Marta Coscia | Università degli Studi di Torino (original) (raw)

Papers by Marta Coscia

Frontiers in Oncology, 2022

Immune-based therapeutic strategies have drastically changed the landscape of hematological disor... more Immune-based therapeutic strategies have drastically changed the landscape of hematological disorders, as they have introduced the concept of boosting immune responses against tumor cells. Anti-CD20 monoclonal antibodies have been the first form of immunotherapy successfully applied in the treatment of CLL, in the context of chemoimmunotherapy regimens. Since then, several immunotherapeutic approaches have been studied in CLL settings, with the aim of exploiting or eliciting anti-tumor immune responses against leukemia cells. Unfortunately, despite initial promising data, results from pilot clinical studies have not shown optimal results in terms of disease control - especially when immunotherapy was used individually - largely due to CLL-related immune dysfunctions hampering the achievement of effective anti-tumor responses. The growing understanding of the complex interactions between immune cells and the tumor cells has paved the way for the development of new combined approaches...

Cancers, 2021

The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutini... more The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation we...

Clinical Lymphoma, Myeloma & Leukemia, 2018

Context: Complex karyotype (CK) is associated with poor prognosis in patients with chronic lympho... more Context: Complex karyotype (CK) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). While mutations in TP53 have been associated with CK, overlap is not complete and the genetic landscape of patients with CLL and CK remains largely undescribed. Design: We performed targeted next generation sequencing with a SureSelect custom panel of 295 genes (Agilent Technologies, Santa Clara, CA) on bone marrow aspirate collected between March 2003 and October 2015 from 71 patients with CLL and CK and compared them to a control group of 90 patients without CK, age and sex-matched. Results: In univariable analyses (UVA), CK was associated with Rai III-IV disease (61% vs 36%, p1⁄40.002), beta-2 microglobulin (B2M) > 4 mg/L (67% vs 40%, p1⁄40.001), del(17p) by FISH (33% vs 9%, p<0.001), and presence of any gene mutation (79% vs 59%, p1⁄40.01). Among patients with CK, the most common mutations (>10% of patients) were TP53 (32%), SF3B1 (15.5%) and NOTCH1 (10...

Blood, 2017

Introduction. In chronic lymphocytic leukemia (CLL), chemoimmunotherapy produced high overall res... more Introduction. In chronic lymphocytic leukemia (CLL), chemoimmunotherapy produced high overall response rates (ORR), prolonged progression free survival (PFS) and overall survival (OS). In the absence of a TP53 disruption, recent European guidelines recommend a chemoimmunotherapy regimen in first-line and in second line in patients who have attained a long PFS with the previous regimen. Uncertainty in the recommendations on first salvage treatment may partially derive from the consideration that the majority of studies have described efficacy data in an aggregate fashion including all relapsed/refractory setting. Since bendamustine and rituximab (BR) is one of most widely adopted second line regimen we performed a retrospective study within the GIMEMA-ERIC network to collect data on the efficacy and the safety of the BR regimen in second-line in a real-world setting. Comparison of the BR data with 114 Italian and UK non-trial patients treated with ibrutinib at first relapse will be p...

Blood, 2012

2898 Background: Notwithstanding the improved results with first-line therapy, CLL remains incura... more 2898 Background: Notwithstanding the improved results with first-line therapy, CLL remains incurable, and patients are destined to relapse after primary treatment. The management of relapsed CLL pts is then dependent on several factors, including age, performance status, previous therapy, response and duration of response to therapy, and time from last therapy. Currently, the optimal treatment for pts with relapsed disease is not known. Bendamustine (BEN) demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. Alemtuzumab (CAM) is active in previously treated pts with CLL refractory to alkylating agents and purine nucleoside analogs. We designed a multicentric, single arm, dose escalation study to determine maximum tolerated dose (MTD) and to evaluate the efficacy and safety of Ben Cam combination in refractory/relapsed CLL pts. Methods: Previously treated CLL pts requiring therapy were ...

