Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re‐evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow‐up, investigator‐assessed complete response (CR) rate (21·0% vs 10·8%), median progression‐free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non‐responders. However, patients with objective response or a CR experienced a significantly longer OS than non‐responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first‐line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.     

Survival and prognostic factors in chronic lymphocytic leukemia

The survival of 137 consecutive chronic lymphocytic leukemia patients, diagnosed between 1960 and 1982 and followed up at the Hematology Clinic of the Chaim Sheba Center, was correlated with demographic, clinical and laboratory data. The median survival time of the whole group was 104 months. Older age, hepatomegaly, anemia, thrombocytopenia and increased percent of lymphocytes in the peripheral blood at diagnosis were all associated with shorter survival. On the other hand, splenomegaly or lymph node enlargement did not influence survival. When divided according to both Rai's and the International Workshop staging systems, the survival of our patients seemed to be better than that reported in most previously published series of similar patients. We assume that this is related to a conservative approach to the treatment of chronic lymphocytic leukemia patients in this center.     

Current approaches to the chemotherapy of B-cell chronic lymphocytic leukemia: a review

Standard therapy has not substantially improved the outcome of patients with chronic lymphocytic leukemia (CLL). However, an increased understanding of the biology and immunology of CLL, and the availability of several new and active chemotherapy agents (eg, fludarabine, 2'-deoxycoformycin [DCF], 2-chlorodeoxyadenosine [CDA]) has stimulated enthusiasm for clinical trials. DCF induces CRs or PRs in 25% of heavily treated patients. Fludarabine has been associated with a response rate of greater than 50% in previously treated patients, and greater than 70% in untreated patients, with almost a third of these achieving a CR. Currently, phase I and II clinical trials are evaluating combinations of these drugs with each other or with conventional agents (eg, fludarabine/chlorambucil [CLB]/prednisone [P]; DCF/CLB/P; fludarabine/DCF; fludarabine/P) in previously treated patients. To facilitate comparison of these regimens, each study is adhering to the NCl-Working Group guidelines for eligibility and response criteria, and toxicity assessment. A collaborative phase III trial will then compare the most promising of these regimens with "standard" chemotherapy in previously untreated patients. The widespread availability of these clinical trials will allow clinicians ready access to the new treatments.     

Staging and prognosis of chronic lymphocytic leukemia

Three hundred ninety-one cases of chronic lymphocytic leukemia (CLL) from the Tumour Registry of Manitoba, spanning a 20-year period from January 1960 to December 1979, were reviewed. Survival curves were developed using the staging systems of Rai and Binet. A clear separation in survival was found utilizing the system of Binet. Also, there was a significant increase in the development of secondary malignancies (observed, 53; expected, 31, p<0.01). However, there was no significant increase in secondary malignancies if only those malignancies occurring at least six months after the diagnosis of chronic lymphocytic leukemia was made were analyzed (observed, 38; expected, 29, p=0.26). This suggests that the increase in secondary malignancies is not treatment-related, and may be due to the underlying disease. Received from the Sections of General Internal Medicine and Oncology, Department of Internal Medicine, St. Boniface General Hospital, University of Manitoba, Winnipeg, Manitoba.     

The utility of a prognostic index for predicting time to first treatment in early chronic lymphocytic leukemia: the GIMEMA experience

Background

A prognostic index based on widely available clinical and laboratory features was recently proposed to predict survival in patients with previously untreated chronic lymphocytic leukemia. We assessed the utility of this index for predicting time to first treatment in early chronic lymphocytic leukemia.

Design and Methods

An observational database of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto), which included 310 patients with newly diagnosed Binet stage A chronic lymphocytic leukemia who were observed at different primary hematology centers during the period 1991 – 2000, was used for the purpose of this study.

