Monoclonal B‐cell lymphocytosis is closely related to chronic lymphocytic leukaemia and may be better classified as early‐stage CLL

The World Health Organization classification uses a cut‐off point of 5·0 × 10⁹/l cells with a chronic lymphocytic leukaemia (CLL)‐phenotype in peripheral blood to discriminate between monoclonal B‐lymphocytosis (MBL) and B‐CLL. This study analysed 298 MBL patients by multi‐parameter flow cytometry, chromosome banding analysis (CBA)/fluorescence in situ hybridization (FISH), and IGHV mutation status and compared them with 356 CLL patients. In MBL, CBA more frequently revealed a normal karyotype and FISH identified less frequently del(6q), del(13q) (as sole alterations), and del(17)(p13). Within the MBL cohort, a shorter time to treatment (TTT) was found for ZAP‐70‐positivity, 14q32/IGH‐translocations (CBA), del(11)(q22·3) (FISH) and unmutated IGHV status. Higher CD38 and ZAP‐70 expression, del(11)(q22·3) (FISH), trisomy 12 (FISH), and 14q32/IGH‐translocations (CBA) were correlated with a shorter TTT in the combined cohort (MBL + CLL); a sole del(13)(q14) (FISH) correlated with longer TTT. Regarding overall survival, unmutated IGHV status and ‘other’ alterations (CBA) had an adverse impact. There was no correlation between the concentration of CLL‐cells and TTT or overall survival. Multivariate analysis confirmed a negative impact on TTT for del(11)(q22·3)/ATM, trisomy 12 (both by FISH), and 14q32/IGH‐translocations by CBA. These data emphasize a close relationship between MBL and CLL regarding clinically relevant parameters and provide no evidence to strictly separate these entities by a distinct threshold of clonal B‐cells.     

Prognostic importance of soluble CD23 in B‐cell chronic lymphocytic leukemia

Soluble CD23 (sCD23) was proposed as a marker of disease activity and as an important prognostic parameter in B‐cell chronic lymphocytic leukemia (B‐CLL). In this study, prognostic significance of sCD23 in B‐CLL was examined according to its temporal relationship with the known clinical parameters of the disease, CD38 and ZAP‐70. Serum sCD23 levels of 36 B‐CLL patients, followed up in our clinic between 1999 and 2005, and 15 healthy subjects were measured with enzyme‐linked immunosorbent assay. The mean serum sCD23 level of the B‐CLL patients (210.72 ± 193.67 and 6–600 U/ml) was significantly higher than the control group (18.20 ± 14.30 and 6–50 U/ml). Seventy‐eight percent of the B‐CLL patients with lymphocyte doubling time (LDT) <12 months and 24% of patients with LDT >12 months had high sCD23 levels (P = 0.008). Meanwhile, 81% of the patients with diffuse bone marrow infiltration and 33% of patients with nondiffuse infiltration had high levels of serum sCD23 (P = 0.029). A significant difference was found between B‐CLL patients with Binet stages A and C (P = 0.009). Peripheral blood flow cytometry of the patients revealed a significant CD38 expression in patients with high serum sCD23 levels (P = 0.002). Similarly, an increased bone marrow zeta‐chain associated protein kinase‐70 (ZAP‐70) expression was seen in patients with high serum sCD23 levels (P = 0.009, correlation co‐efficient was 0.714). Cumulative and the progression free survivals of the patients with low serum sCD23 levels were 60.1 ± 5.7 months [95% confidence interval (CI); 49.0–71.2] and 51.1 ± 6.6 months (95% CI; 38.0–64.1), respectively. However, they were 43.8 ± 6.5 months (95% CI; 31.0–56.6) and 26.5 ± 6.4 months (95% CI; 14.0–39.1) in patients with high levels. Serum sCD23 is increased in B‐CLL patients and can be used in the clinical follow‐up of the disease in prediction of the tumor mass and prognosis.     

