High-dose therapy and autologous stem cell transplant does not result in long-term disease-free survival in patients with recurrent chemotherapy-sensitive ALK-negative anaplastic large-cell lymphoma.

Primary systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) has a poor prognosis. This study sought to determine if high-dose therapy and ASCT results in long-term disease-free survival (DFS) in patients with recurrent, chemotherapy-sensitive ALK-negative ALCL. All patients with non-Hodgkin's lymphoma (NHL) who underwent ASCT at Wake Forest University and Upstate Medical University from 1 January 1990 to 12 December 2002 were reviewed to determine if they had T-, B- or null-cell NHL that was CD30+/CD15-/ALK negative. In all, 16 patients were thus identified as having ALK-negative ALCL. All 16 patients underwent ASCT at the time of first relapse and form the basis of this report. Median age of the 16 patients was 51 years. There were 11 males and five females. International prognostic index scores in 12 patients at the time of relapse were: low 3, LI 6 and HI 3. Of 15 patients, 13 relapsed after ASCT; one patient was lost to follow-up. Median progression-free survival for the 15 patients was 12 weeks (3-212+ weeks). Of 15 patients, 10 have died; nine of recurrent disease. Median overall survival for the 15 evaluable patients was 72 weeks. In our experience, high-dose therapy and ASCT does not produce long-term DFS in patients with recurrent chemotherapy-sensitive ALK-negative ALCL.

Fatal EBV-related post-transplant lymphoproliferative disorder (LPD) after matched related donor nonmyeloablative peripheral blood progenitor cell transplant.

A 39-year-old male underwent a nonmyeloablative stem cell transplant (NMAPBPCT) from his HLA-matched sister for recurrent anaplastic large cell lymphoma in CR-2, receiving fludarabine, cyclophosphamide, and rabbit antithymocyte globulin for the preparative therapy. The patient was readmitted on day+33 for persistent culture-negative fevers. He rapidly developed marked elevations of alkaline phosphatase and bilirubin. Liver biopsy showed a periportal infiltrate of large immunoblastic appearing cells. The tumor cells did not stain for CD3/CD20/CD30 and alk protein, but did stain for CD79a/LCA and CD43. In situ hybridization for Epstein-Barr virus (EBV) RNA (EBER 1) was strongly positive in the periportal infiltrating lymphocytes. Fluorescence in situ hybridization (FISH) studies revealed female (XX) cells in the tumor cells and male (XY) in the surrounding hepatic parenchymal cells. The patient developed severe lactic acidosis, oliguric renal failure and expired on day+44. Both donor and patient had positive IgG serologies for EBV VCA and EBNA pretransplant. The donor also had a positive IgM titer for EBV VCA in the pretransplant specimen. The LPD may have been related to the intense immunosuppression of the preparative therapy and the presence of recent EBV infection in the donor.

Hematologic toxic reaction to radiation therapy adjuvant to autologous peripheral blood stem cell transplantation for recurrent or refractory Hodgkin disease.

PURPOSE: To evaluate the hematologic toxic reaction to external-beam radiation therapy after high-dose chemotherapy with peripheral blood stem cell (PBSC) support in patients with Hodgkin disease. MATERIALS AND METHODS: A retrospective study of 30 cases of Hodgkin disease in patients who underwent high-dose carmustine, etoposide, and cyclophosphamide chemotherapy with PBSC support was performed. Thirteen patients underwent radiation therapy (28.8-39.0 Gy) a median of 45 days after PBSC repeat infusion. RESULTS: Radiation therapy was delivered as planned, without interruption, in all patients. Five patients developed thrombocytopenia (one with grade 1 thrombocytopenia; two, grade 2; and two, grade 3) and included three with progressive disease prior to radiation therapy and two with a history of prior irradiation. None developed a bleeding complication or required transfusion support. Five patients who underwent irradiation had thrombocytopenia (three with grade 1 and two with grade 2) 100 days after PBSC repeat infusion, compared with three patients (two with grade 1 and one with grade 3) who did not undergo posttransplantation irradiation. At the most recent follow-up, no patient without evidence of disease had a platelet count of less than 100 x 10(9)/L. CONCLUSION: External-beam radiation therapy was well tolerated in the posttransplantation setting in patients with Hodgkin disease. Thrombocytopenia was common but was not related to clinical complications.

Chest radiographic features of engraftment syndrome.

