Hemoglobin brigham (alpha2Abeta2100 Pro--Leu). Hemoglobin variant associated with familial erythrocytosis.

Erythrocytosis associated with the presence of a hemoglobin with increased oxygen affinity has been reported for 10 hemoglobin variants, most of which demonstrate altered electrophoretic mobility. Several members of a family were found to have erythrocytosis, and both the whole blood and the hemoglobin exhibited increased oxygen affinity. Phosphate-free hemoglobin solutions had a normal Bohr effect and reactivity to 2,3-diphosphoglycerate. The electrophoretic properties of the hemoglobin were normal, but on peptide mapping of a tryptic digest of the isolated beta-chains, a normal betaT11 peptide and an abnormal betaT11 with greater R(f) were seen. Analysis of the abnormal peptide showed the substitution of leucine for the normal proline at beta100 (helical residue G2).The hemoglobin variant, designated Hb Brigham, serves to emphasize the necessity for detailed evaluation of the structure and function of hemoglobin in familial erythrocytosis even with electrophoretically "normal" hemoglobin.

Central nervous system (CNS) relapse following chemotherapy of WF rat acute myelogenous leukemia: a model for human CNS leukemia.

The treatment of central nervous system (CNS) involvement in human acute myelogenous leukemia (AML) presents a serious therapeutic dilemma. In an attempt to study the pathophysiology of this diseases in an animal model, the incidence and sites of detection of CNS leukemia were evaluated in inbred rats receiving chemotherapy for the transplantable WF AML. Eight of 100 rats with untreated WF AML demonstrated CNS leukemia at death with concomitant widespread visceral infiltrates, ascites, bone marrow involvement, and peripheral blood leukemia. Similarly, 6 of 120 rats (5%) failing to attain a complete remission following adriamycin. Cytoxan, or cytosine arabinoside chemotherapy demonstrated CNS leukemia in addition to systemic disease at death. In contrast, 70 of 75 rats (93.3%) achieving a complete remission subsequently relapsed in the CNS, either in combination with widespread systemic disease in 48 (64.0%) or with minimal evidence of systemic relapse in 22 (29.3%). There was a greater frequency of detectable cerebral compared to spinal cord infiltrates in relapsing rats. The WF AML appears to be a valuable model for study of the mechanism and ultimately the prevention of CNS relapse following chemotherapy in human AML.

Technique for preclinical evaluation of continuous infusion chemotherapy with the use of WF rat acute myelogenous leukemia.

A technique was developed for continuous iv infusion chemotherapy in an inbred rat model of acute myelogenous leukemia. Polyethylene tubing was inserted surgically into the internal jugular vein of adult WF rats, burrowed sc to the base of the tail, and connected to an infusion pump. A flexible spring was sutured at the base of the tail and fastened to the cage wall; it protected the infusion catheter and allowed movement of the rat within the cage. This technique was used to compare bolus with continuous infusion therapy with adriamycin, cytosine arabinoside, and neocarzinostatin. Only small differences were noted in host toxicity and in antitumor effect against tumor grown as a subcutaneous myeloblastoma. Nearly three times more neocarzinostatin was required by continuous infusion for an effect equivalent to that of bolus injection. In contrast, continuous infusion of methotrexate with concurrent thymidine infusion prevented toxicity, enhanced the antitumor effect, and prolonged survival. This infusion system should facilitate rapid preclinical evaluation of drugs considered for constant iv infusion therapy.

Immunologic abnormalities in patients with malignant lymphoproliferative diseases.

The B- and T-lymphocyte distribution was studied in 45 patients with malignant lymphoproliferative diseases. Eight patients with untreated Hodgkin's disease had normal mean percentages of complement receptor lymphocyte (CRL) cells and T-cells; however, the mean absolute number of T-cells was decreased. T-lymphocytes were also decreased in 3 patients with Hodgkin's disease treated 7-24 months previously. The number of T-lymphocytes increased markedly in all patients after treatment. Lymphocyte surface markers in non-Hodgkin's lymphoma showed distinctive patterns. Patients with leukemic reticuloendotheliosis or "hairy cell leukemia" characteristically had low percentages of CRL but normal or increased percentages of surface immunoglobulin-positive lymphocytes. The mean percentage and number of T-lymphocytes in this group were normal. Eight patients with nodular lymphocytic lymphoma and 2 patients with nodular lymphocytic-histiocytic lymphoma had normal mean numbers of CRL but decreased numbers of T-lymphocytes. Of 6 patients with diffuse lymphocytic lymphoma, 4 had elevated percentages and numbers of CRL. Despite low percentages, normal numbers of T-lymphocytes were found in 3 of these patients.

