CD19+ lineage chimerism, an early biomarker after anti-CD19 CAR-T cell therapy in patients previously receiving a hematopoietic stem cell transplantation

Abstract

Treatment targeting CD19 by a chimeric antigen receptor expressed on T cells (anti-CD19 CAR-T) has led to a breakthrough in the management and treatment of relapsed and refractory B- cell acute lymphoblastic leukemia (B-ALL). After infusion, the efficacy of anti-CD19 CAR-T is monitored by bone marrow negative minimal residual disease and the absence of peripheral CD19+ B lymphocytes (B-cell aplasia). In patients who have received an allogenic Hematopoietic Stem Cell Transplantation (HSCT) prior to treatment with anti-CD19 CAR-T, monitoring lineage-specific chimerism could be helpful. We found that on 4 patients who received anti-CD19 CAR-T cells after HSCT and achieved early complete response, CD19+ lineage mixed chimerism but not CD3+ lineage mixed chimerism monitored by molecular techniques anticipated earlier than B-cell aplasia determined by flow cytometry, lack of effectiveness of anti-CD19 CAR-T and leukemia relapse. Donor lymphocyte infusions (DLIs) did not prevent relapse but recovered CD3+ full donor chimerism. We suggest that continuous lineage chimerism analysis should be done routinely in patients who receive anti-CD19 CAR-T cells after HSCT and achieve complete remission because it can support early treatment intervention. However, the role of DLI in this setting is unclear, so further prospective studies should be developed.

Impact of disease burden and late loss of B cell aplasia on the risk of relapse after CD19 chimeric antigen receptor T Cell (Tisagenlecleucel) infusion in pediatric and young adult patients with relapse/refractory acute lymphoblastic leukemia: role of B-cell monitoring

“…These data suggested that BCA could be a suboptimal strategy for predicting not only CD19 negative but also CD19-positive relapses. In addition, CD19-positive lineage chimerism monitored by molecular techniques in patients who received CAR-T19 after allo-SCT, could anticipate relapse earlier than loss of BCA B-cell by MFC ( 17 ),…”

Determinants of outcomes and advances in CD19‐directed chimeric antigen receptor therapy for B‐cell acute lymphoblastic leukemia

“…Management of patients with early loss of BCA after CAR‐T cell therapy is challenging, and there is limited data to support optimal treatment. Early loss of BCA within 6 months after infusion of CAR‐T indicates loss of function, limited expansion, and persistence of the CAR‐T cells, resulting in BCA loss being used as a biomarker to recommend alloHSCT or CAR‐T reinfusion 4,49 . Some proposed mechanisms of loss of BCA are immune‐mediated rejection and development of anti‐mouse antibodies.…”

“…Loss of functional CAR‐T cells, as measured by loss of BCA, adversely affected the risk of CD19+ leukemic relapse (HR 34; 95% CI, 2.1–552; p = .01) while hazard ratio for all relapses regardless of CD19 was 3.5 (95% CI, 1.01–11.88; p = .04).Management of patients with early loss of BCA after CAR‐T cell therapy is challenging, and there is limited data to support optimal treatment. Early loss of BCA within 6 months after infusion of CAR‐T indicates loss of function, limited expansion, and persistence of the CAR‐T cells, resulting in BCA loss being used as a biomarker to recommend alloHSCT or CAR‐T reinfusion 4,49 . Some proposed mechanisms of loss of BCA are immune‐mediated rejection and development of anti‐mouse antibodies.…”