French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.

Clinical characteristics and prognostic factors of plasmablastic lymphoma patients: analysis of 135 patients from the LYSA group.

Background: Plasmablastic lymphoma (PBL), initially described in 1997 in the oral cavity of HIV positive patients, is now recognized as a distinct aggressive and rare entity of diffuse large B-cells lymphoma by the World Health Organization (WHO) classification. Since the original description, others cases have been reported. However, these are largely derived from case reports or small series limiting any definitive conclusions on clinical characteristics and outcome. Patients and methods: The clinical, biological, pathological features and outcome of a cohort including 135 patients with PBL, from LYSA centers in France and Belgium, were reported and analyzed. Results: The median age was 58 years, with a male predominance. The cohort was divided into 56 HIV-positive patients, 17 post-transplant patients and 62 HIV-negative/non-transplanted patients. Within HIV-negative/non-transplanted, a relative immunosuppression was found in most cases (systemic inflammatory disease, history of cancer, increased age associated with weakened immune system). We have also described a new subtype, PBL arising in a chronic localized inflammatory site, without any sign of immunosuppression. At presentation, 19% of patients showed oral involvement. Immunophenotype showed CD138 positivity in 88% of cases and CD20 negativity in 90% of cases. Chemotherapy was administered to 80% of patients, with a complete response (CR) rate of 55%. The median overall survival (OS) was 32 months. In univariate analysis, HIV positive status showed better OS when compared with HIV negative status. In multivariate analysis, International Prognostic Index score, chemotherapy and CR were associated with survival benefit. Conclusion(s): This cohort, the largest reported to date, increases the spectrum of knowledge on PBL, rarely described. However, specific guidelines to clarify treatment are lacking, and may improve the poor prognosis of this rare disease.

ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia.

The European Society for Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (i) the elderly patient, (ii) prognostic factors suitable for clinical use and (iii) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address four clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were then presented to the entire panel and a consensus was reached. This manuscript presents recommendations dedicated to the second area of interest, i.e. prognostic factors suitable for clinical use. The four topics [i.e. interim positron emission tomography (PET), TP53 mutations, cell of origin (COO) and minimal residual disease (MRD)] were primarily chosen because of the bulk of available data together with the lack of clear guidance regarding their use in clinical practice and within clinical trials. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. The panel acknowledged that detection of TP53 inactivation by deletion or mutation in CLL should be implemented in clinical practice (level of evidence I, strength of recommendation A). Due to their potentially high prognostic value, at least in some lymphoma entities, implementation of interim PET, COO and MRD was highly recommended in the context of clinical trials. All expert panel members approved this final article.

Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience.

We retrospectively evaluated the role of rituximab (R) in maintenance treatment after autologous stem cell transplantation performed in patients with relapsed follicular lymphoma. We compared the outcome of 67 follicular lymphoma (FL) patients according to the use of rituximab maintenance (RM) or not. All patients received rituximab plus chemotherapy before autologous stem-cell transplantation (ASCT). Patients received median of two lines of prior therapy. The RM schedule was one injection of rituximab every 3 months for 2 years. Median follow-up is 4.6 years. The 3-year progression-free survival (PFS) after ASCT was 86 % with RM vs. 46 % without (p = 0.0045). Median is not reached in the RM arm vs. 31 months in non-RM arm. The 3-year OS was 96 % with RM vs. 78 % without (p = 0.059). The present monocentric study shows that 2 years of RM after ASCT significantly increases response duration for non-naive rituximab relapsed FL patients compared with observation.

90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas.

