Papers by Stefania Ciolli
Blood, Nov 5, 2021
Until recently, MM was defined using strict clinical pathological criteria that required evidence... more Until recently, MM was defined using strict clinical pathological criteria that required evidence of specific end-organ damage (CRAB) attributable to the underlying clonal plasma cell disorder. In the case of absence of end-organ damage, patients with clonal plasma cell proliferation were diagnosed either with monoclonal gammopathy of undetermined significance (MGUS) or with smoldering multiple myeloma (SMM). Further, on one hand there have been on-going revisions of the diagnostic criteria for MM and SMM, on the other there have also been revisions of the molecular classification of these disorders; namely, staging and risk. These revisions regarding both the diagnostic criteria and the molecular classification of these disorders are very important because recent advances in understanding these disorders have led to significant progress in the treatment of MM and SMM, in our understanding of disease biology, and in prognostic evaluation for cancer patients. The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that helps in clinical care, comparing clinical trial data. The RISS will be of importance in the clinic in terms of counseling patients regarding prognosis, as well as in clinical trials to compare outcomes across clinical trials. The initial cytogenetic classification of SMM also has implications for prognosis as patients with t(4;14) translocation, 17p deletion, and 1q amplification have a higher risk of progression from SMM to MM. Although patients with trisomies are considered to have a better prognosis when diagnosed with MM, they have a higher risk of progression from SMM to MM compared to patients with t(11;14). It is possible that trisomic MM manifests earlier with more obvious bone disease, producing in essence a lead-time bias. Thus, the time from SMM to MM is shortened while the time from MM to death appears longer. There are several molecular subtypes of MM, associated with several unique differences in disease presentation and prognosis. For example, trisomic MM appears to respond particularly well to lenalidomide-based therapy, while t(4;14) MM requires bortezomib-based induction and maintenance for good outcome. In terms of clinical presentation, t(4;14) MM appears to have a lower propensity for bone disease at diagnosis, while t(14;16) MM is often associated with high levels of serum free light chains (FLC) and a higher risk of acute renal failure at diagnosis. Disease biology in MM is best reflected based on the molecular subtype of the disease and the presence or absence of specific cytogenetic abnormalities. The abnormalities such as t(4;14), t(14;16), t(14;20), gain(1q), del(1p), and del(17p) influence disease course, response to therapy, and prognosis in MM. In our center we evaluated the cytogenetics data at the onset of the disease, after 1st line therapy, after transplantation and during maintenance therapy to analyze any changes in the cytogenetic panel and additional anomalies and if all this is correlated with the characteristics of the disease, patient, and risk predictor. In particular, we evaluated 160 patients and analyzed the clinical evolution in patients in which monosomies 13 and/or 14 were present, currently not classifiable in prognostic terms. The significance of these monosomies was evaluated based on the various stages of the disease and the type of therapy administered. Disclosures No relevant conflicts of interest to declare.
Cytogenetic and Genome Research, Oct 7, 1999
PubMed, Sep 1, 2013
Recent biological advances have provided the framework for novel therapeutic strategies in oncolo... more Recent biological advances have provided the framework for novel therapeutic strategies in oncology. Many new treatments are now based on standard cytotoxic drugs plus biologic agents. In Multiple Myeloma, a plasma cell neoplasm characterized by a severe bone disease, biologic drugs such as proteasome inhibitors and immunomodulatory agents, above their antineoplastic efficacy have a beneficial effects on bone disease. Bortezomib, a clinically available proteasome inhibitor active against myeloma, induces the differentiation of mesenchymal stem/progenitor cells into osteoblasts, resulting in new bone formation. Immunomodulatory drugs (e.g., thalidomide and lenalidomide), which are active against myeloma, also block the activity of bone-resorbing osteoclasts. These data reflect the utility of targeting endogenous mesenchymal stem/progenitor cells for the purpose of tissue repair and suggest that combining different classes of agents that are antineoplastic and also inhibit bone destruction and increase bone formation should be very beneficial for myeloma patients suffering from severe bone disease.
