Mantle cell lymphomas (MCLs) represent a clinically aggressive lymphoma subtype with a poor prognosis. To explore a potential progress in outcome a historical comparison was performed using data from ...the Kiel Lymphoma Study Group (KLSG; 1975 to 1986) and the German Low Grade Lymphoma Study Group (GLSG; 1996 to 2004).
All patients with the histologically confirmed diagnosis of advanced-stage nonblastoid MCL were eligible. To minimize the potential heterogeneity of different risk profiles frequency matching was pursued. In addition, we adjusted for potential confounding variables by multiple Cox regression.
A total of 520 patients were assessable, 150 from KLSG and 370 from GLSG studies. The median overall survival was 2.7 years for KLSG patients as compared with 4.8 years for GLSG patients (P < .0001). The 5-year survival rates were 22% in the KLSG group (95% CI, 13% to 31%) as compared with 47% for GLSG treated patients (95% CI, 38% to 55%). The hazard ratio adjusted for performance status, lactate dehydrogenase, and age was 0.44 for GLSG patients (95% CI, 0.32 to 0.59).
Median overall survival of patients with advanced nonblastoid MCL almost doubled during the past 30 years. Potential reasons for this apparent improvement in overall survival include the application of anthracycline-containing regimens and new approaches, such as antilymphoma antibodies or stem cell transplantation. Advances in general supportive care, new diagnostic tools, and general improvement of life span might have also reinforced this effect. However, our results are questioning the validity of historical comparisons which had been frequently applied in previous trials.
Purpose: Mantle cell lymphomas (MCL) represent a lymphoma subtype with an especially poor long term prognosis. Although various therapy strategies have been applied within the last 30 years, MCL is ...still considered incurable by conventional chemotherapy.
Patients and methods: To determine whether patient outcome has improved during the last decades, we compared data from the “Kiel lymphoma group” (KLG) collected in the years 1975–1986 with data from the “German lymphoma study group” (GLSG) of the years 1996–2004. To minimize potential heterogeneity of risk profiles of the two patient populations, frequency matching was pursued. Additionally, the effects of other potential prognostic parameters were adjusted by a Cox proportional hazard model.
Results: A total of 520 patients were evaluable for analysis. The median overall survival significantly increased from 2.7 years up to 4.8 years (p<0.0001; hazard ratio (HR) 0.44) and 5-year-survival of advanced MCL more than doubled from 22% 95% CI, 13% to 31% to 47% 95% CI, 38% to 55%. Multivariate analysis identified a poor performance status (HR 2.26), a high LDH level (HR 1.75), and age (HR 1.38) as additional prognostic variables.
Conclusion: Patients with advanced MCL benefit from the progress of medical treatment resulting in almost doubling of overall survival during the last 3 decades, even though relapses are regularly observed.
Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) ...initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m2 for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight BW with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.
The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). ...Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.
Combination chemotherapy with fludarabine plus cyclophosphamide (FC) was compared with the standard regimen of fludarabine monotherapy in first-line treatment of younger patients with chronic ...lymphocytic leukemia (CLL). Between 1999 and 2003, a total of 375 patients younger than 66 years who predominantly had advanced CLL were randomly assigned to receive either fludarabine (25 mg/m2 for 5 days intravenously, repeated every 28 days) or FC combination therapy (fludarabine 30 mg/m2 plus cyclophosphamide 250 mg/m2 for 3 days intravenously, repeated every 28 days). Both regimens were administered to a maximum of 6 courses. FC combination chemotherapy resulted in significantly higher complete remission rate (24%) and overall response rate (94%) compared with fludarabine alone (7% and 83%; P < .001 and P = .001). FC treatment also resulted in longer median progression-free survival (48 vs 20 months; P = .001) and longer treatment-free survival (37 vs 25 months; P < .001). Thus far, no difference in median overall survival has been observed. FC caused significantly more thrombocytopenia and leukocytopenia but did not increase the number of severe infections. In summary, first-line treatment with FC increases the response rates and the treatment-free interval in younger patients with advanced CLL.
