scholarly journals CAR-T Therapy Followed By Unrelated Cord Blood Transplantation for the Treatment of Children and Young Adults Relapsed/Refractory B-Cell ALL: Superior Survival but Relatively High Post-Transplant Relapse

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4818-4818
Author(s):  
Guangyu Sun ◽  
Baolin Tang ◽  
Xiang Wan ◽  
Wen Yao ◽  
Kaidi Song ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Cord Blood Transplantation ◽  
T Cell Therapy ◽  
Free Survival ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Car T Cell Therapy ◽  
Car T ◽  
Unrelated Cord Blood

Abstract Relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) has poor long-term survival even after chimeric antigen receptor (CAR)-T cell therapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies supported that CAR-T therapy followed by allo-HSCT is benefit for improving long-term leukemia free survival (LFS). Since probably a stronger graft versus leukemia (GVL) effect of unrelated cord blood transplantation (UCBT), it is uncertain whether consolidative UCBT is suitable for R/R B-ALL after CAR-T therapy. Here, we conducted a retrospective comparative study for R/R B-ALL patients receiving UCBT in our transplantation center. Totally 43 cases with R/R B-ALL who underwent UCBT were assigned to CAR-T group (patients achieved CR or CRi by CAR-T cell therapy before bridging to UCBT, n = 21) or non-remission (NR) group (n = 22). The median time from CAR-T infusion to UCBT was 62 (range, 42-185) days. All patients achieved neutrophil engraftment by day 42 in CAR-T group. The 180-day cumulative incidence of platelet engraftment was higher in CAR-T group than in NR group (90.5% vs 65.7%, P = 0.16). Incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) were 28.6% and 23.8% in CAR-T group, which were both tendency lower than in NR group (45.5% and 31.8%, P = 0.32 and P = 0.63, respectively). No patient suffered from extensive chronic GVHD in CAR-T group, which was lower than in NR group (9.1%, P = 0.23). Lower 2-year cumulative incidence of transplant-related mortality (TRM), and higher probabilities of 2-year overall survival, leukemia free survival (LFS), graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) were found in CAR-T group (4.8% vs 28.2%; 75.0% vs 37.7%; 49.8% vs 23.0%; 42.4% vs 14.8%; P = 0.037, 0.005, 0.028 and 0.017; respectively). However, 2-year cumulative incidence of relapse was comparably high between CAR-T and NR group (26.7% vs 38.3%; P = 0.41). CAR-T therapy followed by UCBT has a superior survival for R/R B-ALL, but remains relatively high post-transplant relapse rate. Prevention of relapse after UCBT is warranted in this patient cohort. Disclosures No relevant conflicts of interest to declare.

Unrelated Cord Blood Transplantation for Children with Juvenile Myelomonocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2021-2021
Author(s):  
Franco Locatelli ◽  
Adrienne B.M. Madureira ◽  
Vanderson Rocha ◽  
Pierre Teira ◽  
Martin Champagne ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Monosomy 7 ◽  
Free Survival ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Unrelated Cord Blood ◽  
Myelomonocytic Leukemia

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for children with juvenile myelomonocytic leukemia (JMML). A recent study from the European Working Group of MDS in Childhood (EWOG-MDS) reported a 5-year probability of event free survival of 55% (n=48), and 49% (n=52) in children transplanted from either an HLA identical sibling or an unrelated volunteer, mainly donating bone marrow (BM) cells. As in the EWOG-MDS analysis only 7 children received unrelated cord blood transplantation (UCBT), we decided to further investigate the role of UCBT in 42 children with JMML, reported to the Eurocord-EBMT and EWOG-MDS registries. Median age at transplantation of the 42 children was 2.6 years (range 0.6–7); 29 patients were males and 13 females. Cytogenetic analysis was available in all patients but one: 10 patients had monosomy 7, 4 other abnormalities, while the remaining 27 children had a normal karyotype. Seven patients underwent splenectomy before UCBT. Conditioning included Busulfan in 78% of patients, while the most common graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporin-A and steroids. In donor-recipient pairs, histocompatibility was determined by serology or low resolution molecular typing for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 locus. The donor was HLA identical in 7 cases, 1-antigen disparate in 18 and with 2 or more disparities in 14. Median number of nucleated cells infused was 6.8 × 107/Kg (range 2–50). The 60-day cumulative incidence (CI) of engraftment was 76%%, with a median time to neutrophil and platelet recovery of 27 (range 14–51) and 50 (range 15–180) days, respectively. In multivariate analysis an age at UCBT younger than 2.6 years (hazard ratio, HR=0.27; 95% confidence interval=0.13–0.57; p=0.0005) and the use of a more HLA-compatible donor (HR=0.38; 95% confidence interval=0.16–0.89; p=0.03) predicted better engraftment. CI of grade II-IV acute and chronic graft-versus-host disease (GvHD), and of transplantation-related mortality (TRM) were 31%, 16%, and 33%, respectively. The CI of TRM of our cohort of patients is higher than the 2-year TRM CI of 16% in children with JMML given unrelated donor HSCT reported in the EWOG-MDS analysis. Eleven children relapsed, the 2-year CI of relapse being 22%. In comparison, in the EWOG-MDS study, the 2-year CI of relapse of unrelated HSCT recipients was 36%. The CI of relapse was 30% in patients with monosomy 7 as compared to 19% in the remaining children (p=0.64). With a median follow-up of 36 months (range 3–102), the 2-year disease-free survival (DFS) of the overall cohort was 45%; patients younger or older than 2.6 years had a DFS of 66% and 26% respectively, p=0.01. In multivariate analysis, only age at UCBT was associated with increased DFS (HR=2.98; 95% confidence interval=1.21–7.34; p=0.02). These data indicate that UCBT is a suitable option for children with JMML lacking an HLA-compatible relative and suggest that the search for an unrelated cord blood unit be initiated simultaneously to that for unrelated BM donors. Cord blood offers the advantage of nearly immediate availability of stem cells and allows to perform HSCT even in the presence of donor HLA disparities.

