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Polycythemia vera (PV) is a burdensome, chronic myeloproliferative neoplasm characterized by activating mutations in Janus kinase 2, erythrocytosis, and bone marrow hypercellularity. The goals of treatment are to achieve hematocrit and blood count control to ultimately reduce the risk of thrombohemorrhagic events and improve PV-related symptoms. Treatment is risk-stratified and typically includes cytoreduction with hydroxyurea or interferon formulations in first line for high-risk disease. However, inadequate response, resistance, or intolerance to first-line cytoreductive therapies may warrant introduction of second-line treatments, such as ruxolitinib. In this review, I detail preferred treatment and patient management approaches following inadequate response to or intolerance of first-line treatment for PV.

Thrombocytopenia in patients with myelofibrosis (MF) is prognostically detrimental and poses a therapeutic challenge. MF patients with thrombocytopenia are considered high-risk by most prognostic models and their distinct phenotype has given rise to the emerging concept of cytopenic MF. Yet, the mechanisms underlying thrombocytopenia in MF are poorly understood.This study aimed to highlight the genetic mechanisms driving low platelet counts in treatment-naive MF patients, establish their phenotypic correlates, and assess prognostic factors specific to this group of patients.The authors found that most patients presenting with low platelets had a clear thrombocytopenia-specific genetic abnormality involving a U2AF1 Q157 mutation, deletion 20q, molecular complexity (three or more mutations), or high-risk karyotype. Etiologic clustering did not correlate with prognosis; however, thrombocytopenic patients were found to have unique prognostic variables including low serum albumin and mutations of SRSF2 and TP53. This led to the proposal of a prognostic model (SRSF2, albumin, TP53 score) that stratifies thrombocytopenic patients as low, intermediate, or high-risk with corresponding median survivals of 93.5, 29.5, and 7.2 months, respectively.This study demonstrates that thrombocytopenia in MF is driven by different genetic mechanisms and is not uniformly high-risk. As novel agents with improved hematologic safety profiles enter the treatment landscape, thoughtful, risk-adapted therapeutic decisions will be required for MF patients with thrombocytopenia.A significant minority of patients with myelofibrosis (MF) present with low platelets. Historically, these patients have been viewed as having "high-risk" disease, but this may not be uniformly true. Our study shows that there are various different causes for low platelets in MF, some of which represent high-risk disease whereas others do not. Additionally, our study shows that genetic mutations affecting the genes SRSF2 and TP53 are uniquely problematic in this group, as is a low serum albumin level. This study helps to risk-stratify MF patients with thrombocytopenia, thereby providing more information to guide informed and individualized treatment decisions.

Up to 20% of patients with myeloproliferative neoplasms (MPN) will progress to blast phase (MPN-BP). Outcomes are dismal, with intensive chemotherapy providing little benefit. Low-intensity therapy is preferred due to better tolerability, but the prognosis remains poor. Allogeneic stem cell transplant (AHSCT) is still the only potential for long term survival.To better evaluate the initial treatment approach in MPN-BP, we performed a single-institution retrospective analysis of 75 patients with MPN-BP treated at Moffitt Cancer Center between 2001 and 2021. Patients were stratified by initial treatment: best supportive care (BSC), hypomethylating agent (HMA)-based therapy or intensive chemotherapy (IC).Median overall survival (mOS) for the entire cohort was 4.8 months (BSC 0.8 months, HMA 4.7 months, and IC 11.4 months). Among IC patients, improved survival was evident in those that received AHSCT (mOS 40.8 months vs. 4.9 months, p.01). Most patients that underwent AHSCT were initially treated with IC (p.01). All patients that underwent AHSCT had achieved complete response (CR) or CR with incomplete hematological recovery (CRi). On multivariate analysis, factors associated with improved survival were receipt of therapy (HMA or IC) (P = .017), CR/CRi (P = .037) and receipt of AHSCT (p.001).We show that active treatment with IC improves survival, but it is mostly tied to receipt of AHSCT. IC is a reasonable approach in appropriate patients as it can provide an effective bridge to AHSCT. Other treatment strategies such as molecularly targeted therapy and novel agents are desperately needed.

