Q1 2024: Additional information and data in acute leukemia

April 5, 2024

Autolus Therapeutics announces acceptance of Biologics License Application (BLA) for obecabtagene autoleucel (obe-cel) as a potential treatment for relapsed/refractory Adult B-cell ALL.

Obe-cel is a CD19 CAR T cell investigational therapy designed to overcome the limitations in clinical activity and safety compared to current CD19 CAR T cell therapies. Obe-cel is designed with a fast target binding off-rate to minimize excessive activation of the programmed T cells. Clinical trials of obe-cel have demonstrated that this “fast off-rate” profile reduces toxicity and T cell exhaustion, resulting in improved persistence and leading to high levels of durable remissions in r/r Adult ALL patients. The results of the FELIX trial, a pivotal trial for adult ALL, are being prepared for regulatory submissions with the FDA and EMA. Autolus is conducting a Phase 1b study in paediatric patients with ALL and aggressive B-NHL and iIn collaboration with UCL, obe-cel is currently being evaluated in a Phase 1 clinical trials for B-NHL.

The BLA submission is based on data from the Pivotal Phase 2 FELIX study of obe-cel in adult r/r B-ALL. Autolus plans to submit a Marketing Authorization Application for obe-cel in relapsed/refractory ALL to the European Medicines Agency (EMA) in the first half of 2024.

Press release –> read here.

Takeda Announces U.S. FDA Approval of Supplemental New Drug Application (sNDA) for ICLUSIG® (ponatinib) in Adult Patients with Newly Diagnosed Ph+ ALL. Press release –> read here

A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with R/R ALL:

Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in ALL and may synergize with conventional chemotherapy. In this trial, patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated R/R ALL. Further development of venetoclax-based combinations in ALL is warranted. (Ref: https://doi.org/10.1182/bloodadvances.2023012231)


Limited efficacy for ibrutinib and venetoclax in T-prolymphocytic leukemia: results from a phase 2 international study –> read here


Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML

Molecular failure in NPM1-mutated AML inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment.

Venetoclax–based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy. (Ref: https://doi.org/10.1182/bloodadvances.2023011106)

Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy

Assessment of measurable residual disease (MRD) is strongly prognostic in patients with NPM1-mutated AML treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype.

A study analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%.

In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information. (ref: https://doi.org/10.1182/blood.2023021579)