Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia

Here we present the 3-year results of ZUMA-4, a phase I/II multicenter study evaluating the safety and efficacy of KTEX19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Phase I explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities. Thirty-one patients were enrolled; KTE-X19 was administered to 24 patients (median age 13.5 years, range 3-20; median follow-up 36.1 months). No dose-limiting toxicities were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33% in all treated patients, 75% in patients given the dose of 2×106 CAR T cells/kg, 27% in patients given the dose of 1×106 cells/kg in the 68 mL formulation, and 22% in patients given the dose of 1×106 cells/kg in the 40 mL formulation; the percentages of patients experiencing grade ≥3 neurologic events were 21%, 25%, 27%, and 11% respectively. Overall complete remission rates (including complete remission with incomplete hematologic recovery) were 67% in all treated patients, 75% in patients given 2×106 CAR T cells/kg, 64% in patients given 1×106 cells/kg in the 68 mL formulation, and 67% in patients given 1×106 cells/kg in the 40 mL formulation. Overall minimal residual diseasenegativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplantation. In the 1×106 (40 mL) group (recommended phase II dose), the median duration of remission censored at allogeneic stem-cell transplantation and median overall survival were not reached. Pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia achieved high minimal residual disease-negative remission rates with a manageable safety profile after a single dose of KTE-X19. Phase II of the study is ongoing at the dose of 1×106 CAR T cells/kg in the 40 mL formulation. ClinicalTrials.gov: NCT02625480

Abatacept Is Effective for Gvhd Prophylaxis after Unrelated Donor Stem Cell Transplantation (URD SCT) for Severe Sickle Cell Disease (SCD)

Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year overall survival (OS) and event-free survival (EFS) of 79% (95% CI 59-90) and 69% (95% CI, 48-82) respectively following reduced intensity conditioning (RIC).1 Though the RIC approach provided successful engraftment in the majority, the transplant approach was not considered safe for widespread adoption due to high rates of graft-versus-host disease (GVHD) especially in children >13 years, a predominant cause of mortality. Strategies to minimize GVHD were essential if URD SCT was to be considered with curative intent in SCD. Aim/Method Multicenter trial (NCT03128996) with the primary objective of determining EFS in non-malignant disorders at one-year was amended as follows. The phase I SCD cohort included conditioning with hydroxyurea, proximal alemtuzumab, fludarabine, and melphalan in patients with 8/8 HLA-matched URD (-A, -B, - C and -DRB1).1 Thiotepa (8 mg/kg) was added in 7/8 HLA-mismatched SCT. GVHD prophylaxis included a calcineurin inhibitor and methotrexate as previously described. Abatacept (10 mg/kg) was administered on days -1, +5, +14, +28, +60, +100, +180, +270 and +365 based on efficacy described against acute GVHD with early dosing after SCT for malignant disorders.2,3 The latter 3 doses were omitted in cord transplant recipients. Result Thirteen children (7-21 years) underwent SCT (8/8 URD marrow- 7; 7/8 URD marrow or cord-6) primarily for stroke (N=6), ≥3 severe vaso-occlusive pain crises (N=4) or ≥2 acute chest syndrome episodes per year (N=3). The conditioning regimen was well tolerated. One patient had primary graft rejection after CMV infection (7%) and had autologous recovery. All other patients engrafted; neutrophils at median of 18 days (10-24), platelets at median of 28 days (16-39) and are surviving free of SCD with median follow-up of 12 months (range 4-59). Myeloid lineage donor chimerism was >95% and lymphoid was 39%- 100% at day+100. Two-year OS and EFS was 100% and 92.3% (95% CI, 6.57-35.7), respectively. The day+100 incidence of grade II-IV and III-IV acute GVHD incidence was 23% and 15% respectively. One-year incidence of chronic GVHD was 38%. However, only one patient (7%) developed extensive cGVHD. One patient (7%) developed posterior reversible encephalopathy syndrome and recovered. Viral replication in blood was detected in 7 of 13 patients (7 CMV, 1 EBV reactivation). No patient developed EBV PTLD or required EBV-related intervention. Conclusion In comparison to previous experience1 with RIC and URD SCT, our early observations are (1) a lower incidence of PRES (7 vs 34%) (2) low incidence of severe acute GVHD (15% vs 17% grade III -IV) despite mismatched donors, (3) low incidence of extensive chronic GVHD (7% vs 38%) and (4) no mortality despite patient age (10/13 were >13 years old). We attribute this gain to avoiding steroid use, and the benefit of including abatacept into the treatment regimen. The engraftment, safety, and immune reconstitution profile continue to be monitored in this ongoing trial now accruing in a Phase II cohort. As we and others work toward expanding donor options for SCD transplants, we submit that all alternate donor transplants for severe SCD are experimental and should be performed on clinical trials that track success and pitfalls. Reference: 1. Shenoy S et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016 Nov 24; 128(21): 2561-2567. 2. Koura et al. In vivo T cell costimulation blockade with abataceptfor acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant. 2013 Nov; 19(11): 1638-49. 3. Watkins BK et al. T cell co-stimulation blockade with CTLA-4 Ig (Abatacept) for acute GVHD prevention in HLA-matched and mismatched unrelated donor transplantation: Results of a Phase 2 trial. Abstract 65. ASTCT Meetings, Houston 2019. Figure Disclosures Shah: Jazz pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Abatacept, FDA approved for rheumatoid arthritis is a fusion protein that inhibits T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs).It is used for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation in this stud

