P365: sequential blinatumomab with reduced intensity chemotherapy for older adults with newly diagnosed ph- b-precursor acute lymphoblastic leukemia – final results of the allg all08 study

Background: The advent of pediatric inspired regimens has improved the outcome for younger adults with Acute Lymphoblastic Leukaemia (ALL), however this comes at a considerable toxicity burden limiting its applicability in older adults. The Australasian Leukaemia and Lymphoma Group (ALLG) undertook a phase 2 proof-of-concept (POC) study of Blinatumomab with RI chemotherapy in adults with newly diagnosed (newDx) Ph neg BCP-ALL. Aims: To assess response, the effectiveness and tolerability of the combination of Blinatumomab with RI chemotherapy following a debulking steroids and chemotherapy for newDx Ph- B-ALL in older adults. Methods: The ALLG ALL8 study (ACTRN12617000084381) is a phase II POC study for patients fit for treatment with a Hyper-CVAD-like regimen (between 40-65 years) with newly diagnosed Ph neg B-lineage ALL. Patients with CNS involvement were excluded. A steroid pre-phase (Prednisolone 100mg daily for 7 days) was followed by a disease debulking phase of cyclophosphamide 150mg/m2 BD day 1-3, vincristine 2mg day 1 & 11 and dexamethasone 10mg/m2 day 1-4 and 11-14. Patients then received alternating cycles of Blinatumomab (at 9mcg/d for the first 7 days of cycle 1 followed by 28mcg/d until day 28) with B-cycles of Hyper-CVAD (Methotrexate 1g/m2 day 1, Cytarabine 3g/m2 BD day 2,3, Methylprednisolone 50mg BD day 1-3) (figure 1) for a total of 4 cycles. All received intrathecal prophylaxis with methotrexate, cytarabine and hydrocortisone prior to blinatumomab treatment blocks and day 1 and 8 of each B-cycle, total of 8 doses. High-risk patients (MLL translocations, hypodiploid, complex karyotype or MRD positive at TP3) were recommended for allogeneic stem cell transplant while others continued to receive 24 months of POMP maintenance. Minimal residual disease testing was performed at a centralised EuroMRD accredited laboratory. MRD positivity was defined as a detectable level of ≥ 1 x 10-4. This is the analysis of the final endpoint as at 14th February 2023. POC criteria were defined on an observed event free rate of ≥ 63%. Results: 30 subjects were enrolled (21 (70%) Male), with a median age of 51.7 years (39.5 – 66.5 years) with 14 (47%) ECOG 0, 12 (40%) ECOG 1, and 4 (13%) ECOG 2 at time of study entry. 5 (17%) subjects had high-risk cytogenetics. 100% of subjects attained composite CR (CR/CRi) with 28 (93%) attaining this by the end of 1B, and a further 2 by the end of cycle 2B. MRD response was ≤10-4 in 19/27 (70%) of subjects at the end of 1B and 20/24 (83%) of subjects at the end of 2B. The estimated EFS at 24 months was 60.4% (median EFS 36.1 mo) with OS at 24 months of 78.6% (median OS NR). This was insufficient to meet the pre-specified proof-of-concept criteria. The regimen was well tolerated with the major toxicity being infective (53 episodes of infection). There were 2 episodes of cytokine release syndrome (1 grade 3), and 7 episodes of grade 3 neurological toxicity (1 myelopathy and 4 neuropathy related to chemotherapy and 2 episodes of neurotoxicity related to blinatumomab). 4 patients proceeded to alloHSCT. Summary/Conclusion: Blinatumomab with chemotherapy was well tolerated with a high rate of remission and deep MRD responses in the majority of patients. Responses appeared durable with this lower intensity treatment approach despite a low rate of allogeneic stem cell transplantation and the exclusion of anthracyclines and asparaginase from treatment. Despite failing to meet proof-of-concept criteria the EFS and OS were encouraging for older ALL patients and demonstrates the feasibility of combining low-intensity chemotherapy with blinatumomab in older adults with BCP-ALL.Keywords: B cell acute lymphoblastic leukemia, Acute lymphoblastic leukemia