Pediatric Donor Cell Acute Lymphoblastic Leukemia Following Bone Marrow Transplant for GATA2 Mutation.

Donor cell leukemia is a rare complication following hematopoietic stem cell transplant (HSCT). There are currently few reports in children and only rare, reported cases of donor-derived myelodysplastic syndrome/acute myeloid leukemia in patients with an underlying germline GATA2 mutation. Most reported cases are myeloid in origin and occur following related HSCT. We present a 3-year-old female who developed a donor-derived B-cell acute lymphoblastic leukemia 2 years post unrelated HSCT for GATA2 germline mutation.

Chimeric antigen receptor T-cell therapy for marrow and extramedullary relapse of infant acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cells, engineered autologous T-cells that target antigens found in leukemia, have shown durable remissions in relapsed acute lymphoblastic leukemia (ALL). Infant ALL with KMT2A rearrangements (KMT2Ar) is a rare, aggressive form of leukemia associated with extramedullary disease both at diagnosis and at relapse, and overall outcomes for these patients are dismal. Here we report the successful use of tisagenlecleucel, a CAR T-cell product approved for relapsed/refractory ALL, in a patient with KMT2Ar infant ALL who was treated for combined marrow and extramedullary (renal) relapse.

Systemic Lupus Erythematosus, Evans Syndrome, and Neurofibromatosis: An Unusual Combination in Pediatric Patient.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems. Patients can have hematologic manifestations, including Evans syndrome (ES), which is characterized by immune-mediated thrombocytopenia and anemia. The association of neurofibromatosis 1 (NF1) with autoimmune disorders is rarely reported. We will review the literature for this combination of disorders and describe a case of a 16-year-old girl who presents with immune-mediated cytopenias and is diagnosed with SLE, ES, and NF1. There are 7 reported cases of SLE and NF1 and only 2 are pediatric cases. There are no reports of the combination of SLE, ES, and NF1.

INSPIRED Symposium Part 5: Expanding the Use of CAR T Cells in Children and Young Adults.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy in relapsed/refractory (r/r) B cell malignancies, including in pediatric patients with acute lymphoblastic leukemia (ALL). Expanding this success to other hematologic and solid malignancies is an area of active research and, although challenges remain, novel solutions have led to significant progress over the past decade. Ongoing clinical trials for CAR T cell therapy for T cell malignancies and acute myeloid leukemia (AML) have highlighted challenges, including antigen specificity with off-tumor toxicity and persistence concerns. In T cell malignancies, notable challenges include CAR T cell fratricide and prolonged T cell aplasia, which are being addressed with strategies such as gene editing and suicide switch technologies. In AML, antigen identification remains a significant barrier, due to shared antigens across healthy hematopoietic progenitor cells and myeloid blasts. Strategies to limit persistence and circumvent the immunosuppressive tumor microenvironment (TME) created by AML are also being explored. CAR T cell therapies for central nervous system and solid tumors have several challenges, including tumor antigen heterogeneity, immunosuppressive and hypoxic TME, and potential for off-target toxicity. Numerous CAR T cell products have been designed to overcome these challenges, including "armored" CARs and CAR/T cell receptor (TCR) hybrids. Strategies to enhance CAR T cell delivery, augment CAR T cell performance in the TME, and ensure the safety of these products have shown promising results. In this manuscript, we will review the available evidence for CAR T cell use in T cell malignancies, AML, central nervous system (CNS), and non-CNS solid tumor malignancies, and recommend areas for future research.

Practice Preferences for Consolidative Hematopoietic Stem Cell Transplantation Following Tisagenlecleucel in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia.

