Results from the Phase 1 Portion of a Trial of Oral Ixazomib Combined with Chemotherapy in Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoma in Children, Adolescents and Young Adults: A Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

ACKNOWLEDGEMENT Proteasome inhibitors potentiate anti-tumor effects of standard cytotoxic chemotherapy in childhood leukemia. Ixazomib is an oral proteasome inhibitor that has a shorter proteasome dissociation half-life than bortezomib, which leads to a higher tumor-to-blood ratio inhibition. We performed a phase 1 trial to determine the dose limiting toxicities (DLT), Recommended Phase 2 Dose (RP2D) of ixazomib in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoma (LL). Patients ≤ 21 years of age with relapsed or refractory ALL (with ≥ 5% detectable disease in the marrow) or LL were eligible. Ixazomib was combined with 28-day blocks of well-established, relapsed ALL backbone chemotherapy. Block 1 contained vincristine (1.5 mg/m 2/dose IV Days 1, 8, 15, 22), dexamethasone (5 mg/m 2/dose IV or oral twice daily Days 1-14), PEG-asparaginase (2500 IU/m 2/dose IV Days 2, 15) and daunorubicin (60 mg/m 2/dose IV Day 1) (VXLD). An optional Block 2 contained vincristine (1.5 mg/m 2/dose IV Day 1), dexamethasone (3 mg/m 2/dose oral twice daily Days 1-5), methotrexate (1000 mg/m 2/dose IV over 36 hours Day 8), PEG-asparaginase (2500 IU/m 2/dose IV Day 9), cyclophosphamide (440 mg/m 2/dose IV Days 15-19) and etoposide (100 mg/m 2/dose IV Days 15-19). An additional optional Maintenance Block contained vincristine (1.5 mg/m 2/dose IV Day 1), prednisone (20 mg/m 2/dose oral twice daily Days 1-5), mercaptopurine (75 mg/m 2/dose oral daily) and methotrexate (20 mg/m 2/dose oral weekly). Intrathecal therapy was given throughout with agents and dosing based on the patient's CNS disease status upon study entry. Ixazomib was given orally and tested at two dose levels (DL) (DL1: 1.6 mg/m 2/dose; DL2: 2 mg/m 2/dose) using a 3+3 design and was given during Block 1 on Days 1, 4, 8 and 11; during Block 2 on Days 1, 4, 8, 15 and 18 and during Maintenance on Days 1, 8 and 15. DLTs during Block 1 only were utilized to make DL escalation decisions and determine the RP2D. Patients without Down Syndrome (DS) entered Cohort A, used to determine the P2RD. Patients with DS were eligible for a 1 DL lagging descriptive-only Cohort B. Ten patients were treated; nine in Cohort A (n = 3 at DL1 and n = 6 at DL2) and one in Cohort B (DL1). Median age (range) at study entry was 10.5 years (5 - 20 years). Nine patients had B-ALL and one had T-ALL. Most were heavily pretreated with a median (range) of 3.4 (1 - 7) previous remission attempts with six having had prior immunotherapy and three patients having had at least one prior hematopoietic stem cell transplant. After Block 1, two patients received Block 2 and one received Maintenance. In Block 1 of Cohort A, non-hematological Grade 3/4 adverse events (AE) possibly, probably or definitely related to ixazomib or the backbone chemotherapy were limited and included neutropenic fever (n = 7), increased AST (n = 3), increased ALT (n = 2) and hypokalemia (n = 2). Two septic events occurred (n = 1 in Cohort A (Grade 3) and n = 1 in Cohort B (Grade 4)). Block 2 and Maintenance AEs were not significantly different than those seen in Block 1. No deaths or DLTs occurred. Response assessment showed that at DL1 two of three patients had a Complete Remission (CR) both of whom were Minimal Residual Disease (MRD) negative (-) and at DL2 three of six patients had a CR, two of whom were MRD- and two patients had a CR with incomplete count recovery (CRi). The overall response rate (CR + CRi) was 78% (7 of 9 patients). With a minimum of 20 months of follow-up six of nine patients in Cohort A and the single patient in Cohort B are still alive. All three deceased patients died of disease progression. Ixazomib can be combined with standard chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric relapsed ALL including those with DS. The RP2D of Ixazomib combined with chemotherapy is 2 mg/m 2/dose, which is being used in the ongoing phase 2/expansion cohort of the study. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Takeda Pharmaceuticals Company provided the investigative drug and funding in support of this trial

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children’s Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents

Higher doses of tisagenlecleucel associate 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

Optimal fludarabine lymphodepletion is associated with improved outcomes following 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

HLH-like toxicities predict poor survival following 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

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

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

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

PurposeTisagenlecleucel 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.MethodsWe 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.ResultsIntent-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.ConclusionCommercial 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