Further characterization of the circulating cell in chronic lymphocytic leukemia.

Peripheral lymphocytes from normal individuals and from patients with chronic lymphocytic leukemia (CLL) were cultured in vitro for 1-7 days. The growth response to phytohemagglutinin (PHA) was quantitated by the incorporation of tritiated uridine into RNA nucleotide during a 2-hr pulse with the radioisotope. While the maximum response in PHA-stimulated normal cultures appeared at 2-3 days, CLL cultures required 5-7 days to develop their maximal response, which was 50%-60% of the normal magnitude. Dilution of the number of normally reactive lymphocytes by culturing them with totally unreactive, mitomycin-treated cells produced a normal 72-hr maximal response, no matter what proportion of unreactive cells was included in the PHA-stimulated cultures. In addition, the response of peripheral lymphocytes from patients with myeloblastic leukemia, where large numbers of unreactive myeloblasts diluted the normal small lymphocytes, a depressed reaction occurred at the anticipated 2-3 days. Nylon fiber-adherent lymphocytes consisting of 85% immunoglobulin (Ig)-bearing cells responded minimally to PHA, but showed no evidence of a delay. When isolated from CLL patients, both fiber-adherent cells (Ig-bearing) as well as non-fiber-adherent (sheep erythrocyterosetting) cells responded to PHA in a delayed fashion. Similarly, a case of CLL, in which 93.5% of the circulating lymphocytes bore sheep red blood cell receptors, showed its peak response to PHA at 7 days. Therefore, using surface marker criteria considered characteristic of normal T cells and B cells, the delayed response to PHA on the part of CLL lymphocytes was independent of thymic or nonthymic origin.     

B cell surface marker analysis of synovial fluid cells in a patient with monoarthritis and chronic lymphocytic leukemia.

We describe a women with clinically quiescent chronic lymphocytic leukemia who developed monoarthritis consistent with her known diagnosis of osteoarthritis. Because of the concurrent chronic leukemia, we were concerned with the possibility of leukemic arthritis. Immunofluorescence of synovial fluid cells demonstrated an increase in B cells that failed to demonstrate monoclonality as determined by light chain class expression. However, biopsy of synovial tissue revealed leukemic infiltration. Local radiation therapy resolved the monoarthritis.     

Clinical staging of chronic lymphocytic leukemia.

A method of clinical staging of chronic lymphocytic leukemia (CLL) has been proposed which is based on the concept that CLL is a disease of progressive accumulation of nonfunctioning lymphocytes: stage O, bone marrow and blood lymphocytosis only; stage 1, lymphocytosis with enlarged nodes; stage II, lymphocytosis with enlarged spleen or liver or both; stage III, lymphocytosis with anemia; and stage IV:lymphocytosis with thrombocytopenia. Analysis of 125 patients. in the present series showed the following median survival times (in months) from diagnosis: stage 0, is greater than 150; stage I 101; stage II, 71; stage III, 19; stage IV, 19, The median survival for the entire series was 71 mo. The prognostic significance of the stage remained even after adjustment was made for age and sex. However, both sex and age were shown to be poor predictors of survival after adjustment for stage. The method of staging proved to be a reliable predictor of survival whether used at diagnosis or during the course of the disease. The proposed staging system was an equally accurate indicator for survival when applied to two other previously published studies of large series of patients     

Progression and survival studies in early chronic lymphocytic leukemia.

To investigate the natural history of stage A chronic lymphocytic leukemia (CLL) we reviewed 84 such patients. Among 74 cases evaluable for disease progression, 22 (29.6%) progressed to more advanced clinical stages (9 to stage B, 13 to stage C); the actuarial estimation of such an event at 4 years was 30% (95% CI: 26.3% to 33.6%). Despite a linear trend toward an increasing risk (r = .92), the hazard function analysis showed a constant pattern of progression, suggesting a lack of correlation of such an event with time (r = .04). Furthermore, disease progression when analyzed as a time-dependent variable had a clear-cut impact on survival (P less than .001). With the aim of identifying a subgroup of patients with low probability of disease progression and death, we applied to our set of patients four different proposals for subclassifying stage A. All methods were similar in terms of sample size, 5-year survival rate, and disease progression risk, suggesting that the choice between different proposals is somewhat arbitrary. Whatever the criteria are for defining "smoldering" CLL, such patients (accounting in the present study for 20.5% of overall series and 46.7% of stage A patients) should not be treated until progression occurs.     

Clinical, immunophenotypic and cell cyclic analysis in chronic lymphocytic leukemia

15 cases of chronic lymphocytic leukemia (CLL) were immunophenotyped with a panel of monoclonal antibodies. 13 cases were B-CLL, which was characterized by CD20+, HLA-Dr+, SmIg+ and CD5+/Em+. 2 cases were T-CLL, one with Ts phenotype and HLA-Dr+ T-Cll in the other. The ratio of G0 + G1 cells in bone marrow of CLL was 91.1 +/- 2.3% (76.0 +/- 5.1% in controls), while S + G2M cells was 8.9 +/- 2.3% (23.9 +/- 5.1% in controls). The ratios of various cyclic cells were similar in bone marrow and in peripheral blood. Prolymphocytoid transformation developed in the late stage in 3 CLL patients. The clinical course, cytochemistry and immunologic changes in CLL were also analysed.     