About the time of hematopoietic engraftment, patients undergoing autologous hematopoietic stem cell transplantation in the form of peripheral blood stem cell transplantation (PSCT) may develop an "engraftment syndrome" that includes fever, skin rash, and capillary leak. This condition is usually self-limited, as opposed to other early complications of bone marrow transplantation such as infection and drug reactions. This article describes the chest radiographic manifestations of engraftment syndrome. The medical records and chest radiographs of 50 consecutive breast cancer patients who underwent PSCT were retrospectively reviewed. Engraftment syndrome was diagnosed if the expected clinical findings occurred at the time of engraftment of neutrophils and no other cause was identified. The chest radiographs were correlated with the clinical course. Sixteen patients were found to have engraftment syndrome (32%). Of these, eight had abnormal radiographs. Radiographic findings consisted of pleural effusions and interstitial pulmonary edema. No patient progressed to adult respiratory distress syndrome. Interstitial pulmonary edema and pleural effusions were observed in association with engraftment syndrome from PSCT. Correlation of these findings with clinical history and neutrophil count is important so that engraftment syndrome can be distinguished from other causes of fever.

Extramedullary granulopoiesis mimicking recurrent lymphoma after prolonged administration of human recombinant granulocyte colony-stimulating factor.

Human recombinant granulocyte colony-stimulating factor (G-CSF) has become a treatment of choice for neutropenia of diverse etiologies. We describe a 71-year-old man who, while receiving G-CSF for graft failure after peripheral blood stem cell transplant, developed dramatic extramedullary granulopoiesis that mimicked recurrent lymphoma.

Efficacy of alpha interferon and hydroxyurea in late phase refractory myeloproliferative disease.

Three patients are described with late-stage myeloproliferative diseases, two with accelerated phase chronic myelogenous leukemia (CML) and one with refractory polycythemia vera (P vera), who achieved hematologic control after the addition of interferon (IFN) to hydroxyurea therapy. Both the CML patients continue to have a sustained clinical remission at 12 and 38 months. The patient with P vera had failed several previous treatments including busulfan, P32, hydroxyurea, and anagrelide, but became responsive after interferon use followed by reintroduction of hydroxyurea. Our observations support the efficacy of IFN alpha and hydroxyurea combination in late-phase myeloproliferative disease and warrants further clinical investigation.

A phase I trial of recombinant human macrophage colony-stimulating factor by rapid intravenous infusion in patients with refractory malignancy.

Twenty patients with advanced cancer for which there was no effective standard therapy or whose disease was refractory to standard therapy were treated with recombinant macrophage colony-stimulating factor (rM-CSF). The rM-CSF was administered by intravenous bolus infusion for 5 consecutive days every other week for 2 treatment weeks. The doses administered ranged from 30 to 33,000 micrograms/m2/day. There was no intrapatient dose escalation. There were minimal to no systemic side effects seen, except for acute dyspnea noted in three patients. The dyspnea was felt to be related to the rate of infusion and did not recur in one patient given additional rM-CSF at a slower infusion rate. The major hematologic effect seen was a mild decrease in platelet count, which began to recover while the patients continued to receive the rM-CSF. The clearance of rM-CSF was dose dependent. Lower doses resulted in a saturable mechanism felt to represent cellular uptake. Clearance at higher doses demonstrated both a first-order mechanism at high serum rM-CSF concentrations, representing renal clearance, as well as a saturable mechanism at low serum concentrations. The maximum mean serum half-life was reached at dose levels of greater than or equal to 3,690 micrograms/m2 and was in the range of 234-258 min. By this route of administration, rises in absolute monocyte count were slight and seen only at doses of greater than or equal to 450 micrograms/m2 during the second therapy week. The maximum tolerated dose was not reached in this study because of lack of availability of rM-CSF.

Hypercalcemia with excess serum 1,25 dihydroxyvitamin D in lymphomatoid granulomatosis/angiocentric lymphoma.

Hypercalcemia has been described in a variety of granulomatous and lymphoproliferative disorders in association with elevated serum levels of 1,25-dihydroxyvitamin D. In such cases, hypercalcemia appears to be the consequence of excessive production of 1,25(OH)2D by the lymphocyte/macrophage line. The authors report a patient with lymphomatoid granulomatosis/angiocentric lymphoma who developed hypercalcemia with extreme elevation in serum 1,25(OH)2D. Therapy with steroids reduced the serum calcium and 1,25(OH)2D levels to normal. Hypercalcemia has not previously been reported in lymphomatoid granulomatosis/angiocentric lymphoma. The distinctive features of this malignancy, and the derangement in the metabolism of 1,25(OH)2D in lymphoproliferative disorders in general, are discussed.

