Background: Both CIMF and MDS/MPD are clonal hematopoietic disorders characterized by cytogenetic abnormalities and myelofibrosis with resultant organomegally. Arsenic Trioxide (ATO) has demonstrated efficacy in MDS in two multicenter trials, including patients with MDS/MPD. Ascorbic acid (AA) enhances the activity of ATO by depleting intracellular glutathione. Thalidomide (Thal), in combination with ATO or steroids, is efficacious in patients with MDS and in patients with CIMF.
Methods: We conducted a multicenter trial of Thal (50mg/d PO x 2 weeks, then 100mg/d), ATO (0.25mg/kg IV d1-5 of week 1, then twice weekly weeks 2–12), Dexamethasone (4mg/d PO x 5d every 4 weeks), and AA (1000mg PO 1–2 hours prior to each ATO infusion) over a 12-week cycle in patients with CIMF or MDS/MPD, from 1/05 to 7/07. Patients continued on Thal for an additional 3 months. Bone marrow was assessed at baseline and after week 12, as was spleen size. The primary endpoint was response as defined by the Modified International Working Group (IWG) treatment response criteria for MDS, and the IWG criteria for myelofibrosis with myeloid metaplasia (MMM).
Results: Twenty-eight patients have been enrolled; 27 were evaluable for response. The median age was 66.5 years; 23 patients (82%) had MDS/MPD: 8 with CMML and 15 with MDS/MPD-u, with cytogenetics of: normal (13), +22p (1), +8 (2), −Y (1), +9 (1), −12p (1), complex (2), unknown (2). Five patients (18%) had CIMF with cytogenetics of: normal (3), dup Chr6 (1), unknown (1); Of 14 patients tested, 5 had the JAK2V617F mutation: 1 with CIMF and 4 with MDS/MPD. No patient had the MPL515 mutation. Thirteen patients had splenomegally, and 15 received prior therapies, including erythropoietin agents (9), 5-azacytidine (2), hydroxyurea (1), anagrelide (2), investigational agents (1), and prednisone (2). Median baseline lactate dehydrogenase (LDH), leukocyte count, and platelet count were: 300U/L, 12.1k/L, and 126.5k/L, respectively. Reasons for starting therapy included anemia (8 (29%)), thrombocytopenia (9 (32%)), or disease-related symptoms (11 (39%)). Seven patients (25%) did not complete the entire 12 week course of therapy: 3 withdrew consent, 1 had a low platelet count, 2 due to an adverse event, and 1 due to no response. Responses occurred in 7 patients (26% of total, 35% of those completing 1 cycle of therapy): 6 (21%) by the IWG MMM criteria, 4 (14%) by the IWG MDS criteria, and 3 (11%) by both. Using the IWG MMM criteria, 1 patient with MDS/MPD had a partial remission and 5 had clinical improvement: 2 with MDS/MPD and 1 with CIMF had hemoglobin responses, and 2 had a spleen response. Using the modified IWG MDS criteria, 1 patient with CIMF and 2 with MDS/MPD had erythroid responses; 1 with MDS/MPD had a platelet response. No patient with a JAK2V617F mutation responded. Grade3/4 non-hematologic toxicities included edema (4), fatigue (4), pleural effusion (2), dyspnea (3), motor and sensory neuropathy (1), pericardial effusion (1), zoster (1), and hematoma (1). There were no thrombotic episodes.
Conclusion: The TADA regimen is well-tolerated and yields clinical responses in patients with MDS/MPD or CIMF, even in the absence of the JAK2V617F mutation.
Disclosure:Consultancy: Sekeres - Celgene, Pharmion. Research Funding: Sekeres - Celgene; Maciejewski - Genzyme; Raza - Celgene, Pharmion. Membership Information: Sekeres - Celgene, Pharmion; Maciejewski - Celgene, MGI Pharma, Amgen, Alexion; Raza - Celgene, Pharmion, Amgen, CTI. Off Label Use: Thalidomide for MDS/MPD. Arsenic trioxide for MDS/MPD.