Although follicular lymphoma (FL) is usually graded as FL1-2, FL3A, and FL3B, some borderline cases can be observed and led us to investigate the clinicopathologic diversity of grade 3 FL (FL3). ...Among 2449 FL patients enrolled in Lymphoma Study Association (LYSA) trials, 1921 cases with sufficient material underwent a central pathologic review. The resulting diagnoses comprised 89.6% FL1-2 (n=1723), 7.2% FL3A (n=138), and 0.5% purely follicular FL3B (n=9). The remaining 51 unclassifiable cases (2.7%) exhibited high-grade features but did not meet WHO criteria for either FL3A or FL3B; and were considered as “unconventional” high-grade FL (FL3U). FL3U morphological pattern consisted of nodular proliferation of large cleaved cells or small-sized to medium-sized blast cells. Compared with FL3A, FL3U exhibited higher MUM1 and Ki67 expression, less
BCL2
breaks and more
BCL6
rearrangements, together with a higher number of cases without any
BCL2
,
BCL6
or
MYC
rearrangement. FL3U harbored less frequent mutations in
BCL2
,
KMT2D
,
KMT2B
, and
CREBBP
than FL3A.
MYC
and
BCL2
were less frequently mutated in FL3U than FL3B. Rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone treated FL3U patients had a worse survival than FL1-2 patients with similar follicular lymphoma international prognostic index and treatment. These results suggest that high-grade FLs encompass a heterogeneous spectrum of tumors with variable morphology and genomic alterations, including FL3U cases that do not strictly fit WHO criteria for either FL3A or FL3B, and display a worse outcome than FL1-2. The distinction of FL3U may be useful to allow a better comprehension of high-grade FLs and to design clinical trials.
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this ...study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.
•Outcome of patients progressing/relapsing after CAR T-cell treatment is poor, especially in case of relapse within 30 days.•Salvage immunomodulatory treatment may offer better outcomes compared to ...standard immuno-chemotherapy.
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Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a major advance in the treatment of relapsed/refractory aggressive B-cell lymphomas. However, a significant number of patients experience failure. Among 550 patients registered in the French registry DESCAR-T, 238 (43.3%) experienced progression/relapse, with a median follow-up of 7.9 months. At registration, 57.0% of patients presented an age-adjusted International Prognostic Index of 2 to 3, 18.9% had Eastern Cooperative Oncology Group performance status ≥2, 57.1% received >3 lines of treatment prior to receiving CAR T-cells, and 87.8% received bridging therapy. At infusion, 66% of patients presented progressive disease, and 38.9% had high lactate dehydrogenase (LDH). Failure after CAR T-cell treatment occurred after a median of 2.7 months (range: 0.2-21.5). Fifty-four patients (22.7%) presented very early failure (day D 0-D30); 102 (42.9%) had early failure (D31-D90), and 82 (34.5%) had late (>D90) failure. After failure, 154 patients (64%) received salvage treatment: 38.3% received lenalidomide, 7.1% bispecific antibodies, 21.4% targeted treatment, 11% radiotherapy, and 20% immunochemotherapy with various regimens. Median progression-free survival was 2.8 months, and median overall survival (OS) was 5.2 months. Median OS for patients failing during D0-D30 vs after D30 was 1.7 vs 3.0 months, respectively (P = .0001). Overall, 47.9% of patients were alive at 6 months, but only 18.9% were alive after very early failure. In multivariate analysis, predictors of OS were high LDH at infusion, time to CAR-T failure <D30, and high C-reactive protein at infusion. This multicentric analysis confirms the poor outcome of patients relapsing after CAR T-cell treatment, highlighting the need for further strategies dedicated to this population.
With any successful innovation comes some failure. By studying outcomes from a French registry, Di Blasi and colleagues highlight in this month’s CME article both the transformational nature of CAR T cells for relapsed aggressive B-cell lymphomas and the poor outcomes for patients progressing after this therapy. They report predictors and patterns of progression as well as outcomes with chemotherapy, targeted small molecules, and bispecific biologicals as salvage
The prognosis of elderly patients with diffuse large B-cell lymphoma (DLBCL) is worse than that of young patients. An attenuated dose of chemotherapy-cyclophosphamide, doxorubicin, vincristine, and ...prednisone plus rituximab (R-miniCHOP)-is a good compromise between efficacy and safety in very elderly patients. In combination with R-CHOP (R2-CHOP), lenalidomide has an acceptable level of toxicity and may mitigate the negative prognosis of the non-germinal center B-cell-like phenotype. The Lymphoma Study association conducted a multicentric, phase III, open-label, randomized trial to compare R-miniCHOP and R2-miniCHOP.
