Cost-Effectiveness of interferon alfa-2b added to chemotherapy for high-tumor-burden follicular non-Hodgkin's lymphoma.

UNLABELLED: Recent data from GELF (Groupe d'Etude des Lymphomes Folliculaires) have shown that the addition of interferon alfa-2b (IFN) to a doxorubicin-containing regimen (CHVP: cyclophosphamide, doxorubicin, teniposide and prednisone) prolongs both progression-free survival and overall survival in high-tumor-burden follicular non-Hodgkin's lymphoma. This gain must be weighed against the incremental toxicity and cost of IFN over CHVP alone and the objective here was, to determine the marginal cost-effectiveness of additive IFN in the specific setting of high-tumor-burden follicular non-Hodgkin's lymphoma. Meta-analysis of GELF trial results employing a Markov model was used with three health states: No Progression, Progressive Disease, and Death. Treatment response, survival and toxicity data are drawn from the GELF study. The current study is based on the final analysis of 242 patients (J Clin Oncol 1998;16:2332-2338), with a six year median follow-up for overall survival (median overall survival: not reached for CHVP + IFN vs 5.6 years for CHVP Only, p = 0.008). MEASUREMENTS: Quality of life data (utilities) are taken from studies with similar dosing of IFN, from Q-TwiST (quality adjusted time without symptoms or toxicity) analysis of the GELF data and from a panel of experts gathered to develop treatment models for high-tumor-burden follicular non-Hodgkin's lymphoma. Costs and quality-adjusted years of life saved were discounted at 3% per annum. SETTING: Costs determined for university medical centers in the United States. Results showed that, at the median cohort age of 52, IFN add 9.9 quality-adjusted months at an added cost of $13,900 (marginal cost-effectiveness of $16,900 per quality-adjusted life year, or QALY). A more complex, two-stage model approximates the actual cohort survival curves much better than a simple, one-stage model, but both models yield essentially the same marginal cost-effectiveness. Sensitivity analysis to quality of life on IFN shows marginal cost-effectiveness ranging from $15,200/QALY (no penalty for IFN) to $21,300/QALY (20% quality adjustment, greater than that reported). The model is quite insensitive to the probability of IFN toxicity. The model is moderately sensitive to the efficacy of IFN in delaying progression, particularly in the first 18 months (pProgI), but the marginal cost-effectiveness does not rise to $50,000/QALY until pProgI increases 220% from the baseline. Although the model is moderately sensitive to the cost of IFN (cIFN), marginal cost-effectiveness is below $50,000/QALY for values of cIFN below $2580/month (baseline cIFN = $850/month, corresponding to a marginal cost-effectiveness of $16,900/QALY in the baseline case). If the model is modified to reflect the 14% overall survival advantage at five years found in trials utilizing more intensive initial chemotherapy (including the GELF trial), then the marginal cost-effectiveness drops to $11,900/QALY in the baseline case. In condusion, based on data from the GELF study, low-dose interferon alfa-2b is cost-effective when added to CHVP therapy in the treatment of high-tumor-burden follicular non-Hodgkin's lymphoma. The analysis is robust: the model employs very conservative assumptions, and additive IFN remains cost-effective over wide ranges of variables in sensitivity analyses. The marginal cost-effectiveness is best expressed as being in the range of $12,000/QALY to $17,000/QALY in the baseline case. A simple Markov model can be used to describe treatment regimens with distinct periods of therapy.

Cytarabine added to interferon improves the cost-effectiveness of initial therapy for patients with early chronic phase chronic myelogenous leukemia.

The French Chronic Myeloid Leukemia Study Group prospective randomized study results indicate that the addition of cytarabine to alpha interferon (IFN-alpha) increases the rate of major cytogenetic response and prolongs survival in patients with early chronic phase chronic myelogenous leukemia (CML). The French group study design permitted a single crossover to include or discontinue cytarabine or interferon. Endpoints were overall survival, complete hematologic remission (CHR) at six months, and major cytogenetic response at 12 months. We modified a published Markov model that compared IFN-alpha alone to IFN-alpha plus cytarabine and included the possibility of crossover as in the French study. The model permits allogeneic and autologous stem cell transplantation (SCT), and follows cytogenetic response and acceleration of CML through death. Treatment response, toxicity, and survival are drawn from the French Chronic Myeloid Leukemia Study Group population of 810 patients on an intention-to-treat model. Survivals are extended to 62 months based on currently available follow-up. Costs from a United States oncology specialty institution, and state utilities from previous research and a quality-adjusted Time Without Symptoms or Toxicity analysis of the subject study were discounted at 3% per annum. At the median cohort age of 50, cytarabine offers 21 months of added median survival to IFN-alpha, which itself is superior to conventional chemotherapy by 21 months. Cost-effectiveness estimates for cytarabine added to IFN-alpha range from $7,000 per quality-adjusted life year (QALY) to $35,000 per QALY, under all plausible assumptions superior to IFN-alpha alone. The model is sensitive to the quality of life on therapy, as well as to remission rate with additive cytarabine, although the cost-effectiveness calculations are robust over the entire range of clinical assumptions. Based on data from the French study, cytarabine added to IFN-alpha substantially improves the cost-effectiveness of initial therapy for early chronic phase CML.

