Clinical features, therapy patterns, outcomes and prognostic factors of solitary plasmacytomas: a report of the Israeli Myeloma Study Group.

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% - recurrent SP, 36.8% - active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy.

COVID-19 among patients with hematological malignancies: a national Israeli retrospective analysis with special emphasis on treatment and outcome.

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease (p = 0.036) and mortality (p = 0.023), hypertension with severe/critical disease (p = 0.046) and hospitalization (p = 0.001), active haemato-oncological treatment with hospitalization (p = 0.009), and remdesivir treatment was associated with decreased mortality (p = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.

Venetoclax is safe and efficacious in relapsed/refractory AML.

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.

Primary autoimmune myelofibrosis: A case report in a child.

Autoimmune myelofibrosis (AIMF) is an uncommon cause of myelofibrosis associated with favorable outcome. Primary AIMF, AIMF without a known systemic autoimmune disorder, has been described in adults, but never in children. Here, we present, for the first time, an apparent case of primary AIMF in a 15-year-old boy admitted with profound hypoproliferative anemia.

BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study.

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.

Outcomes of light-chain amyloidosis patients treated with first-line bortezomib: a collaborative retrospective multicenter assessment.

Light-chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non-selected 'real-world' AL patients, treated with first-line bortezomib-based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty-eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co-administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First-line bortezomib-based regimen resulted in favorable response and survival in newly diagnosed patients. Co-administration of an alkylating agent improved outcome without increasing treatment-related toxicity.

Higher infection rate after 7- compared with 5-day cycle of azacitidine in patients with higher-risk myelodysplastic syndrome.

INTRODUCTION: Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS: Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS: After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patient's age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION: Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.

Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective multicenter study.

Hypomethylating agents have become the standard therapy for patients with high-risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA-treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high-risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29-92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered.

Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3.

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease.

Endothelial function in patients with sickle cell anemia during and after sickle cell crises.

BACKGROUND: Prior studies have demonstrated increased adherence of sickle cell erythrocytes to vascular endothelial cells. While decreased production of nitric oxide and increased production of adhesion molecules have been implicated in this pathophysiology, the relative contribution of these mechanisms during acute sickle cell crises as compared to steady state conditions have not been elucidated. METHODS AND RESULTS: We studied 10 consecutive young adult patients presenting with a sickle cell crisis. Endothelial function was evaluated by a non-invasive brachial artery shear stress method. Serum levels of adhesion molecules were obtained during the crisis. Both brachial artery responsiveness and serum levels of adhesion molecules were then repeated at steady state. Ten age and gender matched volunteers served as a control group. Impaired endothelial function and impaired endothelium-independent vasodilatation were observed in all sickle cell patients during both steady state and during crisis. Flow mediated dilation (FMD)% was 3.25+/- 2.76% during crisis, 4.57+/- 4.11 at steady state, compared with the control group FMD of 11.64+/- 7.69% (p< 0.001). Flow independent dilation was 10.35+/- 11.3% during crisis, 10.03+/- 6.52% at steady state, compared with control group FID of 24.17+/- 11.87% (p< 0.001). Levels of cell adhesion molecules and markers of inflammation were increased in sickle cell crisis patients compared with the control group: sCD40 ligand levels during the acute crisis were over twice the level of normal matched volunteers (p=0.02), and similarly significant increases were seen for E-selectin (p=0.008), ICAM-1 (p=0.037) and VCAM-1 levels (p=0.01). The levels of each of these biomarkers was not significantly increased during acute crises as compared to patients' recovery state. CONCLUSIONS: Sickle cell anemia patients have severe systemic endothelial dysfunction as demonstrated by both brachial artery assessment and increased serum levels of adhesion molecules. These abnormalities characterize not only the sickle cell crisis but also the steady state pathophysiology of sickle cell anemia.

The role of T-lymphocyte subpopulations in acute myocardial infarction.

T lymphocytes have the potential to affect atherosclerosis at different stages of the process. They play an active role in acute myocardial infarction (AMI) and myocardial damage, and may affect the clinical outcome of patients with coronary artery disease. CD40 ligand expression on T lymphocytes promotes the expression of matrix-degrading enzymes in vascular smooth muscle cells and may thus establish a new pathway of immune-mediated destabilization of the human atheroma. The major class of T lymphocytes present in atherosclerotic lesions is CD4+. CD4+ cells differentiate into Th1 and Th2 lineage in response to the local milieu of cytokines. Much of the emphasis in atherosclerosis research is focused on the role of Th1 type responses.