Chronic myelocytic leukemia. Origin of some lymphocytes from leukemic stem cells.

In three patients with chronic myelocytic leukemia who were heterozygous at the X-linked glucose-6-phospháte dehydrogenase locus, lymphocytes were studied to determine if they had the same stem cell origin as the leukemic myeloid cells. Normal tissues such as skin had both B and A glucose-6-phosphate dehydrogenase isoenzymes, but the leukemic myelogenous cells displayed only one isoenzyme type, consistent with their clonal origin. A population of cells with undoubted thymus-derived (T)-lymphocyte characteristics had both isoenzymes. Presumably, then, these T cells did not arise from the leukemic stem cell, either because they antedated the development of leukemia in that stem cell or, more likely, because they arose from progenitors not involved by the disease. In contrast, another population of lymphocytes showed only one isoenzyme type, suggesting that it arose from the chronic myelocytic leukemia stem cell. However, although this population contained many cells with the characteristics of bone marrow-derived (B) lymphocytes, it is not certain that the single enzyme produced by the cells over all can be attributed to B lymphocytes rather than to contaminating non-B-lymphoid cells.

Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.

BACKGROUND: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. PURPOSE: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). METHODS: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. RESULTS: The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group. CONCLUSIONS: We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.

Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia.

The Ph chromosome abnormality is involved in the pathogenesis of almost all patients with chronic myelocytic leukemia (CML). Previous studies on the B-lymphoid cell lineage in two patients with Ph-positive CML suggest that there may also be a clonal Ph-negative stage in CML and that the Ph-positive stage arises by subclonal expansion. To determine whether this is a frequent or a rare occurrence, 14 additional glucose-6-phosphate dehydrogenase (G6PD)-heterozygous patients with CML were studied. In five of these patients there was a statistically significant excess of Ph-negative B-lymphoid cell lines expressing the same G6PD type expressed in the corresponding CML clone. In no case was an excess of B-lymphoid lines expressing the opposite G6PD type recovered. These data provide further evidence that in some patients the Ph chromosome arises in a pluripotent stem cell from a pre-existing Ph-negative clone that enjoys a growth advantage.

Partial exchange transfusion as treatment for hemoglobin SC disease in pregnancy.

Serious infarctions and embolic events can complicate the course of pregnant patients with hemoglobin SC disease. In two cases, partial exchange transfusion preceded recovery in severely ill pregnant women with hemoglobin SC disease. There seem to be pathophysiological correlations for the observed clinical findings, and there are potential beneficial effects of partial exchange transfusion. Based on our experience, partial exchange transfusion should be considered as a means of reversing the often fatal complications attending hemoglobin SC disease and pregnancy. The exchange should be of sufficient volume to ensure a postexchange level of hemoglobin A of at least 30%.

Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage.

Glucose-6-phosphate dehydrogenase (G-6-PD) isoenzymes types of granulocytes were determined in eight women with chronic myelocytic leukemia (CML). The patients were heterozygous at the X-linked G-6-PD locus for the common gene, GdB, and a variant, such as GdA, so that both B and A enzyme types were found in skin cells. In contrast to these normal cells, only one G-6-PD type was found in CML granulocytes. The fact that such single-enzyme phenotypes are found in CML granulocytes, but not in nonleukemic granulocytes, provides strong evidence that the disease has a clonal origin. Single-enzyme phenotypes were also found in erythrocytes, platelets and cultured blood macrophages indicating that these cells have a common stem cell which is the site of the abnormality in CML. In the one studied patient, no evidence was found for involvement of cultured marrow fibroblasts. Clonal origin of CML virtually excludes cell recruitment as a sole pathogenetic mechanism. Either the leukemia arises as a consequence of a rare initial event in a single cell, or a series of events occurs in a clone such that it evolves into CML, or both.

Choriocarcinoma as a cause of thyrotoxicosis.

