Search

AbstractAccess to allogeneic and autologous hematopoietic stem cell transplantation (SCT) remains inadequate despite its curative potential across hematologic malignancies. In 2015, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) established the Shared Care Model (SCM) with a primary aim of enhancing SCT access for HHC patients. The SCM comprises several components: an SCT-dedicated nurse-navigator, a health-information exchange for record sharing, telemedicine, and ongoing training of HHC clinicians in transplant patient selection and management. We evaluated the SCM’s impact on SCT access across 126 patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma from 2016-2020. The SCM facilitated 34 referrals. Socio-economic status of HHC referrals by Area Deprivation Index was significantly inferior (38 vs. 14, p < 0.001) when compared to 3,108 non-SCM referrals to MSK during the same period. Allogeneic recipients spent 68-247 days away from home, and autologous recipients 15-48, both requiring few subsequent visits to MSK. [ABSTRACT FROM AUTHOR]

The boundary between myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) has been revised in the latest World Health Organization classification of myeloid malignancies. These changes were motivated by the description of a subgroup of MDS patients identified as oligomonocytic chronic myelomonocytic leukemia (OM-CMML) at risk of evolving into overt CMML. Various studies will be reviewed describing the clinical and biological features of MDS patients evolving to CMML. The efforts to discover biomarkers enabling the identification of these patients at the time of MDS diagnosis will be discussed. Finally, the molecular landscape of these patients will be presented with a specific focus on the biallelic inactivation of TET2 in light of its functional impact on hematopoietic stem cells, granule-monocytic differentiation, and its tight interplay with inflammation. [ABSTRACT FROM AUTHOR]

AbstractThe mutations in SRSF2 and TET2 genes are frequently present in various myeloid neoplasms. The potential impact of SRSF2/TET2 co-mutations on patient survival is incompletely understood. We identified 412 patients with SRSF2/TET2 co-mutations from our NextGen sequencing database of around 8000 patients and reported likely the largest cohort study. Our study demonstrated the presence of these co-mutations in a spectrum of myeloid neoplasms, which show different genetic and molecular characteristics. Most of the patients with these co-mutations had normal karyotype. Interestingly, our study provided insights into the prevalence of additional mutations such as ASXL1, RUNX1, and KRAS with this co-mutation and their potential impact on patients’ prognosis. We found that ASXL1, RUNX1, and KRAS can negatively impact these patients’ survival with different impacts in different morphological diagnosis categories, suggesting a complex interaction between these genes. This study underscores the need for personalized approaches in the treatment of myeloid neoplasms. [ABSTRACT FROM AUTHOR]

AbstractIn 2022, the World Health Organization (WHO) and International Consensus Classification (ICC) recognized TP53 as an entity-defining alteration in myeloid neoplasms, yet with differing criteria that could lead to discrepant diagnoses and affect clinical trial eligibility. We studied 67 patients with TP53 mutant myeloid neoplasms, reclassifying them using both criteria. While most cases fulfill the criteria for TP53 mutant defined entities, most discrepancies were found in cases with ≥20% blasts. Patients were stratified into three groups based on blast count (<10%, 10–19%, and ≥20%) which revealed comparable clinicopathologic features, genetic characteristics, and outcomes. Notably, patients with ≥10% blasts had shorter overall survival compared to those with <10% blasts (8.1 vs. 12.4 months; p = 0.03). This study is among the few to examine TP53 mutant myeloid neoplasms as a single entity and suggests that the 10% blast count threshold could serve as a gateway to a more harmonized classification for these patients. [ABSTRACT FROM AUTHOR]

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant. [ABSTRACT FROM AUTHOR]

Hematopoietic cell transplantation (HCT) has evolved to an essential treatment in younger and more recently in elderly patients with myelodysplastic syndrome (MDS), the age group with the highest incidence. Less intense conditioning regimens and improvements in supportive therapy have reduced considerably transplant related mortality and in the same time increased the access to this curative treatment. Timing of HCT in the course of the disease assumes a crucial role. Detection of disease progression, geriatric assessment, comorbidity evaluation, and identification of transplant-specific risks are becoming increasingly important in this context. Novel statistical methods, molecular biomarkers, and quantification of tumor burden pre- and post-HCT will play an essential role in years to come. More effective and less toxic treatments to reduce the tumor burden before and/or after HCT are expected to improve the outcome. In this review article we discuss the current views and what we can expect. [ABSTRACT FROM AUTHOR]

Management of higher-risk myelodysplastic syndromes (HR-MDS) is challenging in the real world. We studied 200 patients with HR-MDS within a large US community hospital network. We describe the clinical presentation, patient-related factors, prognostic characteristics, treatment patterns, clinical outcomes and resource utilization. Patients with HR-MDS, treated in our community setting, were elderly (median age 76 years) with a high comorbidity burden. First-line therapy was hypomethylating agent (HMA) monotherapy (20%), lenalidomide (2%), and venetoclax (2%), while the rest were treated with supportive care. Sixty-one percent of the 200, were subsequently hospitalized within 6 months of initial diagnosis. Overall survival was 11.8 months. Curative transplantation was infrequent, HMA-based therapy was underutilized, responses were not durable, most patients became transfusion-dependent or transformed to AML, and resource utilization was substantial and was highly correlated with total in-hospital days. There is a clear unmet need for tolerable treatments that can produce durable remissions in this population. [ABSTRACT FROM AUTHOR]

