Safety, outcomes and T cell characteristics in patients with relapsed or refractory MDS or CMML treated with atezolizumab in combination with guadecitabine
Mené sur 33 patients atteints d'un syndrome myélodysplasique ou d'une leucémie myélomonocytaire chronique réfractaire ou récidivant (âge médian : 73 ans), cet essai de phase I/II évalue la dose maximale tolérée de la guadécitabine en combinaison avec l'atézolizumab et l'efficacité, du point de vue du taux de réponse globale et de la survie globale, de cette combinaison
Purpose: We hypothesized that resistance to hypomethylating agents (HMAs) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a PD-L1 antibody with an HMA. Materials and Methods: We conducted a phase 1/2, multicenter clinical trial for patients with MDS not achieving an IWG-response after at least 4 cycles of an HMA "refractory" or progressing after a response "relapsed" with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 days 1-5 with fixed-dose atezolizumab: 840mg IV days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival. Results: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No DLTs were observed in Phase I. There were 3 (9%) deaths in ≤30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAEs) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, 5 grade1). ORR was 33% (95% CI: 19, 52%) with 2 complete remission (CR), 3 hematologic improvement (HI), 5 marrow CR, 1 partial remission (PR). Median overall survival (mOS) was 15.1 (95% CI: 8.5, 25.3) months. Conclusion: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with R/R MDS and CMML.