Necrobiotic xanthogranuloma with IgA multiple myeloma: a case report and literature review.

The association between necrobiotic xanthogranuloma of the dermis and paraproteinemia and/or B-cell malignancy is best described in the ophthalmologic literature. We report a case which occurred in the eyelid and orbit of a 64 year old man that led to the diagnosis of an IgA multiple myeloma. To our knowledge, this is the first report of an IgA type paraproteinemia and IgA type multiple myeloma associated with necrobiotic xanthogranuloma.

Inducible lymphokine-activated killer (LAK) cell activity in the peripheral blood of patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).

Therapy with recombinant interleukin-2 (rIL-2) induces clinical response in a significant number of patients with refractory malignant disease. Very few patients with non-Hodgkin's lymphoma (NHL) have been treated with rIL-2. The present study sought to determine if peripheral blood mononuclear cells (PBM) from patients with relapsed/refractory non-Hodgkin's lymphoma could be induced in vitro to generate LAK cell activity. PBM from 28 patients with relapsed/refractory NHL were incubated for 7 days in rIL-2 to determine their ability to lyse the LAK cell sensitive Daudi cell line. The PBM from all patients were able to generate LAK activity after in vitro incubation in rIL-2. Approximately one third of the patients' PBM samples generated less activity than activity generated in the PBM sample from normal control donors. However, two-thirds of patient samples were able to generate activity equal to or greater than that of the controls. The degree of LAK activity generated by the patients' PBM did not correlate either with histologic subtype or amount of prior chemotherapy. The amount of LAK activity an individual generated (control or patient) tended to remain stable over time.

A phase I trial of subcutaneously administered recombination tumor necrosis factor to patients with advanced malignancy.

Nineteen patients with advanced cancer for which there was no effective standard therapy or whose disease was refractory to standard therapy were treated with recombinant tumor necrosis factor (rTNF). The rTNF was administered subcutaneously for 5 consecutive days every other week for 3 treatment weeks. The doses administered ranged from 5 micrograms/m2/day to 150 micrograms/m2/day. There was no intrapatient dose escalation. Systemic side effects of chills, fever, hypotension, nausea, vomiting, and headache were mild and self-limiting. At the maximum tolerated dose of 150 micrograms/m2/day, five of seven patients experienced moderate to severe thrombocytopenia. Mild rapid declines in total leukocyte count occurred within 60-90 min of administration of the drug, followed by a rise in the total leukocyte count by 120 min. When the total daily dose was administered in a single subcutaneous site, skin ulceration and necrosis occurred at the 100 micrograms/m2/day dose. By giving the total daily dose in two subcutaneous sites, the maximum tolerated dose increased to 150 micrograms/m2/day, and there was no further skin ulceration or necrosis. Skin necrosis occurred in the abdomen and thigh but not on the upper extremity at the 100 micrograms/m2/day dose given in a single site. There was no other significant organ toxicity. No rTNF was detectable in the serum even at the highest doses. No antibodies to TNF developed in any of the patients. The recommended dose of rTNF for Phase II trials given for 5 days subcutaneously is 150 micrograms/m2/day divided into two or more sites.

Differential effect on fresh and cultured T cells of PHA-induced changes in free cytoplasmic calcium: relation to IL-2 receptor expression, IL-2 production, and proliferation.

PHA stimulation of both freshly isolated and IL-2-dependent cultured T cells induced a rapid rise in intracytoplasmic calcium concentration. Chelation of extracellular calcium with EGTA resulted in a failure of PHA to induce a rise in intracytoplasmic calcium, resulting in the fresh T cells in an inhibition of IL-2 production, IL-2 receptor expression, and proliferation. However, cultured T cells grown in recombinant IL-2 were able to re-express IL-2 receptors and proliferate in response to PHA stimulation in the presence of EGTA. Thus the PHA-induced signal for expression of IL-2 receptors and T-cell proliferation differs in fresh and cultured T cells and required extracellular calcium in fresh but not in cultured T cells.

