Tolerability and Anti-Leukemic Activity of Ara-C, Topotecan, and Gemtuzumab Ozogamicin [ATGO] in Advanced MDS and AML: Interim Analysis of Phase I/II Data.

Advanced myelodysplastic syndrome and secondary or relapsed AML are difficult to treat, with CR rates following standard induction chemotherapy below those for de novo AML. We are examining a novel induction approach using the anti-CD33-calicheamicin conjugate gemtuzumab ozogamicin (GO) in combination with conventional chemotherapy. Methods and Patient Population: We present data from an ongoing phase I/II study, demonstrating the activity and tolerability of the combination in patients with MDS and AML. 32 pts (19 pts from phase I, 13 from phase II) were assigned to receive cytarabine 2 g/m 2 over 4 hours once daily, and Topotecan 1.5 mg/m 2 by continuous infusion daily on days 1–5. GO was then given on day 6 at a dose of 3 mg/m 2 (7 pts), 4.5 mg/m 2 (16 pts), or 6 mg/m 2 (7 pts); 2 additional pts did not receive the GO because of intercurrent events. The MTD of GO was established at 4.5 mg/m 2 , which was used in phase II. The study population consisted of 13 pts with advanced MDS (IPSS 2–3), 13 pts with secondary AML, and 6 pts with relapsed AML. Median age was 64 (34–77). Results: ATGO was generally well tolerated. Bacterial infections, including 9 bacteremic episodes, were the most common non-hematologic complications. Two cases of reversible but unexplained grade 3 delirium were seen at 6 mg/m 2 GO, meeting study criteria for dose-limiting toxicity. Only one case (3%) of clinical venoocclusive disease (VOD/SOS) occurred, in the single subject who received a second (half) dose of GO on day 16. Asymptomatic grade 3 hepatic transaminase elevations occurred in 8 pts (25%). There were 4 deaths (12.5%) prior to day 40: 2 infectious, 1 CNS bleed, and 1 sudden death. Based on intent to treat, 17 pts (53%) achieved complete remission, with or without full platelet recovery (15 CR, 2 CRp) after one cycle of induction. Following ATGO induction, 12 of the 17 responders went on to receive post-remission therapy consisting of allogeneic hematopoietic cell transplantation (HCT) for 8 pts (7 using reduced intensity conditioning), or standard consolidation alone (3 pts). Post-remission therapies, including HCT, were not associated with VOD/SOS or peculiar toxicities. As expected, achievement of CR after ATGO was associated with improved overall survival (p=0.043). Estimated 2 year OS for all pts is 34% (49% for responders vs. 14% for non responders). There was a trend toward improved survival in younger pts. Cytogenetic class, type of disease (MDS v. AML), and administration of prior chemotherapy were not significant predictors of either CR or OS. 15 pts (47%) are alive, with a median follow-up of 242 days (37–1182); 7 are currently in CR, including 5 of the 8 pts who received allogeneic HCT. Conclusions: Our data show that ATGO is well tolerated and without associated VOD after a single delivered dose of GO. The pathophysiology of the reversible delirium in the highest GO dose cohort remains unclear, but no neurologic effects were observed at the lower dose levels. The CR rate is promising, as is the ability to deliver post-remission therapy including HCT, in this challenging patient population.