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Myelodysplastic syndromes (MDS) form a clinically and molecularly heterogeneous disease group. Precise risk stratification remains crucial for choosing optimal management strategies. Several conventional prognostic scoring systems have been developed and validated in the MDS population. These risk models divide patients into prognostic subgroups based on clinical and cytogenetic characteristics. Lack of dynamicity, variable risk estimate across models, and heterogeneity within intermediate-risk group are the limitations of traditional models like IPSS-R, with questionable relevance of these scoring systems in treated MDS patients. Recent progress in next-generation sequencing techniques has improved understanding of the distribution and prognostic importance of recurrent genetic mutations in MDS. Early studies have suggested that incorporating mutations in risk stratification could supplement IPSS-R in further refining the model's performance in predicting overall survival and risk of transformation to acute myeloid leukemia and should translate into a molecularly driven prognostication approach in the near future. [ABSTRACT FROM AUTHOR]

The utility of the International Working Group (IWG) 2006 response criteria for myelodysplastic syndromes (MDS) as a surrogate endpoint for outcomes is unclear. We assessed the validity of the IWG 2006 response criteria in a large cohort of higher‐risk MDS patients (pts) treated at centers from the MDS Clinical Research Consortium. The best overall response rate (ORR) by IWG 2006 criteria to first‐line therapy among 597 evaluable pts was 38% and include complete response (CR) 16%, marrow CR (mCR) 2%, partial response (PR) 10%, hematological improvement (HI) 10%, stable disease (SD) 33%, and progressive disease (PD) 24%. CR was associated with a better overall survival (OS) compared to all other response groups (P < 0.001). Among 470 pts treated with hypomethylating agent (HMA) as first‐line therapy, the overall Response Rate, defined as HI or better was 39%. The median OS from time of best response was 21 mo, 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P < 0.001). We validated those results in a separate cohort of 539 higher‐risk MDS pts treated at Moffitt Cancer Center who received first‐line HMA therapy, particularly addressing the value of mCR and mCR+HI. mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI. In conclusion, CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher‐risk MDS pts. Any response associated with restoration of effective hematopoiesis is associated with better outcome. [ABSTRACT FROM AUTHOR]

• Glasdegib in HMA-refractory MDS and CMML has limited single-agent activity. • 56% of heavily pretreated, primarily high-risk MDS patients had stable disease after glasdegib administration. • Stable disease or better was an independent covariate for improved overall survival. • Results support investigation of glasdegib in novel drug combinations. Hypomethylating agent (HMA) failure myelodysplastic syndrome (MDS) patients have poor outcomes and urgent need for novel therapies. Hedgehog pathway signaling upregulation plays a central role in myeloid neoplasm pathogenesis and leukemia stem cell survival. We evaluated the efficacy and safety of the smoothened inhibitor glasdegib in HMA-failure MDS (n = 35, median age 73 years). According to the International Prognostic Scoring System and the MD Anderson Global Risk Model, 54% and 77% had higher risk disease, respectively. Overall response was 6% (n = 2), and best response was marrow complete remission with hematologic improvement in both patients. Median OS and median follow-up were 10.4 and 42.8 months, respectively. Drug response/stable disease (SD) resulted in better OS than treatment failure (20.6 [95% CI, 10.4-] vs 3.9 months [95% CI, 0.7–9.1]; P <.0001). Response/SD was confirmed to be an independent covariate for improved OS (P <.0001). Grade 3 or higher infections occurred in 11% of patients (n = 4); non-hematologic toxicities were rare. Early mortality (< 30 days) occurred in 11% of patients (n = 4). Glasdegib was well tolerated among HMA-failure MDS patients, although single-agent activity was limited. SD or better resulted in notably superior OS. These results support further investigation of glasdegib, potentially in novel drug combinations, in MDS patients. [ABSTRACT FROM AUTHOR]

Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p < 10 −4 ) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS. [ABSTRACT FROM AUTHOR]

Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100000× 109/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ≥35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ≥50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. [ABSTRACT FROM AUTHOR]

