Phase I Study of Gemcitabine, Fludarabine and Mitoxantrone for Relapsed or Refractory Leukemia.

Purpose: To estimate the maximum tolerated duration (MTD) of gemcitabine given as a continuous infusion in combination with fludarabine and mitoxantrone for patients with relapsed or refractory leukemia.Patients and Methods: Patients received gemcitabine at 10mg/m2/min (day 1) with fludarabine at 25mg/m2/day for 5 days (days 1–5) and mitoxantrone at 10mg/m2/day for 3 days (days 1–3). The duration of gemcitabine infusion was escalated using the modified continuous assessment method (mCRM) at 3 hour increments (3, 6, 9, 12, and 15 hours). This three-drug regimen was build upon our previous studies with fludarabine, mitoxantrone and continuous infusion gemcitabine (Blood2003;102:250b Abstract). The MTD was estimated as the duration of gemcitabine infusion in combination with fludarabine and mitoxantrone at which 33% of the patients would experience a dose limiting toxicity (DLT). DLT was defined as either neutropenia for more than 28 days with less than 5% blasts in the marrow, a non-hematologic grade 4 toxicity lasting ≥ 3 days, or a non-hematologic grade 3 toxicity lasting ≥ 7 days.Results: Ten patients with relapsed or refractory leukemia have been treated so far since Aug 2004 and fully evaluated. The median age was 55 years (range 30 – 67). The median number of prior regimens was 3 (range 1 – 5) and the median range of prior cycles was 4 (range 1 – 6). As expected, hematologic toxicity, mucositis and nausea were common but did not meet criteria for DLT in any patient. One patient had parainfluenza lung infection with alveolar hemorrhage and this was the only DLT on the study. 2/10 patients achieved CR. Both patients are alive, 20 weeks and 52 weeks later, respectively but have received further therapy in the form of chemotherapy or allogeneic stem cell transplantation.Toxicity by Duration of Gemcitabine Infusion Duration of Infusion (hrs) # of Patients with DLT/Total Probability of Toxicity at this Dose Probability that Dose is MTD 3 0/1 0.001 0.0 6 0/2 0.009 0.005 9 0/3 0.1 0.22 12 1/4 0.36 0.59 15 0/0 0.6 0.18Conclusion: Only one patient on this study had a DLT. This combination therapy is myelotoxic and has some anti-leukemia activity with 2/10 patients achieving CR. The duration of gemcitabine infusion as part of the above three drug regimen will be studied further on this ongoing study to more accurately estimate the MTD and determine if phase II trials are warranted.

Duke Scholars

Author Cristina Gasparetto Medicine, Hematologic Malignancies and Cellular Therapy