Trimetazidine reduces contrast-induced nephropathy in patients with renal insufficiency undergoing coronary angiography and angioplasty: A systematic review and meta-analysis (PRISMA).

OBJECTIVES: This systematic review and meta-analysis assesses the utility of trimetazidine (TMZ) to prevent contrast induced nephropathy (CIN) in patients with renal insufficiency undergoing coronary angiography and angioplasty. MATERIALS AND METHODS: This meta-analysis was formulated and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of databases was conducted by 2 researchers independently for clinical trials, comparing hydration plus TMZ vs conventional hydration alone for prevention of CIN through January 2020. All patients had renal insufficiency (defined as GFR < 89 ml/minute/1.73 m2) and the outcome of interest was the incidence of contrast induced acute kidney injury. The odds ratio (OR) was estimated with 95% confidence interval (CI). Heterogeneity was reported with the I2 statistic, using a fixed-effects model, and >50% of I2 was considered to be statistically significant. RESULTS: Eleven studies, 1611 patients, met the inclusion/exclusion criteria: 797 patients comprised the TMZ plus hydration group and the remaining 814 patients comprised the control (hydration only) group. Heterogeneity was low I2 = 0%, P = .84, and the heterogeneity of each study was also low. The incidence of CIN in the TMZ plus hydration group was 6.6% (53/797), while the incidence of CIN in the control (hydration only) group was 20% (165/814). Pooled analysis of all studies showed TMZ reduced incidence of CIN compared to saline hydration alone (OR risk 0.30, 95% CI 0.21, 0.42, P < .0001). CONCLUSION: TMZ added to hydration reduces CIN in renal insufficiency patients undergoing coronary angiography.

Gender Differences in Faculty Rank and Leadership Positions Among Hematologists and Oncologists in the United States.

PURPOSE: Gender disparity persists in academic medicine. Female faculty are underrepresented in leadership positions and have lower research output. We studied gender differences in faculty rank and departmental leadership and contributing factors among academic hematologists and oncologists in the United States. METHODS: For clinical faculty at 146 hematology or oncology fellowship programs listed in the Fellowship and Residency Electronic Interactive Database, we collected data on demographics, academic rank, and research output using the Doximity and Scopus databases. We compared unadjusted characteristics of men and women by using 2-sided t tests and χ2 tests where appropriate. To predict probability of full professorship or leadership position among men versus women, we performed multivariable logistic regression analysis adjusted for clinical experience in years, number of publications, h-index, clinical trial investigator status, National Institutes of Health funding, and workplace ranking (top 20 v not). RESULTS: Two thousand one hundred sixty academic hematologists and oncologists were included. Women composed 21.9% (n = 142) of full professors, 35.7% (n = 169) of associate professors, and 45.4% (n = 415) of assistant professors. Thirty percent (n = 70) of departmental leaders were women. Female faculty, compared with male faculty, had a lower mean h-index (12.1 v 20.9, respectively; P < .001) and fewer years of professional experience since fellowship (10 v 16 years, respectively; P < .001). After adjusting for duration of clinical experience, academic productivity, and workplace ranking, the odds of obtaining professorship (odds ratio [OR], 1.05; 95% CI, 0.71 to 1.57; P = .85) or divisional leadership (OR, 0.57; 95% CI, 0.20 to 1.58; P = .28) for female physicians were not different compared with male physicians. CONCLUSION: Gender disparity exists in senior ranks of academic hematology and oncology; however, gender is not a significant predictor in achieving professorship or department leadership position.

Therapeutic Advances in the Management of Smoldering Myeloma.