BACKGROUND Previous studies have suggested that many patients with myelodysplastic syndromes (MDS) have an incomplete understanding of their disease, which may influence adherence to prescribed regimens and outcomes. METHODS To better understand physician and patient perceptions about MDS and MDS therapy, the authors conducted 2 surveys in February 2012: 1 for patients with MDS and 1 for health care professionals (HCPs) who cared for patients with MDS. Patient and HCP surveys consisted of 57 and 49 questions, respectively, assessing understanding of MDS, perceptions of specific treatments, barriers to treatment adherence, and treatment experience. RESULTS In total, 477 complete patient responses and 120 complete HCP responses were received. Among patient responders, 63% were aged ≥60 years, and 42% had received at least 1 disease-modifying therapy. Of the 61 physician responders, 57% practiced in an academic setting, and 43% practiced in the community; 71% of the 59 nonphysician HCPs worked in the community setting. Only 10% of patients agreed that MDS represented 'cancer' compared with 59% of physicians and 46% of nonphysician HCPs ( P < .001). Only 29% of patients reported that MDS was ever 'curable' compared with 52% of physicians ( P < .001). Physicians viewed the potential benefits of active therapy as greater than patients, but patients perceived the actual treatment experience more positively than physicians and differed from physicians in perceived reasons for stopping therapy. CONCLUSIONS Physicians, nonphysician HCPs, and patients with MDS have disparate views of MDS characteristics and the value and limitations of treatments for MDS. Improved communication and education may increase understanding and achieve better treatment adherence and patient outcomes. Cancer 2014;120:1670-1676. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

The multi-kinase inhibitor rigosertib ( ON 01910. Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to determine the pharmacokinetic profile, maximum-tolerated dose ( MTD), safety, and clinical activity of an oral formulation of rigosertib in patients with myelodysplastic syndromes ( MDS). For pharmacokinetic studies, patients received rigosertib in single escalating weekly doses. To determine the MTD, patient cohorts received escalating doses of rigosertib twice daily for 14 d of a 21-d cycle. Overall, 37 patients were treated. Rigosertib exposure increased with escalating oral doses. Mean absolute oral bioavailability ranged from 13·9% (fed) to 34·8% (fasting) in 12 patients treated at the 560 mg b.i.d. dose level. Dose-limiting toxicity (grade 3 dysuria and shortness of breath) occurred at the 700 mg b.i.d. dose. Five patients experienced grade 3 non-haematological toxicity, including symptoms of urothelial inflammation, hypotension and syncope, fatigue and abdominal pain. Encouraging signs of clinical activity included two bone marrow complete remissions in refractory anaemia with excess blasts type 1 patients previously treated with azacitidine. In addition, four patients each achieved transfusion independence and haematological improvements. In conclusion, oral rigosertib is bioavailable and well tolerated, and has clinical activity in patients with MDS. [ABSTRACT FROM AUTHOR]

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (Hl-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to lntermediate-1-risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid non-responders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, Hl-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving Hl-E. In 19 non-del(5q) patients, 4 (21.1%) showed Hl-E. Mean baseline serum EPO in non-del(5q) patients was lower In monotherapy and CT responders than in NR (not statistically significant). Thrombocy-topenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)-sponsored intergroup study. This study Is registered at www. clinicaltrials.gov as NCT00910858. [ABSTRACT FROM AUTHOR]

