Elizabeth Trehu

Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma

PURPOSE To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent and mantle-cell lymphoma (MCL). PATIENTS AND METHODS Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/microL (500/microL if documented bone marrow involvement); and platelet count more than 50,000/microL. RESULTS Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkins lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7). CONCLUSION These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.

Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

PURPOSE Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkins lymphoma. PATIENTS AND METHODS Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstroms macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.

Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity

PURPOSE To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. PATIENTS AND METHODS Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. RESULTS Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkins disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenströms macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07). CONCLUSION Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.

Phase I and Pharmacokinetic Study of Bortezomib in Combination with Idarubicin and Cytarabine in Patients with Acute Myelogenous Leukemia

Purpose: Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML). Experimental Design: Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m2 with idarubicin 12 mg/m2 on days 1 to 3 and cytarabine 100 mg/m2/day on days 1 to 7. Results: A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and ≥60 years, n = 5). There were 22 patients of ≥60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m2, were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean ± SD, 41.9 ± 17.1 L/h/m2) and third (18.4 ± 7.0 L/h/m2) doses. Increased bone marrow expression of CD74 was associated with CR. Conclusions: The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m2.

Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma

PURPOSE A randomized, double-blind, placebo-controlled trial was performed to compare the toxicity and biologic effects of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus the recombinant human soluble p75 tumor necrosis factor (TNF) receptor immunoglobulin G (IgG) chimera (rhuTNFR:Fc) with high-dose IL-2 alone in patients with advanced melanoma and renal cell carcinoma. PATIENTS AND METHODS Twenty patients with advanced melanoma or renal cell carcinoma were randomized to receive IL-2 (Chiron, Emeryville, CA) 600,000 IU/kg every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) combined with placebo or the rhuTNFR:Fc fusion protein (Immunex, Seattle, WA) 10 mg/m2 on days 1 and 15 and 5 mg/m2 on days 3, 5, 17, and 19. The impact of rhuTNFR:Fc on IL-2 toxicity and biologic effects was evaluated. RESULTS No clinically significant difference in toxicity was observed in the two treatment arms. The adjusted median number of IL-2 doses administered during cycle 1 was 24.5 (range, seven to 28) and 21.5 (range, five to 27) for the placebo and rhuTNFR:Fc arms, respectively (P = .544). IL-2-induced TNF bioactivity, neutrophil chemotactic defect, and serum IL-6, IL-8, and IL-1 receptor antagonist (IL-1RA) induction were suppressed by rhuTNFR:Fc. Two of nine assessable patients (22%) on IL-2/placebo and three of 10 patients (30%) on IL-2/rhuTNFR:Fc responded. CONCLUSION Despite evidence of in vitro neutralization of TNF functional activity and partial inhibition of other secondary biologic effects of IL-2, rhuTNFR:Fc does not reduce the clinical toxicity associated with high-dose IL-2 therapy. These results suggest that the toxicity and antitumor effects of IL-2 treatment are independent of circulating TNF.

Induction of circulating soluble tumour necrosis factor receptor and interleukin 1 receptor antagonist following interleukin 1α infusion in humans

The aim of this study was to investigate circulating levels of tumour necrosis factor soluble receptor p55 (TNFsrp55) and interleukin 1 receptor antagonist (IL-1ra) in cancer patients undergoing treatment with IL-1 alpha. Patients were treated with 0.03 micrograms/kg IL-1 alpha administered intravenously over a 30 min interval daily for five consecutive days. Plasma TNFsrp55 levels rose dramatically and peaked (24.5 +/- 3.6 ng/ml) within 1 h after the first IL-1 alpha infusion. Thereafter, the levels rapidly declined and reached baseline levels within 24 h. The increases observed on days 3 and 5 of treatment were less pronounced but the reductions in peak levels were not statistically significant. IL-1ra levels increased less abruptly after an IL-1 alpha infusion than did TNFsrp55 levels and peaked (25.3 +/- 5.1 ng/ml) within 2 h of the start of the IL-1 alpha infusion. Levels then rapidly declined reaching baseline values within 24 h. As with TNFsrp55 levels, peak IL-1ra levels observed on days 3 and 5 of treatment were less than those measured on day 1. IL-1 alpha and IL-1 beta levels were consistently below the threshold of detection of the RIAs employed in these studies. Likewise, with the exception of a single time point in one of the four patients studied, TNF-alpha was undetectable in all plasma samples assayed.(ABSTRACT TRUNCATED AT 250 WORDS)

A method for the detection of erythrocyte-bound interleukin-8 in humans during interleukin-1 immunotherapy

