Increased risk of melanoma in patients with chronic lymphocytic leukaemia

Introduction. Chronic lymphocytic leukaemia (CLL) is a malignant clonal lymphoproliferative disorder characterised by the accumulation of atypical mature CD5/CD19/CD23-positive B lymphocytes, predominantly in blood, bone marrow, lymph glands, liver and spleen. Chemotherapy protocols with the inclusion of nucleotide analogues, alkylating drugs and monoclonal antibodies are currently the standard of treatment. FCR (fludarabine, cyclophosphamide, rituximab) is one of the most effective protocols. CLL may lead to various immunologic disorders resulting in an increased risk of a malignant neoplasm. This paper aims to present a demonstration of a case of the combination of chronic lymphocytic leukaemia and stomach cancer, and an attempt to establish — based on literature data — a link between the diagnosed stomach adenocarcinoma and the main disease.Materials and methods. Authors have analysed the case history, laboratory and instrumental data and the treatment of a patient with chronic lymphocytic leukaemia and stomach adenocarcinoma.Results and discussion. The patient E., 63 yo, was diagnosed with chronic lymphocytic leukaemia in 2016. The patient was started on FCR chemotherapy protocol (Fludarabine, 70 mg days 2-4 of CT, Endoxan 500 mg days 2-4 of the cycle, Rituximab 700 mg day 1 od CT) in June 2018. When the patient came to the BSMU hospital for a chemotherapy cycle in August 2018, gastric endoscopy was performed; tissue pathology examination resulted in the diagnosis of stomach adenocarcinoma. A concilium of surgeons, oncologists and haematologists made a decision to perform a gastrectomy with the oesophageal resection and Roux anastomosis.Conclusion. Having used a clinical case as an example and reviewed available literature, the authors have demonstrated that either CLL or the immunosuppressed status served as the causal factors for the development of the adenocarcinoma. The development of stomach adenocarcinoma in patients with chronic lymphocytic leukaemia makes the course and outcome of the main disease much more severe. A decision regarding the management strategy for such patients has to make individually every time, taking into account the severity of the oncological disease; this impacts on the choice of the treatment protocol. All the cases of spontaneous remissions in patients with lymphocytic leukaemia must be screened extensively in order to facilitate early diagnosis of malignant neoplasms.

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Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study

British Journal of Cancer ◽

10.1038/bjc.2013.381 ◽

2013 ◽

Vol 109 (5) ◽

pp. 1287-1290 ◽

Cited By ~ 24

Author(s):

S Beiggi ◽

J B Johnston ◽

M D Seftel ◽

M W Pitz ◽

R Kumar ◽

...

Keyword(s):

Follicular Lymphoma ◽

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

Population Based ◽

Second Malignancies ◽

Population Based Study ◽

Canadian Population ◽

Increased Risk

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Poor functional antibody responses are present in nearly all patients with chronic lymphocytic leukaemia, irrespective of total IgG concentration, and are associated with increased risk of infection

British Journal of Haematology ◽

10.1111/bjh.13455 ◽

2015 ◽

Vol 171 (5) ◽

pp. 887-890 ◽

Cited By ~ 2

Author(s):

Helen M. Parry ◽

Jane Birtwistle ◽

Alison Whitelegg ◽

Chris Hudson ◽

Tina McSkeane ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

Antibody Responses ◽

Risk Of Infection ◽

Increased Risk

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Incidence of Non-Melanoma Skin Cancers in Patients with Chronic Lymphocytic Leukaemia: A Retrospective Study in a Bay of Plenty, New Zealand Population

Blood ◽

10.1182/blood-2021-147766 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4692-4692

Author(s):

Andrew Weston ◽

Marie Hughes ◽

Gillian Corbett ◽

Neil Graham ◽

Franz Strydom

Keyword(s):

New Zealand ◽

Chronic Lymphocytic Leukaemia ◽

Cancer Registry ◽

Lymphocytic Leukaemia ◽

Whole Body ◽

Control Group ◽

Skin Damage ◽

Skin Cancers ◽

Increased Risk ◽

Melanoma Skin

Abstract Background/Aims: Chronic lymphocytic leukaemia (CLL) incurs an increased risk of developing second primary malignancies (SPMs). The pathogenesis underpinning this increased SPM risk is attributable to synergism between genetic aberrations, chronic immune suppression / dysfunction and CLL treatments. Specifically, CLL associated skin cancer is a well-documented phenomenon, with common malignancies such as squamous (SCC) and basal cell (BCC) carcinomas occurring at higher frequencies in CLL patients and are often of a more aggressive phenotype. The incidence of non-melanoma skin cancers (NMSCs) among New Zealand CLL patients is unknown, as NMSCs are not required to be reported to the New Zealand Cancer Registry. Accordingly, this study aimed to analyse the incidence of NMSC in CLL patients from the Bay of Plenty region of New Zealand. Methods: We conducted a retrospective analysis of 213 CLL patients, who were referred to Bay of Plenty District Health Board (BOPDHB) between 2015 and 2020, for the occurrence of SPMs. Clinical notes were reviewed for the demographics of sex, age at time of CLL diagnosis, CLL treatments received and occurrence and type of NMSCs. A control group of 76 patients referred to BOPDHB haematology, for anaemia or thrombocytopenia, of which the cause subsequently remained unknown and was not associated with lymphoproliferative disease, was reviewed for primary malignancy (PM), occurrence and type. NMSC incidence was also compared to a local data, on overall NMSC incidence in the general Bay of Plenty population, in 2015. Results: The predominant SPM types occurring in this CLL patient group were NMSCs. A total of 249 and 170 histological diagnoses of SCC and BCC were made in our group of CLL patients, respectively. Of the 213 CLL patients, 48.8% had a diagnosis of at least one NMSC, with median time between CLL and NMSC diagnosis of 5 years (range, -6 to 19 years). CLL patients that were diagnosed with NMSC developed a mean number of 3.93 ± 2.94 separate lesions, compared to 2.6 ± 1.7 lesions in our control population. Note: comparison of NMSC incidence data between CLL group and Bay of Plenty population Conclusion: Patients with CLL are at increased risk of developing multiple NMSC lesions. Therefore, we believe CLL patients should be assessed by dermatologists or general practitioners for whole-body skin examination, 6 monthly following their CLL diagnosis. This strategy promotes early diagnosis, and patient education on importance of sun protection strategies to reduce NMSC risk. This is essential to the ongoing care of CLL patients in a NZ context, given the increased incidence of NMSC associated with CLL, in combination with the high levels of UV exposure and skin damage among the NZ general population. This study also highlights how NMSC disease burden is likely to be significantly underestimated due to a lack of data collection on these malignancies by the New Zealand Cancer Registry. Disclosures No relevant conflicts of interest to declare.