BACKGROUND: The proposed MD Anderson Risk Model Score (MDAS) for myelodysplastic syndromes (MDS) refines outcome discrimination compared with the International Prognostic Scoring System (IPSS). We applied the MDAS to Moffitt Cancer Center (MCC) MDS patients to validate its prognostic utility. METHODS: This was a retrospective analysis of MDS cases, as defined by World Health Organization criteria, from the Moffitt database, with confirmatory chart review. RESULTS: A total of 775 patients evaluated between January 2001 and December 2009 were included. Patients were reclassified by MDAS as low (20.6%), intermediate-1 (31%), intermediate-2 (21%), high risk (16.1%), and unknown (11.2%). Median overall survival (OS) from diagnosis was 92, 49, 27, and 14 months for low, intermediate-1, intermediate-2, and high-risk MDAS groups, respectively ( P < .005). Median OS from referral was 61, 28, 15, and 8 months ( P < .005), respectively. Among 484 patients classified by IPSS as low or intermediate-1 risk, 25% were up-staged as intermediate-2 or high risk by MDAS; 4 prognostically distinct subgroups were identified among lower risk IPSS categories with median OS of 93, 53, 31, and 18 months ( P < .005). Among 201 intermediate-2 or high-risk IPSS patients, 15.4% were down-staged to intermediate-1 by MDAS, with 3 groups identified by MDAS having median OS of 33, 23, and 14 months. Acute myeloid leukemia transformation rate was highest among high-risk MDAS (50.4%). In Cox regression analysis, higher risk MDAS predicted inferior OS (hazard ratio 1.42; P < .005) independent of IPSS. CONCLUSIONS: Our data validated MDAS' prognostic value. MDAS is complementary to IPSS and refines prognostic precision. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Epidemiology and outcome of myelodysplastic syndromes (MDS) in the United States is not well recognized. MDS became reportable to the Surveillance, Epidemiology, and End Results Program (SEER) in 2001. We report first study of MDS among large population in the Veteran Affair system. Patients and methods: There are approximately 127 VA Medical Centers diagnosing and/or treating Cancer patients. The data collected by the medical centers cancer registries is aggregated as the VA Central Cancer Registry (VACCR). We used the VACCR to analyze VA patients with MDS diagnosed between 1995 and 2006. The cases were identified using ICD-03 histology codes for MDS. Results: A total of 2242 MDS cases were registered during the period analyzed. The median overall survival (OS) was 2.1 years, but varied by French-American-British category. Median OS for patients with RA, RARS and RAEB was 3.4, 4.9, and 0.7 years, respectively. No differences in OS were observed by race. Conclusion: Outcome of MDS in the VA was similar to what is described in literature and reported by the SEER Program. Appropriate coding for WHO subtypes, IPSS and treatment details are needed in all MDS registries to facilitate comparisons across populations. [Copyright &y& Elsevier]

Abstract: Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m2 days 3–7, Cytarabine 2gm/m2 days 3–7, G-CSF 300mcg days 2–7, and escalating doses of imatinib mesylate given on days 1–15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24–333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned. [Copyright &y& Elsevier]

We conducted a retrospective record review to determine the frequency of venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL). All records from 1990 to 2001 of patients with the diagnosis of DLBCL at a tertiary care hospital were reviewed. Those with transformation from low-grade lymphoma, central nervous system lymphoma, HIV-related lymphoma or with incomplete records were excluded. All episodes of symptomatic VTE confirmed by imaging studies that were either present at diagnosis or occurred during initial treatment were identified. VTE occurred in 27 of 211 patients (12.8%). Stage I disease was associated with a low risk, whereas a high international prognostic index score increased risk. Of patients with VTE, thrombosis was present at diagnosis in 37% and occurred during the first chemotherapy cycle in 22% and during the first three cycles in 82%. The median survival of patients with VTE was 1.04 years [95% confidence interval (CI) = 0.75 – 1.33] compared to 5.2 years (95% CI 1.8 – 8.6) for those without VTE ( P = 0.038). We conclude that VTE is a frequent complication of DLBCL that occurs particularly at diagnosis and during initial therapy, and it is associated with a worse prognosis. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are heterogeneous group of neoplastic clonal stem cell diseases characterized by dysplastic morphological features and clinical bone marrow failure. The FAB (French-American-British) system served as the gold standard for MDS classification for more than two decades. The WHO classification, built on the backbone of FAB classification, is an attempt to further improve the prognostic value of MDS classification as well as establish its clinical utility as a tool to select different treatments. In this article we review the epidemiology, pathogenesis, molecular biology, diagnosis and classification of MDS. We highlight the major differences between the FAB classification and the WHO MDS classification. We discuss in more detail the experience of using the new WHO classification since its publication and review the studies that tried to validate the prognostic value of the new classification or apply it to predict clinical responses to various treatments. [ABSTRACT FROM AUTHOR]

Oxaliplatin is a third generation platinum compound used in patients with advanced colorectal carcinoma. Recently, the mechanism of a rare drug-induced immune thrombocytopenia in patients receiving oxaliplatin has been described. This complication is caused by oxaliplatin-dependent antibodies directed against platelet surface glycoproteins, and is unrelated to myelosuppression. In this report, we describe two patients who developed thrombocytopenia immediately soon after receiving oxaliplatin. Sensitization presumably had occurred after receiving oxaliplatin during preceding courses of multiagent chemotherapy that included oxaliplatin. [ABSTRACT FROM AUTHOR]

