Rasim Gucalp

Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma.

PURPOSEnTo determine better the activity of high-dose interleukin-2 (IL-2) either alone or in combination with interferon alfa-2b (IFN; Schering-Plough, Kenilworth, NJ) in patients with metastatic renal cell carcinoma, the IL-2 Working Group initiated a randomized phase II trial.nnnPATIENTS AND METHODSnPatients were randomly assigned to receive treatment with either IL-2 (Chiron Corp, Emeryville, CA) 1.33 mg/m2 (approximately 600,000 IU/kg) alone or IL-2 0.8 mg/m2 and IFN 3 x 10(6) U/m2 administered by bolus intravenous injection every 8 hours, days 1 to 5 and 15 to 19 (maximum, 28 doses). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and normal organ function. After 28 patients were entered onto each arm, the IL-2/IFN arm was closed because of a failure to meet predetermined efficacy criteria. An additional 43 patients (total, 71) were assigned to receive IL-2 alone.nnnRESULTSnToxicities were similar for both study arms. Hypotension requiring pressors was the most frequent dose-limiting toxicity. Only 11 of 99 patients experienced severe toxicity; there were no irreversible side effects or treatment-related deaths. Responses were seen in three of 28 patients (11%) on IL-2/IFN (three partial responses [PRs] lasting 14, 7, and 7 months) and 12 of 71 patients (17%) on IL-2 alone (four complete responses [CRs] and eight PRs). Six of the partial responders on IL-2 and two on IL-2/IFN experienced greater than 90% reduction in tumor mass. Ten of the 12 responders to IL-2 have ongoing responses of 12+ to 26+ months in duration.nnnCONCLUSIONnWe conclude that both IL-2 and IL-2/IFN therapy have activity in metastatic renal cell carcinoma. In particular, therapy with high-dose IL-2 alone produces meaningful and durable responses with manageable and reversible toxicity. This study supports the contention that high-dose IL-2 represents the treatment of choice in selected patients with advanced renal cell carcinoma.

Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia.

PURPOSEnThis multicenter, double-blind, randomized trial was performed to determine the efficacy and safety of pamidronate disodium (APD) in comparison to etidronate disodium (EHDP) in the treatment of cancer-related hypercalcemia.nnnPATIENTS AND METHODSnSixty-five male and female adult patients with cancer and corrected calcium levels of greater than or equal to 12.0 mg/dL after 24 hours of hydration were randomized to receive either 60 mg APD given as a single 24-hour infusion or 7.5 mg/kg EHDP given as a 2-hour infusion daily for 3 days.nnnRESULTSnAPD normalized corrected calcium levels in 70% (21 of 30) of patients, whereas EHDP did so in 41% (14 of 34) of patients (P = .026). The mean corrected serum calcium level decreased from 14.6 to 10.5 mg/dL in the APD-treated group and from 13.8 to 11.6 mg/dL in the EHDP-treated group within the first week of treatment. There was no difference in response to APD in patients without versus those with bone metastases (78% v 67%). Both drugs were well tolerated.nnnCONCLUSIONnThis study demonstrated that a single 60-mg infusion of APD is safe and more effective than EHDP given at the dose of 7.5 mg/kg for 3 days in the treatment of cancer-related hypercalcemia.

Denosumab for treatment of hypercalcemia of malignancy.

CONTEXTnHypercalcemia of malignancy (HCM) in patients with advanced cancer is often caused by excessive osteoclast-mediated bone resorption. Patients may not respond to or may relapse after iv bisphosphonate therapy.nnnOBJECTIVEnWe investigated whether denosumab, a potent inhibitor of osteoclast-mediated bone resorption, reduces serum calcium in patients with bisphosphonate-refractory HCM.nnnDESIGN, SETTING, AND PARTICIPANTSnIn this single-arm international study, participants had serum calcium levels corrected for albumin (CSC) >12.5 mg/dL (3.1 mmol/L) despite bisphosphonates given >7 and ≤30 days before screening.nnnINTERVENTIONnPatients received 120 mg sc denosumab on days 1, 8, 15, and 29 and then every 4 weeks.nnnMAIN OUTCOME MEASURESnThe primary endpoint was the proportion of patients with CSC ≤11.5 mg/dL (2.9 mmol/L) (response) by day 10. Secondary endpoints included response by visit, duration of response, and the proportion of patients with a complete response (CSC ≤10.8 mg/dL [2.7 mmol/L]) by day 10 and during the study.nnnRESULTSnPatients (N = 33) had solid tumors or hematologic malignancies. By day 10, 21 patients (64%) reached CSC ≤11.5 mg/dL, and 12 patients (33%) reached CSC ≤10.8 mg/dL. During the study, 23 patients (70%) reached CSC ≤11.5 mg/dL, and 21 patients (64%) reached CSC ≤10.8 mg/dL. Estimated median response duration was 104 days. The most common serious adverse events were hypercalcemia worsening (5 patients, 15%) and dyspnea (3 patients, 9%).nnnCONCLUSIONSnIn patients with HCM despite recent iv bisphosphonate treatment, denosumab lowered serum calcium in 64% of patients within 10 days, inducing durable responses. Denosumab may offer a new treatment option for HCM.

Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma

Interleukin (IL-4) is a pluripotent cytokine that stimulates proliferation of activated T-cells and has antineoplastic activity against human renal tumors in animal systems. In phase I trials, IL-4 could be tolerated at doses up to 20 micrograms/kg, with dose-limiting toxicities consisting of fever, fluid retention, nasal congestion, and mucositis. We report the results of two separate Phase II trials of IL-4 in 30 patients with metastatic malignant melanoma and 19 patients with advanced renal cancer. IL-4 was administered intravenously every 8 h for 14 doses in two 5-day courses separated by a 9-day interval. The first 27 patients were treated at a dose of 800 micrograms/m2, but after three of these patients developed cardiac toxicities, the dose was decreased to 600 micrograms/m2. One complete response occurred in a patient with metastatic melanoma (duration > or = 30 months). No responses were seen among the patients with renal cancer. The most frequent side effects were fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were also common. Hypotension was infrequent, but transient weight gain due to fluid retention was common. The major life-threatening toxicities were cardiac and gastrointestinal. Suspected cardiac ischemia was observed in two patients, pericarditis in one, and arrhythmias in two. Three patients had major upper gastrointestinal bleeding without evidence of local tumor. We conclude that IL-4, when given as a single agent on this schedule at maximum tolerated dose, does not possess meaningful activity in renal cancer or melanoma.

Denosumab for Patients With Persistent or Relapsed Hypercalcemia of Malignancy Despite Recent Bisphosphonate Treatment

Hypercalcemia of malignancy (HCM), caused primarily by tumor-induced bone resorption, may lead to renal failure, coma, and death. Although HCM can be treated with intravenous bisphosphonates, patients may not respond or may relapse on therapy. Denosumab binds the bone resorption mediator RANKL. In this single-arm, open-label, proof-of-concept study, HCM patients with albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL (Common Terminology Criteria for Adverse Events grade ≥3) despite recent intravenous bisphosphonate treatment received subcutaneous denosumab on days 1, 8, 15, and 29, and then every 4 weeks. The primary endpoint was the proportion of patients with CSC 11.5mg/dL or less (grade ≤1) within 10 days of denosumab initiation. In a prespecified interim analysis, 15 patients received denosumab (median CSC = 13.6mg/dL). Time to response and response duration were analyzed with Kaplan–Meier methods. All statistical tests were two-sided. By day 10, 12 patients (80%; 95% exact confidence interval [CI] = 52% to 96%) responded (CSC ≤11.5mg/dL); median response duration was 26 days. Ten patients (67%; 95% exact CI = 38% to 88%) had complete responses (CSC ≤10.8mg/dL) by day 10. Denosumab may offer a new treatment option for HCM. Clinicaltrials.gov identifier: NCT00896454.

Lymphoid lineage-associated features in acute myeloid leukaemia: phenotypic and genotypic correlations

Summary. This study is intended to establish biological correlation between the expression of lymphoid associated features in acute myeloid leukaemia (AML). In 62 AML patients, predominantly enrolled on Eastern Cooperative Oncology Group (ECOG) treatment protocols, in whom immunoglobulin (Ig) as well as T‐cell receptor beta chain (TCR‐beta) gene rearrangement analyses had been performed, morphology, cytochemistry, antigen profile and karyotype were reviewed retrospectively. Nuclear reactivity with anti‐TdT antibody was demonstrated in 34 patients (55%) and confirmed by ribonuclease protection assay in all patients tested. Five TdT‐protein negative patients were TdT‐transcript positive. Lymphoid antigens (lyA) were detected in 24 of 51 cases tested (47%) with B‐cell antigens (CD19. CD10) being restricted to TdT+ AML (P= 0.03). Only two patients had Ig heavy, none had Ig light chain or TCR‐beta gene rearrangements. Although both patients with rearranged Ig loci were TdT+, either by protein or RNA analysis, the low incidence of such rearrangement within the TdT* AML group (6%) argues against a significant association between the presence of TdT and crosslineage Ig gene rearrangements in AML. While FAB‐diagnoses did not differ between TdT+ and TdT or lyA+ and lyA− AML, particular immunophenotypic features correlated with TdT positively, e.g. the presence of early antigens, CD34 and HLA‐DR, and the absence of the more mature myelo‐monocytic antigens, CDw65 and CD14. Certain cytogenetic abnormalities were associated with TdT+ AML such as inv(16) (p13q22) or t(16:16) (p12;q22) (five patients; P= 0.03) and t(8;21) (q22;q22) (three patients). A greater number of TdT− than TdT* AML patients had only normal karyotypes (P= 0.06). Neither immunophenotypic nor karyotypic correlations could be established for lyA4 AML.

Nonlymphocytic leukemias and myelodysplastic syndromesTranslocation t(12;19)(q13;q13.3): A new recurrent abnormality in acute nonlymphocytic leukemia with atypical erythropoiesis☆

A new reciprocal, apparently balanced translocation between chromosomes 12 and 19, t(12;19)(q13;q13.3), was detected in 5% (3/59) of patients with FAB M1 or M2 acute nonlymphocytic leukemia. In either case, this translocation was part of complex but different cytogenetic abnormalities. None of the patients had a significant response to therapy. In one instance, however, the translocation was found at first relapse after 2 years of complete remission, and no information regarding the karyotype at disease onset was available. Hematologically common to these patients were marked marrow erythroid hyperplasia and severely abnormal erythropoiesis despite normal serum B12 and folate levels. A direct association between t(12;19) and these hematologic findings will have to be established as more cases with this chromosomal abnormality are identified.