A molecular scoring system (IPSS-M) was recently proposed for myelodysplastic syndrome (MDS). We conducted a retrospective study of adults with MDS referred 2019–2021. The primary outcomes were leukemia-free survival (LFS) and overall survival (OS). One hundred and forty-four patients diagnosed between 2011 and 2021 were analyzed. After IPSS-M re-stratification, 33% of patients were up-staged and 11% down-staged. Median follow-up was 2.8 years and 53 patients died (37%). Cumulative incidence of acute myeloid leukemia (AML) transformation was 20% at 3 years post-diagnosis. International Prognostic Scoring System (IPSS), revised version (IPSS-R) was significantly associated with LFS (log-rank p = 9.2e–05; 'very high' vs. 'low' risk HR = 3.85, p = 5.8e–04) and OS (log-rank p = 7.2e–06; 'very high' vs. 'low' HR = 5.09, p = 1.7e–04). IPSS-M was also a significant predictor of LFS (log-rank p = 1.1e–06; 'very high' vs. 'low' HR = 4.97, p = 2.2e–05) and OS (log-rank p = 4.8e–07; 'very high' vs. 'low' HR = 6.42, p = 2.5e–05) while providing better discrimination than IPSS-R for both outcomes. This mutation-incorporating prognostic index has greater discriminative potential than IPSS-R to predict AML transformation and any-cause mortality. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases without a care standard and show variability in treatment outcomes. This Spanish, observational, prospective study ERASME (CEL-SMD-2012-01) assessed the evolution of newly diagnosed and treatment-naïve high-risk MDS patients (according to IPPS-R). 204 patients were included: median age 73.0 years, 54.4% males, 69.6% 0-1 ECOG, and 94.6% with comorbidities. Active treatment was the most common strategy (52.0%) vs. stem cell transplantation (25.5%) and supportive care/watchful-waiting (22.5%). Overall (median) event-free survival was 7.9 months (9.1, 8.3, and 5.3); progression-free survival: 10.1 months (12.9, 12.8, and 4.3); and overall survival: 13.8 months (15.4, 14.9; 8.4), respectively, with significant differences among groups. Adverse events (AEs) of ≥3 grade were reported in 72.6% of patients; serious AEs reported in 60.6%. 33.1% of patients died due to AEs. Three patients developed second primary malignant neoplasms (median: 8.2 months). Our study showed better outcomes in patients receiving active therapy early after diagnosis. [ABSTRACT FROM AUTHOR]

We present a systematic review and meta-analysis to evaluate outcomes after venetoclax (VEN) with hypomethylating agents (HMA) in myelodysplastic syndromes (MDS). We performed a literature search on PubMed, Cochrane Library, EMBASE, and Clinicaltrials.gov. After screening 2004 manuscripts, 16 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. We analyzed the outcomes of 373 patients from 11 retrospective studies and five phase 1 b clinical trials. Pooled complete response with or without hematological recovery was 60% (95% CI 0.49–0.7, I2= 67%, n = 373). Hematopoietic cell transplantation was performed in 32% of patients (95% CI 0.2–0.46, I2= 62%, n = 187). Overall mortality was 45% (95% CI 0.31–0.59, I2=54%, n = 140). VEN-HMA combination therapy demonstrated promising outcomes in MDS. Prospective randomized data is needed to ascertain the benefit of VEN and its impact in MDS patients. [ABSTRACT FROM AUTHOR]

Although the effect of gene mutations on overall response rate (ORR) and overall survival (OS) in myelodysplastic syndrome (MDS) treated with hypomethylating agents (HMAs) has been explored, the effect is still controversial. We performed this meta-analysis to investigate the effect. The pooled odds ratio (OR) and 95% confidence interval (CI) for ORR and the pooled hazard ratio (HR) and 95%CI for OS were chosen to estimate the effect. The pooled OR of TET2 was 0.73 (95%CI: 0.59–0.91, p = 0.005) and the pooled OR of ASXL1 was 1.38 (95%CI: 1.12–1.71, p = 0.003). As for prognosis, the pooled HR of RUNX1 was 1.45 (95%CI: 1.15–1.85, p = 0.002). The pooled HR of TP53 was 2.30 (95%CI: 1.83–2.90, p < 0.001) and the pooled HR of U2AF1 was 1.41 (95%CI: 1.15–1.74, p = 0.001). There was no statistical difference shown in other genes. Therefore, TET2 mutation and ASXL1 wild-type were the predictor of better response to HMAs. Mutations of TP53, RUNX1, and U2AF1 were associated with poor prognosis in MDS. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) have a major impact on quality of life (QoL). We performed a post hoc analysis of two multicenter trials of azacitidine-based disease-modifying therapy for patients with MDS and low blast count acute myeloid leukemia (AML), to identify factors associated with QoL. 231 patients were included (median age 70 years). At baseline, higher initial hemoglobin, but not neutrophil or platelet count, was associated with better global QoL and physical function (p < 0.001 and p = 0.001, respectively). During therapy, increase in hemoglobin was associated with improvement in QoL and physical function (p = 0.005 and p < 0.001, respectively). Lower initial hemoglobin was associated with higher dyspnea and fatigue scores (p < 0.001 and p = 0.001, respectively), and hemoglobin response was associated with improvement in dyspnea and fatigue (p < 0.001 for each). In patients with MDS and low blast count AML, hemoglobin level was strongly correlated with global QoL, physical functioning, dyspnea and fatigue, both before and during azacitidine-based therapy. [ABSTRACT FROM AUTHOR]

Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter's methylation. Patients with low RRM1 levels had a high RRM1 methylation status (p = 0.005) and a better response to treatment with 5-azacytidine (p = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels (p = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS. [ABSTRACT FROM AUTHOR]

To evaluate whether outcomes following allogeneic hematopoietic cell transplantation differ according to disease type, a three-way comparison for patients with de novo acute myeloid leukemia (AML) (n = 3318), AML evolving from myelodysplastic syndromes (MDS) (n = 208), and MDS with excess blasts (MDS-EB) (n = 994) was performed. The 5-year probabilities of overall survival (OS) for de novo AML, AML evolving from MDS, and MDS-EB were 60%, 42%, and 41% (p < 0.001), respectively. Multivariate analysis revealed that, compared to de novo AML, AML evolving from MDS was associated with a higher risk of NRM (p = 0.030) and MDS-EB with a higher risk of relapse (p < 0.001), both leading to lower OS (p = 0.010 and p < 0.001, respectively). These findings demonstrate inter-disease differences in post-transplant outcomes and highlight the needs to reduce NRM for AML evolving from MDS and to reduce relapse for MDS-EB. [ABSTRACT FROM AUTHOR]

TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design. [ABSTRACT FROM AUTHOR]

Treatment for acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy is a major challenge for clinicians. We enrolled 154 patients ineligible for intensive chemotherapy who were prescribed D-IA regimen (decitabine 15–20 mg/m2 days 1 to 3–5, followed by idarubicin 3 mg/m2 for 5–7 days and cytarabine 30 mg/m2 for 7–14 days). For AML and MDS patients, the overall response rate after two cycles was 66.4% and 76.6%, respectively, and the 2-year overall survival rates were 29% and 31%, respectively. Fourteen (13.1%) AML and five (10.6%) MDS patients underwent allo-HSCT after complete remission. The allo-HSCT group survival time was significantly longer than the control group (median survival time not reached in HSCT group, 13 and 18.5 months in non-HSCT AML and MDS group). We concluded that D-IA regimen was effective and well tolerated for patients with AML or higher-risk MDS ineligible for intensive chemotherapy. [ABSTRACT FROM AUTHOR]

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation. [ABSTRACT FROM AUTHOR]

The low grade chronic lymphoproliferative disorders include chronic lymphocytic leukemia, Waldenstroms macroglobulinemia, follicular lymphoma and hairy cell leukemia. Traditionally considered incurable, these disorders have been associated with a risk of haematological and solid organ malignancies secondary to both the underlying disease and the associated treatment. The introduction of purine analogues into treatment paradigms has seen increased rates of therapy related myelodysplasia reported and it remains unclear yet on the impact the targeted novel therapies play in the development of secondary cancers. We review the rates of secondary malignancy in the chronic lymphoproliferative disorders with a particular focus on the role of the purine analogues in the development of therapy related MDS. [ABSTRACT FROM AUTHOR]

Azacitidine (AZA) maintenance following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may reduce relapse risk and improve survival. Given logistic and toxicity-related challenges, identifying subgroups appropriate for this approach is an unmet need. Using data from two centers, we retrospectively compared event-free survival (EFS) and overall survival (OS) of AML and MDS patients who received AZA maintenance (n = 59) with historic controls (n = 90). Controls were selected according to the following criteria: no death, relapse, or Grade III–IV acute GVHD for 100 days after transplant. In multivariable analysis, AZA maintenance yielded significantly improved EFS (p = 0.019) and OS (p = 0.011). Outcomes differed according to regimen intensity. For reduced-intensity transplant, EFS (p = 0.004) and OS (p = 0.004) were significantly improved and equivalent to myeloablative transplant. A significant benefit following myeloablative transplant was not observed. Within the limitation of its retrospective nature, this study suggests that AZA maintenance improves outcomes following reduced-intensity HCT, comparable to myeloablative HCT. [ABSTRACT FROM AUTHOR]

Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies. [ABSTRACT FROM AUTHOR]

For most patients with higher-risk myelodysplastic syndromes (HR-MDS) the hypomethylating agents (HMA) azacitidine and decitabine remain the mainstay of therapy. However, the prognosis mostly remains poor and aside from allogeneic hematopoietic stem cell transplantation no curative treatment options exist. Unlike acute myeloid leukemia, which has seen a dramatic expansion of available therapies recently, no new agents have been approved for MDS in the United States since 2006. However, various novel HMAs, HMA in combination with venetoclax, immune checkpoint inhibitors, and targeted therapies for genetically defined patient subgroups such as APR-246 or IDH inhibitors, have shown promising results in early stages of clinical testing. Furthermore, the wider availability of genetic testing is going to allow for a more individualized treatment of MDS patients. Herein, we review the current treatment approach for HR-MDS and discuss recent therapeutic advances and the implications of genetic testing on management of HR-MDS. [ABSTRACT FROM AUTHOR]