Background: The development of novel therapies for the myelodysplastic syndromes (MDS) is hampered by inadequate trial recruitment. Factors contributing to low trial accrual are incompletely understood.Methods: This study analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium to compare the characteristics of participants in interventional trials with those of patients who did not enroll in a trial.Results: Data were identified for 1919 patients with MDS, and 449 of these patients (23%) participated in an interventional clinical trial. The median age of all patients was 68 years, and 64% were male. Patients who participated in trials were significantly younger than nonparticipants (P = .014), and men were more likely to participate in a trial (71% of trial participants were male, whereas 61% of nonparticipants were; P < .001). Race and ethnicity were not associated with trial enrollment. Patients in more affluent ZIP codes had a higher participation rate (P < .001). Patients with intermediate- and high-risk disease according to the revised International Prognostic Scoring System were overrepresented (P = .004), and trial participants less frequently had treatment-related disease (P < .001). In multivariable analyses, participation in a clinical trial was associated with a reduced hazard of death (P = .004). Even at large referral centers, only a minority of patients with MDS enrolled in interventional trials.Conclusions: Restrictive trial eligibility criteria that exclude patients with MDS on account of age, comorbidities, or a history of another cancer are limit enrollment of MDS patients to clinical trials. Gaining insight into the barriers to trial accrual may help investigators and study sponsors to design trials that will accrue more rapidly and augment treatment options for patients with MDS. [ABSTRACT FROM AUTHOR]

Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2–6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1–24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov , NCT03682536 (active, not recruiting). Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69–80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8–37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20–73]) versus epoetin alfa (27 weeks [19–55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. Celgene and Acceleron Pharma. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) constitute a group of heterogeneous hematopoietic neoplasms characterized by ineffective erythropoiesis, anemia, and/or cytopenias. Supportive care for patients with MDS involves frequent red blood cell transfusions, which places patients with ongoing transfusional dependence (TD) at risk for iron overload (IO). Development of IO and tissue iron deposition can increase the risk of cardiac, hepatic, and endocrine toxicities, infection, and progression to acute myeloid leukemia. Iron chelation therapy (ICT) is an option for lower-risk MDS patients to reduce their degree of IO and possibly improve survival; use of these agents in thalassemia patients with TD and IO has been associated with reduced IO-associated complications and better survival. At present, there are several barriers to the regular use of ICT, such as a lack of randomized trial evidence and consistent guidance on diagnosis of IO and when to implement ICT, as well as barriers in adherence to/tolerability of ICT. [ABSTRACT FROM AUTHOR]

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25–48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusions: Targetable mutations are frequent in EM‐AML and EM‐site NGS is warranted for selecting potential targeted therapies for patients with EM‐AML. Next‐generation sequencing (NGS) on extramedullary (EM) tissue revealed at least one potentially targetable alteration in 52% of patients with EM acute myeloid leukemia treatment with IDH inhibitors led to complete response in three of four patients with IDH1 or IDH2 mutations identified on EM‐site NGS. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusions: 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.Lay Summary: 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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Summary: Splicing factor 3B subunit 1 (SF3B1) somatic mutation in the context of therapy‐related myelodysplastic syndromes (t‐MDS) has not been well defined. In a large cohort of patients with MDS, those with known SF3B1 somatic mutation were compared as de novo MDS (n = 289) and t‐MDS with mutant SF3B1 (SF3B1mut; n = 31). Baseline characteristics, concomitant mutations, and acute myeloid leukaemia (AML) transformation were similar between the two groups. The median overall survival (OS) of de novo MDS SF3B1mut was significantly longer compared to t‐MDS SF3B1mut but not significantly different when adjusted for comorbidities. Comparing t‐MDS wild‐type SF3B1 (SF3B1WT; n = 241) to t‐MDS SF3B1mut (n = 31), complex cytogenetics were seen in 37.4% versus 10.3% (p = 0.009), tumour protein p53 (TP53) mutation was 36.1% versus 10% (p = 0.004), and AML transformation was 34.4% compared to 12.9% (p = 0.016) respectively. OS was significantly shorter in SF3B1WT versus SF3B1mut. When applying the International Working Group for Prognosis of MDS (IWG‐PM) proposed SF3B1 criteria, OS was significantly shorter in SF3B1mut t‐MDS compared to de novo MDS SF3B1mut with no significance in AML transformation. Survival was compared between t‐MDS SF3B1mut who met the new proposed IWG‐PM criteria to t‐MDS SF3B1mut who did not meet criteria to survival of SF3B1WT t‐MDS. OS was 53 versus 22 and 18 months respectively (p = 0.006). AML transformation was 0%, 26.7% and 32.3% (p = 0.021). Leukaemia‐free survival was not reached among the three. [ABSTRACT FROM AUTHOR]

