A Pilot Study To Test the Efficacy of a Combination of Gleevec with Thalidomide in Patients with Idiopathic Primary Myelofibrosis, Myelofibrosis with Myeloid Metaplasia and Myelodysplastic Syndromes Who Present with Myelofibrosis.

Purpose: Prompted by the finding that Gleevec can reduce marrow fibrosis in patients with CML who present with myelofibrosis, we sought to evaluate the safety and efficacy of a novel combination of thalidomide and imatinib mesylate (Gleevec®) for treatment of patients with myelofibrosis with myeloid metaplasia and myelodysplastic syndrome who presented with Grade 3/4 myelofibrosis. The rationale for this combination is that the anti-angiogenic and anti-TNF effects of thalidomide may be potentiated by the anti-TGF-b, anti-PDGF effects of Gleevec to reduce marrow fibrosis in this group of patients.

Methods: We enrolled and treated 19 patients with MDS, (RA: 9, RAEB: 9, CMMoL:1) with IPSS score (Low: 3, Int-1: 11, Int-2: 4, High: 1) fulfilling the inclusion criteria. 7 patients had a normal karyotype, 2 patients with del 5q alone, 3 patients with del 5 q with other abnormalities, 2 patients with complex karyotype, and 5 with others. In this study we treated patients with Thalidomide starting at a dose of 100 mg per day escalating to 400 mg per day and Gleevec at 600 mg per day. Treatment was continued for one year or until disease progression. Response to treatment was assessed at 16 weeks of treatment according to the International Working Group (IWG) criteria, and dose modifications were employed according to set criteria per protocol.

Results: Three of nineteen patients responded, with overall response rate of 15.8%. Two patients (10.5%) had complete response. One patient (RAEB-I, del 5q and trisomy 8) achieved CR at 16 weeks and continued to be in CR for 9 months with a follow up bone marrow biopsy showing no overt evidence of the previously diagnosed myelodysplastic syndrome by morphology or flow cytometry. The second patient (RAEB-II, normal karyotype) achieved CR at 1 year of treatment, however developed grade 3 peripheral neuropathy and subsequently, Thalidomide was held; this patient continues to be in CR todate while on Gleevec monotherapy. Finally, one patient (5.3%) had a partial response at 16 weeks for 5 months. Four patients died during treatment due to progressive disease; all other patients did not respond. Most patients tolerated that treatment well, three patients developed grade 3 neutropenia, one patient developed grade 3 pulmonary toxicity, and one patient developed grade 3 peripheral neuropathy, these adverse events were managed by dose reduction/interruption.

Conclusion: Thalidomide and Gleevec is a relatively well-tolerated regimen that can be considered for treatment of a small subset of patients with myelofibrosis and MDS. The finding that the combination led to reduction of bone marrow fibrosis in responding patients is intriguing and warrants further investigation.