Sequential administration of gemtuzubab ozogamicin (GO) and intensive chemotherapy for remission induction in previously untreated patients with AML over the age of 60: Interim results of the EORTC leukemia group AML-15A phase II trial (2001)

Gemtuzumab ozogamicin (CMA-676, Mylotargâ„¢), a conjugate of a humanized anti-CD33 monoclonal antibody linked to the cytotoxic antibiotic calicheamicin, has shown significant antileukemic activity in relapsed AML with a favorable side-effect profile. The EORTC-LG is performing a phase II study to determine the feasibility and activity of GO frontline therapy followed by intensive chemotherapy combining mitoxantrone, cytarabine and etoposide (MICE) as remission induction strategy for previously untreated elderly pts with standard risk (age 61-75 yrs and WHO PS grade 0/1) AML (FAB M3 excluded). GO was administered iv over 2 hrs at 9 mg/m2 for 2 doses on days 1 and 15. Within 7 days from response assessment to GO (between day 28 and 35 following last infusion, or sooner in case of leukemia progression), pts were starred on the MICE regimen (1 or 2 courses). Here we report the preliminary results from the 34 pts who are presently evaluable for response and toxicity. The median age was 68 yrs (range 61-73); 26 pts had primary AML and 8 secondary AML; CD33 positivity was documented in 30 pts (88%). Significant (grade 3/4 by NCI-CTC criteria) non-hematologic adverse events after GO included (33 pts evaluable): hypersensitivity syndrome (3%), hemorrhage (3%), DIC (6%). arrhythmia (6%). liver dysfunction and/or VOD (6%), febrile neutropenia (24%), infection (24%). A clinical response to GO was documented in 17 pts (50%); 9 (26.5%) achieved a complete remission (CR = <5% blasts in the marrow, â‰¥1,500 neutrophils/Î1⁄4L, and â‰¥100,000 platelets/Î1⁄4L), and 3 (8.8%) a complete remission with incomplete platelet recovery (CRp), for an overall response rate of 35.3% (95% CI 19.7%-53.5%); 5 additional pts (14.7%) entered a partial remission (PR = 5-10% marrow blasts). Response to GO was not restricted to CD33+ disease since 2/4 pts with CD33- AML also responded (1 CR, 1 CRp). There was 1 early death from ARDS, and 16 pts (47%) failed to respond to GO (2 died of leukaemia progression). Overall, 23 of the 31 surviving pts (74.2%) have received the planned MICE regimen (3 too early; 5 off study for refusal/violation)). Other than myelosuppression. grade 3/4 toxicities included hemorrhage (9%), DIC (9%), arrhythmia (9%), liver dysfunction (13%), febrile neutropenia (14%), infection (36%); 4 pts (17.4%) died during hypoplasia from infection (2), VOD (1) and multi-organ failure (1), respectively. Evaluation of treatment outcome at the end of the whole induction program showed the following results; 13 pts (38.2%) were in CR and 3 in CRp (8.8%) for an overall response rate of 47% (95% Cl 29.8%-64.9%); 1 pt (2.9%) maintained a PR induced by GO; 12 (35.3%) were resistant disease failures and 5 (14.7%) died of toxicity. 14 pts are currently alive in remission with a median follow-up from CR/ CRp of 64 days (range 0-146). So far relapse has occurred in 2 CR pts (both failed GO) respectively after 39 and 106 days. Out of the 34 pts, 11 have died. With a median follow-up of 4 months, the estimates of survival rate at 4 and 6 months are 65% (SE= 10%) and 57% (SE=11.6%), respectively. The interim results from this study suggest that the sequential combination of GO and intensive chemotherapy is a feasible and active treatment strategy for elderly pts with AML. Patient accrual is continuing.