Pattern Of Bone Marrow Infiltration Research Articles

Serum Levels of Soluble CD23, but not Soluble CD25, Predict Disease Progression in Early Stage B-Cell Chronic Lymphocytic Leukemia

Serum levels of the soluble forms of CD23 (sCD23) and CD25 (sCD25) were prospectively analyzed with respect to their prognostic relevance in early stage B-cell chronic lymphocytic leukemia (B-CLL). SCD23 and sCD25 levels were determined in 105 patients with newly diagnosed B-CLL (Binet stage A). In 93 of the patients, these levels were correlated with other already established indicators for risk of disease progression, including the histologic pattern of bone marrow infiltration, lymphocyte doubling time (LDT), and the serum level of thymidine kinase (TK). High serum levels of both sCD23 and of sCD25 were associated with a diffuse bone marrow infiltration, a LDT ≤12 months, and elevated (>5 U/L) serum TK, respectively. Moreover, examination of the clinical course of 76 untreated patients showed that high levels of sCD23, but not of sCD25, at initial diagnosis were linked with disease progression. Furthermore, in a stepwise Cox regression model, high levels of sCD23 and a short LDT were shown to be strong predictors of progressive disease within the first year of disease presentation. Therefore, it appears to be justified to incorporate sCD23 levels into the risk profile of early stage B-CLL and to take them into account for stratification in risk-adapted treatment strategies.

The bone-marrow infiltration pattern in B-cell chronic lymphocytic leukemia is not an important prognostic factor. Danish CLL Study Group.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p < 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

An aggressive subtype of B‐CLL is characterized by strong CD44 expression and lack of CD11c

In a retrospective study based on 107 B-CLL patients, the expression of the adhesion molecules CD44, CD11a, CD11b, CD11c, CD18, CD25 and CD54 was analysed in bone marrow cryostat sections by immunohistochemistry. CD44 expression clearly identified two subgroups of B-CLL patients with different clinical course. In particular, CD44-positive patients presented with advanced disease, more often displayed a diffuse pattern of bone marrow infiltration, and had a worse prognosis. 33/61 patients positive for CD44 died within the observation period compared to 7/46 patients negative for CD44 (P = 0.0012). Multivariate analysis emphasized the independent prognostic value of CD44 expression for overall survival (P = 0.022). In contrast, patients positive for CD11c showed a longer survival, with 9/40 patients dying within the observation period compared to 31/67 negative for CD11c (P = 0.0013). Patients lacking CD11c were in advanced Rai and Binet stage. Multivariate analysis confirmed CD11c as a relevant independent prognostic marker (P = 0.033). Moreover, CD11c was able to separate patients with significantly different prognosis in the subgroup of CD44-positive cases. 4/18 patients positive for CD44 and CD11c died before median survival time was reached. Patients positive for CD44 but negative for CD11c had an adverse prognosis: 29/43 patients died, median survival time was 33.4 months. Our results indicate that CD44 positivity and CD11c negativity are associated with more advanced disease and worse prognosis in B-CLL and suggest CD44-positive/CD11c-negative cases represent a more aggressive form of the disease.

Clinical and prognostic significance of bone marrow involvement in patients with diffuse aggressive B-cell lymphoma.

We studied the effect of morphology and extent of bone marrow (BM) infiltrate on the survival of patients with diffuse aggressive B-cell non-Hodgkin's lymphoma (NHL), along with clinical features. Sixty adult patients with diffuse aggressive B-cell NHL and BM involvement at the time of presentation were studied. All patients were uniformly staged and treated with a curative high-dose chemotherapy regimen. BM involvement was assessed according to the cytology, pattern of infiltration, and extent of involvement, and was correlated with overall survival (OS) and failure-free survival (FFS). Patients with BM involvement that consisted of > or = 50% large cells or BM involvement of > or = 70% had a poorer OS (P = .065 and P = .055, respectively). Those who presented with an infiltrate of less than 50% large cells and an international prognostic index (IPI) of < or = 3 had a significantly longer postrelapse survival time (P = .003). A diffuse or interstitial pattern of BM involvement was predictive of both poor OS and FFS (P = .008 and .009, respectively). Multivariate analysis indicated that only IPI (P = .0005) and pattern of BM infiltration (P = .009) were independent predictors of OS, and only the former was predictive of FFS (P = .03). The IPI is predictive of OS and FFS, while BM involvement with a diffuse or interstitial pattern is associated with significantly poorer OS. Patients with BM infiltration that involved > or = 70% of the marrow or contained > or = 50% large cells had poor OS, but more patients need to be studied to determine the significance. Two parameters, IPI < or = 3 and BM large cells less than 50%, identify a group of patients with long-term survival after relapse.