The AVIDA registry evaluated azacitidine usage and effectiveness in unselected patients with myelodysplastic syndromes (MDS) in community practice. Treating physicians made all treatment decisions. Hematologic improvement (HI) and transfusion independence (TI) assessments used International Working Group (IWG) 2000 criteria. Enrolled were 421 patients with MDS (n = 228 International Prognostic Scoring System [IPSS] lower-risk, n = 106 higher-risk, 86 patients unclassified) from 105 US sites. Median follow-up was 7.6 months (range: 0.1-27.6). HI and red blood cell TI rates were similar regardless of administration route or dosing schedule. Safety and tolerability were consistent with previous reports. The AVIDA registry data support azacitidine effectiveness and safety in patients with lower- or higher-risk MDS treated in community practice. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) represent a heterogeneous group of acquired clonal hematopoietic disorders characterized by peripheral blood cytopenias, paradoxical BM hypercellularity, ineffective hematopoiesis, and increased risk of leukemic transformation. Risk stratification, using different prognostic scores and markers, is at the core of MDS management. Deletion 5q [del(5q)] MDS is a distinct class of MDS characterized by the haploinsufficiency of specific genes, microRNAs, and proteins, which has been linked to increased sensitivity to the drug lenalidomide. Phase II and III clinical trials have demonstrated the efficacy of lenalidomide in improving clinical outcomes of patients with del(5q) MDS, including reduction in red blood cell transfusion requirements and improvements in quality of life. Lenalidomide has also demonstrated some activity in non-del(5q) lower-risk MDS as well as higher-risk MDS, especially in combination with other agents. In this paper, we review the pathogenesis of del(5q) MDS, the proposed mechanisms of action of lenalidomide, the major clinical trials that documented the activity of lenalidomide in different MDS populations, potential predictors of benefit from the drug and suggested mechanisms of resistance, and the use of combination strategies to expand the clinical utility of lenalidomide in MDS. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes are premalignant diseases characterized by cytopenias, myeloid dysplasia, immune dysregulation with association to autoimmunity, and variable risk for acute myeloid leukemia transformation. Studies of FOXP3+ regulatory T cells (Tregs) indicate that the number and/or activation state may influence cancer progression in these patients. Focusing on patients with a lower risk for leukemia transformation, 18 (34.6%) of 52 patients studied displayed an altered Treg compartment compared with age-matched controls. Delineation of unique Treg subsets revealed that an increase in the absolute number of CD4+FOXP3+CD25+CD127lowCD45RA-CD27- Tregs (effector memory Tregs [TregEM]) was significantly associated with anemia (p = 0.046), reduced hemoglobin (p = 0.038), and blast counts ≥ 5% (p = 0.006). In healthy donors, this TregEM population constitutes only 2% of all Tregs (one to six Tregs per microliter) in peripheral blood but, when isolated, exhibit greater suppressive activity in vitro. With a median follow-up of 3.1 y (range 2.7-4.9 y) from sample acquisition, increased numbers of TregEM cells proved to have independent prognostic importance in survival estimates, suggesting that enumeration of this Treg subset may be a more reliable indicator of immunological escape than FOXP3+ T cells as a whole. Based on multivariate analyses, TregEM impacted survival independently from myeloblast characteristics, cytopenias, karyotype, and comorbidities. Based on these findings, TregEM cell expansion may be synonymous with human Treg activation and indicate microenvironmental changes conducive to transformation in myelodysplastic syndromes. [ABSTRACT FROM AUTHOR]

The article discusses a study on the clinical outcomes in patients with acute myeloid leukemia (AML) resulting from myelodysplastic syndrome (MDS) after undergoing induction chemotherapy. Age, cytogenetic profile and an antecedent of MDS or myeloproliferative neoplasm are cited as the prognostic factors in AML. Results of the study show that complete response (CR)/CR with low platelets was at 59% for the whole group following induction chemotherapy. Novel treatment is recommended for AML patients already treated for MDS/myeloproliferative neoplasm.

