This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1-5), followed by venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1-5. The use of Bruton\'s tyrosine kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities.

Combination chemoimmunotherapy (CIT) consisting of anti-CD20 has improved the progression-free survival (PFS) and overall survival (OS) of patients with chronic lymphocytic leukaemia (CLL). We performed a comprehensive synthesis of prognostic factors in patients with CLL on combined CIT with anti-CD20 antibodies compared with standard chemotherapy alone or targeted therapy.We searched the MEDLINE and academic search complete electronic databases as well as clinicaltrials.gov (from inception up to 01 August 2022) for randomised controlled trials examining chemoimmunotherapy and targeted therapy in patients with CLL. The risk of bias and the quality of evidence was assessed using the quality in prognostic studies tool (QUIPS).A total of 10 prognostic factors were identified and evaluated in patients with CLL on anti-CD20 antibody-containing CIT. The predictive value of the following prognostic factors was confirmed and associated with poor patient outcomes; deletion 17p (HR = 3.39), Immunoglobulin heavy chain variable region gene mutation status (HR = 0.96) and β2-microglobulin (HR = 1.41).Conventional predictive factors may have retained prognostic value and could be useful in the stratification of patients who may be non-responsive to CIT.Trial registration: International Prospective Register of Systematic Reviews (PROSPERO) registry (CRD42021218997).

Acalabrutinib is a second generation Bruton\'s tyrosine kinase inhibitor and was recently approved in the treatment of chronic lymphocytic leukaemia. We undertook a systematic review and meta-analysis of randomised controlled trials to determine the risks of acalabrutinib-related second primary malignancies (SPM) and nonmelanoma skin cancers (NMSC). The incidence of SPM was 4.7% higher in the acalabrutinib arm compared to control arm with risk ratio (RR) of 1.76 (5.32 vs 3.2 per 100 person-years). Notably, NMSC was the most common SPM, and the incidence was 2.56 per 100 person-years in the acalabrutinib group versus 1.12 per 100 person-years in the control group (RR 2.43). Long-term follow-up and future studies are necessary to define the actual relationship and their risk factors.

Non-Hodgkin lymphoma (NHL) increased continuously since the last century in developed countries. While they are considered as disease in elder ages, a remarkable increasing incidence is also observed in German children and juveniles. The higher rates are interpreted by the changes in classification because diseases such as chronic lymphocytic leukaemia were also identified as NHL. Considerable rates of NHL were found in nuclear workers and liquidators of Chernobyl, i.e. in cases of low-dose chronical exposures. In Germany, we noticed three workers who developed NHL after decontamination of nuclear facilities. The bone marrow is generally considered as target organ for ionizing radiation, but NHL is obviously induced in the whole pool of lymphocytes. Therefore, the dosimetry in cases of typical occupational external and internal exposure must be revised. A high radiation sensitivity for NHL is a possible suspect and likely reason which may partly explain the continuous rise of the diseases in populations underlying the current increases of medical diagnostic exposure. NHL is also induced in children and juveniles with a history of diagnostic X-rays.

Leukaemia cutis (LC) describes infiltration of the skin by leukaemia cells, resulting in clinically identifiable cutaneous lesions. LC has a wide range of clinical manifestations, which can make it difficult to distinguish LC from other skin changes. In a group of patients, LC can be the first manifestation of leukaemia, therefore skin biopsy is crucial for the diagnosis. In this mini review, we discuss various types of leukaemia most frequently represented in leukaemia cutis, in both children and adults and skin changes in multiple myeloma, focusing on the clinical presentation of LC and prognosis in patients.

The ability of ionising radiation to induce lymphoma is unclear. Here, we present a narrative review of epidemiological evidence of the risk of lymphoma, including chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM), among various exposed populations including atomic bombing survivors, industrial and medical radiation workers and individuals exposed for medical purposes. Overall, there is a suggestion of a positive dose dependent association between radiation exposure and lymphoma. The magnitude of this association is highly imprecise, however, with wide confidence intervals frequently including zero risk. External comparisons tend to show similar incidence and mortality rates to the general population. Currently, there is insufficient information on the impact of age-at-exposure, high versus low linear energy transfer (LET) radiation, external versus internal or acute versus chronic exposures. Associations are stronger for males than females, and stronger for non-Hodgkin lymphoma (NHL) and MM than for Hodgkin lymphoma (HL), while the risk of radiation induced CLL may be non-existent. This broad grouping of diverse diseases could potentially obscure stronger associations for certain subtypes, each with a different cell-of-origin. Additionally, the classification of malignancies as leukaemia or lymphoma may result in similar diseases being analysed separately while distinct diseases are analysed in the same category. Uncertainty in cell-of-origin means the appropriate organ for dose response analysis is unclear. Further uncertainties arise from potential confounding or bias due to infectious causes and immunosuppression. The potential interaction between radiation and other risk factors is unknown. Combined, these uncertainties make lymphoma perhaps the most challenging malignancy to study in radiation epidemiology.