Increased peripheral blood normal myeloid progenitor cells (CFU‐GM) in chronic lymphocytic leukemia: A perspective for autologous peripheral blood stem cell transplantation

We assayed granulocyte-macrophage committed progenitor cells (CFU-GM) in the peripheral blood of 34 patients with chronic lymphocytic leukemia (CLL) and 12 normal individuals. The patients were divided into separate groups on the basis of previous therapy (i.e. analysis performed at diagnosis, during and after chemotherapy) and clinical features of the disease (i.e. disease stage, pattern of bone marrow infiltration, peripheral blood lymphocytosis). The mean CFU-GM colony count of the patients was 30 times higher than that of the controls (206.4 +/- 197.8 (SD) CFU-GM per 5 x 10(5) cells plated versus 6.5 +/- 3.6). There was no statistical difference in the numbers of circulating CFU-GM between the patients studied at diagnosis (257 +/- 215.4 CFU-GM/5 x 10(5) cells) and those studied during (117.6 +/- 169.2 CFU-GM/5 x 10(5) cells) or after chemotherapy (207.5 +/- 105.9 CFU-GM/5 x 10(5) cells), although a trend towards a higher recovery of myeloid progenitors was observed as a function of time elapsing from the last treatment. In addition, we found no significant difference in the in vitro CFU-GM growth of patients grouped according to their disease stage, pattern of bone marrow infiltration and degree of peripheral blood lymphocytosis. In conclusion, our data indicate that intensification with peripheral blood stem cell support may be feasible in CLL, since progenitor cells of myeloid-monocytic series are markedly increased in the peripheral blood of these patients. Moreover, it is possible to extend this kind of therapy to patients who have undergone previous extensive chemotherapy and who might have persisting bone marrow infiltration.

CD23 antigen density is related to serum gamma globulin level, bone marrow reticulin pattern, and treatment in B chronic lymphocytic leukemia.

The CD23 antigen density was evaluated by a cytofluorometric technique in 55 patients with chronic lymphocytic leukemia. The quantification method was based on the use of biological standards in indirect immunofluorescence. The CD23 antigen density was correlated with the percentage of CD23 positive cells, but antigen density appeared to be a more informative parameter. CD23 antigen density was lower in stage B than in stages A or C patients, and higher in patients undergoing chemotherapy or previously treated than in untreated patients. There was a significant negative correlation between CD23 antigen density and serum gamma globulin and IgG levels, that existed only in patients in an advanced stage of the disease. CD23 antigen density was higher in patients with abnormal bone marrow reticulin pattern. Serum gamma globulin level was lower in these patients, as well as in patients with prognostically unfavorable histologic bone marrow infiltration pattern. These data emphasize the interest of antigen density as an additional parameter and the complex relationship between CD23 expression, hypogammaglobulinemia, bone marrow histologic findings, and treatment in chronic lymphocytic leukemia.

6 Chronic lymphocytic leukaemia: Prognostic factors and natural history

In the past 20 years, important progress has been made in the understanding of the natural history and prognosis of chronic lymphocytic leukaemia (CLL). Based on the notion that the clinical manifestations of CLL are due primarily to the progressive accumulation of lymphocytes over time, several prognostic factors have been identified. The prognostic value of parameters reflecting tumour burden (i.e. lymphadenopathy, splenomegaly, anaemia and/or thrombocytopenia due to bone marrow failure), first identified empirically, has been confirmed in multivariate analyses of large series of patients. Furthermore, clinical staging systems that group the most relevant of these factors have also been developed. Patients in early stage (Binet A; Rai 0) have a long survival which, in some cases, may match that of the general population. In contrast, patients with advanced stage (Binet C; Rai III or IV) have a median survival < 2 years. The major limitation of staging systems is that they do not give information about the likelihood of progression for patients in early stage. Nevertheless, haemoglobin level, blood lymphocyte count, lymphocyte doubling time and bone marrow infiltration pattern are useful to identify subsets of patients in early stage with different progression and survival rates, with the 'smouldering' form of the disease being identified fairly accurately. With all these advances, therapy in CLL can now be indicated on a more rational basis. However, further biological insight is needed to elucidate the mechanism accounting for the different forms of the disease.