PubMed, Mar 1, 2004
Background and objectives: The deletion of the long arm of chromosome 5 is common in myelodysplas... more Background and objectives: The deletion of the long arm of chromosome 5 is common in myelodysplastic syndromes (MDS) but is not limited to the 5q- syndrome as it is also seen in acute myeloid leukemia (AML), where it is often associated with other karyotypic aberrations. The aim of this study was to investigate whether deletions of known suppressor sequences occur in myeloid malignancies associated with 5q-. Design and methods: Thirty patients with MDS or AML were selected for the presence of a 5q karyotypic deletion, either isolated (19 cases) or associated with other chromosome changes (11 cases). Multiple fluorescent in situ hybridization (FISH) in interphase nuclei was applied in all cases using a panel of eleven probes for known suppressor genes or loci deleted in MDS/AML. Metaphase FISH was also performed to clarify discrepancies between conventional and molecular cytogenetics. Results: No additional deletions were found in nineteen cases with an isolated 5q-. Mono-allelic deletions where found in 9/11 cases, 3 of which were related to monosomies by conventional cytogenetics. Interphase-FISH showed p53, AML1, D13S25, NF1, or Ikaros in six out of nine (66%) patients with 5q- and additional karyotypic changes. Metaphase FISH was helpful in assigning some of these cryptic events to non-proliferating cells. Interpretation and conclusions: Our study emphasizes that isolated 5q- is the marker of a highly stable clone in both MDS and AML. AML with isolated 5q- are molecularly closer to 5q- syndrome than to AML with complex changes. Interphase-FISH data strongly support a mutator phenotype underlying complex karyotypes with a 5q deletion.
Journal of Chemotherapy, Dec 1, 2004
The incidence of fungal infections and the role of liposomal amphotericin B (Ambisome) in proven ... more The incidence of fungal infections and the role of liposomal amphotericin B (Ambisome) in proven and probable infections were evaluated in acute leukemic patients, intolerant to conventional amphotericin B. During 1999-2002, 307 febrile episodes occurred in 231 patients. Fungi were responsible for 3% of bloodstream infections. Ambisome was employed in 5 fungal sepsis (1 Candida albicans, 1 C. famata, 1 C. tropicalis, 1 C. krusei, 1 Geotrichum capitatum) 2 Aspergillosis, 2 probable fungal pneumonia cases. A favorable response was achieved in 78% of patients (4 fungemia, 2 aspergillosis, 1 probable), an unfavorable response in 1 C. krusei fungemia and in 1 probable pneumonia. Our antimicrobial pattern documented a high resistance rate to azoles. We concluded that Ambisome is an effective and well tolerated agent and its introduction has changed the outcome for many patients, although in some refractory diseases other strategies must be considered.
Blood, Dec 6, 2014
The front-line therapy for CLL young and fit patients is chemo-immunotherapy with Fludarabine-Cyc... more The front-line therapy for CLL young and fit patients is chemo-immunotherapy with Fludarabine-Cyclophosphamide and Rituximab (FCR). However, around three quarter of the patients with a newly diagnosed CLL are 65 years or older, with approximately 42% being older than 75 years and with age-related comorbidities. FCR regimen results in a significant myelosuppression and high rates of early and late infections. Hence, other less toxic regimens are under evaluation. Recently the German CLL study group reported an interim analysis of the CLL10 trial, who compared FCR vs Bendamustine-Rituximab (BR). The response rates to the 1st-line treatment with BR or FCR were comparable, and BR could be an alternative 1st-line treatment for medically fit pts. Notably, this study showed that pts treated with BR were often older (median 71 vs. 65 yrs; p<0.0001) and frequently with comorbidities (67% vs. 62%), suggesting that it may be a suitable option for this wide subpopulation. Here we report retrospective data from 12 Italian centres focused on the evaluation of efficacy and safety of BR in elderly SLL/CLL patients. Data on 70 untreated SLL/CLL patients with age ≥ 65 years assigned to receive front-line therapy with 6 monthly courses of Bendamustine (90 mg/sm at days 1-2) and RTX (375 mg/sm at day 1 for the first course, then 500 mg/sm for subsequent cycles) were collected. The primary end points were the Overall Response (CR/PR) and toxicity rates. Responses, evaluated at 2 months after the end of therapy, were defined according to the updated National Cancer Institute-Working Group guidelines. Seventy patients (47 males and 23 females) with a median age of 72 years (range, 65-87 years) were included in the study. Eight patients (11.4%) were unfit (CIRS score =/> 7). All patients had an ECOG performance status ranging from 0 to 2. Twenty-nine of 70 patients had Binet stage C, 12 patients were Binet A, 29 Binet B. Thirty-nine patients showed karyotype abnormalities at FISH analysis (data available in 54/70 patients). High risk FISH karyotype according to Döhner´s hierarchical model was detected in 17 patients (14 with del 11q, 3 with del 17p). Ten of them had del(13q14), 12 had trisomy 12 and 15 had normal karyotype. The analysis of the IGHV status, available in 50 patients, showed 25 patients with somatic mutation and 25 patients with germ-line