Mutations in the tumor suppressor gene TP53 are detected in 5–10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n = 75; 90%) and therapy-related malignancies (n = 32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (GO) remained available to US clinicians through an open-label expanded-access protocol (NCT02312037) until GO was reapproved. Patients were aged ≥3 months with relapsed/refractory (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndrome, or acute promyelocytic leukemia (APL), and had exhausted other treatment options. Three hundred and thirty one patients received GO as monotherapy for R/R AML (n = 139), combination therapy for R/R AML (n = 183), or treatment for R/R APL (n = 9). Corresponding treatment discontinuations occurred in 68, 39, and 33% of patients. All-causality grade 5 AEs occurred in 52, 22, and 22% of patients in the monotherapy, combination, and APL groups, respectively. Corresponding grades 3 and 4 treatment-related AEs were reported in 60, 55 and 78% of patients. Hepatotoxicity occurred in five patients: veno-occlusive disease (n = 4) and drug-induced liver injury (n = 1). GO was generally well tolerated in patients with R/R AML or APL. Most frequent treatment-related grade ≥3 AEs were hematologic AEs. Clinicaltrials.gov identifier: NCT02312037 [ABSTRACT FROM AUTHOR]

Optimal conditioning chemotherapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains uncertain. Myeloablative regimens such as fludarabine/busulfan are favored over reduced-intensity fludarabine/melphalan (Flu/Mel); however, it is not known if Flu/Mel is inferior. We analyzed hematopoietic cell transplantation recipients with AML and MDS who received fludarabine with once-daily intravenous busulfan targeted to either area under the curve (AUC) 5300 µM*L/min (Flu/Bu 5300) (n = 246) or AUC 3500 µM*L/min (Flu/Bu 3500) (n = 81), or Flu/Mel (n = 69). Flu/Bu regimens were compared separately to Flu/Mel. After 2-year follow-up, no differences in overall or relapse-free survival were found between Flu/Bu 5300 or 3500 versus Flu/Mel though relapse rates were significantly higher; 33.1% (p = 0.024), 44.6% (p = 0.002), versus 19.4%, respectively. Flu/Bu 5300 (p = 0.008) and Flu/Bu 3500 (p < 0.001) groups were prognostic for relapse compared to Flu/Mel. Flu/Mel yields lower relapse rates and similar survival benefit when compared to Flu/Bu 3500 or 5300 µM*L/min. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) is increasingly employed for diagnosis, risk stratification, and management of patients with myelodysplastic syndrome (MDS). We aimed to describe beliefs and practice patterns among providers who treat MDS patients with respect to the utility of NGS in diagnosis, risk stratification, prognosis, and treatment decisions at various points along the disease trajectory, response assessment, and development of institutional guidelines for MDS-specific molecular profiling. Using a 23-question web-based survey in May–June 2018, we identified a widespread use of molecular profiling with MDS-specific panels (N = 53; 39%) and general panels including MDS-related genes (N = 63; 47%), with the majority done at diagnosis (92%). We found substantial variations in genes tested in assays, providers beliefs, practices, testing logistics, and interpretation of results, and recognized multiple challenges limiting a wider utilization of molecular profiling. High-quality data are needed to develop evidence-based guidelines for the role of NGS in the care of MDS patients. [ABSTRACT FROM AUTHOR]

For over a decade the hypomethylating agents (HMA) azacitidine and decitabine have been the mainstay of therapy for myelodysplastic syndrome (MDS). There is a critical need to improve frontline therapy, given that only up to half of high-risk MDS patients will respond to HMA therapy, and responses are short-lived. Currently, a key strategy has been to combine HMAs with other novel agents to improve patient outcomes. While synergy of agents is the goal of combination therapy, combinations often come at the cost of increased side effects that are often intolerable in this vulnerable population. The purpose of this review is to critically examine clinically relevant HMA combinations and discuss the future of MDS management. [ABSTRACT FROM AUTHOR]