Three patients with choriocarcinoma had clinical and biochemical evidence of hyperthyroidism. Diminution in the thyrotoxicosis closely paralleled the fall in human chorionic gonadotrophin (hCG) levels. Three patients originally presented to internal medicine units as a problem of hemoptysis. Thyroid-stimulating hormone bioassay activity was demonstrated in the serum of all three patients prior to therapy. Recently evidence has been presented that hCG has intrinsic thyrotropic activity and that in conditions, such as hydatidiform mole, in which serum hCG levels are grossly elevated this thyrotropic activity can be sufficient to produce hyperthyroidism. Two of our cases supported the concept that hCG was also the substance with thyroid-stimulating activity in patients with choriocarcinoma. The third case left open the possibility that, in addition to the thyroid-stimulating activity of hCG, there may also be the production of a true ectopic thyroid-stimulating hormone (TSH). It is considered that the development of biochemical and clinical thyrotoxicosis in patients with choriocarcinoma depends upon the duration of the choriocarcinoma and the level of hCG.

PIP: The cases of 3 patients with advanced metastatic choriocarcinoma and biochemical and clinical evidence of hyperthyroidism are reported. The thyroid-stimulating hormone (TSH) bioassay activity was increased in all 3 patients before chemotherapy. All patients had clinical signs and symptoms of overt thyrotoxicosis although goiter was present in only 1. Sinus tachycardia was present in all. The 1st symptom in all 3 cases was hemoptysis. An X-ray appearance of multiple pulmonary metastases was also present. There was biochemical evidence of improvement in thyrotoxicosis after chemotherapy. This improvement paralleled the fall in urinary human chorionic gonadotropin (HCG). As treatment, intermittent oral 5-day courses of methotrexate and iv actinomycin D were given at 3-week intervals. In 2 of the cases the ratio of bioassayable thyrotropic activity to HCG found in the serum was similar to the ratio in patients with hydatidiform moles. In the other case the ratio was much higher. It appears that the development of biochemical and clinical hyperthyroidism in patients with choriocarcinoma depends on the duration of the choriocarcinoma and the serum level of HCG. Findings suggest that there may be production of another TSH in addition to the thyrotropic activity of high HCG levels.

Asbestos-associated neoplasms of B cell lineage.

Three different neoplasms of B cell lineage, chronic lymphocytic leukemia, immunoglobulin A (IgA) myeloma and immunoglobulin G (IgG) myeloma were detected in three patients who had heavy occupational exposure to asbestos dust. Two of the patients had coexistent pulmonary asbestosis, whereas the third patient had a pleural mesothelioma subsequent to his initial presentation with myeloma. Defective cell-mediated immunity and hyperactivity of B cell function have previously been noted in patients with asbestosis. We suggest the possibility that these asbestos-related immunologic derangements may predispose to the development of immunoproliferative and lymphoproliferative neoplasms, since such tumors have been observed in a variety of other settings, characterized by protracted hyperactivity of the immune system.

Lymphoid and plasma cell malignancies: asbestos-related disorders of long latency.

We have identified 13 asbestos workers with lymphoplasmacytic neoplasms: six with chronic lymphocytic leukemia, four with IgG myeloma, two with IgA myeloma, and one with histiocytic lymphoma. The subjects' occupations were varied, but all had experienced protracted asbestos exposure (ranging from 3-37 years). Tumor latency periods were similar to other known asbestos-related malignancies and ranged from 16-41 years. Stigmata of asbestos-related pulmonary disease were evident in 12 subjects. Malignant pleural mesotheliomas co-existed with IgG myelomas in two individuals, an association which seems unlikely to be fortuitous. It has been speculated previously that asbestos may be a lymphoid system carcinogen. Our findings strongly support this view and indicate that patients presenting de novo with lymphoproliferative neoplasms should be investigated for previous occupational or environmental exposure to asbestos.

The occurrence of an auto-immune hemolytic anemia with anti-U specificity in a patient with myelodysplastic syndrome.