sequences. Zap-70 data were available for 37/70 pts, 19 of them (51.3%) were Zap-70 positive. CD38 was available for 52 patients: it was positive in 27/52 pts (51.9%). (Table 1) A mean number of 5.46 courses of BR were given and the Bendamustine dose was reduced by more than 10% in 39 patients (55,7%). The main reason for dose reduction was haematological toxicities. The ORR rate was 88,6%,with 22 patients (31.4%) obtaining a CR and 40 patients (57,2%) obtaining a PR. Progression Free Survival, Time To Retreatment and Overall Survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only the presence of del17 resulted to affect the response rate (p= 0.023) and PFS (p<0.001). Grade 3-4 hematological toxicity was recorded in 25 patients (35,7%). Extra-hematological toxicity grade I-III (skin reactions, gastrointestinal and cardiovascular symptoms, infusion related reactions, etc). was noticed in 35 patients (50,0%). Eleven patients (15.7%) were admitted to the hospital. Retrospective data from this group of elderly CLL patients indicate that Benda-R front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a Bendamustine dose reduction until 70 mg/sm. Even in this cohort of patients we confirmed del17 as a bad prognostic parameter. Table 1: Patients’ clinical-biological characteristics. Median age at diagnosis 72 years (range 65-87) M:F 47/23 CIRS score =/>7 8/70 pts (11.4%) PB lymphocytes 33.203/mmc Binet stage A 12/70 pts (17.2%) Binet stage B 29/70 pts (41.4%) Binet stage C 29/70 pts (41.4%) ZAP70>20% 19/37 pts (51.3 %) CD38> 30% 27/52 pts (51.9%) Beta2microglobulin increased 51/59 pts (86.4%) IgVH homology < 98% 25/50 pts (50%) Normal FISH 15/54 pts (27.8%) del 13q 10/54 pts (18.5%) +12 12/54 pts (22.2%) del 11q 14/54 pts (25.9%) del 17p 3/54 pts (5.6%) Bulky syndrome 16/70 pts (22.9%) PB, peripheral blood; IgVH, immunoglobulin heavy chain variable genes; FISH, Fluorescent In Situ Hybridization. Disclosures No relevant conflicts of interest to declare.
Hematological Oncology, Jun 1, 2021
Blood, Nov 5, 2020
INTRODUCTION. Kinase inhibitors and glycoengineered monoclonal antibody, such as obinutuzumab (G)... more INTRODUCTION. Kinase inhibitors and glycoengineered monoclonal antibody, such as obinutuzumab (G), have significantly changed the treatment landscape of chronic lymphocytic leukemia (CLL). Both like the BTK inhibitor ibrutinib (IB) and obinutuzumab plus chlorambucil (G-CHL) are approved as first line therapy in CLL patients unfit for a fludarabine-base treatment. While IB has proved to be superior to bendamustine-rituximab in a phase 3 trial and an ongoing retrospective ERIC study, no head-to-head comparison has been done for IB vs G-CHL in a real-world evidence study. The aim of this study was to compared the clinical efficacy of the fixed duration G-CHL treatment vs continuous treatment with IB. METHODS. The inclusion criteria for this observational study were patients with a diagnosis of CLL, requiring treatment according to the iwCLL guideline (Hallek M, Blood 2018) and considered unfit for fludarabine-base therapy by the treating physician belonging to the Italian CLL campus. Patients received ibrutinib 420mg daily until progression or unacceptable toxicity, while G was administrated at 100mg on day 1, 900mg on day 2 and 1000mg on days 8 and 15 of the 1st cycle, then at 1000mg from cycles 2-6. Chlorambucil was administrated according to the local policy. An IGHV gene sequence homology ³98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). TP53 disruptions (TP53dis) included deletions and mutations. Progression-free survival (PFS), time-to-next treatment (TTNT) and overall survival (OS) were calculated according to the iwCLL 2018 guideline. Minimal residual disease (MRD), assessed by flow cytometry, was considered undetectable when <10-4 (uMRD4). Survival curves were compared with the log-rank test and p<0.05 was considered as significant. The study was approved by the ethic committee of Padua university hospital. RESULTS. We recruited 284 CLL patients from 16 hematologic centers, 104 were treated with G-CHL and 180 with IB as first-line treatment. Once TP53dis cases were excluded, 102 patients treated with G-CHL and 80 treated with IB were included for further analysis. Among patients managed with G-CHL the median age was 75 years and 20% were older than 80 years, 47% had a CIRS≥6 (range 2-18), 68% had a clearance creatinine <70ml/min, 60% showed a Rai stage III-IV, 32% were U-IGHV and 11% harbored 11q deletion by FISH. Patients treated with IB displayed a better renal function (p=0.0011) and were enriched in U-IGHV cases (p=0.0001). After a median follow-up of 21 months, 23 patients relapsed (20 G-CHL, 3 IB), 16 required a subsequent treatment (14 G-CHL, 2 IB) and 17 died (10 G-CHL and 7 IB). Two patients in the IB arm developed Richter syndrome. After 8 months from the start of treatment, the overall response rates in the G-CHL and IB arms were 86% vs 77% (p=0.1480), including 25% vs 6% complete remissions (CR, p=0.0013) and 61% vs 71% partial responses (PR, p=0.6320). Remarkably, an uMRD4 by flow-cytometry was documented in 42% and 9% of G-CHL patients in the peripheral blood and bone marrow, respectively. The median PFS was 33 months for G-CHL arm, but not reached for IB patients. The 24months PFS, TTNT and OS was 67% vs 91% (p=0.0012), 83% vs 97% (p=0.0128) and 89% vs 95% (p=0.5314) for