Molecular abnormalities in B‐cell chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia is the commonest adult leukaemia, however the pathogenesis is largely unknown. Since the 1980s specific chromosomal abnormalities have been identified, of which the commonest are deletions of chromosomes 6q, 11q23, 13q14 and 17q13 and trisomy 12. The search for the responsible oncogenes at these sites has proved to be extremely frustrating. There are many oncogenes at 11q23 but the exact gene(s) responsible have yet to be identified. Germline abnormalities of the ATM gene occur in about 18% of patients compared to a normal population carriage of 0.5% but not all studies agree that ATM is the gene responsible. Unfortunately, despite the identification of various minimally deleted regions and the full sequencing of 13q14 no oncogenes have been identified. All original studies suggested the presence of a autosomally recessive tumour suppressor gene at this site but more recent studies suggest this may not be the case and the pathogenesis is more complex than first thought. Similarly, no genes have been identified at 6q or on chromosome 12. We know that the p53 tumour suppressor gene at 17p13 is an important prognostic indicator but it occurs in a minority of patients (about 15%), usually in patients with advanced disease, and therefore probably is not of aetiological importance.     

Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience

While the renal complications of plasma cell dyscrasia have been well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who underwent kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between January 1995 and June 2014, 49 of 4,024 (1.2%) patients with chronic lymphocytic leukemia (n=44) or monoclonal B-cell lymphocytosis (n=5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All five membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone-based regimens had recovery of renal function compared to 0/3 patients treated with rituximab with or without steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/6). Thrombotic microangiopathy primarily occurred as a treatment-related toxicity of pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who develop renal failure and/or nephrotic syndrome.     

High intracellular content of cyclin‐dependent kinase inhibitor p27Kip1 in early‐ and intermediate stage B‐cell chronic lymphocytic leukemia lymphocytes predicts rapid progression of the disease

Previous studies showed that peripheral blood lymphocytes of B‐cell chronic lymphocytic leukemia (B‐CLL) displayed a high intracellular level of cell cycle inhibitory protein p27^Kip1. It has been suggested that its’ high expression may confer them survival advantage and lead to unfavorable prognosis, but the prognostic significance of p27^Kip1 expression for previously untreated, non‐advanced stage B‐CLL was not established. We studied a relationship between the intracellular level of p27^Kip1 of lymphocytes of early‐ and intermediate stage B‐CLL patients and their spontaneous apoptosis in vitro, as well as prognostic significance of p27^Kip1 in B‐CLL lymphocytes for the risk of disease progression. Intracellular p27^Kip1 content of peripheral blood lymphocytes obtained from 48 previously untreated 0–II Rai stage B‐CLL patients was determined by flow cytometry. The viability and apoptosis of those lymphocytes after 72‐h culture were also assessed. During the follow‐up period (6–71 months, median 59.5), we recorded the time elapsed to the doubling of lymphocyte count, progression to a higher Rai stage and the appearance of indications for cytostatic treatment. The p27^Kip1 expression was neither correlated with initial lymphocyte count, CD38 expression, cell viability nor spontaneous apoptosis ratio after 72‐h culture. Higher p27^Kip1 level was related to the probability of earlier occurrence of each of three above‐mentioned events. We did not find a prognostic significance of in vitro cell viability nor apoptosis as to the risk of disease progression. Our results indicate that elevated intracellular p27^Kip1 level in leukemic lymphocytes of early‐ and intermediate stage B‐CLL patients contributes to rapid progression of the disease.     

