Two autologous anti‐CD19 chimeric antigen receptors (CAR) T cells (axicabtagene ciloleucel axi‐cel and tisagenlecleucel tisa‐cel) are commercially approved in Europe for relapsed/refractory (R/R) ...diffuse large B cell lymphoma (DLBCL). We performed a retrospective study to evaluate patterns of use, efficacy and safety for axi‐cel and tisa‐cel. Data from 70 patients who underwent apheresis for commercial CAR T cells between January 2018 and November 2019 in our institution were retrospectively collected. Sixty‐one patients were infused. The median age at infusion was 59 years old (range 27‐75 years). The median number of prior therapies was 3 (range, 2‐6). The overall response rates (ORRs) at 1 month and 3 months were 63% and 45%, respectively, with 48% and 39% achieving a complete response (CR), respectively. After a median follow‐up after infusion of 5.7 months, the median progression‐free survival (PFS) was 3.0 months (95% CI, 2.8‐8.8 months), and the median overall survival (OS) was 11.8 months (95% CI, 6.0‐12.6 months). In multivariate analysis, factors associated with poor PFS were the number of previous lines of treatment before CAR T cells (≥4) (P = .010) and a C reactive protein (CRP) value >30 mg/L at the time of lymphodepletion (P < .001). Likewise, the only factor associated with a shorter OS was CRP >30 mg/L (P = .009). Cytokine release syndrome (CRS) of any grade occurred in 85% of patients, including 8% of patients with CRS of grade 3 or higher. Immune cell‐associated neurotoxicity syndrome (ICANS) of any grade occurred in 28% of patients, including 10% of patients with ICANS of grade 3 or higher. Regarding efficacy and safety, no significant difference was found between axi‐cel and tisa‐cel. This analysis describes one of the largest real‐life cohorts of patients treated with axi‐cel and tisa‐cel for R/R aggressive B cell lymphoma in Europe.
Background aims Starting from experimental data proposing hematopoietic stem cells as candidates for cardiac repair, we postulated that human peripheral blood (PB) CD34+ cells mobilized by ...hematopoietic growth-factor (G-CSF) would contain cell subpopulations capable of regenerating post-ischemic myocardial damages. Methods In a phase I clinical assay enrolling seven patients with acute myocardial infarct, we directly delivered to the injured myocardium autologous PB CD34+ cells previously mobilized by G-CSF, collected by leukapheresis and purified by immunoselection. In parallel, we looked for the eventual presence of cardiomyocytic and endothelial progenitor cells in leukapheresis products of these patients and controls, using flow cytometry, reverse transcription-quantitative (RTQ)–polymerase chain reaction (PCR), cell cultures and immunofluorescence analyzes. Results The whole clinical process was feasible and safe. All patients were alive at an average follow-up of 49 months (range 24–76 months). Improvement of heart function parameters became obvious from the third month following cell reinjection. Left ventricular ejection fraction values progressively and dramatically increased with time, associated with PetScan demonstration of myocardial structure regeneration and revascularization and New York Heart Association (NYHA) grade improvement. Furthermore, we identified PB CD34+ cell subpopulations expressing characteristics of both immature and mature endothelial and cardiomyocyte progenitor cells. In vitro CD34+ cell cultures on a specific medium induced development of adherent cells featuring morphologies, gene expression and immunocytochemistry characteristics of endothelial and cardiac muscle cells. Conclusions Mobilized CD34+ cells contain stem cells committed along endothelial and cardiac differentiation pathways, which could play a key role in a proposed two-phase mechanism of myocardial regeneration after direct intracardiac delivery, probably being responsible for the long-term clinical benefit observed.
The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon ...alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients ...aged over 65. We have now re-examined the classic prognostic factors, adding an assessment of the mutation status of TP53. Patients (n=74; median age 73 years) were treated with the RiBVD combination. Median Progression Free Survival (mPFS) was 79 months, and median Overall Survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level below 3.6 g/dL (Alb<3.6 g/dL) were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, p=0.014) was obtained for TP53mt versus TP53wt, and 3.6 (1.39-9.5, p=0.009) for Alb<3.6 g/dL vs Alb≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PFs: TP53mt (HR: 5.9 (1.77-19.5, p=0.004)), Alb<3.6 g/dL (HR: 5.2 (1.46-18.5, p=0.011)), and ECOG=2 (HR: 3.7 (1.31-10.6, p=0.014)). Finally, a score combining TP53 status and albumin level distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.
