Paul A. Bunn

Phenotypic characterization of cutaneous T-cell lymphoma. Use of monoclonal antibodies to compare with other malignant T cells

We studied the surface-antigen pattern of T cells in peripheral blood and cell lines from patients with advanced cutaneous T-cell lymphoma (CTCL) or T-cell acute lymphoblastic leukemia. The antigen patterns of cutaneous T-cell lymphoma cells from peripheral blood and established cell lines were nearly identical; the cells were negative for human thymus antigen (OKT6 and NA1/34), positive for pan-T-cell (OKT3, 17F12, 10.2, and 9.6) and helper-T-cell-subset (OKT4) antigens, and negative for T-cell-subset antigens 3A1 and OKT8. In contrast, the phenotypes of malignant T cells from patients with acute lymphoblastic leukemia were heterogeneous, with at least five patterns of reactivity. The T-cell-specific antibody 3A1 was the only monoclonal reagent that clearly distinguished the peripheral-blood T cells in CTCL (3A1-) from those in acute lymphoblastic leukemia (3A1+). Moreover, 3A1 was the most reliable T-cell marker in acute lymphoblastic leukemia. We conclude that circulating CTCL (Sézary) T cells are homogeneous in their antigen phenotype and are derived from a well-differentiated 3A1-, OKT4+, OKT8- helper-T-cell subset.

Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte a interferon therapy for mycosis fungoides.

RECOMBINANT leukocyte A interferon is a highly purified single molecular species of alpha interferon that is produced by recombinant-DNA methods and has been shown to have biologic activity.1 The c...

Prospective staging evaluation of patients with cutaneous T-cell lymphomas. Demonstration of a high frequency of extracutaneous dissemination.

A prospective pretreatment staging evaluation was done on 49 consecutive patients with mycosis fungoides or the Sézary syndrome to study patterns of disease spread and prognostic factors. Routine staging procedures included complete blood count, blood chemistries, chest roentgenogram, lymphangiogram, radionuclide scans, bone marrow aspiration and biopsy, liver biopsy, and lymph node biopsy. Special evaluations included cytogenetic analysis, electron microscopy, and T-cell cytology. Extracutaneous lymphoma was documented by light microscopy in 51% of patients and by the three special procedures in 88%. Extracutaneous lymphoma was most frequent in blood and lymph nodes; 18% of patients had visceral involvement. Patients with generalized erythroderma had a higher frequency of extracutaneous disease than did patients with cutaneous plaques and tumors by both light microscopy and special studies. Survival was directly related to the type of skin involvement and the presence or absence of extracutaneous disease. Systemic dissemination of cutaneous T-cell lymphoma is frequent, generally asymptomatic, and develops early via the circulation. These findings may explain why cutaneous therapies are associated with a high frequency of relapse.

Role of prophylactic cranial irradiation in prevention of central nervous system metastases in small cell lung cancer. Potential benefit restricted to patients with complete response

Abstract The records of 332 patients with small cell lung cancer treated on National Cancer Institute protocols between 1970 and 1980 were reviewed to evaluate the association of prophylactic cranial irradiation with the development of central nervous system metastases and survival. Stage of disease, involvement of liver, bone marrow, and bone, and the degree of response to systemic therapy were prognostic features significantly associated with the development of central nervous system metastases. Prophylactic cranial irradiation had no influence on leptomeningeal, spinal, or epidural metastases, but a significant reduction In intracerebral metastases was observed. There was also a statistically significant improvement in overall survival in patients who received prophylactic cranial irradiation (p

Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis.

The clinical course of cutaneous T cell lymphoma (mycosis fungoides and Sezary syndrome) is generally indolent, but in occasional patients becomes fulminant. We found that biopsies from patients with accelerating disease can reveal cytologic transformation from previously observed small, convoluted lymphocytes to large cells that are similar to cells seen in large-cell lymphoma. The cerebriform nuclei characteristic of malignant T cells can only rarely be identified. Of 150 cutaneous T cell lymphoma patients we treated from 1976 to 1984, cytologic transformation was identified in 12 after review of peripheral blood smears and biopsies from skin, lymph nodes, and visceral sites. Patients who developed cytologic transformation were initially characterized by advanced stage (11 of 12), with lymph node effacement (seven of 11) and erythroderma (five of 12). The tumor cell DNA content after transformation was aneuploid (four of four), and the ability to form rosettes with sheep erythrocytes was retained in transformed cells (three of three). The median time from diagnosis of cutaneous T cell lymphoma to cytologic transformation was 21.5 months (range, 4 to 64), and the median survival from transformation was only 2 months (range, 0 to 19+). We conclude that cytologic transformation in cutaneous T cell lymphoma represents a distinct clinicopathologic entity, characterized by an aggressive clinical course.

