Abstract

Background: Arsenic trioxide(As2O3) has proven clinical efficacy in relapsed acute promyelocytic leukemia, and is currently being studied in the upfront setting. At micromolar doses, As2O3 induces apoptosis and cellular differentiation, promotes histone acetylation, and inhibits tumor angiogenesis. In preclinical MDS studies, As2O3 inhibits proliferation of malignant hematopoietic cells, and increases rates of apoptosis in short term cultures. Notably, pre-treatment with GM-CSF increases sensitivity of cells to the effect of As2O3. Single agent clinical activity has also been demonstrated in MDS and multiple myeloma.

Methods: As2O3 was combined with GM-CSF in pts with MDS in a phase II trial. Eligible patients included those with Low/Int-1 and Int-2/High risk disease. Pts received treatment with As2O3 0.25 mg/Kg d1–d5 the first week, then twice a week for 9 weeks, then 2 weeks off. The cycle was repeated if a response was observed. GM-CSF was administered twice a week for the entire cycle. Pt characteristics are summarized in the table below.

Toxicity: Grade 3 and 4 study related AEs included peripheral neuropathic pain (1/7), febrile neutropenia (2/7), infection (4/7), abdominal pain (2/7), thrombocytopenia (2/7), hypoxia (1/7), chills associated with infusion (1/7), VT despite normal electrolytes (1/7), AV block (1/7). Results. 7 pts were enrolled (5M/2F), RA (1), RARS (3) and RAEB (3). A minor hematologic response was seen in one patient with RARS. One patient with RAEB2 showed a reduction of marrow blast count from 15% to < 5% after one cycle. 3 pts completed less than one cycle and response could not be assessed.

Conclusion: The data suggest that As2O3 with GM-CSF is active in MDS, however with significant side effects. The study of As2O3 with the newer approved agents such as 5-azacitidine or lenalidomide should be undertaken, but done sequentially in order to minimize any overlapping toxicities.

Patient Characteristics and Results

PatientAgeMDS SubtypeCytogeneticsIPSSNumber of CyclesResponseOverall Survival months)
Nl: normal, RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB1: refractory anemia with excess blasts 1; Int risk: intermediate risk; IPSS: international prognostic scoring system 
76 RARS Nl Int risk-1 Minor HI-E 28+ 
75 RAEB1 Nl Int risk-2 PR 10 
78 RA Nl Int risk-1 SD 
69 RAEB1 Nl Int risk-1 <1 NA NA 
58 RARS Nl Int risk-1 SD 25+ 
65 RARS 7 del, 20 del Int risk-2 SD NA 
62 RAEB1 Complex: 3q-, abn ch 12, 5q-, -7, 2 ring ch8, trisomy 22 Int risk-2 <1 NA NA 
PatientAgeMDS SubtypeCytogeneticsIPSSNumber of CyclesResponseOverall Survival months)
Nl: normal, RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB1: refractory anemia with excess blasts 1; Int risk: intermediate risk; IPSS: international prognostic scoring system 
76 RARS Nl Int risk-1 Minor HI-E 28+ 
75 RAEB1 Nl Int risk-2 PR 10 
78 RA Nl Int risk-1 SD 
69 RAEB1 Nl Int risk-1 <1 NA NA 
58 RARS Nl Int risk-1 SD 25+ 
65 RARS 7 del, 20 del Int risk-2 SD NA 
62 RAEB1 Complex: 3q-, abn ch 12, 5q-, -7, 2 ring ch8, trisomy 22 Int risk-2 <1 NA NA 

Disclosures: Phase II of arsenic trioxide in MDS.; Research support for the phase II study by Cell Therapeutics.; Honorarium for data presentation meeting 2002.

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