High dose cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) in the treatment of follicular, low grade non-Hodgkin's lymphoma: CALGB 9150.

The main objectives of this study were to determine the feasibility of administering high doses of cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) every 14-21 days to patients with follicular small cleaved cell lymphoma. For each patient, the treatment was not considered feasible if fewer than four cycles of cyclophosphamide chemotherapy could be administered on schedule (i.e. at least every 29 days) or (1) hospitalization of the patient for longer than three days was necessary for neutropenic fever (38 degrees C) or bacteriologically documented infection in > 50% of the cycles, or (2) grade > or = 2 hemorrhage in association with thrombocytopenia of grade > or = 3 severity occurred in > 50% of the cycles or (3) non-hematologic toxicity (excluding nausea/vomiting and alopecia) of grade > or = 3 occurred in > 50% of cycles. The goal was to have a treatment program feasible in 75% or more of the treated patients. The secondary objectives were to determine the toxicities, the complete and partial response rates, and the time to treatment failure (TTF). The trial also attempted to assess the effectiveness of this treatment program in eradicating Bcl-2 rearrangements by PCR, and to assess complete remission duration in relationship to PCR results in patients who respond to this chemotherapy program. Patients were required to have histologically documented non-Hodgkin's lymphoma of the subtypes follicular, predominantly small cleaved cell (IWF-B) or follicular mixed, (IWF-C). Patients were required to have Stage IV disease including histologic evidence of bone marrow involvement. Measurable disease was required and patients were also required to have one of the following risk factors: > or = 2 extranodal sites, node or nodal group > or = 5 cm. Submission of fresh bone marrow for molecular genetic studies for the presence of Bcl-2-Ig fusion DNA was mandatory in previously untreated patients. Patients had to be between 18 and physiologic age 55 years (carefully selected patients over age 55 years were also eligible), expected survival > 2 years, performance status 0-1, and have adequate renal, hepatic and bone marrow function, and a cardiac ejection fraction > or = 50%. Cyclophosphamide 4.5 g/m2 i.v. was given with mesna every 14 days with rhG-CSF support. Twenty-nine patients were accrued to this trial. The median follow-up time is 5.0 years, with a range of 2.5-6.7 years. The overall response rate was 75% (9 CRs 37.5%, 9PRs 37.5%). The median duration of survival is 5.53 years. The 1-year estimated probability of freedom from treatment failure was 50% and of survival at 1 year was 92%. No strong association was observed between TTF and age, symptomatic stage, histology performance status, number of extranodal sites or baseline Bcl-2 status. At 3 years the survival of all patients was 78% and failure free survival was 17%. 15 (62%) of the 24 eligible previously untreated patients met the criteria for feasibility specified in the protocol. The 95% CI for the feasibility rate is (44 and 82%). Twenty-two of the 24 (92%) previously untreated patients had specimens submitted for testing for Bcl-2 rearrangements. Thirteen of the 22 (59%) were found to have rearrangements at baseline. Post-treatment specimens were submitted for seven of the 13 patients. Four of the seven converted to Bcl-2 negative following treatment. Eight of 13 Bcl-2 positive patients (62%) had a clinical response to treatment. The 95% exact binomial CI for the total response rate in this subgroup is (28 and 88%). This study demonstrates that repetitive doses of cyclophosphamide at 4.5 g/m2 every two weeks with rhG-CSF support can be administered to selected younger patients with advanced follicular lymphoma with morphologic involvement of the bone marrow with acceptable non-hematologic toxicity.

Fine needle aspiration of signet-ring cell lymphoma. A case report with differential diagnostic considerations.

BACKGROUND: Signet-ring cell lymphoma is an unusual morphologic variant of non-Hodgkin's lymphoma that, although well described histologically, is scarcely mentioned in the cytology literature. Its main significance lies in its potential for diagnostic confusion with more common lesions containing signet-ring cells. CASE: A 50-year-old, white male presented with a two-month history of persistent cervical lymphadenopathy and fatigue. Fine needle aspiration of a 2-cm, left, submandibular lymph node revealed classic signet-ring cells among small and large lymphoid cells. Also noted were multivacuolated cells. The background of the smears showed many vacuolated structures analogous to the lymphoglandular bodies seen in lymphoid proliferations without signet-ring cells. CONCLUSION: The differential diagnosis of signet-ring cell lesions by fine needle aspiration includes signet-ring cell lymphoma, sinus histiocytosis and metastatic adenocarcinoma, liposarcoma and melanoma. When confronted with such an aspirate, additional material should be obtained for immunocytochemical or flow cytometric analysis.

