Successful Treatment of Chimeric Antigen Receptor T Cell Therapy in Refractory or Relapsed Acute Leukemia Patients with TP53 alterations
Authors: Qu Changju , Yin Jia , Kang Liqing , Li Zheng , Dai Haiping , Zhu Xiaming , Yu Lei , Wu Depei , Tang Xiaowen 
Published: November 2019

Backgrounds: Refractory or relapsed(R/R) acute leukemia (AL) patients with TP53 alterations have a dismal outcome with current therapy. Recently, chimeric antigen receptor T cells (CAR-T) therapy has emerged as a novel immunotherapy modality in treating patients with R/R acute B lymphocytic leukemia (B-ALL) patients, with consistently high response rates and durable remissions and even cures across multiple studies. However, successful treatment of CAR-T therapy in R/R AL with TP53 alterations has been a challenge. Here, we conducted a phase II trial testing efficacy and toxicities of CAR-T therapy in R/R AL patients with TP53 alterations.
Methods: The second generation CAR-T cells were successfully made from 9 patients' autologous lymphocytes and 2 donors' allogeneic lymphocytes and qualified tests were done before infusion to patients. CAR constructs used were humanized CAR targeting CD19, CD22 or tandem CD19 and CD22 according to the expression levels of each target on blasts. In this ongoing trial, 11 R/R AL patients with TP53 alterations (10 with TP53 mutations and 1 with TP53 deletions) including 2 relapsed after allo- allogeneic hematopoietic stem cell transplantation were included to evaluate the efficacy and safety of CAR-T therapy. Among the enrolled 11 R/R patients, 9 patients were diagnosed with B-ALL, 1 was diagnosed with acute myeloid leukemia (AML) and 1 was diagnosed with mixed phenotype acute leukemia (MPAL) (B-ALL and AML). After leukapheresis, all patients received fludarabine-based lymphodepletion chemotherapy with FLAG regimen (Fludarabine 30mg/m2 × 5d, Cytarabine 2g/m2 × 5d and Granulocyte-colony stimulating factor 300ug ×6d) in two cases, FC regimen (Fludarabine 30mg/m2 × 3d and Cyclophosphamide 300mg/m2 × 3d) in five cases, and FC+DAC regimen (Decitabine 50mg × 3d, Fludarabine 30mg/m2 × 3d and Cyclophosphamide 300mg/m2 × 3d) in four cases. Two days after chemotherapy, autologous/allogeneic CAR-T cells were infused within 2 to 4 days in a dose-escalation.
Results: With a median (range) dose of 1×107/kg (0.1-1.5×107/kg) CAR-T cells, we observed a high response rate with 10/11 (90.9%) evaluated R/R patients achieved complete remission (CR) and 9/11 (81.8%) patients achieved molecular CR (mCR). Moreover, Most cases (8/11, 72.7%) only experienced mild to moderate cytokine release syndrome (CRS) and no neurological toxicity were observed. With a median follow-up of 10 months, 3 cases died of progressive disease including 1 case failed to response to CAR-T therapy, 1 case achieved CR and relapsed after CAR-T therapy and 1 case achieved mCR after CAR-T therapy and relapsed after the following allo-HSCT, and the left 8 cases still kept in mCR and alive. The one-year overall survival (OS) and leukemia-free survival (LFS) rates were 68.4% and 78% respectively. The 2-year cumulative incidence of relapse was 22.2%, and the non-relapse mortality rate was 0%.
Further subgroup analysis showed that all 6 cases who received decitabine therapy (DAC group) achieved and maintained in mCR, while only 2 cases achieved and kept in mCR and 3 cases died from progressive disease in the cases without receiving decitabine therapy (Non-DAC group). The median OS and LFS for Non-DAC group was 10 and 16.375 months respectively, while the median OS and LFS for DAC group were unreached. Relative IL-6 and CRP levels increased dramatically in DAC group than that in Non-DAC group. However, there were no significant difference on treatment related toxicities between cases in DAC group and Non-DAC group.
Conclusions: Our trial indicates that CAR-T therapy is a safe and powerful salvage approach to R/R AL patients with TP53 alterations and application of decitabine may fuel CAR-T therapy and reduce the relapse rate without increasing therapy related mortality incidences in this high risk population.

Disclosures
No relevant conflicts of interest to declare.