Analysis of factors affecting acute transformation in chronic myelomonocytic leukemia.
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Acute Disease↗
Biomedical subjects
S Molica
Publications and source records attributed to S Molica.
Recombinant alpha-2a interferon in treatment of B-chronic lymphocytic leukemia. A preliminary report with emphasis on previously untreated patients in early stage of disease.
Eleven previously untreated patients with B-chronic lymphocytic leukemia (B-CLL) (eight in Binet's stage A, two in stage B and one in stage C) received therapy with alpha-2a interferon (Roferon AR, Hoffman, La Roche) at a rather low dose (3.0 MU) given intramuscularly three times a week for a total of 14 weeks. In all cases an objective, although transient, response as measured by a decrease in the absolute lymphocyte count was observed (P less than 0.05). In four patients an increase in the absolute number of granulocytes in the peripheral blood could be detected. Characteristically the response was obtained early after starting treatment (median 4 weeks). None of the patients achieved a complete remission. Interestingly, a stage C patients with thrombocytopenia not due to hypersplenism and a non-diffuse pattern of bone marrow disease obtained significant improvement in the platelet count. Interferon was well tolerated by most patients without major toxicity. These results suggest that alpha-interferon may be useful in the therapy of previously untreated B-CLL patients with a low tumor burden.
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Analysis of factors associated with short-term survival in chronic myelomonocytic leukemia.
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Second neoplasms in chronic lymphocytic leukemia: analysis of incidence as a function of the length of follow-up.
Among 191 chronic lymphocytic leukemia (CLL) patients seen at our institution over an 18-year period, 13 (6.8%) were found to have a second neoplasm (sN). A neoplasm associated with CLL was diagnosed concurrently in 7 cases and subsequently in 6, respectively. Although a trend toward a more frequent incidence in male patients older than 65 years with a more aggressive form of leukemia and who needed therapy could be detected, the clinical characteristics of these 13 patients did not differ significantly from those of the general population of CLL patients. The analysis of the sN risk as a function of the length of follow-up, by calculating the actuarial risk and the hazard function plot, provides important information on the natural history of sN appearing in CLL. The actuarial risk of sN at 5 years was 9.7% or 6.9%, respectively, according to whether we did or did not consider cases of cutaneous carcinomas. The smoothed hazard function showed a pattern of decreasing rate over the first year, a rise to 3.0% by the third year, and no increasing risk later in the follow-up. This trend was associated with a high incidence of sNs synchronous with CLL, and with a clustering of sNs among patients who died early, before reaching median survival. In addition, the early appearance of the sN risk is analogous to the renal transplant experience and suggests that sNs may result from impaired immune surveillance.
Adult↗
Alpha interferon in the treatment of chronic myelomonocytic leukemia.
This study aimed at evaluating the effectiveness of alpha interferon (IFN) in chronic myelomonocytic leukemia, a disease for which therapeutic options are still unsatisfactory. Fourteen sequential unselected patients received recombinant alpha-2b IFN (Intron-A, Schering-Essex) 3 megaU/day, progressively elevated to 10 megaU/day in non responders. Rate and type of response were evaluated in the 10 patients who completed a minimum treatment period of three months. Monocytosis, present in all patients by definition, was reduced in 8 of these 10; neutrophils decreased in 5 of 7 patients with high initial values. Signs of ineffective hemopoiesis were generally not influenced by the treatment, nor were organomegaly and hypergammaglobulinemia, when present; however, in 4 patients the Hb level improved with treatment. IFN treatment failed to improve in vitro growth of GM colonies, but there was improvement of the cluster/colony ratio, due to decrease number of clusters. Lysozyme production by pathologic monocytes was inhibited in the presence of IFN in vitro. Tolerance was variable: three patients interrupted the treatment for unmanageable side effects. These results show that alpha IFN can be effective in CMML patients with prominent proliferative aspects.
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Prognostic features and therapeutical approaches in B-cell chronic lymphocytic leukemia: an update.