Patients of age 80 years or older with untreated DLBCL were randomly assigned into the R-miniCHOP21 group or the R2-miniCHOP21 group for six cycles and stratified according to CD10 expression and age. The first cycle of rituximab was delivered by IV on D1 after a prephase and then delivered subcutaneously on D1 of cycles 2-6. Lenalidomide was delivered at a dose of 10 mg once daily on D1-D14 of each cycle. The primary end point was overall survival (OS).
A total of 249 patients with new DLBCL were randomly assigned (127 R-miniCHOP and 122 R2-miniCHOP). The median age was 83 years (range, 80-96), and 55% of the patients were classified as non-GCB. The delivered dose for each R-miniCHOP compound was similar in both arms. Over a median follow-up of 25.1 months, the intention-to-treat analysis revealed that R2-miniCHOP did not improve OS (2-year OS 66% in R-miniCHOP and 65.7% in R2-miniCHOP arm,
= .98) in the overall population or in the non-GCB population. Grade 3-4 adverse events occurred in 53% of patients with R-miniCHOP and in 81% of patients with R2-miniCHOP.
The addition of lenalidomide to R-miniCHOP does not improve OS. Rituximab delivered subcutaneously was safe in this population.
The GAINED phase 3 trial (ClinicalTrials.gov identifier: NCT01659099) evaluated a PET-driven consolidative strategy in patients with diffuse large B-cell lymphoma. In this post hoc analysis, we aimed ...to compare the prognostic value of the per-protocol PET interpretation criteria (Menton 2011 consensus) with the change in the SUVmax (ΔSUVmax) alone. Methods: Real-time central review of 18F-FDG PET/CT was performed in 581 patients after 2 cycles (PET2) and 4 cycles (PET4) of immunochemotherapy using the Menton 2011 criteria, combining the ΔSUVmax (cutoffs of 66% and 70% at PET2 and PET4, respectively) and the Deauville scale. In "special cases," when the baseline SUVmax was less than 10.0 or the interim residual tumor SUVmax was greater than 5.0, the Menton 2011 experts' consensus agreed that the ΔSUVmax may not be reliable and that the Deauville score is preferable. Prognostic values of Menton 2011 and ΔSUVmax were evaluated by Kaplan–Meier analyses in terms of progression-free survival (PFS). Results: Seventeen percent of patients at PET2 (100/581) and 8% at PET4 (49/581) had PET-negative results by ΔSUVmax but were considered to have PET-positive results according to Menton 2011 with residual SUVmax of greater than 5.0. For the population with PET2-positive results, 2-y PFS was 70% (range, 58%–80%) with ΔSUVmax alone, whereas the outcome tended to be better for those who were considered to have PET-positive results by Menton 2011, 81% (range, 72%–87%). Conversely, all 10 patients with baseline SUVmax of less than 10.0 had PET2-positive results by ΔSUVmax but were considered to have PET2-negative results by Menton 2011. These patients had the same 2-y PFS as patients with PET2-negative/PET4-negative results, indicating that the ΔSUVmax yielded false-positive results in this situation. Conclusion: We recommend the use of the ΔSUVmax alone rather than the Menton 2011 criteria for assessing the interim metabolic response in patients with diffuse large B-cell lymphoma, except when the baseline SUVmax is less than 10.0.
