Abstract: This article was originally published without an Open Access but due to the authors final decision to opt for Open Choice this correction was created. PubDate: 2019-12-02
Abstract: Abstract Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response—particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts. PubDate: 2019-12-02
Abstract: Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) could be the only curative therapy for patients with relapsed/refractory acute leukemia (RRAL). Many reports have described unmanipulated haploidentical HSCT (HID-HSCT) using high-dose antithymocyte globulin (ATG). However, the transplant outcomes of HID-HSCT using very low-dose ATG (thymoglobulin, 2–2.5 mg/kg) and methylprednisolone (mPSL, 1 mg/kg) for patients with RRAL have not been reported. We compared the outcomes of 46 patients with RRAL who underwent HID-HSCT using very low-dose ATG (thymoglobulin) and mPSL with the outcomes of 72 patients who underwent non-HID-HSCT. Patient characteristics differed regarding conditioning intensity (myeloablative; 19.6% in HID-HSCT vs. 61.1% in non-HID-HSCT, P < 0.001) and having undergone multiple HSCT (26.1% vs. 11.1%, P = 0.045). However, we found no significant differences in the 1-year overall survival (OS, 31.7% vs. 29.1%; P = 0.25), disease-free survival (DFS, 20.5% vs. 23.7%; P = 0.23), cumulative incidence of relapse (CIR, 40.0% vs. 42.8%; P = 0.92), non-relapse mortality (NRM, 39.5% vs. 33.5%; P = 0.22), or 100-day grade II–IV acute graft-versus-host disease (32.6% vs. 34.7%; P = 0.64) following HID-HSCT vs. non-HID-HSCT, respectively. Subgroup analysis stratified by disease and intensity of conditioning regimen demonstrated the same results between HID-HSCT and non-HID-HSCT. Furthermore, multivariate analysis showed that HID-HSCT was not an independent prognostic factor for OS (hazard ratio (HR) = 0.95 [95% confidence interval (CI), 0.58–1.58]), DFS (HR = 1.05 [95%CI, 0.67–1.68]), CIR (HR = 0.84 [95%CI, 0.48–1.47]), or NRM (HR = 1.28 [95%CI, 0.66–2.46]). In summary, transplant outcomes for RRAL were comparable in the HID-HSCT and non-HID-HSCT groups. HID-HSCT using very low-dose ATG and mPSL for RRAL may be a viable alternative to non-HID-HSCT. PubDate: 2019-11-30
Abstract: Abstract Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL. PubDate: 2019-11-27
Abstract: Abstract In multiple myeloma (MM) patients, 18F-FDG-PET/CT allows either the detection of disease spread by using visual parameters based on the Italian Myeloma criteria for PET Use (IMPeTUs) or the direct measurement of metabolic tumor burden by volume-based parameters such as metabolic tumor volume (MTV). The purpose is to evaluate the contribution of visual and volumetric parameters in the prediction of progression-free survival (PFS) and overall survival (OS) in MM patients. Forty-seven patients in stage IIIA who had undergone whole-body 18F-FDG-PET/CT were retrospectively evaluated. In each patient, visual parameters were determined and compared with volumetric parameters for PFS and OS prediction after a mean follow-up period of 53 months. Among the visual and volumetric parameters tested, a statistically significant difference was found between maximum standardized uptake value, MTV, total lesion glycolysis, and number of lytic lesions of patients with (n = 26) or without (n = 21) progression (p = 0.0400, p = 0.0065, p = 0.015, and p = 0.0220, respectively) and of dead (n = 24) vs survivors (n = 23) (p = 0.0171, p = 0.0037, p = 0.0060, and p = 0.0270, respectively). At univariate and multivariate analysis, MTV and hemoglobin were predictive of both PFS (p = 0.008) and OS (p = 0.0026). The best MTV discriminative value assessed by receiver operating characteristic curve analysis for predicting both PFS and OS was 39.4 ml. By Kaplan-Meier analysis and log-rank test, PFS and OS were significantly better in patients with MTV ≤ 39.4 ml (p = 0.0004 and p = 0.0001, respectively) as compared with those having an MTV higher than the cutoff. The volume-based parameter MTV determined by 18F-FDG-PET/CT may be used in the prediction of PFS and OS in myeloma patients. PubDate: 2019-11-27