A unique surface marker profile in T-cell acute lymphocytic leukemia

A 5-yr-old girl with acute lymphocytic leukemia presented with moderate hepatomegaly, marked splenomegaly, but no evidence of a mediastinal mass. The peripheral blood white count was 270 x 10(9)/liter with 99% leukemic cells. Surface marker analysis showed the lymphoblasts to be E- rosette negative and complement receptor positive. The patient's leukemic cells were unreactive with anti-p23,30, which detects Ia-like antigens, and strongly reactive with A99 anti-T-cell serum, which reacts with normal human thymocytes and peripheral blood T cells. The percentage of leukemic cells bearing complement receptors diminished during relapse. The leukemic cells obtained at diagnosis and during relapse were nonreactive to mitogens and alloantigens and failed to stimulate proliferation of normal lymphocytes in mixed lymphocyte culture. There was no evidence for active suppression of normal lymphocyte reactivity mediated by the leukemic cells. The surface marker and functional profile of these leukemic cells is consistent with that of an early stage in T-cell maturation.     

True small lymphocytic T-cell chronic lymphocytic leukemia lacking the CD3 molecule and TCR-alpha beta on its cell surface

We report a case of T-cell chronic lymphocytic leukemia (T-CLL) in which the lymphocytes were small and mature, did not have cytoplasmic granulation, and appeared to be similar to those of B-cell chronic lymphocytic leukemia (B-CLL). Immunophenotyping of the lymphocytes revealed CD2+, CD4+, CD5+, and CD25+ on the cell surface, but expression of the CD3 and TCR-alpha beta molecules was localized only in the cytoplasm. The clinical course was as indolent as that of B-CLL, and the patient was able to undergo open-heart surgery. Thus, we confirmed that true T-CLL is able to exist as a counterpart of B-CLL.     

Mantle cell lymphoma mimicking chronic lymphocytic leukemia

A 62-year-old male was admitted to our hospital complaining of dyspnea in March, 2002. He had remarkable bone marrow invasion with a significant number of leukemic cells, anemia and thrombocytopenia. In addition he had generalized lymphadenopathy including a bulky mass in the left cervix. Surface marker analysis of abnormal cells showed CD 5+, 10-, 19+, 20+, 23+, and kappa+, and immunohistochemistry revealed cyclin D1-positive cells. Chromosome analysis showed del(11q). The patient was diagnosed as having mantle cell lymphoma, stage IVB, and received combination chemotherapy. He could not obtain complete remission and died after 29 months. We found it very difficult in this case to make a differential diagnosis between mantle cell lymphoma and chronic lymphocytic leukemia. We report on this case and summarize the problem of the differential diagnosis.     

E rosette formation in B cell chronic lymphocytic leukemia.

We describe a patient with B cell chronic lymphocytic leukemia whose B lymphocytes showed the capacity to form rosettes with sheep red blood cells during prolymphocytoid transformation of the disease. In this case, rosette formation was found to be related to the presence of the classic E rosette receptor since the leukemic cells were recognized by the OKT11 monoclonal antibody. This feature was not shown at diagnosis. Evaluation of this phenomenon is discussed.     

Clinical features and outcome of familial chronic lymphocytic leukemia

The prognostic impact of the presence of a familial trait was analyzed in 1449 patient with chronic lymphocytic leukemia (CLL). A family history of hematologic malignancy (HM) was identified in 181 cases (12.5%) and recorded more frequently among female than male patients (HM: p < 0.05; CLL: p < 0.05). The relative was affected by CLL in 89 cases (6%). Familial and sporadic cases showed non-statistically different proportions of advanced stages (10.8 vs 7.1%) and patients requiring therapy (55 vs 60%) and a similar survival probability at 10 years (67 vs 66%). These data suggest that in CLL the presence of a familial trait does not imply an adverse prognosis.     

Hematopoietic stem cell aging and chronic lymphocytic leukemia pathogenesis

Human malignancies develop through the multistep acquisition of critical somatic mutations during the clinical course. Regarding hematological malignancies, recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are considered to directly originate from differentiated mature lymphocytes; however, we previously reported that the propensity to generate clonal B cells had already been acquired at the HSC stage in CLL patients. Similarly, HSC involvement has been reported in the pathogenesis of mature T cell lymphomas. These studies indicate that, in mature lymphoid, if not all, malignancies, HSCs should be considered as the critical cellular target in the oncogenic process. The prevalence of these hematological malignancies dramatically increases with age, and the effect of aging HSCs should thus be taken into account when investigating the stepwise malignant transformation process of these age-associated malignancies.