Southwest Oncology Group Study S0530: A Phase 2 Trial of Clofarabine/ Cytarabine for Relapsed/ Refractory Acute Lymphocytic Leukemia.

Patients were treated at SWOG institutions from February 2007 through July 2008. Clo was supplied by Genzyme. This protocol was reviewed and approved through each institution's review board. Eligibility criteria included: age ≥ 16 years, relapsed or refractory ALL (excluding Burkitts or mixed lineage leukemia), Zubrod performance status 0-2. CTGF expression was analyzed by triplicate RT-PCR on pre-treatment samples. Expression of the nucleoside transporters (hENT1, hCNT3, dCK) was analyzed by immunohistochemistry. All patients received treatment with Clo 40 mg/m²/d and Cy 1 g/m²/d on Days 1-5. Response was assessed between Days 28-35. Patients with a partial remission (a 50% decrease in marrow blast percentage) could receive re-induction therapy. CR was defined as < 5% marrow blasts, neutrophils > 1,000/μL, platelets ≥ 100,000/μL, and no evidence of extramedullary disease. CRi was defined the same as CR but the platelet count could be < 100,000/μL. Patients with a CR could receive one cycle of consolidation therapy. Patients were to be accrued in 2 stages. In the first stage, 20 patients were to be registered. If at least 2 CR/ CRis were observed, an additional 15 patients were to be accrued (87% power to conclude that an agent with a response rate of 30% warrants further study).

The study met criteria to proceed to the second stage. Thirty-seven patients were enrolled. One patient is excluded from the analysis because treatment was not started due to high liver function tests after registration. Of the 36 evaluable patients, the median age was 41 years (range: 20-68), median WBC 5200/μL (range 900-93,700), and 23 patients (64%) were male. The median time from initial diagnosis to registration was 14 months (range 1-52 months). Nineteen patients (53%) were in first relapse, 7 (19%) in subsequent relapse, 1 (3%) with an unknown number of relapses, and 9 (25%) refractory. Two patients had received prior allogeneic BMT. Thirty-two patients have died, with 10 deaths occurring during protocol treatment and 7 of these deaths attributable to treatment [infection (3), pleural effusion (1) DIC (1), hypotension/ renal failure/ cardiac arrhythmia (1), multiorgan failure (1)]. Three patients received re-induction, and 1 patient received consolidation therapy. The CR/CRi rate was 17% (95% CI 6-33%), and median overall survival 3 months. At least 8 patients proceeded to BMT after completing protocol therapy. The number of patients accrued to this study was relatively small and the CR rate was low. Therefore, it is unlikely that any statistical differences in CR rate would be found, with respect to expression of various biologic correlates. However, there was a trend for patients with higher expression of CTGF having an inferior OS (p=0.13). In addition, although 70% of patients had high levels of hENT1 expression, only 33% and 44% of patients respectively had high levels of hCNT3 and dCK, which could serve as a mechanism of resistance to nucleoside analog therapy.

The CR/CRi rate in this study was modest. This regimen does not exhibit sufficient activity to warrant further testing unless it was significantly altered. However, this was a heavily pre-treated, poor risk population of patients. Of interest, low expression of nucleoside transporters and high expression of CTGF may predict response and OS. Larger prospective studies will be needed to confirm this. Therapies directly targeting these latter pathways or working independently of these pathways may help improve the prognosis of patients if these results are confirmed.

Advani:Genzyme: Honoraria, Research Funding. Off Label Use: The combination of clofarabine/ cytarabine is investigational. Radich:Novartis: Research Funding. Lancet:Genzyme: Consultancy. Stuart:Genzyme: Research Funding.