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Article: Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL.

Guarente, Valerio / Sportoletti, Paolo

2021 Volume 13, Issue 6

Abstract: Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment ... ...

Abstract	Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment.
Language	English
Publishing date	2021-03-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13061280
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Article: Case Report: Contrasting BCL2 Upregulation With Venetoclax in a Case of Refractory Lymphomatoid Papulosis and Progressive Chronic Lymphocytic Leukemia.

Guarente, Valerio / Martino, Giovanni / Dorillo, Erica / De Falco, Filomena / Rompietti, Chiara / Sorcini, Daniele / Brogna, Mariangela / Cardinali, Valeria / Ascani, Stefano / Marra, Andrea / Sportoletti, Paolo

Frontiers in oncology

2021 Volume 11, Page(s) 729106

Abstract: A 57-year-old man affected by high-risk progressive chronic lymphocytic leukemia (CLL), primary resistant to first-line chemoimmunotherapy, developed a type A lymphomatoid papulosis (LyP) during a second progression of CLL. The two blood tumor entities ... ...

Abstract	A 57-year-old man affected by high-risk progressive chronic lymphocytic leukemia (CLL), primary resistant to first-line chemoimmunotherapy, developed a type A lymphomatoid papulosis (LyP) during a second progression of CLL. The two blood tumor entities were clonally unrelated. LyP presented with a diffuse (>90% body surface area) cutaneous rash and was characterized by intensely pruriginous dusky nodules (n = 10) and red flat-topped papules (n = 60). No response to topical corticosteroids and psoralen plus ultraviolet A (PUVA) phototherapy was observed. In order to effectively treat progressive
Language	English
Publishing date	2021-09-09
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.729106
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Article ; Online: NK Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications.

Sportoletti, Paolo / De Falco, Filomena / Del Papa, Beatrice / Baldoni, Stefano / Guarente, Valerio / Marra, Andrea / Dorillo, Erica / Rompietti, Chiara / Adamo, Francesco Maria / Ruggeri, Loredana / Di Ianni, Mauro / Rosati, Emanuela

International journal of molecular sciences

2021 Volume 22, Issue 13

Abstract: Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. ... ...

Abstract	Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.
MeSH term(s)	Biomarkers ; Cell Communication ; Disease Management ; Disease Susceptibility ; Humans ; Immune System/immunology ; Immune System/metabolism ; Immunotherapy/adverse effects ; Immunotherapy/methods ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis ; Leukemia, Lymphocytic, Chronic, B-Cell/etiology ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; Ligands ; Protein Binding ; Receptors, Natural Killer Cell/genetics ; Receptors, Natural Killer Cell/metabolism ; Treatment Outcome ; Tumor Escape/genetics ; Tumor Escape/immunology
Chemical Substances	Biomarkers ; Ligands ; Receptors, Natural Killer Cell
Language	English
Publishing date	2021-06-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22136665
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Article ; Online: Richter's transformation in the heart.

Marra, Andrea / Adamo, Francesco / Baldoni, Stefano / Laurenti, Maria Elena / Giansanti, Michele / Pasquino, Stefano / Bigerna, Barbara / Sorcini, Daniele / Stella, Arianna / Guarente, Valerio / Limongello, Roberto / Perriello, Vincenzo / Martino, Giovanni / Ascani, Stefano / Falini, Brunangelo / Sportoletti, Paolo

The Lancet. Oncology

2021 Volume 22, Issue 7, Page(s) e341

MeSH term(s)	Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomarkers, Tumor/genetics ; Cardiac Surgical Procedures ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/immunology ; Cell Transformation, Neoplastic/pathology ; Diagnosis, Differential ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/immunology ; Lymphoma, Large B-Cell, Diffuse/pathology ; Lymphoma, Large B-Cell, Diffuse/therapy ; Myocardium/immunology ; Myocardium/pathology ; Predictive Value of Tests ; Treatment Outcome
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-06-29
Publishing country	England
Document type	Case Reports ; Research Support, Non-U.S. Gov't
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(21)00153-4
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Article ; Online: Immune correlates of protection by vaccine against SARS-CoV-2 in patients with chronic lymphocytic leukaemia.