Virus and cell requirements for Friend virus granulocytic leukemogenesis in long-term bone marrow cultures of NIH swiss [N:NIH(S)] mice.

The effect of hematopoietic stem cell age on leukemogenesis in vitro was tested in nonrecharged, corticosterold-supplemented NIH Swiss [N:NIH(S)] mouse long-term bone marrow cultures infected with Friend murine leukemia virus of anemia-inducing strain (F-MuLV-A) or spleen focus-forming virus (SFFV) [Rauscher murine leukemia virus (R-MuLV)], a pseudotype virus derived by rescue of the SFFV genome from SFFV-Balb/3T3 clone A31 nonproducer cells with clonal helper R-MuLV. Cultures at 33 degrees C derived from 10-day-old or adult mouse marrow generated colony-forming unit culture granulocytic macrophage (CFUc) progenitor cells for over 20 weeks and colony-forming unit spleen cells for 14 weeks and generated permanent granulocytic leukemia cell lines after infection with F-MuLV-A at week 1, 2, or 4 but not at week 8. Leukemia lines were of granulocyte phenotype whether induced by F-MuLV-A or SFFV (R-MuLV) and synthesized myeloperoxidase and lysozyme but were restricted in ability to generate superoxide in response to phorbol myristate acetate stimulation. Cultures (31 degrees C) infected with temperature-sensitive (ts) helper virus mutant pseudotypes of SFFV as well as SFFV (R-MuLV) generated granulocytic leukemia lines, whereas only SFFV (R-MuLV) pseudotype virus-infected cultures became leukemic at 37 degrees C. R-MuLV wild type or ts mutant helper virus infection alone increased cell proliferation and numbers of CFUc but did not generate leukemia. These data indicated that gene(s) specific to F-MuLV-A or a virus rescued from SFFV-Balb/3T3 clone A31 nonproducer cells are required for transformation in vitro of a hematopoietic stem cell present in early but absent in late bone marrow cultures.

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Paradoxical effect of radiation on tumor incidence in the rat: implications for radiation therapy.

The high incidence of leukemia in the Fischer rat is reduced by radiation to an incidence below that seen spontaneously. Fractionating the radiation decreased this effect. In contrast, mammary tumors increased with dose until reaching a plateau at the highest doses. Fractionation had little effect. These results are consistent with a hypothesis suggesting that tumor incidence due to radiation is the result of competing processes of tumor induction and cell killing.

Constitutive and inducible granulocyte-macrophage functions in mouse, rat, and human myeloid leukemia-derived continuous tissue culture lines.

Fourteen continuous tissue culture cell lines derived from mouse, rat, or human granulocyte-macrophage cancers were studied for expression of spontaneous and inducible markers of differentiated cells. Five cell lines (two mouse, two rat, and one human) synthesized myeloperoxidase spontaneously, and a fifth mouse line showed biochemically inducible enzyme. Twelve lines (6 mouse, 3 rat, and 3 human) produced lysozyme (muramidase), and all had detectable beta-glucuronidase. Superoxide generation was detected in one mouse, and three human cell lines following stimulation with phorbol myristate acetate. Maturation to differentiated polymorphonuclear leukocyte or macrophage morphology was induced in 3 cell lines (2 mouse and 1 human) following culture in diffusion chambers in total-body-irradiated rats. In vitro morphological differentiation was inducible in one (mouse) cell line exposed to casein, thioglycolate, or plasma from irradiated rats or mice. These findings indicate that mammalian cell lines derived from granulocyte-macrophage cancers stably express several combinations of differentiation markers. The patterns of expression of these markers did not always correlate with the morphological stage of differentiation.