Mantle cell lymphoma (MCL) is an aggressive lymphoma with accepted risk factors such as proliferation markers. To date, the different follicular dendritic cell (FDC) patterns have never been analyzed ...in comparison with the overall survival time. Lymph node biopsy specimens from 96 patients were analyzed by conventional morphology and immunohistochemistry with antibodies against cluster differentiation (CD)20, CD5, CD23, cyclin D1, and FDC (Ki-M4P). Two groups can be distinguished with different FDC patterns: a nodular pattern in 79 cases and a diffuse pattern in 17 cases. A Kaplan-Meier analysis revealed significantly better survival for the nodular group (p=0.0312). This group was subdivided into a group with a nodular FDC pattern similar to the FDC distribution in primary follicles (PF-nodular in 72 cases) and one with a nodular FDC pattern resembling the colonization of germinal centers (GCs) by tumor cells (GC-nodular in seven cases). A Kaplan-Meier analysis showed that patients with MCL with a PF-nodular FDC pattern had a significantly better clinical outcome than patients with the other two patterns (p=0.0033). If only cases with classical cytology (n=79) were analyzed (blastoid types excluded), patients with a PF-nodular FDC pattern had a better clinical outcome (p=0.0008). The distribution of FDC in MCL is a diagnostic tool for identifying patients with a better clinical prognosis.
Follicular dendritic cells (FDC) are located within follicles of secondary lymphoid tissue and in lymph nodes of patients with germinal center cell-derived non-Hodgkin lymphomas. Reliable antigenic ...phenotyping of FDC within tissue sections has been difficult due to simultaneous labeling of the surrounding germinal center cells. Using an enzyme cocktail to digest human tonsils and cervical lymph nodes with subsequent fractionation by albumin gradient centrifugation, cell isolates containing up to 20% FDC were obtained. This preparation allowed the determination of antigenic phenotype on individual FDC. Molecules expressed by FDC were detected by an isotype-specific immunocytochemical double-labeling procedure, i.e. a monoclonal antibody (mAb) specific for FDC (KiM4 or DRC1) in conjunction with a mAb reactive against an additional antigenic determinant. Nonspecific binding of mAb to immunoglobulin Fc receptors located on FDC membranes was avoided by incubation of cells with human IgG aggregates prior to immunostaining. The results revealed that isolated FDC from these lymphoid tissues express transferrin receptors, the intercellular adhesion molecule 1, class II antigens, the B cell antigens CD20 and CD21, and the myelomonocytic properties CD11b and CD14. Immunoglobulin mu or gamma heavy chains and the B cell antigens CD23 and CD24 are detected on 50% of an isolated FDC population. These FDC are negative for the T helper cell antigen CD4, the B cell cell antigens CD19 and CD22, the immunolobulin alpha and delta chains and the S-100 protein. FDC isolated from lymph nodes of patients with low-grade malignant non-Hodgkin lymphoma, identified by DRC1 or KiM4 mAb, presented the same antigenic profile as seen on FDC from nonmalignant tissue. This suggests that FDC from lymphoma tissue isolated in this manner have the same properties as those found in normal tissue.
The transcriptional regulator GATA1 is crucially involved in megakaryocytopoiesis and erythropoiesis. Mutations of the gene which is located on the X chromosome have been associated with platelet and ...red blood cell abnormalities. We identified a family with a GATA1 (G208R) mutation in whom a low male birth rate and frequent miscarriages among heterozygous females suggested increased fetal death in male hemizygotes. Female mutation carriers had normal or near normal hemoglobin levels and platelet counts ranging from normal to severely reduced, probably reflecting skewed X chromosome inactivation. Platelets were dimorphous, and thrombocytopenia was associated with erythroblastosis. The only living male mutation carrier had severe macrothrombocytopenia with life-threatening bleeding episodes, moderate to severe anemia, eosinopenia, skeletal abnormalities, and abundant extramedullary hematopoiesis. Long-term sequelae in the 50-year-old patient included unilateral nephrectomy following misinterpretation of paraspinal hematopoiesis as renal cancer, spinal stenosis which was possibly favored by progressive bone marrow expansion, and severe secondary gout.
The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B‐cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 ...patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m2 in a 30‐min IV infusion, d 1–3, and cyclophosphamide 250 mg/m2 in a 30‐min IV infusion on d 1–3. Cycles were repeated every 28 d. Twenty‐one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute‐sponsored Working Group, were recorded in 29 out of 32 assessable patients (90·6%). Twenty‐four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69·4%, 16·7% and 16·7%) respectively. Other side‐effects were uncommon. No treatment‐related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side‐effect. These results warrant further study on the FC combination in randomized trials.
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