Blood, 2019

Introduction: T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a surface receptor mainly... more Introduction: T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a surface receptor mainly expressed by CD8+, regulatory T lymphocytes and natural killer (NK) cells, but not by normal B cells. It performs as an inhibitory immune checkpoint, activated through binding of CD155. TIGIT competes with CD226 for CD155 binding, resulting in opposite outcomes: while CD226 enhances cytotoxicity of T lymphocytes and NK cells, TIGIT exerts immunosuppressive effects. Whether TIGIT engagement triggers an alternative signaling cascade, or whether it simply prevents CD226 activation, remains an open point. Tumor-infiltrating T lymphocytes generally express high levels of the molecule, together with the other checkpoint inhibitor PD-1. On this basis, antagonist antibodies targeting TIGIT are under evaluation to restore immunity and treat cancer patients, alone or in various combinations. Chronic lymphocytic leukemia (CLL), the most common adult leukemia, is characterized by a highly heterogen...

Frontiers in Oncology

Two main variants of Richter syndrome (RS) are recognized, namely, the diffuse large B-cell lymph... more Two main variants of Richter syndrome (RS) are recognized, namely, the diffuse large B-cell lymphoma (DLBCL) and the Hodgkin’s lymphoma (HL) variant. Clonal relationship, defined as an identity of the immunoglobulin heavy chain variable (IGHV) region sequence between chronic lymphocytic leukemia (CLL) and RS clones, characterizes patients with a poor prognosis. Due to method sensitivity, this categorization is performed without considering the possibility of small-size ancillary clones, sharing the same phenotype with the preexisting predominant CLL clone, but with different IGHV rearrangements. Here we describe and molecularly profile the peculiar case of a patient with a CLL-like monoclonal B-cell lymphocytosis (MBL), who sequentially developed a DLBCL, which occurred concomitantly to progression of MBL to CLL, and a subsequent HL. Based on standard IGHV clonality analysis, DLBCL was considered clonally unrelated to the concomitantly expanded CLL clone and treated as a de novo lym...

Cancers

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chro... more The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in ide...

American Journal of Hematology

Journal of Personalized Medicine

Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a si... more Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. Methods: An observational, retrospective study was carried out; patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. Results: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90–97%); after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses; the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis wer...

Cancers

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Synd... more The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on ...

Blood

The placebo controlled CLLM1 trial evaluated the efficacy of lenalidomide maintenance treatment i... more The placebo controlled CLLM1 trial evaluated the efficacy of lenalidomide maintenance treatment in patients with high-risk chronic lymphocytic leukemia (CLL) in first remission after chemoimmunotherapy (CIT). Upon observation of three cases with acute lymphoblastic leukemia (ALL) in overall 56 lenalidomide treated patients (5.4%), the study treatment was prematurely stopped. Using next generation sequencing of B cell and T cell receptor (TR) rearrangements, we here report common clonal B cell ancestry between CLL and ALL in one of those three patients, in whom both diseases shared the same VDJ- as well as crosslineage TR rearrangements. Chromosomal/mutation analyses indicated that in this patient the ALL developed from a common B cell precursor which lacks genomic lesions acquired in the CLL subclone, but shares a BIRC3 frameshift deletion (p.L421fs*). In two cases we found independent IGH rearrangements indicating de novo ALL development from a different B cell clone. A retrospecti...

Blood

Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in... more Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in poor-risk chronic lymphocytic leukemia (CLL) and are widely administered to patients with relapsed/refractory (R/R)-CLL. Given the activity of ibrutinib in high-risk CLL patients, including those with del17p/TP53 mutation or germline IGHV genes, we assumed that this drug could diminish the prognostic utility of the CLL-IPI, because the outcome of patients with high- and very high-risk CLL-IPI scores may improve. Recently, Soumerai et al (Lancet Hematology, 2019) proposed a new risk score for overall survival (OS) based on four accessible markers, called BALL (β2-microglobulin, anemia, LDH, last therapy), in the setting of R/R-CLL patients receiving chemo-immunotherapy or targeted therapies in clinical trials. This model segregates CLL patients into three groups with significantly different OS. This multicenter, observational retrospective study aimed at validating the proposed BALL scor...

