IBRORS-MCL study: a Spanish retrospective and observational study of relapsed/refractory mantle-cell lymphoma treated with ibrutinib in routine clinical practice.

This retrospective study evaluated 66 patients diagnosed with relapsed and/or refractory mantle cell lymphoma (R/R MCL) treated with ibrutinib in Spain in routine clinical practice. At diagnosis, patients had a median age of 64.5 years, 63.6% presented with intermediate/high sMIPI (simplified prognostic index for advanced-stage mantle cell lymphoma), 24.5% had the blastoid variant, and 55.6% had a Ki67 > 30%. Patients had received a median of 2 prior lines of therapy (range 1-2; min-max 1-7). Overall response rate was 63.5%, with 38.1% of patients achieving complete response (CR). With a median duration of ibrutinib exposure of 10.7 months (range 5.2-19.6; min-max 0.3-36), the median progression-free survival (PFS) and overall survival (OS) were 20 months [95% confidence interval (CI) 8.8-31.1] and 32 months (95% CI 22.6-41.3), respectively, and were not reached in patients achieving CR. No grade ≥ 3 cardiovascular toxicity or bleeding was reported. This study supports that treatment with ibrutinib leads to high response rates and favorable survival outcomes in patients with R/R MCL.

Panel Sequencing for Clinically Oriented Variant Screening and Copy Number Detection in Chronic Lymphocytic Leukemia Patients.

According to current guidelines, in chronic lymphocytic leukemia (CLL), only the TP53 molecular status must be evaluated prior to every treatment's initiation. However, additional heterogeneous genetic events are known to confer a proliferative advantage to the tumor clone and are associated with progression and treatment failure in CLL patients. Here, we describe the implementation of a comprehensive targeted sequencing solution that is suitable for routine clinical practice and allows for the detection of the most common somatic single-nucleotide and copy number variants in genes relevant to CLL. We demonstrate that this cost-effective strategy achieves variant detection with high accuracy, specificity, and sensitivity. Furthermore, we identify somatic variants and copy number variations in genes with prognostic and/or predictive value, according to the most recent literature, and the tool provides evidence about subclonal events. This next-generation sequencing (NGS) capture-based target assay is an improvement on current approaches in defining molecular prognostic and/or predictive variables in CLL patients.

RELINF: prospective epidemiological registry of lymphoid neoplasms in Spain. A project from the GELTAMO group.

Lymphomas are a large, heterogeneous group of neoplasms with well-defined characteristics, and this heterogeneity highlights the importance of epidemiological data. Knowledge of local epidemiology is essential to optimise resources, design clinical trials, and identify minority entities. Given there are few published epidemiological data on lymphoma in Spain, the Spanish Lymphoma and Autologous Bone Marrow Transplant Group created the RELINF project. The aim of this project is to determine the frequencies and distribution of lymphoid neoplasms in Spain and to analyse survival. We developed an online platform for the prospective collection of data on newly diagnosed cases of lymphoma in Spain between January 2014 and July 2018; 11,400 patients were registered. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) were the most frequent lymphomas in our series. Marginal B cell lymphoma frequency was higher than that reported in other studies, representing more than 11% of mature B cell lymphomas. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) was the most common subtype of T cell lymphoma, and NK/T cell lymphomas were more frequent than expected (5.4% of total). Hodgkin's lymphoma accounted for 12% of lymphoproliferative syndromes. Overall survival was greater than 90% at 2 years for indolent B cell lymphomas, and approximately 60% for DLBCL, somewhat lower than that previously reported. Survival was poor for PTCL-NOS and angioimmunoblastic T cell lymphoma, as expected; however, it was somewhat better than that in other studies for anaplastic large cell anaplastic lymphoma kinase lymphomas. This is the first prospective registry to report the frequencies, distribution, and survival of lymphomas in Spain. The frequencies and survival data we report here are globally consistent with that reported in other Western countries. These updated frequencies and survival statistics are necessary for developing appropriate management strategies for neoplasias in the Spanish population.

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.

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.

Predictive value of interim ¹8F-FDG-PET/CT for event-free survival in patients with diffuse large B-cell lymphoma homogenously treated in a phase II trial with six cycles of R-CHOP-14 plus pegfilgrastim as first-line treatment.

OBJECTIVE: The predictive value of interim PET/computed tomography (I-PET/CT) in diffuse large B-cell lymphoma (DLBCL) is controversial. Our aim was to evaluate the predictive value of I-PET/CT for an event-free survival. PATIENTS AND METHODS: We analyzed patients with DLBCL included in a prospective clinical trial who were treated with six cycles of dose-dense R-CHOP followed by pegfilgrastim and who had undergone an I-PET/CT (after two cycles) and a final PET [F-PET/CT (60 days after the sixth cycle)]. Event was defined as nonresponse, relapse, or death. RESULTS: A total of 69 patients were included. Their median age was 60 years; 54% were male, 25% had bulky disease, and 67% had an International Prognostic Index of 0-2. The median follow-up duration was 28.8 months. I-PET/CT was positive in 34 (49%) patients and F-PET/CT was positive in 12 (17.4%). The 3-year event-free survival was 86% for patients who were I-PET/CT negative as against 64% for those who were I-PET/CT positive (P=0.036). The negative and positive predictive values, sensitivity, and specificity of I-PET/CT for an event were 83, 32, 65, and 56%, respectively. In a multivariate analysis including baseline characteristics, I-PET/CT, and F-PET/CT, F-PET/CT was the only significant predictor (P<0.0005). CONCLUSION: In patients with DLBCL treated with dose-dense R-CHOP plus pegfilgrastim, a negative I-PET/CT is highly predictive of a favorable outcome and a positive I-PET/CT is of limited clinical value. These results do not support treatment intensification after a short course of chemotherapy based solely on a positive I-PET/CT.

R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study.

BACKGROUND: The role of re-treatment with rituximab in aggressive B-cell lymphomas still needs to be defined. This study evaluated the influence of prior exposure to rituximab on response rates and survival in patients with diffuse large B-cell lymphoma treated with rituximab plus etoposide, cytarabine, cisplatinum and methylprednisolone (R-ESHAP). DESIGN AND METHODS: We retrospectively analyzed 163 patients with relapsed or refractory diffuse large B-cell lymphoma who received R-ESHAP as salvage therapy with a curative purpose. Patients were divided into two groups according to whether rituximab had been administered (n=94, "R+" group) or not (n=69, "R-" group) prior to R-ESHAP. RESULTS: Response rates were significantly higher in the R- group in the univariate but not in the multivariate analysis. In the analysis restricted to the R+ group, we observed very low complete remission and overall response rates in patients with primary refractory disease (8% and 33%, respectively), as compared to those in patients who were in first partial remission (41% and 86%) or who had relapsed disease (50% and 75%) (p<0.01 in both cases). Overall, 60% and 65% of patients in the R+ and R- groups, respectively, underwent stem-cell transplantation after the salvage therapy. With a median follow-up of 29 months (range, 6-84), patients in the R+ group had significantly worse progression-free survival (17% vs. 57% at 3 years, p<0.0001) and overall survival (38% v 67% at 3 years, p=0.0005) than patients in the R- group. Prior exposure to rituximab was also an independent adverse prognostic factor for both progression-free survival (RR: 2.0; 95% CI: 1.2-3.3, p=0.008) and overall survival (RR: 2.2; 95% CI: 1.3-3.9, p=0.004). CONCLUSIONS: R-ESHAP was associated with a high response rate in patients who were not refractory to upfront rituximab-based chemotherapy. However, the survival outcome was poor for patients previously exposed to rituximab, as compared to in those who had not previously been treated with rituximab.