Different hematological diseases induced by type C viruses chemically activated from embryo cells of different mouse strains.

Type C RNA viruses can be induced by certain chemicals from cells of many mouse strains. Both C58 and BALB/c cells have been shown to contain endogenous viruses that are designated N-tropic because they grow preferentially in cells of NIH Swiss mouse origin. While demonstrating many similar biological and immunological properties, the C58-induced virus is around 10-fold more infectious per physical particle than the N-tropic virus of BALB/c cells. In the present studies, inoculation of these viruses into newborn NIH Swiss mice led to the development of diseases associated with splenomegaly and lymphadenopathy at similar frequency in each group. The disease induced by C58-MuLV was histophathologically diagnosed as lymphoblastic leukemia and was highly malignant following transplantation into newborn mice. The histopathological appearance of spleens from BALB/c virus-affected animals was distinguishable, demonstrating instead myeloid metaplasia or myelogenous leukemia. These findings provide evidence that different endogenous mouse type C viruses can induce distinct diseases in the same mouse strain. Furthermore, they implicate the N-tropic virus endogenous to C58 cells as a major factor in the development of lymphoblastic leukemia that occurs at high frequency in that strain.

Leukemia following chemotherapy for breast cancer.

Leukemia following chemotherapy for breast cancer was studied among patients diagnosed during 1973-1985 within the population-based tumor registries in the Surveillance, Epidemiology, and End Results Program. Among 13,734 women given initial chemotherapy, 24 developed acute nonlymphocytic leukemia (ANLL) compared to 2.1 expected based on general population rates (observed/expected = 11.5; 95% confidence interval = 7.4-17.1). Overall, 58 excess ANLL occurred per 100,000 women-years at risk for patients treated with chemotherapy. The cumulative incidence was 0.7% at 10 years. Risk remained high over all periods of observation up to 9 years after treatment. Among 7974 women treated only with surgery during 1973 and 1974, a period before the widespread use of adjuvant chemotherapy for breast cancer, ANLL was not significantly increased (observed = 7, expected = 5.1). A case-control study was then conducted in Connecticut to evaluate in more detail the risk associated with adjuvant chemotherapy in the general population. Among 20 cases (17 incident leukemias and 3 deaths due to preleukemia) and 60 matched controls, alkylating agents were linked to an 11.9-fold risk of ANLL and preleukemia (95% confidence interval = 2.6-55). Chemotherapy regimens including melphalan were related to a higher risk of leukemic conditions than those including cyclophosphamide. These data suggest that women in the general population treated with adjuvant chemotherapy for breast cancer are at an increased risk of leukemia, that the risk remains high among long-term survivors, and that risk differs by type of alkylating agent administered.

Leukemia risk following radiotherapy for breast cancer.

To evaluate further the relationship between high-dose radiotherapy and leukemia incidence, a nested case-control study was conducted in a cohort of 22,753 women who were 18-month survivors of invasive breast cancer diagnosed from 1935 to 1972. Women treated for breast cancer after 1973 were excluded to minimize the possible confounding influence of treatment with chemotherapeutic agents. The cases had histologically confirmed leukemia reported to the Connecticut Tumor Registry (CTR) between 1935 and 1984. A total of 48 cases of leukemia following breast cancer were included in the study. Two controls were individually matched to each leukemia case on the basis of age, calendar year when diagnosed with breast cancer, and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. Local radiation doses to each of the 16 bone marrow components for each patient were reconstructed; the dose averaged over the entire body was 530 rad (5.3 Gy). Based on this dosage and assuming a linear relationship between dose and affect, a relative risk (RR) in excess of 10 would have been expected. However, there was little evidence that radiotherapy increased the overall risk of leukemia (RR = 1.16; 90% confidence interval [CI], 0.6 to 2.1). The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not significantly increased (RR = 1.8; n = 10); nor was the risk for all other forms of leukemia (RR = 1.0; n = 38). There was no indication that risk varied over categories of radiation dose. These data exclude an association between leukemia and radiotherapy for breast cancer of 2.2-fold with 90% confidence, and provide further evidence that cell death predominates over cell transformation when high radiation doses are delivered to limited volumes of tissue.

Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD).

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.

