Prognostic features and survival in young adults with early/intermediate chronic lymphocytic leukemia (B-CLL): a single institution study.

Information regarding natural history and prognostic factors for early/intermediate B-cell chronic lymphocytic leukemia (B-CLL) in young adults is limited. We analysed 62 young adults (< or = 50 years old) with early/intermediate B-CLL who were seen at our institution during initial diagnosis over a 15-year period. These patients had been followed for a median duration of 7 years. Median age for the entire group was 44 years and 72% were > or = 40 years old. Actuarial median survival from initial diagnosis for the entire group was 140 months. Upon univariate analysis, significant survival advantage was observed in patients with Rai stages 0 and 1 versus stage II disease (median survival 140 versus 60 months, p = 0.01) and in those with lymphocyte doubling time (LDT) of > 1 year versus < or = 1 year (median survival 150+ versus 94 months, p = 0.06). Similarly there was a trend towards longer survival in patients with a leucocyte count of < or = 50,000/microliters when compared to those with higher counts although the difference was not statistically significant. The bone marrow infiltration pattern was not prognostically useful. Upon multivariate analysis, only Rai stage and LDT were prognostically useful. Patients who did not respond to initial therapy with alkylating agents had the worst prognosis, with a median survival of only 19 months. Assessment of presenting clinical stage, LDT, and degree of initial treatment response may prompt earlier consideration of alternative therapeutic modalities such as purine nucleoside analogs or bone marrow transplantation in younger patients with early/intermediate B-CLL.

Splenectomy in advanced chronic lymphocytic leukemia: a single institution experience with 50 patients.

PURPOSE: To assess the efficacy of splenectomy in the treatment of refractory cytopenias associated with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: The histories of 57 patients with CLL who underwent splenectomy at the Mayo Clinic between 1975 and 1991 were retrospectively reviewed. Of the 57 patients, 50 underwent splenectomy for reasons directly related to their disease process such as cytopenias or symptomatic splenomegaly. The histories from these 50 patients were studied to assess the response to splenectomy and the operative morbidity and mortality. RESULTS: Ninety-four percent of patients were in Rai stage III or IV with extensive marrow infiltration, massive splenomegaly, and cytopenias refractory to chemotherapy. A positive response to splenectomy was defined at 3 months of follow-up as: (1) a hemoglobin level of 11 g/dL or greater in a patient with a preoperative value less than 11 g/dL; or (2) a platelet count of 100 x 10(3)/mm3 or greater in a patient with a preoperative value less than 100 x 10(3)/mm3. A positive response was achieved in 77% of patients with anemia, 70% of patients with thrombocytopenia, and 64% of patients with both anemia and thrombocytopenia. The response was sustained at 1 year of follow-up in 86%, 84%, and 85% of the patients, respectively. Postoperative transfusion requirements decreased correspondingly. The operative morbidity was 26%, and the operative mortality was 4%. The mean duration of hospitalization was 9.8 days (median: 9 days; range: 5 to 24 days). The actuarial median survival after splenectomy was 41 months in responders and 14 months in nonresponders. We found no preoperative parameters that were clearly predictive of a poor hematologic response. In particular, outcome was not affected by preoperative spleen size or the degree of marrow infiltration by CLL. All patients with symptomatic splenomegaly had an improved sense of well-being. CONCLUSION: In this, the largest single institution study to date, we found splenectomy to be efficacious in providing durable remissions of refractory cytopenias and in relieving symptomatic splenomegaly in the majority of patients with CLL. The procedure is associated with a low perioperative mortality. Although the impact on survival is uncertain, the improved peripheral blood counts may allow the administration of adequate doses of myelosuppressive chemotherapy.

A clinical update on chronic lymphocytic leukemia. II. Critical analysis of current chemotherapeutic modalities.

Not all patients with B-cell chronic lymphocytic leukemia require therapy. Patients with stable early stage disease do not need treatment, whereas those with progressive early stage disease or advanced stage disease do. The standard initial therapeutic regimen is orally administered chlorambucil and prednisone. The overall response rate to initial chemotherapy is approximately 80%; the median duration of response is 2 years. Conventional chemotherapy, however, does not provide long-term remission for patients in whom the disease becomes refractory to chlorambucil. For such patients, alternative treatment approaches including the use of purine nucleoside analogues or bone marrow transplantation may be considered. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are three analogues of the naturally occurring deoxypurine nucleoside, deoxyadenosine, and all have shown activity in chronic lymphocytic leukemia. Overall response rates of 57 to 79% have been reported with use of fludarabine. A dose-related toxic effect is myelosuppression. Experience with bone marrow transplantation is limited. The number of eligible patients with histocompatible sibling donors is low. The future role of allogeneic bone marrow transplantation in patients with B-cell chronic lymphocytic leukemia will depend on the ability to identify poor-risk groups and the long-term therapeutic efficacy of the purine nucleoside analogues or other new agents.

