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Article ; Online: Novel therapies and combinations in CLL refractory to BTK inhibitors and venetoclax.

Scarfò, Lydia

Hematology. American Society of Hematology. Education Program

2022 Volume 2022, Issue 1, Page(s) 316–322

Abstract: Patients with chronic lymphocytic leukemia (CLL) refractory to covalent BTK and BCL2 inhibitors have a new unmet clinical need. Standard treatment options are able to obtain only limited and short-lasting disease control associated with reduced overall ... ...

Abstract	Patients with chronic lymphocytic leukemia (CLL) refractory to covalent BTK and BCL2 inhibitors have a new unmet clinical need. Standard treatment options are able to obtain only limited and short-lasting disease control associated with reduced overall survival, and thus these patients have become ideal candidates for enrollment in clinical trials. Favorable results have been obtained with the use of noncovalent BTK inhibitors (roughly 70% overall response rate regardless of the actual resistance or intolerance to previous covalent BTK inhibitors) and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (with complete responses in up to 45% of cases and an undetectable measurable residual disease rate of 65% in the bone marrow). These 2 approaches should be considered valid options in this setting, although not yet approved. For young fit patients achieving remissions with salvage treatments, the option of allogeneic stem cell transplantation should be discussed as the outcome appears to be unaffected by number and type of previous targeted agents. Novel treatment strategies interfering with different mechanisms of CLL cell survival and proliferation are warranted, including small molecules with novel targets (eg, CDK9, MCL1, ERK inhibitors), CAR T cells targeting different antigens, CAR natural killer cells, or bispecific antibodies.
MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Antigens, CD19 ; Immunotherapy, Adoptive/methods ; Remission Induction ; Antineoplastic Agents/therapeutic use
Chemical Substances	Antigens, CD19 ; venetoclax (N54AIC43PW) ; Antineoplastic Agents
Language	English
Publishing date	2022-12-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2084287-9
ISSN	1520-4383 ; 1520-4391
ISSN (online)	1520-4383
ISSN	1520-4391
DOI	10.1182/hematology.2022000344
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Article ; Online: COVID-19 prophylaxis: half-full or half-empty glass?

Scarfò, Lydia / Cuneo, Antonio

Blood

2023 Volume 141, Issue 2, Page(s) 130–132

MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Neoplasms
Chemical Substances	tixagevimab ; cilgavimab (1KUR4BN70F)
Language	English
Publishing date	2023-02-01
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022018858
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: CLL and COVID-19: light at the end of the tunnel?

Scarfò, Lydia / Herishanu, Yair

Blood

2022 Volume 140, Issue 5, Page(s) 407–409

MeSH term(s)	COVID-19 ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/therapy
Language	English
Publishing date	2022-08-03
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022017071
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Chemo-immunotherapy for Older Patients with Chronic Lymphocytic Leukemia - Time to Retire?

Scarfò, Lydia / Tedeschi, Alessandra

HemaSphere

2019 Volume 3, Issue 4, Page(s) e278

Language	English
Publishing date	2019-08-07
Publishing country	United States
Document type	Editorial
ISSN	2572-9241
ISSN (online)	2572-9241
DOI	10.1097/HS9.0000000000000278
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Article ; Online: Are we finally getting personal? Moving towards a personalized approach in chronic lymphocytic leukemia.

Albi, Elisa / Capasso, Antonella / Schiattone, Luana / Ghia, Paolo / Scarfò, Lydia

Seminars in cancer biology

2022 Volume 84, Page(s) 329–338

Abstract: With its heterogeneous biological features and clinical course, chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in the Western world, is a paradigmatic condition requiring a tailored approach and a precise knowledge of the biology ... ...

Abstract	With its heterogeneous biological features and clinical course, chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in the Western world, is a paradigmatic condition requiring a tailored approach and a precise knowledge of the biology behind each individual patient. This personalized management is becoming even more crucial, since, after decades of preclinical work unravelling the key role of the B-cell receptor (BcR) signalling pathways and the anti-apoptotic mechanisms in CLL cell survival and proliferation, we have now BcR and BCL2 inhibitors available in clinical practice. Thanks to this, we are now able to exploit specific biomarkers to tailor our treatment strategies and improve long-term disease control, patient outcome and quality of life. That notwithstanding, as the disease itself remains incurable, novel challenges and unmet clinical needs have risen from the introduction of novel targeted agents, including mechanisms of resistance at both genetic and epigenetic levels. In this review, we summarize the currently established predictive biomarkers (i.e. IGHV mutation status and TP53 gene disruption) that should be applied in clinical practice to inform treatment decision in 2021 but also discuss the most promising prognostic biomarkers (B-cell receptor stereotypy, complex karyotype, somatic gene mutations, measurable residual disease - MRD) that might become key to define the management of our patients in a near future.
MeSH term(s)	Adult ; Antineoplastic Agents/therapeutic use ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Mutation ; Prognosis ; Quality of Life ; Receptors, Antigen, B-Cell/genetics
Chemical Substances	Antineoplastic Agents ; Receptors, Antigen, B-Cell
Language	English
Publishing date	2022-01-26
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2022.01.009
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Article ; Online: Acalabrutinib: a highly selective, potent Bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia.

