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Anti-CLL1 CAR T-cell therapy proposed for paediatric relapsed/refractory AML

By Lynda Williams, medwireNews Reporter

 

Phase 1/2 trial findings indicate that autologous chimeric antigen receptor (CAR) T-cell therapy based on the C-type lectin-like molecule-1 (CLL1) may be feasible for children with refractory or relapsed acute myeloid leukaemia (R/R-AML).

Chunfu Li (Taixin Hospital, Dongguan, China) and co-workers write in Leukemia that their findings for anti-CLL1 CAR T-cell therapy in eight children show “a very encouraging outcome with a safe and manageable profile and high targeting efficacy”.

The multicenter trial recruited six boys and two girls, aged a median of 12 years (range 8–16 years), who had relapsed or refractory disease and had previously received between two and five rounds of chemotherapy (n=6) or haematopoietic stem cell transplantation (HSCT, n=2).

After 3–5 days of lymphodepletion conditioning with cyclophosphamide and fludarabine, the children were given an anti-CLL1 CAR-T cell infusion of 0.35–1.0 x 106/kg cells. Most children received 1 million anti-CLL1 CAR-T cells/kg and one patient received 0.8 million cells. One patient received just 0.35 million cells/kg due to “inefficient” in vitro expansion, write Li et al.

Before conditioning, the median AML tumour burden in the children was “relatively high” at 46.2% (range 14.2–92.4%) and the median CLL1 positivity on AML blasts was 88.5% (range 65.0–96.0%), they add.

Cytokine release syndrome (CRS) occurred at grade 1 in five patients and grade 2 in three patients, and this was confirmed by interleukin-6 monitoring which showed a significant increase in the first month after infusion.

However, the researchers emphasize that there was “no observable toxicity on all the organs we examined”.

Moreover, there were no cases of neurotoxicity, including immune effector cell-associated neurotoxicity syndrome, which the investigators suggest may have been prevented by the “timely treatment of CRS” with the interleukin-6 antagonist tocilizumab or dexamethasone.

Nevertheless, they caution that “[i]t is likely that pre-existing neurological issues, tumor burden, or CAR-T cell dosage could affect the neurotoxicity occurrence” and note that further monitoring is required in this ongoing study.

Overall, four of the eight patients achieved a morphological leukaemia-free state (MLFS) and minimal residual disease (MRD) negativity and one patient experienced MLFS but was positive for MRD.

In addition, one patient achieved complete remission with incomplete haematological recovery and was positive for MRD and one patient achieved partial remission. One patient had stable disease and cleared the CLL1-positive blasts, so their blast count decreased from 93.1% to 84.6%, leaving only CLL1-negative and CD33-positive blasts.

The researchers note that the children showed “significant cytopenia” before their CAR-T infusion and six patients underwent allogenic HSCT a median of 44 days after CAR-T therapy.

Of the two patients who did not undergo allogeneic HSCT, one patient showed recovery of neutrophil and platelet counts on day 60 after CAR-T infusion and one patient had an increased neutrophil count on day 20.

Acknowledging the “myelosuppression effect of anti-CLL1 CAR-T cells”, the team suggests that “bridging to [allogeneic] HSCT after anti-CLL1 CAR-T treatment might be beneficial to the R/R AML patients.”

During follow-up of the patients who underwent allogeneic HSCT, one patient relapsed and died with graft-versus-host disease 2 months after transplantation, and another relapsed and died with progressive disease. The remaining four patients were alive and in complete remission, with the longest follow-up at data cutoff being 26 months.

Of the two patients who did not undergo allogeneic HSCT, one patient retained a complete response for 12 months before relapse and the second patient with stable disease died from progressive disease and lung infection 2 months after infusion.

Li and co-authors note that AML blast burden at baseline did not significantly correlate with response to CAR T-cell therapy.

However, they postulate that “patients with more than 80% of CLL1 positivity on AML blasts may benefit from single anti-CLL1 CAR-T treatment”, but that for “patients with less than 80% of CLL1 positivity on AML blasts, an additional CAR to target a different tumor antigen may be beneficial to achieve complete deletion of AML cells.”

The investigators conclude: “Together, our findings highlighted the effective and safe characteristics of anti-CLL1-based CAR-T cell therapy in children with R/R-AML.

 

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Leukemia 2022; doi.10.1038/s41375-022-01703-0

https://pubmed.ncbi.nlm.nih.gov/36151140/