Thrombotic thrombocytopenic purpura: treatment with plasmapheresis.

Twenty-one episodes of thrombotic thrombocytopenic purpura (TTP) were treated with plasmapheresis. Adjunctive agents included corticosteroids, aspirin, dipyridamole, and vincristine. There were 17 patients; 12 were female. The median age was 41 years. Most patients presented with neurologic symptoms. Thrombocytopenia was profound with a mean initial platelet count of 14,900/mm3. The mean hematocrit on presentation was 26.7% and the mean LDH 1300 IU/L. Eighteen episodes responded completely following plasmapheresis/plasma exchange (86%). Response was prompt, the initial rise in platelet count occurred after a mean of four exchanges, and complete response (a platelet count over 150,000/mm3) was obtained after a mean of nine exchanges. Four of the episodes treated were relapses that occurred in three patients. All responders are alive with a median duration of follow-up of 20 months. The three patients who failed to respond have died. This report extends recent observations that the addition of plasmapheresis/plasma exchange to the therapy of TTP has significantly improved the outlook for patients with this disorder.

Interleukin-2 production in the neonatal mouse.

Neonatal mouse spleen and thymus cells fail to produce interleukin-2 (IL-2) in vitro. In vitro IL-2 production by spleen cells begins to develop between 20 and 27 days of age and reaches adult levels at 40 days of age. Thymus cells do not develop the ability to produce IL-2 in vitro. Addition of neonatal spleen, neonatal thymus, or adult thymus cells to adult spleen cell cultures inhibits IL-2 production. Treatment of the added cells with mitomycin does not abrogate their suppressor activity. Soluble factors, obtained from three-day cell cultures of neonatal spleen, neonatal thymus, or adult thymus also suppress IL-2 production in adult spleen cell cultures. Addition of interleukin-1 raises IL-2 production in adult thymus, neonatal spleen, or neonatal thymus cell cultures slightly, but the IL-2 productivity is still considerably lower than that of adult spleen in the absence of IL-1. The results indicate that suppressor cells for IL-2 production are present in neonatal spleen and thymus. The splenic suppressor cell activity disappears after birth, but thymic suppressor cell activity is retained into adulthood.

Thyrotoxic thyroiditis after radiotherapy for Hodgkin's disease.

Exposure of the thyroid gland to ionizing radiation has been associated with a variety of abnormalities. Among these are tardive hypothyroidism and an increased risk of developing thyroid nodules and cancer. Although acute thyroiditis has been known to complicate radioactive iodine 131 therapy, it has rarely been associated with external beam irradiation. Thyrotoxic painless thyroiditis developed in two patients after mantle-field irradiation for Hodgkin's disease.

Impaired interleukin regulation of the phytohemagglutinin response in Hodgkin's disease.

Patients with active Hodgkin's disease (HD) often demonstrate an impaired T-cell proliferative response to phytohemagglutinin (PHA). The present study examined if interleukin regulation of the PHA response was defective in HD. The Hodgkin's PHA response was impaired at all concentrations of PHA utilized. Indomethacin increased the proliferative response but did not bring it to control levels. Stimulation of the cells with both PHA and irradiated Ia+ B cells normalized proliferation despite identical PGE2 concentrations as in the PHA alone cultures. Hodgkin's monocytes produced normal amounts of interleukin 1 (IL-1). Interleukin 2 (IL-2) production by Hodgkin's T cells was decreased in the PHA stimulated cultures, but was normal in the PHA and Ia+ cell stimulated cultures. In response to PHA stimulation alone, Hodgkin's T cells expressed less IL-2 receptor than control cells. The data suggest the diminished PHA response in HD is due to impaired IL-2 production resulting in diminished IL-2 receptor expression. However, when an Ia+ cell source is added to PHA as an additional stimulator, both TCGF production and proliferation are normalized. Monocytes serve to modulate the magnitude of the PHA response through production of both interleukin 1 and PGE2. However, in the presence of sufficient IL-2 production the influence of monocytes is minimized.

T cell growth factor required for optimal induction of T cell growth factor receptor expression in phytohemagglutinin-stimulated T cells.

