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 750 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 alr and Chalandon 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 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%).
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 protocol Thomas 2010).r
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