Sorcini, Daniele / De Falco, Filomena / Gargaro, Marco / Bozza, Silvia / Guarente, Valerio / Cardinali, Valeria / Stella, Arianna / Adamo, Francesco Maria / Silva Barcelos, Estevao Carlos / Rompietti, Chiara / Dorillo, Erica / Geraci, Clelia / Esposito, Angela / Arcaleni, Roberta / Capoccia, Silvia / Mameli, Maria Grazia / Graziani, Alessandro / Moretti, Lorenzo / Cipiciani, Alessandra /

Riccardi, Carlo / Mencacci, Antonella / Fallarino, Francesca / Rosati, Emanuela / Sportoletti, Paolo

British journal of haematology

2022 Volume 201, Issue 1, Page(s) 45–57

Abstract: In chronic lymphocytic leukaemia (CLL) the efficacy of SARS-CoV-2 vaccination remains unclear as most studies have focused on humoral responses. Here we comprehensively examined humoral and cellular responses to vaccine in CLL patients. Seroconversion ... ...

Abstract	In chronic lymphocytic leukaemia (CLL) the efficacy of SARS-CoV-2 vaccination remains unclear as most studies have focused on humoral responses. Here we comprehensively examined humoral and cellular responses to vaccine in CLL patients. Seroconversion was observed in 55.2% of CLL with lower rate and antibody titres in treated patients. T-cell responses were detected in a significant fraction of patients. CD4
MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; COVID-19 Vaccines/therapeutic use ; Tumor Necrosis Factor-alpha ; SARS-CoV-2 ; Seroepidemiologic Studies ; COVID-19/prevention & control ; Antineoplastic Agents/therapeutic use ; Interferon-gamma ; Vaccines
Chemical Substances	COVID-19 Vaccines ; Tumor Necrosis Factor-alpha ; Antineoplastic Agents ; Interferon-gamma (82115-62-6) ; Vaccines
Language	English
Publishing date	2022-12-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.18602
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Article ; Online: Prediction of outcomes in chronic lymphocytic leukemia patients treated with ibrutinib: Validation of current prognostic models and development of a simplified three-factor model.

Molica, Stefano / Giannarelli, Diana / Visentin, Andrea / Reda, Gianluigi / Sportoletti, Paolo / Frustaci, Anna Maria / Chiarenza, Annalisa / Ciolli, Stefania / Vitale, Candida / Laurenti, Luca / De Paoli, Lorenzo / Murru, Roberta / Gentile, Massimo / Moia, Riccardo / Rigolin, Gian Matteo / Levato, Luciano / Giordano, Annamaria / Del Poeta, Giovanni / Stelitano, Caterina /

Deodato, Marina / Ielo, Claudia / Noto, Alessandro / Guarente, Valerio / Coscia, Marta / Tedeschi, Alessandra / Gaidano, Gianluca / Cuneo, Antonio / Foa', Robin / Trentin, Livio / Mauro, Francesca Romana

American journal of hematology

2022 Volume 97, Issue 5, Page(s) E176–E180

MeSH term(s)	Adenine/analogs & derivatives ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Piperidines ; Prognosis ; Protein Kinase Inhibitors/adverse effects
Chemical Substances	Piperidines ; Protein Kinase Inhibitors ; ibrutinib (1X70OSD4VX) ; Adenine (JAC85A2161)
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Letter
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.26502
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Article ; Online: GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations.