Treatment with tisagenlecleucel (tisa-cel) achieves excellent complete remission rates in children and young adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), but approximately 50% maintain long-term remission. Consolidative hematopoietic stem cell transplantation (cHSCT) is a potential strategy to reduce relapse risk, but it carries substantial short- and long-term toxicities. Additionally, several strategies for management of B cell recovery (BCR) and next-generation sequencing (NGS) positivity post-tisa-cel exist, without an accepted standard. We hypothesized that practice preferences surrounding cHSCT, as well as management of BCR and NGS positivity, varies across tisa-cel-prescribing physicians and sought to characterize current practice preferences. A survey focusing on preferences regarding the use of cHSCT, management of BCR, and NGS positivity was distributed to physicians who prescribe tisa-cel for children and young adults with B-ALL. Responses were collected from August 2022 to April 2023. Fifty-nine unique responses were collected across 43 institutions. All respondents prescribed tisa-cel for children and young adults. The clinical focus of respondents was HSCT in 71%, followed by leukemia/lymphoma in 24%. For HSCT-naive patients receiving tisa-cel, 57% of respondents indicated they made individualized decisions for cHSCT based on patient factors, whereas 22% indicated they would avoid cHSCT and 21% indicated they would pursue cHSCT when feasible. Certain factors influenced >50% of respondents towards recommending cHSCT (either an increased likelihood of recommending or always recommending), including preinfusion disease burden >25%, primary refractory B-ALL, M3 bone marrow following reinduction for relapse, KMT2A-rearranged B-ALL, history of blinatumomab nonresponse, and HSCT-naive status. Most respondents indicated they would pursue HSCT for HSCT-naive, total body irradiation (TBI) recipients with BCR before 6 months post-tisa-cel or with NGS positivity at 1 or 3 months post-tisa-cel, although there was variability in responses regarding whether to proceed to HSCT directly or provide intervening therapy prior to HSCT. Fewer respondents recommended HSCT for BCR or NGS positivity in patients with a history of HSCT, in noncandidates for TBI, and in patients with trisomy 21. The results of this survey indicate there exists significant practice variability regarding the use of cHSCT, as well as interventions for post-tisa-cel BCR or NGS positivity. These results highlight areas in which ongoing clinical trials could inform more standardized practice.

Current Trends and Outcomes in Cellular Therapy Activity in the United States, Including Prospective Patient-Reported Outcomes Data Collection in the Center for International Blood and Marrow Transplant Research Registry.

The Center for International Blood and Marrow Transplant Research (CIBMTR) prepares an annual set of summary slides to summarize the trends in transplantation and cellular therapies. For the first time in the 2023 summary slides, the CIBMTR incorporated data for patients receiving chimeric antigen receptor T cell (CAR-T) infusions. In addition, data on patient-reported outcomes (PROs) are included. This report aims to update the annual trends in US hematopoietic cell transplantation (HCT) activity and incorporate data on the use of CAR-T therapies. A second aim is to present and describe the development, implementation, and current status of PRO data collection. In August 2020, the CIBMTR launched the Protocol for Collection of Patient-Reported Outcomes Data (CIBMTR PRO Protocol). The CIBMTR PRO Protocol operates under a centralized infrastructure to reduce the burden to centers. Specifically, PRO data are collected from a prospective convenience sample of adult HCT and CAR-T recipients who received treatment at contributing centers and consented for research. Data are merged and stored with the clinical data and used under the governance of the CIBMTR Research Database Protocol. Participants answer a series of surveys developed by the Patient Reported Outcomes Measurement Information System (PROMIS) focusing on physical, social and emotional, and other measures assessing financial well-being, occupational functioning, and social determinants of health. To complement traditionally measured clinical outcomes, the surveys are administered at the same time points at which clinical data are routinely collected. As of September 2023, PRO data have been collected from 993 patients across 25 different centers. With the goal of incorporating these important patient perspectives into standard clinical care, the CIBMTR has added the PRO data to Data Back to Centers (DBtC). Through expanding the data types represented in the registry, the CIBMTR aims to support holistic research accounting for the patients' perspective in improving patient outcomes. CIBMTR PRO data aim to provide a foundation for future large-scale, population-level evaluations to identify areas for improvement, emerging disparities in access and health outcomes (eg, by age, race, and ethnicity), and new therapies that may impact current treatment guidelines. Continuing to collect and grow the PRO data is critical for understanding these changes and identifying methods for improving patients' quality of life.

INSPIRED Symposium Part 2: Prevention and Management of Relapse Following Chimeric Antigen Receptor T Cell Therapy for B Cell Acute Lymphoblastic Leukemia.

Although CD19-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) for relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) has been transformative in inducing and sustaining remission, relapse rates remain unacceptably high, with approximately 50% of children and young adults experiencing relapse within the first year postinfusion. Emerging strategies to extend the durability of remission involve the use of prognostic biomarkers to identify those at high risk of relapse or incorporate strategies aimed to enhancing functional CAR T cell persistence. Nonetheless, with antigen loss/down-regulation or evolution to lineage switch as major mechanisms of relapse, optimizing single antigen targeting alone is insufficient. Here, with a focus on relapse prevention strategies, including postinfusion surveillance and treatment approaches being explored to optimize post-CAR-T management (eg, combinatorial antigen targeting strategies, preemptive hematopoietic cell transplantation), we review the current state of the art in the prevention and management of post CAR-T relapse. We highlight the advancements in the field and identify gaps in the literature to guide future research in optimizing the prevention and management of post-CAR-T relapse in children and young adults with B-ALL.