BACKGROUND: The International Myeloma Working Group has defined smoldering multiple myeloma (SMM) as the presence of 10%-60% plasma cells in the bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end-organ damage (an increased calcium level, renal failure, anemia, and destructive bone lesions). AREAS OF UNCERTAINTY: Patients considered to have SMM should not have any myeloma-defining events or amyloidosis. Different risks factors classify SMM into low-, intermediate-, or high-risk categories. The rate of progression from SMM to symptomatic myeloma is ∼10% per year during the first 5 years of diagnosis. SMM requires frequent follow-up ∼every 3 months during the first 5 years as compared to monoclonal gammopathy of undermined significance, which usually requires follow-up every 6-12 months after the first year of diagnosis. DATA SOURCES: A literature search was performed from electronic bibliographic databases: MEDLINE (Ovid SP/PubMed), EMBASE, the Cochrane Library (Cochrane Database of Systematic Reviews), and Cochrane Central Register of Controlled Trials and from annual meeting abstracts from inception to May 2017. THERAPEUTIC ADVANCES: This review presents the literature and available data that support or do not support early treatment of high-risk SMM (HR-SMM) and provides evidence-based recommendations for management of SMM patients. Despite emerging data recommending early treatment of HR-SMM, we predict the SMM category may disappear in the near future and patients will be diagnosed with either multiple myeloma or monoclonal gammopathy of undermined significance. CONCLUSIONS: Success with early therapy trials for HR-SMM is largely due to patients meeting current criteria for multiple myeloma that may have been classified as SMM and, therefore, benefitted from therapy. Based on current practices and the literature, SMM should be managed with close follow-up. Based on available data, we suggest SMM to only be treated in clinical trial settings.

Pomalidomide-Based Regimens for Treatment of Relapsed and Relapsed/Refractory Multiple Myeloma: Systematic Review and Meta-analysis of Phase 2 and 3 Clinical Trials.

INTRODUCTION: Pomalidomide (Pom) has demonstrated synergistic antiproliferative activity in combination regimens as a result of its distinct anticancer, antiangiogenic, and immunomodulatory effects. This review aimed to compare outcome measures of different Pom regimens for relapsed/refractory multiple myeloma. METHODS: A comprehensive literature search identified a total of 1374 studies. Thirty-five studies assessing 4623 subjects met the inclusion criteria: phase 2/3 trial, ≥ 2 prior lines of therapy, and clearly documented efficacy outcomes like overall response rate (ORR), overall survival, and progression-free survival. Statistical analyses for meta-analysis was performed by CMA version 3 and Cochrane Q statistics (P < .05 considered significant, I2 index for heterogeneity). A random effects model was used if there was significant heterogeneity (P ≥ .05 over I2 ≥ 50%). RESULTS: Pooled analysis showed ORR 47.1% across all Pom-based (2- and 3-drug) regimens. Stratified analysis for efficacy outcomes (pooled ORR [%] and mean progression-free survival [months]) are reported. With doublet regimen, Pom with low-dose dexamethasone (LoDex) was the most common regimen (35.7%, 6.1 months), and overall survival was 14.37 months. With triplet regimens, pooled ORR was 61.9% (I2 = 87.3%). These included bortezomib + Pom + LoDex (83.5%, 15.7 months), carfilzomib-Pom + LoDex (77.1%, 15.3 months), Pom + LoDex-bendamustine (74.2%), Pom-dexamethasone-daratumumab (64.5%), Pom + LoDex-cyclophosphamide (59.4%, 9.5 months), and Pom + LoDex-doxorubicin (32%). Leading adverse events were myelosuppression, with mean incidences of grade 3 or higher neutropenia, anemia, and thrombocytopenia of 47.6%, 26.5%, and 20.8%, respectively. Mean incidence of grade 3 or higher nonhematologic adverse events were infections 29.1%, pneumonia 13.8%, and fatigue 10%. CONCLUSION: Three-drug Pom regimens yielded double the response rates compared to Pom + LoDex (pooled ORR, 61.9% vs. 35.7%), with bortezomib + Pom + LoDex and carfilzomib-Pom + LoDex demonstrating better outcomes than other regimens.

Role of High-dose Chemotherapy and Autologous Stem Cell Transplantation for Relapsed Ewing's Sarcoma: A Case Report with Focused Review of Literature.

We report a case of a patient with relapsed Ewing's sarcoma (ES). After receiving conventional chemotherapy (CC) and noticing chemosensitivity of the disease, we proceeded to give the patient two separate cycles of HDCT consisting of a melphalan/busulfan regimen in the first cycle and etoposide/melphalan in the second cycle. The patient proceeded to get an autologous stem cell transplant (ASCT) after each cycle of HDCT. Our patient, despite multiple poor prognostic factors, including advanced age and multiple sites of disease relapse, showed a one-year event-free survival. Relapsed ES is associated with a poor prognosis. No treatment regimen has yet been established as a standard of care in patients with relapsed ES. We conducted a focused literature review to assess the efficacy of high-dose chemotherapy (HDCT) followed by ASCT in patients with relapsed ES. Given the improved survival outcome with HDCT followed by ASCT in our patient, we propose that its role in relapsed ES needs further assessment through large prospective, randomized controlled studies.