the G-CHL and IB arms, respectively. Interestingly, the depth of response influenced PFS only in the G-CHL arm both in terms of clinical response (the median PFS was 8, 29 and 38 months for no responding, PR and CR patients) and MRD status (the 24 months PFS was 82% vs 50% and 100% vs 58% for uMRD4 vs MRD+ evaluated on peripheral blood and bone marrow). While the PFS was significantly better with IB than with G-CHL in U-IGHV (p=0.007), it was superimposable for M-IGHV patients (p=0.1946). Dose reductions or discontinuations were recorded in 39% and 44% of patients in the G-CHL and IB arms. Atrial fibrillation and infections occurred in 2% and 6% (p=0.0442), and in 25% and 17% (p=0.1455) of patients in the G-CHL and IB arms, respectively. CONCLUSIONS. The Italian experience with G-CHL confirms the marked efficacy and safety of this combination, in particular for patients who reach a CR and/or an uMRD4. The continuous treatment with ibrutinib provides a better disease management in CLL patients unfit for fludarabine-base therapy, but some on them - particularly those with a M-IGHV status - can achieve a long-term disease control with a fixed duration obinutuzumab-based chemoimmunotherapy. Visentin: Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Mauro:Takeda: Membership on an entity's Board of Directors or advisory committees; Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale:Janssen: Honoraria. Ciolli:Janssen: Honoraria; Abbvie: Research…
American Journal of Hematology, Dec 21, 2021
Department of Internal Medicine, NYU Langone School of Medicine, New York, New York, USA Departme... more Department of Internal Medicine, NYU Langone School of Medicine, New York, New York, USA Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA Department of Hematology, Montefiore Medical Center, Bronx, New York, USA Department of Medicine-Hematology, Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
Leukemia Research, Nov 1, 2014
By using the GRADE system we produced the following recommendations for the use of bendamustine i... more By using the GRADE system we produced the following recommendations for the use of bendamustine in the first-line treatment of CLL: (1) bendamustine with rituximab is recommended in elderly fit patients potentially eligible to FCR; (2) Bendamustine alone is recommended in patients who are candidate to chlorambucil alone; (3) Rituximab-bendamustine is recommended in patients not eligible to FCR, but suitable to receive rituximab. Consensus-based recommendations addressed evidence-orphan issues concerning the use of bendamustine in genetically-defined high-risk patients and the appropriate dose of bendamustine as single agent or in association with rituximab.
Leukemia Research, Oct 1, 2015
The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyc... more The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyclophosphamide-rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine-rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients. Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety. Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70mg/m(2).
Haematologica, Apr 19, 2018
W e performed an observational study on the efficacy of bendamustine and rituximab (BR) as first ... more W e performed an observational study on the efficacy of bendamustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The
Farmeconomia. Health economics and therapeutic pathways, Feb 6, 2020
Background Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder character... more Background Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of monomorphic B-cells in peripheral blood, bone marrow, spleen, and lymph nodes. CLL represents the most common form of leukemia of adults in Western countries [1]. The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI) reports an incidence of 4.9 new cases per 100,000 men and women per year [2]. CCL is most frequently diagnosed among people aged 65-74 with a median age at diagnosis of 70 years (about two third ≥65 years) and this malignancy is more common among men
American Journal of Hematology, Jun 1, 1996
To prevent heat illnesses, a high index of suspicion should be maintained during a heat wave or w... more To prevent heat illnesses, a high index of suspicion should be maintained during a heat wave or while using unacclimatized workers in heavy labor. Employers should measure wet bulb globe temperature index (which correlates with deep body temperature) and plan work schedules within permissible threshold limit values [ 3 ]. In this respect, the workers' compensation insurer can provide critical technical know-how to its insureds; this will reduce heat-related injuries and claim expense. We hypothesize that the observed thrombocytopenia and leukopenia were caused by thermolysis since they were noted on the first day of heat exhaustion and progressively improved. Circulating platelets and neutrophils have a relatively short life span of 10 days and 10 hours, respectively [4]; this may explain their prompt replenishment from bone marrow. Although thrombocytopenia (with disseminated intravascular coagulation) is often observed in heat stroke [1,5], this is the first report of this potentially serious complication in a mild heat illness.
Haematologica, Jun 8, 2017
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Papers by Stefania Ciolli