PETHEMA-BLIN-01/PET069014 (BLIN-01)

Overview

The PETHEMA Spanish group treats patients with high-risk Philadelphia chromosome-negative ALL, aged 18 to 55 years, based on the MRD clearance as assessed by flow cytometry at a centralised evaluation centre. Patients with MRD \< 0.1% (\< 1×10-3) after induction and \< 0.01% (\< 1×10-4) after early consolidation are assigned to receive chemotherapy (late consolidation and maintenance). Early consolidation chemotherapy consists of three cycles including high doses of MTX, ARA-C and ASP, together with vincristine and dexamethasone. The same therapy is repeated in the late consolidation period if MRD after early consolidation is \< 0.01% (\< 1×10-4). Maintenance therapy is then administered for up to 2 years from the CR date. These patients do not receive allo-HSCT if they maintain adequate MRD clearance. Despite having adequate MRD clearance, a proportion of patients (around 25%) experience relapse, which makes other approaches necessary to try to decrease the relapse rate. Intensifying currently existing chemotherapy regimens is not likely to increase the cure rate and would likely significantly increase toxicity. The use of targeted immunotherapeutic agents such as blinatumomab, which has demonstrated efficacy and safety in patients with R/R ALL and in patients with ALL and MRD+, seems to be a promising option \[30-33\]. Therefore, it would be interesting to assess the potential efficacy of using blinatumomab in CR patients to reduce the MRD more frequently and more intensely during the early and late consolidation period. Our hypothesis is that blinatumomab will further reduce the level of MRD and this could lead to a decrease in the relapse rate in these patients. This trial will replace the third early consolidation cycle with a cycle of blinatumomab, and the same will be done in the late consolidation period. We hope that this strategy will increase the extent of the MRD response and prevent relapses. Moreover, and as a secondary objective, we will investigate the safety of blinatumomab administration after the administration of high-dose chemotherapy including MTX, ARA-C and ASP

In the pre-phase, patients receive treatment according to routine clinical practice at Spanish sites, in accordance with the PETHEMA protocol for patients with high-risk ALL (ALL-AR-11), with: Prednisone (PDN) 60 mg/m2, PO or IV until complete characterisation of the ALL, for a maximum of 7 days, Triple intrathecal therapy, Methotrexate (MTX) 12 mg, ARA-C: 30 mg, Hydrocortisone 20 mg. Standard induction chemotherapy that these patients receive according to routine clinical practice at Spanish sites, in accordance with the PETHEMA protocol for patients with high-risk ALL (ALL-AR-11), consists of: Vincristine (VCR) 1.5 mg/m2 (maximum dose 2 mg) IV days 1, 8, 15 and 22,Daunorubicin (DNR) 45 mg/m2 IV days 1, 8, 15 and 22, prednisone 60 mg/m2 per day, IV or PO, days 1 to 14,30 mg/m2 per day, IV or PO, days 15 to 21, 15 mg/m2 per day, IV or PO, days 21 to 28,E. coli L-asparaginase (L-ASP) (Kidrolase®) 10,000 IU/m2, IV, days 16-20, 23-27,Intrathecal TIT chemotherapy day 1\* (if not administered in the pre-phase) and 22, Methotrexate (MTX) 12 mg, ARA-C: 30 mg, Hydrocortisone 20 mg, G-CSF (SC or IV) from day 15 until neutrophils \> 1000/µl. Following the administration of induction therapy, a bone marrow analysis will be performed with morphological, genetic and molecular study if necessary, with a centralised MRD determination by MFC. In the case of a complete morphological response and MRD \< 0.1% (\< 1×10-3), the patient will be enrolled in the trial and receive consolidation and maintenance treatment according to protocol. Consolidation - CYCLE 1 Early consolidation chemotherapy that the patients will receive in the first cycle (21 days) consists of: dexamethasone 20 mg/m2 per day, PO or IV days 1-5, 10 mg/m2 per day, PO or IV day 6, 5 mg/m2 per day, PO or IV day 7, 2.5 mg/m2 per day, PO or IV day 8, Vincristine 1.5 mg/m2 per day, IV (maximum 2 mg) days 1 and 8, Methotrexare 3g/m2, IV in 24 hours, E. coli L-asparaginase (L-ASP) (Kidrolase®): 20,000 IU/m2, IV, day 3,Triple intrathecal therapy day 1. Consolidation - CYCLE 2 Early consolidation chemotherapy that the patient will receive in the second cycle (21 days) consists of: * Dexamethasone: * 20 mg/m2 per day, PO or IV days 1-5. * 10 mg/m2 per day, PO or IV day 6. * 5 mg/m2 per day, PO or IV day 7. * 2.5 mg/m2 per day, PO or IV day 8. * ARA-C: \- 2 g/m2 every 12 hours, over 3 hours, days 1 and 2. Halve the ARA-C for patients over 50 years of age. * E. coli L-asparaginase (L-ASP) (Kidrolase®): 20,000 IU/m2, IV, day 3. Halve the dose for patients over 50 years of age as the toxicity of any type of ASP increases with age. * Triple intrathecal therapy day 4 (administered that day to keep the intrathecal therapy separate from the high-dose ARA-C). Consolidation - CYCLE 3 In the third early consolidation cycle, the investigational drug blinatumomab will be administered. * Blinatumomab 28 μg/day as a continuous infusion, IV over 4 weeks. * Triple intrathecal therapy day 1. Late consolidation Two weeks after completing the blinatumomab treatment, in the case of MRD \< 0.01% (\< 1×10-4), patients will receive 2 blocks of intensive chemotherapy (identical to those in early consolidation), separated by 3 weeks, followed by a treatment cycle with blinatumomab, the investigational medicinal product, for 4 weeks. After administering late consolidation therapy, a bone marrow study will be conducted. In the case of MRD \< 0.01% (\< 1×10-4), the patient will receive maintenance treatment. If this MRD level is not achieved, the patient will be withdrawn from the study and undergo a haematopoietic stem cell transplantation, according to routine clinical practice at Spanish sites. The maintenance therapy that patients will receive in this phase of the trial will consist of continuous chemotherapy administration (mercaptopurine and methotrexate) with reinductions for up to one year from CR