María José Terol

This retrospective study involving 225 centers assessed TP53 and IGHV molecular status and stereotyped BcR IG subsets in a large cohort of patients with CLL in Spain using data from the RED53 project. Three analytical reference centers determined the mutational status of treatment-naïve CLL patients requiring treatment following the ERIC guidelines between May 2016 and March 2021. Of 1097 patients included (58.4% men), 90.8% had unmutated TP53 . Of the 100 patients (9.2%) with mutated TP53 , most (97.0%) had single-hit TP53 mutations, of which 88.3% were pathogenic. IGHV-UM mutational status (57.8%) was slightly more common than IGHV-M (33.2%). Of patients with mutated TP53 , 66.7% had IGHV-UM and 30.0% IGHV-M. Stereotyped Ig BCR subsets were identified in 9.2% of patients, with the most frequent being CLL#1 (23.2%), CLL#2 (24.0%), and CLL#6 (10.7%). The frequencies of TP53 and IGHV mutations were similar to those reported in other international series. The RED53 project enabled molecular testing to be incorporated into routine practice to guide treatment decisions.

Le virus T lymphotropique humain de type 1 (HTLV-1) est l’agent étiologique d’une forme rare et très agressive de leucémie de l’adulte (ATL). Le processus leucémogène a longtemps été attribué à la seule action de l’oncoprotéine Tax. Cependant, une nouvelle protéine virale, appelée HBZ (HTLV-1 bZIP factor), a été découverte en 2002. Elle est codée par le brin complémentaire du génome proviral et transcrite en antisens à partir du LTR3’. HBZ s’est avéré être un acteur clef de la prolifération et de la transformation des cellules T infectées, et donc du développement de l’ATL. La présente étude propose de nouvelles pistes quant aux mécanismes par lesquels HBZ induit la survie et la prolifération cellulaire. Nous avons montré que la protéine HBZ stimule l’expression de la neurotrophine BDNF et que les cellules de patients ATL surexpriment à la fois BDNF et son récepteur TrkB. De plus, ces patients présentent une concentration sérique anormalement élevée de la forme mature de BDNF, suggérant l’existence d’une boucle autocrine/paracrine BDNF/TrkB. L’activité de cette boucle a été confirmée in vitro et promeut la survie des cellules infectées par HTLV-1. D’autre part, nous avons découvert qu’HBZ dérégule l’expression du suppresseur de tumeur JunD dans les cellules T infectées, et induit celle de l’isoforme potentiellement oncogène ΔJunD. La production de ΔJunD résulterait d’une altération des mécanismes d’initiation de la traduction par HBZ. Nos résultats montrent aussi que ΔJunD promeut la prolifération et la transformation cellulaire en l’absence de sérum. Nous proposons donc que son expression pourrait contribuer à l’évolution des cellules T infectées en cellules leucémiques.

PURPOSE: An unmet need remains for more effective therapies for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), especially high-grade B-cell lymphoma (HGBCL). We present the primary analysis of a phase Ib/II study (ClinicalTrials.gov identifier: NCT03533283 ) investigating efficacy and safety of glofitamab plus polatuzumab vedotin (Glofit-Pola) in patients with R/R LBCL, including HGBCL and those who received previous chimeric antigen receptor (CAR) T-cell therapy. METHODS: Patients received 1,000 mg obinutuzumab on Cycle (C)1 Day (D)1 (once daily). Polatuzumab vedotin (1.8 mg/kg) was given on C1D2 and D1 of C2–6 (21-day cycles; once daily). Glofitamab was given as step-up doses in C1 (D8, 2.5 mg; D15, 10 mg) followed by 30 mg on D1 of C2–12 (21-day cycles; once daily). Polatuzumab vedotin was given for six fixed-duration cycles, and glofitamab for 12. RESULTS: As of September 2, 2024, 129 patients with LBCL (HGBCL; n = 44, 34.1%), received ≥1 dose of study treatment. The median age was 67 years (range, 23-84), and 63.6% were male. Patients had received a median of 2 (range, 1-7) previous lines of treatment (previous CAR T-cell therapy, n = 28, 21.7%). The independent review committee–assessed overall response rate was 78.3% (complete response rate, 59.7%). The median progression-free survival and overall survival (OS) were 12.3 and 33.8 months, respectively (median OS follow-up time, 32.7 months). The most common adverse event (AE) was cytokine release syndrome (43.4%; grade 1-2: 41.9%; one grade 5 event). Grade 3-4 AEs occurred in 58.9% of patients; 9.3% had grade 5 AEs, and 14.7% discontinued treatment because of AEs. CONCLUSION: Glofit-Pola demonstrated high efficacy and durable responses, with manageable safety, in heavily pretreated patients with R/R LBCL, including patients with HGBCL and previous CAR T-cell therapy failure.

