demonstrated promising data in multiple myeloid malignancies.

Moving beyond ruxolitinib failure in myelofibrosis: evolving strategies for second line therapy.

INTRODUCTION: Ruxolitinib has been the cornerstone of pharmacologic therapy for myelofibrosis for over a decade. However, the last several years have witnessed the regulatory approval of other Janus kinase (JAK) inhibitors for myelofibrosis, i.e. fedratinib, pacritinib, and US approval of momelotinib is widely anticipated in 2023. AREAS COVERED: Due to the multifaceted clinical presentation of myelofibrosis, a watertight definition of ruxolitinib failure has remained elusive, as "progression" on ruxolitinib can take many forms and management is highly nuanced. Yet, the availability of other JAK inhibitors and potential future availability of non-JAK inhibitor agents for myelofibrosis make a consensus on management of ruxolitinib failure critically important. This consensus paper summarizes a discussion between multiple academic and community physician experts, a pharmacist and an advanced practice provider around the issues to be considered for the optimal care of patients with myelofibrosis whose disease is refractory to or does not respond adequately to ruxolitinib, or who exhibit intolerance to ruxolitinib. EXPERT OPINION: The panel identified several areas of consensus, as well as some areas where more data to inform evidence-based practice are needed. In some situations, maintaining ruxolitinib while adding another agent, e.g. to address anemia, is appropriate, whereas in others, switching to a different drug has merit.