B‐cell receptor configuration and adverse cytogenetics are associated with autoimmune hemolytic anemia in chronic lymphocytic leukemia

The development of autoimmune hemolytic anemia (AIHA) in patients with chronic lymphocytic leukemia (CLL) is associated with specific biological features. The occurrence of AIHA was hereby investigated in a retrospective series of 585 CLL patients with available immunoglobulin heavy chain variable (IGHV) gene status. AIHA occurred in 73 patients and was significantly associated with an IGHV unmutated (UM) status (P < 0.0001) and unfavorable [del(17)(p13) and del(11)(q23)] cytogenetic lesions (P < 0.0001). Stereotyped HCDR3 sequences were identified in 29.6% of cases and were similarly represented among patients developing or not AIHA; notably, subset #3 was associated with a significantly higher risk of AIHA than the other patients (P = 0.004). Multivariate analysis showed that UM IGHV, del(17)(p13) and del(11)(q23), but not stereotyped subset #3, were the strongest independent variables associated with AIHA. Based on these findings, we generated a biological risk score for AIHA development according to the presence of none (low risk), one (intermediated risk), or two (high risk) of the independent risk factors. Overall, our data indicate that UM IGHV status and/or unfavorable cytogenetic lesions are associated with the risk of developing secondary AIHA in CLL patients and suggest a possible role of specific stereotyped B‐cell receptor subsets in a proportion of cases. Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.     

Humoral and cellular immune responses to recombinant herpes zoster vaccine in patients with chronic lymphocytic leukemia and monoclonal B cell lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL) are clonal B-cell disorders associated with an increased risk of infections and impaired vaccination responses. We investigated the immunogenicity of recombinant zoster vaccine (RZV) in these patients. Individuals with MBL/untreated CLL and Bruton tyrosine kinase inhibitor (BTKi)-treated CLL patients were given two doses of RZV separated by 2 months. Responses assessed at 3 and 12 months from the first dose of RZV by an anti-glycoprotein E ELISA antibody assay and by dual-color Interferon-γ and Interleukin-2FLUOROSPOT assays were compared to historic controls matched by age and sex. About 62 patients (37 MBL/untreated CLL and 25 BTKi-treated CLL) were enrolled with a median age of 68 years at vaccination. An antibody response at 3 months was seen in 45% of participants, which was significantly lower compared to historic controls (63%, p = .03). The antibody response did not significantly differ between MBL/untreated CLL and BTKi-treated CLL (51% vs. 36%, respectively, p = .23). The CD4+ T-cell response to vaccination was significantly lower in study participants compared to controls (54% vs. 96%, p < .001), mainly due to lower responses among BTKi-treated patients compared to untreated MBL/CLL (32% vs. 73%, p = .008). Overall, only 29% of participants achieved combined antibody and cellular responses to RZV. Among participants with response assessment at 12 months (n = 47), 24% had antibody titers below the response threshold. Hypogammaglobulinemia and BTKi therapy were associated with reduced T-cell responses in a univariate analysis. Strategies to improve vaccine response to RZV among MBL/CLL patients are needed.     

Clonal cell surface structures related to differentiation, activation and homing in B-cell chronic lymphocytic leukemia and monoclonal lymphocytosis of undetermined significance

Cell surface structures related to differentiation, activation and "homing" were identified on the leukemic cell clone in blood of 64 patients with a monoclonal B-cell lymphoproliferative disorder. Patients were selected with regard to clinical signs and symptoms of the disease. 39 patients had progressive chronic lymphocytic leukemia of B-cell type (B-CLL): 16 with lymph node enlargement and 14 with progressive lymphocytosis as the most prominent symptom, respectively. 1 patient had an isolated splenomegaly and 8 had symptoms from enlarged lymph nodes, lymphocytosis and/or splenomegaly. 25 patients had an isolated monoclonal B-cell lymphocytosis in blood and bone-marrow but no other signs or symptoms of the disease. The lymphocytosis in these patients was considered to be of "undetermined significance" and the term B-cell lymphocytosis of undetermined significance (B-MLUS) was used. Patients with a prominent lymphadenopathy and/or splenomegaly had CD22+ leukemic cells while in patients with a progressive lymphocytosis the B-cell clone expressed Leu-8. Thus, CD22 might be related to the homing capacity of B lymphocytes for lymphnodes and spleen, while Leu-8 might define a circulating B-cell subset. In B-MLUS about 50% of the monoclonal B cells co-expressed Leu8 which is consistent with a more differentiated phenotype compared to B-CLL with progressive lymphocytosis. The CD22 expression was mostly low in B-MLUS although a few patients showed high values. The expression of receptors for growth factors (CD23, CD25, CD71) was higher in B-CLL compared to B-MLUS patients (p less than 0.001), which is consistent with a difference in lymphocyte activation stage and/or response to growth factors.     