A clinical update on chronic lymphocytic leukemia. I. Diagnosis and prognosis.

B-cell chronic lymphocytic leukemia (B-CLL) is a relatively indolent hematologic malignant disease that, despite a good response to nonaggressive orally administered chemotherapy, currently remains incurable. The overall median duration of survival is more than 5 years, and the presence of anemia or thrombocytopenia adversely affects prognosis. B-CLL is readily diagnosed because of the characteristic and specific phenotypic expressions of the neoplastic cells. Clinical staging continues to be the best prognostic indicator in B-CLL. In addition, cytogenetic status, pattern of leukemic infiltration in the bone marrow, and lymphocyte doubling time are now considered to have additional prognostic value. In this article, the diagnostic evaluation of lymphocytosis is discussed, and an updated analysis on the prognostic determinants of B-CLL is provided. The second part of this clinical update, which reviews current chemotherapeutic modalities, will be published in the subsequent issue of this journal.

Role of immunotyping in chronic lymphocytosis: review of the natural history of the condition in 145 adult patients.

We investigated the clinical value of immunotyping in 145 consecutive adult patients with absolute or relative lymphocytosis: 132 (91%) had B-cell lymphocytosis, 5 (4%) had T-cell lymphocytosis, 2 (1%) had hairy cell leukemia, and 6 (4%) had reactive lymphocytosis. Of the five patients with T-cell lymphocytosis, four were best categorized as having T gamma-chronic lymphoproliferative disease and had an indolent clinical course. Of the 132 patients with B-cell lymphocytosis, 121 (92%) had B-cell chronic lymphocytic leukemia (B-CLL), and 11 (8%) had small cleaved ("lymphosarcoma") cell leukemia. Patients with small cleaved cell leukemia had a worse clinical outcome than did those with B-CLL. We further analyzed the surface immunoglobulin (sIg) and CD20 (B-1) antigen expression patterns in B-CLL to determine whether any correlation existed with clinical outcome. A subset of patients with B-CLL in whom sIg was expressed in less than 20% of their lymphocytes had the best clinical outcome. HLA-DR (Ia-like) antigen typing helped identify B-CLL cases with minimal or no sIg expression. CD20 (B-1) antigen was weak or undetectable in most cases of B-CLL. Patients with B-CLL who had CD20 (B-1) in more than 20% of their lymphocytes did not have a different prognosis. Our data provide the incidence and natural history of the various subsets of CLL in a series of patients at a single institution. The type and extent of immunotyping necessary and practical in the clinical management of patients with CLL are explored.

True malignant histiocytosis.

OBJECTIVE: To attempt to distinguish cases of true malignant histiocytosis from the clinical syndromes of so-called malignant histiocytosis with use of recent methods. DESIGN: We retrospectively studied the laboratory data and clinical course of Mayo patients who had clinical syndromes of so-called malignant histiocytosis and reviewed available paraffin-embedded tissue specimens to identify the nature of the malignant cells. MATERIAL AND METHODS: After elimination of cases of infection-associated hemophagocytic syndrome, we reviewed and studied seven cases of so-called malignant histiocytosis in patients who had undergone assessment at Mayo Clinic Rochester between 1973 and 1993. We identified histiocytes by using current morphologic, cytochemical, and immunohistochemical methods. The clonal nature of the malignant cells was identified with morphologic, cytogenetic, and molecular genetic studies. RESULTS: Only one of the seven cases had a true histiocytic origin. The malignant cells were T cells in three other cases (the cells were also CD30+ in two cases), CD30+ cells only in one case, epithelial cells in one case, and an undetermined cell type (stained positively only with antitrypsin) in one case. CONCLUSION: True malignant histiocytosis is an exceedingly rare disease, and only a few reports have clearly identified the histiocytic origin of the malignant cells. Previously, the lack of monoclonal antibodies specific to histiocytes and the absence of techniques for performing molecular genetic studies on paraffin-embedded tissue prevented the study of such cases. With newer techniques cases of true malignant histiocytosis can now be identified.

T-cell large granular lymphocytic leukemia and pure red cell aplasia in a patient with type I autoimmune polyendocrinopathy: response to immunosuppressive therapy.

