Lymphoproliferated disorders involving large granular lymphocytes (LGL) can be divided into a common T-cell subset (CD3+, CD8+) and a rarer natural killer (NK)-cell subset (CD2+, CD3-). The immunophenotype, clinical pathologic features, and cytogenetic and molecular genetic analyses are reported for seven patients with NK-cell-LGL proliferation. The typical immunophenotype was CD2+, CD3-, CD4-, CD11b+, and CD16+ or CD56+. A low but variable percentage of cells were CD8+ or CD57+. Unusual phenotypes with CD2- (1 of 7), CD11b- (1 of 7), or CD16-/CD56- (1 of 7) cells were seen. Strong NK-cell activity was observed in all cases, indicating that none of the NK-cell markers (CD11b, CD16, CD56, CD57) is essential for NK-cell activity. One patient died shortly after diagnosis from coexistent refractory multiple myeloma and another patient died within 1 month from the LGL proliferation. The other patients had been followed for 12 to 70 months, with a median follow-up period of 38 months. There was no progression of their LGL proliferation. Lymphocyte counts varied from 3.3 x 10(3)/microL to 58.4 x 10(3)/microL at the time of diagnosis. Unexplained anemia and neutropenia were observed in one patient. Cytogenetic abnormalities were detected in two of four patients studied with t(6;12) in one and der(5), der(6), and der(11) in the other. The approximately T gamma and T beta genes were in the germline configuration and Epstein-Barr virus DNA was undetectable in five of five patients studied. Natural killer-cell LGL proliferations were morphologically indistinguishable from T-cell LGL proliferations. However, the two were immunophenotypically and genotypically distinct and NK-cell activity was consistently observed in the former. Most of the NK-cell proliferations also were chronic indolent disorders and the incidence of associated cytopenias seemed to be lower than T-cell LGL proliferations.
A case of pulmonary T-cell lymphoma in an Acquired Immune Deficiency Syndrome (AIDS) patient is presented. Morphologically, it belonged to the large cell, immunoblastic category of the Working Formulation and demonstrated a helper/inducer phenotype. Clinically there was no association with manifestations of human T-lymphotropic virus (HTLV)-I related lymphoma and the patient was seronegative for HTLV-I and HTLV-II antibodies. High-grade B-cell lymphomas occur with an increased frequency in patients with AIDS but the occurrence of a peripheral T-cell lymphoma in AIDS has not been documented before. The case is discussed in the context of current concepts of AIDS-related lymphomagenesis.
The authors performed a Phase I study to assess the toxicity and hematologic effect of recombinant human interleukin-2 (rIL-2) in seven children with advanced malignancies. The rIL-2 was given as a bolus injection of 1 or 3 X 10(6) U/m2/dose three times a week (Monday, Wednesday, and Friday) for 3 weeks. No life-threatening toxicity occurred with the dose of 1 X 10(6) U/m2 of rIL-2. At a dose of 3 X 10(6) U/m2, therapy had to be terminated due to cardiovascular toxicity in two patients. Toxic effects at low-dose rIL-2 included fever, nausea, vomiting, and mild hypotension. High-dose rIL-2 toxicity included fluid retention, increased creatinine, oliguria, elevated liver enzymes, and significant hypotension. Immunologic studies showed that rIL-2 caused a drop in the number of circulating peripheral blood mononuclear cells, T-cells, and natural killer cells which returned to pretherapy levels or above by 24 to 48 hours. The rIL-2 exerted no growth or stimulatory activity on the leukemic cell population. To the authors' knowledge, this is the first report of a Phase I study of IL-2 therapy in children.
In order to determine if recombinant interleukin-2 (rIL-2) can induce lymphokine-activated killer (LAK) cells able to lyse autologous leukemic cells, we incubated peripheral blood (PB) mononuclear cells from children with acute leukemia with 50 U/ml rIL-2 for 5 days. These PB effector cells were then tested for their ability to lyse autologous leukemic cells in a 51CR release assay. The PB cells before incubation with rIL-2 showed little or no cytotoxicity for autologous blasts (range, 0 to 12%; mean, 2%). However, after incubation with rIL-2, PB cells from four of five children with acute lymphoblastic leukemia (ALL) at diagnosis or in relapse, and from six of eight children with ALL in remission were able to lyse autologous blasts. The percent lysis (range) was 0 to 69% (mean, 37%) for the former group, and 0 to 113% (mean, 43%) for the latter group. The PB cells from three patients (one in relapse and two in remission) failed to develop LAK activity after incubation with rIL-2. However, in each case cytotoxicity versus K562 was increased after incubation with rIL-2. Furthermore, in a Phase I study of rIL-2 for the treatment of refractory leukemia, a patient was treated with rIL-2 for 3 weeks (nine injections of 3 x 10(6) U/m2 each). Her fresh PB mononuclear cells developed a low level of cytotoxicity (11% lysis) against her autologous blasts during this time. The finding that rIL-2 in vitro and in vivo induces LAK cells with cytotoxicity against autologous leukemic cells provides the rationale for the clinical trial of this agent in the treatment of children with ALL.
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