B‐cell receptor configuration and adverse cytogenetics are associated with autoimmune hemolytic anemia in chronic lymphocytic leukemia

Maura, Francesco; Visco, Carlo; Falisi, Erika; Reda, Gianluigi; Fabris, Sonia; Agnelli, Luca; Tuana, Giacomo; Lionetti, Marta; Guercini, Nicola; Novella, Elisabetta; Nichele, Ilaria; Montaldi, A.; Autore, Francesco; Gregorini, Anna Ines; Barcellini, Wilma; Callea, Vincenzo; Mauro, Francesca Romana; Laurenti, Luca; Foà, Robin; Neri, Antonino; Rodeghiero, Francesco; Cortelezzi, Agostino

doi:10.1002/ajh.23342

Cited by 31 publications

(30 citation statements)

References 25 publications

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“…22, 23 Our study cohort was at increased risk for the development of AIC given the long median duration of CLL, high median number of prior therapies, and relatively high percentage of patients with unmutated IGHV. 24 As an indicator of this risk, 26% of the patients had experienced a least one episode of AIC prior to study enrollment, which is one of the higher reported AIC rates in studies of CLL patients. 2, 25 Despite this, a low rate of treatment emergent AIC was seen, suggesting that ibrutinib reduces the risk of AIC development.…”

Section: Discussionmentioning

confidence: 99%

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia

et al. 2015

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Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AIC). Ibrutinib is an irreversible inhibitor of Bruton’s Tyrosine Kinase approved for treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib as participants in therapeutic clinical trials at the Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment emergent AIC cases were identified. Prior to starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1 000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

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Section: Discussionmentioning

confidence: 99%

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia

et al. 2015

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“…IGHV mutational status analysis was performed on total RNA using family‐specific IGHV primers for the leader region, in agreement with ERIC recommendations . Amplicons were analyzed by capillary electrophoresis and sequenced by Ab3130 Genetic Analyzer (Applied Biosystems, Life Technologies Corporation, USA) as previously described . Sequences were aligned to IMGT database and analyzed using IMGT/VQUEST software in order to detect VDJ rearrangement.…”

Section: Methodsmentioning

confidence: 99%

“…In order to detect stereotyped BCR, complete sequences of 34 patients were analyzed as previously described , comparing them with known stereotyped sequences .…”

Section: Methodsmentioning

confidence: 99%

B-cell receptor configuration and mutational analysis of patients with chronic lymphocytic leukaemia and trisomy 12 reveal recurrent molecular abnormalities

et al. 2013

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Trisomy 12 (+12) is the third most frequent cytogenetic aberration in chronic lymphocytic leukaemia (CLL) retrievable both as the sole chromosomal abnormality or in association with additional alterations. NOTCH1 mutations are known to be more prevalent among +12 patients, whereas mutations of FBXW7, a gene involved in NOTCH1 degradation, that lead to the constitutional activation of NOTCH1 have not been investigated in this setting. We analyzed a unicentric cohort of 44 +12 patients with CLL for mutations of TP53, NOTCH1 and FBXW7 genes, and we correlated them with B-cell receptor (BCR) configurations. FBXW7, TP53 and NOTCH1 mutations were identified in 4.5%, 6.8% and 18.2% of patients, respectively. FBXW7 and NOTCH1 mutations appeared in a mutually exclusive fashion, suggesting that both aberrations might affect the same biological pathway. We found that 44.1% of +12 CLL patients had stereotyped B-cell receptors, which is significantly higher than that observed in patients with CLL and no +12 (27%, p = 0.01). Subsets #1, #8, #10, #28 and #59 were the most represented stereotyped patterns, and IGHV4-39*01 was the gene configuration most commonly used. There was a significantly higher risk for Richter's syndrome (RS) transformation in patients with NOTCH1 or FBXW7 mutations, with four of the seven (57%) patients developing RS and characterized at least by one of the two abnormalities. These observations suggest that, similarly to the aberrations of NOTCH1, FBXW7 gene mutations may also result in cell proliferation and evasion from apoptosis in patients with +12 CLL. Together with the extremely high frequency of stereotyped BCRs and RS transformation, these abnormalities appear to cluster in these CLL patients with additional chromosome 12, suggesting a connection with the prognosis of the disease.

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“…Данные о безопасности и эффективности ибрутиниба в качестве монотерапии или в сочетании с глюкокортико-стероидами у больных с ХЛЛ, отягощенным аутоиммун-ным гемолизом, продемонстрированы в ряде междуна-родных исследований [18][19][20][21][22][23][24][25][26].…”

Section: Introductionunclassified

Possibilities of therapy recurrent b-cell chronic lymphocytic leukemia associated with autoimmune complications: data from literature and personal observation

Goryacheva¹,

Sorokina²,

Al-Radi³

et al. 2018

Med. sov.

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B‐cell receptor configuration and adverse cytogenetics are associated with autoimmune hemolytic anemia in chronic lymphocytic leukemia

Cited by 31 publications

References 25 publications

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia

B-cell receptor configuration and mutational analysis of patients with chronic lymphocytic leukaemia and trisomy 12 reveal recurrent molecular abnormalities

Possibilities of therapy recurrent b-cell chronic lymphocytic leukemia associated with autoimmune complications: data from literature and personal observation

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