Carboplatin in previously treated multiple myeloma. A Cancer and Leukemia Group B phase II trial.

Carboplatin 400 mg/m2 per month was evaluated as a single agent in 15 patients with multiple myeloma who had had one prior chemotherapy regimen. All but three were judged to have had some degree of refractoriness to prior therapy. Hematologic toxicity was frequent and sometimes severe. There were no responses. Further evaluation of standard-dose single-agent carboplatin in refractory myeloma does not appear warranted.

Immunohistochemical identification of P-glycoprotein in previously untreated, diffuse large cell and immunoblastic lymphomas.

Expression of P-glycoprotein has been linked to multidrug resistance in cancer cell lines and human tumors. We investigated the frequency and clinical significance of P-glycoprotein immunoreactivity in 57 previously untreated diffuse large cell and immunoblastic lymphomas. Banked frozen tissue, which had been obtained prior to chemotherapy, was tested for reactivity with 2 monoclonal antibodies (MRK16 and C219) that recognize different domains of P-glycoprotein, using an immunoperoxidase technique. Thirteen of 57 lymphomas (23%) showed strong staining of greater than 50% of neoplastic cells; 15 of 57 (26%) showed labeling of a minority (11-50%) of neoplastic lymphocytes; 14 of 57 (25%) yielded equivocal results (reactivity in less than 10% of cells); and 15 of 57 (26%) were negative for P-glycoprotein. The 2 monoclonal antibodies were comparable in reactivity. Expression of MDR-1 mRNA was determined in 6 cases with sufficient available tissue, and did not correlate well with the percentages of cells reactive for P-glycoprotein by immunohistochemistry. Thirty-nine of our 57 patients completed multiagent chemotherapy. Contrary to our expectations, we found that P-glycoprotein immunoreactivity did not decrease the likelihood of response to induction chemotherapy. Median survival also was not adversely affected.

Large granular lymphocytes from B-chronic lymphocytic leukemia patients inhibit normal B cell proliferation.

Large granular lymphocytes (LGL) may exert regulatory influences on B cell immunoglobulin synthesis. We, therefore, investigated the influence of LGL from controls and B cell chronic lymphocytic leukemia patients (B-CLL) on control B cell proliferation to costimulation with the F(ab')2 fragment of goat antihuman mu and B cell growth factor (BCGF). Purified LGL (greater than 90% by morphology) from control and B-CLL peripheral blood were added in various concentrations to purified control B cells and incubated with anti-mu and BCGF for 3 days. [3H]-thymidine uptake of B cells was then measured. There was no proliferation of control or CLL LGL alone to the costimulatory signals of the F(ab')2 fragments of goat antihuman mu chain and BCGF. Addition of control LGL to equal numbers of control B cells did not blunt control B cell responsiveness to BCGF (with control LGL 8,649 +/- 298 cpm vs. control B cells alone 8,336 +/- 556 cpm, mean +/- SEM). When control LGL were increased to 10:1 LGL:B cell ratio, the maximal inhibition by control LGL of control B cell proliferative response to BCGF was 23%. In contrast, addition of CLL LGL at a 1:1 LGL:B cell ratio resulted in marked impairment of the control B cell proliferative response to BCGF (with CLL LGL 3,586 +/- 954 cpm vs. control B cells alone 8,649 +/- 298 cpm). Inhibition by CLL LGL occurred in a cell-concentration-dependent manner. No difference in CLL LGL's inhibitory effect on either resting or activated control B cell responsiveness to BCGF was noted. Inhibition of de novo protein synthesis (by cycloheximide inhibition) of CLL LGL did impair CLL LGL's inhibitory capacity for BCGF-induced B cell proliferation. A possible explanation for these findings includes the possibility that a subgroup of LGL with B cell suppressive activity may have expanded as a host response to the B cell leukemia or as part of the disordered cell regulation in B-CLL.

Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis.

B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B-cell Ig production/secretion by CD16+, CD3- blood cells.

Immunobiology of malignant B cells and immunoregulatory cells in B-chronic lymphocytic leukemia.

This article reviews pertinent immunobiologic features of the malignant B cell and the circulating immunoregulatory cells (T and NK) that characterize B-CLL.

Natural killer function in B-chronic lymphocytic leukemia.