Population level survival of patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) is inferior to clinical trials. Using SEER-Medicare data, we identified 2086 MDS patients diagnosed in 2004–13, aged ≥66 years at diagnosis, and receiving ≥1 HMA cycle after 2005. We used multivariate logistic regression and Cox proportional hazards models to assess the impact of provider experience on persistent HMA therapy and overall survival (OS), respectively. Median number of HMA cycles was 4 and median OS was 10 months. Thirty-two percent of patients were treated by providers with ≥1 prior HMA initiation in the last 2 years and were more likely to receive ≥4 cycles of HMA therapy (OR = 1.29, 95% CI = 1.06–1.57; p =.01). No significant association was found between MDS or HMA initiation volume and survival. In conclusion, while HMA initiation volume was associated with persistent HMA treatment, neither MDS nor HMA initiation volumes were associated with OS in older MDS patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to identify biomarkers predictive of the outcome of patients with high-risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (AZA). We prospectively examined the association between NK-cytotoxic activity, myeloid-derived suppressor cells (MDSCs), and T-regulatory cells (Tregs) on the overall survival (OS) of patients. Patients with NK-cytotoxicity above a critical threshold had a longer duration of response and survived longer than patients with severe impairment of NK-cytotoxicity. The numbers of MDSCs, and Tregs in the PB of patients after a short exposure to AZA were not different from normal donors. In conclusion, the results of our study suggest that the therapeutic activity of AZA is at least partly mediated by an immunomodulatory effect. To our knowledge, this is the first study reported so far, that shows a positive correlation between NK cytotoxicity and OS of AZA-treated patients. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome unclassifiable (MDS-U) is a small subtype of myelodysplastic syndromes (MDS). However, rare literature exists in terms of natural progression and clinical outcome of patients with MDS-U. In the present study, we investigated the characteristics and the clinical outcomes of patients categorized as MDS-U based on 2008 World Health Organization criteria (WHO) in a single center comparing to other MDS groups. Out of eight hundred and two patients who met WHO criteria for MDS at our institution, ninety patients (11%) were initially classified as MDS-U. Upon pathological review, only half of the cases were confirmed to be MDS-U. With follow up, half of the MDS-U cases were reclassified to another subtype. We found neither significant difference in median overall survival nor in risk of transformation to acute myeloid leukemia when comparing MDS-U to other MDS groups. Additional larger studies are needed to confirm our results. [ABSTRACT FROM AUTHOR]

Hypomethylating agents (HMA) are the standard of care for treatment of myelodysplastic syndromes (MDS). HMA-failure MDS has extremely poor prognosis. This study was designed to explore the utility of eltrombopag in post-HMA failure MDS patients. Patients were treated in one of two arms: eltrombopag as monotherapy (Arm A), or with continuation of HMA (Arm B). The starting eltrombopag dose was 200 mg orally daily. Twenty-nine patients with a median age of 72 years (42–84) were enrolled. The median number of prior treatment was 1 (1–5). Seven (24%) patients were enrolled in cohort A and 22 (76%) in cohort B. One early death (<30 days) occurred in cohort B due to infection/sepsis. Of 28 evaluable patients, 3 (11%) in cohort B experienced platelet improvement. Median overall survival was 12 months. This study demonstrated modest platelet improvement in some, without evidently increased toxicity or increased risk of leukemia progression. [ABSTRACT FROM AUTHOR]

We retrospectively studied 133 myelodysplastic syndrome patients receiving decitabine during January 2009 and September 2017. The dose of 15 mg/m2/d (n = 83) and 20 mg/m2/d (n = 50) had comparable overall response rates (ORR) (51.8% vs. 52.00%) and complete remission rate (CRR) (15.66% vs. 22.00%). The 15 mg/m2/d group had a lower incidence of grade 3/4 neutropenia (60.24% vs. 88.00%, p <.05) and thrombocytopenia (65.06% vs. 88.00%, p <.05). The 15 mg/m2/d group had a longer median overall survival (OS) (21.60 months vs. 15.23 months, p =.02). The same results were seen in refractory anemia with excess blasts (RAEB) patients: The 15 mg/m2/d group also had comparable ORR, CRR, decreased hematological toxicities and longer OS. Further analysis suggested that survival benefit of 15 mg/m2/d group was mainly in those patients with lower risk stratification. In conclusion, 15 mg/m2/d decitabine is associated with a lower incidence of hematological toxicities and longer OS and may be more suitable for patients with relatively lower risk. [ABSTRACT FROM AUTHOR]

We analyzed the mutational profile of idiopathic cytopenia of undetermined significance (ICUS) compared with that of myelodysplastic syndrome (MDS). Targeted sequencing of 88 genes associated with myeloid malignancies was performed using samples of bone marrow mononuclear cells from ICUS and MDS patients. Forty patients with ICUS and 128 patients with MDS were included in this study. The median mutational burden was 0.7 mutation/person in the ICUS group and 2.2 mutation/person in the MDS group. ASXL1 (seven patients) was the most frequently mutated gene. ASXL1 was an independent significant prognostic factor for event-free survival (EFS) and overall survival (OS) (hazard ratio (HR) = 10.07 and 30.63, p =.004 and.003, respectively). The ASXL1 mutation which is frequently detected in elderly patients is a molecular predictor for pancytopenia and survival in patients with ICUS. A larger prospective study is needed to validate the role of this genetic mutation in an ICUS prognosis. [ABSTRACT FROM AUTHOR]

