Long-term outcome following treatment of hairy cell leukemia with pentostatin (Nipent): a National Cancer Institute of Canada study.

We have previously demonstrated that pentostatin (Nipent; SuperGen, San Ramon, CA) is highly effective in the treatment of hairy cell leukemia and report here the long-term outcome of this study. Pentostatin was administered intravenously in cycles of 4 mg/m2 weekly x 3 repeated every 8 weeks. Patients who achieved a complete remission (CR) received two further cycles for consolidation. Of 28 evaluable patients, 25 achieved a CR and three a partial remission. Twenty-three patients are alive at a median follow-up duration of 118 months (range, 55 to 133 months). Of the 25 patients who achieved a CR, 14 (56%) remain in CR at a median of 119 months (range, 109 to 133 months) from the time of CR. Nine additional patients relapsed at a median time of 49 months (range, 15 to 122 months). Only three of the relapsed patients have required treatment: two patients who received cladribine achieved CRs; the third received interferon-alpha and died from hairy cell leukemia. The three patients in partial remission continue to have normal blood counts at 58, 105, and 120 months. Five patients have developed a second malignancy: one mycosis fungoides and four solid tumors. Three patients died from the second malignancies. There were no treatment-related deaths due to toxicity or opportunistic infection. Pentostatin is a highly effective agent for hairy cell leukemia and produces prolonged remissions in the majority of patients.

Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study.

PURPOSE: Therapy of hairy cell leukemia has markedly improved. Interferon alfa-2a and pentostatin are active agents. The National Cancer Institute organized an intergroup trial to compare these agents prospectively in untreated patients. METHODS: Patients were randomized to receive either interferon alfa-2a (3 x 10(6) U subcutaneously three times per week) or pentostatin (4 mg/m2 intravenously every 2 weeks). Patients who did not respond to initial treatment were crossed over. RESULTS: Of 356 patients on study, 313 were eligible. Among interferon patients, 17 of 159 (11%) achieved a confirmed complete remission and 60 of 159 (38%) had a confirmed complete or partial remission. Among pentostatin patients, 117 of 154 (76%) achieved a confirmed complete remission and 121 of 154 (79%) had a confirmed complete or partial remission. Additional patients achieved criteria for complete remission, but lacked confirmatory follow-up evaluation. Response rates were significantly higher (P < .0001) and relapse-free survival was significantly longer with pentostatin than interferon (P < .0001). The median follow-up duration is 57 months (range, 19 to 82). Myelosuppression was more frequent with pentostatin (P = .013). A multivariate logistic regression analysis of the confirmed complete remissions on pentostatin showed the following factors to be important for achieving a complete remission: high hemoglobin level (two-tailed P = .024), young age (P = .0085), and no or little splenomegaly (P = .0029). CONCLUSION: Both agents were well tolerated. Pentostatin produced higher response rates, and the responses were durable. Patient age and clinical status had an impact on outcome with pentostatin. Pentostatin is effective therapy for hairy cell leukemia.

Pancreatitis arthritis with periarticular fat necrosis.

We describe the case of a 76-year-old man hospitalized for 14 months because of a complicated hip fracture who developed pancreatitis and polyarthritis. He had no evidence of subcutaneous fat necrosis away from his joints and his pancreatitis was virtually asymptomatic otherwise. Polyarthritis is a rare complication of this disorder, and rarer still is polyarthritis without evidence of subcutaneous fat necrosis elsewhere.

Sensitivity of PCR in detecting monoclonal B cell proliferations.

AIMS: To evaluate the rapid detection of various forms of monoclonal B cell proliferations by using the polymerase chain reaction (PCR) to identify clonal immunoglobulin heavy chain genomic rearrangements. METHODS: Thirty four B cell lymphomas defined by morphology, immunophenotyping, and positive immunoglobulin heavy chain gene rearrangements detected by Southern blot analysis were examined. An additional 22 cases representing miscellaneous lymphoproliferative and non-lymphoproliferative disorders were also studied. RESULTS: Monoclonal rearrangements were identified in 19 (56%) cases of B cell lymphoma. The method was less sensitive in the detection of follicular centre cell lymphomas (15 of 28, or 54%) than non-follicular centre cell lesions (four of six, or 67%). Monoclonal rearrangement was not identified in 19 control cases, including T cell lymphomas, Hodgkin's disease, reactive lymphadenopathy and metastatic carcinoma. Three cases showed positive immunoglobulin gene rearrangement by PCR but were negative on Southern blotting. Two of these cases had definite clinical, morphological, and immunophenotypic evidence of monoclonal B cell proliferation suggesting that PCR could, on occasion, pick up cases missed by Southern blotting and that the two methods are complementary in clonal lymphoproliferative disease diagnosis. The third case represented a "false positive" PCR reaction involving a colonic adenocarcinoma. CONCLUSIONS: PCR analysis, using the primer sequences outlined in this study, will detect about 55% of clonal lymphoproliferative proliferations with increased sensitivity for non-follicular centre cell lesions. With these levels of detection in mind, this testing strategy can still be especially useful in cases which prove diagnostically problematic with standard morphological and immunophenotypic analysis, and in instances where the quantity and type of diagnostic material is limiting (needle aspirates and cellular fluids).

