Successful treatment with fludarabine and cyclophosphamide in a VEXAS syndrome patient with associated myelodysplastic syndrome: a case report and systematic review.

Vacuoles, E1 syndrome, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a chronic inflammatory disorder that affects various organ systems. It is associated with hematologic malignancies and is generally refractory to therapies. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered for selected patients. We report a case wherein systemic and hematological manifestations completely resolved in a patient with VEXAS and associated myelodysplastic syndrome (MDS), following the administration of fludarabine and cyclophosphamide as part of the preparation for allo-HSCT. We conducted a systematic literature review and included 86 patients with VEXAS syndrome and associated MDS. Most cases presented with musculoskeletal involvement (71%) and anemia (72%) with lower-risk MDS. Most patients responded to corticosteroids (CS) but had a recurrence of symptoms with CS taper and were refractory to other immunosuppressive agents. Hypomethylating agents and Janus kinase inhibitors achieved a complete response in some cases. Further research is needed to develop more effective treatment strategies.

Outcomes with allogeneic hematopoietic stem cell transplantation in TP53-mutated myelodysplastic syndrome: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated myelodysplastic syndromes (MDS). A literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov. After screening 626 articles, eight studies were included. Data were extracted following the PRISMA guidelines and analyzed using the meta-package by Schwarzer et al. We analyzed 540 patients. The pooled median 3 (1-5) year overall survival was 21% (95% CI 0.08-0.37, I2=91%, n=540). The pooled relapse rate was 58.9% (95% CI 0.38-0.77, I2=93%, n=487) at a median of 1.75 (1-3) years. The pooled 4-year progression- free survival was 34.8% (95% CI 0.15-0.57, I2=72%, n=105). Outcomes of Allo-HSCT for TP53-mutated MDS patients remain poor, with 21% OS at three years; however, Allo-HSCT confers a survival advantage as compared to non-transplant palliative therapies. Our findings suggest the need to explore novel therapeutic agents in prospective clinical trials.

Lenalidomide and Eltrombopag for Treatment of Low- or Intermediate-Risk Myelodysplastic Syndrome: Result of a Phase II Clinical Trial.

PURPOSE: Thrombocytopenia is a serious complication of myelodysplastic syndromes (MDS) associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS. PATIENTS AND METHODS: We conducted a Phase II multicenter trial of ELT and LEN in adult patients with low- or intermediate-1-risk MDS with symptomatic or transfusion-dependent anemia or thrombocytopenia (NCT01772420). Thrombocytopenic patients were started on ELT and subsequently treated with LEN after platelets were increased. Patients without thrombocytopenia were started on LEN monotherapy and treated with ELT if they became thrombocytopenic. RESULTS: Fifty-two patients were enrolled; mean age was 71 years (range 34-93). Overall response rate (ORR) in the intention-to-treat population was 35% (18/52). ELT monotherapy led to ORR of 33.3% (7/21), 29% achieving hematologic improvement (HI)-Platelets, and 24% bilineage responses. LEN monotherapy had 38% ORR (6/16) with all responders achieving HI-Erythroid. Fifteen patients received both ELT and LEN with ORR of 33.3%, 20% achieved HI-Erythroid, and 20% HI-Platelets with 13% bilineage responses. Median duration of response was 40 weeks for ELT (range 8-ongoing), 41 weeks (25-ongoing) for LEN, and 88 weeks (8.3-ongoing) for ELT/LEN. Non-hematologic grade 3-4 treatment-related adverse events were infrequent. Among patients on ELT, 2 had major bleeding events, 1 had a reversible increase in peripheral blasts, and 1 developed marrow fibrosis after 6 years on ELT. CONCLUSIONS: ELT and LEN are well tolerated and effective in achieving hematologic improvement in patients with low-/intermediate-risk MDS.

Targeting inflammation in lower-risk MDS.

The myelodysplastic syndromes (MDS) are a heterogeneous group of malignant hematopoietic stem cell disorders characterized by ineffective growth and differentiation of hematopoietic progenitors leading to peripheral blood cytopenias, dysplasia, and a variable risk of transformation to acute myelogenous leukemia. As most patients present with lower-risk disease, understanding the pathogenesis of ineffective hematopoiesis is important for developing therapies that will increase blood counts in patients with MDS. Various inflammatory cytokines are elevated in MDS and contribute to dysplastic differentiation. Inflammatory pathways mediated by interleukin (IL) 1b, IL-6, IL-1RAP, IL-8, and others lead to growth of aberrant MDS stem and progenitors while inhibiting healthy hematopoiesis. Spliceosome mutations can lead to missplicing of genes such as IRAK4, CASP8, and MAP3K, which lead to activation of proinflammatory nuclear factor κB-driven pathways. Therapeutically, targeting of ligands of the transforming growth factor ß (TGF-ß) pathway has led to approval of luspatercept in transfusion-dependent patients with MDS. Presently, various clinical trials are evaluating inhibitors of cytokines and their receptors in low-risk MDS. Taken together, an inflammatory microenvironment can support the pathogenesis of clonal hematopoiesis and low-risk MDS, and clinical trials are evaluating anti-inflammatory strategies in these diseases.