The clinical impact of ecotropic viral integration site 1 (EVI1) expression status in myelodysplastic syndromes (MDS) is poorly defined. Here, we investigate the expression of EVI1 and its associated clinical and cytogenetic characteristics in 398 MDS patients. High EVI1 levels (EVI1high) were found more frequently in Higher-risk MDS patients. Other cytogenetic abnormalities over-represented among EVI1high cases included complex karyotype, del(5q), monosomy 7, and 12q-compared with EVI1low MDS. No specific gene mutation was found different between EVI1high and EVI1low patients, except for a high proportion of TP53 mutation in the EVI1high group. For EVIhigh patients, mean number of gene mutations was higher than that in EVI1low patients. No definite correlation was found between EVI1 expression and MDS prognosis. However, for Higher-risk MDS patients, EVI1high patients have poorer survival rate compared with EVI1low patients. Moreover, EVI1high was an adverse prognostic marker for MDS with excess blasts subtype. The addition of EVI1 could deteriorate the survival of MDS patients with chromosome 3 abnormalities, del(5q-) or monosomy 7. Taken together, EVI1 overexpression is a poor prognostic marker for higher-risk MDS group and could be included in risk stratification for MDS patients. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events. One patient had a decrease in transfusion requirements and another demonstrated hematologic improvement suggesting a signal for clinical activity. In vitro correlative studies indicated biological effects on immune cells following vaccination. Although only a pilot study, results are encouraging that an immunotherapeutic approach with a whole-cell vaccine may be feasible in MDS patients. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time. [ABSTRACT FROM AUTHOR]

In this prospective trial, the efficacy of azacitidine in lower-risk myelodysplastic syndromes (LR-SMD) lacking del(5q) was compared to best supportive care (BSC) at 1:1. The primary endpoint was the achievement of erythroid hematologic improvement (HI-E) after nine cycles. Thirty-six patients received at least ≥1 cycle. HI-E was confirmed 44.4% randomized to Aza and in 5.5% of patients receiving BSC (p < .01). After entry in Aza extension period, transfusion independence was achieved in all Aza responders with a median duration of 50 weeks (range: 17-231). No significant differences were observed in secondary endpoints. Importantly, variant allele frequency (VAF) of some mutated genes (RET, SF3B1, ASXL1) decreased after 9 months of treatment in Aza-responder patients. In conclusion, LR-MDS patients lacking del5q and resistant to ESAs, who receive 5 days Aza, achieve TI in a substantial proportion of cases and results in modifications in mutational landscape. [ABSTRACT FROM AUTHOR]

The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases. CTLA-4 inhibition may be especially effective in treating late post-allogeneic stem cell transplant relapse of AML in patients with limited or no graft versus host disease. Immune checkpoint inhibition, specifically PD-1 inhibition, demonstrated limited single agent efficacy in patients with relapsed AML and with MDS post-hypomethylating therapy. Rationally designed combinations of PD-1 inhibitors with standard anti-leukemic therapy are needed. Hypomethylating agents such as azacitidine, up-regulate PD-1, PD-L1, and PD-L2 in patients with AML/MDS and up-regulation of these genes was associated with the emergence of resistance. The combination of azacitidine and PD-1/PD-L1 inhibition may be a potential mechanism to prevent or overcome resistance to 5-azacitidine. A number of such combinations are being evaluated in clinical trials with early encouraging results. Immune checkpoint inhibition is also an attractive option to improve relapse-free survival or eliminate minimal residual disease post induction and consolidation by enhancing T-cell surveillance in patients with high-risk AML. The ongoing clinical trials with checkpoint inhibitors in AML/MDS will improve our understanding of the immunobiology of these diseases and guide us to the most appropriate application of these agents in the therapy of AML/MDS. [ABSTRACT FROM AUTHOR]

Multiple studies have associated elevated body mass index (BMI) and increased incidence of hematologic malignancies, including myelodysplastic syndrome (MDS). The purpose of the present study was to evaluate the association between BMI at diagnosis and overall survival (OS) in a retrospective cohort of 92 patients with MDS. The median age at diagnosis was 63 (14–84) years. The median BMI was 22.75 (15.94–34.26) kg/m2. Eleven (12.0%) patients were underweight, 64 (69.6%) were normal weight, 17 (18.5%) were overweight or obese. Three-year OS rates differed significantly when the three BMI groups were compared (p = .0449). Multivariate Cox regression analysis indicated that normal weight (versus underweight) had a marginally significant effect on OS (hazard ratio = 0.456,p = .127), and overweight/obese (versus underweight) had a significant effect on OS (hazard ratio = 0.171,p = .015). Further investigations are required to elucidate the mechanisms responsible for this association. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are clonal stem cell disorders marked by bone marrow failure with varying degrees of cytopenias. MDS are characterized by the accumulation of complex genetic alterations that influence disease pathogenesis and outcomes. Given the heterogeneity of MDS patients, multiple prognostic scoring systems have been developed to predict patient outcomes. Most focus primarily on untreated patients in whom outcomes are predicted accurately only at diagnosis; their application dynamically, during the disease course and especially after hypomethylating agent (HMA) failure, may not be accurate. In this focused review, we discuss the utility of established MDS prognostic models and a novel tool at the time of HMA failure, along with the strengths and limitations of each. [ABSTRACT FROM AUTHOR]

We examine the infective complications occurring during azacitidine (AZA) therapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A retrospective review of patients receiving ≥1 cycle of AZA for MDS or AML was performed. Patient demographics, infection prophylaxis/episodes and outcomes were evaluated. Sixty eight patients received 884 AZA cycles. Bacterial infections occurred in 25% of cycle-1 and 27% of cycle-2 AZA therapy. Febrile neutropenia complicated 5.3% of AZA cycles, bacteremia 2% and invasive Aspergillosis 0.3%. Using Poisson modeling, a very high IPSS-R (RR 10.26, 95% CI 1.20, 87.41,p= .033) was identified as an independent risk factor for infection. Infection-related attributable mortality was 23%. The burden of infection is high in AZA-treated patients, associated with high attributable mortality. Over 25% of AZA cycles 1 and 2 were complicated by infection, predominantly bacterial, rates dropping to <10% after cycle-5. [ABSTRACT FROM PUBLISHER]