CD13 Expression in B-Cell Chronic Lymphocytic Leukemia is Associated with the Pattern of Bone Marrow Infiltration

The ectopic expression of the cell surface peptidase CD13 (aminopeptidase N) and of three other myelomonocytic antigens i.e. CD33, CD14 and CD15 was analyzed by flow cytometry in neoplastic lymphocytes from 81 consecutive patients with B-cell chronic lymphocytic leukemia (B-CLL). CD13 and CD14 antigens were detected on lymphocytes from 30% and 60% of patients respectively whilst a smaller percentage of samples was found positive for CD15 (5%) and CD33 (12%). The presence of CD13 and CD33 antigens on neoplastic B cells showed a statistically significant association with the two most important clinicopathologic prognostic factors in B-CLL: the clinical stage (CD13, p < 0.01; CD33, p < 0.05—Rai and Binet staging systems) and the pattern of bone marrow infiltration (CD13, p < 0.001; CD33, p = 0.02). A multiple logistic regression analysis showed that the increased risk of CD13 positive patients (13.7 fold higher than in CD13 negative cases; p = 0.001) of presenting a diffuse pattern of bone marrow infiltratio...

Aberrations of chromosome 6 in 193 newly diagnosed untreated cases of chronic lymphocytic leukemia

Aberrations of chromosome 6 were observed in 11 of 193 cases of chronic lymphocytic leukemia diagnosed January 1, 1984–November 1, 1988 and investigated cytogenetically within 30 days after diagnosis. The 6p was rearranged in 5 cases: 4 balanced and 1 unbalanced translocation. The 6q was involved in 6 cases: 4 deletions and 2 balanced translocations. Three of the del(6q) may be identical: del(6)(q13q27). In two cases there were no additional aberrations. Aberrations of chromosome 6 correlated significantly with an advanced clinical stage, diffuse pattern of bone marrow infiltration, and increased SmlgM-fluorescence intensity. All these factors are associated with poor prognosis. Although the number of cases with 6q aberrations is still too small and the observation period too short to show significant influence on survival, the presence of 6q aberrations at diagnosis may prove useful in delineating a subtype of chronic lymphocytic leukemia with poor prognosis.

Cytogenetic studies in 77 patients with chronic lymphocytic leukemia: correlations with clinical, immunologic, and phenotypic data.

Cytogenetic analyses by G-banding and/or Q-banding techniques of polyclonal B cell mitogen-stimulated peripheral blood lymphocytes in 77 patients with chronic lymphocytic leukemia were carried out in the present study. Adequate metaphases were obtained in 65 patients (84%). Of 29 patients with abnormal karyotypes, ten (34%) had trisomy 12 as the sole abnormality, eight (28%) had trisomy 12 in combination with other karyotypic changes, and the remaining 11 had various karyotypic changes other than trisomy 12. There was a significant relationship between the abnormal karyotype and disease status, clinical stage, lymphocyte count, bone marrow infiltration pattern, monoclonal IgM gammopathy, and urinary monoclonal-free light chain status. Six of seven patients (87%) with trisomy 12 only had stage 0-11 disease, whereas all eight patients with trisomy 12 with other changes had stage III or IV disease (P less than .02). However, of nine patients with other karyotypic changes without trisomy 12, five had stage 0-II and four had stage III or IV disease. These observations suggest that trisomy 12 may be the primary or the earliest karyotypic change in a majority of aneuploid patients with chronic lymphocytic leukemia, and that other karyotypic changes in addition to trisomy 12 may develop as a result of clonal evolution, dedifferentiation, or therapy. Of nine patients in whom autopsy studies were carried out, four were found to have diffuse histiocytic lymphoma or Richter's syndrome (three with trisomy 12 in combination with other chromosome changes and one with normal karyotype). Our findings clearly demonstrate that cytogenetic study may be of value in the clinical and prognostic evaluation of patients with chronic lymphocytic leukemia.

Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data.

Bone marrow biopsies were prospectively performed on 75 patients with chronic lymphocytic leukemia (CLL). There was a highly significant relationship (p less than 0.002) between clinical stages and bone marrow infiltration patterns. Ten (50%) of 20 patients with diffuse patterns died; the estimated median survival time for these patients was 87 months. In contrast, only six (11%) of 55 patients with nondiffuse patterns died; the estimated median survival time for these patients could not be computed. When both clinical stage and infiltration pattern were evaluated for survival, a highly significant association between clinical stage and survival time was still observed (p less than 0.003) whereas bone marrow infiltration pattern was no longer significant. A significant association was also observed between bone marrow infiltration patterns and absolute lymphocyte counts (p less than 0.0005), Fc-receptor-positive cells (p less than 0.002), 3H-thymidine uptake of leukocytes (p less than 0.01), serum alkaline phosphatase levels (p less than 0.05), monoclonal urinary-free light chain status (p less than 0.05), and cytogenetics of leukemic cells (p less than 0.05). These observations lead to the conclusion that in an overall prognostic evaluation of patients with CLL, although bone marrow histopathology may have no additional value over a well-established clinical staging system, as a whole, it may be of clinically predictive value in disease progression of patients with stage I and II.

Patterns of bone marrow involvement in chronic lymphocytic leukemia and small lymphocytic (well differentiated) non-Hodgkin's lymphoma. Its clinical significance in relation to their differential diagnosis and prognosis.

Forty-eight patients with chronic lymphocytic leukemia (CLL), and 12 patients with small (well differentiated) lymphocytic lymphoma (WDL) were histologically evaluated for their pattern of bone marrow (BM) involvement. Four different types of BM infiltration were recognized: nodular (N), interstitial (I), nodular and interstitial (mixed) and diffuse (D). The pattern of BM involvement was compared with the clinical, laboratory, and survival status in all patients. The extent of the disease in CLL patients, was determined by the Rai and the International Workshop on CLL Staging Systems, while in WDL patients the Ann Arbor staging system was used. In the CLL group the N pattern was found in 8%, the I in 33%, the mixed in 31%, and the D in 27% of the patients. Based on the International Workshop on CLL Staging System, the I pattern of BM involvement was more frequently found in Stage A (56%), the mixed in Stage B (68%), and the D in Stage C disease (90%). All CLL patients with D pattern required treatment from the beginning, contrary to CLL patients with the other patterns, in whom therapy was required in less than 50%. Similarly, deaths were more common in the D pattern in whom therapy pattern than in the other patterns. In the WDL patients BM involvement was found in 4 of 12, (33%) and its pattern of positivity was always nodular, although most patients (10 of 12) had advanced disease. It is concluded that the frequency of BM involvement may contribute in the differential diagnosis of WDL from CLL. In addition, the pattern of BM infiltration correlates very well with the International Staging System for CLL, and the pattern of BM positivity in CLL patients also has prognostic significance.

Prognostic significance of bone-marrow patterns in chronic lymphocytic leukaemia.

Bone-marrow biopsy has been performed in 63 cases of chronic lymphocytic leukaemia (CLL). Four different histological patterns were observed: (a) interstitial (lymphoid infiltration without displacement of fat cells) in 12 cases; (b) nodular (abnormal lymphoid nodules without interstitial infiltration) in 10 cases; (c) mixed (combination of the first two patterns) in 21 cases; and (d) diffuse (replacement of both haemopoietic and fat cells by lymphoid infiltration) in 20 cases. Statistical analysis of actuarial curves showed a significant difference of survival probability according to the bone marrow infiltration patterns. Thus, in patients with interstitial or nodular patterns the life expectancy is significantly longer than in those with mixed or diffuse patterns. furthermore, a significant degree of correlation between bone marrow infiltration patterns and different methods of clinical staging in CLL was apparent. The different bone marrow infiltration patterns in CLL probably reflects variations in the amount of lymphoid accumulation during the natural course of this disease. Because of its prognostic significance, bone marrow biopsy should have a place in CLL evaluation and staging.