Chronic lymphocytic leukaemia complicated by chylothorax

Chylothorax is a very rare complication of chronic lymphocytic leukaemia: we describe an 81-year-old woman with chronic lymphocytic leukaemia complicated by chylothorax. Treatment with mediastinal irradiation and chemotherapy was unsuccessful. The pleural effusion resolved after talc pleurodesis.     

How I treat patients with relapsed chronic lymphocytic leukaemia

As front line therapy has improved, the treatment of relapsed chronic lymphocytic leukaemia has become more difficult as the disease becomes resistant and the patient accumulates comorbidities. The outcome for those who relapse after immunochemotherapy with fludarabine, cyclophosphamide and rituximab is strongly influenced by the duration of initial response. Patients who relapse within the first year or with a TP53 abnormality have very high‐risk disease and will not respond to chemotherapy. High dose glucocorticoid and alemtuzumab followed by an allogeneic stem cell transplant is probably the best approach for younger, fitter patients in this category. Those who relapse after 2–3 years without TP53 abnormality will probably respond to their initial therapy again. Relapse within 12–24 months carries an intermediate outlook. Additional options include bendamustine and rituximab, ofatumumab and lenalidomide. New therapies are on the horizon and patients should be discussed with a specialist centre and entered into a clinical trial whenever possible.     

Chronic lymphocytic leukaemia presenting with bilateral breast involvement

The association of chronic lymphocytic leukaemia (CLL) and other tumours has been frequently described. Involvement of the breast by CLL is rare. Only four cases of this association have been described (Haram 1937; Seale et al. 1972; Desablens et al. 1985). We report here a case of B-cell CLL presenting with a lump in the breast which may indicate that the disease has a more aggressive clinical outlook.     

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3.83 per 100 000 person-years for CLL (n = 15 676) and 1.31 for SLL (n = 5382) during 1993-2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1.98) than for SLL (1.67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed- and under-reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies.     

Chronic lymphocytic leukaemia and neuroendocrine cancer

We report a unique association between neuroendocrine cancer and chronic lymphocytic leukaemia (CLL) in a 63-year-old man. Neuroendocrine cancer was resistant to various conventional treatments and following locoregional progression we treated the patient with hypoxic pelvic perfusion of cisplatin 100 mg/m2 plus mitomycin 40 mg/m2, using the stopflow method, for three cycles: a dramatic and surprising reduction of > 75% in the evaluable lesions was observed. The cumulative effect of treatment produced a complete response from CLL. At cytogenetic examination the neuroendocrine cells were diploid, whereas CLL cells showed trisomy 12. Moreover, deletion of the short arm of chromosome 3 was found in both neoplastic populations. Whether the abnormality seen on chromosome 3 in the two diseases represents a critical event is not known.     

Chronic lymphocytic leukaemia: current first-line therapy

There is a major evolution in progress in the first-line therapy of chronic lymphocytic leukaemia. Several recent, large, clinical trials have documented superior outcomes with fludarabine-based therapy compared with treatment with alkylating agents. Monoclonal antibodies, especially rituximab, are establishing an important role for targeted treatment. It is expected that chemoimmunotherapy will become the preferred treatment for many patients in the near future. Specific challenges remain to be answered, however, especially the optimal treatment for the elderly, patients with autoimmune haemolysis and those with P53 deletions and mutations.     

Trinucleotide repeat dynamic mutation identifying susceptibility in familial and sporadic chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) has a strong hereditary component, but an understanding of predisposition genes is poor. Anticipation with familial CLL has been reported, although the molecular mechanism is unknown. Expansion of trinucleotide repeat sequences underlies anticipation observed in neurodegenerative disease. A polymerase chain reaction-based assay was used to analyse the stability of ten CCG- and CAG-trinucleotide repeat tracts in 18 CLL families and 140 patients with the sporadic form of the disease. The study suggests that anticipation, if it occurs in CLL, is not linked to CCG- and CAG-repeat expansion, however, variation in repeat length at certain loci (FRA16A) may permit identification of susceptible family members. In addition, polymorphisms with prognostic significance were identified. These were high length (but not expanded) repeats at FRA11B (P = 0.01), ATXN1 (P = 0.032) and ATXN3 (P = 0.022), all associated with poor risk disease.     