Sportoletti, Paolo / Celani, Letizia / Varasano, Emanuela / Rossi, Roberta / Sorcini, Daniele / Rompietti, Chiara / Strozzini, Francesca / Del Papa, Beatrice / Guarente, Valerio / Spinozzi, Giulio / Cecchini, Debora / Bereshchenko, Oxana / Haferlach, Torsten / Martelli, Maria Paola / Falzetti, Franca / Falini, Brunangelo

Leukemia

2019 Volume 33, Issue 7, Page(s) 1827–1832

MeSH term(s)	Animals ; Biomarkers, Tumor/genetics ; Epigenesis, Genetic ; Female ; GATA1 Transcription Factor/genetics ; GATA1 Transcription Factor/physiology ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia, Myeloid, Acute/etiology ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Mice ; Mice, Knockout ; Mutation ; Nuclear Proteins/genetics ; Prognosis ; Tandem Repeat Sequences ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/physiology
Chemical Substances	Biomarkers, Tumor ; GATA1 Transcription Factor ; GATA1 protein, human ; Gata1 protein, mouse ; Nuclear Proteins ; nucleophosmin (117896-08-9) ; FLT3 protein, human (EC 2.7.10.1) ; Flt3 protein, mouse (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2019-02-12
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-019-0399-7
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Article ; Online: Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice.

Leukemia

2020 Volume 35, Issue 7, Page(s) 1949–1963

Abstract: Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are ... ...

Abstract	Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor
MeSH term(s)	Anemia, Macrocytic/genetics ; Anemia, Macrocytic/pathology ; Animals ; Bone Marrow/pathology ; Cell Cycle/genetics ; DNA (Cytosine-5-)-Methyltransferases/genetics ; Disease Models, Animal ; Erythroid Cells/pathology ; Leukemia, Erythroblastic, Acute/genetics ; Leukemia, Erythroblastic, Acute/pathology ; Mice ; Mice, Knockout ; Repressor Proteins/deficiency ; Repressor Proteins/genetics ; Transcriptome/genetics
Chemical Substances	Bcor protein, mouse ; Repressor Proteins ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA methyltransferase 3A (EC 2.1.1.37)
Language	English
Publishing date	2020-11-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-020-01075-3
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Article: NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the

Baldoni, Stefano / Del Papa, Beatrice / De Falco, Filomena / Dorillo, Erica / Sorrentino, Carlo / Rompietti, Chiara / Adamo, Francesco Maria / Nogarotto, Manuel / Cecchini, Debora / Mondani, Elena / Silva Barcelos, Estevao Carlos / Moretti, Lorenzo / Mameli, Maria Grazia / Fabi, Bianca / Sorcini, Daniele / Stella, Arianna / Giancola, Raffaella / Guardalupi, Francesco / Ulbar, Francesca /

Plebani, Sara / Guarente, Valerio / Rosati, Emanuela / Di Nicola, Marta / Marchioni, Michele / Di Ianni, Mauro / Sportoletti, Paolo

Frontiers in oncology

2021 Volume 11, Page(s) 668573

Abstract: NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact ... ...

Abstract	NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of
Language	English
Publishing date	2021-05-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.668573
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Article: Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib.

Mauro, Francesca Romana / Giannarelli, Diana / Visentin, Andrea / Reda, Gianluigi / Sportoletti, Paolo / Frustaci, Anna Maria / Chiarenza, Annalisa / Ciolli, Stefania / Vitale, Candida / Laurenti, Luca / De Paoli, Lorenzo / Murru, Roberta / Gentile, Massimo / Rigolin, Gian Matteo / Levato, Luciano / Giordano, Annamaria / Del Poeta, Giovanni / Stelitano, Caterina / Ielo, Claudia /

Noto, Alessandro / Guarente, Valerio / Molica, Stefano / Coscia, Marta / Tedeschi, Alessandra / Gaidano, Gianluca / Cuneo, Antonio / Foà, Robin / Martelli, Maurizio / Girmenia, Corrado / Gentile, Giuseppe / Trentin, Livio

Cancers

2021 Volume 13, Issue 13

Abstract: Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, ... ...

Abstract	Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (
Language	English
Publishing date	2021-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13133240
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