Abstract: Abstract Hemoglobin (Hb) F has a modulatory effect on the clinical phenotype of β-thalassemia disease. High expression of Hb F in Hb E-related disorders has been noted, but the mechanism is not well understood. We have examined the association of a novel SNP rs11759328 on ARHGAP 18 gene and other known modulators with a variability of Hb F in Hb E-related disorders. Genotyping of SNP rs11759328 (G/A) was performed based on high-resolution melting analysis. The rs11759328 (A allele) was shown to be significantly associated with Hb F levels (p < 0.05) in heterozygous and homozygous Hb E. High levels of Hb F in both heterozygous and homozygous Hb E were also found to be associated with SNPs in the study of other modifying genes including KLF 1 mutation, rs7482144 (Gγ-XmnI), rs4895441, rs9399137 of (HBS1L-MYB), and rs4671393 (BCL11A). Multivariate analysis showed that KLF1 mutation and SNP rs11759328 (GA) (ARHGAP18) modulated Hb F expression in heterozygous Hb E. For homozygous Hb E, this was found to be related to five modifying factors, i.e., KLF1 mutation, rs4895441 (GG), rs9399137 (CC), rs4671393 (AA), and rs4671393 (GA). These results indicate that a novel SNP rs11759328 is a genetically modifying factor associated with increased Hb F in Hb E disorder. PubDate: 2019-11-27
Abstract: Abstract It is uncertain if different immunomodulatory drugs (IMID) pose distinct thrombotic risk in patients with newly diagnosed multiple myeloma (MM). Among 2397 MM patients from the SEER-Medicare database from 2007 to 2013, 78% received lenalidomide, and 22% received thalidomide. After inverse probability weighting to balance confounders, the 12-month incidences of venous thromboembolism (VTE 10%) and arterial thromboembolism (ATE 5%) were similarly high in both groups. Lenalidomide versus thalidomide had a subdistribution hazard ratio of 1.11 (0.59–2.02) for VTE and a subdistribution hazard ratio of 0.96 (0.45–1.98) for ATE. Overall survival was not significantly different with a hazard ratio of 0.88 (0.60–1.18) for lenalidomide versus thalidomide. Concurrent anticoagulant prophylaxis was infrequently prescribed in < 20% of both groups. Our study demonstrates that despite improvement in myeloma-directed therapy and supportive care, thrombosis remains an important consideration for all IMID-treated MM patients. Appropriate risk stratification and vigilant thromboprophylaxis remain essential to prevent this complication. PubDate: 2019-11-26
Abstract: Abstract Novel anti-myeloma drugs have significantly improved the overall survival (OS) of patients with multiple myeloma (MM). However, not all MM patients treated with these drugs show survival benefits, and biologic and genetic prognostic factors are insufficient to predict the response to treatment. Decreasing treatment-related complications is important to improve the efficacy of treatment in patients with MM. The Controlling Nutritional Status (CONUT) score is a screening method for poor nutritional status, which is associated with poor prognosis in several cancers because it increases the rate of treatment-related complications. We retrospectively analyzed the OS of 64 patients with symptomatic MM and evaluated the correlation between the CONUT score and patient prognosis in MM. The median age at diagnosis was 66 years, and multivariate analysis showed that a high CONUT score (≥ 5; hazard ratio, 3.937; 95% confidence interval, 1.214–12.658; P = 0.022) was an independent prognostic risk factor. Subgroup analysis was performed according to patient age because the choice of treatment strategy, particularly autologous peripheral blood stem cell transplantation (auto-PBSCT), can vary depending on age in MM patients. Younger patients (< 65 years old) who received auto-PBSCT and had a lower CONUT score (0–3) showed a significantly better survival outcome than those with a higher CONUT score (≥ 4) (median OS, not reached vs. 64.1 months; P = 0.011). The CONUT score is simple to calculate and provides a useful prognostic indicator in patients with MM, especially transplant-eligible patients. PubDate: 2019-11-25