Previous work has demonstrated that large granular lymphocytes (LGL) may be suppressive for B cell function. We have investigated the impact of blood LGL from B-CLL patients with and without hypogammaglobulinemia on normal B cell Ig synthesis and proliferation. Purified blood LGL from controls (age and sex matched) and B-CLL patients were added in various concentrations to isolated normal B cells. The cell co-cultures plus mitogens were incubated at 37 degrees C for 5-7 days and both Ig levels in culture supernatants or cell proliferation determined by ELISA or thymidine incorporation respectively. Percoll purified LGL from controls and B-CLL patients were evaluated for their effect on both PWM and anti-Ig/staph protein A (SPA) induced B-cell proliferation. CLL LGL from certain patients were significantly down regulatory only for anti-Ig/SPA induced B cell proliferation. These B-CLL patients were patients with obvious hypogammaglobulinemia. Subsequently, we purified blood LGL subsets from 5-CLL patients with and without hypogammaglobulinemia. Two LGL subsets; CD16+, CD3- and CD16+, CD3+ were purified by flow cytometry. These LGL were then added to control B cells in presence of PWM and Ig levels determined at day 5 of culture. CLL LGL (CD16+, CD3-) from 3 B-CLL patients with hypogammaglobulinemia were clearly down regulatory for Ig levels. The LGL from 3 B-CLL patients with normal serum Ig levels were not suppressive of mitogen induced B cell Ig synthesis/secretion, nor were the LGL (CD16+, CD3- or CD16+, CD3+) from age and sex matched controls (n = 2).(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro correlates of low dose ara-C efficacy: clinical, cytogenetic, and bone marrow culture analysis.

Low-dose Ara-C (10 mg/m2 subcutaneously bid) has been used as an alternative therapy for acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes. We sought to define its therapeutic mechanism by assessing clinical and cytogenetic responses to treatment in conjunction with careful in vitro study of both morphologic and functional characteristics of bone marrow cells cultured with Ara-C. Sixteen patients (12 ANLL, four myelodysplastic syndrome) were treated. All developed pancytopenia and 11 of 12 had bone marrow hypoplasia during treatment. Four had a meaningful clinical response while five more showed in vivo leukemic cell sensitivity to low-dose Ara-C. Seven showed no response. Cells with cytogenetic abnormalities were either decreased in number or eradicated during clinical improvement. Liquid culture of marrow mononuclear cells with Ara-C (.033-.333 micrograms/ml X 7 days) produced little evidence of morphologic or functional differentiation (ten of 11 studied). No functional maturation was observed in cells from clinically responding patients. We conclude that low-dose Ara-C is modestly effective for some patients with ANLL or myelodysplasia. However, no evidence for in vivo leukemic differentiation is suggested by either in vitro culture studies or cytogenetic correlates of clinical response. In vitro marrow culture studies failed to predict clinical response to Ara-C.

Malignant chronic lymphocytic leukemia B cells express interleukin 2 receptors but fail to respond to interleukin 2's proliferative signal.

The functional importance of interleukin 2 (IL-2) receptors in the regulation of malignant B cell proliferation still remains to be clarified. We studied malignant CLL B cells for the presence of IL-2 receptors and responsiveness to IL-2 with respect to proliferation and B cell colony formation. Seven of 25 B-cLL patients studied had reactivity for anti-Tac (mean, 11.8%; range 4-31%). Purified control T cells expressed less than 2% reactivity to anti-Tac. CLL B cell colony forming cells were reactive with anti-Tac in all five patients studied (mean, 24.8%; range, 17-31%). The proliferative response of control and CLL B cells to both a partially purified preparation of IL-2 and recombinant IL-2 (rIL-2) was also examined. Control B cells demonstrated a dose-dependent, enhanced proliferative response to IL-2. At lower IL-2 concentrations (2-200 units/ml), rIL-2 appeared to have a more significant proliferative enhancing effect on control B cells than did the partially purified IL-2 preparation. In contrast, no concentration of the IL-2 preparations enhanced CLL B cells' proliferative response. The monoclonal antibody anti-Tac was capable of inhibiting control B cell responsiveness to IL-2, rIL-2 did not support CLL B cell colony formation. Thus, malignant B cell populations may spontaneously express the Tac antigen in the absence of a functional response to IL-2. The significance of this in the treatment of lymphomas is underscored by the development of new therapeutic strategies which would seek to incorporate the use of immunoregulatory lymphokines such as IL-2.