A Single Institution Experience of Bortezomib for Gvhd in a Pediatric HSCT Population

Background Graft vs Host Disease (GVHD) is a common but revered complication after allogenic hematopoietic stem cell transplants (HSCT). Corticosteroids are the first-line therapy for GVHD, yet a consensus is lacking for second-line therapy in patients who experience worsening of symptoms when doses are reduced after initial response (steroid dependent), or who progress despite optimum steroid therapy (steroid refractory) GVHD. Bortezomib is a first-generation reversible proteasome inhibitor that inhibits T cells and prevents activation of dendritic cells that mediate antigen presentation and cytokine transcription. Though promising in adult clinical trials, there is a paucity of data on children less than 18 years for the prevention and treatment of GVHD. We hereby report on a single institutional case-series of bortezomib in pediatric HSCT treatment of GVHD. Results Our first case, a 7 year old male with history of acute myeloid leukemia, developed stage 1 acute gastrointestinal GVHD 23 days post-HSCT, and stage 4 skin GVHD beginning 39 days post-HSCT. His skin GVHD failed multiple attempts to wean off steroids, hence the addition of bortezomib at 364 days post-HSCT, receiving weekly doses for 30 weeks ranging from 0.5 mg/m2 to 1.0 mg/m2. This allowed us to wean him off prednisone and discontinue all immune suppression without additional flares. Our second case, a 4 year old male, presented with acute stage 4 skin and stage 2 liver GVHD 108 days and 341 post-HSCT, respectively. Bortezomib was started for the skin GVHD after unable to wean him off steroids. He received a total of 15 doses administered weekly and ranging from 0.4 to 0.87 mg/m2. While on bortezomib his skin GVHD resolved allowing discontinuation of steroids and other immune-suppressive agents. He later developed liver GVHD, which was not responsive to bortezomib. Our third case, a 1 year old female, presented with steroid-dependent acute skin GVHD 177 days post-HSCT. She responded remarkably to steroids but experienced multiple flares of skin GVHD any time the steroid dose was reduced below 1 mg/kg/day. After multiple attempts employing different combinations of immunosuppressive regimens, bortezomib was started. She showed initial response to bortezomib at doses ranging from 0.1 mg to 1.3/m2 mg but was unable to be completely weaned off steroids. Our fourth case, a 19 year old male with lung GVHD who was on long-term steroids, received bortezomib after failing steroid dose reduction when combined with sirolimus and extra-corporeal photopheresis. He received weekly doses of bortezomib for 12 weeks, ranging from 0.2 mg to 1.3/m2 mg, that permitted a successful wean off steroids. However, he later died from pulmonary GVHD. Conclusion We hereby report, based on these cases that bortezomib is a safe option for adjuvant GVHD therapy in children after HSCT. It resulted in successful discontinuation of steroids in two of the three patients with skin GVHD. Well-designed studies of GVHD management with bortezomib in pediatrics are necessary to elucidate this initial finding. We plan to explore this further in a multi-center trial. OffLabel Disclosure: Bortezomib is off label - FDA indications are for treatment of multiple melanoma and second line mantel cell lymphom