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; 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.

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.

The classic Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

Komrokji et al examined the proposed international working group proposal to designate SF3B1-mutant myelodysplastic syndrome (MDS) as a unique disease entity, using a single-institution validation cohort of 1779 MDS patients, of whom 320 harbored SF3B1 mutations. They confirmed the demographics of older age, low-risk disease, ring sideroblasts, and low blast percentage. They further confirmed better overall survival that is negatively impacted in those patients with concomitant mutations, high variant allele fraction, and increased blast percentage.

Introduction: Polycythemia vera is a chronic hematologic malignancy frequently presented with constitutional symptoms and associated with an increased risk of thrombosis, hemorrhage, and progression to myelofibrosis or acute myeloid leukemia. Current treatment strategies reduce thrombohemorrhagic risk by controlling blood counts and inhibiting platelets, but often fail to address disease-related symptoms or biologically modify the disease.Areas covered: We review the current paradigm for treating polycythemia vera, highlight areas of unmet need, review therapeutic agents in late stage clinical development, and provide an overarching view of how these emerging agent may fit into the future armamentarium of polycythemia vera treatments.Expert opinion: The shift from focusing solely on secondary prevention of thrombohemorrhagic events to a comprehensive treatment strategy that additionally aims to improve quality of life and prevent disease progression has resulted in a rapidly evolving therapeutic landscape that promises to move the treatment of polycythemia vera out of antiquity into the modern age.

EZH2 mutations in myeloid neoplasms are loss of function type, and have been linked to poor overall survival (OS) in patients with myelodysplastic syndrome (MDS). However, the specific determinants of outcomes in EZH2-mutant (mut) MDS are not well characterized. In this single-center retrospective study, clinical and genomic data were collected on 1774 patients with MDS treated at Moffitt Cancer Center. In our cohort, 83 (4.7%) patients had a pathogenic EZH2 mutation. Patients with EZH2mut MDS were older than EZH2-wild type (wt) group (median age- 72 vs. 69 years, p = 0.010). The most common co-occurring mutation in EZH2mut MDS was ASXL1, with a significantly higher frequency than EZH2wt (54% vs. 19%, p 0.001). Patients with EZH2mut MDS had lower response rates to hypomethylating agents compared to EZH2wt MDS (26% vs. 39%; p = 0.050). Median OS of patients with EZH2mut MDS was 30.8 months, with a significantly worse OS than EZH2wt group (35.5 vs. 61.2 months, p = 0.003) in the lower-risk IPSS-R categories. Among patients with EZH2mut MDS, co-presence of ASXL1 or RUNX1 mutations was associated with inferior median OS compared to their wt counterparts (26.8 vs. 48.7 months, p = 0.031). Concurrent chromosome 7 abnormalities (12%) were also associated with significantly worse OS (median OS- 20.8 vs. 35.5 months, p = 0.002) in EZH2mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2mut MDS.

Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established.In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26).Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p = .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response.Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPNs) are molecularly complex, clinically heterogeneous diseases that exhibit proliferative and dysplastic features. Diagnostic criteria use clinical, pathologic, and genomic features to distinguish between disease entities, though considerable clinical and genetic overlap persists. MDS/MPNs are associated with a poor prognosis, save for MDS/MPN with ring sideroblasts and thrombocytosis, which can behave more indolently. The current treatment approach is risk-adapted and symptom-directed and largely extrapolated from experience in MDS or MPN. Gene sequencing has demonstrated frequent mutations involving signaling, epigenetic, and splicing pathways, which present numerous therapeutic opportunities for clinical investigation.

Background: Obesity has been associated with increased incidence of myelodysplastic syndromes (MDS). Recently intriguing data in mouse models suggested that obesity increases survival in animals wi...