Ghia, Paolo / Dlugosz-Danecka, Monika / Scarfò, Lydia / Jurczak, Wojciech

Leukemia & lymphoma

2021 Volume 62, Issue 5, Page(s) 1066–1076

Abstract: Inhibiting the activity of Bruton tyrosine kinase (BTK) prevents the activation of the B-cell receptor (BCR) signaling pathway, which in turn prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. Acalabrutinib is an ...

Abstract	Inhibiting the activity of Bruton tyrosine kinase (BTK) prevents the activation of the B-cell receptor (BCR) signaling pathway, which in turn prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. Acalabrutinib is an orally available, highly selective, next-generation inhibitor of BTK. Based on the results of two key phase 3 trials (ELEVATE-TN in patients with previously untreated chronic lymphocytic leukemia [CLL] and ASCEND in patients with relapsed or refractory CLL), which demonstrated superior progression-free survival while maintaining favorable tolerability, acalabrutinib was granted US Food and Drug Administration (FDA) approval in 2019 for the treatment of patients with CLL. Acalabrutinib appears to offer similar efficacy but a significantly improved tolerability profile to first-generation agents. Acalabrutinib is a good candidate to combine with other anti-cancer therapies, including B-cell lymphoma 2 inhibitors and monoclonal antibodies, a factor that may help to further improve clinical outcomes in CLL.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase ; Benzamides/therapeutic use ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Protein Kinase Inhibitors/adverse effects ; Pyrazines
Chemical Substances	Benzamides ; Protein Kinase Inhibitors ; Pyrazines ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; acalabrutinib (I42748ELQW)
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428194.2020.1864352
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Zs.A 2997: Show issues

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Article ; Online: Dimethyl itaconate selectively targets inflammatory and metabolic pathways in chronic lymphocytic leukemia.

Sana, Ilenia / Mantione, Maria Elena / Meloni, Miriam / Riba, Michela / Ranghetti, Pamela / Scarfò, Lydia / Ghia, Paolo / Muzio, Marta

European journal of immunology

2023 Volume 53, Issue 10, Page(s) e2350418

Abstract: Chronic lymphocytic leukemia (CLL) co-evolves with its own microenvironment where inflammatory stimuli including toll-like receptors (TLR) signaling can protect CLL cells from spontaneous and drug-induced apoptosis by upregulating IκBζ, an atypical co- ... ...

Abstract	Chronic lymphocytic leukemia (CLL) co-evolves with its own microenvironment where inflammatory stimuli including toll-like receptors (TLR) signaling can protect CLL cells from spontaneous and drug-induced apoptosis by upregulating IκBζ, an atypical co-transcription factor. To dissect IκBζ-centered signaling pathways, we performed a gene expression profile of primary leukemic cells expressing either high or low levels of IκBζ after stimulation, highlighting that IκBζ is not only an inflammatory gene but it may control metabolic rewiring of malignant cells thus pointing to a novel potential opportunity for therapy. We exploited the capacity of the dimethyl itaconate (DI), an anti-inflammatory electrophilic synthetic derivative of the metabolite Itaconate, to target IκBζ. CLL cells, murine leukemic splenocytes, and leukocytes from healthy donors were treated in vitro with DI that abolished metabolic activation and reduced cell viability of leukemic cells only, even in the presence of robust TLR prestimulation. RNA sequencing highlighted that in addition to the expected electrophilic stress signature observed after DI treatment, novel pathways emerged including the downregulation of distinct MHC class II complex genes. In conclusion, DI not only abrogated the proinflammatory effects of TLR stimulation but also targeted a specific metabolic vulnerability in CLL cells.
MeSH term(s)	Animals ; Mice ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Signal Transduction/genetics ; Toll-Like Receptors/metabolism ; Metabolic Networks and Pathways ; Tumor Microenvironment
Chemical Substances	dimethyl itaconate (11JIB0YI93) ; Toll-Like Receptors
Language	English
Publishing date	2023-09-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202350418
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 85: Show issues

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Article ; Online: PYK2 is overexpressed in chronic lymphocytic leukaemia: A potential new therapeutic target.

