TP Miller

The B-cell neoplasms, multiple myeloma and non-Hodgkin's lymphoma, frequently become drug resistant, despite initial responses to chemotherapeutic drugs. Tumor cells from eight patients with clinically drug-refractory disease were evaluated by immuno-histochemical staining for monoclonal immunoglobulin (Ig) expression, nuclear proliferation antigen, P-glycoprotein (P-gly) expression, and other cellular antigens. P-gly was detected on tumor cells from six of eight patients with drug-resistant disease. Of the six patients with P-gly-positive tumors, five patients had advanced multiple myeloma and one had a drug-refractory non-Hodgkin's lymphoma. Cellular RNA analysis confirmed the over-expression of P-gly. In an effort to overcome drug resistance, a pilot study evaluated possible verapamil enhancement of chemotherapy in these eight patients. All patients had developed progressive disease while receiving a regimen containing vincristine and doxorubicin, and seven of eight patients had previously received continuous infusion vincristine and doxorubicin plus oral dexamethasone (VAD). At the time of progressive disease, continuous infusion verapamil was added to the VAD regimen. Three of the eight patients who were refractory to vincristine and doxorubicin alone responded when verapamil was added to VAD. The three patients who responded had P-gly-positive tumors. Verapamil increased the intracellular accumulation of doxorubicin and vincristine in vitro for both a P-gly-positive myeloma cell line and tumor cells from two patients with end-stage myeloma which over-expressed P-gly. The dose-limiting side effect associated with the addition of verapamil to chemotherapy was temporary impairment of cardiac function, manifest as hypotension and cardiac arrhythmia. We conclude that P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance. However, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy. The administration of verapamil along with VAD chemotherapy may partially circumvent drug resistance in patients whose tumors over-express P-gly.

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.

To study the influence of chronologic age on treatment outcome in patients with advanced, diffuse large-cell (histiocytic) lymphoma (DHL), we reviewed the results of two recent Southwest Oncology Group (SWOG) clinical trials. From 1974 to 1982, members entered 307 eligible patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without bleomycin, and CHOP with or without immunotherapy using BCG, levamisole, or both. Complete response (CR) rates declined progressively with advancing age: 65% in those under 40, 60% in the 40 to 54 age group, 55% in the 55 to 64 age group, and 37% in those 65 and older (P = .001). Likewise, survival decreased significantly in older patients: medians were 101 +, 52, 34, and 16 months, respectively (P less than .001). Treatment guidelines included an initial dose reduction of 50% for patients aged 65 or older and for younger patients with bone marrow compromise. Despite protocol specifications, 23 of 81 patients aged 65 or older received initial full-dose therapy. When these patients were compared with younger patients on whom full-dose chemotherapy was started, survival curves, but not CR rates, were still significantly different. There were no significant differences in duration of CR or frequency of treatment complications. These data suggest that older age is associated with a worse prognosis in advanced DHL. Moreover, the initial dose reduction for patients aged 65 or older may have contributed to their inferior outcomes.

The objectives of this study were (1) to determine the clinical presentation and natural history associated with two newly recognized pathologic entities termed mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), including the mucosa-associated lymphoid tissue (MALT) and monocytoid B-cell subcategories, and (2) to determine whether these entities differ clinically from the other relatively indolent non-Hodgkin's lymphomas with which they have been previously classified. We reviewed the conventional pathology and clinical course of 376 patients who had no prior therapy; had stage III/IV disease; were classified as Working Formulation categories A, B, C, D, or E; and received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) on Southwest Oncology Group (SWOG) studies no. 7204, 7426, or 7713. All slides were reviewed by the three pathologists who reached a consensus diagnosis. Age, sex, performance status, bone marrow and/or gastrointestinal involvement, failure-free survival, and overall survival were compared among all the categories. We found that (1) MCL and MZL each represent approximately 10% of stage III or IV patients previously classified as Working Formulation categories A through E and treated with CHOP on SWOG clinical trials; (2) the failure-free survival and overall survival of patients with MZL is the same as that of patients with Working Formulation categories A through E, but the failure-free survival and overall survival of the monocytoid B-cell patients were higher than that of the MALT lymphoma patients (P = .009 and .007, respectively); and (3) the failure-free survival and overall survival of patients with MCL is significantly worse than that of patients with Working Formulation categories A through E (P = .0002 and .0001, respectively). In conclusion, patients with advanced stage MALT lymphomas may have a more aggressive course than previously recognized. Patients with MCL do not have an indolent lymphoma and are candidates for innovative therapy.

The growth fraction of tumors from patients with non-Hodgkin's lymphomas (NHL) has been shown to correlate with survival in retrospective studies. The growth fraction can be evaluated using immunohistochemical techniques employing the Ki-67 monoclonal antibody (MoAb) that marks a nuclear protein present in cycling cells. The purpose of this study was to evaluate the clinical utility of the Ki-67 MoAb for predicting survival. Using a prospective trial design in a multi-institutional cooperative trials group, the proliferative index, clinical outcome, and statistical correlations were independently assessed for previously untreated patients with advanced stages of intermediate- and high-grade histologies of NHL treated on Southwest Oncology Group study (SWOG 8516, Intergroup 0067). The proportion of Ki-67-positive cells was determined on snap-frozen thin tissue sections. A proliferative index of 80% or greater, as determined from prior retrospective studies, identified a group of patients (18%) who had a poor outcome. Overall survival was significantly reduced in these patients with a high Ki-67-associated proliferative index compared with those with a low proliferative index (P = .001). One-year survival estimates were 82% (low proliferative index) versus 18% (high proliferative index). A multivariate regression analysis incorporating commonly used clinical prognostic features confirmed the independent effect of proliferation on survival (relative risk estimate 5.9; 95% confidence interval, 2.2, 16.1). The Ki-67 MoAb identifies a group of patients with rapidly fatal NHL for whom currently available chemotherapy is inadequate.