Long-Term Results of the Imatinib GRAAPH-2003 Study in Newly-Diagnosed Patients with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia..

The combination of imatinib with high-dose chemotherapy has been shown as very promising in patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by several groups. Reported studies all demonstrated a higher response rate and an improved outcome as compared to the pre-imatinib era, but generally with a short follow-up. This was also observed in our GRAAPH-2003 study with complete remission (CR) rate, 18-month disease-free survival (DFS), and 18-month overall survival (OS) of 96%, 51%, and 65%, respectively (de Labarthe et al. Blood 2007). We report here the long-term results of this study with a longer median follow-up of 46 months.

From 2004 to 2005, 45 patients with newly-diagnosed Ph+ ALL (median age, 45 years; range, 16-59 years; 25 males and 20 female) were included in the GRAAPH-2003 study. Briefly, imatinib was started with HAM consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders. Imatinib was administered until allogeneic (if a matched familial donor or an unrelated donor matched at 9 or 10 of 10 HLA antigens) or autologous (if no donor and a good molecular response) stem cell transplantation (SCT). Results were compared with the results of the previous pre-imatinib LALA-94 trial (Dombret et al. Blood 2002).

When compared to the former LALA-94 study, 4-year OS and DFS were estimated at 52% (36-66) versus 20% (14-26) (p=0.0001) and 43% (27-58) versus 20% (14-28) (p=0.002) in the GRAAPH versus LALA cohorts, respectively. In the GRAAPH-2003, all the 22 CR patients with a donor may receive allogeneic SCT in first CR. In addition, 10 CR patients without a donor but low post-HAM BCR-ABL level received autologous SCT. No significant differences were observed between the donor and the no-donor groups in terms of OS (55% versus 54% at 4 years; p=0.80) and DFS (47% versus 39% at 4 years; p=0.40). This result was partly explained by the good outcome observed in patients who received autologous SCT. The 4-year OS in the allogeneic SCT, autologous SCT, and no SCT groups were 55%, 80%, and 25%, respectively (auto versus allo, p=0.16; auto versus no SCT, p=0.008; allo versus no SCT, p=0.05). The 4-year DFS in the allogeneic SCT, autologous SCT, and no SCT groups were 47%, 50%, and 25%, respectively (auto versus allo, p=0.91; auto versus no SCT, p=0.27; allo versus no SCT, p=0.17). Overall, 4-year cumulative incidences of relapse and death in CR were estimated at 24% (14-40) and 32% (20-49), respectively, underlying the toxicity of the whole GRAAPH-2003 strategy. Notably, 7 of the 22 allografted patients died in CR, as compared to only 1 of the 10 autografted patients.

We show here that the beneficial impact of the combination of imatinib with chemotherapy is not transient and is preserved in the long term. Taking into account the good outcome of patients receiving autologous SCT and the toxicity of allogeneic SCT, the place and timing of SCT, as well as the optimal chemotherapy to be delivered with imatinib prior to SCT, must be carefully re-evaluated in further prospective trials.

Dombret:cejgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.