Chronic myelomonocytic leukemia.

Thirty adult patients with CMML were evaluated to determine prognostic factors that might have an impact on conversion to acute leukemia and survival. Neither leukocyte count nor monocyte count correlated with survival. The median survival for all 30 cases was 41 months. Patients with less than 5% marrow blasts had a median survival of 60 months but those with 5-20% blasts had only a 9-month median survival.

Proliferative response of clonal acute myelogenous leukemia cells in localized grafts of normal bone marrow stroma to in vivo stimulation of myelopoiesis.

Bone marrow from inbred Wistar/Furth (W/Fu) rats, normal and 90% replaced by acute myelogenous leukemia (AML), was transplanted, respectively, to the left and right kidneys of adult W/Fu rats. After a transient period of hypocellularity, AML grafts repopulated to pre-transplant cellularity by day 9, whereas normal bone marrow (NBM) grafts required 25 days for repopulation to pre-transplant cellularity. Grafted leukemia cells remained localized to the kidney for 17 days. In NBM grafts phlebotomy accelerated erythroid proliferation, and intrathoracic inoculation of live Escherichia coli accelerated myeloid proliferation; in AML grafts only E. coli injection increased bone marrow proliferation. There was no morphologically detectable differentiation of W/Fu AML cells. These studies provide evidence of a myelopoietic response of AML blast cells in vivo and present a transplantation technique for comparison of localized grafts of leukemic and normal bone marrow in the same animal.

Cell biological effects of total body irradiation on growth and differentiation of acute myelogenous leukemia cells compared to normal bone marrow.

Radiation therapy is used as total body treatment in preparation of the acute myelogenous leukemia (AML) patient for bone marrow transplantation. Many AML patients will have residual leukemia cells at the time of total body irradiation (TBI). In the present study, the effect of TBI on leukemic myeloid cells was compared to the effect on normal marrow granulocytic stem cells (CFUc) in vitro. Little difference from that of normal CFUc was found in the radiosensitivity of two mouse myeloid leukemia cell lines. The effect of TBI on growth of WEHI-3 or J774 cells in millipore diffusion chambers was stimulatory. These AML cell lines as well as others derived from Friend or Abelson virus infected in vitro long term mouse marrow cultures showed some morphologic differentiation by 7 days growth in diffusion chambers in irradiated heterologous rat hosts, but immature cells predominated by day 21. Thus, evidence in murine models of AML indicates that residual AML cells surviving chemotherapy will show no greater susceptibility to radiation killing compared to normal stem cells and will rapidly repopulate the irradiated host.

Treatment of iron overload in adults with continuous parenteral desferrioxamine.

Adult patients with transfusional hemosiderosis were given ascorbic acid and treated with the iron chelator, desferrioxamine B. The drug was administered by continuous subcutaneous or intravenous infusions using a light weight portable constant infusion device. On this regimen, four of the five patients studied were able to excrete significant amounts of iron (greater than 35 mg/da) when receiving a daily desferrioxamine dose of 1.5 to 2.2 g. Continuous subcutaneous infusion was well tolerated and about 80 per cent as effective as intravenous therapy in chelating iron. The number of prior transfusions, the hepatic iron content and the serum ferritin levels appear to be useful in predicting which patients will respond to iron chelation therapy, especially if there is little bone marrow erythropoietic activity. One patient with ineffective erythropoiesis did not have significantly increased hepatic iron stores but responded to the administration of desferrioxamine. Continuous subcutaneously administered desferrioxamine may prove to be adaptable for long-term outpatient therapy, allowing patients with ongoing transfusion requirements to go into negative iron balance. Long-term studies will be needed to demonstrate reversal of endocrine, hepatic and cardiac dysfunction secondary to iron deposition in these patients.

Biologic properties of factor-independent nonadherent hematopoietic and adherent preadipocyte cell lines derived from continuous bone marrow culture.

