A prospective randomized study of alpha-2b interferon plus hydroxyurea or cytarabine for patients with early chronic phase chronic myelogenous leukemia: the International Oncology Study Group CML1 study.

A prospective randomized international study of 143 patients showed no apparent early survival advantage conferred by combining cytarabine, rather than hydroxyurea, with INF as first-line CML therapy. Combinations of alpha-interferon (INF) and chemotherapeutic agents are currently first-line therapy for the majority of patients with chronic myeloid leukemia (CML). The International Oncology Study Group conducted a prospective randomized study comparing INF combined with hydroxyurea or cytarabine. The primary study aim was to compare the survival durations in these patient cohorts. Patients with early chronic phase CML were randomized to receive INF 5 million units (Mu) given five times per week subcutaneously plus hydroxyurea or cytarabine as required to achieve a complete hematologic response and to maintain a WBC count between 2x10(9)/L and 10x10(9)/L and a platelet count between 75x10(9)/L and 100x10(9)/L. Therapy continued as tolerated unless progressive or blast phase disease occurred. At 36 months, the actuarial survival rate was equivalent in both groups: HI group (79 patients) survival was 85% (95% CI, 68-100%), as compared to 95% (95% CI, 79-100%) in the CI group (64 patients). In conclusion if seems that there is no apparent early survival advantage conferred by combining cytarabine, rather than hydroxyurea, with INF as first-line CML therapy.

Prevalence and molecular characterization of beta-thalassemia in Filipinos.

Beta-thalassemia (thal) is a common single-gene disease worldwide. However, the prevalence of beta-thal and the spectrum of beta-globin gene mutations in Filipinos remain unclear. This study sought to answer these two questions. A total of 2954 apparently healthy Filipinos in Taiwan were recruited for a prevalence study. A complete blood count was done in every subject. Those with microcytosis were studied with hemoglobin (Hb) high-performance liquid chromatography to determine the levels of Hb A2 and Hb F. Twenty-seven subjects had elevated levels of Hb A2 (>4.0%). These 27 suspected beta-thal carriers and another 16 beta-thal major patients who were being treated in the Philippines were studied to determine the spectrum of beta-globin gene mutations. Gap-PCR was used to detect the Filipino deletion of beta-thal, and direct sequencing was used to detect point or small mutations in the beta-globin gene. All of the 27 suspected beta-thal carriers had one mutation in the beta-globin gene, resulting in an overall prevalence of 0.9%. The spectrum of beta-thal mutations was similar in the carrier and patient groups. Analysis of the pooled identified seven different mutations in the study population. The Filipino deletion was the most common mutation, accounting for 45.8% (27/59) of the alleles, followed by codon 67 (-TG) (16 alleles), and Hb E (11 alleles). These three mutations accounted for 92% of the Filipino beta-thal alleles. Elucidation of the beta-thal mutations in Filipinos is useful for the genetic counseling and prenatal diagnosis of this disease.

The role of monocytes in human lymphocyte activation by mitogens.

Studies were performed to determine the role of monocytes in human lymphocyte activation by mitogens. Velocity sedimentation at 1 x G in a new apparatus was utilized to obtain highly purified lymphocyte fractions (LF) nearly free of monocytes (0.02 to 0.4%) and a fraction (MF) enriched for monocytes (64 to 92%). The average peak responses of the lymphocyte fractions to phytohemagglutinin, concanavalin A, and pokeweed mitogen were 19, 10, and 9% of the responses achieved with unfractionated lymphocyte cultures containing approximately 20% monocytes. These changes were not attributable to altered dose requirements. When mitomycin-C-treated MF cells were used to reconstitute LF cultures, it was found that 4% monocytes fully restored the response to phytohemagglutinin whereas 8 to 16% monocytes were required for a normal response to the other mitogens. Higher numbers of MF cells produced supranormal responses, with 35 to 50% monocytes resulting in the optimal stimulation. Allogeneic monocytes were able to fully reconstitute the response of LF, and 2-mercaptoethanol (50 microM) was only slightly effective. In exploring possible mechanisms by which monocytes potentiate the mitogenic activity of lymphocytes, it was found that the supernatants of MF cultures could partially, but not completely, reconstitute LF responses, suggesting that contact with MF may be required for optimal effectiveness. Addition of graded numbers of monocytes to LF altered both the kinetics of the response and the peak level of proliferation. Monocyte depletion also resulted in markedly decreased survival of cultured unstimulated LF. These observations suggest a variety of possible effects of monocytes in potentiating mitogenic responses, including contact-mediated interactions with lymphocytes (possibly to present the mitogen optimally); enhancement of proliferation kinetics and the size of the responding subpopulation, and maintenance of a requisite growth factor(s) in the culture. Small differences in the monocyte content of cultured lymphocyte preparations may thus account for many of the often observed variations in mitogen responsiveness.

Spontaneous lymphocyte proliferation and depressed cellular immunity in Hodgkin's disease.

Patients with Hodgkin's disease have increased numbers of spontaneously proliferating circulating lymphocytes. In order to test the relationship between this phenomenon and the in vitro mitogenic response, both spontaneous lymphocyte proliferation and the response to stimulation with phytohaemagglutinin were quantified. In addition, the proliferating lymphocytes were identified autoradiographically and characterized for the presence of lymphocyte surface markers and monocyte markers. Spontaneous thymidine incorporation by lymphocytes from patients with Hodgkin's disease was increased compared with normal controls, and the phytohaemagglutinin response was depressed. A significant inverse relationship was demonstrated between the spontaneous thymidine incorporation on day 0 and the phytohaemagglutinin response on day 3 (P is less than 0.01). The activated lymphocytes were heterogeneous with respect to both morphology and surface markers. These data suggest that the circulating proliferating lymphocytes in Hodgkin's disease are reactive cells and that the quantitative depression in cellular immunity demonstrable in these patients may be related to this chronic reactivity.