Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells

Abstract

Relapse following chimeric antigen receptor (CAR) T-cell therapy directed against CD19 for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) remains a significant challenge. Three main patterns of relapse predominate: CD19 positive (CD19pos) relapse, CD19 negative (CD19neg) relapse, and lineage switch (LS). Development and validation of risk factors that predict relapse phenotype could help define potential pre- or post-CAR T-cell infusion interventions aimed at decreasing relapse. Our group sought to extensively characterize pre-infusion risk factors associated with the development of each relapse pattern via a multicenter, retrospective review of children and young adults with r/r B-ALL treated with a murine-based CD19-CAR construct. Of 420 CAR-treated patients, 166 (39.5%) relapsed, including 83 (50%) CD19pos, 68 (41%) CD19neg, and 12 (7.2%) LS relapses. A greater cumulative number of prior complete remissions was associated with CD19pos relapses, whereas high pre-infusion disease burden, prior blinatumomab non-response, older age, and 4-1BB CAR construct were associated with CD19neg relapses. The presence of a KMT2A rearrangement was the only pre-infusion risk factor associated with LS. The median overall survival following a post-CAR relapse was 11.9 months (95% CI 9-17 months) and was particularly dismal in patients experiencing a LS, with no long-term survivors following this pattern of relapse. Given the poor outcomes for those with post-CAR relapse, study of relapse prevention strategies, such as consolidative hematopoietic stem cell transplant, is critical and warrants further investigation on prospective clinical trials.

Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study

“…One report has suggested this is not the case, 7 and, similarly, outcomes for patients with KMT2Arearranged leukaemias were not significantly different to those without KMT2A rearrangement in our study. Contrary to a congress report of patients with KMT2Arearranged acute lymphoblastic leukaemia of all ages who were treated with tisagenlecleucel, 21 in which a larger proportion of patients had myeloid lineage switch (nine of 38 patients), there were no reports of myeloid lineage switch in our cohort. It is noteworthy that, of three patients who had emergence of CD19-negative disease (one non-response and two relapses), two were in patients with KMT2A-germline leukaemia, and only one had been treated with blinatumomab before receiving CAR T-cell therapy.…”

Applying a clinical lens to animal models of CAR-T cell therapies

“… 44 In clinic, KMT2A-rearranged leukemias, most often seen in infants, are particularly vulnerable to CD19 negative relapses after CD19-directed therapies. 54 , 56 Extensive efforts are underway to model KMT2A-rearranged leukemia (as reviewed in Liao et al. 57 ), which will further elucidate the mechanisms of leukemia lineage switch provoked by CAR-T cell pressure.…”

To B‐ or not to B‐: A review of lineage switched acute leukemia

“…7,[34][35][36][37] A case report of a 25-year-old woman with pro-B ALL at diagnosis, B-ALL 2 years later at first relapse, and then monocytic leukemia 3 months at first relapse was shown by semi-nested PCR to have harbored TAF15-ZNF384 translocations in all three samples. 36 Further, Rayes et al 7(p) identified a KMT2Ar infant leukemia that switched to acute monoblastic leukemia following 15 days of blinatumomab infusion and showed an identical clonal karyotype, [t(4;11)(q21;23), add (19…”

“…It is not surprising, therefore, that some refractory leukemias develop CD19‐negative blasts upon relapse 17,18 . While some relapsed CD19‐negative leukemic blasts show an otherwise identical immunophenotype as the diagnostic disease, rare cases, particularly those that are KMT2A‐ rearranged ( KMT2A r), undergo lineage‐switch at relapse as a mechanism to escape targeted destruction 17–19 . Lamble et al 19 reported 12 of 163 (7.4%) B‐ALL treated with CAR‐T therapy demonstrated lineage switch, with 75% of the lineage switched relapses harboring KMT2Ar .…”

“…While some relapsed CD19‐negative leukemic blasts show an otherwise identical immunophenotype as the diagnostic disease, rare cases, particularly those that are KMT2A‐ rearranged ( KMT2A r), undergo lineage‐switch at relapse as a mechanism to escape targeted destruction 17–19 . Lamble et al 19 reported 12 of 163 (7.4%) B‐ALL treated with CAR‐T therapy demonstrated lineage switch, with 75% of the lineage switched relapses harboring KMT2Ar . Such cases provide a potential pitfall for lineage‐specific minimal residual disease (MRD) assays that rely on using primarily lymphoid‐associated markers, such as CD19, and suggest that myeloid‐oriented flow panels may need to be routinely utilized for such cases.…”