Bortezomib + Low Dose Cytarabine in Int-2 and High Risk MDS. Interim Results of a Phase I/II Trial by the GFM.

Background: We (

Methods: The GFM performed a phase I–II study of BOR in association with low dose AraC (LDAraC) in MDS patients (pts) with intermediate-2 or high IPSS (including RAEB-T). Pts received BOR 1.5 mg/m2 on d 1,4,8,11 and AraC 10mg/m2 d1-14, q 28 days for 4 cycles. In the absence of DLT AraC was increased to 20mg/m2 after cycle 1. Dose reductions were made to BOR (1.3 and 1.0 mg/m2) for NCI-CTCAE >Grade 2 non and >Grade 3 hematologic toxicity. Response was evaluated after 2 and 4 cycles (IWG 2006 criteria). Responding pts could receive up to 4 additional cycles.

Results: 44 pts were included between June 2006 and July 2007 (total 49 planned). 37 pts included >8 weeks before date of first interim analysis (1 Jul 2007), were evaluable. Median age 72 yrs (range 54–88) and M:F ratio 25:12. Diagnosis: 2 RA, 3 RAEB-1, 23 RAEB-2, 7 RAEB-T and 2 MDS with myelofibrosis. Prior treatment: 4 LDAraC, 2 intensive chemotherapy, 3 Azacytidine. IPSS: 18 int-2; 19 high. Karyotype was good, intermediate, poor and not done in 14, 4, 18 and 1 pt, respectively (resp). 25 pts had either poor karyotype or were pretreated. Plts were <100 G/L in 30 pts and ANC <1.5 G/L in 30 pts. Median number of cycles received 2.4 (range 1–8). Five responding pts received 2–4 additional cycles. There were 9 AraC dose escalations and 22 BOR reductions. Death with no evidence of progression (< 8 weeks) occurred in 2 pts (sepsis). Nine of the 37 pts (24%), had responses including 3 CR, 2 PR, 1 marrow CR (mCR) with HI and 3 HI. Of the remaining 26 pts 3 were stable after 4 cycles and 23 had progressed. Responses were seen after 3 or more cycles in 8 pts. 3 of 18 pts (17%) with poor karyotype achieved responses (1CR, 1mCR and 1HI) vs 2 of 4 pts with intermediate karyotype (2CR) and 4 of 14 pts (29%) with favourable karyotype (2PR and 2HI). All 9 responses were seen in the 28 previously untreated pts (32%) vs no responses in the 9 pretreated pts. Duration of CR was 9+, 8+ and 8+ mos, PR was 9+ and 6+ mos, mCR was 5+ mos, and HI was 10+,11+ and 12+ mos resp. 27 patients were alive. The 10 deaths were due to 8 progressions and 2 infectious complications. Hospitalization was required in 22 pts during treatment. Non fatal SAEs were mainly due to infections (14), bleeding (7) and skin eruptions (2). Neurotoxicity was seen in 4 pts (1 Gr 3 and 3 Gr 2).

Conclusion: In this high risk population BOR + LDAraC gave a 24% response rate (32% in previously untreated pts). Responses were seen including in pts with unfavourable karyotype who generally fail LDAraC alone. Neurotoxicity was only seen in 4 patients. However, there was significantly more myelosupression than with LDAraC alone. An update will be given.