Donor‐derivedCD19‐targeted T cell infusion induces minimal residual disease‐negative remission in relapsed B‐cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation

Abstract

Relapse is a common cause of failure in patients with B-cell acute lymphoblastic leukaemia (B-ALL) after haploidentical haematopoietic stem cell transplantation (haplo-HSCT), and non-responders to donor lymphoblastic infusion after HSCT have a very poor prognosis. Although donor-derived CD19-directed chimeric antigen receptor-modified (CAR) T cells can potentially cure leukaemia, their effectiveness and safety have not been confirmed in relapsed B-ALL cases after haplo-HSCT. Between January 2015 and January 2017, two and four patients each received one and two infusions of CAR T cells from haplo-HSCT donors. Five (83·33%) achieved minimal residual disease (MRD)-negative remission; one patient was discharged automatically without evaluation after developing severe thrombotic microangiopathies. Four of five responsive patients relapsed after 2-7 months, and one died of sepsis following MRD-negative remission after a second infusion. None of the other second infusion recipients achieved a second complete remission. Five patients (83·33%) experienced eight courses of grade 1-3 cytokine release syndrome; two were treated with tocilizumab. Two (33·3%) and one patient developed grade 2 and 3 acute graft-versus-host disease (aGVHD), respectively; the former was controlled with glucocorticoids. Donor-derived CAR T-cell infusion seems be effective and safe for relapsed B-ALL after haplo-HSCT, although larger clinical studies are needed.

Mechanisms of resistance to CAR T cell therapy

“…Several groups have now tested donor-derived CAR-based treatment strategies both preclinically 58 and in patients with post-transplant disease relapse using T cells harvested directly from their original allogeneic stem cell donors [59][60][61] . The results of these early studies demonstrate the feasibility of this approach, with only a low frequency of high-grade graft-versus-host disease (GVHD) [59][60][61] . Manufacturing CAR T cells from third-party donors might enable the development of universal, off-theshelf products and is another method to overcome the problem of quantitatively insufficient or poor-quality CAR T cell products 62,63 .…”

Use of Chimeric Antigen Receptor T Cells in Allogeneic Hematopoietic Stem Cell Transplantation

“…Although the CAR-T cells have been used in relapsed/relapse B cells malignancies with good outcomes, the outcome is still poor for nonresponse patient treated by donor lymphocyte infusion (DLI) after allo-HSCT [33]. The outcome is also poor for a patient with a higher burden of disease [34].…”

The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies

“…Thus, ALL patients had higher response rate (81%) than CLL patients (70%) and lymphoma patients (68%) (Figure 3). [20,27,30,34,37,46,52]. There was significant heterogeneity among the studies, with an I 2 of 58, Q = 14 ( Figure 4).…”

“…First, we compared the clinical responses among malignancies type (ALL, CLL and lymphoma). For ALL, RR of 81% (223/277) was observed, with an HR of 0.80 (95% CI: 0.68À0.88, P = 0.000) in 14 clinical trials [25][26][27][28][29]32,35,38,41,46,48,50,52,53]. There was significant heterogeneity among the studies with an I 2 of 64, Q = 36 ( Figure 3).…”

“…In two clinical trials, only remission was reported [17,22], and we calculated them as CRe and PRe. Complete remission with incomplete count recovery, molecular complete remission, continuous complete remission, second complete remission, minimal residual disease remission and bone marrow remission were also reported in the clinical trials [27,33,38,46], thus we combined them for our analysis. We demonstrate the primary outcomes of stable disease and progressive disease of the included clinical trials in Table 1.…”