According to results of a study published in Blood, children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) who had minimal residual disease (MRD) prior to treatment and received high-dose preconditioning chemotherapy were most likely to respond to a second-generation CD-19 chimeric antigen receptor-T cell (CAR-T) therapy.1

Although it has been estimated that 90% or more of pediatric patients with a diagnosis of ALL will respond to multi-agent chemotherapy, the prognosis for those with relapsed/refractory disease remains poor. One CD19-directed CAR-T therapy, tisagenlecleucel, is approved by the US Food and Drug Administration in patients up to age 25 years with B-cell precursor ALL who either have refractory disease or have experienced a second or later relapse.2

This open label, nonrandomized, phase 1 study (Clinical Trial Identifier: NCT01860937), evaluated the toxicity, feasibility, and response of 19-28z CAR-T therapy, a second-generation CD19-directed CAR-T therapy involving “T cells expressing a chimeric receptor composed of an anti-CD19 antibody binding site and intracellular domains from the T-cell coactivating receptors, CD28 and the CD3-zeta chain”3 in children and young adults up to 25 years of age with very high-risk ALL.1  Inclusion criteria included at least 2 relapses, early bone marrow relapse following complete response (CR), intermediate/late CR with poor response to re-induction therapy, or those with refractory disease, or ineligibility for allogeneic hematopoietic stem cell transplantation (allo-HSCT) or additional chemotherapy.1

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The age range of the 25 patients treated with 19-28z CAR-T therapy on study was 1 to 22.5 years, with a median age of 13.5 years. Preconditioning chemotherapy involved high-dose cyclophosphamide (15 patients) and low-dose cyclophosphamide (8 patients), with 3 patients in each subgroup also receiving fludarabine.1

Regarding the feasibility of this approach, the prespecified CAR-T cell dose was achieved for all patients for whom the 19-28z CAR-T therapy procedure was undertaken.1

With respect to treatment toxicity, approximately one-third of patients experienced a grade 3/4 adverse event, including cytokine release syndrome (CRS) and neurotoxicity in 16% and 28% of patients, respectively. With the exception of 1 patient with grade 4 CRS and neurotoxicity who died following refractory Stenotrophomonas septic shock, these adverse events were reversible.1

Of the 24 patients included in the response analysis, 75% achieved either a CR or a CR with incomplete count recovery (CRi). In the subsets of patients receiving preconditioning chemotherapy with either high- or low-dose cyclophosphamide, the CR/CRi rates were 94% and 38%, respectively. Furthermore, treatment response was influenced by disease burden as evidenced by the considerably higher CR/CRi rate in patients with baseline minimal residual disease (ie, less than 5% bone marrow blasts; 93%) compared with morphological evidence of disease at baseline (5% or higher bone marrow blasts; 50%).1

The CR/CRi rate for the subset of patients with pretreatment MRD treated with high-dose cytarabine was 100%.1

Consolidation allo-HSCT was performed in 83% (15) of the patients responding to CAR-T therapy, with a median time from CAR-T infusion to allo-HSCT of 57 days. At a median follow-up of 28.6 months for responding patients, over half of these patients (8) were alive and had no evidence of disease.1

In their concluding remarks, the study authors commented that “this analysis has allowed us to determine the toxicity profile, confirm feasibility, evaluate response of this approach, and provide a direct comparison of the same CD19-specific CAR T cell product that was previously published[3] in adult patients for the same indication.”

The authors went on to highlight the finding of a reversible toxicity profile in the patients within their study as well as the impact of preconditioning chemotherapy dose intensity and minimal pretreatment disease burden on response.

They further noted that “within this cohort, the long-term persistence of response is encouraging, and in our primarily transplant-naive patient population, the ability to proceed to allo-HSCT has demonstrated a favorable overall survival, manageable toxicity, and limited incidence of relapse.”


  1. Curran KJMargossian SKernan NA, et al. Toxicity and response following CD19-specific CAR T cells in pediatric/young adult relapsed/refractory B-ALL [published online October 17, 2019]. Blood. doi:10.1182/blood.2019001641
  2. Tisagenlecleucel (Kymriah). East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
  3. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449-459.