Results

The new prognostic index enabled Binet stage A patients to be divided into two subgroups that differed with respect to time to first treatment (P=0.003). The original prognostic index was derived from a database that included cases observed at a reference academic center; these patients were younger (P<0.0001) and had more advanced disease (P<0.0001) than those in the current investigation, which studied community-based patients whose data were recorded at presentation. With this in mind, we used an optimal cut-off search to determine how best to split patients with Binet stage A disease into different prognostic groups. According to the recursive partitioning (RPART) model, a classification tree was built that identified three subsets of patients who scores were 0–2 (low risk), 3–4 (intermediate risk) and 5–7 (high risk). The probability of remaining free from therapy at 5 years was 100% in the low risk group, 81.2% in the intermediate risk group and 61.3% in the high risk group (P<0.0001).

Conclusions

The results of this study confirm the utility of a new prognostic index for predicting time to first treatment in a large sample series of community-based patients with early stage chronic lymphocytic leukemia at presentation. Our effort to develop a revised scoring method meets the need to separate Binet stage A patients into different prognostic groups in order to devise individualized and tailored follow-up during the treatment-free period.     

Quality of life of patients with chronic lymphocytic leukemia: results of a longitudinal investigation over 1 yr

OBJECTIVES: The aim of this longitudinal study was to determine the long-term quality of life (QoL) of patients with chronic lymphocytic leukemia (CLL) and to investigate the relationship between QoL and sociodemographic and clinical parameters. METHODS: Ninety-seven patients suffering from CLL were asked to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) four times over a period of 1 yr. Clinical data on disease and treatment characteristics were collected from medical records. For the purpose of comparison, EORTC QLQ-C30 scores were collected from 152 age- and gender-matched healthy controls. RESULTS: Seventy-six patients (age: median 68 yr, range 41-89) returned one or more questionnaires and were included in the statistical analysis. Compared with healthy controls CLL patients reported a lower QoL in almost all domains. No differences regarding QoL could be observed between CLL patients who had already received chemotherapy and those who had not. Moreover, female CLL patients were found to have remarkably lower QoL scores in the areas of emotional and social functioning than male patients. CONCLUSION: Patients suffering from CLL could have their QoL improved by more effective symptom management and psycho-oncological support. This could focus on specific symptoms such as fatigue and might have particular benefits for female patients with respect to their emotional and social well-being.     

Rectal cancer associated with chronic lymphocytic leukemia

It has been reported that chronic lymphocytic leukemia (CLL) often occurs concomitantly with other malignant neoplasms. However, because CLL is rare in Japan, there are only a limited number of reports of the occurrence of malignant neoplasia in Japanese patients with CLL. We report here the simultaneous occurrence of rectal cancer and CLL in a 57-year-old man. Because the clinical stage of CLL was Rai system I, we decided, in accordance with the National Cancer Institute–Sponsored Working Group guidelines, to monitor him without therapy for CLL until evidence of disease progression, and we performed abdominoperineal resection of the rectum for the cancer. The small rectal tumor was associated with aggressive lymphangiosis carcinomatosa, and multiple nodal metastases were observed in the pool of CLL cells. He died of rectal cancer 7 months after the operation, and autopsy revealed extensive metastases of the cancer. Cellular and humoral immunity is often impaired in patients with CLL, and the defective immunity in this patient may have had an etiological role in the development and rapid progression of the cancer. In the follow-up of CLL patients, we must always be aware of the possible existence of a second malignant disease. Particular attention should be paid to those with defective immunity, and screening should be performed, especially for pulmonary and gastrointestinal malignancies.     

Prolymphocytic transformation of chronic lymphocytic leukemia: a case report of lengthy survival after intensive chemotherapy

A case of prolymphocytic transformation of chronic lymphocytic leukemia (CLL) is presented in which complete peripheral morphometric remission and lengthy survival were observed after intensive chemotherapy. The case is discussed within the context of the reported therapeutic experience.     

Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial

Background

There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients’ outcome and response to treatment may provide important insights into the biology of the disease.

Design and Methods

We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients’ outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology.

Results

The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72x10⁻⁷) and rs11158493 (PPP2R5E; P=8.50×10⁻⁷). In addition, the 52 single nucleotide polymorphisms associated at P<10⁻⁴ included rs438034 (CENPF; P=4.86×10⁻⁶), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10⁻⁵) and rs2064501 (IL22RA2; P=4.81×10⁻⁵) which map to B-cell genes.