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Bruton's Tyrosine Kinase Inhibitors Impair Fcγriia-Mediated Responses of Healthy Donor Platelets and Chronic Lymphocytic Leukaemia Derived Platelets to Bacteria

Blood ◽

10.1182/blood-2020-142624 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Leigh Naylor-Adamson ◽

Zoe Booth ◽

Simon Hart ◽

Russell Patmore ◽

Sujoy Khan ◽

...

Keyword(s):

Platelet Aggregation ◽

Tyrosine Kinase ◽

Chronic Lymphocytic Leukaemia ◽

Healthy Donor ◽

Lymphocytic Leukaemia ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase ◽

Increased Risk ◽

Treatment Naïve ◽

Granule Release

Platelets play a key role in innate immunity and can interact with bacteria through multiple molecular mechanisms. One key receptor for platelet-bacteria interactions is FcγRIIa, a low affinity IgG immune receptor found on the surface of platelets, which is associated with platelet aggregation, phagocytosis and the release of bactericidal substances and cytokines from alpha and dense granules. The signalling pathways that regulate FcγRIIa mediated platelet responses to bacteria are not fully understood. Downstream of the FcγRIIa receptor is the protein Bruton's tyrosine kinase (Btk) and potentially other Tec family kinases, yet the role of these kinases in platelet-bacteria interactions is unknown. Btk is a therapeutic target in chronic lymphocytic leukaemia (CLL) with inhibitors of Btk (iBtks) including ibrutinib and acalabrutinib. However, iBtks have off-target effects on platelets, inhibiting aggregation with associated haemorrhagic side effects. iBtk treatment is also associated with a higher incidence of infection in CLL patients. The effect of iBtks on platelet immune function has not been evaluated. We hypothesise that Btk has a role in platelet FcγRIIa signalling in response to bacterial agonists, and that iBtks inhibit such responses, contributing towards the increased risk of infection seen with such therapies in CLL. We show that ibrutinib and acalabrutinib inhibit healthy donor FcγRIIa-mediated platelet aggregation, alpha and dense granule release in response to incubation with Staphylococcus aureus and Escherichia coli, and also in response to FcγRIIa crosslinking with the monoclonal antibody IV.3 (anti-FcγRIIa). The observed lack of granule secretion will reduce the bactericidal substances released by the platelet, as well as the amount of cytokine and chemokine secretion limiting cross-talk with other immune cells. Phosphorylation of Btk at tyrosine 223 (a marker of Btk activation) was detected in response to FcγRIIa agonists, and was inhibited by both ibrutinib and acalabrutinib. Little is known about the effect of iBtk treatment on CLL-platelet responses to bacteria. CLL patients tend to be on concurrent medications for comorbid conditions that could alter platelet responses. We show that treatment-naïve and ibrutinib-treated CLL platelets have aggregation and alpha granule release to thrombin receptor activator peptide 6 and ADP comparable to healthy controls, indicating that CLL platelet responses to these FcγRIIa-independent agonists are normal. Moreover, platelets derived from iBtk naïve CLL patients aggregate normally to bacteria in the presence of autologous plasma. However, platelets from ibrutinib-treated CLL patients have significantly inhibited aggregation and alpha granule release in response to S.aureus, E.coli, and IV.3 crosslinking. Moreover, Btk is phosphorylated at Y223 in response to bacterial agonists in treatment-naïve, but not in ibrutinib-treated CLL platelets, highlighting the lack of Btk activation in iBtk-treated patients. An X-linked agammaglobulinaemia (XLA) patient with a known Btk loss of function mutation was examined to investigate if Btk is vital for the FcγRIIa pathway. XLA-derived platelets aggregated normally in response to multiple bacterial species, suggesting Btk is redundant in mediating platelet aggregatory responses to bacteria. These results suggest that other Tec family kinases might have a role in platelet FcγRIIa activation to bacteria, which could be affected by iBtk treatment too. In conclusion, we propose that iBtks impair the FcγRIIa pathway in platelets, reducing platelet-bacteria responses, possibly contributing to the increased risk of infections in observed in CLL. Disclosures No relevant conflicts of interest to declare.

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