Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma.

BACKGROUND: The primary objective of this study was to determine whether addition of the selective P-glycoprotein (P-gp) inhibitor tariquidar (XR9576) to chemotherapy could induce an objective tumor response in patients who previously were resistant to the same agents. The secondary objectives were to evaluate P-gp expression by immunohistochemistry (IHC), to determine functional activity of the P-gp transporter before and after administration of tariquidar with serial technetium-99m ((99m)Tc)-sestamibi scans, and to correlate those parameters with clinical response. METHODS: Seventeen women with Stage III-IV breast carcinoma were included in the study who progressed (n = 13 women) or had stable disease (n = 4 women) on doxorubicin-containing or taxane-containing chemotherapy regimens. During the study, the same chemotherapy was continued without dose modifications, but tariquidar (150 mg intravenously) was added to the treatment regimen. RESULTS: Thirty-six percent of patients had P-gp-positive tumors by IHC, and 5 patients (29%) experienced increases > or = 10% in sestamibi uptake (median increase, 40%; range, 10-63%) after the administration of tariquidar. There was one partial response in a patient who had the greatest increase in sestamibi uptake and who also showed inducible P-gp expression. There was one patient who experienced severe doxorubicin/docetaxel-related toxicity after tariquidar was added to her chemotherapy regimen. CONCLUSIONS: Tariquidar showed limited clinical activity to restore sensitivity to anthracycline or taxane chemotherapy. Functional imaging of the tumor with (99m)Tc-sestamibi scans before and after administration of multidrug-resistance inhibitor may be useful to identify the small subset of patients who could benefit from multidrug-resistance modulation in future trials.

A phase II study of DT fusion protein denileukin diftitox in patients with fludarabine-refractory chronic lymphocytic leukemia.

PURPOSE: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. We tested the safety and efficacy in these patients of a diphtheria fusion protein DAB(389)IL2 (denileukin diftitox) directed against the interleukin 2 receptor that is expressed by CLL cells. EXPERIMENTAL DESIGN: DAB(389)IL2 was administered by 60 min i.v. infusions for 5 days every 21 days at 9 or 18 micro g/kg/day for up to eight cycles. RESULTS: Eighteen patients were treated. The mean age of the patients was 61.8 years. There were 14 males and 4 females. Two had Rai stage I, 6 had Rai stage II, and 10 had Rai stage IV. The mean number of prior treatments was 4.5 (range, 1-11). Responses were evaluated by peripheral CLL counts, computed tomography scans of all nodes and bone marrow biopsies. Twelve patients received greater than or equal to three cycles of DAB(389)IL2 and were evaluable for response. Eleven of 12 patients showed reductions of peripheral CLL cells, with 6 of 11 showing >/==" BORDER="0">95% reductions. Seven of 12 patients showed reductions of node diameters on exam and computed tomography scans, and 2 of 12 showed 60 and 80% shrinkage, respectively. Pre and postbone marrow biopsies showed a reduction in CLL marrow index in 11 patients. Seven of 11 patients had >50% reduction, including >/==" BORDER="0">98% reduction in 3 patients. DAB(389)IL2 produced 2 of 12 (17%) partial remission and 7 of 12 (58%) minimal responses. Progression-free intervals in the responders were 1, 1, 3+, 4, 9, 10, 10+, 14 and 19+ months. Toxicities were mild to moderate and included asymptomatic, transient transaminasemia, fever, asthenia, hypoalbuminemia, nausea, vomiting, myalgias, rash, anorexia, vascular leak syndrome, and elevated creatinine kinase. Antidiphtheria toxin antibody levels were variable and ranged from 0 to 9 micro g/ml (n = 5). CONCLUSIONS: DAB(389)IL2 produced a rapid decrease of leukemic cells in the bone marrow and peripheral blood of most chemotherapy refractory CLL patients. Most patients also tolerated DAB(389)IL2 well, without significant myelosuppression and/or immunosuppression. The prolonged progression-free interval and subjectively observed quality-of-life in responders is intriguing. The results suggest DAB(389)IL2 has biological activity in patients with B-cell CLL. Follow-up studies of combinations or altered schedules or doses to improve the response rate are warranted.

Cefepime versus ticarcillin and clavulanate potassium and aztreonam for febrile neutropenia therapy in high-dose chemotherapy patients.