Abnormal T cell function in early-stage chronic lymphocytic leukemia (CLL) patients.

Significant alterations in T cell subpopulations and function occur in chronic lymphocytic leukemia (CLL) patients. We studied whether abnormalities in peripheral blood T cell parameters were present in 15 untreated early stage CLL patients (ie, Rai stage 0, 1, 2). Seven of the nine patients showed decreased T helper support as compared to control T cells for pokeweed mitogen (PWM)-induced control B cell proliferation (ie, patient 6,063 +/- 1,434 cpm vs control 14,894 +/- 121 cpm). All stage 0 and 1 patients showed a marked impairment of T helper activity for control B cell proliferation (patient T = 7,752 +/- 1,137 cpm vs control T = 14,894 +/- 121 cpm). In a separate assay system, six of nine CLL patients showed T suppressor activity for control B cell proliferation greater than control T cell suppressor activity. Four patients were stage 0 and 1. CLL patients demonstrated markedly impaired T cell support for control B cell immunoglobulin synthesis compared to control T cells (188 +/- 28 vs 869 +/- 56 hemolytic plaque-forming cells (HePFC)/culture, respectively). Control T cells showed increasing support for control B cell immunoglobulin synthesis with increasing T:B cell ratios (869 +/- 56 vs 1,265 +/- 48 HePFC/culture, at 1:1 and 2:1 T:B cell ratios, respectively). In contrast, five of eight CLL patients' T cells showed no improvement in control B cell immunoglobulin synthesis with increasing T:B cell ratios (795 +/- 56 vs 569 +/- 48 HePFC/culture, at 1:1 and 2:1 T:B cell ratios, respectively). There was no direct correlation with CLL T cell-mediated suppression of B cell proliferation and suppression of B cell immunoglobulin synthesis. These studies suggest there is a complex array of abnormal immunoregulatory T cell function in early stage CLL. These include a prominent T helper dysfunction and more variable excessive suppressor activity. The relationship of these findings to the basic disease process remains to be elucidated.

Impaired expression of cell surface receptors for B cell growth factor by chronic lymphocytic leukemia B cells.

Normal human B cell proliferation is controlled by various immunoregulatory signals including the T cell-derived lymphokine B cell growth factor (BCGF). The role of BCGF in the regulation of malignant B cell proliferation is unclear. Therefore, we studied the proliferative response of purified chronic lymphocytic leukemia (CLL) B cells to BCGF. For all CLL patients studied, CLL B cells showed a decreased proliferative response as compared with control B cells for BCGF-induced B cell proliferation (patient 291 +/- 59 cpm v control 3,942 +/- 622, mean +/- SEM). This impaired proliferative response appeared to be intrinsic to CLL B cells since it was not corrected by incubation with increasing concentrations of BCGF. Attainment of normal B cell responsiveness to BCGF requires the processing of an initial activation signal which results in the expression of cell surface receptors for BCGF. Increasing concentrations of the B cell activation signal (the F(ab')2 fragment of goat anti-human mu chain) did not improve CLL B cell responsiveness to BCGF. Three-day activated CLL B cells compared with activated control B cells demonstrated a marked impairment in their ability to absorb out the BCGF activity present in the BCGF preparation (BCGF activity absorbed out, patient 12.8% v control 53%). Pretreatment of CLL B cells with neuraminidase failed to improve either the proliferative response to BCGF or the expression of cell surface receptors for BCGF by the CLL B cells. This study suggests that the impaired responsiveness to BCGF by CLL B cells is the result of impaired expression of cell surface receptors for BCGF when CLL B cells are exposed to activation signals.

Inhibition of B cell growth factor (BCGF) by monoclonal antibodies directed against the C3d receptor (CR2).

Normal human B cell proliferation is controlled by various immunoregulatory signals including the T cell-derived lymphokine B cell growth factor (BCGF). Human BCGF provides the final proliferative signal to normal, activated B cells. We herein show that anti-CR2 monoclonal antibodies inhibit human B cell responsiveness to purified BCGF. Addition of anti-CR2 antibody, AB5, was capable of completely inhibiting BCGF-mediated enhancement of either anti-mu or staphylococcal protein A-activated human B cells (191 +/- 21 cpm vs. 3942 +/- 622 cpm, mean +/- SEM). Inhibition of B cell response to BCGF by AB5 occurred in a dose-dependent manner. Monoclonal antibody anti-B2, which recognizes the same 140-kDa glycoprotein as AB5, in comparable concentrations also inhibited B cell responsiveness to BCGF. Monoclonal antibodies of the same subclass (IgG1) showed no inhibitory effect on BCGF enhancement of B cell proliferation. The F(ab')2 fragment of AB5 generated by pepsin digestion was similarly inhibitory as was the intact Ig. AB5-mediated inhibition was independent of the target B cell state of activation. Both resting and activated B cells (anti-mu or staphylococcal protein A activated) incubated with similar concentrations of AB5 were unresponsive to BCGF. The ability of anti-CR2 antibodies to block BCGF-dependent B cell proliferation suggests that occupancy of C3d membrane receptors may result in modulation of B cell proliferation in physiologic or clinical disease states.

