Pantin, Jeremy

Summary We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty‐seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM‐AHN, 70%), received peripheral blood grafts (89%) and non‐myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post‐transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre‐alloHCT to 1.5% (range 0–8) at 1 year post‐alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3–400 ng/mL) pre‐alloHCT to 18 ng/mL (range 0–481 ng/mL) at 1 year post‐alloHCT. At 1 year, progression‐free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%–77%) and 74% (95% CI, 56%–89%) respectively. In the subset of patients with SM‐AHN, 1‐year PFS and OS were 74% (52%–91%) and 79% (95% CI, 58%–94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM ( n = 27) was 4% (95% CI, 0–14) at 100 days and 15% (95% CI, 4–31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1–28) at 100 days and 21% (95% CI, 6–42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre‐ and post‐ alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Background: Obe-cel is an autologous chimeric antigen receptor (CAR) T cell product with a novel CD19 binding domain CAT conferring a fast antigen off-rate designed to mitigate safety concerns and improve persistence over approved CD19 CAR T therapies. Early results from the pivotal FELIX study Phase IIA cohort (N=94) were recently presented (Roddie C et al. J Clin Oncol 2023;41[16 Suppl]:7000). We report findings from a pooled analysis of all patients (pts) treated to date with obe-cel in the FELIX Phase Ib/II study (NCT04404660), with a focus on pts with low leukemia burden prior to obe-cel infusion. Methods: The FELIX study enrolled adults with R/R B-ALL at screening with either morphological disease ≥5% bone marrow (BM) blasts (Cohort A), or in ≥2 nd complete remission (CR)/CR with incomplete hematologic recovery (CRi) with measurable residual disease (MRD) (Cohort B), or with isolated extramedullary disease (EMD) (Cohort C). The Phase Ib part of the study enrolled Cohorts A and B; the Phase II part enrolled Cohorts A, B, and C. CAR T products were generated from leukapheresis material using an automated process. Pts received bridging therapy as needed and lymphodepletion with fludarabine (4 × 30mg/m 2) and cyclophosphamide (2 × 500mg/m 2). A target dose of 410 × 10 6 CAR T cells was infused as a split dose on Days 1 and 10 based on pre-lymphodepletion BM blast burden. The primary endpoint was overall remission rate (best response of CR/CRi by independent review). Secondary endpoints included duration of remission (DoR), MRD negative remission rate, safety, and CAR T expansion/persistence. This pooled analysis included data from pts treated with obe-cel across all cohorts in the Phase Ib/II parts of the study. Low leukemia burden was defined as morphological remission per investigator assessment (<5% BM blasts without EMD) as measured at screening or at the start of lymphodepletion. Results: Between September 2020 and December 2022, 152 pts were enrolled and underwent leukapheresis. As of 16 March 2023, obe-cel was successfully administered to 126/152 (83%) pts (Phase Ib: Cohort A n=13, B n=3; Phase II: Cohort A n=94, B n=9, C n=7). Baseline characteristics at screening (n=126): median age 46.5 (range 20-81) yrs; Philadelphia positive B-ALL 27%; median 2 (range 1-6) prior lines of therapy; prior blinatumomab/inotuzumab 42%/32%; median BM blast burden 37% (range 0-100) including 23% pts with EMD; prior allogeneic stem cell transplant 44%. At a median follow up of 11.0 (range 0.9-30.6) months, the CR/CRi rate was 77% (95/124 response evaluable pts) with CR rate 57% (71/124). Among MRD evaluable responders, 96% achieved MRD negative status by central flow cytometry analysis. Median DoR was not reached at the current follow up. Low rates of Grade (Gr) ≥3 cytokine release syndrome (CRS; 2.4%) and/or Gr ≥3 immune effector cell associated neurotoxicity syndrome (ICANS; 7.1%) were observed. CAR T expansion was similar across the Phase Ib/II cohorts and CAR T persistence was ongoing in the majority of responders at the current follow up. Preliminary data indicate favorable efficacy and safety in pts with low leukemia burden prior to obe-cel infusion. Among 12 pts with MRD at screening (Cohort B), two pts were not evaluable and 9/10 evaluable pts achieved CR/CRi, with 100% achieving MRD negative status by central flow cytometry analysis post obe-cel. Median DoR was not reached at the current follow up. In this subset, no Gr ≥3 CRS was observed; one pt had Gr ≥3 ICANS. In a subset of 28 pts (across all cohorts) in morphological remission at the time of lymphodepletion, 24/27 (89%) response evaluable pts achieved CR/CRi and 100% of MRD evaluable responders achieved MRD negative CR/CRi by central flow cytometry analysis post obe-cel. Median DoR was not reached at the current follow up. In this subset, no pts experienced Gr ≥3 CRS/ICANS. Conclusions:This pooled analysis of data from all pts treated to date in the FELIX study demonstrates high rates of CR/CRi after obe-cel treatment, durable responses (median DoR not reached), and a favorable safety profile. Preliminary data suggest better outcomes in pts with low leukemia burden at screening/lymphodepletion, with higher rates of deep MRD negative complete remission, median DoR not reached at the current follow up, no Gr ≥3 CRS and one Gr ≥3 ICANS. These data support further exploration of CAR T therapy earlier in the treatment algorithm for adults with ALL.