Role of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for Children and Young Adults with Relapsed Ewing's Sarcoma: A Systematic Review.

BACKGROUND: Relapsed Ewing's sarcoma (RES) is an aggressive malignancy with poor survival. Although high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given after conventional chemotherapy (CC) has shown survival benefits, it is not generally used in the United States for RES. We performed a systemic review to evaluate the benefits of HDCT for RES. METHODS: Literature search involved Medline, Embase, and Cochrane database. We included studies with RES patients treated with HDCT/ASCT. RESULTS: Twenty-four studies with total of 345 reported RES patients that got HDCT were included in final analysis. Seventeen studies had patients with multiple malignancies including RES, while seven had only RES patients. At 2 and 3-5 years, event-free survival (EFS) in studies with only RES patients ranged 42-47% and 20-61% and overall survival (OS) ranged 50-66% and 33-77%, respectively. In studies with combined patients that reported outcomes of RES separately, the EFS at 1-3 and 4 years was 36-66% and 17-50%, respectively. The OS at 1-2 and 3-4 years was 40-60% and 50-70%. CONCLUSIONS: Most studies using HDCT/ASCT as consolidation regimen showed improved survival benefits compared to CC. Randomized controlled studies are needed to determine true clinical benefits of HDCT followed by ASCT in patients with RES.

Management of Recurrent Clostridium difficile Infection During Intensive Chemotherapy and Stem Cell Transplantation for Leukemia: Case with Literature Review.

Immunocompromised patients undergoing chemotherapy for hematologic malignancy and hematopoietic stem cell transplant (HSCT) recipients are at increased risk of Clostridium difficile (C. difficile) infection (CDI). The recurrence of infection and its associated morbidity and mortality are due to multiple risk factors. Diarrhea is common in HSCT recipients, but the diagnosis of diarrhea caused by CDI is a therapeutic challenge due to frequent Clostridium difficile colonization with diarrhea secondary to non-infectious causes. The high recurrence rate is a significant challenge in the treatment of immunocompromised patients. Close monitoring of the patients, timely diagnosis, preventive measures, treatment with antibiotics, and the removal of offending agents can help in the management and cure of the disease. We review the literature on management and describe a patient with acute lymphoblastic leukemia (ALL) with multiple recurrences of CDI during leukemia therapy and allogeneic stem cell transplantation for leukemia.

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review.

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM.

Role of one, two and three doses of high-dose chemotherapy with autologous transplantation in the treatment of high-risk or relapsed testicular cancer: a systematic review.

Approximately 20-30% of patients with metastatic germ cell cancers (GCCs) can develop relapsed or refractory (RR) disease, about 40-50% of patients who relapse after salvage chemotherapy may reach long-term remission. The goal of this review was to identify patients who appear to benefit from high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). To access this, we performed a systematic medical literature review to evaluate the effectiveness of HDCT in the frontline setting, as well as in patients with RR testicular cancer. We searched databases for interventional clinical studies and identified 5883 studies. We selected 49 studies for inclusion, which included a total of 5985 patients. Seventeen studies reported results of newly diagnosed poor-risk GCC patients and 32 studies reported results of RR patients. For newly diagnosed patients with poor prognostic predictors, a risk adjusted strategy using unfavorable tumor marker decline with initial standard chemotherapy regimen and upfront HDCT demonstrated improved outcomes. Our data suggest a minimum of two HDCT cycles with ASCT should be standard of care for patients with RR GCC. Failure of HDCT results in a poor prognosis with only 10% of patients achieving lasting remission with salvage therapy.

Prophylaxis for Hepatitis B Virus Reactivation after Allogeneic Stem Cell Transplantation in the Era of Drug Resistance and Newer Antivirals: A Systematic Review and Meta-Analysis.

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high-risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug-resistant strains. With the availability of newer antiviral agents such as entecavir, telbivudine, adefovir, and tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of 7 databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials.gov (June 21, 2017)). We identified 10 studies, with 2067 patients undergoing allo-HSCT; these primarily evaluated the use of lamivudine and entecavir as prophylaxis against HBVr in patients undergoing allo-HSCT because there were little or no data about adefovir, telbivudine, or tenofovir as prophylaxis in this specific patient population. Thus, included studies were categorized into 2 main prophylaxis groups: lamivudine and entecavir. Results of our meta-analysis suggest that entecavir is very effective against HBVr, although further clinical trials are required to test efficacy of new antivirals and explore the emerging threat of drug resistance.

