Giovanna Cutrona - Academia.edu (original) (raw)

Papers by Giovanna Cutrona

Blood, Nov 1, 1999

weekly. One month after completion of treatment with the anti-CD20 and 2 months after thalidomide... more weekly. One month after completion of treatment with the anti-CD20 and 2 months after thalidomide, he had Hb concentration of 8.6 g/dL, WBC count of 3.6 ϫ 10 9 /L, PLT count of 650 ϫ 10 9 /L, and IgM count of 1180 mg/dL. Two months later, he presented to our department with an Hb concetration of 8.1 g/dL, WBC count of 2.4 ϫ 10 9 /L (neutrophils 60%, lymphocytes 31%, monocytes 9%), and PLT count of 1000 ϫ 10 9 /L. Bone marrow smear and trephine biopsy revealed an hyperplastic marrow with marked dysplasia of the erythrocyte progenitors, highly increased number of markedly dysplastic megakaryocytes, left shifted myeloid series with 20% blasts, and 30% lymphocytic infiltration by small B-lymphoid cells and lymphoplasmacytes (cIg). Immunophenotype of the bone marrow, by flow cytometry, confirmed the presence of an immature blast, cell population that was CD13 ϩ , CD34 ϩ , and CD38 ϩ , and a lymphocytic component that was CD20 ϩ and CD5 Ϫ with light-chain restriction; karyotype was normal. The patient is currently being given hydroxyurea with a PLT count reduction to 740 ϫ 10 9 /L after 2 weeks' administration. It seems that the administration of thalidomide and the anti-CD20 monoclonal antibody was ineffective in controlling the IgM-MGUS problem that subsequently evolved into Waldenstrom macroglobulinemia; on the other hand, it caused a myeloproliferative reaction leading to a myeloproliferative disorder not precisely classifiable, which, however, is currently the major hematologic

Frontiers in Oncology, Aug 2, 2021

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was r... more The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone's biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated b2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same

Blood Cancer Journal, Feb 19, 2019

Microarray analysis of the multiple myeloma (MM) miRNome has unraveled the differential expressio... more Microarray analysis of the multiple myeloma (MM) miRNome has unraveled the differential expression of miRNAs in cytogenetic subgroups, their involvement in the tumor biology and their effectiveness in prognostic models. Herein, the small RNA transcriptional landscape in MM has been investigated exploiting the possibilities offered by small RNAseq, including accurate quantification of known mature species, discovery and characterization of isomiRs, and miRNAoffset RNAs (moRNAs). Matched small RNA-seq and miRNA GeneChip ® microarray expression profiles were obtained in a representative panel of 30 primary MM tumors, fully characterized for genomic aberrations and mutations. RNA-seq and microarray gave concordant estimations of known species. Enhanced analysis of RNA-seq data with the miR&moRe pipeline led to the characterization of 655 known and 17 new mature miRNAs and of 74 moRNAs expressed in the considered cohort, 5 of which (moR-150-3p, moR-24-2-5p, moR-421-5p, moR-21-5p, and moR-6724-5p) at high level. Ectopic expression of miR-135a-3p in t(4;14) patients, upregulation of moR-150-3p and moR-21-5p in t(14;16)/t(14;20) samples, and of moR-6724-1-5p in patients overexpressing CCND1 were uncovered and validated by qRT-PCR. Overall, RNA-seq offered a more complete overview of small non-coding RNA in MM tumors, indicating specific moRNAs that demand further investigations to explore their role in MM biology.

Supplementary Figures S1-S2 and Supplementary Tables S1-S5.

Purpose: To investigate the incidence and clinical relevance of classic and new prognostic marker... more Purpose: To investigate the incidence and clinical relevance of classic and new prognostic markers, IGHV gene mutational status, and chromosomal abnormalities in clinical monoclonal B lymphocytosis (cMBL) compared with Rai stage 0 chronic lymphocytic leukemia (Rai0-CLL).Experimental Design: A group of 136 patients with cMBL and a group of 216 Rai0-CLL cases were investigated prospectively.Results:IGHV-mutated cases were significantly more frequent among cMBLs (P = 0.005), whereas the distribution of CD38 and ZAP-70 positive cases, of patients with NOTCH1 and SF3B1 mutations or exhibiting the major CLL cytogenetic abnormalities, was similar in the two groups. Moreover, no significant differences were found either in IGHV/IGHD/IGHJ gene usage or in the overall prevalence of stereotyped IGHV gene sequences. Cells from cMBL and Rai0-CLL exhibited similar gene and microRNA (miRNA) signatures; in addition, when grouped according to the IGHV mutational status, IGHV-unmutated cases showed d...