Conclusions

Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses. (Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00004218","term_id":"NCT00004218"}}NCT00004218)     

Analysis of T-cell subsets in B-cell chronic lymphocytic leukemia: a correlation with the stage of disease

T-cell subsets were determined by the Leu monoclonal antibodies in the peripheral blood and/or bone marrow of 52 patients with B-cell chronic lymphocytic leukemia (B-CLL) not on therapy at the time of study. The diagnosis of B-CLL required that the leukemic cells expressed surface receptors for "la-like" antigen, Fc fragment of IgG, mouse red blood cells (MRBC), C3-coated red cells (EAC), and low density of monoclonal surface immunoglobulin. The Leu-3a+/2a+ ratio was applied to define the balance between the helper/suppressor subsets in the residual T-lymphocytes. Most patients showed a decrease in the Leu-3a+/2a+ ratios at all stages of disease. The decrease in ratio was mainly related to a decrease in the Leu-3a+ T-cell subset. The more advanced stages of B-CLL were associated with lower Leu-3a+/2a+ ratio, higher total white cell and percent lymphocyte counts. There was no correlation between the proportion of EAC or MRBC rosetting cells and stages of B-CLL. This analysis further suggests that B-CLL is an immunosuppressed state that becomes more pronounced in the advanced stages and is characterized by a progressive decrease in the Leu-3a+ (helper) T-cell subset.     

Chylothorax in chronic lymphocytic leukemia patient

Chronic lymphocytic leukemia (CLL) is rarely complicated by chylothorax: we present a 93-year-old woman with CLL who developed recurrent pleural effusions that were ultimately found to be chylous in nature. Despite eight repeated thoracenteses, she continued to experience re-accumulation of fluid, and therefore, video-assisted thoracotomy with mass ligation of the thoracic duct region plus pleurodesis was performed to resolve the chylothorax. Despite her age and underlying disease, she did well during follow-up. The etiology and management of chylothorax are also reviewed.     

Splenectomy for thrombocytopenia in chronic lymphocytic leukemia

The role of peripheral platelet destruction as a reversible etiology of thrombocytopenia in chronic lymphocytic leukemia (CLL) was evaluated in nine patients with CLL and refractory thrombocytopenia who underwent splenectomy. The patients' ages ranged from 54 to 74 years. Progressive thrombocytopenia refractory to antineoplastic agents and corticosteroids had been present for a mean of 23.4 months. The platelet counts were 4,000-57,000/microliter, and were generally higher in those patients with larger spleens. The spleens ranged from 180 to 4050 gm. Seven patients responded completely to splenectomy, achieving platelet counts greater than 150,000/microliter, and in one other patient, the count rose to greater than 100,000/microliter. The platelet count of one patient failed to respond to surgery. Those patients with massive splenomegaly developed higher, more rapidly rising platelet counts postoperatively. No operative mortality was encountered. Median hospitalization was seven postoperative days. All patients experienced an increased sense of well-being. Median follow-up time is 9 months.     

Coexistence of myelodysplastic syndrome and untreated chronic lymphocytic leukemia with development of acute myeloid leukemia immediately after treatment of chronic lymphocytic leukemia

A 72-year-old man originally seen for anemia and thrombocytopenia was determined to have chronic lymphocytic leukemia (CLL). Bone marrow examination at the time of CLL diagnosis revealed a small but significant population of atypical blasts. Cytogenetic analysis of the bone marrow aspirate disclosed chromosomal abnormalities (-7, +8) suggestive of a myelodysplastic syndrome. Shortly after treatment of the CLL, there was proliferation of the previously noted blast population, which cytochemical studies demonstrated to be of the myeloid series thus indicating acute myeloid leukemia superimposed on CLL. This report presents microscopic, cytogenetic, immunophenotypic, and cytochemical evidence to document the evolution of acute myeloid leukemia in the bone marrow of a patient with CLL after one course of chemotherapy.     