A 73-year-old man with myelodysplastic syndrome developed during the course of his illness auto-immune hemolytic anemia. The association between auto-immune hemolysis and myeloproliferative disease is extremely rare. An even more unique finding is the nature of the antibody which demonstrated single specificity against the U antigen.

Malignant histiocytosis simulating granulomatous disease.

In its clinical presentation, malignant histiocytosis may mimic infections or hematologic neoplasms, and pathologically it may be mistaken for Hodgkin's disease, histiocytic lymphoma, or viral lymphadenitis. The case histories of three patients in whom malignant histiocytosis clinically and pathologically simulated granulomatous diseases are reported. Erythrophagocytosis was not present in the initial bone marrow aspirates from two of the patients. One patient was considered to hve sarcoidosis or Wegener's granulomatosis; the second patient, Weber-Christian disease, and the third patient, a granulomatous disease of infectious origin. Granulomas have been found in tissues of patients who have Hodgkin's disease, but have been found only rarely in association with malignant histocytosis. An explanation for the presence of granulomas in association with malignant histiocytosis is offered: they may represent a phase in the evolution of the disease.

Pernicious anemia in blacks. A study of 64 patients from Washington, D. C., and Johannesburg, South Africa.

In a collaborative study from Washington, D. C., and Johannesburg, South Africa, the clinical, laboratory, and immunologic features of 64 black patients (25 male, 39 female) who had pernicious anemia were studied. Mean age at diagnosis was 53 +/- 20 years (mean +/- SD); 29.6% of the patients were under 40 years of age, and 14% were 30 years of age or younger. This suggests that there may be an earlier age of onset of pernicious anemia amongst blacks than the reported age incidence in whites. Serum anti-intrinsic factor blocking antibodies were found in 25 of 37 patients tested (67.5%). There was a significantly higher incidence of the antibody in women (85%) than in men (50%) (P < 0.01).

Temporal association of marrow eosinophilia with inversion of chromosome 16 in recurrent blast crises of chronic myelogenous leukemia.

We report a patient with Ph+ chronic myelogenous leukemia (CML) whose recurrent blast crises were associated with marrow eosinophilia and inv(16). After intensive chemotherapy, for each blast crisis, the patient reentered chronic phase with disappearance of both the inv(16) and the eosinophilia.

A myelodysplastic syndrome with marrow eosinophilia terminating in acute nonlymphocytic leukemia, associated with an abnormal chromosome 16.

A patient presented with a myelodysplastic syndrome and bone marrow eosinophilia that evolved six months later into an acute nonlymphocytic leukemia (ANLL). Cytogenetic analyses of the bone marrow revealed 86% of the metaphases with 45,X-Y,inv(16)(p13;q22),t(11;17) (q11;q25),del(21)(q13) and 14% of the metaphases with the same abnormalities but with a Y chromosome. The association of ANLL, bone marrow eosinophilia, and abnormal chromosome 16 has previously been reported and has been suggested to have a favorable prognosis. Our patient is unique in that ANLL was preceded by a preleukemic phase associated with bone marrow eosinophilia. When complete remission was achieved, the bone marrow cytogenetics returned to normal, and the eosinophilia disappeared.

Immunocytoma in black and white South Africans.

The clinical and immunochemical presentations of immunocytomata in black and white South African patients are described. Age distribution in white patients is similar to previously published series. However, black patients with multiple myelomatosis and Waldenstrom's macroglobulinaemia on average presented clinically ten and twenty years respectively earlier than white patients. No significnat differences in the various immunochemical classes of multiple myelomatosis was shown despite greater serum immunoglobulin concentrations (especially IgA) in the black population. Age adjusted incidence rates for multiple myelomatosis in South African blacks were as high as those in the United States and Jamaica. This finding contrasts with low rates previously reported in Africa. Furthermore, age adjusted incidence rates for multiple myelomatosis in South African whites were higher than those in whites reported in the United States. There was a higher incidence in blacks of fractures of the thoracolumbar spine with collapse and consequent paraplegia and urinary tract infection. While there was a greater frequency of solitary myeloma in black patients, cases of benign paraproteinaemia were seen only in white patients.

Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis.

The glucose-6-phosphate dehydrogenase (G-6-PD) types and chromosomes of hematopoietic and other tissues were determined in a woman with agnogenic myeloid metaplasia. The patient was heterozygous at the X-linked G-6-PD locus so that both B and A isoenzymes were found in nonhematopoietic cells. In contrast, only one G-6-PD type was found in granulocytes, red cells, and platelets. She also had a distinctive chromosome abnormality in blood cells but not in other tissues. These results indicate that agnogenic myeloid metaplasia is a disorder of a pluripotent stem cell and provide strong evidence that it is of clonal origin. In contrast to blood cells, the patient's cultured marrow "fibroblasts" had normal chromosomes and both B and A G-6-PD types, suggesting that the marrow fibrosis is a secondary abnormality. Thus, at least in this case of agnogenic myeloid metaplasia, the hematopoietic cell proliferation appears to be clonal, and, by inference, possibly neoplastic, whereas the marrow fibrosis is probably not clonal, and therefore appears to be secondary.

Leukaemic involvement of the pleura. A case report.

In chronic myelocytic leukaemia (CML), the pleura is a most uncommon site of extramedullary involvement. A 34-year-old man with CML presented with a massive pleural effusion. His peripheral blood contained few blast cells and the leucocyte alkaline phosphatase level was low. Cytological examination of the pleural fluid revealed cells with the morphological features of myeloblasts and monoblasts. The patient was treated with systemic chemotherapy, with no effect on the leukaemic pleural effusion.

Functional and morphological studies of platelet reactivity with vessel wall subendothelium in chronic myeloproliferative disease.

Mechanisms of thrombus formation in myeloproliferative disease were studied using a technique which visualized platelet-vessel wall interactions under physiological conditions of blood flow. Whole blood from four patients with chronic myelogenous leukaemia and three with thrombocythaemia were pumped through perfusion chambers containing de-endothelialized artery segments. Platelet reactivity with vessel walls (thrombus formation) was measured in sections of vessels by light microscopy and quantitative morphometric analysis. Five patients produced platelet reactivity values of 130--258% of controls while two gave decreased values. The two highest platelet reactivity values occurred in samples with elevated platelet counts and normal haematocrits. In contrast, when anti-platelet drugs were administered to three patients with high platelet counts, reactivity values decreased to 11--34% of controls. Clinical correlations revealed that patients with highest platelet reactivity values (165--258%) were those subjects who also exhibited thrombotic or haemorrhagic complications. Thus absolute platelet count and haematocrit may be major determinants in predicting these complications. Qualitative evaluations of thrombus formations by light and electron microscopy provide further evidence that platelets in myeloproliferative disease also possess qualitative abnormalities.

Childhood and adult acute leukaemia in Johannesburg blacks.

Thirty-four Black patients (14 children and 20 adults) suffering from acute leukaemia were assessed at the haematology clinics of Baragwanath Hospital and Johannesburg General Hospital during a recent 2-year period. It is evident that acute leukaemia in Blacks has become more prevalent in the Johannesburg area than it was 20 years ago, the increase being most striking in the younger age group. The incidence of acute myelocytic and lymphocytic leukaemia in Black children was the same. In adults acute myelocytic leukaemia predominated. The remission rate of 90% achieved in patients with acute lymphoblastic leukaemia was similar to the rates described in Europe and the USA. Results in patients with acute myelocytic leukaemia were less favourable (35% with initial complete remission). The problems of management (limited isolation facilities), complications related to prolonged hospitalization (loss of earnings, problems of visiting), and difficulties with follow-up examination are outlined. In underdeveloped and developing countries, training paramedical personnel to assist with the outpatient care of patients with neoplastic disease might alleviate some of these problems.