Background Richter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS ...patients is usually very poor with short survival (typically <1 year) due to chemoresistance. Indeed, chemoimmunotherapy regimens used in de novo DLBCL failed to induce a significant complete remission rate (CRR) (R-CHOP, 7%; ofatumumab-CHOP, 27%) (Langerbeins et al., AJH 2014; Eyre et al., BJH 2016). CD19-targeted chimeric antigenic receptor (CAR) T-cell therapy such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have been transformative for patients with relapsed/refractory DLBCL. Here, we aimed to investigate the efficacy and safety profile of CD19-CAR T-cell therapy for patients with RS.Methods In this Lymphoma Study Association/ Lymphoma Academic Research Organization (LYSA/LYSARC) study, we conducted an analysis of the DESCAR-T registry which collects real-life data of patients treated with approved CD19-directed CAR T-cell therapies (axi-cel and tisa-cel) since July 1st, 2018 in France. We selected patients with biopsy-proven RS of DLBCL histology, treated by tisa-cel or axi-cel in either the frontline or relapse setting. Data regarding prior CLL history were collected in addition to the DESCAR-T registry data. The data cut-off was April 29th, 2022. The primary endpoint was best CRR according to Cheson IWG 2014 (Lugano Classification) after CAR-T cell infusion. Secondary endpoints were overall response rate (ORR), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (ASTCT Consensus) as well as hematological toxicity (NCI CTCAE v5.0).Results CD19-directed CAR T-cell therapy was planned for 14 patients from January 6th, 2020 to March 2nd, 2022, 12 were infused and subsequently included in the present analysis (1 patient refused the infusion and 1 was not infused due to disease progression). Median age was 60 years (range, 42-76) and sex ratio M/F was 2. CLL cytogenetic features at baseline (when available) were as follows: 2/8 (25%) patients had 17p deletion, 6/8 (75%) 11q deletion and 3/6 (50%) complex karyotype. TP53 mutations were seen in 4/7 (57%) patients. 4/6 (67%) patients harbored unmutated IGHV. Median number of prior therapeutic lines for CLL before RS was 2 (range, 0-9). Of the 12 patients who were infused, 3 (25%) did not receive any prior therapy for CLL. Seven (58%) patients received chemo-immunotherapy, 7 (58%) had been exposed to ibrutinib including 5 (42%) to both ibrutinib and venetoclax. Median time from CLL diagnosis to RS was 7 years (range, 3-22). Ten (83%) patients received ≥ 1 prior lines of therapy for RS (median 3, range 0-3) and bridging therapy was administered to all but one patient. Evaluation for disease status prior CAR T-cell infusion revealed progression for 7 (58%) patients, complete response in 1 (8.3%), partial response in 2 (16.7%) and stable disease in 1 (8.3%) (1 patient non-evaluated).Following CAR T-cell infusion with axi-cel (5 patients) or tisa-cel (7 patients), best CRR was 42% and best ORR was 50%. Ten (83%) patients presented with CRS, 3 (25%) with grade > 2. Tocilizumab was administered to 9 (75%) patients. Five (42%) patients had ICANS, 3 (25%) with grade > 3. Regarding hematotoxicity, 6 (50%) patients presented with grade > 2 thrombocytopenia, 5 (42%) with grade > 2 anemia, and 7 with (58%) grade > 2 neutropenia. One case of macrophage activation syndrome was reported. Three patients were admitted to intensive care. A total of 5 (42%) patients had infections. After a median follow-up of 1.6 months (range, 0-23), 8 (67%) patients were alive, 4 (33%) patients died (2 from CRS and 2 from disease progression).Conclusions CD19-directed CAR T-cell therapy showed high response rates in our series of heavily pretreated RS patients. Frequency of CAR T-cell-specific adverse events was in the range of what is observed in de novo DLBCL while severity appeared higher (Schuster et al., NEJM 2019; Neelapu et al., NEJM 2017). Larger cohort with longer follow-up and prospective trials are warranted to confirm these observations.