In the past few decades important progress has been made in the understanding of chronic lymphocytic leukemia (CLL). Indeed, systematic studies of natural history and prognostic factors have made it possible to predict the outcome of disease. Although clinical stage (i.e. Rai and Binet stages) is the strongest predictor of survival, additional prognostic parameters, including patterns of bone marrow (BM) infiltration, lymphocyte doubling time (LDT), immunophenotype and cytogenetics, have now been identified. Furthermore, criteria of smoldering CLL (i.e. stage A, low lymphocyte count, non-diffuse BM histology, relatively high hemoglobin level, LDT > 12 months) allow identification of a subgroup of patients with indolent course and good prognosis for whom treatment should be delayed, unless progression occurs. Recent meta-analysis of clinical trials has demonstrated no survival advantage for immediate versus referred treatment in low clinical stages. The same considerations apply when comparing combination versus single-drug regimens. Purine analogues like fludarabine, 2'-chlorodeoxyadenosine and 2'-deoxycoformicin are active in CLL. Data on these drugs come from uncontrolled clinical trials; randomized studies are in progress. In addition, some issues concerning the relationship between response and survival, cross-resistance between purine analogues and eradication of the CLL clone, remain still unresolved. There are also increasing data on bone marrow transplants in CLL, although the high treatment-related mortality suggests that this procedure may have some benefit only in selected refractory young CLL patients with adverse features. This review will focus on recent progress in the prognosis and therapy of CLL. Issues that remain controversial will be a matter of discussion.
Adult↗
CD11c expression in B-cell chronic lymphocytic leukemia. A comparison of results obtained with different monoclonal antibodies.
In order to obtain more information on the pattern of CD11c-positivity in otherwise typical B-cell chronic lymphocytic leukemia (CLL), we analyzed immunological and clinico-pathological features of 99 such patients studied with two different monoclonal antibodies (MoAbs). Fifty-two out of 70 (74.2%) patients stained with IOM-11C MoAb and 3 out of 29 (10.3%) patients stained with Leu-M5 MoAb had more than 30% CD11c positive cells (P < 0.0002). The two groups were similar with regard to the expression of B-cell CLL-related antigens (CD5, CD20, CD23), as well as clinico-pathological features (i.e. Binet clinical stage and pattern of bone marrow involvement), thus suggesting that differences in CD11c expression were due to different reactivity patterns of the MoAbs utilized. In our experience, the use of different reagents may affect immunophenotyping results, thus providing conflicting data at times.
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More on CD10-positive cells in the bone marrow of children with immune thrombocytopenia.
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Adult↗
Infections in chronic lymphocytic leukemia. Analysis of incidence as a function of length of follow-up.
BACKGROUND AND METHODS: Infections represent the major cause of death in chronic lymphocytic leukemia (CLL); however, clinical studies dealing with their incidence have yielded inconclusive results. In order to address this issue we reviewed the records of 125 CLL patients (mean age 65.6 yrs; 81 M/44 F; Stage A, 48; Stage B, 37; Stage C, 40) followed up at our institution over a 10-year period. RESULTS: The 125 patients accrued 447 person-years, a mean of 3.8 years per person. There were 199 recorded infections: 47 severe (crude rate 9.8 per 100 person-years) and 72 moderate, respectively. The 5-year risk of developing a severe infection for the whole series was 26% (95% CI: 24.7-27.3%), and 21 out of 71 deaths (29.5%) could be attributed to infectious causes. Despite a linear trend toward increased risk (r = 0.98), hazard function analysis showed a constant pattern of risk (r = 0.30), suggesting a lack of correlation of this event with time. Furthermore, the 5-year risk of developing a severe infection increased to 57.1% (95% CI: 36.4-77.8%) for patients with low IgG levels (less than 6.5 gr/L), and to 68% for those with both low IgG levels and disease stage C. On the other hand, patients who experienced a severe infection more frequently had advanced clinical stage (P < 0.001), low IgG levels (P < 0.01) and diffuse bone marrow (BM) histology (P < 0.05). CONCLUSIONS: Infection is a constant risk in CLL that is associated with shortened survival. Factors such as hypogammaglobulinemia and advanced disease appear to be the major predisposing factors.
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Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study.
BACKGROUND: In a recently reported study, low doses of intravenous immunoglobulins (IVIG) were shown to be as effective as high doses in protecting chronic lymphocytic leukemia (CLL) patients against infections, although a control group was not included. With this background we started a crossover study of low-dose IVIG prophylaxis aimed at investigating its superiority over empirical treatment of infections. MATERIALS AND METHODS: Forty-two CLL patients with hypogammaglobulinemia (IgG < 600 mg/dL) and/or a history of at least one episode of severe infection in the 6 months preceding inclusion in the study were randomly allocated to receive either an infusion of 300 mg/kg IVIG every 4 weeks for 6 months or no treatment. Then they were switched to observation or IVIG for another 12 months; finally, they received IVIG or no therapy for 6 more months. RESULTS: A significantly lower incidence of infectious episodes was observed during IVIG prophylaxis in 30 patients who completed the 6-month period of either observation or IVIG therapy. The same applied to the 17 patients who completed 12 months of either observation or IVIG prophylaxis. Interestingly, the restoration of serum IgG levels obtained in 17 out of 25 patients (mean percent value of IgG increase, 41.8%) did not parallel a decrease in the number of infectious episodes. CONCLUSIONS: A protective effect against infections is demonstrated for low-dose IVIG in the present study. A benefit was shown in patients who completed either 12 or 6 months of IVIG prophylaxis; however, even this low-dose treatment is not a cost effective way to prevent infection in CLL patients.