Abstract: Abstract For acute myeloid leukemia (AML) with nucleophosmin 1 mutation (NPM1m), multiparameter flow cytometry (FCM) and real-time quantitative polymerase chain reaction (RQ-PCR) are used to monitor minimal residual disease (MRD). However, the results of the two methods are sometimes inconsistent. This study was designed to analyze how to address the discordant results of FCM and RQ-PCR in AML patients undergoing chemotherapy, especially when positive FCM (FCM+) and negative NPM1m (NPM1m−) results are detected in the same sample. Our study included 93 AML patients with NPM1m positive (NPM1m+) who received chemotherapy but did not undergo hematopoietic stem cell transplantation. We monitored NPM1m and leukemia-associated immunophenotypes (LAIPs) by RQ-PCR and FCM, respectively, to assess MRD after each chemotherapy course. After each course of chemotherapy, all patients were classified into four groups based on the results of FCM and RQ-PCR: both negative (group 1, FCM−NPM1m−), single positive (group 2, FCM−NPM1m+; group 3, FCM+NPM1m−), or both positive (group 4, FCM+NPM1m+). The results showed that there was not a significant difference in the 2-year cumulative incidence of relapse (CIR) after each course of chemotherapy between group 2 and group 3. Furthermore, patients in groups 2 and 3 had a lower 2-year CIR than those in group 4 and a significantly higher 2-year CIR than those in group 1 after the first two courses. The patients in group 4 had a significantly higher 2-year CIR than those in group 1 after the first two courses. These results suggested that in the MRD monitoring process of AML patients, when the results of FCM and RQ-PCR are inconsistent (especially when FCM is positive and NPM1m is negative), these single-positive results still have predictive significance for relapse. PubDate: 2019-11-25
Abstract: Abstract The combinations of melphalan, bortezomib, and prednisolone (VMP) and of lenalidomide and dexamethasone (Rd) are standard treatment strategies for transplant-ineligible newly diagnosed multiple myeloma (NDMM). To make the most of these two strategies, we investigated the efficacy and feasibility of first-line treatment with 4 cycles of VMP followed by continuous Rd therapy in a multi-institutional phase 2 study in Japanese patients with transplant-ineligible NDMM. Thirty-six patients of median age 74 years old with NDMM initially received 35-day cycles of VMP: oral melphalan (6 mg/m2) and prednisolone (60 mg/m2) on days 1 to 4 and bortezomib (1.3 mg/m2) on days 1, 8, 15, and 22. After 4 cycles of VMP, treatment was switched to 28-day cycles of Rd, which was continued until disease progression or emergence of an unacceptable adverse event (AE) in 33 patients, while one patient who achieved CR after VMP continued VMP at the physician’s discretion. The overall response rates after VMP and after Rd were 66.7% and 86.1%, including CR rates of 5.6% and 36.1%, respectively. In a median follow-up period of 34.3 months, the progression-free survival and overall survival rates at 3 years were 43.2% and 81.3%, respectively. Grade 3–4 hematological AEs included neutropenia (39% with VMP and 24% with Rd) and thrombocytopenia (11% with VMP and 3% with Rd). There was no death due to an AE. In conclusion, sequential therapy with VMP followed by Rd is effective and mostly feasible for transplant-ineligible NDMM. The study is registered as UMIN000034815. PubDate: 2019-11-25
Abstract: Abstract In the present study, the possible activation of cellular immunity in SCD patients was investigated. As immune activation parameters, neopterin concentrations and kynurenine/tryptophan ratio for tryptophan degradation in 35 pediatric patients with sickle cell disease (31 HbSS and 4 HbSß) were determined. Our results have shown that neopterin levels (both urinary and serum) are increased in pediatric patients with sickle cell disease. The increase in neopterin concentration was accompanied by significantly increased biopterin, kynurenine concentration and kynurenine/tryptophan ratio. The mechanism of immune activation and the effects of inflammatory mediators in sickle cell disease are poorly understood, especially in terms of cell-mediated immunity. Further in-vivo and in-vitro studies are required to illuminate the association between neopterin levels and neutrophil activation in sickle cell disease. PubDate: 2019-11-23
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