Chronic lymphocytic leukaemia genetics overview

Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy.     

Chronic lymphocytic leukaemia genomics and the precision medicine era

Massive genomic analyses have underscored the diversity of chronic lymphocytic leukaemia (CLL) between patients. Genetic heterogeneity of tumour clones within a patient may fuel tumour evolution. Several recurrently deregulated intra‐cellular pathways are candidates for targeted therapies that are very promising and are dramatically changing clinical patients’ perspectives. In this review we present an overview of the genetic and epigenetic features of CLL and their clinical and biological implications.     

Lymphoplasmacytic/lymphoplasmacytoid lymphoma: A clinical entity distinct from chronic lymphocytic leukaemia?

Summary Clinical data of 116 patients with chronic lymphocytic leukaemia (CLL) and of 114 patients with lymphoplasmacytic/lymphoplasmacytoid lymphoma (synonym: LP immunocytoma, IC) as diagnosed according to the Kiel classification were compared. This interim evaluation of a prospective multicenter study of the Kiel Lymphoma Study Group characterizes IC the less favorable lymphoma entity as evidenced by a more rapid lymph node enlargement, by a higher incidence of constitutional symptoms and of marked anaemia, and by a higher percentage of patients requiring early treatment. In addition, in IC autoimmune haemolytic anaemia was detected in 11.2% of investigated patients as compared to none of the patients with CLL, and monoclonal gammopathy was disclosed in 34.2% of investigated patients as compared to only three patients with CLL who could be, however, unrecognized cases of IC. Actuarial survival data after a follow-up period of 40 months are in favor of an overall better prognosis of patients with CLL than of patients with IC.Supported by the Deutsche Krebshilfe e. V., BonnPresented in part at the 5 th Meeting of the International Society of Haematology, European and African Division, Hamburg, August 26–31, 1979     

Chronic lymphocytic leukaemia in a patient with essential thrombocythaemia

A patient who developed chronic lymphocytic leukaemia 6 years after an initial diagnosis of essential thrombocythaemia is described. This association, which was not treatment related, is extremely rare and only two other cases have been previously described in the literature.     

Anticipation in familial chronic lymphocytic leukaemia

Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain heritable neurological disorders and in multiple myeloma, non-Hodgkin's lymphoma and other haematological neoplasms. The present study was conducted to determine whether anticipation occurs in familial chronic lymphocytic leukaemia (CLL). Fourteen published reports of multigenerational familial CLL were analysed for anticipation, together with 10 previously unreported families with familial CLL, and the difference in disease-free survival between generations was determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. The age at onset of the studied cases was also compared with that of the Surveillance Epidemiology and End Results (SEER) Program of the U.S. National Cancer Institute. The median ages at onset in the child and parent generations of all families (51.0 and 72.0 years respectively) were significantly different (P < 0.000001), and the null hypothesis was rejected (P < 0.000001). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.00001), but not between the parent generation and the SEER population. Anticipation characterizes familial CLL.     

Bcl10 in chronic lymphocytic leukaemia and T-cell prolymphocytic leukaemia

Bcl10 is a cancer gene recently identified in B-cell lymphomas of mucosa-associated lymphoid tissues. It has been suggested as a target for mutation in multiple types of tumour including follicular lymphoma, T-cell acute lymphoblastic leukaemia and Sezary syndrome. To evaluate further the role of Bcl10 in human adult haematological cancers, we screened for mutations samples from 24 patients with B-cell chronic lymphocytic leukaemia (CLL) and 18 samples from patients with T-cell prolymphocytic leukaemia (T-PLL). No pathogenic mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not involved in the development of CLL or T-PLL and that its involvement may be restricted to other haematological malignancies.     