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately use repeated-measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic laboratory data at ∼3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling to identify latent clusters of patients who follow distinct trajectories with regard to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of 2 major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with the hazard of a thrombotic event (P = .4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall P = .0002). In addition, we found that neither hematocrit nor platelet count was significantly associated with the hazard of thrombosis or disease evolution.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

Recent studies demonstrated that MYC epigenetically regulates AML cell survival and differentiation by suppressing IDH1/2-TET2-5hmC signaling and that MYC overexpression is associated with poor survival outcomes in multiple AML patient cohorts. However, the oncogenic roles of MYC in MDS remain to be explored. A total of 41 patients with de novo MDS were retrospectively identified using the Total Cancer Care database at the Moffitt Cancer Center. A total of 61 % of patients had low MYC expression and 39 % of patients had high MYC expression defined as MYC reactivity by immunohistochemical staining in ≥5% of bone marrow (BM) cells at the time of MDS diagnosis. The median MDS-to-AML progression free survival (PFS) was significantly shorter in the high MYC group (median PFS 9.3 vs. 17.7 months, HR = 2.328, p = 0.013). Further, overall survival (OS) was also shorter in the high MYC patients (median OS 19.7 vs. 51.7 months, HR = 2.299, p = 0.053). Multivariate analyses demonstrated that high MYC expression is an independent poor prognostic factor for the MDS-to-AML progression (HR = 2.275, p = 0.046). Our observations indicate that MYC may play a crucial role in MDS transformation to AML and the underlying mechanisms of MYC-driven MDS clonal expansion and leukemic transformation require further investigation.

Preclinical Rationale: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm for which there are limited therapies. TGFβ plays a pivotal role in the pathobiology of MF by not only promoting bone marrow fibrosis (BMF) and collagen deposition, but also by enhancing the dormancy of normal but not MF hematopoietic stem cells (HSCs). TGFβ has also previously been reported to inhibit normal megakaryocyte (MK) production (Bruno et al Blood 1998). TGFβ1 promotes the synthesis of collagen by normal human mesenchymal stromal cells (MSCs) and activates the TGFβ receptor I/SMAD pathway as well as non-canonical TGFβ pathways. We generated MKs from MF subject mononuclear cells (MNCs) and showed that they elaborated significantly greater levels of TGFβ1 than TGFβ2/3 TGFβ1 treatment reduced the numbers of hematopoietic colonies generated by normal but not MF MNCs. Treatment of MSCs with AVID200, a potent TGFβ1/3 protein trap, significantly decreased MSC proliferation, phosphorylation of SMAD2, and collagen expression. Robust expression of pSMAD2 was observed in the absence of exogenous TGFβ in normal donor or MF-MKs, Addition of AVID200 to -MKs decreased pSMAD2 without affecting total SMAD2/3, indicating that AVID200 blocks the effects of autocrine TGFβ produced by MKs and led to increased numbers of MKs. Moreover, treatment of primary MF MNCs with AVID200 led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies. AVID200 blocked TGFβ1-induced p57Kip2 expression and SMAD2 activation by MF MNCs allowing the normal progenitor cells to preferentially cycle, proliferate, and form hematopoietic colonies. Clinical Trial Design: Based on these findings, a phase 1 trial of AVID200 is ongoing in INT-2/high risk MF subjects resistant or intolerant to ruxolitinib; baseline platelet count of ≥ 25 x 109/L, and grade 2/3 BMF. Subjects received intravenous AVID200 (Lots A and B) in dose cohorts of 180 mg/m2 (A), 550 mg/m2 (A), 180 mg/m2 (B) on Day 1 of a 21 day cycle. Cohorts of 3 subjects with a target toxicity rate of 30% were enrolled to estimate the maximum tolerated dose (MTD). A modified toxicity probability interval design was used. Response was assessed by IWG/ELN criteria after 6 cycles of AVID200. Subjects attaining at least a CI or SD with a decrease in BMF by ≥1 grade, continued AVID200. Clinical Trial Results: 10 subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 and were evaluable for DLT assessment [Table1]. Median time after ruxolitinib discontinuation was 3.5 months (0.5-12.2). No DLTs were observed. Grade 3/4 AEs (regardless of attribution) were observed in 6 (66.7%) subjects. Grade 3/4 non-hematologic AEs observed were epistaxis (1, 11.1%), extraocular muscle paresis (1, 11.1%), fatigue (1, 11.1%) and rash (1, 11.1%). Grade 3/4 hematologic AEs were anemia (3, 33.3%) and thrombocytopenia (2, 22.2%) [Table 2]. The median number of cycles received was 5.7 (range 0 - 12). 5 subjects received 6+ cycles and were evaluable. CI occurred in 2 subjects [anemia, spleen and TSS (n=1); TSS (n=1)] 1 of which is still being treated, 2 subjects had SD, 1 subject with 21% blasts prior to study treatment had progressive MPN-BP. 4 subjects failed to reach response evaluation after 6 cycles, 2 had PD due to increasing splenomegaly, 1 subject received an allogeneic transplant and 1 is still being treated [Cycle 2]. The median platelet count at baseline was 114 (range: 42-290) and 159 after cycle 6 [Figure 1]. Maximum changes in platelets from baseline was +64% [range -73%, 169%] in all subjects. 7 subjects had an increase in platelets from baseline during treatment. 2 subjects normalized their platelet count from thrombocytopenic levels. The effect of AVID200 on BMF is currently being examined. 2 subjects remain on treatment. Conclusions: AVID200 a TGFβ1/3 protein trap is well tolerated in advanced MF subjects. Clinical responses were observed at the 550 mg dose and the expansion efficacy cohorts at doses 2 and 3 are enrolling 12 additional subjects. Furthermore, AVID200 therapy improved thrombocytopenia in MF subjects which may be due to AVID200 inhibiting the effects of TGFβ1 on normal MKpoiesis. Updated subject safety and efficacy data along with correlative data will be presented. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Komrokji:Jazz: Honoraria, Speakers Bureau; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Geron: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria. Gerds:Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding. Migliaccio:Novartis: Research Funding. O'Connor-McCourt:Forbius: Current Employment. Tremblay:Forius: Current Employment. Nadler:Forbius: Consultancy; Nadler Pharma Associates: Current Employment; Symphogen: Consultancy; Iksuda Therapeutics: Consultancy; Tessa Therapeutics: Consultancy. Mesa:Celgene: Research Funding; Genetech: Research Funding; Samus: Research Funding; Promedior: Research Funding; CTI: Research Funding; LaJolla Pharma: Consultancy; Incyte: Research Funding; Sierra Onc: Consultancy; Abbvie: Research Funding; Novartis: Consultancy. Hoffman:Forbius: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Protagonist: Consultancy.

