Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

Abstract

In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…Longer follow-up, focused on the stability of CR for years after infusion, is beginning to be reported and provides both reason for celebration and also a mandate for further optimization of these therapeutics. 138,144,152,173 Thus, recent work from multiple centers in the United States and China have documented high CR rates as well as sustained remissions in patients treated with CD19-CAR-T cells, both with and without additional consolidation, 108,111,[136][137][138][144][145][146][147][148][149][150][151][152][153][154][155]173 striking results given the high-risk patient populations that have been treated. However, it is now clear that for most patients, the CR is not followed by long-term remission, with more than half of patients ultimately relapsing following CAR-T therapy.…”

“…Thus, several recent studies continue to document high (;70% to 90%) remission rates in pediatric and adult patients with B-cell ALL, 144,145,151,152,162,[174][175][176] but with significant relapse rates, even in short-term follow-up, and with a recent long-term analysis by the MSKCC group documenting event-free survival of 6.1 months and overall survival of 12.9 months in patients treated with CAR-T therapy. 173 Markers that distinguish a high risk of relapse vs long-term relapse-free survival after CAR-T therapy are actively being sought. Although greater persistence of CAR-T cells has been correlated with long-term survival in some studies (especially in studies of 4-1BB-containing CARs), 137,138,144,155 this is not a universal finding, and, especially with CD28-containing CARs, long-term survival was most strongly correlated with the development of "deep" minimal residual disease-negative remission after CAR-T therapy and a lower disease burden at the start of treatment.…”

“…Although greater persistence of CAR-T cells has been correlated with long-term survival in some studies (especially in studies of 4-1BB-containing CARs), 137,138,144,155 this is not a universal finding, and, especially with CD28-containing CARs, long-term survival was most strongly correlated with the development of "deep" minimal residual disease-negative remission after CAR-T therapy and a lower disease burden at the start of treatment. 173 Given the early stage of most of the CAR-T-cell studies, additional long-term studies and the discovery of surrogate markers of a sustained response to CAR-Ts are increasingly critical, as they will help inform decision-making about risk stratification post-CAR-T therapy. This risk stratification is of central importance in making decisions about what other therapies (if any) to offer patients who have been treated with CAR-Ts.…”

Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

“…In leukaemia and lymphomas, CAR-T cells were very successful in the clinic [129,130] . The main target investigated in EWS is the glycolipid GD 2 , which is expressed in most EWS tumours at varying levels and against which CAR-T cells have been developed [131] .…”

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib

“…Treatment with blinatumomab, a bispecific T-cell engager (BiTE) with CD19 and CD3 antibody specificity, has significantly improved complete remission (CR), event-free-survival, and overall survival rates for Philadelphia chromosome-negative B-ALL, compared to conventional chemotherapy [5], and has also produced promising results in R/R Philadelphia chromosome-positive (Ph + ) B-ALL [6]. CAR-T cell therapy also has robust activity against R/R B-ALL, with CD19 CAR-T cell therapy producing an unprecedented CR rate of 83% and a median survival of 13 months in heavily pretreated patients [7]. While response rates to anti-CD19 immunotherapies are high, resistance can occur [8-13].…”