Introduction : High-Grade-B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL double hit HGBL-DH or HGBL triple hit HGBL-TH), or not otherwise specified (HGBL NOS), are distinct ...subtypes among Large B-Cell lymphoma (LBCL) considered to be more aggressive diseases. These entities are often resistant to standard chemotherapy (Landsburg, JCO, 2017). CAR-T cell therapy (CAR-T) have changed the treatment landscape of LBCL in chemo resistant LBCL in 3 rd line, and more recently in 2 nd line of treatment. Prognosis with CAR-T seems to be as good in HGBL as in other LBCL subtypes. (Neelapu, NEJM, 2017; Schuster, NEJM, 2019; Zurko, ASH 2022). However, Fluorescence In Situ Hybridation (FISH) study isn't systematically done at diagnosis leading to an underestimation of the diagnosis of HGBL. The aim of this study was to compare the prognosis of a large cohort of patients with HGBL versus other LBCL subtypes, characterized with FISH at diagnosis, in a real life setting, based on the French DESCAR-T registry (NCT04328298). Methods : We collected clinical and pathological data of patients treated for relapsed/refractory LBCL or HGBL in third line or more. Data were collected both at the time of the decision of treatment in multidisciplinary meeting (MDM) and at the time of CAR-T cell infusion. Histology other than de-novo LBCL were excluded. All patients should have been studied with FISH at least with MYC probe. If a MYC rearrangement was identified, a BCL2 and/or BCL6 rearrangement should have been characterized. A p-value <0.05 was significant. Results : Between January 2018 and November 2022, 228 patients meeting the inclusion criteria were included across 14 centers, 73 with HGBL (28 HGBL-DH with MYC- BCL2 rearrangement, 8 HGBL-DH with BCL6 rearrangement, 14 HGBL-TH, 23 HGBL NOS) and 155 with non-HGBL (LBCL with n=19 or without n=136 MYC rearrangement). Characteristics of patients with HGBL vs non-HGBL at eligibility for CAR-T and at infusion of CAR-T cells were similar with no statistical difference. At the time of CAR-T treatment decision, median age was 62 years and the others characteristics were as follows in patients with HGBL vs patients with non-HGBL : ECOG>=2: 9 (12 %) vs 23 (15%), LDH > 1N : 52 (71%) vs 119 (77%) and Ann Arbor stage III-IV : 63 (86%) vs 125 (81%). Median number of prior lines of treatment was 2 (maximum 7 in HGBL vs maximum 9 in non-HGBL). Among the population, 60 (82%) HGBL and 135 (87%) non-HGBL patients received CAR-T cell therapy. In non-treated patients : 5 (39%) vs 8 (40%) had a disease progression and 3 (23%) vs 7 (35%) died. In treated patients, 55 (92%) HGBL vs 126 (93%) non-HGBL received at least one bridging therapy before CAR-T infusion ; and response to bridging therapy was similar among them : 19 (35%) patients with HGBL were in complete or partial response vs 46 (37%) with non-HGBL. Characteristics of treated patients at time of infusion were also similar and as follows in HGBL patients vs non-HGBL patients : 16 (27%) vs 34 (25%) had bulky disease and 16 (27%) vs 31 (23%) had an elevated CRP. 23 (38%) vs 45 (33%) were treated with Tisa-cel and 90 (67%) vs 37 (62%) were treated with Axi-cel. The frequency of Cytokine Release Syndrome (CRS) and Immune effector-Cell Cytotoxicity Syndrome (ICANS) (including grade >=3) did not significantly differ : 56 (93%) patients with HGBL vs 114 (84%) patients with non-HGBL presented CRS and 23 (38%) vs 55 (41%) presented ICANS. Interestingly, more patients were admitted in ICU in the HGBL cohort : 21 (35%) vs 23 (17%) (p=0.009). Macrophage Activation Syndromes was reported for 2 HGBL patients (3%). Median follow-up was 20.5 95 CI, 19.2-25.5 months from eligibility decided in MDM and 18.5 m 95CI, 14.3-23.4 from infusion. Progression free survival (PFS) and Overall survival (OS) were similar in both groups. Since eligibility, median OS was 7.6 m 95 CI, 6.4-18.3 for HGBL patients vs 11.8 m 95 CI, 9.5-22 for non-HGBL (p = 0.062). Since infusion, median PFS was 3.2 m 95CI, 2.8-6.0 for HGBL patients vs 4.5 m 95CI, 3.1-8.7 for non-HGBL (p = 0.103) Figure 1 and median OS was 15.4 m 95CI, 5.6-32.4 for HGBL patients vs 18.3 m 95CI, 8.5-not reached for non-HGBL (p = 0.214). Figure 2 Conclusion : CAR-T cell therapy used in third line or more seems to overcome the poor prognosis of HGBL subtypes as compared to other LBCL subtypes, all characterized with FISH. This observation supports the interest to evaluate the potential benefit of CAR-T earlier in the course of the disease.
Several studies of the working conditions of drivers, and in particular on their pace of work, have enabled a better understanding of the risk factors for road accidents that occur during work. ...However, few studies are available on the risk exposure and working conditions of employees whose occupations involve driving. The purpose of this paper is to identify the different groups of employees occupationally exposed to road risk and to classify them according to working conditions.
