Efficacy
Yanada et al. reported on 80 patients receiving a Japan Adult Leukemia Study Group (JALSG) protocol using imatinib 600 mg from day 8 to day 63 in combination with chemotherapy as induction, with consolidation consisting of alternating imatinib and chemotherapy followed by vincristine, prednisone and imatinib 600 mg for up to 2 years.r The final analysis of the JALSG study included 99 patients with a CR of 97% and a 5-year OS and disease-free survival (DFS) of 50 and 43%, respectively.r Wassman et al. examined imatinib in doses from 400 to 600 mg using a variation of the GMALL protocol.r The French GRAAPH-2005 studyr achieved a CR rate of 98% in the arm randomised to imatinib/prednisone/doxorubicin compared to 91% in those receiving imatinib with a hyper CVAD Part A cycle. Induction deaths were lower with less intensive therapy, but 5-year OS and DFS rates were similar, indicating that tyrosine kinase inhibition may allow a reduction in the intensity of chemotherapy.
Thomas et al. at MD Anderson demonstrated a 75% OS at 2 years using imatinib at a dose of 400 mg on days 1 to 14 of each cycle of hyper CVAD followed by 600 mg for 13 months.r Only 20 patients were enrolled in the trial. A final report was published in 2015 describing an expanded cohort of 54 patients untreated or minimally treated (age 17-84, median 51 years) who received the protocol with the final modified version of imatinib 600 mg days 1 to 14 of induction cycle 1, then 600 mg continuously with courses 2 to 8, followed by escalation to imatinib 800 mg as tolerated during 24 months of maintenance therapy with monthly vincristine and prednisone interrupted by 2 intensifications with hyper CVAD and imatinib, then imatinib indefinitely.r Allogeneic stem cell transplant was performed in CR1 where feasible at the treating clinician’s discretion. 5-year DFS rates were 63% vs 43% with or without haematopoietic stem cell transplant (HSCT), respectively. Minimal residual disease (MRD) monitoring was with quantitative reverse transcription polymerase chain reaction (RT-PCR) on bone marrow samples. These were obtained after the first cycle, at 2-4 month intervals while on hyper CVAD, and at 4-6 month intervals, thereafter. Patients who had not achieved a major molecular response (MMR; defined as BCR-ABL < 0.1% in the marrow) had an inferior 5-year DFS compared to those who achieved at least this depth of response (60% vs. 25%).
Imatinib dose intensity was investigated by Lim et al.,r who used continuous imatinib at a dose of 600 mg commencing day 8 of induction then followed through five courses of consolidation or allogeneic HSCT (age 16-71, median 41 years). Although, the hyper CVAD chemotherapy backbone was not included. Patients who were not transplanted were maintained on imatinib for two years. Among the 82 patients in CR, the 5-year cumulative incidence of relapse and OS rates were 59% and 52%, respectively. The group analysed patients based on initial imatinib dose intensity (IDI), calculated by dividing the total administered dose of imatinib over the first eight weeks of induction by the intended dose of imatinib for the eight weeks. An IDI > 90% compared to < 90% was associated with a median 5-year relapse-free survival (RFS) and OS of 70 months versus 14 months and 39 months versus 17 months, respectively. This suggests maintaining imatinib dose intensity > 90% during the early phase of treatment was an important factor in longer remission-free period and improved survival.
Notable differences to the current eviQ Ph- ALL hyper CVAD protocol include omission of methotrexate in the POMP maintenance schedule and intensification with hyper CVAD and imatinib at months 6 and 13 in 2004 schedule (details not published) (or 6 and 13 in the R-hyper CVAD protocolr).