Chronic lymphocytic leukaemia,monoclonal B‐lymphocytosis and pregnancy: five cases,a literature review and discussion of management

Chronic lymphocytic leukaemia (CLL) occurs rarely with pregnancy and monoclonal B‐Lymphocytosis (MBL) has not previously been described in this setting. CLL is predominantly a disease of the elderly and affects men twice as often as women and hence only an estimated 2% of patients are females of childbearing age. We identified only five reported cases of CLL in pregnancy in the literature. We describe two additional cases, plus three other women with CLL dealing with pregnancy‐related decisions. We review the literature and discuss proposals for management and issues that arise in this relatively uncommon occurrence. In contrast to many other haematological malignancies where longer remissions are typically associated with a lower risk of relapse, most patients with CLL who require treatment will ultimately relapse with current therapy. This complex setting requires careful consideration and well informed patients to assist with decisions related to pregnancy.     

Management of chronic lymphocytic leukemia (CLL) in the era of B‐cell receptor signal transduction inhibitors

The treatment of patients with chronic lymphocytic leukemia (CLL), an indolent B‐cell lymphoma is in the midst of a transformation. There are a large number of promising new therapeutic agents and cellular therapies being studied which exhibit remarkable activity, favorable toxicity profiles, convenient administration schedules, and treatment options are rapidly expanding. The recent advances in the management of CLL exemplify the value of translational medicine. This review highlights key aspects of B‐cell receptor (BCR) signaling in relation to novel inhibitors of the BCR signaling pathway, currently at various stages of preclinical and clinical development. Am. J. Hematol. 90:657–664, 2015. © 2015 Wiley Periodicals, Inc.     

Marked lymphocytosis suggesting chronic lymphocytic leukemia in three patients with hyposplenism

Three patients with hyposplenism of diverse cause are described, in whom marked persistent lymphocytosis suggested the diagnosis of an early phase of chronic lymphocytic leukemia. Absolute lymphocyte counts ranged from 4,900/mm3 to 10,500/mm3. Patient follow-up ranged from 120 months to 294 months. The clinical course and additional test results, including results of lymphocyte surface marker analysis in all three patients and bone marrow biopsy in two, excluded the diagnosis of chronic lymphocytic leukemia. The finding of marked lymphocytosis in the hyposplenic state is emphasized, extending the degree of absolute lymphocytosis previously reported and thereby expanding the differential diagnosis of sustained lymphocytosis. In addition, the normal findings on both bone marrow and surface marker studies, along with the prolonged clinical course, support the contention that this is a benign entity.     

Myasthenic syndrome and oligoclonal lymphocytosis: evolution into chronic lymphocytic leukemia

We report a patient with myasthenic syndrome who, 2 years after diagnosis, developed an oligoclonal lymphocytosis. This disorder was sustained by both κ+ and λ+ CD5+ B-cell clones; over the following year, the white blood cell count increased and phenotypic characterization revealed a clear imbalance in the immunoglobulin light chain ratio (84% κ+). Accordingly, persistence of a κ+ B-cell clone was disclosed by molecular analysis of immunoglobulin heavy chain gene rearrangements. Our results may suggest that prolonged immune system stimulation due to an autoimmune disease can drive a benign lymphoproliferation into a B-cell neoplastic process. Received: 25 June 1997 / Accepted: 22 September 1997