BACKGROUND: Patients with advanced B-cell non-Hodgkin's lymphoma (NHL) refractory to initial chemotherapy or relapsing after autologous stem-cell transplantation have a poor prognosis. Allogeneic stem-cell transplantation after reduced-intensity conditioning (RIC) regimen can be a therapeutic option. However, the high incidence of relapse remains a challenging issue. We speculated that the incorporation of (90)Y-Ibritumomab tiuxetan into a fludarabine-based RIC regimen would improve the lymphoma control without overwhelming toxicity. Our aim was to evaluate the safety of (90)Y-Ibritumomab tiuxetan in association with such a regimen in a prospective multicenter phase II trial. PATIENTS AND METHODS: Thirty-one patients with advanced lymphoma from five distinct institutions were included between February 2008 and October 2010. Thirty patients in complete or partial response after failure of a median of 3 (range, 2-4) previous chemotherapy regimens including autologous transplant in 29 were evaluable for nonrelapse mortality (NRM) at day 100 post-transplant that was the primary end point. RESULTS: With a median follow-up of 32 months (range, 29-60 months), the 2-year event-free and overall survivals of the whole study group were both 80% [95 confidence interval (CI) 60.8% to 90.5%). The 100-day and 2-year post-transplant cumulative incidences of NRM were 3.3% (95% CI 0.2% to 14.9%) and 13.3% (95% CI 5.4% to 33.2%), respectively. The 2-year cumulative incidence of relapse was 6.7% (95% CI 1.7% to 25.4%). The cumulative incidences of grade II-IV and extensive chronic graft-versus-host disease were 27% and 14%, respectively. CONCLUSIONS: For chemosensitive advanced high-risk B-cell lymphoma, the addition of (90)Y-Ibritumomab tiuxetan to a RIC regimen based on fludarabine, busulfan and antithymocyte globulin followed by allogeneic transplant is safe and highly effective. clinicaltrials.gov: NCT00607854.

Upfront allogeneic stem-cell transplantation for patients with nonlocalized untreated peripheral T-cell lymphoma: an intention-to-treat analysis from a single center.

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem-cell transplantation (allo-SCT) can cure relapse/refractory patients, we hypothesized that upfront allo-SCT may provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy. PATIENTS AND METHODS: The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. A human leukocyte antigen-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in 7 cases. RESULTS: After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the 1 and 2-year overall survival (OS) rates were 59% [95% confidence interval (CI) 47-75] and 55% (95% CI 43-71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the 1- and 2-year OS were 76% (95% CI 62-93) and 72.5% (95% CI 58-91), respectively. Toxicity-related mortality (TRM) 1 year after allo-SCT was only 8.2% (95% CI 0-18.5). The 2-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n = 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients. CONCLUSIONS: Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However, one-third of patients remain chemo-refractory and, thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared with other therapeutic approaches in PTCLs requires investigation in randomized studies.

Paradoxical effect of lenalidomide on cytokine/growth factor profiles in multiple myeloma.

BACKGROUND: Lenalidomide is an active immunomodulatory and antiproliferative agent in multiple myeloma. However, the molecular mechanisms driving these activities are not yet fully elucidated. Therefore, we investigated the modulation of the cytokine/growth factor patterns of myeloma cells under LEN treatment. METHODS: Lenalidomide effect on myeloma cell proliferation was investigated in a myeloma cell line collection (n=23) by (3)H-thymidine incorporation. Modulation of the cytokine/growth factor patterns of myeloma cells under LEN treatment was analysed by real-time quantitative PCR. RESULTS: Lenalidomide inhibits the proliferation of two-thirds of myeloma cell lines independently of their genetic background. We demonstrated that LEN increased TNF-α and IL-8 inflammatory cytokines and insulin-like growth factor-1 (IGF-1) growth factor in both sensitive and resistant myeloma cells to LEN. CONCLUSION: Lenalidomide favours a uniform TNF-α and IL-8 inflammatory and IGF-1 secretory profile of myeloma cells, an observation that raises important questions for therapeutic approaches incorporating the agent.

ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.

To complement the existing treatment guidelines for all tumour types, ESMO organizes consensus conferences to focus on specific issues in each type of tumour. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, next to the 11th International Conference on Malignant Lymphoma. The conference convened ∼30 experts from all around Europe, and selected six lymphoma entities to be addressed; for each of them, three to five open questions were to be addressed by the experts. For each question, a recommendation should be given by the panel, referring to the strength of the recommendation based on the level of evidence. This consensus report focuses on the three less common lymphoproliferative malignancies: marginal zone lymphoma, mantle cell lymphoma, and peripheral T-cell lymphomas. A first report had focused on diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukaemia.

Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma.

BACKGROUND: Pixantrone is an aza-anthracenedione with enhanced, preclinical antitumor activity and reduced cardiotoxicity compared with doxorubicin. PATIENTS AND METHODS: We compared the efficacy and toxic effect of CPOP-R (substituting pixantrone for doxorubicin) against CHOP-R in untreated, diffuse large B-cell lymphoma (DLBCL) patients. The primary objective was to demonstrate non-inferiority of CPOP-R by complete response/complete response unconfirmed (CR/CRu) rate. RESULTS: The CR/CRu rate for CPOP-R was 75% versus 84% for CHOP-R. Three-year overall survival was lower for CPOP-R (69% versus 85%) (P = 0.029). Median progression-free survival (PFS) was not reached for CPOP-R and was 40 months for CHOP-R [HR 95% confidence interval (CI) = 1.02 (0.60, 1.76), P = 0.934]. Fewer CPOP-R patients developed congestive heart failure (CHF) (0% versus 6%, P = 0.120), ≥ 20% declines in ejection fraction (2% versus 17%, P = 0.004), or elevations in troponin-T (P = 0.003). CONCLUSIONS: CPOP-R is an active regimen with modestly lower response rates than CHOP-R but similar PFS and event-free survival. This study demonstrates a substantially lower cardiotoxicity of pixantrone compared with doxorubicin when used as first-line therapy in DLBCL.

Lymphoma occurring in patients over 90 years of age: characteristics, outcomes, and prognostic factors. A retrospective analysis of 234 cases from the LYSA.

BACKGROUND: Lymphoma occurring in patients aged 90 or older is not uncommon, and its incidence is expected to increase over time. Management of these patients is difficult given their underlying fragility and the lack of information regarding this population. PATIENTS AND METHODS: We retrospectively analyzed 234 patients diagnosed with lymphoma at the age of 90 years or older (90+) between 1990 and 2012 to describe their characteristics, management, outcomes and prognostic factors. RESULTS: The median age was 92 years; 88% were B-cell lymphomas consisting mainly in diffuse large B-cell lymphoma. The median overall survival (OS) was 7.2 months (range, 0-92 months) for the 227 patients with non-Hodgkin Lymphoma (NHL), with a significant difference between aggressive and indolent NHL (5.2 months versus 19.4 months, respectively). We further analyzed 166 NHL patients for whom detailed characteristics were available. Among these patients, 63.5% received a treatment, either local (7.5%) or systemic (56%). Lymphoma was reported as the main cause of death (40%). Treatment administration was associated with improved OS in patients with aggressive (P < 0.001) but not indolent NHL (P = 0.96). In patients with aggressive NHL, hypoalbuminemia appeared as a strong and independent negative prognostic factor. CONCLUSIONS: The median OS is short in 90+ patients diagnosed with lymphoma but some patients experience prolonged survival. Lymphoma represents the main cause of death in these patients. Treatment may improve survival of selected patients with aggressive but not indolent NHL. Management of these patients may be guided by prognostic factors identified in this study, notably serum albumin.

The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction.

BACKGROUND: Cancer cells are frequently addicted to deregulated oncogenic protein translation. The small molecule 4EG-I selectively inhibits the cap-dependent translation of mRNAs. As multiple myeloma is an incurable disease that requires new therapeutic approaches, we investigated whether targeting the translation initiation pathway could be a target for myeloma therapy. METHODS: Six myeloma cell lines and primary samples were included in this study. The 4EGI-1 effect was determined by AnnexinV staining and caspase activation. Modification of Bcl-2 protein expression was analysed, and the significance of modified proteins was analysed by knock-down experiments. RESULTS: We demonstrated that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E-regulated proteins in myeloma cells. Furthermore, we showed that 4EGI-1 induced strong apoptosis in five out of six myeloma cell lines. Apoptosis is associated with the activation of the intrinsic mitochondrial pathway. The 4EGI-1 triggered Noxa induction only in cells undergoing apoptosis through endoplasmic reticulum (ER) stress. Furthermore, Noxa silencing prevented myeloma cells from 4EGI-1-induced apoptosis. Finally, Noxa induction led to a disruption of Mcl-1/Bim complexes in parallel to the generation of 'Mcl-1-free Noxa'. CONCLUSION: Our results suggested that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for multiple myeloma therapy.

Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS.

BACKGROUND: There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS: Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS: Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience.

BACKGROUND: Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. PATIENTS AND METHODS: We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers. RESULTS: Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1-5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS. CONCLUSIONS: These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen.

Access to early-phase clinical trials in older patients with cancer in France: the EGALICAN-2 study.

BACKGROUND: Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients. PATIENTS AND METHODS: During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute. RESULTS: A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were <70 years and 233 patients (17.7%) were >70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045). CONCLUSIONS: Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent.

18F-fluorodeoxyglucose-positron emission tomography before, during and after treatment in mature T/NK lymphomas: a study from the GOELAMS group.

BACKGROUND: In non-cutaneous T-cell/natural killer (T/NK) lymphomas, the prognostic value of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during or after therapy is unknown. PATIENTS AND METHODS: In this retrospective study, 54 T/NK lymphoma patients were assessed using FDG-PET before (n = 40), during (n = 44) and/or after therapy (n = 31). RESULTS: FDG-PET showed an abnormal FDG uptake in all cases. Interim FDG-PET was negative in 25 of 44 cases. After completion of therapy, 19 of 31 patients reached complete remission with negative FDG-PET. In ALK+ anaplastic large cell lymphomas, the 4-year progression-free survival (PFS) was 80% and the negative predictive value of post-therapy FDG-PET was 83% (n = 9). In ALK- T/NK lymphomas, the 4-year PFS was 59% for patients with a negative interim FDG-PET versus 46% for patients with a positive interim FDG-PET (P = 0.28, n = 35). Similarly, there was no statistical difference in 4-year PFS between negative and positive post-therapy FDG-PET in these lymphomas (51% and 67%, respectively, P = 0.96). The 4-year cumulative incidence of relapse from a negative post-therapy FDG-PET was 53% in ALK- T/NK lymphomas. CONCLUSIONS: Although T/NK lymphomas are FDG-avid at diagnosis, a negative interim or post-therapy FDG-PET does not translate into an improved PFS in ALK- T/NK lymphomas.

BH3-only protein Bik is involved in both apoptosis induction and sensitivity to oxidative stress in multiple myeloma.

BACKGROUND: although gene expression profile of multiple myeloma (MM) patients shows a wide range of Bik/Nbk expression, varying from absent to high, its regulation and function in myeloma cells is poorly understood. Thus, we addressed these questions in MM. METHODS: human myeloma cell lines (HMCLs) and primary purified myeloma cells were studied for Bcl-2 family protein expression by western blot and further correlation analysis was performed. Correlative study between Bik and thyrotroph embryonic factor (TEF) transcription factor expression was analysed by PCR. Stress oxidative response was analysed by flow cytometry. RESULTS: a strong expression of Bik protein was found only in one out of three of HMCL and correlated to Bcl-2 expression (P=0.0006). We demonstrated that Bik could be regulated at the protein level by Bcl-2 and at the transcriptional level by TEF. Bik overexpression sensitises myeloma cells to oxidative stress whereas Bik silencing increases resistance to H(2)O(2) oxidative stress. Furthermore, Bik ectopic expression disrupts Bim/Bcl-2 and Bim/Bcl-xL endogenous complexes triggering Bim release that could induce Bax and Bak activation. CONCLUSIONS: ours results suggest that Bik has a role in both, apoptosis induction and sensitivity to oxidative stress in myeloma cells. Small BH3 mimetic molecules should be considered for further apoptosis-based therapy in myeloma cells expressing endogenous Bik/Bcl-2 complexes.