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels 45%, thereby potentially increasing their risk of thrombosis. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis [Ginzburg Leukemia 2018] and worsens after repeated and/or frequent TP, and often symptomatic from their iron deficiency. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies. In a phase 2 trial in β-thalassemia, PTG-300 leads to a sustained (3-7 days) decrease in serum iron and transferrin saturation (TSAT) but did not demonstrate off-target effects. The current study aims to compare the iron status and phlebotomy requirements in high TP-requiring PV patients before and during treatment with PTG-300 (Figure 1). Methods. PTG-300-04 is a 3-part Phase 2 trial consisting of (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3) a 52-week open label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to enrollment. PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly were adjusted to maintain hematocrit Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. After instruction, each of the patients self-administered the drug at home. Eight subjects have been treated for ≥3 months with PTG-300 (Figure 2a). Three subjects have been randomized. During the open label dose finding portion of the study, all subjects were phlebotomy-free with the exception of one subject. Three subjects completed part 1 (28 weeks) with no TP as compared to 3-5 TP required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two subjects' (Figure 2b). Two subjects had hematocrits transiently >45% but remained below 45% after phlebotomy in one and dose increase in both. Furthermore, erythrocyte numbers decreased (Figure 2c) and MCV increased in all but two subjects. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron-related parameters were consistent with systemic iron deficiency while serum ferritin increased progressively toward normal range. Most frequent adverse events were injection site reaction (ISR) reported by three patients. Most of the reactions were grade 1-2 and were transient in nature and no patient discontinued the drug. Conclusions. The current results indicate that PTG-300 is an effective agent for the treatment of PV, reversing iron deficiency and eliminating the need for TP in PV patients. Elimination of TP requirements for 7 months in TP-dependent PV patients is significant and unexpected. The effect of PTG-300 on PV-related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. PTG-300 looks very promising in eliminating the therapeutic phlebotomies in both low and high-risk patients. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Dynavax: Current equity holder in publicly-traded company. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding; Protagonist: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding. Hoffman:Forbius: Consultancy; Dompe: Research Funding; Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

