We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome–positive (Ph+) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.
Adults with relapsed B-acute lymphoblastic leukemia (ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD−) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated 5 relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD-negative complete remissions as assessed by deep sequencing PCR. Therapy was well tolerated although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Significantly, cytokine elevations directly correlated to tumor burden at the time of CAR modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR modified T cell therapy, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT.
Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed. The clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.
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