Central nervous system (CNS) localisation of chronic lymphocytic leukaemia (CLL) can induce various neurological symptoms. Unfamiliarity with this manifestation causes diagnostic delay. We present two cases of leptomeningeal CLL. These cases and our literature review emphasise that CNS localisation of CLL should be considered in patients with any neurological symptom, irrespectively of the stage and systemic activity of CLL.

With a median age of 72 years at first diagnosis, chronic lymphocytic leukaemia (CLL) is a disease of the elderly. At this age, many patients cannot bear an intensive chemoimmunotherapy like fludarabine, cyclophosphamide and rituximab (FCR), and therapeutic decisions are commonly complicated by a high burden of accompanying comorbidities. Clinical trials, on the other hand, are mostly designed to include a far healthier and younger trial population, with a median age in most studies well below 70 years, leading to an insufficient reflection of clinical reality. With the introduction of new targeted therapies, treatment of CLL is currently undergoing a profound change. New compounds like ibrutinib or idelalisib have enlarged the therapeutic options in treating CLL. However, so far, these oral medications imply continuous intake by the patient, which will at some point lead to the issue of adherence in most patients. In addition, long-term experiences are largely missing. In this setting, one of the oldest chemoactive substances remains a viable option for many CLL patients and their treating physicians: bendamustine, a nitrogen-mustard derivative, has proven to be a safe and efficient agent for treatment of CLL in the first- and second-line setting. In particular, there is some evidence that the substance is relatively well tolerated in elderly and unfit patients. In this review, we summarize the current data on bendamustine in the treatment of elderly and unfit patients with CLL and aim to provide a concise analysis and outlook on the current and future role of this substance in the era of new targeted agents.

Chronic lymphocytic leukaemia (CLL) has a male:female (M:F) ratio 1:1 in tropical Africa. Below the age of 45 years, the M:F is 1:2, while above 45 years; it is 2:1 CLL in younger adults is associated with low socio-economic status (SES) and rural habitation. Clinical and haematological features are the same as in other continents, except that many patients have gross splenomegaly and two populations of lymphocytes in the peripheral blood on light microscopy: it is postulated that with the altered immunity of CLL, recurrent malaria causes a secondary but benign lymphoid hyperplasia. It is hypothesised that the probability of B-cell mutation is increased in an enlarged pool of B-cells resulting from recurrent malaria and other infections. The greatest enhancement occurs in subjects of low SES, who are more exposed to infections, and in grandemultiparae, whose cell-mediated immunity has been depressed repeatedly during pregnancies. A second event could follow transmission of an unidentified virus: transmission is more likely with overcrowding and proliferation more rapid with depression of immunity by malaria and pregnancy. HTLV-1 is associated with CLL, but does not appear to contribute significantly to the peculiar epidemiology of CLL in Africa.

OBJECTIVE: Richter\'s syndrome (RS) refers to high-grade transformation of B-cell chronic lymphocytic leukaemia (CLL), usually to diffuse large B-cell lymphoma, as assessed according to strict World Health Organization (WHO)-defined histological criteria. Although this is a relatively evidence-poor area, the recommended clinical management of high-grade transformation differs considerably from that of relapsed CLL. The \'CHOP-OR\' trial was a single-arm, multicentre, non-randomized phase II National Cancer Research Institute trial in patients with newly diagnosed RS, recruited from across the UK from April 2011 to December 2014. Forty-three patients were enrolled, of whom 37 were ultimately evaluable for response. The aim was to verify the presence of RS in the trial patients and identify pitfalls in the diagnosis of RS.
RESULTS: Two independent, specialist haematopathologists reviewed histological material from 40 available cases enrolled in the CHOP-OR trial to determine whether the submitted diagnosis of RS was correct. Three cases were unavailable for central review. This series represents the largest central review of RS within a prospective trial in the literature to date. Thirty-three of the 40 (82.5%) submitted cases showed features consistent with WHO-defined RS. Reasons for diagnostic uncertainty in discrepant cases included large proliferation centres, variably confluent and serpiginous proliferation centres, and an apparently high proliferation index, sometimes attributable to a thick section or associated normal bone marrow proliferation.
CONCLUSIONS: We discuss the importance of high-quality histological and immunohistochemical sections and strict adherence to WHO criteria in the diagnosis of RS. This study further reinforces the importance of centralized review of cases of haematological malignancy.