Results of a Phase II Study of 506U78 (Nelarabine) in Refractory Indolent B-Cell or Peripheral T-Cell Lymphoma.

BACKGROUND: Compound 506U78 (Nelarabine), a water soluble pro-drug of 9-β-d-arabinofuranosyl-guanine, is demethoxylated by adenosine deaminase to ara-G in lymphoblasts. Intracellular ara-G is then phosphorylated via deoxycytidine kinase and mitochondrial deoxyguanosine kinase to its active 5′-triphosphate, ara-GTP. Ara-GTP, a potent inhibitor of DNA polymerase, also incorporates into DNA resulting in cell death. Studies in children and adult T-cell leukemia and non-Hodgkin’s lymphoma (NHL) have shown activity, but with reversible neurotoxicity as the most prominent adverse event.

METHODS: We report here the results of a phase II study with 506U78 in adults (median age 64, range 33–81) with relapsed or refractory indolent B-cell or peripheral T-cell NHL. Patients had received a median of 2 prior courses of chemotherapy. 506U78 was given at 1.5 g/m²/day IV on days 1, 3, and 5 every 28 days to a maximum of 6 cycles unless toxicity or progressive disease. If after 4 cycles a complete response (CR) or partial response (PR) was not achieved, then treatment was discontinued.

RESULTS: There were 23 patients enrolled including 13 with T-cell and 10 with indolent B-cell NHL. Among 19 assessable for response, the overall response rate (ORR) in T-cell NHL was 4/9 (44%) with 2 CR and 2 PR, while in indolent B-cell NHL the PR was 3/9 (33%) with no CR. In responders, the median time to progression (TTP) was 8 months (range 2–22 months). Sixteen of 22 (73%) patients evaluable for toxicity had grade 3 or 4 adverse events. Neurotoxicity included one grade 3 and one grade 4 event.

CONCLUSION: Compound 506U78 is active as a single agent in T-cell and B-cell NHL. Our response rate was higher than the ORR of 10.5% reported previously in the Czuczman et al. (2004) Blood 104(11) abstract in adults with T-cell NHL and there was less neurotoxicity in our study. This may be related to different dosing regimens (every 28 days vs. every 21 days). Compound 506U78 should be further evaluated in clinical trials.