Introduction: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower‐risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community‐based clinical settings is scarce. This study from the Connect® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR‐MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria. Methods: Ring sideroblasts assessment and molecular testing data were collected from patients with LR‐MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis. Results: Among 489 patients with LR‐MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1. Conclusions: In the Connect® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations. [ABSTRACT FROM AUTHOR]

Thrombocytopenia occurs frequently in patients with myelodysplastic syndromes (MDS), and the survival of patients after failure of hypomethylating agents (HMAs) is poor. We conducted a trial of eltrombopag in patients with MDS, MDS/myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML) with 20–30% myeloblasts after HMA failure and mean baseline platelet count ≤ 50 × 109/L. Eltrombopag was escalated from 50 mg daily up to 200 mg daily. The primary objective was to determine the maximally tolerated dose (MTD). 37 patients were enrolled, and MTD was not reached. Responses were observed in 9 patients (24%), 2 achieving marrow CR with hematologic improvement (HI), 1 marrow CR without HI, and 6 HI. Median overall survival was 7.5 months. Eltrombopag was well-tolerated and yielded modest responses in heavily treated, predominantly higher-risk MDS patients after HMA failure. Future studies should focus on determining characteristics that predict response. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell diseases, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These are acquired clonal disorders resulting from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing leukemia and other adverse outcomes is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated by the National Heart, Lung, and Blood Institute (NHLBI) and is being conducted in collaboration with community hospitals and academic medical centers supported by the National Cancer Institute (NCI). The study will recruit up to 2000 MDS patients or overlapping myeloproliferative neoplasms (MDS/MPN) and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The National MDS Natural History Study (NCT02775383) will offer the world's largest disease-focused tissue biobank linked to longitudinal clinical and molecular data in MDS. Here, we report on the study design features and describe the vanguard phase of 200 cases. The study assembles a comprehensive clinical database, quality of life results, laboratory data, histopathology slides and images, genetic information, hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources will be available to the scientific community for investigator-initiated research. [ABSTRACT FROM AUTHOR]

PURPOSE: We developed an unbiased framework to study the association of several mutations in predicting resistance to hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS), analogous to consumer and commercial recommender systems in which customers who bought products A and B are likely to buy C: patients who have a mutation in gene A and gene B are likely to respond or not respond to HMAs. METHODS: We screened a cohort of 433 patients with MDS who received HMAs for the presence of common myeloid mutations in 29 genes that were obtained before the patients started therapy. The association between mutations and response was evaluated by the Apriori market basket analysis algorithm. Rules with the highest confidence (confidence that the association exists) and the highest lift (strength of the association) were chosen. We validated our biomarkers in samples from patients enrolled in the S1117 trial. RESULTS: Among 433 patients, 193 (45%) received azacitidine, 176 (40%) received decitabine, and 64 (15%) received HMA alone or in combination. The median age was 70 years (range, 31 to 100 years), and 28% were female. The median number of mutations per sample was three (range, zero to nine), and 176 patients (41%) had three or more mutations per sample. Association rules identified several genomic combinations as being highly associated with no response. These molecular signatures were present in 30% of patients with three or more mutations/sample with an accuracy rate of 87% in the training cohort and 93% in the validation cohort. CONCLUSION: Genomic biomarkers can identify, with high accuracy, approximately one third of patients with MDS who will not respond to HMAs. This study highlights the importance of machine learning technologies such as the recommender system algorithm in translating genomic data into useful clinical tools. [ABSTRACT FROM AUTHOR]

The article informs on the association of Enhancer of Zester homolog 2 (EZH2) protein expression by immunohistochemistry in myelodysplasia related neoplasms with mutation status, cytogenetics and clinical outcomes. It informs that EZH2 is mutated in myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms, demonstrating a need for characterization in disease modulation or prognostication. It also informs on treatment of the same.

The article presents a study which analyzed the performance of the Medical Research Council/ Leukemia Research Foundation (MRC/LRF) tool in the prediction of overall survival (OS) in refractory or relapsed-acute myeloid leukemia (RR-AML) patients after therapy with hypomethylating agents (HMAs.) Topics include characteristics of the patients in the study, most common cause of death, and the limited ability the MRC/LRF score to discriminate survival with azacitidine or decitabine therapy.

