Efficacy of assigning treatment for participants with Chronic Myelomonocytic Leukaemia based on their individual molecular results (lenzilumab plus azacitidine versus sodium ascorbate plus azacitidine).

This prospective study will assess whether treatment responses for participants with Chronic Myelomonocytic Leukaemia can be improved by targeting certain mutation sub-groups based on individual molecular profiling. As part of the screening process, participants will be required to have a bone marrow aspirate and trephine. During this procedure, 9 mL of bone marrow aspirate will be collected for central mutation profiling which is a test used to detect certain acquired mutations that can be present in CMML. The most common genes affected in CMML include TET2 and a group of genes belonging to the RAS pathway (NRAS/KRAS/CBL). Both TET2 and RAS pathway genes contribute to CMML, but the way in which they work is different. As a result, we need to tailor our medications specifically to switch them off. Before participants are enrolled in this research study, we will need to assess whether either of these groups of genes have been affected in their case. If they are, the participant may be eligible for this study. Genetic testing is complex and it will take approximately 3 weeks for results to become available. Participants with RAS pathway mutations in will receive lenzilumab in combination with azacitidine, while patients with TET2 mutations will receive sodium ascorbate plus azacitidine. Participants who are found to have both TET2 and RAS pathway mutations (NRAS/KRAS/CBL) will be allocated to the lenzilumab/azacitidine arm of the study. Participants who are negative for both TET2 and NRAS/KRAS/CBL mutations (Variant Allele Frequency [VAF] >= 3%) at screening will be considered screen failures. Drug schedules: Lenzilumab/Azacitidine Arm (total of 24 Cycles). Each Cycle is 28 days. • Azacitidine (subcutaneous) 75 mg/m2 on days 1-5, 8-9 or days 1-7 (for a total of 7 doses per 28 day cycle, at the local institution’s discretion according to the institution's standard Azacitidine protocols). • Lenzilumab (intravenous) 552 mg on days 1 & 15 of Cycle 1. Day 1 only for all subsequent cycles. High Dose Sodium Ascorbate/Azacitidine Arm (total of 24 Cycles). Each cycle is 28 days. • Azacitidine (subcutaneous) 75 mg/m2 on days 1-5, 8-9 or days 1-7 (for a total of 7 doses per 28 day cycle, at the local institution’s discretion according to their standard azacitidine protocol). • Sodium Ascorbate (intravenous) 30 grams on days 1-5, 8-9 or days 1-7 (15 grams for 1st dose only, 30 grams thereafter if no evidence of tumour lysis syndrome). This will be administered on the same days as the azacitidine, according to the institution's standard protocol for azacitidine administration. • Sodium Ascorbate (oral) 1.1 grams on days where intravenous Sodium Ascorbate is not scheduled. Oral dosing will be self-administered at home. During the active treatment phase of the study, participants will be required to attend clinic visits with their doctor on days 1 & 15 of the first cycle, and then on day 1 of each subsequent 28-day cycle to assess how the participant is tolerating the therapy and ensure ongoing safety. In addition to regular safety blood tests throughout each cycle, participants will have disease response assessments scheduled after 3, 6, 12 and 24 cycles of therapy to measure their disease response. Such assessments include blood tests, bone marrow aspirate and trephine, ultrasound of the spleen, physical exam and assessment of transfusion requirements and clinical symptoms. Participants who complete 24 cycles of active treatment will then enter the follow-up phase of the study where they will be followed up every 6 months for 24 months for survival, disease status and further CMML-related treatment. For patients with confirmed progressive disease or relapse during the active treatment phase of the study, further study treatment should cease. They will remain on study and be followed up for disease status, survival and further CMML-related treatment every 6 months until 48 months from Cycle 1, Day 1. During the follow-up period, participants will no longer receive any investigational drugs but are permitted to receive any CMML treatment at the discretion of the treating clinician (including azacitidine who are able to access it). No visits or tests are required as part of the follow-up phase. Participants who continue to receive treatment/care at the study institution and who allow the study team to access their progress notes may not receive any follow-up phone calls. Participants who receive ongoing care at a different institution, and who consent to ongoing follow-up, will have their doctor or study coordinator contact them via a telephone call every six months. This call will take approximately 15 minutes in total.