To develop consensus recommendations for improving the diagnosis and treatment of breakthrough cancer pain (BTcP), including procedural BTcP, the opinions of 107 medical experts in managing patients with cancer in Spain were collected using a two-round Delphi method. Consensus was assessed for 76 items using a Likert scale (1-9). Agreement was reached when the median (MED) score was ≥ 7 and the interquartile range (IQR) ≤ 3, while disagreement was considered when MED was ≤ 3 and IQR was ≤ 3. Consensus was reached on 90% of the statements. Experts agreed on the main characteristics of BTcP, which may have a variable number of episodes per day and occur in patients with opioid-controlled background pain. There was resounding agreement on the need to evaluate pain severity, both background and breakthrough cancer pain, in patients with cancer, involving adequately trained physicians and nursing staff. Procedural BTcP, a subtype of BTcP, is common in cancer diagnosis and/or treatment procedures. For this, premedication with an appropriate fast-acting, short-duration drug is necessary. These findings highlight the need for standardized protocols and specific training to improve the quality of life of patients suffering from BTcP, including procedural BTcP, and the efficiency of healthcare resource management.

The determination of the mutational status in the immunoglobulin variable region is an established prognostic biomarker for chronic lymphocytic leukemia (CLL). The length and inner variability of the variable, diversity, and joining (VDJ) rearranged sequences compromise B-cell clone characterization using next-generation sequencing (NGS), and a standardization is needed to adapt the procedure to the current clinical guidelines. Here, we develop a complete strategy for sequencing the variable domain of the immunoglobulin heavy chain (IGH) locus with a simple, low-cost, and efficient method that enables sequencing using shorter reads (MiSeq 150 × 2), allowing for faster results. Clonality and mutational status determination are performed within the same analysis pipeline. We tested and validated the method using 319 CLL patients previously diagnosed with IGH locus characterized using Sanger sequencing, along with 47 healthy donor samples. The analysis method follows a clone-centered consensus sequence strategy to identify B-cell clones and establish a clonal threshold specific for each patient’s clonality profile, thereby overcoming the limitations of Sanger sequencing which is the gold standard used for determining immunoglobulin heavy variable (IGHV) mutational status.

Purpose:This phase II clinical trial evaluated the combination of ibrutinib with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in patients with nongerminal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).Patients and Methods:The IBDCL trial (NCT02692248) included patients with histologic diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem-cell transplantation. Patients received an induction treatment consisting of six or eight cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate after four cycles.Results:Sixty-four patients were included, 72% of them refractory to the last regimen. The overall response rate and complete remission rate after the fourth cycle were 53% [95% confidence interval (CI), 41–65] and 34% (95% CI, 24–46), respectively. Twenty-four (37%) patients started maintenance, and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4–48.6), the estimated 2-year progression-free survival and overall survival were 18% (95% CI, 8–28) and 26% (95% CI, 14–37), respectively. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (44%), neutropenia (30%), and anemia (14%). Grade ≥3 infectious and cardiovascular treatment-related adverse events were reported in 6 (9%) and 1 (2%) patient, respectively.Conclusions:Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL.

Supplementary Tables and Figures

Supplementary Tables and Figures

Purpose:This phase II clinical trial evaluated the combination of ibrutinib with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in patients with nongerminal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).Patients and Methods:The IBDCL trial (NCT02692248) included patients with histologic diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem-cell transplantation. Patients received an induction treatment consisting of six or eight cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate after four cycles.Results:Sixty-four patients were included, 72% of them refractory to the last regimen. The overall response rate and complete remission rate after the fourth cycle were 53% [95% confidence interval (CI), 41–65] and 34% (95% CI, 24–46), respectively. Twenty-four (37%) patients started maintenance, and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4–48.6), the estimated 2-year progression-free survival and overall survival were 18% (95% CI, 8–28) and 26% (95% CI, 14–37), respectively. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (44%), neutropenia (30%), and anemia (14%). Grade ≥3 infectious and cardiovascular treatment-related adverse events were reported in 6 (9%) and 1 (2%) patient, respectively.Conclusions:Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL.

A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228.