Despite few effective therapies, only a small percentage of patients diagnosed with myelodysplastic syndromes (MDS) in the United States are enrolled in prospective, interventional clinical trials. MDS-specific barriers to trial accrual include a high frequency of elderly patients with comorbid conditions, atypical disease features and uncertainty regarding the diagnosis (because other nonclonal processes also can cause dysplasia and cytopenias), a history of another nonmyeloid neoplasm resulting in therapy-related MDS, rapid disease recurrence after allogeneic stem cell transplantation, and an arbitrary division between MDS and acute myeloid leukemia. In addition, barriers to accrual that are common to other oncology populations, such as difficulty traveling to clinical trial enrollment sites and narrow trial eligibility criteria, also prevent patients with MDS from enrolling in studies. Collectively these barriers must be assessed systematically, and creative solutions are needed to improve outcomes for this needy patient population. [ABSTRACT FROM AUTHOR]

The article discusses the mutational frequencies diagnosed in patients with myelodysplastic-myeloproliferative neoplasms (MDS/MPN-U) using gene sequencing. The median and overall survival rate was analysed for the cohort study. The use of International Prognostic Scoring System and targeted next-generation sequencing in the diagnosis of MDS/MPN-U are also discussed.

The article offers information on a survey which demonstrates widespread variability in definition and management of hyperleukocytosis in acute myeloid leukemia and perceptions regarding indications and contraindications and outcomes related to the use of leukapheresis. It mentions that need for randomized clinical trials to define the role of leukapheresis in the management of hyperleukocytosis.

Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 – 21.7 months), OS reached 29.7 months (95% CI 7.01 – not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT. [ABSTRACT FROM AUTHOR]

Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare entity. We present a multicenter experience of 17 patients with FISH-confirmed FGFR1 rearrangement. The clinical presentation at diagnosis included myeloproliferative neoplasm (MPN) in 4 (24%) patients, acute leukemia (AL) in 7 (41%), and concomitant MPN with AL in 6 (35%). The two most frequently observed cytogenetic abnormalities were t(8;13)(p11.2;q12)(partner gene ZMYM2) and t(8;22)(p11.2; q11.2)(BCR). Seventy-eight percent of tested patients had a RUNX1 mutation, of whom all had AL. Overall response rate to frontline therapy was 69%, and 76% of patients subsequently received allogeneic stem cell transplant (ASCT). After a median follow-up of 11 months, median progression-free survival was 15 months and median overall survival was not reached. In conclusion, FGFR1-rearranged hematologic malignancies present with features of MPN and/or AL. FGFR1 and RUNX1 are therapeutic targets for ongoing and future clinical trials. [ABSTRACT FROM AUTHOR]

Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis. Development of cytopenias was the most common reason for discontinuation (38%) after median treatment time of 3.8 months (mo). The majority of patients received some form of salvage therapy after ruxolitinib discontinuation (n = 42; 66%), with allogeneic hematopoietic stem cell transplant (alloHSCT) (n = 17), being most commonly employed. Lenalidomide, thalidomide, hydroxyurea, interferon, and danazol were used with similar frequency. The response rate to salvage treatment was 26% (8 responses) and responses were most often seen with lenalidomide or thalidomide. Improved outcomes were observed in patients who underwent alloHSCT or received salvage therapy compared to those who did not receive additional therapy. Median overall survival (OS) after ruxolitinib discontinuation was 13 months. These findings show that salvage therapy can provide clinical responses after ruxolitinib discontinuation; however, these responses are rare and outcomes in this patient population are poor. This represents an area of unmet clinical need in MF. [ABSTRACT FROM AUTHOR]

A case study of a 52-year-old woman with a 12-year history of Janus kinase 2-negative essential thrombocythemia treated with anagrelide and hydroxyurea. It mentions the patient undergone Somatic Sequencing that identifies Trametinib-Responsive Myelodysplastic Syndrome. It also mentions the case characterize the Mitogen-Activated Protein Kinase Kinase 2 P298L alteration as activating and amenable to trametinib therapy.