Blood

BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overa... more BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overall management of chronic lymphocytic leukemia (CLL). Although several data derived from clinical trials suggest that ibrutinib increases the risk of atrial fibrillation (AF), the incidence of AF in a real-life cohort of CLL patients is unknown. Furthermore, it would be clinically relevant to identify patients at high risk of AF during ibrutinib. The aim of this study is to report the prevalence and risk factors of AF in ibrutinib-naive CLL, in order to define a predictive model for the development of AF and to test it in a cohort of subjects receiving ibrutinib. METHODS. We retrospectively analyzed data from 860 ibrutinib-naive CLL patients, referred to the Padua University hospital. Comorbidities, clinical and biological prognostic markers were analyzed using the Mann-Whiney, Fisher exact or Chi-square tests, when appropriated. Time to AF (TTAF) and overall survival (OS) were evaluated ...

Blood

BACKGROUND. Mutations in NOTCH1 PEST domain (NOTCH1-M) are present in ~10% of Chronic Lymphocytic... more BACKGROUND. Mutations in NOTCH1 PEST domain (NOTCH1-M) are present in ~10% of Chronic Lymphocytic Leukemia (CLL) patients, result in accumulation of more stable NOTCH1 protein, and associate with poorer prognosis. NOTCH1-M are enriched in unmutated (U) immunoglobulin gene heavy-chain variable region (IGHV) CLL, which show high surface IgM (sIgM) expression and signaling capacity. mRNA translation is a prominent response to B cell receptor (BCR) engagement, increased in U-CLL, and for which therapeutic inhibitors are under active development. In CLL, c-MYC is an essential mediator of BCR-driven translation and direct target of NOTCH1, suggesting the impact of NOTCH1 on anti-IgM-mediated cell growth via MYC. AIMS AND METHODS. Our aim was to investigate the functional role of NOTCH1-M on anti-IgM-mediated signaling, compared to wild-type (WT) NOTCH1. The impact on global mRNA translation was studied using a flow cytometry-based O-propargyl-puromycin (OPP) incorporation assay and polyso...

Frontiers in Oncology, 2022

Immune-based therapeutic strategies have drastically changed the landscape of hematological disor... more Immune-based therapeutic strategies have drastically changed the landscape of hematological disorders, as they have introduced the concept of boosting immune responses against tumor cells. Anti-CD20 monoclonal antibodies have been the first form of immunotherapy successfully applied in the treatment of CLL, in the context of chemoimmunotherapy regimens. Since then, several immunotherapeutic approaches have been studied in CLL settings, with the aim of exploiting or eliciting anti-tumor immune responses against leukemia cells. Unfortunately, despite initial promising data, results from pilot clinical studies have not shown optimal results in terms of disease control - especially when immunotherapy was used individually - largely due to CLL-related immune dysfunctions hampering the achievement of effective anti-tumor responses. The growing understanding of the complex interactions between immune cells and the tumor cells has paved the way for the development of new combined approaches...

Cancers, 2021

The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutini... more The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation we...

Clinical Lymphoma, Myeloma & Leukemia, 2018

Context: Complex karyotype (CK) is associated with poor prognosis in patients with chronic lympho... more Context: Complex karyotype (CK) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). While mutations in TP53 have been associated with CK, overlap is not complete and the genetic landscape of patients with CLL and CK remains largely undescribed. Design: We performed targeted next generation sequencing with a SureSelect custom panel of 295 genes (Agilent Technologies, Santa Clara, CA) on bone marrow aspirate collected between March 2003 and October 2015 from 71 patients with CLL and CK and compared them to a control group of 90 patients without CK, age and sex-matched. Results: In univariable analyses (UVA), CK was associated with Rai III-IV disease (61% vs 36%, p1⁄40.002), beta-2 microglobulin (B2M) > 4 mg/L (67% vs 40%, p1⁄40.001), del(17p) by FISH (33% vs 9%, p<0.001), and presence of any gene mutation (79% vs 59%, p1⁄40.01). Among patients with CK, the most common mutations (>10% of patients) were TP53 (32%), SF3B1 (15.5%) and NOTCH1 (10...

