Imatinib-based regimen allows stem cell transplant in majority of Philadelphia-positive ALL patients

SAN FRANCISCO -- An imatinib-based (Gleevec) regimen induced a similarly high rate of hematological complete response (CR) versus a more intensive imatinib-HyperCVAD regimen in younger adults with de novo Philadelphia-positive acute lymphoblastic leukemia (ALL). However, the rate of molecular response was somewhat lower with the imatinib-based regimen, according to preliminary results of the GRAAPH 2005 study.

"The tendency for better molecular response with Hyper-CVAD did not translate to improved overall survival or decreased relapse. Imatinib plus chemotherapy allowed stem cell transplant in the vast majority of patients [87%], and a trend was observed toward higher overall survival and event-free survival with an imatinib-based regimen," said Yves Chalandon, MD, of GRAALL Group in Lyon, France.

The study enrolled 118 patients with de novo Philadelphia-positive ALL between the ages of 18 and 60 years. Of these, 111 had sufficient follow-up to allow evaluation of induction and consolidation. Median age was 42 years and 60% were male. Patients underwent a seven-day pre-phase steroid regimen (prednisone 60 mg/m²/day), which allowed identification of the BCR/ABL transcript (abstract 12).

Patients in arm A (imatinib-based regimen) received imatinib 800 mg on days 1 to 28 combined with vincristine and dexamethasone. Those in arm B (more intensive regimen) were treated with imatinib 800 g days 1 to 14 of each course combined with HyperCVAD (adriamycin, cyclophosphamide, vincristine, and dexamethasone) for induction. High-dose methotrexate and high-dose cytarabine was used for salvage/consolidation in both arms. Four intrathecal infusions of methotrexate plus cytarabine plus methylprednisolone were included within induction/consolidation courses.

At the end of two courses of induction/consolidation, complete hematologic remission (CR) rate was 100% in arm A and 95% in arm B. One patient died during the first course and two died during the second course (one of these was in CR after induction).

Overall, median number of days to response was 37 (range, 28 to 136 days). Molecular disease was undetectable in 11% at the time of the first evaluation of minimal residual disease (MRD) on day 29 and in 18% at the time of the second MRD evaluation (two weeks after consolidation).

The differences between the two arms in achieving detectable MRD favored arm B at the end of salvage/consolidation chemotherapy (35% in arm A and 45% in arm B for the first MRD evaluation and 48% and 72%, respectively at the second MRD evaluation), but these differences did not translate into significantly improved overall survival.

After two phases of induction/consolidation, 52 patients who were considered candidates received intensification by allogeneic stem cell transplant (n = 41) or autologous stem cell transplant (n = 11) when a donor was not available. The other patients underwent repeated cycles of imatinib-HyperCVAD.

"Following induction, a tendency for more infections and other toxicities was observed in the HyperCVAD arm, but this was not the case after consolidation," Dr. Chalandon said.

Overall disease-free survival was 43% at two years: 54% and 32%, respectively, in arm A and arm B. No difference in relapse rate (around 30%) was seen between the two arms. Treatment-related mortality tended to be lower in arm A after induction/consolidation: 15% versus 33%, respectively. For those patients undergoing allogeneic stem cell transplant, treatment-related mortality was 13% in arm A versus 39% in arm B.

Overall survival at two years was 62%: 68% in arm A and 54% in arm B. This is a big improvement over the 29% two-year overall survival in the pre-imatinib era, said Dr. Chalandon.