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.
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop ...series in September 2016 in Lille, France. The objective of our workshop is to provide a discussion on the conservation and congelation of hematopoietic stem cells in a pediatric setting as well as our recommendations for this technique.
Abstract Although hematopoietic stem cell transplantation (HSCT) offers curative potential for beta-thalassemia major (beta-TM), it is associated with a variable but significant incidence of graft ...rejection. We studied the French national experience for improvement over time and the potential benefit of antithymocyte globulin (ATG). Between December 1985 and December 2007, 108 patients with beta-TM underwent HSCT in 21 different French transplantation centers. The majority of patients received a matched sibling transplant (n = 96) and a busulfan- and cyclophosphamide-based conditioning regimen (n = 95), also with ATG in 57 cases. Ninety-five of the 108 patients survived, with a median follow-up of 12 years. Probabilities of 15-year survival and thalassemia-free survival after first HSCT were 86.8% and 69.4%, respectively. Graft failure occurred in 24 patients, 11 of whom underwent a second HSCT. The use of ATG was associated with a decrease in rejection rate from 35% to 10%. Thalassemia-free survival improved significantly with time, reaching 83% in the 54 patients undergoing HSCT after 1994 (median time of HSCT). In view of the increased risk of graft rejection after matched sibling HSCT, current French national guidelines recommend, for all children at risk for beta-TM, the systematic addition of ATG to the myeloablative conditioning regimen and special attention to optimize transfusion and chelation therapy in the pretransplantation period.
Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal plasma cell proliferation in the bone marrow secreting a monoclonal component. The international standard care ...for eligible patients consists of intensive induction therapy followed by high-dose melphalan and autologous stem cell transplantation (ASCT).
Our study included two groups of newly diagnosed MM patients who received a first-line treatment of double or triple induction, ASCT, with or without consolidation and maintenance. The study participants were treated in Lyon (France) and Oran (Algeria).
The principal aim of this study was to evaluate the long-term outcome after ASCT in these 2 countries with different resources and to evaluate the potential consequences of non-identical access to the same therapeutic arsenal and means of early detection of relapse.
Despite important differences between the 2 countries, we showed a similar overall survival (OS) for the total population and patients who did not relapse and received no chemotherapy after ASCT. Surprisingly, these latter patients concerned 2/3 of Algerian patients and only 1/3 of French patients, explained by differences regarding the definition of relapse and leading to a probable underestimation in Algeria. To better explore this observation, we performed a survival analysis using the instant ratio. We found better survival in France between 0-12 months after ASCT, related to higher non-relapse mortality in Algeria. Furthermore, we showed better survival in Algeria after 48 months. This last result was enhanced by a significant difference in the time to next treatment (TTNT) between Algeria and France (median TTNT of 72.61 months and 32.77 months, respectively). For relapsing patients, we found a better OS in France for patients who received ≤3 lines of treatment after ASCT, and no difference between French patients who received ≥4 therapeutic lines and Algerian patients receiving 1 or 2 lines.
In conclusion, waiting to re-treat MM patients in Algeria, correlated with delayed TTNT, could support the hypothesis of lower healthcare costs and therapeutic savings when comparing France and Algeria. This is strengthened by a similar global long-term OS of the 2 groups.
Background:
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative strategy for high-risk acute myeloid leukemia (AML) patients. However, the risk for disease ...recurrence following allo-HSCT remains significant and associated with poor outcomes. The ability to predict relapse before detectable morphologic recurrence may allow for preemptive interventions, such as immune modulation, donor lymphocyte infusion (DLI), or initiation of hypomethylating agents, to potentially augment graft-versus-leukemia effect. Post-transplantation peripheral blood chimerism analysis, represents a potential tool to predict disease recurrence, although a validated consensus on the use of this technique in the post-allo-HSCT follow-up has not been established yet and its precise role in this setting remains unclear. The aim of our study is to evaluate the impact of chimerism evaluation 3 months after allo-HSCT in AML patients who were in first complete remission (CR1) before transplantation and remained in clinical and morphological CR at day 90 post-transplantation, on overall survival (OS) and relapse incidence.
Patients and methods:
We evaluated 194 AML patients who received allo-HSCT at our center between January 2006 and December 2014 and for whom chimerism follow-up has been performed at 3 months. There were 103 (53%) males and 91 (47%) females with a median age of 43 years (range: 18-67). Patients were classified according to the European LeukemiaNet classification for cytogenetic and molecular biology markers (Dohner et al. Blood 2010), accordingly, 64% patients were unfavorable and 36% were in intermediate II risk group. At allo-HSCT, all patients were in CR1; 136 (70%) received a full intensity conditioning (MAC) and 58 (30%) received a reduced intensity conditioning (RIC). HSC donors were 72 (37%) HLA identical siblings (44 BM and 36 PBSC), 54 (28%) 10/10 HLA matched unrelated donors (35 BM and 19 PBSC), 33 (17%) 9/10 HLA mismatched unrelated donors (16 BM and 17 PBSC) and 35 (18%) double cord blood units (only 7 were 6/6 HLA matched). Chimerism analysis was performed on marrow and/or blood samples every month following allo-HSCT using polymerase chain reaction (PCR) based on informative polymorphic short tandem repeat, a mixed chimerism was defined by having 5% or more of recipient cells.