PDF file - 64K, Supervised analysis comparing cMBL and Rai0-CLL samples. Haetmaps of the differen... more PDF file - 64K, Supervised analysis comparing cMBL and Rai0-CLL samples. Haetmaps of the differentially expressed (A) gene and (B) miRNA. Information about IGHV mutational status ('+' = M, '-' = UM), CD38, ZAP-70, chromosome 12 trisomy, chromosome 17, 11, and 13 deletions ('+' = positive, '-' = negative) are included alongside the patient ID. In the legend bar: turquoise indicates Rai0-CLL and yellow cMBL samples, respectively. The color scale bar represents the relative gene expression changes normalized by the standard deviation, and the color changes in each row represent gene expression relative to the mean across the samples.

PDF file - 22K, Distribution of the most frequently utilized IGHV. The histogram shows the percen... more PDF file - 22K, Distribution of the most frequently utilized IGHV. The histogram shows the percentages of VH sequences used in cMBL compared to Rai0-CLL cases.

Purpose: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable dis... more Purpose: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable disease. To establish the potential pathogenic role of miRNAs, the identification of deregulated miRNAs in CLL is crucial.Experimental Design: We analyzed the expression of 723 mature miRNAs in 217 early-stage CLL cases and in various different normal B-cell subpopulations from tonsils and peripheral blood.Results: Our analyses indicated that CLL cells exhibited a miRNA expression pattern that was most similar to the subsets of antigen-experienced and marginal zone–like B cells. These normal subpopulations were used as reference to identify differentially expressed miRNAs in comparison with CLL. Differences related to the expression of 25 miRNAs were found to be independent from IGHV mutation status or cytogenetic aberrations. These differences, confirmed in an independent validation set, led to a novel comprehensive description of miRNAs potentially involved in CLL. We also identified miRN...

PDF file - 175K, Supplementary Table S1. Clinical and prognostic parameters of cases analyzed by ... more PDF file - 175K, Supplementary Table S1. Clinical and prognostic parameters of cases analyzed by gene expression profiling arrays (45 cMBL and 115 Rai0-CLL) and by miRNA expression profiling arrays (39 cMBL and 111 Rai0-CLL). Supplementary Table S2. List of the 302 modulated genes identified by the supervised multiclass analysis comparing cMBL and Rai0-CLL samples stratified according to IGVH mutational status at the 90th percentile of false discovery rate (FDR) equal to 0. The SAM score(d) and the contrast values of each class are reported for each gene. Negative values indicates down-regulation, positive up-regulation. In bold italic are marked the eight genes that showed different modulation depending on Rai0-CLL or cMBL configuration. Supplementary Table S3. List of the 18 modulated miRNAs in the supervised multiclass analysis comparing cMBL and Rai0-CLL samples stratified according to IGVH mutational status at q-value 0. The SAM score(d) and the contrast values of each class ar...

Cell Reports

Highlights d Trisomy 12 (tri12) human PSCs and tri12 CLL share similar transcriptional perturbati... more Highlights d Trisomy 12 (tri12) human PSCs and tri12 CLL share similar transcriptional perturbations d Drug testing of 44 CLL patient samples identifies EDNRB and IRAK4 as tri12 CLL targets d IRAK4 inhibition selectively targets tri12 CLL in patientderived xenografted mice d IRAK4 inhibition does not impact healthy blood in patientderived xenografted mice

Background In Chronic Lymphocytic Leukemia (CLL) patients, skeletal alterations are more evident ... more Background In Chronic Lymphocytic Leukemia (CLL) patients, skeletal alterations are more evident in progressive disease stages. The detection of reactive cells within Bone Marrow (BM), and the evidence of tissue loss in their long bone shafts, suggest that leukemic B cells overgrowth contribute to bone derangement. Indeed, CLL-cells-released-cytokines enhance osteoclasts formation. CD16, a potential marker of monocytes differentiating toward osteoclasts, categorizes three subtypes: “non-classical”, “intermediate” and “classical”. We aimed to clarify whether the expansion of a specific CD16 + population influence bone homeostasis deregulation. Methods Cytofluorimetric analysis and patients’ whole body X-ray CT scans were used to evaluate a possible correlation between the expansion of a monocytic subset and the entity of bone erosion. In healthy monocytes, the modulation of CD16, RANK and RANKL expression and the evaluation of osteoclasts differentiation, after CLL-conditioned-media ...