In myelodysplastic syndrome (MDS), vascular endothelial growth factor (VEGF) may have regulatory effects on the hematopoietic system and contribute to disease progression. We analyzed by immunocytochemistry VEGF expression in bone marrow (BM) cells from 188 patients with MDS and 96 non-hemopathic subjects. We also measured VEGF BM plasma levels andin vitroVEGF release. Our aims were to evaluate whether VEGF expression abnormalities were associated with relevant laboratory or clinical findings and their possible prognostic value. In MDS, VEGF expression was higher than in controls (p < .0001) and VEGF release was significantly higher in the low-risk cases. A trend to a positive correlation between VEGF myeloid expression and apoptotic rate was observed. High myeloid VEGF levels were independently associated with longer overall survival (p < .0001) and progression-free survival (p = .0002). Our findings suggest that, in MDS, VEGF production and release may contribute to ineffective hematopoiesis, with a potential prognostic role. [ABSTRACT FROM PUBLISHER]

Decitabine is an effective therapy for patients with lower risk myelodysplastic syndrome (MDS). However, the mechanisms of decitabine’s therapeutic effect are not well established. Forty-four lower risk MDS patients received decitabine therapy. 59.1% patients achieved treatment response, and 53.8% patients who were RBC/platelet-dependent cast off the transfusion burden. The median overall survival (OS) was 19.0 months after decitabine treatment. Moreover, polarization toward type 1 in the CD8 + subset was enhanced, and a significantly increased expression of the PD-1, PD-L1, and PD-1/STAT1 ratio was observed in these lower risk MDS. The patients with amplification of PD-1/STAT1 ratio (2–4) achieved longer OS. Thus, our results suggest that the effect mechanism of decitabine toward lower risk MDS may be the moderate increase of PD-1/STAT1, which contributes to hematopoietic improvement. These findings suggest that a different PD-1-related strategy from those used to treat higher risk patients could be used for lower risk MDS patients. [ABSTRACT FROM AUTHOR]

The significance of an isolated trisomy 8 (+8) in the diagnosis of myelodysplastic syndrome (MDS) is not well established. It is common in MDS, but is not considered as an MDS-defining abnormality in the absence of morphologic dysplasia. We evaluated two groups of patients with isolated +8 and either low-grade MDS (LG-MDS) or idiopathic cytopenia of undetermined significance (ICUS). At presentation, ICUS patients had a lower platelet count (85.0 vs 163.5 × 109cells/L;p = 0.02), while MDS patients had more frequent incidence of isolated anemia (64% vs 0%,p = 0.007). A subset (36%) of ICUS patients progressed to MDS or AML. These patients presented with more severe neutropenia (0.9 vs 3.1 × 103/μL,p = 0.01) and a trend toward a higher proportion (>50%) of +8 metaphases compared to those that did not progress (p = 0.05). Thus, ICUS patients with isolated +8 may progress to MDS and AML and deserve close clinical follow-up. [ABSTRACT FROM PUBLISHER]

Abnormal methylation of let-7a-3 has been found in various cancers and may consequently affect their survival. In this study, real-time quantitative methylation specific PCR (RQ-MSP) was used to determine the unmethylation level of let-7a-3 in 95 patients with myelodysplastic syndrome (MDS). The hypomethylation of let-7a-3 promoter was detected in 22 of 95 (23.2%) patients with MDS compared to 4.2% (1/24) of controls (p= 0.0419). Moreover, the frequency of let-7a-3 hypomethylation was higher in older patients (≥70 years) than in younger patients (<70 years). No significant difference was observed in distribution of WHO, IPSS, and cytogenetic classification. However, hypomethylated patients had significantly shorter overall survival than those without hypomethylation (p= 0.007). Moreover both Kaplan–Meier and Multivariate Cox analyses confirmed that let-7a-3 hypomethylation was an independent prognostic risk factor in cohorts of MDS patients with lower-risk disease. Our study suggested that let-7a-3 hypomethylation may predict poor outcome in MDS. [ABSTRACT FROM PUBLISHER]

Coexisting hematopoiesis from donor and recipient origin, called a mixed chimerism status, can occur in patients after myeloablative allogeneic hematopoietic stem cell transplantation. However, its impact on the outcomes of cord blood transplantation (CBT) has yet to be clarified. We retrospectively analyzed 150 adult patients who received myeloablative single-unit CBT for hematological malignancies in our institute. At the median time of first bone marrow analysis of 41 days after CBT, mixed chimerism was observed in 16 of the 150 patients. Among patients with mixed chimerism, 4 patients relapsed. The remaining 12 patients were alive and in remission at a median follow-up of 50 months. Bone marrow-mixed chimerism did not have a significant impact on the incidences of disease-free survival, relapse, or transplant-related mortality after CBT. These data show that early phase mixed chimerism did not have a significant impact on long-term outcomes after myeloablative single-unit CBT for hematological malignancies. [ABSTRACT FROM AUTHOR]