Sbrana, Francesca Vittoria / Fiordi, Benedetta / Bordini, Jessica / Belloni, Daniela / Barbaglio, Federica / Russo, Luca / Scarfò, Lydia / Ghia, Paolo / Scielzo, Cristina

Journal of cellular and molecular medicine

2023 Volume 27, Issue 4, Page(s) 576–586

Abstract: Chronic Lymphocytic Leukaemia (CLL) is the most common adult B-cell leukaemia and despite improvement in patients' outcome, following the use of targeted therapies, it remains incurable. CLL supportive microenvironment plays a key role in both CLL ... ...

Abstract	Chronic Lymphocytic Leukaemia (CLL) is the most common adult B-cell leukaemia and despite improvement in patients' outcome, following the use of targeted therapies, it remains incurable. CLL supportive microenvironment plays a key role in both CLL progression and drug resistance through signals that can be sensed by the main components of the focal adhesion complex, such as FAK and PYK2 kinases. Dysregulations of both kinases have been observed in several metastatic cancers, but their role in haematological malignancies is still poorly defined. We characterized FAK and PYK2 expression and observed that PYK2 expression is higher in leukaemic B cells and its overexpression significantly correlates with their malignant transformation. When targeting both FAK and PYK2 with the specific inhibitor defactinib, we observed a dose-response effect on CLL cells viability and survival. In vivo treatment of a CLL mouse model showed a decrease of the leukaemic clone in all the lymphoid organs along with a significant reduction of macrophages and of the spleen weight and size. Our results first define a possible prognostic value for PYK2 in CLL, and show that both FAK and PYK2 might become putative targets for both CLL and its microenvironment (e.g. macrophages), thus paving the way to an innovative therapeutic strategy.
MeSH term(s)	Animals ; Mice ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Focal Adhesion Kinase 2/genetics ; Focal Adhesion Kinase 2/metabolism ; B-Lymphocytes/metabolism ; Tumor Microenvironment
Chemical Substances	Focal Adhesion Kinase 2 (EC 2.7.10.2)
Language	English
Publishing date	2023-02-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.17688
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Article ; Online: Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death.

Mantione, Maria Elena / Meloni, Miriam / Sana, Ilenia / Bordini, Jessica / Del Nero, Martina / Riba, Michela / Ranghetti, Pamela / Perotta, Eleonora / Ghia, Paolo / Scarfò, Lydia / Muzio, Marta

Cell death & disease

2024 Volume 15, Issue 3, Page(s) 224

Abstract: Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways ... ...

Abstract	Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells.
MeSH term(s)	Mice ; Animals ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Dimethyl Fumarate/pharmacology ; Dimethyl Fumarate/therapeutic use ; NF-kappa B/metabolism ; Leukocytes, Mononuclear/metabolism ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Apoptosis ; Mice, Transgenic
Chemical Substances	Dimethyl Fumarate (FO2303MNI2) ; NF-kappa B ; NF-E2-Related Factor 2
Language	English
Publishing date	2024-03-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06602-z
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Article ; Online: Relevance of Minimal Residual Disease in the Era of Targeted Agents.

Heltai, Silvia / Ghia, Paolo / Scarfò, Lydia

Cancer journal (Sudbury, Mass.)

2019 Volume 25, Issue 6, Page(s) 410–417

Abstract: The evaluation of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) has evolved in parallel with the enormous progresses in the therapeutic armamentarium and the application of cutting-edge diagnostic techniques the CLL community ... ...

Abstract	The evaluation of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) has evolved in parallel with the enormous progresses in the therapeutic armamentarium and the application of cutting-edge diagnostic techniques the CLL community witnessed in the past few years. Minimal residual disease is considered an objective measure of disease status defined by the number of residual leukemic cells detected in a sample of peripheral blood and/or bone marrow as proportion of the total white blood cells and defined undetectable if fewer than 1 CLL cell among 10,000 white blood cells (10 or 0.01%) is detected. In this review, we aim at shedding light on how to evaluate MRD, what we already know about MRD from the experience with chemoimmunotherapy, and why MRD evaluation remains still relevant in the era of targeted agents.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biopsy ; Bone Marrow/pathology ; Flow Cytometry ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/etiology ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Molecular Targeted Therapy ; Neoplasm, Residual/drug therapy ; Neoplasm, Residual/pathology ; Real-Time Polymerase Chain Reaction ; Treatment Outcome
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2019-11-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2018400-1
ISSN	1540-336X ; 1528-9117 ; 1081-4442
ISSN (online)	1540-336X
ISSN	1528-9117 ; 1081-4442
DOI	10.1097/PPO.0000000000000413
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Zs.MO 163: Show issues

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