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis.

Chimeric antigen receptor modified T cells targeting CD19 and CD20 have shown activity in Phase I, II trials of patients with hematological malignancies. We conducted a systematic review and meta-analysis of all published clinical trials studying the role of efficacy as well as safety of CD-19 and CD-20 chimeric antigen receptor-T therapy for B-cell hematologic malignancies. A total of 16 studies with 195 patients were identified. The pooled analysis showed an overall response rate of 61% (118/195) with complete response of 42% (81/195) and partial response of 19% (37/195). Major adverse events were cytokine release syndrome 33%, neurotoxicity 33% and B-cell aplasia 54%. Collectively, the results indicate encouraging response in relapsed/refractory B lymphoma and leukemia, especially in acute lymphoblastic leukemia (ALL) patients.

Coccidioidomycosis, immunoglobulin deficiency: safety challenges with CAR T cells therapy for relapsed lymphoma.

Treatment of patients with relapsed or refractory lymphoma may require allogenic hematopoietic stem cell transplant (HSCT), but treatment of post-transplant relapse disease remains very challenging. Donor lymphocyte infusion and blinatumomab have been used with limited success for the treatment of relapse. Initial data on donor-derived CAR T cells has shown this modality to be safe and highly effective in various hematological malignancies. We present a case of a patient with highly refractory, transformed follicular lymphoma who failed both autologous and allogenic HSCT. Patient achieved long-lasting complete remission with the use of donor origin CD19 CAR T-cell therapy, without any evidence of graft-versus-host disease flare. Our patient later developed disseminated coccidioidomycosis and persistent hypogammaglobulinemia. Immunotherapy using CD19 CAR T cells can be a highly effective salvage modality, especially in cases of focal lymphoma relapse. Long-term immunosuppression secondary to B cell lymphopenia, hypogammaglobulinemia, immunoglobulin subclass deficiency, fungal infections and other infectious complications need to be monitored and promptly treated as indicated.

A Review of Autologous Stem Cell Transplantation in Lymphoma.

PURPOSE OF REVIEW: Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. RECENT FINDINGS: There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review.

CD19, CD20 chimeric antigen receptor T (CAR T) cell therapy has shown promising results for the treatment of relapsed or refractory hematological malignancies. Best results have been reported in acute lymphoblastic leukemia patients with a complete response rate above 80%. Patients who received donor-derived CAR T cells for the relapsed malignancy after stem cell transplantation (allogenic hematopoietic stem cell transplant) were identified from the published trials. A total of 72 patients from seven studies were treated with donor-derived CAR T cells. Only five out of 72 patients (6.9%) developed graft versus host disease. Use of donor-derived CAR T cell for relapse prophylaxis, minimal residual disease clearance or salvage from relapse is therefore highly effective, and risk of graft versus host disease flare is very low. Side effects include cytokine release syndrome, tumor lysis syndrome, B-cell aplasia along with CNS toxicity.

Successful recovery and allogeneic stem cell transplant following chemotherapy-induced severe cardiomyopathy: literature review of management and prognostic factors.

Chemotherapy-induced cardiomyopathy is one of the major possible hazards that can result from potential cardiotoxic agents while treating cancer. Prognostic risk factors include the rate of drug administration, history of hypertension, female gender, extremes of age, previous history of mediastinal irradiation, cumulative dose and pre-existing heart disease. Close monitoring of the patients, timely diagnosis, use of well-known biomarkers including cardiac troponins, NT-ProBNP and imaging studies like 2D Echo or cardiac MRI are essential. Emerging biomarkers include carbonyl reductases (CBR1 and CBR3), aldo-keto reductases (AKR, type 1A1, 1C3, 7A2) and topoisomerase2ß (Top2ß). ß blockers and ACE inhibitors have not only been shown to slow down the progression of cardiac dysfunction but also produce symptomatic improvement. Our case report describes a patient with acute myeloblastic leukaemia who developed severe cardiomyopathy acutely after starting the anthracycline-based regimen. Nevertheless, with timely intervention her symptoms improved and subsequently she successfully received allogeneic stem cell transplantation.