We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged ...65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression,
Ffluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (
<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma.
.
This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim ...analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years 35-89, first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.
Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive neoplasm for which there is still no current consensus on the best therapeutic approach. Most patients respond to intensive ...chemotherapy, but relapses are almost inevitable with median overall survival (OS) in the largest patient series ranging from 8 to 12 months except for patients who could benefit from allogenic hematopoietic stem cell transplantation (allo-HSCT). We present results of the first line treatments used in France between 2000 and 2013 for 86 patients recruited in the French network of BPDCN (abstract ASH 2015 N°78460).
Seventeen patients were treated with acute lymphoid leukemia (ALL)-like therapy (median age : 63 yo) , 19 with acute myeloid leukemia (AML)-like therapy (median age : 40 yo), 16 patients with CHOP-like therapy (median age : 72 yo), 16 patients with NK/T-like therapy (based on high-dose methotrexate and L-asparaginase, ± dexamethasone, median age: 59 yo), and 12 patients received "other treatments" (OT, means variable drugs, median age : 82 yo). Thirty four patients obtained a complete remission (CR) and received HSCT (autologous n=4, or allogeneic n=30). The response rates for CHOP-like and OT groups were 31.3% and 25.0% respectively. For ALL-like, AML-like, and NK/T-like groups, response rates reached 70.6%, 78.9%, and 62.5% respectively (no statistic difference). Relapse rates among responders for CHOP-like and OT groups were 60% and 33.3% whereas there were only 25%, 26.7%, and 20% in ALL-like, AML-like, and NK/T-like groups respectively. For patients who obtained remission, the median of remission duration was 8.0 and 14.0 months for patients who received CHOP-like treatments (n=5) and OT (n=3) respectively and 10.0, 10.0, and 9.0 months for ALL-like (n=11), AML-like (n=14), and NK/T-like groups (n=9) respectively (p = 0.6339).
In preclinical studies, we have shown that BPDCN cells are sensitive in vitro to idarubicine (Angelot Delettre F et al, 2015) so we studied patients receiving idarubicine in first line therapy in our series (n=9). From these 9 patients, 7 obtained CR and only one relapsed after 10 months. The 6 patients in continuous CR without any relapse have received HSCT (allo, n=5 or auto, n=1). Two out of those 6 patients are alive at the time of data collection with a follow-up of 40 and 87 months; the other 4 patients died after the graft, one relapsed after auto-HSCT, and 3 died of infectious complications after allo-HSCT.
The median OS for patients who received HSCT, auto or allo (n=34) and other patients (n = 52) is respectively 49 and 8 months (p < 0.0001, Figure 1). The beneficial effect of HSCT persists independently of age in multivariate analysis.
These results suggest that NK/T-like, AML-like, and ALL-like groups give better results than CHOP-like and OT groups. However, there is no significant statistical difference between AML-like, ALL-like, and NK/T-like groups. Thus it seems to be wise to combine "lymphoid" drugs like methotrexate, L-asparaginase and dexamethasone with "myeloid" drug such as idarubicine. The importance of allogenic stem cell transplantation to sustain remission is clear in this study and other one (Roos-Weil et al, 2013). We also observed a prolonged CR in one patient after auto-HSCT. Based on our results, we will propose the first prospective, multicentric, phase II trial in BPDCN, testing a combination of 3 cycles of methotrexate, L-asparaginase, idarubicine and dexamethasone followed by an allo-HSCT in first clinical remission for all eligible patients or repeated cycle of these drugs for unfit patients with auto-HSCT if possible.
Kaplan-Meier overall survival curves compared by the Log-Rank test in the cohort of 34 HSCT patients (auto and allo, blue line) and 52 non HSCT patients (red line) (p<0.0001). Censured patients are patient's alive or lost (+). OS of HSCT patients is still statistically significative with adjustment of age in multivariate analysis (Cox multivariate).