Clonal proliferations of large granular lymphocytes (LGLs) of T-cell origin characterize T-cell LGL leukemia. This disorder has been described in association with rheumatoid arthritis and other autoimmune phenomena. The presence of endocrinologic abnormalities in patients with T-cell LGL leukemia has not been previously reported, nor has T-cell LGL leukemia been described in patients with endocrinologic abnormalities. Herein we describe a young woman with type I autoimmune polyendocrinopathy, in whom pure red cell aplasia developed in association with clonal proliferation of LGLs. Immunosuppressive therapy with cyclophosphamide resulted in remission of pure red cell aplasia, transient improvement in hypocalcemia, and disappearance of the LGL clone. Clonal proliferation of LGLs may be associated with autoimmune endocrinopathies. Clinicians who are responsible for the care of such patients should be aware of this possible association.

Acute myelomonocytic leukemia: an unusual variant with both granulocytic and monocytic esterases in the leukemic cells.

By using the combination of alpha-naphthyl butyrate esterase and chloroacetate esterase for cytochemical detection of monocytes and granulocytes, respectively, we examined and identified five adult patients with acute myeloid leukemia whose leukemic cells often (20 to 30%) had the characteristics of both monocytes and granulocytes. All five patients were men, 23 to 82 years of age. Two patients had manifestations of preleukemia. One of these two patients had received treatment for lymphoma for 12 months before acute myelomonocytic leukemia was diagnosed. One patient had gum hypertrophy, and two had leukemia cutis. At the time of initial examination, four patients had blood leukocyte counts higher than 80,000/mm3 and one had leukopenia. Four patients received chemotherapy; three responded temporarily but died within 1 year after the myelomonocytic leukemia had been diagnosed. The patient with leukopenia has remained in complete remission for 2 years. With more frequent use of double esterase stains for classification of acute myeloid leukemias, this variant of acute myelomonocytic leukemia should be detected more often and its clinical behavior should be better understood.

Systemic mast cell disease associated with the hypereosinophilic syndrome.

Systemic mast cell disease (SMCD) is an uncommon disorder characterized by a proliferation of mast cells involving the bone marrow, spleen, liver, skin, and lymph nodes. Although rare, the association of SMCD and other hematologic disorders is well established. To our knowledge, however, no previously published reports have described SMCD associated with the hypereosinophilic syndrome (HES). Herein we describe two patients who had SMCD in association with HES. Both patients had evidence of cardiac eosinophilic involvement, and both responded to systemic therapy. SMCD is often associated with eosinophilia and may be associated with HES more frequently than is commonly appreciated. Because congestive heart failure is a major cause of morbidity in patients with HES, cardiac assessment in patients with eosinophilia and SMCD is important in order to identify those with eosinophilic organ involvement and treat them aggressively.

Angiofollicular lymph node hyperplasia and peripheral neuropathy: association with monoclonal gammopathy.

An elderly man was found to have the plasma cell variant of angiofollicular lymph node hyperplasia. His course was complicated by peripheral neuropathy and generalized lymphadenopathy, which improved after a trial of corticosteroid therapy. Although the plasma cell variant has been associated with multiple systemic effects, including the nephrotic syndrome, growth failure, fever, hyperglobulinemia, and anti-erythropoietin-mediated anemia, concurrent peripheral neuropathy has only occasionally been reported. Angiofollicular lymph node hyperplasia should be included in the differential diagnosis of peripheral neuropathy associated with lymphadenopathy or a mediastinal mass. A discussion of the clinical, histologic, and immunopathologic characteristics of angiofollicular lymph node hyperplasia is presented.

T-cell chronic lymphocytic leukemia with morphologic and immunologic characteristics of cytotoxic/suppressor phenotype.

The human cytotoxic/suppressor T-cell subpopulation has characteristic cytoplasmic granules and unique surface antigens that are recognized by OKT8 monoclonal antibody. Using immunocytochemical techniques, we identified three patients with an indolent T-cell lymphoproliferative disorder having morphologic and immunocytochemical characteristics of a cytotoxic/suppressor T-cell phenotype. Review of the literature revealed 22 similar cases, which were frequently associated with neutropenia and anemia. These cases may represent a distinct clinicopathologic entity with an apparently indolent clinical course that differs from other T-cell lymphoproliferative disorders, which are generally considered to be more aggressive diseases.

Frentizole therapy of thrombocytopenia in systemic lupus erythematosus and refractory idiopathic thrombocytopenic purpura.

