Arsenic trioxide, thalidomide and retinoid acid combination therapy in higher risk myelodysplastic syndrome patients

Abstract

Objective

To evaluate the clinical efficacy and safety of arsenic trioxide, retinoic acid and thalidomide combination therapy in higher risk MDS.

Methods

Twenty-one patients diagnosed with higher risk MDS were administered 10 mg/day arsenic trioxide intravenously for 10 days, 40 mg/day retinoic acid orally for 2 weeks and 100 mg/day thalidomide orally for 4 weeks per cycle.

Results

After at least two treatment cycles, 10 patients showed hematologic responses. One achieved CR, one achieved PR, three patients achieved major hematological improvements. The efficacy rate was 24% (5/21), and the response rate was 48% (10/21). The schedule was tolerated well by all patients and toxicities were moderate and reversible.

Conclusion

The combination of arsenic trioxide, retinoic acid and thalidomide could have therapeutic benefit in higher risk MDS with safety.

Introduction

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cell with great heterogeneity in clinical and hematologic findings. Its higher risk groups, meaning IPSS intermediate-2 and high, have median survival times of 1.2 years and 0.4 years respectively, and 5-year survival rates of 7% and 0%, respectively, according to International Prognostic Scoring System (IPSS) [1]. The choice of therapies remains challenging for these patients. Up to date, there are three major options including stem cell transplantation (SCT), AML-type chemotherapy and novel agents. SCT is restricted to only a small subset of patients with MDS because of age limitation, concomitant medical status and donor availability. Long-term follow-up studies showed 3-year survival rates of 23%, similar to patients who received intensive chemotherapy. Failure is due to transplantation-associated mortality and disease recurrence. Chemotherapy also has an increased risk of treatment-related mortality and morbidity, and usually is reserved for younger patients and good performance status. Furthermore, the CR duration is short. Recent years many novel and targeted therapies have been investigated in clinical trials as a result of increasing in our understanding of pathophysiologic pathways in MDS, including arsenic trioxide and thalidomide. Arsenic trioxide monotherapies conducted in Europe and the United States were generally tolerated well and incurred low incidence of severe nonhematologic toxicities. The preliminary results showed overall hematological response rates of 26% and 25%, indicating potential usefulness to treat patients with higher risk MDS. But thalidomide therapy alone was reported a response rate of 19% and suggested to be effective in improving cytopenia in patients with lower-risk disease [2]. Raza et al. conducted a trial of arsenic trioxide and thalidomide combination therapy in treating MDS and showed encouraging result of response in 7 of the 28 patients [3]. As a differentiating agent, retinoid acid was thought to be beneficial in occasional patients with a low success rate.

However, the populations of patients in most various studies were heterogeneous and not confined to the higher risk groups. We proposed that combining drugs targeting the MDS clone and the bone marrow microenvironment simultaneously might work better for these patients. This has prompted us to conduct a trial of arsenic trioxide, thalidomide and retinoid acid combination therapy in higher risk MDS groups, and to evaluate its response and toxicity in current study in order to find a way to improve the survival times and rates in these groups.