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Differential expression of BCL-2 oncoprotein and Fas antigen on normal peripheral blood and leukemic bone marrow cells. A flow cytometric analysis.
BACKGROUND: Fas antigen (Ag) has recently been identified as the putative surface molecule capable of transducing apoptotic signals into cells. Alterations in the expression of proto-oncogene bcl-2 have been implicated in the regulation of apoptosis. MATERIALS AND METHODS: By employing a monoclonal antibody to bcl-2 protein (124 clone) and to Fas Ag (UB2 clone) the expression of these molecules was analyzed at flow cytometry on bone marrow (BM) and peripheral blood (PB) samples from patients suffering from different lymphoid and myeloid leukemic diseases (27 acute non-lymphocytic leukemia [ANLL]; 14 acute lymphocytic leukemia [ALL]; 19 B-cell chronic lymphocytic leukemia [CLL]; 2 Ph1+ chronic myeloid leukemia [CML]; one CD8+ T-cell chronic lymphoproliferative disorders). Results were compared with those observed on normal PB leukocytes and BM B-cell precursors from patients with non-neoplastic hematological disorders. RESULTS: Fas Ag was constitutively expressed by both monocytes and neutrophils, while lymphocytes expressed bcl-2 with no difference between B and T cell subsets. Interestingly, bcl-2 expression was always absent on neutrophils. When dealing with ANLL patients, a relatively low bcl-2 and high Fas Ag phenotype characterized subtypes with granulocytic (M2) or promyelocytic (M3) differentiation. This observation was confirmed in a small number of patients for whom bcl-2 levels were quantified as antibody binding capacity (ABC) in molecules/cell. Leukemic cells from patients with ALL constitutively expressed bcl-2, the pattern of this expression being quantitatively lower than that of immature B-cell precursors. Finally, high bcl-2 and low Fas Ag expression represented a crucial part of the B-cell CLL immunophenotype. CONCLUSIONS: Although based on a small number of patient and control samples, our results suggest that bcl-2 and Fas Ag are coordinately expressed on normal PB leukocytes. Fas Ag is expressed at low levels on B-CLL cells, generally considered long-surviving cells. The relatively lower bcl-2-expression detected in both M2 and M3 subtypes may explain, at least in part, the higher remission rates obtained in these forms of ANLL than in other less differentiated morphological variants.
B-Lymphocytes↗
Prognosis of chronic myelomonocytic leukemia.
BACKGROUND: Cytopenia caused by ineffective hematopoiesis and monocyte overproduction coexist in CMML, providing grounds for discussion to supporters of a dysplastic versus a proliferative identity for CMML. Follow-up information from a large series of patients may contribute to clarifying the position of this infrequent disease. METHODS: We analyzed data from 77 patients followed in five institutions. Thirty-two variables were studied for their influence on survival and on progression to acute leukemia by univariate and multivariate analysis. For some parameters, we performed a quartile analysis to reveal a possible non-monotonic influence on survival. RESULTS: Median survival was 17 months. Evolution to acute leukemia (ANLL) occurred in 11 patients (14%) within a median time of 8 months. Multivariate analysis assigned a poorer prognosis to patients presenting with thrombocytopenia, anemia and leukocytosis. Thrombocytopenia and the presence of circulating blasts were risk factors for transformation to ANLL, while raised serum aspartate transaminase at diagnosis seemed to be associated with a lower probability of blastic evolution. The Bournemouth score for CMML proved to be a valid tool for predicting survival but not acute transformation. CONCLUSIONS: CMML is a severe disease. The prognostic independence of cytopenia (anemia, thrombocytopenia) and leukocytosis underlines the coexistence of aspects typical of myelodysplastic and myeloproliferative syndromes.
Adult↗
Cellular expression and serum circulating levels of CD23 in B-cell chronic lymphocytic leukemia. Implications for prognosis.