Efficacy of booster doses in augmenting waning immune responses to COVID-19 vaccine in patients with cancer.

Anti-COVID-19 immunity dynamics were assessed in patients with cancer in a prospective clinical trial. Waning of immunity was detected 4-6 months post-vaccination with significant increases in anti-spike IgG titers after booster dosing, and 56% of seronegative patients seroconverted post-booster vaccination. Prior anti-CD20/BTK inhibitor therapy was associated with reduced vaccine efficacy.

Seroconversion rates following COVID-19 vaccination among patients with cancer.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. On comparison with solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematologic malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than with mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

Correlation of Coagulation Parameters With Clinical Outcomes During the Coronavirus-19 Surge in New York: Observational Cohort.

IMPORTANCE: COVID-19 has caused a worldwide illness and New York became the epicenter of COVID-19 in the United States from Mid-March to May 2020. OBJECTIVE: To investigate the coagulopathic presentation of COVID and its natural course during the early stages of the COVID-19 surge in New York. To investigate whether hematologic and coagulation parameters can be used to assess illness severity and death. DESIGN: Retrospective case study of positive COVID inpatients between March 20, 2020-March 31, 2020. SETTING: Montefiore Health System main hospital, Moses, a large tertiary care center in the Bronx. PARTICIPANTS: Adult inpatients with positive COVID tests hospitalized at MHS. EXPOSURE FOR OBSERVATIONAL STUDIES: Datasets of participants were queried for demographic (age, sex, socioeconomic status, and self-reported race and/or ethnicity), clinical and laboratory data. MAIN OUTCOME AND MEASURES: Relationship and predictive value of measured parameters to mortality and illness severity. RESULTS: Of the 225 in this case review, 75 died during hospitalization while 150 were discharged home. Only the admission PT, absolute neutrophil count (ANC) and first D-Dimer could significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 2.1 µg/mL. 15% of discharged patients required readmission and more than a third of readmitted patients died (5% of all initially discharged). CONCLUSION: We describe here a comprehensive assessment of hematologic and coagulation parameters in COVID-19 and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments. Furthermore, D-Dimer may be useful to follow up discharged patients.

Low ADAMTS13 Activity Correlates with Increased Mortality in COVID-19 Patients.

The causes of coagulopathy associated with coronavirus disease 2019 (COVID-19) are poorly understood. We aimed to investigate the relationship between von Willebrand factor (VWF) biomarkers, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with balanced distribution of survivors and nonsurvivors. Patients who died had significantly lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, significantly elevated lactate dehydrogenase levels, significantly increased shistocyte/RBC fragment counts, and significantly elevated VWF antigen and activity levels compared with patients discharged alive. These biomarkers correlate with markedly elevated D-dimers. Additionally, only 30% of patients who had an ADAMTS13 activity level of less than 43% on admission survived, yet 60% of patients survived who had an ADAMTS13 activity level of greater than 43% on admission. In conclusion, COVID-19 may present with low ADAMTS13 activity in a subset of hospitalized patients. Presence of schistocytes/RBC fragment and elevated D-dimer on admission may warrant a work-up for ADAMTS13 activity and VWF antigen and activity levels. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of treatments aimed at prevention and/or amelioration of microangiopathy in COVID-19.

The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia.

Mutations in the group of epigenetic modifiers are the largest group of mutated genes in Myelodysplastic Syndromes (MDS) and are very frequently found in Acute Myeloid Leukemia (AML). Our advancements in the understanding of epigenetics in these diseases have helped develop groundbreaking therapeutics that have changed the treatment landscape of MDS and AML, significantly improving outcomes. In this review we describe the most common epigenetic aberrations in MDS and AML, and current treatments that target mutations in epigenetic modifiers, as well as novel treatment combinations, from standard therapies to investigational treatments.

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality.