scholarly journals Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Runxia Gu ◽  
Fang Liu ◽  
Dehui Zou ◽  
Yingxi Xu ◽  
Yang Lu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
T Cell Therapy ◽  
Free Survival ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary. Methods We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). Results Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017–0.601). Conclusions The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy. Trial registration ClinicalTrials.gov: NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687

scholarly journals Clinical Comparison of Incidences, Risk Factors and Outocmes of Chronic Graft-Versus-Host Desease in Unrelated Cord Blood Transplantation and Unrelated Bone Marrow Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1172-1172
Author(s):  
Yuki Asano-Mori ◽  
Atsushi Wake ◽  
Kosei Kageyama ◽  
Daisuke Kaji ◽  
Kazuya Ishiwata ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Unrelated Cord Blood

Abstract Background: Chronic Graft-versus-host disease (GVHD) has been a serious complication after allogeneic transplantation. The difference of incidences, risk factors and outcomes between unrelated cord blood transplantation (uCBT) and unrelated bone marrow transplantation (uBMT) has not been fully evaluated. Patients and Methods: We retrospectively analysed the records of 455 adult patients who underwent uCBT or uBMT for the first time at the Toranomon Hospital between 2002 and 2013, and who survived more than 100 days without relapse within 100 days after transplantation. Pre-engraftment immune reaction (PIR) was defined as unexplained fever in the absence of documented infection with skin eruption, peripheral edema and body-weight gain before engraftment. Acute GVHD was graded according to previously described criteria. Chronic GVHD was classified by both traditional criteria and by the 2005 NIH Consensus Criteria. The probability of developing chronic GVHD was estimated on the basis of cumulative incidence curves. Competing events for chronic GVHD were death or relapse without GVHD. The cox proportional hazards model was used to evaluate the effect of confounding variables on chronic GVHD. We also evaluated the effect of chronic GVHD on relapse and overall survival, where the occurrence of chronic GVHD was treated as a time-varying covariate. Results: A total of 240 patients were diagnosed with chronic GVHD by traditional criteria at a median onset of 123.5 days after transplantation, with the 2-year cumulative incidence of 54.0%. The incidence was significantly lower after uCBT versus uBMT (43.1% vs. 72.8%, P<0.001, Figure1A). About 70% of the patients (n=163) had extensive type, which occurred less frequently after uCBT versus uBMT (25.0% vs. 56.1%, P<0.001, Figure1B). The most common involved organ was skin (78.8%), followed by liver (36.7%) and gastrointestinal tract (33.3%) in the total population. The uCBT patients showed significantly less frequent involvement of the eye, oral cavity, lung and joint compared to the uBMT patients (all P<0.001), while rates of skin, liver and gastrointestinal tract involvement were not different between the two groups (P=0.64, P=0.18 and P=0.34, respectively). For both the uCBT and the uBMT patients, grade II-IV acute GVHD was identified as the only significant risk factor for traditionally-defined any chronic GVHD (HR 1.48, P=0.03 and HR 1.82, P=0.003) and extensive chronic GVHD (HR 2.51 and HR 2.33, both P<0.001). PIR was identified as a significant risk factor for the extensive chronic GVHD after uCBT (HR 1.69, P=0.04). Of all the 240 patients, 124 patients met the NIH-defined classic chronic GVHD, the 2-year cumulative incidence of which was 28.0%. The incidence was significantly lower after uCBT compared to uBMT (20.1 vs. 41.8%, P<0.001, Figure1C). Thirty-two patients fulfilled the criteria for overlap syndrome. The remaining 84 presented with the NIH-defined persistent (n=31), recurrent (n=40) or late-onset (n=13) acute GVHD, the proportion of which was significantly higher after uCBT versus uBMT (43.1% vs. 26.5%, P=0.02). Both the uCBT and the uBMT patients with NIH-defined classic chronic GVHD had significantly better overall survival (HR 0.10, P=0.001 and HR 0.43, P=0.03), while traditionally-defined chronic GVHD did not significantly improve the survival (HR 0.63, P=0.06 and HR 0.92, P=0.81). Although the uBMT patients with traditionally-defined chronic GVHD and those with NIH-defined chronic GVHD had lower risks of relapse (HR 0.36, P=0.001 and HR 0.49, P=0.05), the influence of the chronic GVHD on relapse was not apparent in the uCBT patients (HR 0.76, P=0.23 and HR 0.60, P=0.15). Conclusions: The incidence of chronic GVHD was significantly lower after uCBT compared to uBMT. Typical clinical features of chronic GVHD seems to improve overall prognosis in the uCBT patients, although those might not have full effect on reducing the risk of relapse like in the uBMT patients. Prevention of acute GVHD manifestations occurring more than 100 days might further improve the outcome after uCBT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Fludarabine Exposure Predicts Outcome after CD19 CAR T Cell Therapy in Children and Young Adults with Acute Leukemia; An Exploratory, Observational Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3871-3871