Efficacy of 2'-deoxycoformycin in hairy-cell leukemia: a study of the National Cancer Institute of Canada Clinical Trials Group.

Thirty-one patients with hairy-cell leukemia were treated with 2'-deoxycoformycin (DCF) in a National Cancer Institute of Canada multicenter trial. The DCF was administered in a cycle (4 mg/m2 iv weekly X 3), which was repeated every 8 weeks. Following a complete remission, consolidation was done with two further cycles of DCF. Of 28 patients evaluable for response, 25 obtained a complete remission; 3 had a partial response. To date there has been only one relapse; the median time with no therapy was 429.5 days (range 99-743 days). Toxicity was moderate and included nausea and vomiting, lethargy, and skin rash; with the first cycle of treatment, neutropenia and an increased incidence of fever or infection were also observed. We conclude that low-dose DCF is highly effective in treating hairy-cell leukemia.

Erythroblast multinuclearity in bone marrow and spleen. Congenital dyserythropoietic anemia-like abnormalities without functional evidence of dyserythropoiesis.

A dyserythropoietic syndrome with coincidental immune thrombocytopenia seen during pregnancy is discussed. The morphological and serological results in this case most resemble type II congenital dyserythropoietic anemia. However, functional evidence of dyserythropoiesis was absent and the patient was not anemic. Splenectomy was performed for the resistant thrombocytopenia and microscopic examination of the spleen showed evidence of extramedullary dyserythropoiesis. The significance of these findings is discussed with regard to the spectrum of recognized dyserythropoietic disorders and the unusual discrepancy between the abnormal morphology and the absence of functional dyserythropoiesis.

Studies of human natural killer cells. III. Neutropenia associated with unusual characteristics of antibody-dependent and natural killer cell-mediated cytotoxicity.

A 52-year-old Caucasian man with chronic neutropenia and recurrent infections was found to have an increased proportion of peripheral T lymphocytes having Fc receptors for IgG (T gamma ). Although levels of antibody-dependent cell-mediated cytotoxicity (ADCC) and "natural" killing (NK) by unfractionated lymphocytes were similar to those of a control donor, the frequency of KN cells was markedly increased. Removal of E rosette-forming cells eliminated both NK and ADCC by the patient's peripheral blood, in marked contrast to the enhanced cytotoxicity seen with control lymphocytes. Both normal and patient ADCC and NK functions were removed by depletion of Fc receptor-bearing cells. These depletion experiments proved that all of the patient's killer cells were E rosette-forming T gamma cells, in contrast to the heterogeneous pattern of null gamma and T gamma killer cells seen in the blood of normal donors. The homogeneity of the T gamma proliferation suggested that ADCC and NK were mediated by the same cell type, albeit acting by different mechanisms. The addition of the patient's serum and lymphocytes to chromium-labelled normal granulocytes caused a low but significant level of cytotoxicity, indicating that the patient's neutropenia may have been caused by a similar mechanism in vivo. There was no evidence of complement-dependent serum antibody-mediated neutrophil lysis, but one serum sample taken over the course of the patient's disease agglutinated granulocytes from four of five donors tested.

Microvascular closure in malignant histiocytosis.

Two patients with malignant histiocytosis were found to have capillary occlusion by aggregates of neoplastic histiocytes, in skeletal muscle in one, and in renal glomeruli in the other. One patient had clinical evidence of similar occlusions in the arterioles and capillaries of the ocular fundi. Occlusion of small vessels by tumour cells may explain the confusion of both patients.

Myeloproliferative disorders: a paradox of in-vivo and in-vitro platelet function.