7055 Background: CMML is a heterogenous disease exhibiting features innate to MPN and MDS. Increasing evidence supports a close interplay between systemic inflammation and risk of myeloid malignancies, notably for those with history of infection or autoimmune disease. CMML has been associated with inflammation and end-organ damage related to CKD and CVD. Analysis of gene signatures from CMML-derived monocytes has shown them to be highly proinflammatory. High ferritin may serve as a practical biomarker of disease activity to help identify pts at higher risk of poor outcomes. Methods: Retrospective data was collected from a database of CMML pts treated at Moffitt Cancer Center. Pts were stratified in 2 cohorts based on ferritin levels ( < 1000 or ≥1000 ng/mL). Hyperferritinemia was defined as ferritin > 1000 as seen at diagnosis or during follow-up. Kaplan–Meier was used to estimate OS. Cox regression was used for multivariate analysis. Results: Between August 1995 and October 2020 729 pts with CMML were identified. Median age at diagnosis was 71 (17-95). Out of 571 pts with available ferritin levels 29% (n = 168) developed hyperferritinemia vs 71% (n = 403) who did not. mOS was 32.4 mos (95%CI 30-35 mos). Pts with higher ferritin tended to present with CMML-2 (p = 0.001) and harbor a proliferative phenotype (p = 0.01). They presented with higher marrow cellularity (mean 83%, p = 0.08), PLT (mean 177k, p = 0.038), and lower Hb (mean 9.5, p < 0.05). There was no association with % circulating IMC, monocytes, WBC or ANC at baseline. Hyperferritinemia was associated with more profound fibrosis (p = 0.007), cytopenias (p < 0.05), % peripheral blasts (p < 0.05), RBC and PLT transfusion dependence (p < 0.05). Pts with hyperferritinemia had higher risk disease per IPSS-R, CPSS and all CMML models (p < 0.05); and had higher rates of AML transformation (p < 0.05). Pts were also more likely to require treatment earlier (within 3 yrs of diagnosis) (p < 0.05). ASXL1 (p = 0.002), EZH2 (p = 0.003), and SETBP1 (p = 0.019) mutations were more common among pts with hyperferritinemia. Conversely, TET2 (p = 0.001), CBL (p = 0.028) and SRSF2 (p = 0.003) mutations were less common. mOS for pts with hyperferritinemia was 23.9 mos (95%CI 19.9-27.9 mos), much lower than for those with ferritin < 1000 (mOS 40.5 mos, 95%CI 35.4-45.5 mos) (p < 0.05). In multivariate analysis, hyperferritinemia was a significant independent covariate for OS after adjusting for CPSS, transfusion dependence and disease phenotype (dysplastic vs proliferative) (HR = 0.69; 95%CI 0.53-0.89; p = 0.005). Conclusions: Almost 1/3 of pts with CMML will develop hyperferritinemia. This is associated with more aggressive disease and higher rates of AML transformation leading to dismal outcomes. ASXL1, EZH2, and SETBP1 MTs confer a higher risk of hyperferritinemia. Our findings indicate that hyperferritinemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology and comorbidities in CMML.