Frentizole, an immunosuppressive phenylurea agent, used in a dosage of 4 mg/kg per day, was found to produce quick elevation of platelet counts in three thrombocytopenic patients. Two have systemic lupus erythematosus, and one has resistant idiopathic thrombocytopenic purpura. Corticosteroid dosage could be reduced in all three patients, and thus far platelet counts are being maintained at "safe" levels. Although major toxicity has limited the utility of frentizole, its effect on the platelet counts of these thrombocytopenic patients is of interest.

Peripheral T-cell lymphoma simulating Hodgkin's disease with initial bone marrow involvement.

In a patient who had fever and cytopenias but no peripheral lymphadenopathy, bone marrow biopsy revealed findings consistent with Hodgkin's disease. Subsequently lymph node biopsy specimens showed lymphoma with features more consistent with peripheral T-cell lymphoma. The clinical features of this patient were those that have been ascribed to an atypical clinical form of Hodgkin's disease. This case illustrates the inadequacy of bone marrow examination as the sole criterion for establishing an initial diagnosis of Hodgkin's disease, particularly in relationship to the newly recognized pleomorphic variants of T-cell malignant lymphoma.

Peripheral T-cell lymphomas: histologic, immunohistologic, and clinical characterization.

A review of 40 cases of peripheral T-cell lymphoma identified at our institution between March 1983 and December 1985 revealed a clinically, histologically, and immunologically diverse group of neoplasms that were difficult to classify by conventional histomorphologic criteria for non-Hodgkin's lymphomas. These lymphomas were frequently extranodal at the time of initial manifestation (52%), and their clinical aggressiveness correlated with three major histologic categories--small lymphocytic, diffuse mixed, and large cell. Of the 40 lymphomas, 18 exhibited distinctive histologic features that allowed assignment of these cases into one of four subgroups: (1) angioimmunoblastic lymphadenopathy, (2) lymphomatoid granulomatosis, (3) Hodgkin's-like disease, and (4) Lennert's lymphoma (lymphoepithelioid lymphoma). Study of all our cases that fulfilled the morphologic criteria for lymphomatoid granulomatosis or angioimmunoblastic lymphadenopathy by using immunologic methods for identification of B-cell and T-cell antigens has shown these neoplasms to be peripheral T-cell lymphomas. Therefore, we now consider these earlier proposed entities to be distinct histologic variants of peripheral T-cell lymphoma.

Accessory splenectomy in management of recurrent idiopathic thrombocytopenic purpura.

Residual splenic tissue can occasionally be responsible for recurrent idiopathic thrombocytopenic purpura after splenectomy. Although this is an uncommon phenomenon, we have identified six such patients at the Mayo Clinic in the last 40 years, and a review of the literature revealed nine others. Only 4 of the 15 patients with sufficient follow-up were significantly improved after splenectomy, 1 requiring less medication to control his thrombocytopenia. The presence of residual splenic material is suggested by the absence of Howell-Jolly bodies in the peripheral smear and confirmed by technetium-99m scanning. Accessory splenectomy should be considered as an adjunct to the control of idiopathic thrombocytopenic purpura in previously splenectomized patients but with the realization that remission or improvement in the clinical course may occur in only about one-half of such patients.

Vitamin K-responsive coagulopathy in Henoch-Schölein purpura.

Henoch-Schönlein purpura is classically described as a systemic vasculitis without known platelet or clotting abnormality. A 15-year-old boy with Henoch-Schönlein purpura experienced a major hemorrhagic diathesis that was responsive to parenterally administered vitamin K. We believe that the gastrointestinal vasculitis prevented the absorption of available vitamin K necessary for the synthesis of clotting factors. Early treatment with parenteral vitamin K in similar cases should be considered.

Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis.

OBJECTIVE: To determine whether the stage at the time of diagnosis of chronic lymphocytic leukemia (CLL) had changed during a 55-year period. DESIGN: We conducted a study of the cohort of residents of Olmsted County, Minnesota, who had been diagnosed as having CLL during the period from 1935 through 1989. MATERIAL AND METHODS: By analysis of medical records, patients with CLL were characterized by Rai stage, absolute lymphocyte count, age at diagnosis, need for therapy, and reported cause of death in nonsurvivors. Trends for these variables were analyzed by decade throughout the study period. RESULTS: The overall annual incidence rate of CLL per 100,000 population in Olmsted County increased from 2.6 in the 1935 through 1944 period to 5.4 in the 1975 through 1984 period; however, the increasing rate was found only for those 50 years of age or older and was especially dramatic for those 75 years old or older. Analysis of Rai stage over time demonstrated an increase in the proportion of cases diagnosed as Rai stage 0. In addition, the median absolute lymphocyte count decreased, the median time to initiation of therapy increased, and the median age of patients with Rai stage 0 CLL at the time of diagnosis increased over time. Overall, 54% of patients had received therapy for CLL by the time of last follow-up. Among the nonsurvivors, CLL was documented as the underlying or a contributing cause of death in 69%. CONCLUSION: The overall increase in CLL was thought to be due to enhanced methods of early diagnosis and improved health care for the elderly population. Thus, artifact may best explain the observed trend, although we cannot exclude the possibility of an actual increase in incidence rates over time.