SARS-CoV-2 infections in pediatric and young adult recipients of chimeric antigen receptor T-cell therapy: an international registry report.

BACKGROUND: Immunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%-40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited. METHODS: We created an international retrospective registry of CAR T recipients aged 0-30 years infected with SARS-CoV-2 within 2 months prior to or any time after CAR T infusion. SARS-CoV-2-associated illness was graded as asymptomatic, mild, moderate, or severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C). To assess for risk factors associated with significant SARS-CoV-2 infections (infections requiring hospital admission for respiratory distress or supplemental oxygen), univariate and multivariable regression analyses were performed. RESULTS: Nine centers contributed 78 infections in 75 patients. Of 70 SARS-CoV-2 infections occurring after CAR T infusion, 13 (18.6%) were classified as asymptomatic, 37 (52.9%) mild, 11 (15.7%) moderate, and 6 (8.6%) severe COVID-19. Three (4.3%) were classified as MIS-C. BCA was not significantly associated with infection severity. Prior to the emergence of the Omicron variant, of 47 infections, 19 (40.4%) resulted in hospital admission and 7 (14.9%) required intensive care, while after the emergence of the Omicron variant, of 23 infections, only 1 (4.3%) required admission and the remaining 22 (95.7%) had asymptomatic or mild COVID-19. Death occurred in 3 of 70 (4.3%); each death involved coinfection or life-threatening condition. In a multivariable model, factors associated with significant SARS-CoV-2 infection included having two or more comorbidities (OR 7.73, CI 1.05 to 74.8, p=0.048) and age ≥18 years (OR 9.51, CI 1.90 to 82.2, p=0.014). In the eight patients infected with SARS-CoV-2 before CAR T, half of these patients had their CAR T infusion delayed by 15-30 days. CONCLUSIONS: In a large international cohort of pediatric and young adult CAR-T recipients, SARS-CoV-2 infections resulted in frequent hospital and intensive care unit admissions and were associated with mortality in 4.3%. Patients with two or more comorbidities or aged ≥18 years were more likely to experience significant illness. Suspected Omicron infections were associated with milder disease.

Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns.

Background: Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval. Methods: We conducted a retrospective analysis of real-world tisagenlecleucel utilisation patterns across 185 children and young adults treated between August 30, 2017 and March 6, 2020 from centres participating in the Pediatric Real-World CAR Consortium (PRWCC), within the United States. We described definitions of refractory B-ALL used in the real-world setting and categorised patients by reported Chimeric Antigen Receptor (CAR) T-cell indication, including refractory, 1st relapse and ≥2nd relapse B-ALL. We analysed baseline patient characteristics and post-tisagenlecleucel outcomes across defined cohorts. Findings: Thirty-six percent (n = 67) of our cohort received tisagenlecleucel following 1st relapse. Of 66 evaluable patients, 56 (85%, 95% CI 74-92%) achieved morphologic complete response. Overall-survival (OS) and event-free survival (EFS) at 1-year were 69%, (95% CI 58-82%) and 49%, (95% CI 37-64%), respectively, with survival outcomes statistically comparable to remaining patients (OS; p = 0.14, EFS; p = 0.39). Notably, toxicity was increased in this cohort, warranting further study. Interestingly, of 30 patients treated for upfront refractory disease, 23 (77%, 95% CI 58-90%) had flow cytometry and/or next-generation sequencing (NGS) minimum residual disease (MRD)-only disease at the end of induction, not meeting the historic morphologic definition of refractory. Interpretation: Our findings suggested that tisagenlecleucel response and survival rates overlap across patients treated with upfront refractory B-ALL, B-ALL ≥2nd relapse and B-ALL in 1st relapse. We additionally highlighted that definitions of refractory B-ALL are evolving beyond morphologic measures of residual disease. Funding: St. Baldrick's/Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Virginia and D.K. Ludwig Fund for Cancer Research.

Higher doses of tisagenlecleucel are associated with improved outcomes: a report from the pediatric real-world CAR consortium.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2 to 5.0 × 106 and 0.1 to 2.5 × 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 × 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300 × 106 (n = 48 [27%]), 1.301 to 1.700 × 106 (n = 46 [26%]), 1.701 to 2.400 × 106 (n = 43 [24%]), and 2.401 to 5.100 × 106 (n = 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P = .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard to targeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.

Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research.

The use of HLA-mismatched donors could enable more patients with ethnically diverse backgrounds to receive allogeneic hematopoietic cell transplantation (HCT) in the United States. However, real-world trends and outcomes following mismatched donor HCT for diverse patients remain largely undefined. We conducted this study to determine whether the use of mismatched donor platforms have increased the access to allogeneic HCT for ethnically diverse patients, particularly through the application of novel graft-versus-host disease (GVHD) prophylaxis regimens, and whether outcomes for diverse patients are comparable to those of non-Hispanic White patients. This observational cross-sectional study used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. All patients receiving their first allogeneic HCT in the United States between 2009 and 2020 were included, with a focus on transplantations performed in 2020. Data from patients undergoing allogeneic HCT using bone marrow, peripheral blood, or cord blood from HLA-matched or mismatched related and unrelated donors were analyzed. Specifically, relative proportion of allogeneic HCT was generated as percentage of total for donor type and for patient age, disease indication, GVHD prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. Compared to matched related donor and matched unrelated donor HCT, more ethnically diverse patients received mismatched unrelated donor, haploidentical donor, and cord blood HCT. Although matched unrelated donor remains the most common donor type, the use of haploidentical donors has increased significantly over the last 5 years. Paralleling this increase in haploidentical HCT is the increased use of post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Relative to previous transplantation eras, the most contemporary era is associated with the highest survival rates following allogeneic HCT irrespective of patient race and ethnicity. Nonetheless, disease relapse remains the primary cause of death for both adult and pediatric allogeneic HCT recipients by donor type and across all patient racial/ethnic groups. Ethnically diverse patients are undergoing allogeneic HCT at higher rates, largely through the use of alternative donor platforms incorporating PTCy. Maintaining access to potential life-saving allogeneic HCT using alternative donors and novel GVHD prophylaxis strategies and improving HCT outcomes, particularly disease relapse, remain urgent clinical needs.

HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL.

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.

Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival. METHODS: We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS: The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19-; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19- relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19- 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION: We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19- relapse is distinctly associated with decreased survival outcomes.

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report.

PURPOSE: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel. METHODS: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity. RESULTS: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively. CONCLUSION: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.

Real-world use of tisagenlecleucel in infant acute lymphoblastic leukemia.

Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children <3 years of age were excluded from licensing studies. We retrospectively evaluated data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n = 14). Sixty-four percent of patients (n = 9) achieved minimal residual disease-negative remission after CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.

Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report.

Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range, <1-25 years), and in the non-CNS EM cohort it was 13 years (range, 2-26 years). In patients with CNS disease, 88% (35 of 40) achieved a complete response vs only 66% (10 of 15) with non-CNS EM disease. Patients with CNS disease (both with and without BM involvement) had 24-month OS outcomes comparable to those of non-CNS EM or BM only (P = .41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM-only patients (P = .92). No increased toxicity was seen with CNS or non-CNS EM disease (P = .3). Active CNS disease at time of infusion did not affect outcomes. Isolated CNS disease trended toward improved OS compared with combined CNS and BM (P = .12). R/R EM disease can be effectively treated with tisagenlecleucel; toxicity, relapse, and survival rates are comparable to those of patients with BM-only disease. Outcomes for isolated CNS relapse are encouraging.

Updated Trends in Hematopoietic Cell Transplantation in the United States with an Additional Focus on Adolescent and Young Adult Transplantation Activity and Outcomes.

Hematopoietic cell transplantation (HCT) has been successfully used to treat many malignant and nonmalignant conditions. As supportive care, donor selection, and treatment modalities evolve, documenting HCT trends and outcomes is critical. This report from the Center for International Blood and Marrow Transplant Research (CIBMTR) provides an update on current transplantation activity and survival rates in the United States. Additional data on the use and outcomes of HCT in the adolescent and young adult (AYA) population are included. AYA patients more frequently receive peripheral blood stem cell grafts than pediatric patients, which may reflect differences in practice in pediatric versus adult treatment centers. The proportions of donor types also differ those in adult and pediatric populations. Outcomes for patients in the AYA age range are similar to those of pediatric patients for acute myelogenous leukemia but worse for acute lymphoblastic leukemia. Outcomes for both leukemias are better in AYA patients compared with older adults. Comparing the time periods 2000 to 2009 and 2010 to 2019 revealed significant improvement in overall survival across the age spectrum, but the greatest improvement in the AYA age group.

Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.