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Practice preferences for consolidative HSCT following tisagenlecleucel in children and young adults with B-ALL
McNerney, K. O., Moskop, A., Winestone, L. E., Baggott, C., Talano, J. A., Schiff, D., Rossoff, J., Modi, A., Verneris, M. R., Laetsch, T. W., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Tisagenlecleucel achieves excellent complete remission rates in children and young adults with relapsed or refractory B-acute lymphoblastic leukemia (B-ALL), but approximately 50% maintain long-term remissions. Consolidative hematopoietic stem cell transplant (cHSCT) is a potential strategy to reduce relapse risk but carries substantial short- and long-term toxicities. Additionally, several strategies for management of B-cell recovery (BCR) and next-generation sequencing (NGS) positivity post-tisagenlecleucel exist without an accepted standard. We hypothesized that practice preferences surrounding cHSCT as well as management of BCR and NGS positivity varies across tisagenlecleucel-prescribing physicians and sought to characterize current practice preferences. METHODS A survey focused on preferences regarding the use of cHSCT, management of BCR, and NGS positivity was distributed to physicians that prescribe tisagenlecleucel for children and young adults with B-ALL. Responses were collected from August 2022 to April 2023. RESULTS Fifty-nine unique responses were collected across 43 institutions. All respondents prescribed tisagenlecleucel for children and young adults. The clinical focus of respondents was HSCT in 71% followed by leukemia/lymphoma in 24%. In HSCT-naïve patients receiving tisagenlecleucel, 57% of respondents indicated they made individualized decision for cHSCT based on patient factors, while 22% indicated they would avoid and 21% indicated they would pursue cHSCT where feasible. Select factors influenced >50% of respondents towards recommending cHSCT (either increased likelihood or would always recommend) including pre-infusion disease burden >25%, primary refractory B-ALL, M3 bone marrow following re-induction for relapse, KMT2A-rearranged B-ALL, history of blinatumomab non-response, and HSCT naïve status. Most respondents indicated they would pursue HSCT for HSCT-naïve, total body irradiation candidates with BCR before 6 months post-tisagenlecleucel or with NGS positivity at 1 or 3 months post-tisagenlecleucel, although there was variability about whether to proceed to HSCT directly or give intervening therapy prior to HSCT. The proportion of respondents recommending HSCT for BCR or NGS positivity decreased in those with a history of HSCT, non-TBI-candidates, or trisomy 21. CONCLUSIONS The results of this survey indicate there exists significant practice variability regarding the use of cHSCT as well as interventions for post-tisagenlecleucel BCR or NGS positivity. These results highlight areas for which ongoing clinical trials could inform more standardized practice.
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Comparisons of Long-Term Survival and Safety of Haploidentical Hematopoietic Stem Cell Transplantation After CAR-T Cell Therapy or Chemotherapy in Pediatric Patients With First Relapse of B-Cell Acute Lymphoblastic Leukemia Based on MRD-Guided Treatment
Hu, G., Cheng, Y., Zuo, Y., Chang, Y., Suo, P., Jia, Y., Lu, A., Wang, Y., Jiao, S., Zhang, L., et al
Frontiers in immunology. 2022;13:915590
Abstract
Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9-89.6) vs. 44.4% (95% CI: 15.4-73.4), p = 0.19 and 84.6% (95% CI: 70.6-98.5) vs. 40.0% (95% CI: 12.7-67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.