Cell lines dependent for growth upon an inducer T-cell synthesized glycoprotein factor interleukin-3 have been derived from continuous mouse bone marrow cultures. These factor-dependent (FD) lines have been shown to be multipotential (erythroid/basophil/neutrophil) or (eosinophil/basophil/neutrophil); or are unipotent basophil or neutrophil granulocyte cell lines. Both classes of cloned FD lines have maintained self-renewal in vitro for several years with absolute growth dependence on freshly added IL-3. In four instances, factor-independent (FI) variant cell lines were derived, one by subculture in medium containing hydrocortisone and 25% horse serum and three by evolution of variants from cloned FD lines. One class of (FI) lines demonstrated adherent fibroblast-like morphology with differentiation to differentiated adipocytes in medium containing 10(-5) hydrocortisone. A second class of cell lines evolved from cloned FD lines and each grew in suspension culture to a saturation density over 10-fold greater than that for the parent FD line (greater than 10(7)/ml) and each contained no detectable hematopoietic cellular differentiation markers by histochemistry or cell surface receptors. In contrast to IL-3 dependent cell lines, (FI) cell lines failed to differentiate to mature granulocyte morphology in diffusion chambers in vivo. The FI cell lines formed no detectable CFUs in vivo, did not reconstitute hematopoiesis in irradiated mice and did not form tumors in vivo. The failure of the (FI) lines to form tumors and lack of detectable hematopoietic differentiation capacity indicates that these lines may represent an intermediate state between normally regulated hematopoietic cellular self-renewal and malignant transformation.

Leukemia, lymphoma, and multiple myeloma after pelvic radiotherapy for benign disease.

The relationship between exposure to sparsely ionizing radiation and mortality due to cancers of hematopoietic and lymphopoietic tissues was studied among 12,955 women treated for benign gynecological disorders at any of 17 hospitals in New England or New York State and followed for an average of 25 years; 9770 women were treated by radiation (intracavitary 226Ra, external-beam X rays), while 3185 were treated by other methods, including curettage, surgery, and hormones. The average age at treatment was 46.5 years, and the mean dose to active bone marrow among irradiated women was 119 cGy. Forty deaths due to acute, myelocytic, or monocytic leukemia were observed among irradiated women. This number was 70% higher than expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.7; 90% confidence interval (CI) 1.3-2.3]. A deficit was recorded among nonirradiated women, based on three observed deaths (SMR = 0.5; 90% CI 0.1-1.2). A well-defined gradient in the SMR with dose among exposed women was not detected. The SMR was highest within 5 years after irradiation but remained elevated even after 30 years. The temporal pattern differed by subtype of leukemia: excess mortality due to chronic myelocytic leukemia occurred almost exclusively within the first 15 years, whereas the SMR for acute leukemia, though also elevated, varied little over time. Cancers of lymphoreticular tissue occurred more often than expected based on U.S. mortality rates, but not appreciably differently for irradiated and nonirradiated women. There was little or no evidence of effects attributable to radiotherapy for chronic lymphocytic leukemia [relative risk (RR) = 1.1; 90% CI 0.5-3.0], Hodgkin's disease (RR = 0.9; 90% CI 0.3-3.2), non-Hodgkin's lymphoma (RR = 0.9; 90% CI 0.6-1.6), or multiple myeloma (RR = 0.6; 90% CI 0.3-1.4). These results corroborate previous findings indicating that acute and myelocytic leukemias are the most prominent malignancies after exposure to sparsely ionizing radiation, occurring in excess shortly after irradiation, and that lymphomas are either not caused by radiation or are induced only rarely.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Hairy cell leukemia: diagnosis and management.

Long-term follow-up of 18 patients with hairy cell leukemia seen at a single institution is reported: diagnostic and therapeutic modalities are described. Although the clinical features of this disease are homogeneous, it is frequently misdiagnosed initially. Bone marrow biopsy was diagnostic in all 17 patients studied prior to splenectomy. The presence of circulating "hairy" cells is greatly variable. The cause of pancytopenia is unclear: splenic sequestration was not demonstrated by 51Cr red cell studies in three of four patients. In most patients, splenectomy resulted in amelioration of pancytopenia. No clinical features prior to splenectomy could predict response to surgery. The results of chemotherapy and splenic irradiation were variable and unpredictable. Although bone marrow infiltration persists following splenectomy, this remains the only established therapy in hairy cell leukemia and is usually followed by long, uncomplicated survival.