Clinical implications of cytogenetic studies in cutaneous t-cell lymphoma (CTCL)

Detailed cytogenetic studies were performed in 41 patients with cutaneous T‐cell lymphoma (CTCL): four patients had limited plaques, 13 patients had generalized plaques, eight patients had cutaneous tumors, 16 patients had generalized erythroderma, and four additional patients, who had relatively benign chronic dermatosis, served as controls. Correlating the histologic and cytogenetic results in the various tissues, it was observed that 62% of the peripheral blood specimens were cytogenetically positive but only 49% were morphologically positive; in the lymph node the ratio was 80 versus 45%, and in the bone marrow, 6 versus 3%. These studies demonstrate that chromosome abnormalities are frequently detectable before morphologic changes become apparent. Chromosome banding preparations showed extensive and wide‐ranging heteroploidy; the #1 chromosome was most frequently involved in structural abnormalities while chromosomes #11, 21, and 22 were most frequently involved in numerical abnormalities. These cytogenetic findings support the impression that CTCL is a disease whose various clinical manifestations represent a chronologic sequence, with the cytogenetic findings paralleling the clinical symptoms: patients with minimal chromosomal changes had the best survival and the more extensive the chromosome abnormalities, the more advanced the clinical disease. Clone formation was seen in eight patients and this phenomenon, along with hyperdiploidy and near‐tetraploidy, was associated with a poor prognosis and short survival. We conclude that CTCL progresses from an early phase with extensive chromosomal abnormalities and lack of clone formation to a terminal phase with clone selection. Cytogenetic studies can, therefore, be of significant diagnostic and prognostic value in CTCL.

Patients with Small-Cell Lung Cancer Treated with Combination Chemotherapy with or without Irradiation: Data on Potential Cures, Chronic Toxicities, and Late Relapses After a Five- to Eleven-Year Follow-up

We assessed the outcome in 252 patients with small-cell lung cancer 5 to 11 years after treatment with combination chemotherapy, with or without chest and cranial irradiation, in National Cancer Institute therapeutic trials from 1973 through 1978. Twenty-eight patients (11%) survived free of cancer for 30 months or more. Fourteen patients remain alive without evidence of cancer beyond 5 years (range, 6.4 to 11.3 years), and 7 patients have returned to a lifestyle similar to that before diagnosis. The other 14 patients who were cancer-free at 30 months have developed cancer or died; 6 patients had a relapse, 4 developed or died from non-small-cell lung cancer, and 4 died of unrelated causes. A few patients with small-cell lung cancer (5.6%) may be cured. Thirty-month, cancer-free survival is insufficient to show a cure. Although late toxicities are troublesome, they do not outweigh the benefits of prolonged survival and potential for cure with modern aggressive therapy in small-cell lung cancer.

Cell Surface Differentiation Antigens of the Malignant T Cell in Sezary Syndrome and Mycosis Fungoides

Using a panel of monoclonal antibodies and rabbit heteroantisera, we have studied the cell surface markers of peripheral blood (PB) Sezary cells from six patients with mycosis fungoides or Sezary syndrome, disease grouped within the spectrum of cutaneous T cell lymphomas (CTCL). Furthermore, we have studied two cell lines (Hut 78 and Hut 102) derived from malignant Sezary T cells from CTCL patients. The monoclonal antibody 3A1 defines a major human PB T cell subset (85% of PB T cells) while the antigen defined by the monoclonal antibody 4F2 is present on a subset (70%) of activated PB T cells and on circulating PB monocytes. In contrast to normal subjects in whom 60-70% of circulating PB mononuclear cells were 3A1(+) T cells, PB mononuclear cells from six CTCL patients studied had an average of only 10.6+/-3.2% 3A1(+) T cells. Whereas 85% of E-rosette positive cells from normal individuals were 3A1(+), virtually all E-rosette positive T cells from the Sezary patients were 3A1(-). Two patients with high numbers of circulating Sezary T cells had both aneuploid and diploid PB T cell populations present; after separation of PB T cells into 3A1(+) and 3A1(-) cell suspensions, all 3A1(-) cells were found to be aneuploid. In contrast to normal resting PB T cells which were 4F2(-), all PB Sezary cells were 4F2(+), suggesting a state of activation. The 3A1 antigen was on a variety of acute lymphoblastic leukemia T cell lines (HSB-2, RPMI-8402, MOLT4, CEM) but was absent on the Hut 78 and Hut 102 Sezary T cell lines. Using rabbit anti-human T and anti-human Ia (p23, 30) antisera, we found that all malignant Sezary PB cells tested were killed by anti-T cell antiserum plus complement but not by anti-Ia plus complement. In contrast, Sezary cell lines Hut 78 and 102, were killed by both anti-T cell antiserum and anti-Ia plus complement. Similar to 3A1(-) normal PB T cells, 3A1(-) Sezary PB T cells proliferated poorly to phytohemagglutinin and concanavalin A. However, 3A1(-) Sezary T cells were able to provide T cell help towards pokeweed mitogen-induced in vitro B cell immunoglobulin synthesis, an immunoregulatory function limited to 3A1(+) T cells in normal subjects.Thus, the 3A1 antigen is present on 85% of normal PB T cells, and on most T-acute lymphoblastic leukemia lines tested; in contrast the 3A1 antigen is not present on the majority of circulating malignant Sezary PB T cells nor on T cell lines derived from malignant Sezary T cells. The lack of expression of the 3A1 antigen may be associated with malignant transformation of T cells in CTCL and may be an important marker for tracing the clonal origin of the malignant Sezary T cell.