In vivo and in vitro suppression of T-cell receptor alpha/beta CD4- CD8- T lymphocytes by cyclosporine A.

We treated a patient with a combined immunodeficiency and disease pathology resembling GvHD with cyclosporine. This disorder was characterized by exfoliative dermatitis, lymphadenopathy, and lymphocytosis of a novel T-cell phenotype (CD3+ TCR alpha/beta+ CD4- CD8-). The patient's peripheral blood T cells had elevated cytolytic activity and expressed increased levels of IL2R, HLA-DR, and CD45RO. Treatment with CsA resulted in marked clinical improvement, resolution of the lymphocytosis, and reduced cytolytic activity of peripheral blood T cells. T-cell HLA-DR and IL2R expression was reduced by cyclosporine, but CD45RO remained intact on virtually all circulating T cells. CsA also inhibited the cytolytic activity and cytokine production of in vitro cultured TCR alpha/beta+ CD4- CD8- cell lines. Our data suggest that alleviation of the patient's clinical symptoms resulted from cyclosporine-mediated suppression of proliferation, cytotoxicity, and inflammatory cytokine production of TCR alpha/beta+ CD4- CD8- T lymphocytes in vivo. The response of this patient to cyclosporine, which was similar to that seen in true GvHD, provides further evidence that these conditions share common pathogenetic pathways.

Postnatal development of T lymphocytes in a novel X-linked immunodeficiency disease.

We previously reported an X-linked combined immunodeficiency disease (CID) characterized by immune deficiencies and complicating infections that were more moderate than those found in severe CID (SCID). Since other unstudied males in the family died in infancy, we questioned whether this T cell defect was more profound in early life. Subsequently, the development of blood T cells in an affected newborn male was examined. T cells were virtually undetectable at 48 hr. Over the next several months, CD4+ T cells (principally CD45RO+) rose to levels similar to those found in older affected males, but CD8+ T cells developed more slowly and never attained levels found in other affected males. Thus, this disease in early life mimics SCID and may pose a higher risk of fatal infections to affected individuals during that period. Finally, we speculate that the genetic defect may disrupt intrathymic development or selection of T cells.

Activated and memory T lymphocytes in human milk.

Since activated macrophages and cytokines are found in human milk (HM), a flow cytometry study was conducted to determine whether T cells in HM display phenotypic markers of recent or previous activation. HM was collected during the first 3 d of lactation. The Paint-a-Gate program was used to optimize gating on the lymphocyte population. A mean +/- 1 SD of 4 +/- 3% of total HM leukocytes were lymphocytes and 96 +/- 3% were macrophages and granulocytes (N = 33 subjects). HM lymphocyte populations were further analyzed in five subjects. T cells (CD3+) represented 83 +/- 11% and B cells (CD19+) were 6 +/- 4% of HM lymphocytes. The mean CD4/CD8 ratio of T cells in HM was 0.88 (range 0.40-1.25). This ratio was significantly decreased compared to the peripheral blood (PB) of control adults (P less than 0.02) and postpartum women (P less than 0.02), due mostly to a significant increase in CD8+ CD3+ cells in HM compared to the PB of control adults (P less than 0.002) and postpartum women (P less than 0.05). T cells bearing markers of recent activation were significantly increased in HM compared to the PB of control adults: 85 +/- 7% of CD3+ cells in HM were HLA-DR+ (controls, 10 +/- 4%; P less than 0.001), and 15 +/- 6% of CD3+ cells in HM were IL-2R+ (controls, 6 +/- 2%; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Omenn's syndrome and related combined immunodeficiency syndromes: diagnostic considerations in infants with persistent erythroderma and failure to thrive.