An open labeled randomized trial comparing the efficacy and cost of empirically applied cefepime (C) as monotherapy versus combination therapy consisting of ticarcillin and clavulanate potassium and aztreonam (T/A) was performed in febrile neutropenic patients following high-dose chemotherapy (HDC) +/- radiation, with or without peripheral blood stem cell support. Over a 28-month period, 126 patients were screened and included in the study. Using afebrile status following 3 days of therapy as a primary endpoint, both regimens produced comparable clinical response rates (C = 55% vs. T/A = 61%). Also, the use of vancomycin for resistant gram-positive infections and alteration of gram-negative infection coverage was similar in both groups (C = 40% vs. T/A = 47% and C = 29% vs. T/A = 24%). Both treatment groups had similar needs for empirical antifungal therapy (C = 25% vs. T/A = 22%). There was a postrandomization difference between the two groups in that the "C" group had a significantly higher number of allogeneic transplants and non-stem-cell-supported patients, whereas the "T/A" group had a significantly greater number of autologous peripheral blood stem cell patients (p < 0.0001). Despite this difference, the C group had a significantly lower cost ratio than the T/A group (p = 0.016). In conclusion, we have shown that C treatment of febrile neutropenic patients following HDC results in similar efficacy and lower cost when compared to T/A, despite the inclusion of higher risk patients in the C group.

DAB389IL2 (ONTAK) fusion protein therapy of chronic lymphocytic leukaemia.

Despite multiple new therapeutic options for patients with chronic lymphocytic leukaemia (CLL), the prognosis of patients with relapsed disease is poor. After first-line therapy with fludarabine, alkylating agents, rituximab or combinations of these agents, most patients relapse within a few years. While second-line therapy with alemtuzumab, or other combinations of the above agents, have produced remissions, most of these are partial responses lasting months rather than years. Patients commonly die from progressive disease or infections related to the underlying disease or treatment. The authors sought to develop a novel therapeutic with the capacity to kill chemotherapy-resistant CLL cells and with reduced toxicities to normal tissues. Based on the presence of high affinity interleukin-2 receptor (IL-2R) on CLL cells, therapy of relapsed CLL patients with a diphtheria fusion protein targeting IL-2R - DAB(389)IL2 (ONTAK), Seragen, Inc., Hopkinton, MA, USA) - was tested in a pilot Phase II study. Biological activity and a partial remission were observed with modest drug-related side effects. Based on these encouraging findings, alternative schedules and combinations with agents that may enhance CLL cell expression of IL-2R are being tested. Hopefully, the use of these targeted therapeutic approaches will provide additional therapeutic options with fewer side effects for this common and incurable condition.

Sinus histiocytosis with massive lymphadenopathy and Langerhans cell histiocytosis express the cellular adhesion molecule CD31.

Context.-We investigated expression of the adhesion molecule CD31 in sinus histiocytosis with massive lymphadenopathy (SHML) and Langerhans cell histiocytosis (LCH) because (1) SHML and LCH cells express a variety of cellular adhesion molecules and (2) SHML has been characterized as a reactive histiocytic proliferation, and tissue macrophages (histiocytes) are known to express CD31. Objective.-The purpose of this study was to determine whether SHML and LCH cells express CD31 and whether dual staining with CD31 and S100 facilitates diagnosis of these disease states. Methods.-Formalin-fixed, paraffin-embedded archival tissues were immunohistochemically stained via the labeled streptavidin-biotin method using antibodies against CD31 and S100 protein after heat-induced epitope retrieval. Archival tissues included SHML (n = 2), LCH (n = 10), malignant melanoma (n = 5), sinus hyperplasia (n = 4), granulomas (n = 4), granular cell tumor (n = 6), and normal skin (n = 4). Results.-Normal Langerhans cells in the epidermis were CD31(-)/S100(+); neoplastic Langerhans cells in LCH were CD31(+)/S100(+). Histiocytes in granulomas and in sinus hyperplasia were CD31(+)/S100(-); abnormal histiocytes in SHML were CD31(+)/S100(+). S100(+) tumors (malignant melanoma and granular cell tumor) were CD31(-). Conclusions.-The spectrum of cell types that express CD31 is expanded to include SHML and LCH. We speculate that up-regulation of CD31 in neoplastic Langerhans cells contributes to the migratory capability of LCH cells. CD31 may be a useful nonlysosomal marker of macrophages and their neoplastic counterparts (true histiocytic sarcomas). An immunohistochemical staining panel that includes CD31 and S100 facilitates the diagnosis of SHML and LCH.

Solitary plasmacytoma in the setting of Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is an intriguing disorder characterized by the accumulation of specialized dendritic cells called Langerhans cells in several diverse tissues and body sites. It has been cited in numerous case reports to be associated with a wide variety of malignant neoplasms. Although many hypotheses have been suggested, the basis for such associations remains essentially unknown. We describe another association here that to our knowledge has not been reported thus far: a solitary plasmacytoma occurring at a site of previous involvement by LCH. This constitutes a new addition to the now fairly lengthy list of malignant neoplasms that have been reported to occur in the setting of LCH. The possible reasons for such an association are discussed along with a brief review of LCH.