A Multiple Correspondence Analysis (MCA) was implemented on the 41,727 individuals from the SUMER 2010 survey (Medical Monitoring of Occupational Risk Exposure: SUrveillance Médicale des Expositions aux Risques professionnels) and for 45 variables about working conditions. The analysis used 5 categories of weekly driving exposure as a supplementary variable (variable which is not used to perform the MCA): Non-exposure; Exposed <2 h; Exposed 2–10 hours; Exposed 10–20 hours; and Exposed >20 h. The results of the MCA were used to construct an ascending hierarchical classification.
The first factorial axis differentiates between conventional and unconventional work schedules. Axis 2 differentiates modalities corresponding to the working hours of the most recent working week. The third axis chiefly contrasts persons who have rules to follow with those who have none. An ascending hierarchical classification distinguishes 10 clusters of individuals according to working conditions. Four clusters of employees were excessively exposed to occupational driving. Clusters also have distinct demographic, occupational and psychosocial characteristics.
Analysis of data from the SUMER survey confirms that employees exposed to road risk are particularly affected by atypical work time characteristics, but can be found in all activity sectors and in all types of job.
Background and Significance: Axicabtagene ciloleucel (axi-cel) has demonstrated superior efficacy as second-line therapy (2L) over standard of care chemo-immunotherapy in transplant-eligible patients ...with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). In ZUMA-7 trial, 180 patients were randomized to receive axi-cel in 2L, achieving an estimated 4-year overall survival of 54% after a median follow-up of 47 months. In the ALYCANTE phase II study, 62 transplant-ineligible patients with R/R LBCL were treated with axi-cel as 2L, resulting in a 3-month complete metabolic response rate of 71% with a median progression free survival of 11.8 months. Here, we report the first real-world data of axi-cel as 2L for patients with early R/R LBCL treated in French centers. Study Design and Methods: DESCAR-T is a French nationwide registry collecting real-life data of all patients treated with approved CAR T-cell therapies (NCT04328298). All patients were informed before inclusion in the registry. The goal of the present analysis was to describe patients' characteristics, treatment course, and outcomes of all patients consecutively included in DESCART registry since July 2022, and infused with axi-cel according to the early access program supported by French authorities for patients with LBCL in early relapse (< 1 year) or refractory after a first line treatment. Results: Between July 2022 and March 2023, axi-cel was ordered and leukapheresis was performed for 85 patients. The first axi-cel infusion was performed in September 2022 and enrollment increased rapidly with 51 new patients waiting for a leukapheresis at the time of data cut-off in March 2023. No manufacturing failures occurred, at the data cut-off, 78 patients were infused with axi-cel in 22 centers, and 7 patients died before axi-cel infusion (5 because of progression, 2 from other cause). Among the 78 patients infused, 48 (61.5%) were male, median age was 60 years (range: 23-79), 35% were over 65 years old and 5% over 70 years old. Most patients had primary refractory disease (n = 58, 74.3%), a good performance status (n = 62, 79.5% ECOG 0-1), stage III-IV disease (n = 59, 75.6%) and elevated LDH (n = 48, 61.5%). The median time between leukapheresis and axi-cel infusion was 36 days, and 65 patients (83%) received bridging therapy, primarily immuno-chemotherapy (n = 57, 73%). At the time of lymphodepletion, patients had progressive (n = 35, 54%) or stable disease (n = 6, 9%), with only 23 patients (29%) responding to bridging therapy. The median follow-up since CAR-T-cells infusion was 1.1 month (range: 0-6). Safety information was reported for 65 patients: CRS occurred in 95% of patients, however only 3 patients (<5%) had a grade 3 or higher CRS. Neurotoxicity occurred in 43% of the cases, with 6 patients (9%) presenting grade 3 or higher toxicity. Furthermore, 13 patients (21%) were transferred to intensive care unit. Four patients (5%) died, 3 from lymphoma progression (missing data for the remaining patient). Among the 52 patients with at least 1 month of follow-up: the overall response and complete response rates at 1 month were 76.9% and 57.7% respectively (Figure 1). Conclusion: These preliminary results demonstrated that axi-cel in 2L for R/R LBCL is feasible and safe in real-life for transplant and non-transplant eligible patients. Although follow-up of our population remains short, early assessments of response are in line with those described in ZUMA-7 study. Inclusion in DESCART registry is on-going and updated results with at least 3 months of follow-up since infusion will be presented at the meeting.
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