A 4-month-old male infant had a 2-month history of an exfoliative erythroderma and alopecia. Recurrent mucosal infections, diffuse lymphadenopathy, hepatosplenomegaly, lymphocytosis and eosinophilia, anemia, and failure to thrive later developed. Investigation revealed a combined immunodeficiency with T cells of an unusual phenotype in his peripheral blood, skin, and lymph nodes. Our patient's clinical manifestations most closely resemble Omenn's syndrome, a rare form of autosomal recessive combined immunodeficiency.

A novel X-linked combined immunodeficiency disease.

A novel X-linked combined immunodeficiency disease was found in five living males in an extended family in the United States. The age of the affected males ranged from 2.5 to 34 yr. The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections. The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes. Thus, affected males in this family carry an abnormal gene on their X chromosome that results in a combined immunodeficiency that is distinct from previously reported disorders.

Double-negative (CD4- CD8-) T cells with an alpha/beta T cell receptor. Non-MHC-restricted cytolytic activity and lymphokine production.

T cell lines with a novel phenotype (CD3+ TCR-alpha/beta+ CD4- CD8-) were developed from the peripheral blood of a patient with a combined immunodeficiency and tissue injury resembling graft-vs-host disease. One of these IL-2-dependent T cell lines demonstrated non-MHC-restricted cytolytic function against tumor targets, syngeneic and allogeneic fibroblasts, and PHA blasts from allogeneic donors. The other cell line only became cytotoxic in the presence of lectin or anti-CD3 antibody. The two cell lines also differed in their expression of the T-200 gene products CD45RO (gp180) and CD45RA (gp220). Both cell lines produced tumor necrosis factor-alpha and -beta and IFN-gamma activity when activated with mitogens or PMA and IL-1. The in vitro functions of these T-cell lines suggest a potential role for alpha/beta double-negative T lymphocytes in tissue injury resembling graft-vs-host disease.

Simultaneously occurring condylomata acuminata, carcinoma in situ and verrucous carcinoma of the vulva and carcinoma in situ of the cervix in a young woman. A case report.

A case of simultaneously occurring condylomata acuminata, carcinoma in situ and verrucous carcinoma of the vulva and carcinoma in situ of the cervix was seen in a 26-year-old woman. In situ DNA hybridization on sections of the condyloma acuminata and verrucous carcinoma yielded DNA sequences for human papillomavirus 6.

A comprehensive immunotopographic map of human thymus.

We have achieved a comprehensive immunotopographic mapping of human thymus by using a large battery of monoclonal antibodies and the methodological refinement of comparative serial tissue section immunohistochemistry, allowing analysis of multiple phenotypes in the same tissue site. Previous immunohistochemical studies of thymus have concentrated on the majority T-cell and epithelial cell populations. Besides demonstrating the complexity of T-cell antigenic expression (e.g., simultaneous cortical expression of Leu 2, Leu 3, CALLA, Tdt, and Leu 6), we delineate surprisingly complex B-cell zones (e.g., septal B-follicles with DRC+C3d+ dendritic cells and zonal maturation of B-cells). Whereas septal B-follicles were found in 25% of cases, medullary B-cells were universally present as a substantial minority component. This expanded immunotopographic knowledge of the complex T-, B-, epithelial, and reticulum cell neighborhoods suggests that the thymus is an organ capable of a broad repertoire of immunological responses, not limited to T-cell development.

Delineation of a novel pre-B cell component in plasma cell myeloma: immunochemical, immunophenotypic, genotypic, cytologic, cell culture, and kinetic features.

A novel pre-B cell component in direct and cultured myeloma bone marrow material has been delineated by using immunochemistry and flow cytometry techniques. Our phenotypic studies suggest a novel hybrid expression of pre-B and plasma cell antigens with coexpression of cytoplasmic mu, common acute lymphoblastic leukemia antigen, terminal deoxynucleotidyl transferase, and plasma cell antigens (PCA-1 and PC-1). This suggests that myeloma pre-B-like cells are aberrant malignant cells and not normal pre-B lymphocytic counterparts. With the advantage of a pure and stable source of these cells from M3 culture to allow molecular characterization, we performed one- and two-dimensional gel electrophoresis and Western blotting. We found that the cytoplasmic mu in myeloma pre-B-like cells has a molecular weight of 74,000 daltons and an isoelectric point of 6.3 and that it is strikingly homogeneous and discrete in size and charge compared with standard secretory mu, which suggests an aberrant, mutant, or monoclonal form of mu. Monoclonality was further evidenced by heavy- and light-chain immunoglobulin gene rearrangements demonstrated with JH and C kappa probes. We also established that this novel myeloma pre-B component is a major proliferative element as determined by double-labeling experiments with phenotype coupled to labeling/proliferative indexes. Our stimulatory studies indicate some capacity of these cells to mature on exposure to phorbol esters. These myeloma pre-B cells may represent the stem cell or self-renewal component in myeloma. Our establishment of these cells in long-term culture offers a considerable asset in studying the immature cells, which may be critical to the immortalization of myeloma.

