Obinutuzumab plus bendamustine for relapsed/refractory chronic lymphocytic leukemia and predictive and prognostic impact of genetic alterations: the phase II GABRIELL study.

GABRIELL was a phase II single-arm study to evaluate the efficacy and safety of obinutuzumab plus bendamustine for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Seventy-two patients with active disease received treatment for up to six 28-day cycles. Overall response rate was 78.6% with a median progression-free survival (PFS) of 26 months, and overall survival (OS) not reached at the end of follow-up (36 months). Undetectable measurable residual disease (≤0.01%; 36.4% in bone marrow and 53.4% in peripheral blood) correlated with a significantly longer PFS and OS (vs. >0.01). Common grade ≥3 adverse events (76.4%) were neutropenia (58.3%), thrombocytopenia (26.4%) and febrile neutropenia (11.1%). TP53 disruption was the only independent predictive factor for response (Hazard ratio; HR: 0.228). Unmutated immunoglobulin heavy chain variable region (HR: 16.061) was a negative prognostic factor for PFS. In conclusion, the combination of obinutuzumab plus bendamustine is an active and generally adequately-tolerated treatment for R/R CLL.

Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM).

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

Real-World Characteristics and Outcome of Patients Treated With Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia in Spain (IBRORS-LLC Study).

BACKGROUND: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain. PATIENTS: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. RESULTS: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade ≥3 adverse events were infections (12.2%) and bleeding (3%). Grade ≥3 AF occurred in 1.5% of patients. CONCLUSION: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations.

Choroidal lymphoma diagnosed by polymerase chain reaction-based clonality assessment.

PURPOSE: To report a case of primary choroidal lymphoma that was confirmed by polymerase chain reaction-based clonality testing. CASE REPORT: A 50-year-old woman presented with unilateral progressive vision loss. Fundus examination and B-ultrasonography demonstrated diffuse choroidal thickening without vitritis. Pars plana vitrectomy and subretinal biopsy were performed, and histopathologic analysis revealed choroidal B-cell lymphoid hyperplasia without evidence of neoplasia. Extraocular extension was ruled out, and transitory improvement was observed with oral steroids. After 1-year follow-up, she was referred to our hospital and clonality testing was performed using the samples taken months before. First, we used a forensic DNA extraction kit, and then, a multiplex polymerase chain reaction was carried out using the IgH Rearrangements Molecular Analysis Kit. Clonal rearrangement was identified for the immunoglobulin heavy chain framework regions 1 and 2, and B-cell choroidal lymphoma was confirmed. The patient began treatment with intravitreal rituximab, but no response was observed. Finally, complete regression was achieved using external beam radiotherapy. CONCLUSION: Polymerase chain reaction-based clonality testing can be a valuable tool to confirm a choroidal lymphoproliferative process.

A critical evaluation of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura.

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy caused by inhibitory autoantibodies against ADAMTS13 protein. Until recently, the combination of plasma exchange (PEX) and immunosuppression has been the standard front-line treatment in this disorder. However, aTTP-related mortality, refractoriness, and relapse are still a matter of concern. Areas covered: The better understanding of the pathophysiological mechanisms of aTTP has allowed substantial improvements in the diagnosis and treatment of this disease. Recently, the novel anti-VWF nanobody caplacizumab has been approved for acute episodes of aTTP. Caplacizumab is capable to block the adhesion of platelets to VWF, therefore inhibiting microthrombi formation in the ADAMTS13-deficient circulation. In this review, the characteristics of caplacizumab together with the available data of its efficacy and safety in the clinical setting will be analyzed. Besides, the current scenario of aTTP treatment will be provided, including the role of other innovative drugs. Expert opinion: With no doubt, caplacizumab is going to change the way we treat aTTP. In combination with standard treatment, caplacizumab can help to significantly reduce aTTP-related mortality and morbidity and could spare potential long-term consequences by minimizing the risk of exacerbation.

Therapeutic plasma exchange: Review of current indications.

Therapeutic plasma exchange (TPE) is the extracorporeal technique performed in an apheresis device were patient's plasma is separated from whole blood and removed, while the cellular blood components are returned to the patient together with a replacement fluid. By the extracorporeal removal of pathological substances and the replacement of deficient plasma components, it constitutes an important tool for the management of several disorders and it is a well-known and established treatment for numerous diseases. Additionally, overall available data confirm the safety and efficacy of TPE. Nevertheless, the quality of the evidence supporting the utility and efficacy of the procedure is diverse. This review attempts to compile the current indications of TPE in different disorders according to an extensive and updated literature review, with special focus on its present role and its validity in the twenty-first century medicine.

Brentuximab vedotin in Hodgkin lymphoma and anaplastic large-cell lymphoma: an evidence-based review.

Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) account for ~10% and 2%-3% of all cases of lymphoid neoplasms, respectively. Up to 30% of patients with HL are refractory or relapse after first-line therapy, and elderly patients with HL represent a subgroup of patients with suboptimal responses to the currently available treatments. Five-year overall survival for ALCL patients is 50%-80% with conventional chemotherapy. Therefore, new therapeutic approaches are needed for these groups of patients. Brentuximab vedotin is a chimeric IgG1 anti-CD30 antibody-drug conjugate that has all the features that are necessary to make a substantive difference with the standard therapies in patients with HL and ALCL: a novel mechanism of action, single-agent activity, non-cross-resistance, and safety both in the relapsed-refractory and in the front-line setting. This review provides an update of the results of the most relevant clinical trials including brentuximab vedotin for patients with HL and ALCL conducted to date.

Relationship Between Glucocerebrosidase Activity and Clinical Response to Enzyme Replacement Therapy in Patients With Gaucher Disease Type I.

The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualization, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leucocytes were studied: enzyme activity at 15 min. post-infusion (Act75 ) reflects the amount of enzyme that is distributed in the body post-ERT infusion, and accumulated glucocerebrosidase activity during ERT infusion (Act75-0 ) indicates the total drug exposure during infusion. The clinical response was evaluated based on criteria established by Pastores et al. and Gaucher Severity Score Index. Statistical analysis included ROC analysis and area under the curve test. Act75 and Act75-0 were found to be moderate predictive markers of an optimal clinical response (area under the ROC of Act75 was 0.733 and Act75-0 was 0.817). Act75-0 showed statistical significance in its discriminative capacity (p < 0.05) for obtaining an optimal response to ERT. The cut-off point was 58% (RR = 1.800; 95% CI: 1.003-3.229; p < 0.05). Moreover, Act75 showed a significant and inverse correlation with the Gaucher Severity Score Index, and Act75 and Act75-0 presented a significant correlation with residual enzyme activity at diagnosis. Markers based on glucocerebrosidase activity have a good correlation with clinical response to ERT. Therefore, it could provide supporting clinical data for dose management in GD1 patients.

Immunotherapy for the treatment of Hodgkin lymphoma.

INTRODUCTION: Most patients with Hodgkin lymphoma (HL) enjoy durable remissions following front-line treatment but 30% of patients are refractory or relapse after first line therapy. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) can cure an additional 50-55% of relapsing patients but new treatments are needed for patients with HL who are refractory or relapse after ASCT. Immunotherapy has emerged as a promising treatment for the management of these patients. The availability of the anti-CD30 antibody brentuximab vedotin and new targeted drugs such as immune checkpoint inhibitors, show promising clinical activity in patients with HL and are important milestones for the management of patients with HL particularly for those who have progressed after standard initial therapy and ASCT. Areas covered: Overview of the results from the most relevant clinical trials including monoclonal antibody-based therapy in HL. Phase 2 and phase 3 trials including brentuximab vedotin and immune checkpoints inhibitors in patients with Hodgkin lymphoma have been reviewed. In addition, the potential impact of these new therapies in the management of patients with newly diagnosed HL has also been addressed. Expert commentary: Anti-CD30 antibody brentuximab vedotin and immune checkpoint inhibitors have shown promising results in patients with relapsed and refractory HL. Administration of these therapies earlier in the course of the disease might reduce the proportion of relapsed or refractory patients and, subsequently, minimize the number of patients undergoing high-dose therapy and autologous stem cell transplantation. We have little doubt that this will have substantial effects on the outcome for future generations of HL patients.

Cellular Uptake of Glucocerebrosidase in Gaucher Patients Receiving Enzyme Replacement Treatment.

BACKGROUND: Enzyme replacement therapy (ERT) is currently the standard treatment for patients with Gaucher disease type I (GD1), but the pharmacokinetics have hardly been studied. This study aimed to quantify in vivo enzyme activity in peripheral leukocytes from patients receiving long-term treatment with imiglucerase or velaglucerase for GD1, and set out to assess the process of enzymatic uptake by peripheral leukocytes. METHODS: A prospective semi-experimental study was conducted. Four time points for blood withdrawal were planned per patient to quantify the intra-leukocyte enzymatic activity. In order to assess the uptake process, the rate of enzyme uptake by leukocytes (Rupt) and the rate of enzyme disappearance from the plasma (Rdis) were estimated. RESULTS: Eight GD1 patients were included. Intra-leukocyte activity was 24.31 mU/mL [standard deviation (SD) 6.32 mU/mL; coefficient of variation (CV) 25.96 %] at baseline and 27.14 mU/mL (SD  6.96 mU/mL; CV 25.65 %) at 15 min post-perfusion. The relationships with the administered dose were linear. The Rupt value was 37.73 mU/mL/min [95 % confidence interval (CI) 25.63-49.84] and showed a linear correlation with the administered enzyme dose (p < 0.05), and the Rdis value was 189.43 mU/mL/min (95 % CI 80.31-298.55) and also showed a linear correlation with the dose (p < 0.05). CONCLUSION: This was the first in vivo study to quantify the accumulated enzymatic activity in patients receiving ERT for GD1. It showed that intra-leukocyte activity at baseline and at 15 min post-perfusion could be used as a possible marker for therapeutic individualization in patients receiving ERT for GD1.