Frontiers in Oncology

Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B cell... more Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B cells with low surface immunoglobulins (IG). About 40% of CLL clones utilize quasi-identical B cell receptors, defined as stereotyped BCR. CLL-like stereotyped-IG rearrangements are present in normal B cells as a part of the public IG repertoire. In this study, we collected details on the representation and features of CLL-like stereotyped-IG in the IGH repertoire of B-cell subpopulations purified from the peripheral blood of nine healthy donors. The B-cell subpopulations were also fractioned according to the expression of surface CD5 molecules and IG light chain, IGκ and IGλ. IG rearrangements, obtained by high throughput sequencing, were scanned for the presence of CLL-like stereotyped-IG. CLL-like stereotyped-IG did not accumulate preferentially in the CD5+ B cells, nor in specific B-cell subpopulations or the CD5+ cell fraction thereof, and their distribution was not restricted to a sing...

Expert Opinion on Investigational Drugs, 2020

Introduction. Patients with TP53 dysfunction, assessed by del(17p) or TP53 mutations, respond poo... more Introduction. Patients with TP53 dysfunction, assessed by del(17p) or TP53 mutations, respond poorly to chemo-immunotherapy and fare better with the new therapies (BCR and BCL-2 inhibitors); however, it is unclear whether their response is similar to that of patients without anomalies or whether there is currently an adequate determination of TP53 dysfunction. Area covered. A literature search was undertaken on clinical trials and real-world experience data on patients with TP53 dysfunction treated with different protocols. Moreover, data on the TP53 biological function and on the tests currently employed for its assessment were reviewed. Expert opinion. Although TP53 dysfunction has less negative influence on the new biological therapies, patients with these alterations, particularly those with biallelic inactivation of TP53, have a worst outcome with these therapies than those without alterations. At present, a determination of TP53, particularly with next generation sequencing (NGS) methodologies, may be sufficient for the identifications of the patients unsuitable for chemo-immunotherapy, although integration with del(17p) would be advisable. For the future, more extensive determinations of the TP53 status, including functional assays, may become part of the current armamentarium for a better patient stratification and treatment with newer protocols.

American Journal of Hematology, 2021

Ibrutinib (IB) has been initially approved for naïve patients' treatment with chronic lymphocytic... more Ibrutinib (IB) has been initially approved for naïve patients' treatment with chronic lymphocytic leukemia (CLL) based on its superiority over chlorambucil. 1 Two subsequent large phase 3 randomized trials demonstrated a longer progression-free survival (PFS) in IB treated cases compared to those receiving rituximab (R) combined with fludarabine (F) and cyclophosphamide (C, FCR) 2 or with bendamustine (BR). 3

study suggests that the SC route of administration of alemtuzumab is not as effective as IV in th... more study suggests that the SC route of administration of alemtuzumab is not as effective as IV in the treatment of T-PLL; a series of 16 patients receiving 1st line therapy with IV alemtuzumab has shown an OR of 94% with 88% CR. It is therefore advisable that IV treatment should be used. Pentostatin is an effective agent to augment response. Allogeneic HPCT should be used as consolidation therapy when possible.

Drug Design, Development and Therapy, 2021

Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they b... more Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptideconjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased offtarget cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third-or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.

Frontiers in Oncology, 2020

The human TP53 locus, located on the short arm of chromosome 17, encodes a tumour suppressor prot... more The human TP53 locus, located on the short arm of chromosome 17, encodes a tumour suppressor protein which functions as a tetrameric transcription factor capable of regulating the expression of a plethora of target genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation. TP53 is the most commonly mutated gene in human cancer cells and TP53 germ-line mutations are responsible for the cancer-prone Li-Fraumeni syndrome. When mutated, the TP53 gene generally presents missense mutations, which can be distributed throughout the coding sequence, although they are found most frequently in the central DNA binding domain of the protein. TP53 mutations represent an important prognostic and predictive marker in cancer. The presence of a TP53 mutation does not necessarily imply a complete P53 inactivation; in fact, mutant P53 proteins are classified based on the effects on P53 protein function. Different models have been used to explore these never-ending facets of TP53 mutations, generating abundant experimental data on their functional impact. Here, we briefly review the studies analysing the consequences of TP53 mutations on P53 protein function and their possible implications for clinical outcome. The focus shall be on Chronic Lymphocytic Leukemia (CLL), which also has generated considerable discussion on the role of TP53 mutations for therapy decisions.

European Journal of Haematology, 2021

ObjectivesTo compare the capacity of ibrutinib (IB) and idelalisib‐rituximab (IDELA‐R) of prolong... more ObjectivesTo compare the capacity of ibrutinib (IB) and idelalisib‐rituximab (IDELA‐R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only.MethodsA real‐life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study.ResultsAt an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA‐R vs IB HR = 0.5, 95% CI = 0.36‐0.71) although with some limitations due to the non‐randomized and retrospective nature of the study and to the lower number of patients in the IDELA‐R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into th...