Display omitted
Recher:Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Deconinck:CHUGAI: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; LFB loboratory: Consultancy; JANSSEN: Other: Travel for international congress; PFIZER: Research Funding; ROCHE: Research Funding.
▪
Background:
Eight RCHOP/21 cycles followed by Rituximab maintenance is considered the standard of care for first line therapy in elderly MCL patients in Europe (1). However,complete clinical (CR) ...and molecular responses (MR) to therapy remain suboptimal(CR rate 30-35%, MR after 8 cycles 67 %). Regimen combining Rituximab and Bendamustine and more recently proteasome inhibitor Bortezomib (Velcade®) with CHOP regimen (VcR-CAP) demonstrated superior CR rates and PFS compared to R-CHOP. We have investigated the RiBVD regimen (Rituximab, Bendamustine,Velcade® and Dexamethasone) in a prospective phase II trial by the LYSA group.
Aims of the study:
The primary objective was to improve the median PFS by 6 months over the current 18 months PFS obtained with RCHOP when given without maintenance (ref Lenz, JCO 2005). The secondary objectives were to investigate the prognostic impact of molecular and FDG-PET responses on survival..
Methods and Material:
All patients aged 65 or older with a diagnosis of MCL were treated by the RiBVD regimen if they fulfilled the following inclusion criteria: AAstage II-IV, PS < 3, no other neoplasm, no active HIV or HBV or HCV infections, no renal (creatinin clearance > 20ml/mn) or cardiac dysfunction, no diabetes. The RiBVD regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1, 2, Dexamethasone 40 mg IV on D2 and Bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with valacyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Patients were scheduled to receive a total of 6 cycles, if they achieved at least PR at 4 cycles. The IWG criteria, with and without FDG-PET, were used to define responses after 4 and 6 cycles. FDG-PET response was evaluated in each center with the five-point scale visual method of Deauville. Molecular responses (MR) were evaluated centrally by RQ-PCR using patient specific IGH VDJ targets as previously described (2).
Results:
Seventy six patients were recruited in one year (from November 2011 to December 2012), 74 were evaluable 2 patients were excluded because HBV positivity (n=1) or misdiagnosis (n=1). Fifty four samples were centrally reviewed for diagnosis, 45 were classic form of MCL, 9 pleomorphic variant and one patient had a DLBCL. Clinical characteristics of the 74 patients were: Median age 73 yo (64-83), sex ratio M/F = 2 (49/25), AAstage II/III-IV = 4/70, PS 0-1/2 = 63/11, MIPIscore low/intermediate/high= 3/19/50 (2 undetermined). The median follow-up is 21 months. Thirteen patients died because of lymphoma progression (n=7), cardiac arrest (n=2) or in one case each,pneumonia, Progressive Multifocal LeukoEncephalopathy, pancreatic carcinoma or of unknown causes. After 4 cycles the ORR was 86% (n=64) and CR/CRu 57% (n=42). After 6 cycles, the CR/CRu raised to 74% (n=55) the PR rate was 9% (n=7), 2 patients had a stable disease, 4 progressed and 5 had died during the treatment. The complete MR rate after 6 months on blood samples or bone marrow was respectively 83% (43/50) and 74 % (32/43). At 24 months, the PFS was 69% and the OS 80%. The MIPI score (high vs low/int) and the blood MR after 6 cycles were the only two statistically prognostic factors for PFS and OS. Toxicities were essentially hematologic with grade 3 or 4 neutropenia and thrombocytopenia in 51% and 36% of the cases, respectively. The main grade 3 or 4 extra-hematologic toxicities were fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%).
Conclusion:
The RiBVD regimen can be safely administered as first line therapy to elderly patients with MCL. Toxicities are mild and manageable. With 74% of CR/CRu, a 2 year PFS of 69% and 86% of patients achieving an MRD negative status in the blood after 6 cycles, without maintenance therapy, the RiBVD regimen is identified as a highly effective, well tolerated, first line treatment for elderly MCL patients.
Reference : 1 - Kluin Nelemans HC et al, NEJM 2012, 2 - Gimenez E et al, BJH 2012
Gressin:mundipharma: Consultancy. Off Label Use: Bendamustine and Bortezomib did not have authorization to their use in first line for MCL in France. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Le Gouill:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Consultancy.
PDF
