Prognostic and Predictive Effect of IGHV Mutational Status and Load in Chronic Lymphocytic Leukemia: Focus on FCR and BR Treatments

Visentin, Andrea; Facco, Monica; Gurrieri, Carmela; Pagnin, Elisa; Martini, Veronica; Imbergamo, Silvia; Frezzato, Federica; Trimarco, Valentina; Severin, Filippo; Raggi, Flavia; Scomazzon, Edoardo; Pravato, Stefano; Semenzato, Gianpietro; Trentin, Livio

doi:10.1016/j.clml.2019.03.002

Cited by 29 publications

(33 citation statements)

References 37 publications

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“…Peripheral blood B lymphocytes were derived from 23 age-matched healthy donors and 66 patients diagnosed with treatment-naïve CLL followed at Padua University Hospital and diagnosed according to international workshop of CLL 2018 guidelines [49]. The biological and clinical characteristics of CLL patients were evaluated as previously reported [50,51] and listed in Table 1. Cytopenia was defined as hemoglobin <100 g/L, absolute neutrophil count <1000/µL, platelets <100,000/µL.…”

Section: Patients Cell Separation and Culture Conditionsmentioning

confidence: 99%

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

Severin

Frezzato

Visentin

et al. 2019

Cancers

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The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche.

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Section: Patients Cell Separation and Culture Conditionsmentioning

confidence: 99%

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

Severin

Frezzato

Visentin

et al. 2019

Cancers

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“…The BCR and CD20 play a key role in the pathogenesis of CLL as exemplified by the high efficacy of BTK inhibitors, such as ibrutinib, and obinutuzumab, a glycoengineered anti‐CD20 monoclonal antibody 56 . Peripheral neuropathy in CLL may be due to different causes, as among which viral infections (varicella zoster virus, VZV; hepatitis C virus, HCV), iatrogenic (ibrutinib, lenalidomide), immune‐mediated, rarely neuropathy is secondary to invasion by leukemic cells 29‐64 or light chain amyloidosis 65 . In a single centre cohort of more than 800 CLL patients, we identified 19 (2.2%) subjects who developed neuropathy during the follow‐up, with an estimated incidence by time to neuropathy development of 2.1% and 6.9% after 10 and 20 years from the CLL diagnosis, respectively 29 .…”

Section: Non‐hodgkin Lymphoma‐related Peripheral Neuropathiesmentioning

confidence: 99%

From pathogenesis to personalized treatments of neuropathies in hematological malignancies

Briani

Visentin

Cerri³

et al. 2020

J Peripheral Nervous Sys

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The peripheral nervous system may be involved at any stage in the course of several hematological diseases, the most common being monoclonal gammopathies (of undetermined significance or malignant) or lymphomas. The underlying pathogenic mechanisms are different and therapies aim at targeting the dangerous either B‐cell or plasma cell clones. Recently, high‐throughput technologies, and next‐generation sequencing have increased our knowledge of hematological diseases pathogenesis by the identification of somatic mutation affecting pivotal signaling pathways. Accordingly, new target therapies are used that may also be borrowed for treatment of neuropathies in hematological diseases.

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“…The CLL B-cell HV gene family was assigned as previously described. 19,20 HV gene sequences were determined by amplifying 5 μl of the original cDNA using the appropriate HV leader and HC primers. PCR products were sequenced directly after purification with Wizard PCR Preps (Promega, Madison, WI) using an automated genetic analyser (3130 ABI Applied Biosystems, Foster City, CA, USA).…”

Section: Chromosome Banding Analysismentioning

confidence: 99%

The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia

et al. 2019

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BACKGROUND: Complex karyotype (CK) is a heterogeneous category with a negative impact in chronic lymphocytic leukaemia (CLL). Our group has recently reported that CK patients with major structural abnormalities (i.e. CK2) are characterised by a worse prognosis, as compared to other lesions within CK(CK1). METHODS: We performed a multicentre retrospective study to test whether the combination of CK subtypes with IGHV status could be a relevant prognostic and predictive tool. RESULTS: Among 522 patients 13% harboured CK2, 41% CK1 and/or U-IGHV (U-CK1) and 46% M-IGHV without any CK subtypes (M-noCK). After a median follow-up of 5.8 years, CK2 patients had the shortest TTFT (5-year TTFT 31%, 39 and 81%, p < 0.0001) and OS (5-year OS 67%, 85 and 93%, p < 0.0001) as compared to U-CK1 or M-noCK cases, regardless of TP53 abnormalities. CK2 patients also had the worst outcome after chemoimmunotherapy. In fact, the median TTNT after FCR or BR was 1.86 and 4.79 years for CK2 and U-CK1, but not reached for M-noCK patients (p < 0.0005). CONCLUSIONS: We herein suggest that the combined assessment of the IGHV mutational status and CK subtypes refines the prognostication of CLL, allowing to identify M-IGHV patients without any CK subtypes who are characterised by an indolent disease and excellent outcome after chemoimmunotherapy.

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Prognostic and Predictive Effect of IGHV Mutational Status and Load in Chronic Lymphocytic Leukemia: Focus on FCR and BR Treatments

Cited by 29 publications

References 37 publications

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

From pathogenesis to personalized treatments of neuropathies in hematological malignancies

The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia

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