Interleukin-8 (IL-8) has been recently shown to bind to human erythrocytes with high affinity and is therefore potentially difficult to detect in serum or plasma. IL-8 is transiently elevated in the serum of baboons after the administration of interleukin-1 alpha (IL-1 alpha). The objective of this study was to investigate whether IL-8 can be detected in the plasma or in detergent-lysed erythrocytes from cancer patients undergoing treatment with IL-1 alpha. Using a specific radioimmunoassay (RIA), plasma IL-8 was detected within 1-2 h after the first IL-1 alpha infusion. Thereafter, the levels declined rapidly and after 4-8 h were undetectable. Erythrocyte-bound IL-8 was detectable 1-2 h after the increase in plasma levels. The erythrocyte-bound IL-8 levels were higher than those measured in plasma and remained elevated long after the plasma levels had become undetectable. Erythrocyte membranes accounted for all of the erythrocyte-associated IL-8, as IL-8 was undetectable in the cytosol after erythrocyte lysis. The assay used in these studies detects IL-8 in erythrocyte lysates when it cannot be measured in plasma and may therefore be useful in monitoring IL-8 production in vivo.

Possible myocardial toxicity associated with interleukin-4 therapy

Interleukin (IL)-4 is a cytokine produced by T lymphocytes, which may play a role in allergic inflammatory processes through its stimulatory effects on immunoglobulin E production and mast cells. In this report, we describe a patient with metastatic melanoma involving the heart who had biopsy-proven myocarditis after treatment with high-dose IL-4. Because of the uncharacteristic predominance of polymorphonuclear and mast cells in the inflammatory infiltrate of this patients myocardium, we postulate a unique mechanism of IL-4-associated myocarditis. Three other patients treated with IL-4 had less well-defined cardiac abnormalities, suggesting that patients receiving IL-4 may be at risk for cardiac toxicity. Additional studies will be necessary to confirm such an association.

Suppression of IL-2-induced SAA gene expression in mice by the administration of an IL-1 receptor antagonist

The hepatic acute phase response induced by the administration of interleukin (IL)-2 is most likely mediated by secondary cytokines. In this investigation, we examined the role of endogenous IL-1 in the synthesis of the hepatic acute phase protein serum amyloid A (SAA) during IL-2 treatment. The injection of IL-2 induced SAA gene expression in the liver. The concurrent administration of an IL-1 receptor antagonist (IL-1RA) markedly reduced hepatic SAA mRNA levels and, to a lesser extent, SAA protein levels in the serum. Although IL-1 is an inducer of IL-6 production, the administration of the IL-1RA had no effect on circulating IL-6 levels in IL-2-treated mice. These findings suggest that the production of IL-1 is an important factor in the induction of SAA mRNA in mice undergoing immunotherapy with IL-2.

Update on a phase (ph) 2 study of bortezomib in patients (pts) with relapsed or refractory indolent or aggressive non-Hodgkin's lymphomas (NHL).

6581 Background: Proteasome inhibition disrupts many cell cycle checkpoints and pathways that lead to apoptosis. Preclinical and ph 1 studies suggested the proteasome inhibitor bortezomib (VELCADE™, Vc) was active in lymphoma. METHODS The primary objective of this ph 2 study was to document the response rate (RR) and toxicity of Vc in pts with relapsed or refractory NHL. Pts ≥ 16 yr, with relapsed or refractory mantle cell (MCL, gp A) or other B cell lymphomas (gp B) were eligible. Pts received Vc 1.5 mg/m2 IV on d1, 4, 8 and 11 q21d, were restaged q2 cycles, and treated for up to 6 cycles unless removed from study. RESULTS 45 pts: 32 males, 13 females, median age 60 yr (range 45-81), were enrolled. There were 25 pts in gp A and 20 pts in gp B, including 10 diffuse large cell lymphoma (DLCL), 4 follicular lymphoma (FL), 3 transformed (t) FL, 2 small lymphocytic lymphoma (SLL), 1 Waldenströms macroglobulinemia (WM). Gp A had 3 median prior therapies (range 1-6); gp B had 4 (range 1-12). In gp A, of 21 evaluable (ev) pts, there were 11 responders: 3 CR, 1 CRu (unconfirmed CR), and 7 PR (RR = 52.3%), 2 MR, 2 no change (NC), 6 POD (progression of disease). Mean DOR (duration of response) was 5.7 mo (1.2-15 mo). In gp B, there were 8 ev DLCL with 1 PR (DOR 4 mo), 1 NC, 6 POD; 4 ev FL with 2 MR, 1 NC, 1 POD; 1 ev tFL with POD; 2 ev SLL with 1 NC, 1 POD; 1 WM pt had PR. Grade 3/4 toxicities were GI (5 pts), hypotension/fatigue (6 pts), neuropathy (1 pt with prior vinca/taxanes), and pneumonia (2 pts); hematologic toxicities were neutropenia (8) (only 1 pt with ANC <500) and thrombocytopenia (14 pt) (only 1 pt with platelets <10; most entered with platelets <30-50). 2 patients died: 1 had Cryptococcus meningitis, 1 had generalized zoster with encephalitis. CONCLUSIONS This study showed remarkable activity of Vc in MCL and encouraging results in other B cell lymphomas. Future studies will include combinations of Vc with other chemotherapy and/or biological agents. [Table: see text].