Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia.

BACKGROUND: Both gallium nitrate and pamidronate are highly effective for acute control of cancer-related hypercalcemia. However, the proportion of patients who actually achieve normocalcemia has varied in published reports. Therefore, we conducted an exploratory, randomized, double-blind trial that compared the efficacy and safety of gallium nitrate and pamidronate in hospitalized patients with cancer-related hypercalcemia. PATIENTS AND METHODS: Eligible patients with hypercalcemia, defined as albumin-adjusted serum calcium > or = 12.0 mg/dL after intravenous hydration, were stratified on the basis of tumor histology (i.e., epidermoid or nonepidermoid) and by study site. Patients were then randomly assigned to receive intravenous gallium nitrate 200 mg/m2 daily for 5 days or intravenous pamidronate 60 mg (increased during the study to 90 mg for patients with initial serum calcium > or = 13.5 mg/dL) followed by placebo infusions for 4 days. The primary endpoint of the study was comparison of the proportion of patients who achieved normocalcemia. RESULTS: Sixty-four patients were randomized, and all patients were evaluable for efficacy and safety. Normocalcemia was achieved in 22 of 32 (69%) patients treated with gallium nitrate compared with 18 of 32 patients (56%) treated with pamidronate. Patients randomized to pamidronate with initial serum calcium > or = 13.5 mg/dL did not respond better to 90 mg (3 of 6; 50%) than to 60 mg (7 of 13; 54%), or compared with the response to gallium nitrate in this subset (15 of 21; 71%). Response to pamidronate was also lower in patients with epidermoid cancers (33%, vs 68% for gallium nitrate). Duration of normocalcemia was examined using both an intent-to-treat analysis irrespective of response and an analysis that examined only responding patients. By intent-to-treat analysis, the median duration of normocalcemia was 1 day for the pamidronate group and 7 days for the gallium nitrate group. Estimated normocalcemic duration in responders was 10 days for the pamidronate group and 14 days for the gallium nitrate group. Both drugs were well tolerated, and clinically significant nephrotoxicity was not observed in either treatment group. DISCUSSION: Gallium nitrate appears to be at least as effective as pamidronate for acute control of cancer-related hypercalcemia. Results from this trial suggest that gallium nitrate may be particularly useful in patients with epidermoid cancers or severe hypercalcemia at baseline, and in patients who have previously exhibited a poor response to bisphosphonates.

Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo.

This study identified missense mutations in the ligand binding domain of the oncoprotein PML-RARalpha in 5 of 8 patients with acute promyelocytic leukemia (APL) with 2 or more relapses and 2 or more previous courses of all-trans retinoic acid (RA)-containing therapy. Four mutations were novel (Lys207Asn, Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had been previously identified (Arg272Gln; normal RARalpha1 codon assignment). Five patients were treated with repeat RA plus phenylbutyrate (PB), a histone deacetylase inhibitor, and one patient experienced a prolonged clinical remission. Of the 5 RA + PB-treated patients, 4 had PML-RARalpha mutations. The Gly289Arg mutation in the clinical responder produced the most defective PML-RARalpha function in the presence of RA with or without sodium butyrate (NaB) or trichostatin A. Relapse APL cells from this patient failed to differentiate in response to RA but partially differentiated in response to NaB alone, which was augmented by RA. In contrast, NaB alone had no differentiation effect on APL cells from another mutant case (Pro407Ser) but enhanced differentiation induced by RA. These results indicate that PML-RARalpha mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RARalpha was not correlated with clinical response to RA + PB treatment, and suggest that the response to RA + PB therapy in one patient was related to the ability of PB to circumvent the blocked RA-regulated gene response pathway.