Results:
At day 90 after transplantation, all patients remained in clinical and cytological CR at time of chimerism evaluation, 155 (80%) had a full donor chimersim (FDC) and 39 (20%) had a mixed chimerism (MC) ranging from 65% to 95% of donor cells. Among patients with MC, 9 (23%) received increasing doses of DLI (5 of them reached FDC at 6 months), while 20 (51%) could not receive DLI (7 because transplanted from cord blood, and 13 because of the presence of GVHD), the rest of patients were left with a transient MC and regained FDC during follow-up.
After a median follow-up of 34 months (range: 4-96) for the surviving patients, the median OS in patients with FDC was not reached with a 3 years probability of 62% (95% CI: 58-66), and for patients with MC, it was 18 months (12-24) with a 3 years probability of 32% (95% CI: 23-41), (p=0.01). Twenty-two patients in the MC group have progressed during the follow-up and 17 among them died from disease progression. The cumulative incidence of relapse at 3 years was 25% (95% CI: 21-29) for FDC patients and it was 70% (95% CI: 62-80) for MC patients, (p<0.001). The impact of mixed chimerism was still valid in multivariate analysis after including patient age, type of donor, HSC source and risk group, and was independent from the intensity of the conditioning regimen with a Hazard Ratio of 4.7, and a 95% CI: 2.6-8.4, p<0.001.
Conclusion:
We demonstrated that chimerism evaluation at day 90 after allo-HSCT is an independent predictor of disease relapse in patients who remain in CR at that time and significantly impacts on long term survival. The standardization of this evaluation may lead to the identification of patients with high-risk of relapse risk suggesting the need of early preemptive intervention.
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Nicolini:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Purpose of the Report
We aimed to evaluate the role of
18
F-FDG PET/CT in predicting patient outcome following chimeric antigen receptor T (CAR T) cells infusion in aggressive B-cell lymphoma.
...Methods
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F-FDG PET/CT data before leukapheresis, before CAR T-cell infusion and 1 month (M1) after CAR T-cell infusion, from 72 patients were retrospectively analyzed. SUVmax, total lesion glycolysis (TLG), metabolic tumor volume (MTV), and parameters describing tumor kinetics were calculated for each
18
F-FDG PET/CT performed. The aim was to evaluate the prognostic value of
18
F-FDG PET/CT metabolic parameters for predicting progression-free survival (PFS) and overall survival (OS) following CAR T-cell therapy.
Results
Regarding PFS, ∆MTV
pre-CAR
and ∆TLG
pre-CAR
were found to be more discriminating compared with metabolic parameters at preinfusion. Median PFS in patients with a ∆MTV
pre-CAR
of less than 300% was 6.8 months (95% confidence interval CI, 2.8 months to not reached) compared with 2.8 months (95% CI, 0.9–3.0 months) for those with a value of 300% or greater (
P
= 0.004). Likewise, median PFS in patients with ∆TLG
pre-CAR
of less than 420% was 6.8 months (95% CI, 2.8 months to not reached) compared with 2.7 months (95% CI, 1.3–3.0 months) for those with a value of 420% or greater (
P
= 0.0148). Regarding OS, metabolic parameters at M1 were strongly associated with subsequent outcome. SUVmax at M1 with a cutoff value of 14 was the most predictive parameter in multivariate analysis, outweighing other clinicobiological variables (
P
< 0.0001).
Conclusions
Disease metabolic volume kinetics before infusion of CAR T cells seems to be superior to initial tumor bulk itself for predicting PFS. For OS, SUVmax at M1 might adequately segregate patients with different prognosis.
Although delayed hemolytic transfusion reaction (DHTR) has been widely recognized as a serious complication of red blood cell transfusion in patients with sickle cell disease (SCD), there is no ...consensus on its optimal management. Discontinuation of transfusion is recommended, whereas corticosteroids and immunoglobulins are considered to be beneficial. We report 2 children with sickle cell anemia who were diagnosed with DHTR and experienced a subsequent neurologic event in the course of treatment with corticosteroids. The role of corticosteroids as possible precipitating factors of neurologic complications is discussed. Pending a better understanding of the chain of events of DHTR, SCD children with DHTR should receive steroids with great caution.
In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical ...progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.
•Germ-line CEBPA mutations are highly penetrant, causing early-onset de novo AML associated with favorable survival outcomes.•Familial CEBPA-mutated AML displays a unique model of disease progression, with recurrence caused by novel, independent leukemic episodes.
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