Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis

ObjectivesCytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to perform a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. MethodsData sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google up to October 8, 2020. Study eligibility criteria were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. ResultsOf 1156 citations, 24 studies were eligible (five RCTs and 19 cohorts). Five RCTs at low risk of bias, with 1325 patients, examined the effect of tocilizumab on short-term mortality; pooled RR was 1.09 (95%CI 0.80–1.49, I2 = 0%). Four RCTs with 771 patients examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.71 (95%CI 0.52–0.96, I2 = 0%), with a corresponding number needed to treat of 17 (95%CI 9–100). Among 18 cohorts at moderate risk of bias with 9850 patients, the pooled adjusted RR for mortality was 0.58 (95%CI 0.51–0.66, I2 = 2.5%). This association was observed over all degrees of COVID-19 severity. Data from the RCTs did not show a higher risk of infections or adverse events with tocilizumab: pooled RR 0.63 (95%CI 0.38–1.06, five RCTs) and 0.83 (95%CI 0.55–1.24, five RCTs), respectively. ConclusionsCumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. We did not observe a higher risk of infections or adverse events with tocilizumab use. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment

Blastic plasmacytoid dendritic cell neoplasm: challenges in diagnosis and treatment with potential of venetoclax as an alternative to vincristine in high-risk patients—a case report

Abstract Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and challenging cancer for diagnosis and treatment. Accurate diagnosis plays a crucial role guiding appropriate treatment, typically involving high-intensity lymphoblastic leukemia regimens which typically include vincristine. However, the use of vincristine may be particularly limited in patients with pre-existing neuropathy or individuals at high risk of developing it. Here, we present a case of BPDCN that was initially diagnosed as marginal zone lymphoma (MZL) and subsequently as non-specific T-cell lymphoma, thus highlights the importance of accurate diagnosis and modified treatment. Case presentation A 49-year-old Arab man with a medical history of diabetes, peripheral neuropathy, hypertension, and depression presented with widespread, painless multiple skin lesions. After undergoing a biopsy at another institution, the patient was initially diagnosed with MZL, and received two cycles of bendamustine and rituximab. However, the disease relapsed and was later diagnosed with non-specific T-cell lymphoma, which proved refractory to a single cycle of CHOP chemotherapy. The patient was subsequently referred to our centre, where a comprehensive evaluation revealed BPDCN with a unique finding on bone marrow exam: signet ring plasmacytoid dendritic cells. Due to the patient's pre-existing neuropathy and previous treatment, we administered the Hyper-CVAD regimen with a 50% reduction in vincristine dosage, which resulted in an excellent response. During the second part of cycle one, when new skin lesions started appearing, venetoclax was added to the treatment regimen. Subsequently, we discontinued vincristine due to worsening neuropathic pain and neuropathy-related weakness. Venetoclax was continued in cycle two and led to a complete response. The patient achieved a disease-free state for the first time in disease course, maintaining it for a period of over six weeks before experiencing a relapse. Conclusions Accurate diagnosis is crucial for guiding appropriate treatment. Our case highlights the challenges associated with diagnosis and treatment, as well as the potential of venetoclax as an alternative to vincristine, particularly in patients with pre-existing neuropathy or those at a high risk of developing it. Further research is needed to evaluate the effectiveness of BCL2 inhibitors as a replacement for essential drugs and its potential as a bridging therapy until patients can undergo a stem cell transplant

Bispecific Antibodies in Hematological Malignancies: A Scoping Review

Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin’s lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations

Impact of cluster of differentiation 20 expression and rituximab therapy in classical Hodgkin lymphoma: Real world experience

The prognostic impact of CD20 expression and rituximab therapy in classical Hodgkin lymphoma (cHL) is unclear. Among 310 patients, CD20 was expressed in 66 (22%) cases. The 3-year PFS was 75.1% for CD20+and 70% for CD20− (p = 0.36). The 3-year PFS was 84.7% for the rituximab group and 67.8% for the no rituximab group (p = 0.23). Only constitutional symptoms and positive interim PET/CT were significantly associated with worse outcome, HR 3.2 (1.14–9.01; p = 0.028) and 4.3 (2.27–8.1; p < 0.0001), respectively. Neither CD20 expression nor rituximab use significantly impacted outcome

A systematic review and network meta-analysis comparing azacitidine and decitabine for the treatment of myelodysplastic syndrome

Abstract Background Hypomethylating agents (HMA), azacitidine, and decitabine are frequently used in the management of myelodysplastic syndromes (MDS). However, there are no clinical trials that have directly compared these agents. We conducted a systematic review and indirectly compared the efficacy of azacitidine to decitabine in MDS. Methods We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) through June 28, 2018, without language or time restrictions. Studies were screened by two independent reviewers, and differences were resolved by consensus. The fixed effect model and adjusted indirect comparison methods were used to pool relative risks (RR) of major outcomes of interest (mortality, response rate, quality of life, hematologic improvement, hospitalization, leukemia transformation, transfusion independence). Results Only four trials met the eligibility criteria. Two trials compared azacitidine to the best supportive care (BSC) and included 549 patients, and the other two compared decitabine to BSC and included 403 patients. The risk of bias was unclear overall. Compared to BSC, azacitidine was significantly associated with lower mortality (RR = 0.83, 95% CI 0.74–0.94, I 2 = 89%) whereas decitabine did not significantly reduce mortality (RR = 0.88, 95% CI 0.77–1.00, I 2 = 53%). Both drugs were associated with higher partial and complete response compared to BSC. Indirect comparisons were not statistically significant for all the studied outcomes, except for complete response where azacitidine was less likely to induce complete response compared to decitabine (RR = 0.11, 95% CI = 0.01–0.86, very low-certainty evidence). Conclusions Azacitidine and decitabine are both associated with improved outcomes compared to BSC. The available indirect evidence comparing the two agents warrants very low certainty and cannot reliably confirm the superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patient preferences, adverse effects, drug availability, and cost

Guide lines for management of adult histiocytic disease

BACKGROUND: Histiocytic disease is a diverse disease, characterized by multisystem involvement, diagnosis and management can be challenging. Guidelines are important tool to provide evidence-based management; however, guidelines for management of adult histiocytic disease are scarce. METHODOLOGY: A multidisciplinary team from Saudi Arabia developed guidelines to manage the adult histiocytic disease with an intention to provide standard of care for diagnosis and management of the most frequently encountered subtypes of adult histiocytic disease in the region. RESULTS: Detailed guidelines to different categories of histiocytic disease were finalized after review of many international guidelines and extensive literature review. CONCLUSION: Local guidelines for adults histiocytic disease was developed and can be shared with different hematology centers