Impaired responsiveness to B cell growth factor in a patient with common variable hypogammaglobulinemia.

Common variable hypogammaglobulinemia (CVH) is a clinical syndrome that includes a diverse group of patients with heterogeneous defects resulting in impaired B cell proliferation and terminal differentiation into mature plasma cells capable of normal immunoglobulin synthesis and secretion. In this study, we report our identification of a previously undescribed intrinsic B cell defect in a patient with CVH. This patient's B cells showed a marked impairment in hemolytic plaque-forming cell (HePFC) formation compared with control B cells (15 v 80 HePFCs per culture, respectively). In addition, this patient's B cells displayed decreased B cell colony formation compared with control B cells (5 +/- 2 v 93 +/- 8, respectively). When examined for their responsiveness to phytohemagglutinin-T cell conditioned media (PHA-TCM), the patient's B cells displayed impaired B cell proliferation compared with control B cells (stimulation index [SI] 1.3 +/- 0.20 v 26 +/- 1.4 with 20% control PHA-TCM [vol/vol]). Impaired proliferation by the patient's B cells persisted with increasing concentrations of B cell growth factor (BCGF). Additionally, PHA-TCM prepared from the patient's T cells when compared with control PHA-TCM consistently showed less support for control B cell proliferation (SI 1.27 +/- 0.21 v 26 +/- 1.4, respectively). In coculture studies of B cell proliferation and immunoglobulin synthesis, patient's T cells showed no evidence of an enhanced suppressive effect or decreased helper effect. This patient's immune defects involve, first, an intrinsic B cell defect characterized by an impaired responsiveness to BCGF's proliferation signal and, second, impaired production of BCGF by the patient's T cells.

Low-dose ARA-C fails to enhance differentiation of leukaemic cells.

Nine patients with acute myelogenous leukaemia were treated with low-dose ARA-C (10 mg/m2, q 12h) for a planned 21 d. Complete remission was attained in only one patient (11.1%). Definite cytoreductive effect was seen in four additional patients. There was one treatment-related death. Haematologic toxicity occurred in all nine patients with sever thrombocytopenia most prominent. Severe hepatotoxicity precluded further ARA-C treatment in one patient. Because of toxicity only two patients were able to complete their scheduled 3 week courses of low-dose ARA-C. No evidence of ARA-C induced differentiation of leukaemic cells was noted on follow-up bone marrow examination during or shortly after the treatment course. The utility and indication for low-dose ARA-C therapy of AML remains to be determined.

Simultaneous presentation of relapsing Hodgkin's disease and treatment-related non-Hodgkin's lymphoma.

A 55-year-old white man was diagnosed in 1975 with Hodgkin's disease stage IIA, mixed cellularity. He was treated with 4,500 rads to an inverted-Y field followed by six cycles of MOPP and remained in complete remission. In 1983 a right axillary lymph node biopsy showed recurrent Hodgkin's disease, mixed cellularity. While receiving his initial chemotherapy he developed persistent epigastric distress. Endoscopic gastric biopsy demonstrated a diffuse large-cell non-Hodgkin's lymphoma. Surface marker studies confirmed the separate identity of these two malignant lymphoproliferative processes. This represents the first reported simultaneous occurrence of relapsing Hodgkin's disease with treatment-related non-Hodgkin's lymphoma.

Laminin selectively enhances monocyte-macrophage-mediated tumoricidal activity.

