Myelofibrosis: Current unmet needs, emerging treatments, and future perspectives.

The current standard-of-care for treatment of myelofibrosis (MF) comprises inhibitors of the Janus kinase (JAK)/signal transducers and activators (STAT) pathway; however, despite their ability to alleviate symptoms, they do not appear to modify underlying disease and have not demonstrated substantial survival benefit. Allogeneic-hematopoietic stem cell transplantation remains the only curative option for patients with MF but is limited to a subset of high-risk and fit patients. Early disease modification could positively affect disease trajectory for lower risk patients with MF as well as those with conditions that can precede MF, such as polycythemia vera and essential thrombocythemia. Here, the authors discuss critical unmet needs in the MF treatment paradigm, including: the need for safe, impactful therapies for lower risk patients, thus allowing intervention when success is most likely; better development of first-line therapies (likely highly novel or combination strategies) for intermediate-risk/higher risk patients; and approved drugs to manage cytopenia. Finally, a consensus definition of disease modification is needed that informs trial design, allowing the development of clinical end points that enable understanding of therapies and responses and that facilitate the development of therapies that work according to this definition. Through close collaboration between clinicians, patients, and the pharmaceutical industry, better efforts to define benefit and identify patients most likely to benefit from a particular combination or treatment strategy should enable the development of more effective and safe treatments to extend and improve quality of life for patients with MF.

Myeloproliferative neoplasms in the adolescent and young adult population: A comprehensive review of the literature.

Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR-ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well-tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. FUNDING: Sierra Oncology.

Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

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.

ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Comparative clinical and molecular landscape of primary and secondary myelofibrosis: Superior performance of MIPSS70+ v2.0 over MYSEC-PM.

Comparative clinical characteristics, molecular landscape and prognosis scoring for primary (PMF) and secondary myelofibrosis (SMF).

Meaningful Symptomatic Change in Patients With Myelofibrosis From the SIMPLIFY Studies.

OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies.

BACKGROUND: In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS). METHODS: This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation. RESULTS: The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0-70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%-73%] vs. 57% [95% CI, 49%-64%]; hazard ratio, 1.53; 95% CI, 1.01-2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT. CONCLUSIONS: These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS. PLAIN LANGUAGE SUMMARY: Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue. Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments. Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment. Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

Inferring the dynamics of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose.

Myeloproliferative neoplasms and splanchnic vein thrombosis: Contemporary diagnostic and therapeutic strategies.

Myeloproliferative neoplasms (MPNs) are the most common etiologies of primary splanchnic vein thrombosis, present in almost forty percent of patients with Budd-Chiari syndrome or portal vein thrombosis. Diagnosis of MPNs can be difficult in these patients because key characteristics, such as elevated blood cell counts and splenomegaly, are confounded by portal hypertension or bleeding complications. In recent years, diagnostic tools have improved to provide more accurate diagnosis and classification of MPNs. Although bone marrow biopsy findings remain a major diagnostic criterion, molecular markers are playing an increasing role not only in diagnosis but also in better estimating prognosis. Therefore, though screening for JAK2V617F mutation should be the starting point of the diagnostic workup performed in all patients with splanchnic vein thrombosis, a multidisciplinary approach is needed to accurately diagnose the subtype of myeloproliferative neoplasm, recommend the useful additional tests (bone marrow biopsy, search for an additional mutation using targeted next-generation sequencing), and suggest the best treatment strategy. Indeed, providing a specific expert care pathway for patients with splanchnic vein thrombosis and underlying myeloproliferative neoplasm is crucial to determine the optimal management to reduce the risk of both hematological and hepatic complications.

Revisiting Diagnostic performances of serum erythropoïetin level and JAK2 mutation for polycythemias: analysis of a cohort of 1090 patients with red cell mass measurement.

We assessed the diagnostic performances of erythropoietin and JAK2 mutations in 1,090 patients with suspected polycythemia who were referred for red cell mass (RCM) measurement. In patients with a high haematocrit and/or haemoglobin level, a low erythropoietin level (<=3·3 mUI/ml) and JAK2 mutation showed comparable positive predictive value (PPV) for true polycythemia (RCM>=125%), 92·1% and 90% respectively. A very-low erythropoietin level (<=1·99 mUI/ml) had a PPV of 100% for polycythemia vera (PV) diagnosis. We confirmed the correlations between RCM, erythropoietin and JAK2 variant allelic frequency in PV patients. This study prompts the need to revisit the role of EPO in PV diagnostic criteria.

Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2V617F myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S ) in a large family diagnosed with JAK2V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN.

Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations.

Genes encoding the RNA splicing factors SF3B1, SRSF2, and U2AF1 are subject to frequent missense mutations in clonal hematopoiesis and diverse neoplastic diseases. Most "spliceosomal" mutations affect specific hotspot residues, resulting in splicing changes that promote disease pathophysiology. However, a subset of patients carries spliceosomal mutations that affect non-hotspot residues, whose potential functional contributions to disease are unstudied. Here, we undertook a systematic characterization of diverse rare and private spliceosomal mutations to infer their likely disease relevance. We used isogenic cell lines and primary patient materials to discover that 11 of 14 studied rare and private mutations in SRSF2 and U2AF1 induced distinct splicing alterations, including partially or completely phenocopying the alterations in exon and splice site recognition induced by hotspot mutations or driving "dual" phenocopies that mimicked 2 co-occurring hotspot mutations. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis and illustrate the utility of molecular assays to inform precision medicine by inferring the potential disease relevance of newly discovered mutations.

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.

The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes.

BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

Perspective: Pivotal translational hematology and therapeutic insights in chronic myeloid hematopoietic stem cell malignancies.

Despite much of the past 2 years being engulfed by the devastating consequences of the SAR-CoV-2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show-cased at the 15th Post-American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th-10th December 2020 and 7th-10th October 2021, respectively. The inaugural Post-ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data.

In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population.