Blood, 2017

Introduction. In chronic lymphocytic leukemia (CLL), chemoimmunotherapy produced high overall res... more Introduction. In chronic lymphocytic leukemia (CLL), chemoimmunotherapy produced high overall response rates (ORR), prolonged progression free survival (PFS) and overall survival (OS). In the absence of a TP53 disruption, recent European guidelines recommend a chemoimmunotherapy regimen in first-line and in second line in patients who have attained a long PFS with the previous regimen. Uncertainty in the recommendations on first salvage treatment may partially derive from the consideration that the majority of studies have described efficacy data in an aggregate fashion including all relapsed/refractory setting. Since bendamustine and rituximab (BR) is one of most widely adopted second line regimen we performed a retrospective study within the GIMEMA-ERIC network to collect data on the efficacy and the safety of the BR regimen in second-line in a real-world setting. Comparison of the BR data with 114 Italian and UK non-trial patients treated with ibrutinib at first relapse will be p...

Blood, 2012

2898 Background: Notwithstanding the improved results with first-line therapy, CLL remains incura... more 2898 Background: Notwithstanding the improved results with first-line therapy, CLL remains incurable, and patients are destined to relapse after primary treatment. The management of relapsed CLL pts is then dependent on several factors, including age, performance status, previous therapy, response and duration of response to therapy, and time from last therapy. Currently, the optimal treatment for pts with relapsed disease is not known. Bendamustine (BEN) demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. Alemtuzumab (CAM) is active in previously treated pts with CLL refractory to alkylating agents and purine nucleoside analogs. We designed a multicentric, single arm, dose escalation study to determine maximum tolerated dose (MTD) and to evaluate the efficacy and safety of Ben Cam combination in refractory/relapsed CLL pts. Methods: Previously treated CLL pts requiring therapy were ...

Blood, 2019

Introduction: T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a surface receptor mainly... more Introduction: T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a surface receptor mainly expressed by CD8+, regulatory T lymphocytes and natural killer (NK) cells, but not by normal B cells. It performs as an inhibitory immune checkpoint, activated through binding of CD155. TIGIT competes with CD226 for CD155 binding, resulting in opposite outcomes: while CD226 enhances cytotoxicity of T lymphocytes and NK cells, TIGIT exerts immunosuppressive effects. Whether TIGIT engagement triggers an alternative signaling cascade, or whether it simply prevents CD226 activation, remains an open point. Tumor-infiltrating T lymphocytes generally express high levels of the molecule, together with the other checkpoint inhibitor PD-1. On this basis, antagonist antibodies targeting TIGIT are under evaluation to restore immunity and treat cancer patients, alone or in various combinations. Chronic lymphocytic leukemia (CLL), the most common adult leukemia, is characterized by a highly heterogen...

Frontiers in Oncology

Two main variants of Richter syndrome (RS) are recognized, namely, the diffuse large B-cell lymph... more Two main variants of Richter syndrome (RS) are recognized, namely, the diffuse large B-cell lymphoma (DLBCL) and the Hodgkin’s lymphoma (HL) variant. Clonal relationship, defined as an identity of the immunoglobulin heavy chain variable (IGHV) region sequence between chronic lymphocytic leukemia (CLL) and RS clones, characterizes patients with a poor prognosis. Due to method sensitivity, this categorization is performed without considering the possibility of small-size ancillary clones, sharing the same phenotype with the preexisting predominant CLL clone, but with different IGHV rearrangements. Here we describe and molecularly profile the peculiar case of a patient with a CLL-like monoclonal B-cell lymphocytosis (MBL), who sequentially developed a DLBCL, which occurred concomitantly to progression of MBL to CLL, and a subsequent HL. Based on standard IGHV clonality analysis, DLBCL was considered clonally unrelated to the concomitantly expanded CLL clone and treated as a de novo lym...

Cancers

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chro... more The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in ide...

American Journal of Hematology

Journal of Personalized Medicine

Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a si... more Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. Methods: An observational, retrospective study was carried out; patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. Results: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90–97%); after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses; the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis wer...