Immunologic complexity of lymphoblastic lymphoma.

Twelve patients with a histologic diagnosis of lymphoblastic lymphoma (LBL) were studied immunologically using the methodologic refinement of comparative serial section immunochemistry. By this means, we demonstrate complex LBL phenotypic profiles, revealing 3 major immunologic subtypes: immature T cell, 7 cases; intermediate or mature T cell, 3 cases; immature B cell (pre-pre-B), 2 cases. This phenotypic diversity challenges the basic belief that all LBL are the same. Our immature T-cell cases with frequent simultaneous Leu 2/3/6/9/CALLA/Tdt expression correspond to cortical thymic phenotypes; our mature T-cell phenotypes with Leu 9/la expression and absent L6/Tdt correspond either to medullary thymocytes or post-thymic T cells; our pre-pre-B phenotypes with simultaneous Tdt/CALLA/B4 expression correspond to common acute lymphocytic leukemia (ALL) phenotypes. Mature T-LBL phenotypes are similar to "novel" peripheral T-cell lymphoma phenotypes. Scant or absent Tdt expression in mature LBL is not an isolated antigenic change but a complete phenotypic profile difference from immature T-LBL. The major T- and B-cell phenotypes of LBL might have therapeutic significance. Treatment among LBL phenotypes may need to vary as with acute lymphocytic leukemia phenotypes. Further study is needed; in the meantime, comparative serial section immunotyping promises substantial utility in revealing the immunologic complexity of the lymphomas.

The immunoarchitecture of cutaneous pseudolymphoma.

The immunoarchitecture of five cutaneous pseudolymphomas was studied by staining serial sections for T- and B-cell and dendritic reticulum cell (DRC) antigens with monoclonal antibodies, and compared with that of reactive lymph nodes and cutaneous lymphoma. In four cases compartmentalization of B and T cells was observed, analogous to findings in reactive lymph nodes. In two of these cases the immunoarchitectural features were strikingly similar to those of reactive lymph nodes. Both had distinct follicles with germinal centers, and in one distinct mantle zone formation was seen. B cells in the follicles were polyclonal, with kappa chain predominance. The germinal centers showed the expected intercellular and/or dendritic pattern of immunoglobulin heavy chain, B2, and DRC-antigen expression. T cells admixed in the germinal centers were overwhelmingly of the T-helper type. The B-cell compartments in the other two cases showed some subtle immunologic evidence of aberrance, but the weight of evidence suggested reactive/aberrant rather than malignant processes. The T-cell compartments in all four cases showed a predominance of T-helper and a minority of T-suppressor/cytotoxic cells. All contrasted with the lymphomas, which showed B-cell monoclonality, markedly deranged T-subset proportions, or novel T-cell phenotypes. Although the main focus of this study was cases involving substantial populations of both B and T cells, preliminary observations were made in one case in which a predominance of T cells and prominent epidermotropism simulated mycosis fungoides. Quantitative ultrastructural analysis in this case suggested a reactive T-cell process. Leu-6-positive Langerhans cells were increased in the epidermis and dermis in all five cases, and in the dermis they were found almost exclusively in T-cell compartments. It is proposed that this distribution is the anatomic correlate to the known functional role of Langerhans cells in antigen processing/presentation and T-cell activation. In the cutaneous "lymph node equivalent," Langerhans cells are analogous to interdigitating reticulum cells of reactive lymph nodes in distribution and, probably, in function. The DRC found in the germinal centers in two cases were probably antigenically identical and functionally analogous to those in germinal centers of reactive lymph nodes. Immunologic phenotyping of serial cutaneous sections may aid in distinguishing reactive from neoplastic lymphoid lesions. Immunoarchitectural analysis promises to be a powerful tool for the study of lymphoproliferative disease.

Peripheral T-cell lymphoma: aggressive disease with heterogeneous immunotypes.