The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2-2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination. [ABSTRACT FROM AUTHOR]

Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher-risk myelodysplastic syndromes (HR-MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real-life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24-month median survival observed with azacitidine in the landmark AZA-001 trial has not been replicated in population-based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR-MDS is significantly lower than what was observed in the AZA-001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front-line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR-MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider-scale enrollment in front-line HR-MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017;123:3662-3672. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

First-line therapy for higher-risk myelodysplastic syndromes (MDS) includes decitabine (DAC) or azacitidine (AZA). Variables have not identified differential response rates between these. We assessed the influence of patient sex on outcomes including overall survival (OS) in 642 patients with higher-risk MDS treated with AZA or DAC. DAC-treated patients (35% of females, 31% of males) had marginally better OS than AZA-treated patients (p = .043), (median OS of 18.7 months versus 16.4 months), but the difference varied strongly by sex. Female patients treated with DAC had a longer median OS (21.1 months, 95% CI: 16.0–28.0) than female patients treated with AZA (13.2 months, 95% CI: 11.0–15.9;p = .0014), while for males there was no significant difference between HMAs (median OS 18.3 months with DAC versus 17.9 months for AZA,p = .59). The biological reason for this variability is unclear, but may be a consequence of differences in cytidine deaminase activity between men and women. [ABSTRACT FROM PUBLISHER]

Background: The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine.Methods: A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy.Results: Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%).Conclusions: The combination of azacitidine with pracinostat did not improve outcomes in patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994-1002. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms.Methods: We did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123 357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP.Findings: We identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 [33%] of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight [62%] of 13 cases vs 15 [27%] of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52-25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three [38%] of eight patients) and TP53(three [38%] of eight patients), whereas controls most often had TET2 mutations (six [40%] of 15 patients). In most (four [67%] of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two [33%] of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone.Interpretation: Patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk.Funding: Moffitt Cancer Center. [ABSTRACT FROM AUTHOR]

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 EZH2 mut 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 EZH2 mut MDS was ASXL1 , with a significantly higher frequency than EZH2 wt (54% vs. 19%, p < 0.001). Patients with EZH2 mut MDS had lower response rates to hypomethylating agents compared to EZH2 wt MDS (26% vs. 39%; p = 0.050). Median OS of patients with EZH2 mut MDS was 30.8 months, with a significantly worse OS than EZH2 wt group (35.5 vs. 61.2 months, p = 0.003) in the lower-risk IPSS-R categories. Among patients with EZH2 mut 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 EZH2 mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2 mut MDS. • Incidence of EZH2 mutation in MDS is 4.7%. • EZH2 -mutant MDS commonly harbored concurrent deleterious ASXL1 and RUNX1 mutations. • EZH2 mutation in MDS is associated with lower response rate to HMA. • Presence of chromosome 7 abnormalities confer inferior OS in EZH2 -mutant MDS. • EZH2 -mutant MDS had worse OS compared to wild type in patients with lower-risk MDS. [ABSTRACT FROM AUTHOR]

An important pathogenetic distinction in the classification of myeloproliferative neoplasms (MPNs) is the presence or absence of the BCR-ABL fusion gene, which encodes a unique oncogenic tyrosine kinase. The BCR-ABL fusion, caused by the formation of the Philadelphia chromosome (Ph) through translocation, constitutes the disease-initiating event in chronic myeloid leukemia. The development of successive BCR-ABL-targeted tyrosine-kinase inhibitors has led to greatly improved outcomes in patients with chronic myeloid leukemia, including high rates of complete hematologic, cytogenetic, and molecular responses. Such levels of treatment success have long been elusive for patients with Ph-negative MPNs, because of the difficulties in identifying specific driver proteins suitable as drug targets. However, in recent years an improved understanding of the complex pathobiology of classic Ph-negative MPNs, characterized by variable, overlapping multimutation profiles, has prompted the development of better and more broadly targeted (to pathway rather than protein) treatment options, particularly JAK inhibitors. In classic Ph-negative MPNs, overactivation of JAK-dependent signaling pathways is a central pathogenic mechanism, and mutually exclusive mutations in JAK2, MPL, and CALR linked to aberrant JAK activation are now recognized as key drivers of disease progression in myelofibrosis (MF). In clinical trials, the JAK1/JAK2 inhibitor ruxolitinib - the first therapy approved for MF worldwide - improved disease-related splenomegaly and symptoms independent of JAK2V617F mutational status, and prolonged survival compared with placebo or standard therapy in patients with advanced MF. In separate trials, ruxolitinib also provided comprehensive hematologic control in patients with another Ph-negative MPN - polycythemia vera. However, complete cytogenetic or molecular responses with JAK inhibitors alone are normally not observed, underscoring the need for novel combination therapies of JAK inhibitors and complementary agents that better address the complexity of the pathobiology of classic Ph-negative MPNs. Here, we discuss the role of tyrosine-kinase inhibitors in the current MPN-treatment landscape. [ABSTRACT FROM AUTHOR]