BACKGROUND: CD23 is a functionally relevant molecule in B-cell chronic lymphocytic leukemia (CLL) which mediates growth and differentiation signals in B-cells. An intriguing feature of CD23 is its ability to be cleaved from the cell surface and released into the serum. MATERIALS AND METHODS: Serum levels of soluble CD23 (sCD23) were determined with a sandwich enzyme immunoassay at the time of diagnosis in 90 previously untreated CLL patients, in order to evaluate whether they reflected disease activity and tumor load. Results were correlated with those dealing with CD23 expression on leukemic cells to verify whether the cellular counterpart determines serum levels. RESULTS: CD23 was detected on peripheral blood mononuclear cells (PBMC) from 78 out of 90 (86.6%) B-CLL patients, without correlation with clinical stage. Circulating levels of sCD23 in the serum of patients with CLL were highly elevated in comparison to 15 normal controls (p < 0.0005); this increase reflected tumor mass as defined by either clinical stage (p < 0.0005) or bone marrow (BM) histology (p < 0.0005). Neither percentage nor absolute number of CD23+ cells correlated with circulating levels. Interestingly, life expectancy was significantly shorter in patients with higher serum levels of sCD23 (p < 0.0005). When integrated into the Binet clinical staging system, sCD23 led to isolation of two subgroups with different prognosis among intermediate-risk patients. Furthermore, longitudinal studies support the idea that sCD23 can be utilized as an indicator of disease progression. CONCLUSIONS: sCD23 is a highly sensitive and suitable marker with prognostic potential in B-CLL.
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Clinico-prognostic implications of increased levels of soluble CD54 in the serum of B-cell chronic lymphocytic leukemia patients. Results of a multivariate survival analysis.
BACKGROUND AND OBJECTIVE: Although less specific than sCD23, sCD54 levels have clinico-prognostic relevance in B-cell chronic lymphocytic leukemia (CLL). Since serological markers are now emerging as potentially important in CLL, we tried to verify whether sCD54 might complement clinical stages. METHODS: Serum levels of sCD54 were determined at the time of diagnosis in 115 previously untreated CLL patients. Results were correlated with clinicobiological parameters as well as with survival. RESULTS: Life-expectancy was significantly shorter in patients with higher serum levels of sCD54 (p < 0.001); however, in a Cox's multivariate survival analysis, the only variables which entered the regression model at a significant level were bone marrow (BM) histology (p = 0.03) and lymphocyte doubling time (LDT) (p = 0.04). Interestingly, when LDT was excluded from analysis the only significant variables were clinical stages (p < 0.05) and sCD54 (p < 0.05). These results suggest that sCD54 and LDT give similar prognostic information. INTERPRETATION AND CONCLUSIONS: In CLL, sCD54 is a reliable prognostic parameter whose value is independent of clinical stages. When investigated in relation to clinical outcome, serum levels of sCD54 were able to predict progression to a more advanced clinical stage. On the basis of these data, an integrated clinico-biological classification which separates intermediate risk into two prognostic subgroups is proposed.
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Clinical and prognostic evaluation of bone marrow infiltration (biopsy versus aspirate) in early chronic lymphocytic leukemia. A single center study.
BACKGROUND AND OBJECTIVE: Recently published studies dealing with chronic lymphocytic leukemia (CLL) patients in early clinical stage reported that bone marrow (BM) biopsies and aspirates can be considered complementary methods of evaluating the extent of BM involvement. Consequently, we designed the present study to investigate the clinical and prognostic implications of BM biopsies and aspirates in a series of stage A CLL patients followed-up in a single center. PATIENTS AND METHODS: BM biopsy sections and aspirate smears obtained at the time of diagnosis from 102 CLL stage A patients were retrospectively evaluated. Results were correlated with clinical and hematological features as well as with survival and disease-progression risk. RESULTS: Diffuse (D) BM histology was detected in 10 patients (9.8%) while 21 (20.5%) displayed lymphocyte infiltration (LI) > 80%. Twenty-six patients (25.4%) died with a 5- and 10-year survival probability of 85% and 50%, respectively. The survival of patients with D-BM histology was significantly shorter than that of patients with non-diffuse (non-D) histology (p < 0.05). Interestingly, when considering only CLL-related deaths (i.e. leukemia progression, infections) were considered, there was an increase in the statistical significance of BM histology (p = 0.01). There was no difference in life expectancy in cases with LI either using different cut-off levels (i.e. 70% and 80%) or excluding non-CLL related deaths. According to our experience, disease progression could only be predicted by BM histology (p = 0.008), while LI was not useful for forecasting progression to more advanced stages (p = NS). INTERPRETATION AND CONCLUSIONS: In patients with early CLL, BM histology provides more reliable information regarding the clinical outcome of the disease than LI.
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Comparative flow cytometric evaluation of bcl-2 oncoprotein in CD5+ and CD5- B-cell lymphoid chronic leukemias.