7061 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials, including in MF patients (pts) with thrombocytopenia. MOMENTUM is a pivotal phase 3 study of symptomatic and anemic MF pts previously treated with a JAK inhibitor (JAKi) testing MMB vs DAN. This analysis evaluated MOMENTUM pts with baseline (BL) platelet counts (PLT) ≤150 x 109/L. Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb 9/L. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks. Primary endpoint: TSS response (≥50% reduction from BL) rate at wk 24. Key secondary endpoints, assessed sequentially at wk 24: RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 60 (74%) of 81 MMB pts and 25 (58%) of 43 DAN pts with BL PLT ≤150 x 109/L completed the 24-week randomized treatment (RT) phase. Median BL TSS were 29 (MMB) and 24 (DAN), Hgb were 7.9 (MMB) and 8.0 (DAN) g/dL, and PLT were 67 x 109/L (MMB) and 64 x 109/L (DAN). Prior JAKi was ruxolitinib in 124 pts (100%) and fedratinib in 6 pts (5%). Efficacy results are in Table. These results are consistent with the overall ITT analysis set (N=195). Most common Gr ≥3 TEAEs in the RT phase were thrombocytopenia (MMB, 31%; DAN, 16%) and anemia (MMB, 7%; DAN, 14%); Gr ≥3 bleeding events occurred in 9% of MMB and 5% of DAN pts. TEAEs led to study drug discontinuation in 15% of MMB and 19% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN [HR (95% CI)=0.490 (0.195, 1.235)]. Additional analyses of pts with BL PLT 9/L (N=100) and BL PLT 9/L (N=31) show similar treatment effects of MMB vs DAN. Conclusions: In thrombocytopenic MF pts who were symptomatic and anemic, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses and showed comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF pts. Clinical trial information: NCT04173494. [Table: see text]

7002 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials. This pivotal phase 3 study of MF patients (pts) previously treated with a JAK inhibitor (JAKi) tested MMB vs DAN on key symptom, anemia, and spleen volume endpoints at 24 weeks (wks). Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb 9/L. BL TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%). All primary and key secondary endpoints were met (Table). Most common Gr ≥3 TEAEs in the RT phase of the study were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). Gr ≥3 infections occurred in 15% of MMB and 17% of DAN pts. Peripheral neuropathy occurred in 5 (4%) of MMB (all Gr ≤2) and 1 (2%) of DAN (Gr ≤2) pts in the RT phase, and none discontinued study drug. Overall, TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN (HR=0.506, p=0.0719). Conclusions: In symptomatic and anemic MF pts, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF pts with anemia. Clinical trial information: NCT04173494. [Table: see text]

Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPNs) are molecularly complex, clinically heterogeneous diseases that exhibit proliferative and dysplastic features. Diagnostic criteria use clinical, pathologic, and genomic features to distinguish between disease entities, though considerable clinical and genetic overlap persists. MDS/MPNs are associated with a poor prognosis, save for MDS/MPN with ring sideroblasts and thrombocytosis, which can behave more indolently. The current treatment approach is risk-adapted and symptom-directed and largely extrapolated from experience in MDS or MPN. Gene sequencing has demonstrated frequent mutations involving signaling, epigenetic, and splicing pathways, which present numerous therapeutic opportunities for clinical investigation.

Context: Chronic myelomonocytic leukemia (CMML) is characterized by marked clinical heterogeneity. Generally associated with poor outcomes, median overall survival (mOS) is 3 years. Multiple prognostic models consider cardinal clinical, cytogenetic, and molecular features as critical for estimating individual risk and outlining treatment. Identification and longitudinal assessment of features of interest have become important for predicting which patients tend to have a more indolent course compared to those who will progress. Objective: To identify patients with more indolent CMML and analyze disease features at the time of diagnosis. Design: Retrospective cohort of patients with CMML treated at Moffitt between 1995–2020. Patient Population: 729 patients with CMML. Interventions: Data were collected retrospectively. Patients were stratified into 2 cohorts: those remaining in observation for >3 years versus those who required treatment Main Outcome Measures: Correlation between baseline characteristics and treatment initiation within 3 years, OS. Results: Out of 729 patients, 68.3% were male (498), and 88.5% were Caucasian (645). Median age at diagnosis was 71 (17–95) years. A total of 123 patients (17%) did not require treatment within 3 years of diagnosis. mOS was 70 mo among those who did not require early treatment, compared to 25 mo for those who did (p Conclusions: A small subset of CMML patients (17%) have a more indolent disease course. Clinical and molecular features at diagnosis can be assessed to identify them. Next, we aim to identify changes in clinical and molecular features from baseline immediately anteceding the need for treatment to establish whether they predict disease evolution.