Eleven patients with mature or peripheral T-cell lymphoma (PTL), other than mycosis fungoides, were identified using an extensive battery of T- and B-cell markers. Eight cases had a histologic diagnosis of either diffuse large cell or mixed lymphoma, three of small cell type. All cases had one or more "mature" T-antigens and an absence of B- and immature T-antigens. Assessment of T-antigens included E-rosettes (Er), anti-Leu 1-7 and Tdt. The authors delineated striking heterogeneity of T-antigen expression: 9 different immunotypes in 11 cases. Subset T-antigen assessment indicated T-helper neoplastic cells in five cases and T-suppressor in two. The remaining four had universal T-antigens alone. Seven cases appeared to have "novel" T-phenotypes not corresponding to normal T-ontogeny phenotypes. Novel or idiosyncratic phenotypes may be a key characteristic of PTL. Since no single T-antigen, including Er and Er receptor (Leu-5), was expressed in all cases, a battery of monoclonal antibodies is necessary to detect PTL. Clinically, the authors found PTL unexpectedly aggressive, despite mature immunotype. Most patients were elderly (median age 69); all had extranodal disease with cutaneous involvement (six cases) most frequent. Responses to chemotherapy frequently proved transient, with median survival of nine months. A fulminant course was noted even with localized presentation. Clinical outcome suggests PTL requires new therapeutic strategies.

Immunotopography of splenic lymphoma of small cleaved B-cell type.

Using a battery of monoclonal antibodies on snap-frozen sections, we delineated the immunoarchitecture of two splenic small cleaved cell lymphomas (SCL). Both cases had light- and heavy-chain restricted immunoglobulin (lg) expression signifying replacement of splenic white pulp by a single B-cell clone. Both the monotypia and aberrant topography of lg expression in SCL contrasted with the usual polyclonal, zonal lg expression in reactive splenic B-cell zones. Pan B antigens (B1, B4, and L14) were constant in expression as expected for B-cell neoplasms, while B-cell maturation antigens (B2, IgD, and CALLA) were variably expressed, suggesting that different SCL may derive from separate phases of B-cell ontogeny. Close association of SCL with dendritic reticulum cells suggests SCL may derive from splenic secondary follicles or home to these sites. The variable T-cell component detected by a T-cell panel (Leu 1-9) indicates the substantial range of T-cell reactivity in splenic SCL. We emphasize the immunologic aberrancy of splenic SCL when compared to normal splenic B-cell immunotopography. Further, we illustrate the utility of serial tissue section immunochemistry in revealing complex neoplastic cell phenotypes and in revealing the relationships of reactive cells to neoplastic cells.

Further delineation of the immunoarchitecture of the human spleen.

Using a battery of monoclonal antibodies directed at B and T cell antigens, we delineate the immunotopography of the human spleen. The tissue section immunohistochemical methods employed demonstrate the complexity of white pulp reactivity with both light and heavy chain immunoglobulin expression appearing polyclonal. Zonal expression of heavy chains suggests an anatomic basis for the known sequence of heavy chain switching due to immunoglobulin gene rearrangement. Localization of universal B-cell antigen, B1, delineates the entire B-cell zone whereas antibodies directed at universal T antigens (e.g. Leu 1, 4, 9) delineate the T cell zone. Leu 14 demonstrates striking B-zone staining in normal spleen and in hairy cell leukemia, suggesting that leukemic cells in this disease arise from Leu 14+ B cells. Leu 2a staining occurs not only on lymphoid cells but probably also on sinusoidal endothelial lining cells.

Anatomic-ultrasound correlations for intraoperative open chest imaging of coronary artery atherosclerotic lesions in human beings.

This study was performed to further validate a method for intraoperative ultrasound imaging of coronary arteries. Ultrasound images of coronary atherosclerotic lesions were compared with anatomic specimens of the coronary arteries obtained from open chest human subjects. The anatomic specimens were derived from four cardiac transplant recipients, accepted as candidates for transplantation because they had severe diffuse atherosclerotic disease, and one patient who died in the early postoperative period after a coronary artery bypass procedure. Twenty-six ultrasonically imaged atherosclerotic areas of the coronary arteries in these patients were compared with formalin-fixed and decalcified anatomic specimens. Specific ultrasound appearances for atherosclerotic lesions were observed, including 1) discrete (focal) stenosing fibrous/atheromatous plaques; 2) diffuse nonobstructive fibrous/atheromatous disease (detectable even in anatomically small vessels); 3) complete occlusion by fibrous/atheromatous lesions or organizing thrombus; and 4) "shadowing," an ultrasound pattern characteristic of significant calcification within atherosclerotic plaques. As part of this study, a new 12 MHz water path probe was evaluated for coronary artery scanning. The new probe allowed improved access to coronary arteries and increased detail of anatomic visualization. Both the performance of the new high resolution probe and the knowledge gained by the anatomic correlations obtained in this study should aid the development of intraoperative coronary artery scanning for surgical localization of atherosclerotic disease during coronary bypass surgery.