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Three-year results from phase 1 of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia
Wayne, A. S., Huynh, V., Hijiya, N., Rouce, R. H., Brown, P. A., Krueger, J., Kitko, C. L., Ziga, E. D., Hermiston, M. L., Richards, M. K., et al
Haematologica. 2022
Abstract
The 3-year results are presented for ZUMA-4, a phase 1/2 multicenter study evaluating the safety and efficacy of KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory (R/R) Bcell acute lymphoblastic leukemia (B-ALL). Phase 1 explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Of 31 enrolled patients, KTE-X19 was administered to 24 (median age 13.5 years, range 3-20; median follow-up 36.1 months). No DLTs were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33%, 75%, 27%, and 22% in the all-treated, 2×106, 1×106 (68 mL formulation), and 1×106 (40 mL formulation) CAR T cells/kg groups; 21%, 25%, 27%, and 11% of patients experienced grade ≥3 neurologic events, respectively. Overall complete remission (CR) rates (including CR with incomplete hematologic recovery) were 67%, 75%, 64%, and 67% in the all-treated, 2×106, 1×106 (68 mL), and 1×106 (40 mL) CAR T cells/kg groups, respectively. Overall minimal residual disease (MRD)-negativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplant (alloSCT). In the 1×106 (40 mL) group (recommended phase 2 dose), median duration of remission censored at alloSCT and median overall survival were not reached. Pediatric/adolescent patients with R/R B-ALL achieved high MRD-negative remission rates with manageable safety profile after a single dose of KTE-X19. Phase 2 is ongoing at the 1×106 CAR T cells/kg (40 mL) dose.
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Chimeric Antigens Receptor T Cell Therapy Improve the Prognosis of Pediatric Acute Lymphoblastic Leukemia With Persistent/Recurrent Minimal Residual Disease in First Complete Remission
Hu, G. H., Cheng, Y. F., Zuo, Y. X., Chang, Y. J., Suo, P., Wu, J., Jia, Y. P., Lu, A. D., Li, Y. C., Wang, Y., et al
Frontiers in immunology. 2021;12:731435
Abstract
BACKGROUND The presence of minimal residual disease (MRD) is an independent risk factor for poor prognosis in patients with acute lymphoblastic leukemia (ALL). Moreover, the role of chimeric antigen receptor T-cell (CAR-T) therapy in patients with MRD is currently unclear. METHODS We conducted a prospective study to investigate the role of CAR-T therapy in patients with persistent/recurrent MRD-positive ALL in first remission. RESULTS A total of 77 patients who had persistent/recurrent MRD were included. Of these patients, 43 were enrolled in the CAR-T group, 20 received chemotherapy as a bridge to allogeneic hematopoietic cell transplantation (allo-HSCT), and 14 patients received intensified chemotherapy. MRD negativity was achieved in 90.7% of the patients after CAR-T infusion. Patients who received CAR-T therapy had a higher 3-year leukemia-free survival (LFS) than patients who did not (77.8% vs. 51.1%, P = 0.033). Furthermore, patients in the CAR-T group had a higher 3-year LFS than those in the chemotherapy bridge-to-allo-HSCT group [77.8% (95% CI, 64.8-90.7%) vs. 68.7% (95% CI, 47.7-89.6%), P = 0.575] and had a significantly higher 3-year LFS than those in the intensified chemotherapy group [77.8% (95% CI, 64.8-90.7%) vs. 28.6% (95% CI, 4.9-52.3%), P = 0.001]. Among the patients who received CAR-T therapy, eight were not bridged to allo-HSCT, and six (75%) remained in remission with a median follow-up of 23.0 months after CAR-T infusion. CONCLUSIONS Our findings show that CAR-T therapy can effectively eliminate MRD and improve survival in patients with a suboptimal MRD response.
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Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy
Hu, G. H., Zhao, X. Y., Zuo, Y. X., Chang, Y. J., Suo, P., Wu, J., Jia, Y. P., Lu, A. D., Li, Y. C., Wang, Y., et al
Leukemia. 2021
Abstract
Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P?=?0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.
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Single-center experience suggests donor lymphocyte infusion may promote long-term survival in children with high-risk acute lymphoblastic leukemia
Liberio, N., Robinson, H., Nugent, M., Simpson, P., Margolis, D. A., Malarkannan, S., Keever-Taylor, C., Thakar, M. S.
