Assessment of Two Doses of Infliximab in Patients with Low/Intermediate Risk IPSS Myelodysplastic Syndrome (MDS): An EORTC Leukemia Group (LG) Randomized Phase II Trial (06023).

Introduction: There is strong evidence that the cytopenia(s) in MDS might be caused by excessive, cytokine induced, intramedullary apoptotic death of progenitor hematopoietic cells. TNFα is a key cytokine that may trigger and sustain the excessive apoptosis processes in early disease. Infliximab is a chimeric human-murine monoclonal antibody with high affinity for human TNFα. Infliximab effectively prevents TNFα specific signaling in immune mediated inflammatory diseases. The therapeutic potential of suppressing TNFα mediated apoptosis in MDS was investigated.

Patients and methods: The EORTC LG conducted an open label 2-arm randomized, Simon 2-stage design, phase II study, with the primary objective of assessing the activity of two different dose levels of Infliximab, as single agent, in patients (pts) with low-/intermediate-risk MDS according to IPSS. Activity was assessed by response rate, using the International Working Group criteria: Complete Response (CR) + Partial Response (PR) + Hematological Improvement (HI). Toxicity was assessed as a secondary objective.

Results: Between February 2004 and March 2006, 37 eligible/evaluable pts (targeted sample size for the analysis of first stage) were randomly assigned to receive Infliximab, 3 mg/kg (18 pts) vs 5 mg/kg (19 pts), intravenously on days 1 and 15, thereafter every 4 weeks, for a total of 8 courses. Baseline characteristics by treatment arm (3 mg/kg vs 5 mg/kg) were: median age (65 vs 69 years); IPSS risk score: low (2 vs 6 pts), Intermediate-1 (14 vs 10 pts), Intermediate-2 (2 vs 3 pts); cytogenetic risk group: good (9 vs 12 pts), intermediate (5 vs 4 pts), unknown (4 vs 3 pts). Treatment applicability (3 mg/kg vs 5 mg/kg): 20 pts (10 vs 10) completed the 8 cycles of therapy, and 17 pts (8 vs 9) stopped earlier due to: progressive disease (2 vs 4), excessive toxicity (3 vs 0), patient’s refusal (2 vs 2), death due to an unrelated cause (1 vs 1), other reasons (0 vs 2). Activity (3 mg/kg vs 5 mg/kg): 3 pts responded to treatment in the 3 mg/kg arm: 1 CR, 1 PR and 1 HI (neutrophils), while no patient responded in the 5 mg/kg arm. A total of 21 pts (7 vs 14) had stable disease, 11 pts (7 vs 4) had documented disease progression and 2 pts were inevaluable for response (1 vs 1). After a median follow-up of 1.5 years, 8 pts (6 vs 2) died. Adverse events: 3 out of 18 patients died due to infections in the 3 mg/kg arm vs 0/19 in the 5 mg/kg arm. Two of the lethal infections were considered likely related to protocol treatment: one patient developed a fatal mucormycosis during treatment and one patient developed a fatal sepsis shortly after the eighth Infliximab infusion and thereafter also had documented progression to AML. There were few other AE/toxicities.

Conclusion: Infliximab in the 3 mg/kg dose/schedule showed some activity in this study. Infliximab has limited activity as single agent but may warrant further investigation in combination with other active agents. Patients must be monitored closely for occurrence of severe infections.