Author(s):  
Linde Dekker ◽  
Friso Calkoen ◽  
Yilin Jiang ◽  
Hilly Blok ◽  
Maike Spoon ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcome ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Free Survival ◽  
Cell Numbers ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract The addition of fludarabine to cyclophosphamide as lymphodepleting regimen prior to adoptive transfer of CD19 chimeric antigen receptor (CAR) T cells significantly improves CAR T cell expansion and correlates with longer B cell aplasia and a decreased probability of developing a CD19+ relapse (Gardner, 2017). Dosing of fludarabine is currently based on body surface area. We previously showed that this leads to a highly variable plasma exposure that correlates with clinical outcome after allogeneic hematopoietic cell transplantation (Langenhorst, 2019). We therefore hypothesized that optimal exposure of fludarabine might be of clinical importance in the CD19 CAR T setting. An observational cohort analysis was conducted with data from 26 consecutive patients receiving tisagenlecleucel as treatment for refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL; table 1). Prior to CAR T cell infusion, patients received fludarabine on 4 consecutive days at a daily dosage of 30 mg/m 2 and cyclophosphamide on 2 consecutive days at a daily dosage of 500 mg/m 2. Fludarabine concentrations were measured longitudinally after fludarabine infusion using a liquid chromatography mass spectrometry method. The total exposure (Area Under the Curve (AUC 0−∞)) was subsequently determined using a fludarabine population pharmacokinetic model (Langenhorst, 2019). The study was performed in accordance with the Declaration of Helsinki. The primary outcome parameter was leukemia free survival, defined as the time between CAR19 T cell infusion and the moment of measurable leukemic blasts (&gt;5% or &gt;0.01% by two subsequent measurements). The effect of fludarabine on leukemia free survival and the secondary outcome measures CD19+ relapse and B cell aplasia were explored using martingale residuals and further identified by fitting univariable Cox Proportional Hazards models. In addition, Kaplan Meier and cumulative incidence curves were plotted and compared with log-rank tests. To compare CAR T cell numbers over time in peripheral blood, the AUCs were computed and compared between exposure groups with the Mann-Whitney test. Analyses were performed using R4.03 with packages pknca, survival and survminer. The fludarabine AUC 0−∞ was highly variable, resulting in a large range of 8.7-21.8 mg*h/L. Exposure of fludarabine was shown to be a predictor for leukemia free survival, B cell aplasia, and CD19+ relapse following CAR T cell infusion. Minimal event probability was observed at a cumulative fludarabine exposure ≥14 mg*h/L and underexposure was therefore defined as an AUC 0−∞ &lt;14 mg*h/L. In the underexposed group, leukemia free survival was lower (p&lt;0.001; Figure 1A) and the occurrence of CD19+ relapse was higher (p&lt;0.0001; figure 1B) compared to the group with an AUC 0−∞ ≥14 mg*h/L. Furthermore, the duration of B cell aplasia was shorter (p=0.009) and the AUCs of CAR T cell numbers lower (p=0.03) in the underexposed group. No significant differences in baseline characteristics were present between the two exposure groups. To our knowledge, this is the first study describing the effect of fludarabine exposure on outcome in a cohort of paediatric and young adults receiving CD19 CAR T cell therapy as treatment for B-ALL. These preliminary results suggest that optimizing fludarabine exposure may have a relevant impact on leukemia free survival following CAR T cell therapy. However, it should be noted that multivariate regression models are needed to show consistency of the relationship between fludarabine exposure and outcome. The limited number of patients did not allow for inclusion of potential covariates that may influence clinical outcome into the analysis. Therefore, our results need to be confirmed in a larger cohort. In conclusion, clinical outcome in patients receiving CAR19 T cell therapy might be improved by the optimization of fludarabine exposure in the lymphodepleting regimen. LD and FC contributed equally to this study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-term remission in multiply relapsed enteropathy-associated T-cell lymphoma following CD30 CAR T-cell therapy

2020 ◽  
Vol 4 (23) ◽  
pp. 5925-5928
Author(s):  
Timothy J. Voorhees ◽  
Nilanjan Ghosh ◽  
Natalie Grover ◽  
Jared Block ◽  
Catherine Cheng ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Key Points ◽  
Car T

Key Points CD30 CAR T-cell therapy promoted a prolonged remission in a patient with multiply relapsed EATL.

Sign in / Sign up

Export Citation Format

Share Document