A Phase I/II, National, Multicenter, Open Label Study of Bortezomib (Velcade) and Fludarabine, Cytarabine and Idarubicin (Flag-Ida) (V-Flag-Ida) in Pts with Relapsed and/or Refractory Acute Myeloblastic Leukemia (AML).

Abstract 4140

In vitro studies conducted by our group have shown that proteasome inhibition induced cytotoxicity both in cell lines as well as fresh cells obtained from AML patients and this effect is potentiated by the addition of cytarabine and idarubicin. Based on these data we design this dose escalation study with three sequential dose levels of cytarabine (Phase I) and expansion of the cohort at the MTD up to 40 patients. The objectives were to define the appropriate dose of cytarabine in combination with bortezomib plus fludarabine and idarubicin as well as to analyze the efficacy and safety profile of this combination. In addition we wanted also to explore the activity of a second course of bortezomib used as monotherapy to reduce minimum residual disease (MRD), measured using flow cytometry.

During the Phase I, the first 9 patients were distributed into 3 cohorts of 3 patients each, in order to test three dose levels of cytarabine (200 mg/m², 500 mg/m², 1000 mg/m² on days 1 to 4) in combination with the other drugs of the Flag scheme (fludarabine at dose of 30 mg/m² on days 1 to 4, and idarubicin, at dose of 10 mg/m² on days 1 to 3), plus bortezomib, at dose of 1.3 mg/ m² iv twice a week (days 5, 8, 12 and 15), followed by a rest period of 12 days (days 16 to 28). In absence of progression or unacceptable toxicity, a second cycle was started consisting of Bortezomib as monotherapy twice weekly (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21). Responding patients with acceptable toxicity were planned to repeat the same sequential scheme. DLT was defined as the occurrence of grade 3-4 nonhematological cytarabine-related toxicity probably enhanced by bortezomib. MTD was defined as the dose level below which 2 out of 3 patients had a DLT.

Between April 2008 and June 2009, 31 patients were included and 20 of them are evaluable. Median age was 56 years (26-75); three patients had prior myelodysplasia. Median of previous lines of therapy received was 2 (1-3). Seven patients had previously received a Flag-Ida–based salvage scheme. Eleven out of the twenty patients had relapsed AML, while the remaining nine patients were refractory to the last line of therapy.

No DLT was observed during the phase I of the trial and 1000 mg/m m² was defined as the appropriate dose of cytarabine to be used during the phase II. Three patients developed Gr3 mucositis, one in the cohort 2 and two at the cohort 3, and one additional patient presented Gr3 fluid retention and cardiac failure at the last cohort resolved with appropriate therapy. One patient died at day +14 of the first cycle due to sepsis and 19 out of the 20 patients were evaluable for efficacy. Five out of the 19 evaluable patients responded to cycle 1 (25%), including 3 CR (15%), one CRp (5%) and one PR (5%). Four out the five responding patients received a consolidation cycle with bortezomib as monotherapy; one of them converted the PR into CRp; in another patient in CR by morphology but with a positive MRD after cycle1, the consolidation cycle with bortezomib as monotherapy was able to induce a MRD negative status. In the remaining two patients MRD was already negative after cycle 1 and therefore the efficacy of bortezomib as monotherapy could not be measured. If we focus on the 14 patients who have received cytarabine at MTD the CR increases to 28%. None of the patients who had previously failed to Flag-Ida responded to the current combination. As far as toxicity is concerned, the most relevant Gr3-4 AEs after the first cycle were: mucositis in 10%, infection in 25%, cardiac failure in 5%, skin rash in 5% and PN in 10%. With the consolidation cycle, two out of 4 patients developed Gr3-4 PN and the two other patients had the same AE at cycle 3, but PN was Gr2; one of them received the fourth planned cycles and the other discontinued after the third cycle due to sepsis. Nevertheless, these two patients remain alive in CR.

In conclusion, the efficacy of the scheme proposed is modest (20% of CR/CRp). PN was the most important AE who limited the continuation with the treatment, suggesting that the combination of bortezomib plus cytarabine could enhance the neurotoxicity. Nevertheless, this study also shows that bortezomib single agent has an antileukemic activity since it was able to convert a PR into CRp and to eradicate the MRD in another patient.