Pediatric blood & cancer. 2019;:e27950
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Abstract
BACKGROUND Donor lymphocyte infusion (DLI) is often used to treat leukemic relapse after hematopoietic cell transplantation (HCT). However, the relationship between outcomes and distinct DLI cellular composition has not been previously reported. Additionally, there are limited published data on efficacy in pediatrics. We evaluated whether DLI cellular content and development of graft-versus-host disease (GVHD) impacted disease and influenced overall survival (OS) in children receiving DLI for recurrent leukemia. METHODS We performed an Institutional Review Board-approved, retrospective study investigating all consecutive DLIs given to patients at the Children's Hospital of Wisconsin between 1980 and 2018. Analyses were conducted using Mann-Whitney, Fisher exact, and chi-square tests. RESULTS Thirty patients ≤20 years old with hematologic malignancies (myeloid [AML/MDS/CML/JMML], n = 23; lymphoid [ALL], n = 7) received DLI to treat post-transplant relapse. We found no significant difference in OS or development of GVHD based on CD3, CD4, CD8, CD56, or CD19 DLI cellular composition. With a median follow-up of 0.69 (range, 0.04-16.61) years, OS at five years was 32% +/- 9%. The lymphoid group had a five-year survival rate at 71% +/- 17% compared with the myeloid group at 22% +/- 9%, although not statistically significant (P = 0.11). The development of GVHD did not affect OS (P = 0.62). CONCLUSION Here, we report a single-center, long-term experience of pediatric DLIs. Surprisingly, many children with ALL were able to achieve durable remissions. Although cellular composition did not have a significant effect on GVHD or OS in our small study, engineering DLI products to maximize specific effector cell populations could be one strategy to improve efficacy.
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ADCC can improve graft vs leukemia effect after T- and B-cell depleted haploidentical stem cell transplantation in pediatric B-lineage ALL
Schlegel, P., Jung, G., Lang, A. M., Doring, M., Schulte, J. H., Ebinger, M., Holzer, U., Heubach, F., Seitz, C., Lang, B., et al
Bone marrow transplantation. 2019;54(Suppl 2):689-693
Abstract
Posttransplant relapsed B-cell precursor ALL can be cured by 2nd hematopoietic stem cell transplantation (HSCT) in 20% of patients. The major cause of death after second HSCT is leukemic relapse. One reliable predictor for survival after 2nd-HSCT are posttransplant MRD levels. Patients with detectable or increase of MRD are likely to relapse. Patients in complete molecular remission show the best leukemia-free survival and lowest cumulative incidence (CI) of relapse. As patients who undergo second or subsequent HSCT are high-risk patients, we evaluated the prophylactic use of the chimeric Fc-optimized CD19-4G7SDIE-mAb. Posttransplant relapsed CD19(+) BCP-ALL patients, who underwent a second or subsequent haplo-HSCT from a T- and B-cell depleted graft received posttransplant prophylactic CD19-4G7SDIE-mAb treatment on compassionate use in complete molecular remission, to increase the antileukemic activity of the new reconstituting immune system by recruiting Fc-expressing effector cells. NK cells recovered early and robust. The 3 year overall survival in 15 evaluable patients was 56%, the 3 year event-free survival was 55% and the CI of relapse 38%. Compared to a historical control group, the CI of relapse was markedly lower and consecutively the EFS higher. Posttransplant-targeted therapy may overcome the need for unspecific GvL effect of undesired GvHD, that can cause severe morbidity and mortality. Due to a low adverse event profile the CD19-4G7SDIE-mAb may be suitable for broad administration to consolidate posttransplant MRD negativity.
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Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel
Porter, D., Frey, N., Wood, P. A., Weng, Y., Grupp, S. A.
Journal of hematology & oncology. 2018;11(1):35
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Editor's Choice
Abstract
BACKGROUND Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. DISCUSSION The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale. CONCLUSION We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.
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Pre-Emptive Immunotherapy for Clearance of Molecular Disease in Childhood Acute Lymphoblastic Leukemia after Transplantation
Rettinger, E., Merker, M., Salzmann-Manrique, E., Kreyenberg, H., Krenn, T., Durken, M., Faber, J., Huenecke, S., Cappel, C., Bremm, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(1):87-95
Abstract
Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69+/-.06 for the cohort without IT and .69+/-.10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21+/-.05, 3-year CITRM, .10+/-.04; IT patients: 3-year CIR, .18+/-.09, 3-year CITRM .13+/-.07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.