Cancers

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Synd... more The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on ...

Blood

The placebo controlled CLLM1 trial evaluated the efficacy of lenalidomide maintenance treatment i... more The placebo controlled CLLM1 trial evaluated the efficacy of lenalidomide maintenance treatment in patients with high-risk chronic lymphocytic leukemia (CLL) in first remission after chemoimmunotherapy (CIT). Upon observation of three cases with acute lymphoblastic leukemia (ALL) in overall 56 lenalidomide treated patients (5.4%), the study treatment was prematurely stopped. Using next generation sequencing of B cell and T cell receptor (TR) rearrangements, we here report common clonal B cell ancestry between CLL and ALL in one of those three patients, in whom both diseases shared the same VDJ- as well as crosslineage TR rearrangements. Chromosomal/mutation analyses indicated that in this patient the ALL developed from a common B cell precursor which lacks genomic lesions acquired in the CLL subclone, but shares a BIRC3 frameshift deletion (p.L421fs*). In two cases we found independent IGH rearrangements indicating de novo ALL development from a different B cell clone. A retrospecti...

Blood

Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in... more Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in poor-risk chronic lymphocytic leukemia (CLL) and are widely administered to patients with relapsed/refractory (R/R)-CLL. Given the activity of ibrutinib in high-risk CLL patients, including those with del17p/TP53 mutation or germline IGHV genes, we assumed that this drug could diminish the prognostic utility of the CLL-IPI, because the outcome of patients with high- and very high-risk CLL-IPI scores may improve. Recently, Soumerai et al (Lancet Hematology, 2019) proposed a new risk score for overall survival (OS) based on four accessible markers, called BALL (β2-microglobulin, anemia, LDH, last therapy), in the setting of R/R-CLL patients receiving chemo-immunotherapy or targeted therapies in clinical trials. This model segregates CLL patients into three groups with significantly different OS. This multicenter, observational retrospective study aimed at validating the proposed BALL scor...

Blood

BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overa... more BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overall management of chronic lymphocytic leukemia (CLL). Although several data derived from clinical trials suggest that ibrutinib increases the risk of atrial fibrillation (AF), the incidence of AF in a real-life cohort of CLL patients is unknown. Furthermore, it would be clinically relevant to identify patients at high risk of AF during ibrutinib. The aim of this study is to report the prevalence and risk factors of AF in ibrutinib-naive CLL, in order to define a predictive model for the development of AF and to test it in a cohort of subjects receiving ibrutinib. METHODS. We retrospectively analyzed data from 860 ibrutinib-naive CLL patients, referred to the Padua University hospital. Comorbidities, clinical and biological prognostic markers were analyzed using the Mann-Whiney, Fisher exact or Chi-square tests, when appropriated. Time to AF (TTAF) and overall survival (OS) were evaluated ...

Blood

BACKGROUND. Mutations in NOTCH1 PEST domain (NOTCH1-M) are present in ~10% of Chronic Lymphocytic... more BACKGROUND. Mutations in NOTCH1 PEST domain (NOTCH1-M) are present in ~10% of Chronic Lymphocytic Leukemia (CLL) patients, result in accumulation of more stable NOTCH1 protein, and associate with poorer prognosis. NOTCH1-M are enriched in unmutated (U) immunoglobulin gene heavy-chain variable region (IGHV) CLL, which show high surface IgM (sIgM) expression and signaling capacity. mRNA translation is a prominent response to B cell receptor (BCR) engagement, increased in U-CLL, and for which therapeutic inhibitors are under active development. In CLL, c-MYC is an essential mediator of BCR-driven translation and direct target of NOTCH1, suggesting the impact of NOTCH1 on anti-IgM-mediated cell growth via MYC. AIMS AND METHODS. Our aim was to investigate the functional role of NOTCH1-M on anti-IgM-mediated signaling, compared to wild-type (WT) NOTCH1. The impact on global mRNA translation was studied using a flow cytometry-based O-propargyl-puromycin (OPP) incorporation assay and polyso...