Familial chronic lymphocytic leukaemia: a survey and review of published studies

B-cell chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia. To gain insight into the role of inherited factors in the disease, we have conducted a survey of the family histories of 268 CLL patients and have reviewed published familial cases and epidemiological studies. The results of our survey and published studies strongly support the hypothesis that a subset of the disease can be ascribed to a genetic predisposition. The most likely genetic model for inherited predisposition appears to be dominantly acting genes with pleiotropic effects because in many families CLL appears to be associated with other lymphoproliferative disorders.     

B-chronic lymphocytic leukaemia in Latvia: Epidemiological aspects

Abstract: As in western Europe and the USA, chronic lymphocytic leukaemia (CLL) in Latvia is the most prevalent type of leukaemia. A total of 1509 newly diagnosed cases of B-cell chronic lymphocytic leukaemia entered the study, 440 of whom were followed up at the Latvian Haematology Centre. The main peculiarities of the study were: 1) the higher incidence of the disease in Latvia as compared with other regions of the former USSR and with western countries, 2) a lower male-to-female ratio than in most other countries and 3) a higher morbidity among the Latvian population in comparison with the Russian. A positive correlation between the disease stage and survival was confirmed, but no precise individual prognosis in an early stage of the disease was possible.     

Molecular pathogenesis of chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.     

Sequential changes in the bone marrow trephine biopsy in B-cell chronic lymphocytic leukaemia

Background: Trephine biopsy of the bone marrow is integral to both diagnosis and prognosis in B-cell lymphocytic leukaemia (B-CLL), but its usefulness would be enhanced by more information on the type, degree and rate of change that occur over time in histologic pattern and lymphocytic infiltration.
Aims: To investigate these changes by serial trephine biopsy in totally untreated patients, in treatment-free intervals in treated patients and during intervals of treatment.
Methods: In 82 patients with predominantly early B-CLL observed for a median of 65 months (13–331), 309 trephine biopsies were carried out, a median of three (two to eight) per patient. The biopsies were classified into nodular, interstitial, mixed and diffuse patterns. Lymphocytic infiltration was subjectively graded into minimal (< 20%), intermediate (20–50%) and majority (> 50%) categories and all changes were compared.
Results : Intensity of infiltration increased through this histologic range, as did the relative risk of death. Survival of patients with > 50% involvement was significantly poorer than those with < 50%. Changes in both lymphocyte numbers and pattern occurred slowly in early disease but quickened as the leukaemia advanced. Under treatment, lymphocytes decreased but the histology did not alter significantly. Examining the marrow for disease progression should be part of regular follow-up. It may help identify the minority of patients with early disease which will run a more active course and in whom early therapy may yet be indicated. We recommend biopsy at two-yearly intervals in early disease, more frequently as the leukaemia advances. The minimal, intermediate and majority classification in addition to the histologic pattern is a useful grading. (Aust NZ J Med 1993; 23: 470–476.)     

Multidrug resistance mechanisms in chronic lymphocytic leukaemia

We evaluated the presence of P-glycoprotein (P-gp)-170, multidrug resistance protein (MRP), lung resistance protein (LRP)-56 and Bcl-2 in CD19-positive cells from 100 cases of chronic lymphocytic leukaemia (CLL). P-gp-170 was found in 73% of the CLL cases with no significant difference regarding stage or previous treatment. LRP-56 protein was homogeneously distributed with no differences for stage or treatment. MRP protein was detected at a low level of expression in 49.4% of CLL patients with no differences for stage or treatment. Bcl-2 protein was expressed at a high level in all CLL patients and higher levels were found in the advanced stage. This leads us to conclude that P-gp, MRP, LRP-56 and Bcl-2 are frequently expressed in CLL. P-gp, MRP and LRP are not correlated to stage or previous treatment. Bcl-2 is higher in advanced-stage patients. The clinical and biological significance of these zMDR mechanisms in CLL remains to be fully explained.     

Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection. In contrast, the use of idelalisib is associated with a 2-fold risk for severe infection and opportunistic infections. Venetoclax does not appear to be associated with additional infection risk. The evolving spectrum of pathogens responsible infections in CLL patients, especially those with relapsed and refractory disease are described, and prevention strategies (prophylaxis, monitoring and vaccination) are proposed.