Blinatumomab in Combination with an Intensive Pediatric Protocol Results in High Rates of Day 79 MRD Negativity in Adolescent and Young Adult Acute Lymphoblastic Leukemia - Preliminary Results of the Australasian Leukaemia and Lymphoma Group (ALLG) ALL09 "Sublime” Study

Background Paediatric inspired regimens have improved outcomes in AYA ALL but results remain inferior compared to children. Historically, this has been associated with the poor tolerance of paediatric regimens as well as the unique biology of AYA ALL. Our previous AYA ALL trial, ALLG ALL06 demonstrated that a BFM based protocol could be administered to pts 15-40 years in a similar timeframe to children with estimated 3 yr DFS 72.8% and 3 yr OS 74.9%. In ALL06, only day 79 (end consolidation) MRD negativity was associated with improved DFS and OS while BMI ≥30kg/m² was associated with inferior OS. The anti-CD19 bispecific T cell engager, blinatumomab has been associated with improved outcomes in both relapsed/refractory and MRD-positive CD19+ pre-B ALL. The primary objective of the ALLG ALL09 "SuBliME” trial was to assess whether the substitution of standard multi-agent cytotoxics with blinatumomab in protocol I phase 2 (consolidation) of a BFM based protocol in de novo AYA CD19+ ALL would be associated with improved day 79 MRD negativity rates and subsequent improvements in DFS and OS when compared to the ALL06 trial.

Methods Previously untreated pts with CD19+ Ph-negative ALL were eligible for enrolment. ALL09 differed from ALL06 by replacing standard cyclophosphamide, cytarabine and 6MP chemotherapy with 28 days of infusional blinatumomab in protocol I and II phase 2 therapy but was similar to ALL06 in all other phases including protocol I phase I, protocol M, protocol II phase I and maintenance to a total of 2 yrs of therapy. MRD was assessed centrally using RQ-PCR assays with a sensitivity of 10^-4 or greater at day 33 and day 79 of protocol I and reported according to EuroMRD criteria. Stratification to high risk (HR) therapy was based on diagnostic and treatment response criteria with the aim of eliminating MRD prior to allogeneic transplantation (SCT) if a suitable donor was available or further intensive chemotherapy. ALL09 utilised a Simon 2-stage design, with every patient enrolled to receive blinatumomab. The comparator arm was the ALL06 study. The primary endpoint (percentage of pts who achieved MRD negativity by day 79) was assessed on a modified intention to treat (mITT) population consisting of all ITT patients who 1. commenced blinatumomab at day 36 and 2. had informative MRD at day 79.

Results 55 pts were enrolled on ALL09 from 04/19 to 04/22. Median age was 25 (16-39) years. 54.5% were male. Presenting WCC was <100 x 10⁹/L in 91%. Extramedullary disease was present in 7.3% (CNS disease in 5.5%). Most (75.5%) pts had B lymphoblastic leukaemia / lymphoma NOS by WHO criteria; n=2 had t4:11. Of 55 eligible pts, n=4 had no MRD marker, n=1 treatment related death in protocol I phase 1, n=1 had progressive disease, and n=1 withdrew consent leaving n=48 in the mITT cohort. Morphological CR was achieved in 68% at day 15, 94.9% by day 33 and 100% of evaluable pts by day 79. There have been 2 relapses and 2 deaths to date (n=1 relapse death). N=25 pts experienced 53 AE's in protocol I phase II including thromboembolic event (n=3), peripheral neuropathy (n=3), cytokine release syndrome (n=2), febrile neutropenia (n=2) and seizure (n=1). MRD results were available in 47 pts at day 33 and 48 pts at day 79. Day 33 and day 79 MRD results were as follows: MRD^neg 16/47 (34.0%) and 34/48 (70.8%), MRD^lowpos (<5 x 10^-4) 18/47 (38.2%) and 10/48 (20.8%) and MRD^pos (≥5 x 10^-4) 13/47 (27.8%) and 4/48 (8.4%). 20% of pts to date have proceeded to HR therapy with n=6 proceeding to SCT as of last follow up. For the Simon's 2-stage primary endpoint there was a significant improvement in the rate of day 79 MRD negativity from an estimated 60% in ALL06 to 70.8% in the mITT population in ALL09 (p=0.037).

Conclusion Substituting standard cytotoxic therapy with the novel bispecific T cell engaging antibody blinatumomab in protocol I phase 2 of a BFM based protocol appeared tolerable and was associated with a significantly higher rate of end-consolidation MRD negative remission than our previous ALL06 protocol. While these results should be confirmed in larger studies, using a Simon's 2-stage design has allowed us to demonstrate the preliminary efficacy of this approach using an MRD endpoint with demonstrated prognostic significance in ALL06 and other trial cohorts. We plan to take this protocol forward in a larger cohort while introducing novel therapies in HR blocks to improve MRD negativity rates in those already exposed to blinatumomab prior to SCT.

Greenwood:Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding. Fleming:Novartis: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Fong:Abbvie: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Blinatumomab is a bispecific T cell engager antibody construct that selectively binds with high affinity to CD19 (expressed on cells of B-lineage origin) and CD3 (expressed on T cells). It is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL) and for the treatment of minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukaemia (ALL) in patients in complete haematological remission.