A patient with features of a myeloproliferative disorder developed an acute multisystems illness and died. In-vitro platelet aggregation was imparied, but necropsy revealed widespread platelet-rich thromboemboli and multiple organ infarctions. It is suggested that platelets are damaged during disseminated intravascular platelet aggregation (DIPA) and that disaggregation of platelet thrombi and recirculation of platelets give rise to their subsequent hypofunction when tested in vitro.

Malignant lymphoma of the thyroid gland.

Malignant lymphoma of the thyroid gland is a rare entity; only 200 cases have been reported to date since 1960. Four patients with this disease presented at the Kingston clinic of the Ontario Cancer Treatment and Research Foundation. Those with localized malignant lymphoma, particularly the histiocytic types, responded favourably to resection of as much of the tumour as possible and subsequent local radiation with cobalt-60 telecurietherapy (3000 to 4000 rads in 3 to 4 weeks). The results of local radiation alone after a biopsy in patients with inoperable localized diseases are encouraging; it is possible, but not yet established, that some of these patients are cured. It has been suggested that the tumour is dependent on thyroid-stimulating hormone but conclusive evidence is not yet available.

Distribution of storage iron as body stores expand in patients with hemochromatosis.

The relative distribution of storage iron between bone marrow and liver has not been adequately studied in patients with iron-loading disorders. To help clarify this we assessed iron metabolism in patients with iron overload and in control subjects with cirrhosis but no excess body iron. In 4 patients with advanced iron overload studied late in the course of their illness, excess hemosiderin was present in both bone marrow and liver, as expected. In contrast, 2 patients with idiopathic hemochromatosis whose excess iron had been depleted by phlebotomy subsequently developed progressive hepatic parenchymal and reticuloendothelial (RE) deposition of iron, yet marrow hemosiderin remained sparse. Moreover, surface radioactivity over the liver after an oral dose of 59Fe. These results suggest that during the initial stages of hemochromatosis there is a dissociation in the rate of iron accumulation between the bone marrow and liver. Excess hemosiderin appears to be deposited predominantly and preferentially in hepatic storage sites until the later stages of the disease.

Serum ferritin, cobalt excretion and body iron status.

Serum ferritin concentration was measured by immunoradiometric assay in 64 subjects. It was closely related to the size of body iron stores measured by hemosiderin content of bone marrow in all subjects and by the deferoxamine test in 10 patients with iron overload. Urinary cobalt excretion, an indirect measure of iron absorption, was inversely related to hemosiderin content of bone marrow in 34 patients aged 18 to 72 with or without liver disease, but this relation did not hold in a group of 20 student volunteers aged 17 to 30, indicating that the test is unreliable in young people. A strong inverse correlation was demonstrated between values for cobalt excretion and serum ferritin in the 34 patients and between those for iron absorption and serum ferritin in the 20 students. Serum ferritin concentration appears to reflect accurately the iron status of the healthy individual but high values in liver disease must be interpreted with caution.

Cobalt excretion test for the assessment of body iron stores.

Iron absorption is under delicate control and the level of absorption is adjusted to comply with the body's need for iron. To measure the intestinal setting for iron absorption, and thereby indirectly assess body iron requirements, cobaltous chloride labelled with (57)Co or (60)Co was given by mouth and the percentage of the test dose excreted in the urine in 24 hours was measured in a gamma counter. Seventeen control subjects with normal iron stores excreted 18% (9-23%) of the dose. Increased excretion, 31% (23-42%), was found in 10 patients with iron deficiency anemia and in 15 patients with depleted iron stores in the absence of anemia. In contrast, 12 patients with anemia due to causes other than iron deficiency excreted amounts of radiocobalt within the normal control range. In patients with iron deficiency, replenishment of iron stores by either oral or parenteral iron caused the previously high results to return to normal.Excretion of the test dose was normal in portal cirrhosis with normal iron stores but it was markedly increased in patients with cirrhosis complicated by either iron deficiency or endogenous iron overload. It was also raised in primary hemochromatosis. Excretion of the dose was reduced in gluten-sensitive enteropathy. Gastrointestinal surgery and inflammatory disease of the lower small intestine had no effect on the results except that some patients with steatorrhea had diminished excretion.The cobalt excretion test provides the clinician with a tool for the assessment of iron absorption, the detection of a reduction in body iron stores below the level that is normal for the subject in question, the differentiation of iron deficiency anemia from anemia due to other causes, and the investigation of patients with iron-loading disorders.