Decitabine (DAC) is commonly used for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Previous studies have indicated DAC sequentially combined with idarubicin was an effective treatment for myeloid neoplasms. Therefore, a clinical study was conducted of the sequential combination of DAC followed by low-dose idarubicin/cytarabine in high-risk myeloid neoplasms. A total of 30 patients with a diagnosis of high-risk MDS, AML evolving from MDS or relapsed/refractory AML were enrolled in the study. DAC was administered 20 mg/m2daily for 3 consecutive days. Idarubicin (3 mg/m2/day) was administered 24 h after the last administration of DAC for 5–7 consecutive days, combined with cytarabine (30 mg/m2/day) for 7–14 days. The overall complete remission rate was 66.67%. The results demonstrate that epigenetic priming with decitabine followed by low-dose idarubicin/ytarabine has an increased anti-leukemia effect compared to traditional chemotherapy in high-risk myeloid neoplasms. [ABSTRACT FROM AUTHOR]

This study followed 28 patients with myelodysplastic syndromes (MDS) who showed a rise of bone marrow (BM) erythroids to ≥ 50% following three cycles (1–60) of hypomethylating agent (HMA) therapy. If BM blasts were calculated as a percentage of non-erythroids, 12 (42.9%) patients met the diagnostic criteria for acute erythroleukemia, erythroid/myeloid (AEL). However, none of the patients showed clonal cytogenetic evolution or new mutations. When compared to 47de novoAEL patients, these 12 patients were less anemic and thrombocytopenic, had less complex karyotypes (p = 0.044) and showed a longer survival, either calculated from diagnosis (p < 0.001) or from the time of AEL (p = 0.005). These findings illustrate that ≥ 50% erythroids may appear in BM post-HMA therapy, likely a combination of reduction of BM granulocytes (p < 0.001) and promotion of normal or abnormal erythroid proliferation. Enumeration of blasts as a percentage of non-erythroid cells may lead to a diagnosis of AEL and mis-interpretation as disease progression. [ABSTRACT FROM AUTHOR]

The efficacy of second allogeneic stem cell transplantation (SCT2) using cord blood (CB) for patients with relapsed hematological malignancies after initial allogeneic stem cell transplantation (SCT1) is unknown. We analyzed the results of SCT2 using single-unit unrelated CB in 34 adult patients with relapsed hematological malignancies after SCT1 in our institution. The patients had acute myeloid leukemia (n = 23), acute lymphoblastic leukemia (n = 7), chronic myelogenous leukemia (n = 2), and myelodysplastic syndrome (n = 2). The cumulative incidence of neutrophil and platelet engraftment was 81.6% at 30 days and 68.5% at 100 days, respectively. With a median follow-up of 40 months, the probability of overall survival at 3 years was 29.0%. The cumulative incidence of relapse and transplant-related mortality at 3 years were 60.7% and 27.2%, respectively. The use of CB could offer the opportunity to receive SCT2 for patients who experienced disease relapse after SCT1 without HLA-identical related or unrelated donors. [ABSTRACT FROM AUTHOR]

Existing data suggest that myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) peak in incidence 5–10 years following exposure to ionizing radiation, while most publications report less than 5 years of follow-up after radioimmunotherapy (RIT). We report the rate of secondary MDS/AML among 60 patients treated with two front-line sequential chemotherapy-RIT trials with over 11 years of follow-up. Among 35 patients evaluated after fludarabine-RIT and 25 patients evaluated after CVP (cyclophosphamide, vincristine, prednisone)-RIT treatment, the crude, cumulative and Kaplan–Meier rates of MDS/AML at 11 years of follow-up from the combined trials were 0.12/person, 0.010/person-year and 14% (95% confidence interval [CI] 5–24%), respectively. Additionally, we found that patients treated with RIT consolidation appear to have durable remissions but that relapses after 10 years do occur. Studies of efficacy and secondary MDS/AML that report fewer than 10 years of follow-up likely underestimate risk. [ABSTRACT FROM AUTHOR]

The serum albumin (SA) level has been reported to be an independent prognostic biomarker that may serve as a surrogate representative of disease biology in patients diagnosed with myelodysplastic syndrome (MDS). However, its prognostic ability has not been tested in a model adjusting for comorbidities. We analyzed 200 patients who were diagnosed as havingde novoMDS. Median overall survival (OS) of all patients was 25 months and median leukemia-free survival (LFS) was 24 months. Median OS according to the SA level groups of ≤ 3.5, 3.6–4.0 and > 4.0 mg/dL were 24, 39 and 77 months, respectively. SA level remained an independent predictor of both LFS and OS even when adjusting for the hematopoietic cell transplant comorbidity index (HCT-CI) and the International Prognostic Scoring System (IPSS) or World Health Organization classification-based Prognostic Scoring System (WPSS). Our findings indicate that SA level at the time of diagnosis is a significant and independent predictor of LFS and OS even when adjusting for commonly used prognostic systems and comorbidities. [ABSTRACT FROM PUBLISHER]