Bone Marrow Transplantation | 2021
Decitabine may improve CAR-T efficacy in refractory/relapsed acute leukemia patients carrying TP53 alterations
Abstract
TP53 is a tumor suppressor gene and its inactivation promotes tumor growth and resistance to chemotherapy. Acute leukemia (AL) patients with TP53 alterations present with poor prognosis due to high failure rates to conventional standard chemotherapies and a high risk of relapse. Chimeric antigen receptor T cells (CAR-T) therapy has demonstrated high response rates in patients with refractory/ relapsed (R/R) acute B lymphocytic leukemia (B-ALL) [1]. However, TP53 alterations impede the efficacy of CAR-T therapy and the rate of relapse is high due to loss of antigen in these patients, which is a common problem associated with CAR-T therapy [2]. Up to now, there is only one trial reported by Pan et al. which included a subgroup of AL patients with TP53 alterations underwent CAR-T therapy. In this trial, patients with TP53 alterations presented with poor response to CAR-T therapy. Among the enrolled 51 CAR-T treated B-ALL patients, there were 4 nonresponders and 3 of which were those with TP53 alterations [3]. In this study, we reported the institutional experience at the First Affiliated Hospital of Soochow University from eleven CAR-T treated R/R AL patients (nine B-ALL, one acute myeloid leukemia, and one B-lymphoid/myeloid biphenotypic mixed phenotype acute leukemia) with TP53 alterations (ten with TP53 mutations and one with TP53 deletion) drawn out from three ongoing phase II trials testing efficacy and toxicities of CAR-T therapy in R/R AL patients (http://ClinicalTrials.gov, NCT03919240, NCT03614858, NCT03896854). This study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University. All patients provided written informed consent. Patients’ characteristics, toxicities, and responses to CAR-T are shown in Table 1. This cohort included four females and seven males. The median age was 15 (8–59) years old. Ten cases (except patient 7) carried complex chromosomal aberrations with TP53 alterations detected in all cases. Two cases (patients 2 and 5) underwent prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) before CAR-T therapy. The second generation 4-1BB-based CAR-T cells targeting CD19, CD22, or tandem CD19 and CD22 were successfully made from nine patients’ and two donors’ (for patients 2 and 5) lymphocytes and provided by the Unicar-Therapy Bio-medicine Technology Co. (Shanghai, China). Quality tests were performed before infusion to patients as previously described [4]. After CAR-T, six cases bridged to allo-HSCT. Furthermore, six cases received additional decitabine (DAC) therapy named DAC group and the other five cases without DAC therapy named non-DAC group. In DAC group, four cases (patients 3, 5, 9, and 11) received CAR-T therapy with DAC as a part of lymphodepletion therapy; four cases (patients 6, 9, 10, and 11) bridged to allo-HSCT after CAR-T therapy, chosen DAC as a part of These authors contributed equally: Changju Qu, Yaohua Song, Jia Yin