BACKGROUND AND OBJECTIVES: Levels of intracellular bcl-2 oncoprotein have been found to be increased in leukemic cells of CD5+ B-chronic lymphocytic leukemia (CLL) patients. However, it is not clear whether bcl-2 overexpression is a peculiar feature of CD5+ B-CLL. Based on this background we carried out a quantitative flow cytometric evaluation of intracellular bcl-2 levels on leukemic cells of CD5+ and CD5- B-CLL. METHODS: We assessed in flow cytometry levels of bcl-2 protein using a quantitative indirect immunofluorescence assay (QIFI kit) on samples from 46 previously untreated CD5+ B-CLL patients. Results were compared with those obtained on either normal peripheral blood B-lymphocytes or leukemic cells from 7 CD5- B-CLL patients intentionally selected for statistical comparison. RESULTS: A relatively homogeneous amount of bcl-2 protein which did not reflect either clinical-biological features at the time of diagnosis nor in vivo response to therapy was found. Results expressed as antibody binding capacity (ABC) accounted for a mean value of 12.2 +/- 1.5 x 10(3) molecules/cell (range, 6.4-13 x 10(3) molecules/cell). Levels of bcl-2 detected on CD5+ B-CLL leukemic cells were significantly lower than those of B peripheral blood lymphocytes from healthy donors (p = 0.0001). The same applied when comparing CD5+ and CD5- B-CLL patients (bcl-2 ABC, 8.07 +/- 0.26 x 10(3) molecules/cell vs. 12.2 +/- 1.5 x 10(9) molecules/cell; p = 0.0001). INTERPRETATION AND CONCLUSIONS: According to the role of bcl-2 in preventing apoptosis, our results indicate that differences in the pattern of expression of such an oncoprotein, might, at least in part, explain the more aggressive clinical course of CD5- B-CLL forms.
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Prognostic value of biological variables in B-cell chronic lymphocytic leukemia. Can we improve upon clinical parameters?
BACKGROUND AND OBJECTIVE: Cellular and molecular features including tumor cell proliferation, immunophenotype, adhesion molecule expression and release, and karyotypic abnormalities have been linked with survival in B-cell chronic lymphocytic leukemia (CLL) patients. Although information provided from these studies makes it possible to better appreciate the biological heterogeneity of the disease, it is not clear whether they may substitute clinical features in the prognostic assessment of CLL patients. The objective of this article is to analyze the performance of new prognostic variables, keeping in mind that clinicians should give priority to less expensive biological assays. INFORMATION SOURCES: In the present review, we examined personal papers in this field, and articles or abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART: Clinico-prognostic staging systems do not provide criteria accurate enough to identify patients with progressive disease. Although several in vitro methods have been utilized to evaluate tumor cell proliferation and to correlate this parameter with long-term survival, it is difficult to translate the results of kinetic studies into prognosis. Interestingly, prognostic implications of kinetic parameters are exemplified by clinical studies based on lymphocyte doubling time (LDT). Attempts to correlate immunophenotype with prognosis have yielded inconclusive results. This is probably due to the absence of strict immunological criteria. The membrane instability of CD23, rapidly cleaved into a soluble form, provides a highly specific and reliable serum marker. Expression of myelomonocytic antigens (i.e., CD11b, CD13) appears to be restricted to patients with CD5- CLL. Both cellular expression and release in the serum of some adhesion molecules (i.e., CD54, CD44 standard) have been linked with prognosis. The increased use of fluorescence in situ hybridization (FISH) techniques, which make it possible to identify karyotypic abnormalities even in cases with inadequate mytoses, has contributed to a better definition of incidence and clinical relevance of karyotypic abnormalities in CLL. Trisomy 12 is significantly associated with atypical morphological and/or immunological features, high proliferative activity and poor prognosis; the prognostic effect of 11q deletions is consistent in patients under 55 years of age. Usually, in absence of the rearrangement of the bcl-2 locus, B-CLL cells express bcl-2 gene product, whose intracellular levels do not correlate with clinical stages but do correlate with survival, thereby suggesting a possible independent prognostic value. Finally, p53 tumor suppressor gene has been associated with resistance to therapy with fludarabine. PERSPECTIVES: Even though prognostic assessment of CLL patients is generally based on clinical staging systems new biological parameters which reflect the clinical heterogeneity of the disease are under evaluation. Whether in the future clinicians will substitute biological variables for clinical features is matter of debate. The prognostic value of biological parameters is hampered, in some instances, by the small number of patients presenting these features (i.e., 11q deletions in 20%, p53 mutations in 15%). More likely, biological parameters might be incorporated into clinico-prognostic models thus leading to the formulation of a clinical-biological system for CLL.
Cell Division↗