Recent evidence indicates that laminin may be involved in the phenotypic behavior and metastasis of certain tumor cells. We examined the effect of laminin on monocyte-macrophage killing of two human tumor lines, Malme-3M melanoma and CAK-I renal carcinoma. Laminin enhanced both monocyte- and macrophage-mediated tumoricidal activity against human melanoma cells but did not promote monocyte and macrophage killing of CAK-I renal carcinoma cells. Laminin promoted substratum adherence of melanoma cells in a concentration-dependent manner but had no effect on adhesion of the renal carcinoma cells. The monocyte-macrophage cytotoxicity promoted by laminin paralleled its effects on cell substratum adhesion. In addition to an effect on adhesion, laminin also promoted migration of the melanoma cells but not of the renal carcinoma cells. Laminin did not promote the adhesion of monocytes or macrophages. Laminin may promote monocyte-macrophage tumor cytotoxicity by increasing the interaction of tumor and effector cells through its effect on target or tumor cells.

The influential T cell in B-cell neoplasms.

Investigations of human B-cell malignancies have generally focused on the monoclonal B-cell populations. Until recently there has been little emphasis on the thymus (T) lymphocyte in these disorders. Current studies, however, suggest that quantitative and qualitative disorders of T cells are generally seen both in chronic lymphocytic leukemia and in multiple myeloma. This review will focus on two major concepts. First, it will define the quantitative and functional T-cell abnormalities in B-cell malignancies including evidence suggesting a causal link between the T-cell abnormalities and certain observed disease manifestations in chronic lymphocytic leukemia and multiple myeloma. Secondly, it will review data demonstrating that these T cells may be influenced by in vivo and in vitro manipulations and will outline some of the possible resultant clinical effects.

Alterations in human natural killer cell activity and monocyte cytotoxicity induced by zinc deficiency.

Zinc deficiency alters lymphocyte and monocyte function in man and animals. A patient with isolated zinc deficiency was found to have lymphopenia (420 lymphocytes/microliter), depressed T-cell mitogen response (48% of normal control), increased numbers of circulating T-suppressor cells (OKT8 reactive cells) and decreased circulating T-helper cells (OKT4 reactive cells). Activity of the patient's natural killer (NK) cells was 1 lytic unit/10(6) cells (normal 10 to 40), and monocyte cytotoxicity (MC) was four times that of normal controls. Zinc repletion in vivo improved the peripheral lymphocyte count, corrected the abnormal OKT8-to-OKT4 ratio, normalized T-cell response to mitogen, improved NK function, and lowered MC to control values. A divalent cation chelator, 1,10-orthophenanthroline (OP), was used to simulate zinc deficiency in vitro. T-cells exposed to OP are nonresponsive to mitogen unless zinc is added. NK function of lymphocytes from normal donors exposed to OP was depressed in a time- and dose-dependent manner. NK activity of peripheral blood lymphocytes (PBL) from 12 normal donors exposed to 50 microM OP for 16 hr was 10.3 +/- 7 lytic units/10(6) cells (mean +/- S.E.M.) vs. 32.6 +/- 14 for cells incubated in medium alone. When monocytes were exposed for 16 hr to 50 microM OP, however, MC significantly increased to a range two to five times that of control. OP-induced alterations of lymphocyte and monocyte function was reversed by the addition of 50 microM zinc but not calcium or magnesium. Since NK activity and MC are thought to be important in host tumor immunity, alterations in zinc metabolism may have important implications for human tumor immune surveillance mechanisms.

Chronic lymphocytic leukemia progenitor cells carry the antigens T65, BA-1, and Ia.

CLL B cells may be induced to form B-cell colonies in vitro. Colonies formed are monoclonal and appear to reflect the circulating malignant B-cell clone in vitro. Using hybridoma-produced monoclonal antibodies (MAB) and an in vitro B-cell colony assay, we have provided a characterization of the antigenic phenotype of the clonogenic CLL B cell. B-cell colony growth in both patients and normals was not altered by prior incubation with either MAB or complement (C') alone. CLL B-cell colony formation was markedly reduced after treatment with T101 and C', while normal colonies were unaffected (8 +/- 2 versus 107 +/- 10). None of the residual CLL B-cell colonies after T-101 and C' treatment reacted with T-101. However, BA-1 and la reactivity were still seen in residual CLL B-cell colonies following T-101 treatment. In contrast, a similar percentage reduction of B-cell colony growth was seen for both normals and CLL patients following treatment with BA-1 (76% versus 81%) and Q5/13 (89% versus 92%). These studies suggest that the CLL progenitor cell is characterized by the phenotype la+, BA-1+, T-101+. Better definition of the CLL progenitor cell has potential implications with regards to clinical utilization of MAB in the treatment of CLL.