Oncogene expression in T-cell lymphoproliferative disorders.

We have investigated the expression of oncogenes and other related genes in eleven patients with T-cell lymphoproliferative disorders and ten patients with other hematologic malignancies. The phenotypes of the T-cell disorders were determined using monoclonal antibodies specific for helper or suppressor subsets. RNA preparations were isolated from peripheral blood mononuclear cells and/or lymph node sections, 5'-end labeled with gamma-32P-ATP, and hybridized under stringent conditions to an excess of nitrocellulose-bound specific cloned DNA; autoradiographs were analysed by microdensitometry. Results revealed increased expression of K-ras, v-fps, transferrin receptor, alpha-tubulin and alpha-interferon in at least five of six helper T-cell lymphoproliferative disorders, while five of five suppressor T-cell disorders demonstrated levels of hybridization to these clones no higher than background. However, studies of T-suppressor disorders demonstrated enhanced levels of beta-interferon-specific RNA in five of five patients, an increase apparent in three of six T-helper chronic lymphoproliferative disorders. These results demonstrate different patterns of gene expression evident in T-helper and T-suppressor abnormalities.

Correlation of clinical outcome with the degree of surface immunoglobulin (sIg) expression in B-cell chronic lymphocytic leukemia.

Peripheral blood from 121 consecutive adult patients with B-cell chronic lymphocytic leukemia (B-CLL) was immunophenotyped, and three groups with differing surface immunoglobulin (sIg) expression patterns were identified: Group A, 82 patients (68%) with weak sIg expression in greater than 20% of the circulating lymphocytes; Group B, 16 patients (13%) with either undetectable sIg or weak sIg expression limited to less than 20% of the lymphocytes; and Group C, 23 patients (19%) with strong sIg expression in greater than 20% of the lymphocytes. The histories of these patients were reviewed retrospectively, and the median follow-up in Groups A, B, and C was nine, ten, and nine years, respectively. Disease progression, defined as the development of cytopenia(s) (hemoglobin less than or equal to 100 g/L [less than or equal to 10 g/dL] or platelet count less than 100 X 10(9)/L [less than 100 X 10(3) microL]) and/or the development of newly palpable splenomegaly or lymphadenopathy, was least in Group B (6%) versus Group A (34%) versus Group C (30%) (P = 0.08). The incidence of hypogammaglobulinemia among patients who had protein electrophoresis performed was 7% in Group B versus 46% in Group A versus 45% in Group C (P = 0.036). The authors conclude that adult patients with B-CLL in whom sIg is undetectable or weakly expressed in less than 20% of the circulating lymphocytes may have an even more indolent clinical course than those with more widespread sIg expression.

Heterogeneity and clinical relevance of the intensity of CD20 and immunoglobulin light-chain expression in B-cell chronic lymphocytic leukemia.

In a prospective study, peripheral lymphocytes of 93 previously untreated patients with B-cell chronic lymphocytic leukemia (B-CLL) were evaluated with flow cytometry for the intensity of CD20 and surface immunoglobulin (sIg) light-chain (LC) expression. Molecules of equivalent soluble fluorescence were used to classify intensity of surface antigen expression as "strong," "moderate," or "weak." Despite reproducible morphological consistency with B-CLL, variability in intensity of CD20 and sIg light chain expression was substantial. CD20 intensity was classified as weak in 62% of patients, moderate in 12%, and strong in 26%. Expression of sIg light chain was weak in 76% and strong in 24%. The patients were followed up for a median of 3.1 years. Intensity of expression of CD20 and sIg light chain was not correlated with any presenting feature at the time of phenotyping, including clinical stage and degree of lymphocytosis or organomegaly. Similarly, clinical course of the disease, time to progression, response to therapy, and overall and treatment-free survival were not predictable from the intensity of CD20 or sIg light chain expression. In conclusion, bright expression of CD20 or sIg light chain is not an unusual feature in B-CLL and may not influence clinical presentation or short-term prognosis.