Evidence and Efficacy
Philadelphia positive acute lymphoblastic leukaemia has historically responded poorly to induction chemotherapy regimens with lower CR rates than Philadelphia negative ALL and a median overall survival of 8 months.r The addition of imatinib to standard protocols has demonstrated efficacy in comparison to historical controls however dosing strategies vary. This review will summarise the data from recent trials and provide a recommendation for the optimal dosing strategy of imatinib in combination with hyper CVAD in patients deemed able to tolerate intensive induction chemotherapy.
More than 800 patients have been enrolled in multiple trials examining the use of imatinib in ALL. Studies by Yanada et al,r de Labarathe et al,r Thomas et al,r Bassan et al,r Wassman et al,r Chalandon et alr and Lim et alr have all demonstrated CR rates of 90 to 95%. These protocols used a variety of imatinib dosing schedules allied to various chemotherapy regimens during the induction, consolidation and maintenance phases.
Yanada et al reported on 80 patients receiving a 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 overall and disease-free survival 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 randomized 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 disease free survival rates were 63% vs 43% with or without SCT, respectively. Minimal residual disease monitoring was with quantitative 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 disease free survival compared to those who achieved at least this depth of response (60% vs. 25%).
Imatinib dose intensity was investigated by Lim et alr who used continuous imatinib at a dose of 600 mg commencing day 8 of induction then followed through five courses of consolidation or allogeneic haematopoietic cell transplant (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 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 Philadelphia negative 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).
Toxicity with Hyper CVAD and imatinib were similar to toxicities experienced with Hyper CVAD only. The following table is from the initial report on 20 patients.r
© Blood 2004
Notable toxicities reported in the final report on the extended cohort include the following.r
|Infections in induction
|Infections in consolidation