Pulmonary toxicity with combined modality therapy for limited stage small-cell lung cancer.

To assess the pulmonary toxicity of radiation therapy combined with chemotherapy v chemotherapy alone, we reviewed the clinical course of 80 patients with limited stage small-cell lung cancer treated in a randomized prospective trial. Life-threatening pulmonary toxicity, defined as bilateral pulmonary infiltrates extending beyond radiation ports with symptoms requiring hospital admission, developed in 11 patients (28%) receiving combined modality therapy and in two (5%) receiving chemotherapy alone. Eight of these 13 patients died from pulmonary complications with no clinical evidence of tumor in five. Pulmonary toxicity initially presented at a median of 63 days (range, 21 to 150 days) after the start of combined modality therapy and at a median of 217 days after chemotherapy alone. Biopsies obtained in 11 patients with severe toxicity revealed only interstitial fibrosis with no evidence of an infectious agent. Review of pretreatment parameters such as age, performance status, and radiation portal area failed to reveal any significant differences between patients with or without pulmonary complications. However, initial pulmonary function tests (PFTs) revealed a significantly lower vital capacity (P = .03) and forced expiratory volume (FEV/1.0 second) (P = .04) in patients with subsequent pulmonary complications. Pulmonary toxicity was significantly more common with combined modality therapy than with chemotherapy alone (P = .017) and worse than expected with radiotherapy alone. Six- or 12-month PFTs in completely responding patients revealed improvement within the chemotherapy alone group and no clear trend within the combined modality group. For the group treated with radiation therapy and chemotherapy, there was significantly less improvement after 6 or 12 months in the forced vital capacity (P less than .005) and FEV/1.0 second (P less than .005) than observed for the group treated with chemotherapy alone. Despite the increased incidence of pulmonary toxicity, overall survival favored the combined modality arm (P = .07). Enhanced local control and disease-free survival appeared to compensate for the initial increased pulmonary morbidity and mortality in the group with combined modality therapy.

Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sézary syndrome.

We previously demonstrated that recombinant interferon alfa-2a (IFN-alfa) in a dose of 50 X 10(6) U million units (MU)/m2 intramuscularly (IM) three times per week has efficacy against mycosis fungoides (MF) and the Sézary syndrome (SS). However, this regimen given to patients with refractory disease was uniformly complicated by toxicities requiring major dose reductions. The present study was designed to determine if intermittent high-dose IFN-alfa would preserve efficacy and decrease toxicity in a similar patient population. Twenty-four patients with advanced disease refractory to one or more standard therapies received IFN-alfa, 10 MU/m2 IM on day 1 followed by 50 MU/m2 IM on days 2 to 5 every 3 weeks; after the first four cycles, stable and partially responding patients underwent dose escalation to twice the starting dose. One complete (CR) and six partial responses (PRs) were observed (response rate, 29%; 95% confidence interval, 13% to 51%) lasting 4 to 19 months (median, 8 months). No improvement in objective response was seen in the eight patients who received dose escalation. Dose reductions were necessary in eight of 22 patients receiving one or more cycles of therapy. Weighted mean dose rate intensity for patients on this study over the first four cycles of treatment was 65.5 MU/m2/wk compared with 73.2 MU/m2/wk over the first 12 weeks of treatment in patients from the previous study, in which all 19 patients receiving more than 1 week of treatment required dose reduction. IFN-alfa is effective against previously treated MF and the SS and is better tolerated on this intermittent schedule.