Background: NPM1 is commonly mutated in AML and represents a distinct entity under the WHO 2016 classification. It is one of the few mutations that can potentially support favorable risk by ELN 2017. Mutations that are highly specific for secondary AML (sMT) including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 (Lindsley et al.) have been shown to confer poor prognosis. Objective: In this study, we explore the outcomes in patients with NPM1 mutated AML. Methods: This was a retrospective study of NPM1 AML mutated patients who were treated at the Moffitt Cancer Center from 2013-2020. Only those with NPM1 mutations and NGS performed at diagnosis were included in the study (n=115). Kaplan-Meier, univariate, and multivariate analyses were performed. Results: Of the 115 patients (54M/85F, median age 61 at diagnosis), majority had de novo AML (83.5%). Over half of them had favorable risk (55.7%), followed by intermediate risk (35.6%), and adverse risk (8.7%). Almost 80% had normal cytogenetics at the time of diagnosis. Common co-mutations included DNMT3A (47.8%), FLT3-ITD (39.1%), TET2 (20%), FLT3-TKD (18.3%), IDH1 (18.3%), and IDH2(16.5%). sMT occurred in 16.5% of the entire cohort and 17.2% among those with ELN favorable risk. Patients with sMT have a significantly lower rates of relapse freedom after CR/CRi (26.3% vs 52.1%, p=0.047). Numerically, higher rates of relapse after CR/CRi (47.4% vs 34.4%, p=0.301) and higher rates of never achieving CR/CRi (26.3% vs 13.5%, p=0.175). Among favorable risk, OS was 14. 7 months for sMT vs not reached for those without sMT (p Conclusions: Our findings suggest NPM1 mutated AML patients with sMT have significantly worse prognosis despite being classified as favorable risk by ELN 2017 at diagnosis. This may have treatment implications in the need for and/or timing of HCT. Further studies and larger datasets are needed to confirm these observations.

Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of MF, it is not without limitations. In an effort to improve treatment for MF patients, there have been significant efforts to identify combination strategies that build upon the substantial benefits of JAK inhibition. Early efforts to combine agents with additive therapeutic profiles have given way to rationally designed combinations hoping to demonstrate clinical synergism and modify the underlying disease. In this article, we review the preclinical basis and existing clinical data for JAK inhibitor combination strategies while highlighting emerging strategies of particular interest.

Anemia in myelofibrosis (MF) occurs frequently, is poorly addressed by US Food and Drug Administration-approved JAK inhibitors, and negatively impacts quality of life. Immunomodulatory imide agents (IMiDs) such as thalidomide and lenalidomide are among the limited treatment options that have demonstrated anemia benefit in single-arm studies.To better understand the comparative impact of lenalidomide and thalidomide in MF patients, we analyzed 176 consecutive MF patients who received lenalidomide or thalidomide for at least 4 weeks. We sought to understand the variability in patient populations receiving lenalidomide versus thalidomide, to assess the efficacy of these agents, and to investigate clinical or genomic features that predict response.Clinical benefit (CB) was assessable in 83 lenalidomide- and 67 thalidomide-treated patients. Thalidomide-treated patients were more likely to have thrombocytopenia (P .001) and high-risk disease (P = .02). Forty-one (49%) lenalidomide-treated patients were deemed to have CB, predominantly due to anemia benefit. Similarly, 28 (42%) of thalidomide-treated patients had CB attributable to anemia benefit. Overall survival was similar for lenalidomide- and thalidomide-treated patients (P = .51). Lenalidomide-treated patients with CB had longer overall survival than those who did not (P = .01). High-risk mutations were found in 12 (41%) of 29 and 20 (57%) of 35 patients treated with lenalidomide and thalidomide, respectively (P = .32). Splicing mutations were common in both cohorts, though thalidomide-treated patients were more likely to have a high-risk SRSF2 or U2AF1 Q157 mutation (P = .01).Overall, in this retrospective analysis, lenalidomide and thalidomide showed similar rates of CB in a cohort of MF patients that frequently harbored splicing mutations.