Proliferation of normal human T cells in vitro requires activation of resting T cells by lectin or antigen. This stimulation initiates a series of events which includes elaboration of T cell growth factor (TCGF), expression of TCGF receptors, and, ultimately, cellular proliferation. We sought to determine if TCGF was required for expression of the TCGF receptor in phytohemagglutinin (PHA)-stimulated normal human T cells. Utilizing dexamethasone (DEX), a known inhibitor of TCGF production, reductions in T cell proliferation, TCGF production, and TCGF receptor expression, as measured by TCGF adsorption and Tac acquisition, were demonstrated after PHA stimulation. When exogenous partially purified TCGF was added to DEX-containing cultures, the DEX inhibition of proliferation and TCGF receptor expression was completely reversed. These experiments were reproduced utilizing both highly purified TCGF from the Jurkat cell line and purified TCGF synthesized by bacteria from cloned TCGF DNA. Short-term experiments showed TCGF to be capable of restoring Tac antigen expression after DEX inhibition in the absence of cellular proliferation. These results indicate that TCGF is required for optimal expression of Tac antigen-associated TCGF receptors in PHA-activated T cells.

Inverse relationship between constitutive gamma interferon production and human T-cell lymphoma/leukemia virus expression in cultured T lymphocytes.

Particular interest in human T lymphocyte lymphoma/leukemia virus (HTLV) derives from the close association of HTLV with several types of human mature T lymphocyte malignancies and the strong possibility that HTLV is the causative agent of this group of leukemias and lymphomas. This is the first report to show that HTLV expression in T lymphocytes cultured in vitro is inversely proportional to constitutive gamma interferon production. Of 16 fresh T lymphocyte cultures established from patients with mature T lymphocyte neoplasias, 3 were grown continuously for over 3 years and 13 were grown for 2 to 8 months in culture. Of the 16 cultures, 9 were HTLVp19 positive and interferon negative, whereas the remaining 7 were HTLVp19 negative or weakly positive and also interferon positive (12 to 105 U/ml). The prototype HTLV-positive T-cell line (HUT102) was examined over a long-term culture and after selective cell cloning for high virus yield. Results indicate that early-passage, low-HTLV-producing HUT102 cells constitutively produced significant levels of gamma-immune interferon. In late-passage and cloned HUT102 cells, an increase in HTLV production was concordant with a decrease in constitutive interferon production and the loss of mature T lymphocyte antigens. Transformation of human umbilical cord blood lymphocytes by HTLV was possible only after cocultivation with the non-interferon, high virus-producing, cloned HUT102 T lymphocytes. The inverse relationship between interferon and HTLV production was also observed when normal human umbilical cord blood and adult T lymphocytes were transformed by HTLV and maintained in culture.

The autologous mixed lymphocyte reaction in cord blood lymphocytes: altered kinetics and magnitude of proliferative response compared to the adult autologous mixed lymphocyte reaction.

In the autologous mixed lymphocyte reaction (AMLR) T lymphocytes proliferate in response to stimulation by autologous non-T mononuclear cells. The AMLR has characteristics of a cell mediated immune response, and is thus thought to play a role in immune regulation. Cord blood lymphocytes often function differently than do adult lymphocytes. To determine if the AMLR in cord blood differed from that of adults, the kinetics and magnitude of the proliferative response in the AMLR was studied in 20 cord bloods and 14 adults. The magnitude of the AMLR was significantly lower in the cord cells compared to the adult response on all days tested except days 1 and 2. On the first 2 days of culture the cord cells had a higher proliferative response than the adult cells, but this could be accounted for by the high spontaneous proliferation in the cord cells.

Functional diversity within the suppressor phenotype as defined by monoclonal antibody in T-cell prolymphocytic leukemia.

A patient with T-cell prolymphocytic leukemia (T-PLL) is described. The malignant T-cells from the patient were predominantly Leu-2-positive, indicating a suppressor phenotype. The cells were then tested to determine their functional capabilities. The patient's Leu-2-positive cells initially suppressed B-cell proliferation, as predicted by their phenotype but later functioned as T helper cells in the pokeweed mitogen system without a change in phenotype. The cells also responded inadequately to alloantigen and mitogen despite addition of exogenous T-cell growth factor (TCGF). Leu-2-positive prolymphocytes from the spleen of the patient were constitutive producers of TCGF. Surface phenotype using monoclonal antibody was inadequate to predict T-cell function of the cells from this patient with T-PLL. In addition, these data suggest there may be functional subpopulations within the OKT8+ phenotype. Constitutive TCGF production by malignant post-thymic T-cells may represent a mechanism by which these cells sustain their own growth.