BACKGROUND: Mortality in coronavirus disease of 2019 (COVID-19) is associated with increases in prothrombotic parameters, particularly D-dimer levels. Anticoagulation has been proposed as therapy to decrease mortality, often adjusted for illness severity. OBJECTIVE: We wanted to investigate whether anticoagulation improves survival in COVID-19 and if this improvement in survival is associated with disease severity. METHODS: This is a cohort study simulating an intention-to-treat clinical trial, by analyzing the effect on mortality of anticoagulation therapy chosen in the first 48 hours of hospitalization. We analyzed 3,625 COVID-19+ inpatients, controlling for age, gender, glomerular filtration rate, oxygen saturation, ventilation requirement, intensive care unit admission, and time period, all determined during the first 48 hours. RESULTS: Adjusted logistic regression analyses demonstrated a significant decrease in mortality with prophylactic use of apixaban (odds ratio [OR] 0.46, p = 0.001) and enoxaparin (OR = 0.49, p = 0.001). Therapeutic apixaban was also associated with decreased mortality (OR 0.57, p = 0.006) but was not more beneficial than prophylactic use when analyzed over the entire cohort or within D-dimer stratified categories. Higher D-dimer levels were associated with increased mortality (p < 0.0001). When adjusted for these same comorbidities within D-dimer strata, patients with D-dimer levels < 1 µg/mL did not appear to benefit from anticoagulation while patients with D-dimer levels > 10 µg/mL derived the most benefit. There was no increase in transfusion requirement with any of the anticoagulants used. CONCLUSION: We conclude that COVID-19+ patients with moderate or severe illness benefit from anticoagulation and that apixaban has similar efficacy to enoxaparin in decreasing mortality in this disease.

Evidence for secondary thrombotic microangiopathy in COVID-19.

The causes of coagulopathy associated with COVID-19 disease are poorly understood. We aimed to investigate the relationship between markers of endothelial activation, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with equal distribution of survivors and non-survivors. Patients who died had significantly lower ADAMTS13 activity, significantly higher LDH, schistocytes and von Willebrand Factor levels compared to patients discharged alive. Only 30% of patients with an initial ADAMTS13 activity <43% survived vs. 60% with ADAMTS13 ≥43% who survived. In conclusion, COVID-19 may manifest as a TMA-like illness in a subset of hospitalized patients. Presence of schistocytes on admission may warrant a work-up for TMA. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of TMA treatments in COVID-19.

Natural history and clinical outcomes in patients with portal vein thrombosis by etiology: A retrospective cohort study.

BACKGROUND: Portal vein thrombosis (PVT) is an unusual-site thrombosis commonly encountered in patients with malignancies, cirrhosis, and acute abdominal inflammatory conditions (AIC). Current recommendations suggest that anticoagulation may improve recanalization rates but there is limited information on venous thromboembolism (VTE) recurrence rates and whether the etiologies of PVT respond similarly with anticoagulation. OBJECTIVE: To characterize the natural clinical course and outcomes of patients diagnosed with PVT based on etiology. PATIENTS/METHODS: Patients with a diagnosis of PVT between 2005 and 2015 who were followed for at least one year and had revised imaging at 12 months ±â€¯3 months were identified. Comorbidities, demographics, anticoagulation choice and clinical outcomes including VTE recurrence, cavernous transformation, PVT recanalization, progression and mortality were obtained. RESULTS: Of 698 patients diagnosed with PVT, 85 patients were evaluable according to criteria: 54 had cirrhosis (63.5%), 15 malignancy (17.6%) and 16 AIC (18.8%). Mean age was 55.6 ±â€¯13.1 years. At presentation, 40% patients were symptomatic and 29.4% received anticoagulation. Patients with AIC were anticoagulated more frequently compared to those with malignancy or cirrhosis (87.5% vs. 33.3% vs. 11.1%). Overall, patients with cirrhosis had lower rates of PVT progression (0% vs. 13.3%, p = 0.02) and patients with AIC had higher rates of cavernous transformation compared to cirrhosis or malignancy-associated PVT (31.3% vs. 7.4% vs. 0%, p = 002). Among untreated patients, those with malignancy had significantly higher rates of VTE recurrence and PVT progression than patients with cirrhosis (20% vs. 4.2% and 20% vs. 0%). CONCLUSIONS: The natural course of PVT differs among etiologies. In the absence of anticoagulation, patients with malignancy are more prone to VTE recurrence and PVT progression compared to patients with cirrhosis. Given the high rate of VTE recurrence at 12 months in patients with malignancy-associated PVT, anticoagulation should be considered for this group.