Background Cytogenetic profile is an essential parameter in myelodysplastic syndromes (MDS) risk stratification by both International Prognostic Symptom Score (IPSS) and Revised (R)-IPSS. Almost one-half of patients with MDS have normal cytogenetics by metaphase karyotype. Here we report the yield of MDS fluorescence in situ hybridization (FISH) panel detecting cytogenetic abnormalities in these patients and its impact on risk stratification. Patients and Methods Among patients with normal metaphase karyotype, we assessed those patients who had cytogenetic abnormalities detected by an MDS FISH panel, which included probes for del (5), del (7), del (20), trisomy 8, and del (17p). Risk stratification was calculated by both IPSS and R-IPSS. Results Of 1600 patients with MDS with normal metaphase karyotype, 53 (3%) patients had cytogenetic abnormality detected by MDS FISH panel. Integrating the MDS FISH panel cytogenetics (IPSS + FISH restaging) resulted in upstaging the score, where 53% of low-risk IPSS were upstaged to intermediate (int)-1, 56% of int-1 were upstaged to int-2, and 78% of int-2 were upstaged to high risk. Based on the R-IPSS, 61% of very low-risk patients, all low-risk patients, 92% of intermediate-risk patients, and 50% of high-risk patients with FISH abnormalities were upstaged, respectively. Conclusion The yield of MDS FISH panel detecting cytogenetic abnormalities in patients with normal karyotype by G-banding is low and may not warrant ordering the panel in all patients. Among the 3% of patients with normal karyotype who had cytogenetic abnormality detected by FISH, the risk score assignment by IPSS and R-IPSS was upstaged.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by clonal overproduction of platelets and an increased risk of thrombohemorrhagic complications. Patients are risk stratified by driver mutation, age, and thrombotic history and treated to reduce the risk of thrombotic and hemorrhagic events. The significance of platelet number as a risk factor or treatment goal is unclear. Despite the preponderance of data failing to demonstrate an association, there exists a pervasive belief that higher platelet counts correlate with an increased thrombotic risk. In fact, the association between thrombocytosis and bleeding is more clearly supported. Variability in regional consensus guidelines contributes to the uncertainty. This article reviews the data that shed light on the importance of platelet count in patients with ET.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

A genetically inspired prognostic scoring system (GIPSS) that stratifies primary myelofibrosis (PMF) patients by genetic variants alone was recently proposed. While non-inferior to the dynamic international prognostic scoring system (DIPSS), the lack of overlapping prognostic variables between the models leads to increased risk for disagreement between two valid prognostic models and presents a challenging clinical situation. In an external cohort of 266 molecularly annotated myelofibrosis (MF) patients, we demonstrated that the GIPSS model significantly differentiated between four risk groups (low, int-1, int-2, high) with median OS that was not reached, not reached, 60.5 and 28.9 months, respectively. High-risk patients had significantly inferior leukemia-free survival (LFS) (P < 0.0001). We identified a cohort of prognostically ambiguous patients (n = 39) in which GIPSS and DIPSS models differed by ≥2 risk groups. Among these patients, a similar proportion were up-staged by DIPSS (n = 19) and GIPSS (n = 20). Patients upstaged by GIPSS (genetically high-risk) had a trend toward inferior OS compared with patients upstaged by DIPSS (clinically high-risk) (P = .08) and significantly worse LFS (P = .04). Patients deemed intermediate-2 and high-risk by GIPSS who underwent allogeneic transplant had improved OS compared with those that did not (P = .04). GIPSS is a valid disease-specific prognostic system and outperforms DIPSS in patients where the two models disagree. Additionally, while GIPSS was developed for PMF; the current study shows, however, that the contemporary genetic model performs equally well for both primary and secondary myelofibrosis.