Intensive Timed Sequential Chemotherapy Followed by a Single Pegfilgrastim (Neulasta) Administration in Patients with High-Risk Acute Myeloid Leukemia (AML): Preliminary Results of the EMA-2000/Neu Trial.

Following a dose-escalation study performed in order to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection (45mg/m²) combined with timed-sequential chemotherapy, a phase II trial (EMA-2000 regimen) was performed in high-risk AML. EMA-2000 regimen was effective (complete remission: 63%), but extra-hematologic toxicity appeared very high (53% of severe infections). In order to decrease toxicity, the same regimen was proposed between February 2004 and May 2006 followed by a single administration of Pegfilgrastim.

Twenty-four patients entered the study and received mitoxantrone 45 mg/m² on day 1 in combination with cytarabine (500 mg/m² on days 1 to 3 and 8 to 10) and etoposide (200 mg/m² on days 8 to 10) followed (after checking for the absence of blast in bone marrow aspirate performed at day 11) at day 12 by 6 mg of Pegfilgrastim administered by subcutaneous route. Overall, 15 patients (63%) achieved complete remission (CR) and 9 patients had resistant disease. Median time to achieve CR was 43 days. CR achievement was related to leukemia stage [50% (2/4 patients) in refractory AML and 65% (13/20 patients) in relapsed AML]. Median time to granulocyte recovery > 0.5 × 10⁹/l was 28 days. Median time to platelet recovery > 50 × 10⁹/l was 30 days. The predominant non-hematologic toxicity remained infections with 54% of septicemia and 62% of localized infections. Other severe extra-hematologic toxicity (WHO grade > 2) were mucositis (50%), nausea and vomiting (33%), and diarrhea (17%). Pegfilgrastim was well tolerated. Nine of the 15 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 3 patients, allogeneic stem cell transplantation (SCT) in 3 patients, and autologous SCT in 3 patients. Median DFS was 11.5 months with an estimated 2-year DFS rate of 37%. DFS was related to first CR duration (p = 0.01). Median OS was 12.5 months with a 2-year OS rate of 32%.

Response to therapy, toxicity and survival were compared to those of our previous EMA-2000 regimen. Patient populations were matched on age, leukemia stage, performance status, and FAB subtypes. Outcome was similar regarding CR rate and extra-hematologic toxicity. Neutrophil and platelet recovery was only 2 days and 4 days shorter with the new regimen. However median DFS and OS, and 2-year survival estimate appeared better with the new regimen (11.5 months with 37% 2-year DFS vs 7.2 months with 16%; and 12.5 months with 32% vs 8.1 months with 18% respectively). This was confirmed whatever was the result of induction therapy. In patients achieving CR, median OS was 18.4 months with 61% 1-year OS vs 9.3 months with 36%, while in patients with no CR, median OS was 9.7 months with 44% 1-year OS vs 3.7 months with 8%. These results suggest a potential differentiating or immune-regulating effect of Pelfilgrastim. None of the patients with initial hyperleukocytosis (> 10 × 10⁹/l), who failed to achieve CR, recovered on a hyperleukocytosic mode. Biological explorations and a randomized study are warranted for confirming our results.