Baff serum level predicts time to first treatment in early chronic lymphocytic leukemia

We analyzed the correlation between well‐established biological parameters of prognostic relevance in B‐cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgVH), ZAP‐70 and CD38 expression] and serum levels of B cell–activating factor (BAFF of the TNF family) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 169 previously untreated CLL patients in Binet stage A. Higher levels of BAFF were more frequently associated with female gender (P = 0.02), younger age (P = 0.01), Rai stage 0 (P = 0.002), higher platelet count (P = 0.005), mutated IgVH disease (P = 0.002), higher occurrence of normal cytogenetic profile or presence of 13q deletion (P = 0.02), low ZAP‐70‐ (P = 0.003), and CD38‐expression (P = 0.02). Maximally selected log‐rank statistic plot identified a serum BAFF concentration of 0.313 ng/mL as the best cut‐off (P < 0.0001). This threshold recognized two subsets of patients with different TFT (P < 0.0001). Because in multivariate analysis soluble BAFF [Hazard ratio (HR), 8.23; confidence Interval (CI) 95%,3.0–22.6, P < 0.0001] and mutational status of IgVH (HR = 2.60; CI 95% 1.10–6.14, P = 0.03) maintained the discriminating power their combined effect on clinical outcome was assessed. When three groups were considered: ( 1 ) low‐risk (n = 93), patients with concordant IgVH_mut and higher soluble BAFF; ( 2 ) intermediate‐risk (n = 50), patients with IgVH_mut and low BAFF levels or IgVH_unmut and soluble higher BAFF;( 3 ) high‐risk (n = 26), patients with concordant IgVH _unmut and low soluble BAFF, the 2‐yr TFTs were, respectively, 95%, 85%, and 41% (P < 0.0001). In conclusion, our results indicate that in early B‐cell CLL, the biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables.     

Membranous glomerulonephritis in chronic lymphocytic leukemia

We present a case of chronic lymphocytic leukemia associated with nephrotic syndrome. Renal biopsy revealed membranous glomerulonephritis accompanied by interstitial monoclonal lymphocytic infiltration. Combination therapy with cyclophosphamide, vincristine, and prednisone (COP) was successful in inducing an effective response in chronic lymphocytic leukemia. Improvement of renal function and proteinuria was also observed.     

Autoimmune hyperthyroidism and thrombocytopenia developing in a patient with chronic lymphocytic leukemia

A 56-year-old white man is described whose course of chronic lymphocytic leukemia (CLL) was complicated by the occurrence of the autoimmune hyperthyroidism/thrombocytopenia syndrome. The implications of this syndrome on the treatment of CLL are discussed.     

Concomitant chronic lymphocytic leukemia and acute myeloid leukemia with an uncommon immunophenotype

We report a case of simultaneous diagnosis of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), in which the use of flow cytometry analysis allowed the demonstration of two different cell populations and the study of both immunophenotyping patterns with a large panel of monoclonal antibodies (MoAbs). CLL cells showed a typical immunophenotype with coexpression of B cell markers with CD5, CD23, CD43, and weak surface immunoglobulin light chain restriction expression, whereas the AML population had a very uncommon phenotype with expression of myeloid markers and CD56 and lack of expression of other natural killer (NK) antigens, CD34 and HLA-DR. After chemotherapeutic treatment of AML with two induction courses, the patient achieved complete remission of the AML with persistence of a CD19/CD5 positive population. After consolidation chemotherapy, this latter population was no longer detectable despite the presence of lymphoid nodules in a bone marrow biopsy. Six months after diagnosis, the patient relapsed with AML and died shortly afterwards. Am. J. Hematol. 56:281–287, 1997. © 1997 Wiley-Liss, Inc.     

10例慢性淋巴细胞白血病免疫表型分析

目的：探讨慢性淋巴细胞白血病（CLL）的免疫分型。方法：应用流式细胞仪对10例CLL患者外周血进行淋巴细胞表面抗原检测。结果：10例CLL患者CD19抗原阳性表达率为100%。其中1例患者CD5、CD19、CD20、HLA-DR、CD3、CD13均阳性,且CD34表达率大于10%;另有1例为CD5、CD19、CD20、HLA-DR阳性且伴CD7阳性。CD5、CD19、CD20、HLA-DR同时阳性的患者为50%。结论：CLL以B细胞慢淋为主,免疫分型对慢淋的诊断及鉴别诊断具有重要意义,其免疫分型可存在伴系表达。