DORIANA GRAMEGNA
Verified @dfci.harvard.edu
MEDICAL ONCOLOGY
DANA FARBER CANCER INSTITUTE
Scopus Publications
Scopus Publications
Eugenio Morelli, Mariateresa Fulciniti, Mehmet K. Samur, Caroline Ribeiro, Leon Wert-Lamas, Jonathan E Henninger, Annamaria Gulla, Anil Aktas Samur, Katia Todoerti, Srikanth Talluri,et al.
American Society of Hematology
Long noncoding RNAs (lncRNA) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell growth dependency to lncRNA genes in multiple myeloma (MM), and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that a MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell growth dependency acting in a microRNA- and DROSHA- independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1 (ACC1). Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent anti-tumor effects both in vitro and in vivo in three pre-clinical animal models, including a clinically relevant PDX-NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.
Doriana Gramegna, Diego Bertoli, Chiara Cattaneo, Camillo Almici, Alessandro Re, Angelo Belotti, Erika Borlenghi, Gaetana Lanzi, Silvana Archetti, Rosanna Verardi,et al.
Springer Science and Business Media LLC
Vittorio Ruggero Zilioli, Domenico Albano, Annalisa Arcari, Francesco Merli, Alessandra Coppola, Giulia Besutti, Luigi Marcheselli, Doriana Gramegna, Cristina Muzi, Moana Manicone,et al.
Wiley
Elderly classical Hodgkin lymphoma (cHL) (ecHL) is a rare disease with dismal prognosis and no standard treatment. Fitness‐based approaches may help design appropriate treatments. Sarcopenia has been associated with an increased risk of treatment‐related toxicities and worse survival in various solid tumours, but its impact in ecHL is unknown. The aim of this retrospective multicentre study was to investigate the prognostic role of sarcopenia in ecHL.
Erika Borlenghi, Chiara Cattaneo, Elisa Cerqui, Silvana Archetti, Diego Bertoli, Daniela Bellotti, Doriana Gramegna, Giulia Soverini, Margherita Oberti, Francesca Schieppati,et al.
Wiley
Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High‐dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate‐risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long‐term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML‐01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high‐risk AML (adverse cytogenetic, isolated FLT3‐internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19–75), were considered standard‐risk and received the NILG AML‐01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+‐PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1‐2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment‐related mortality was 3/160 (1.8%). After a median follow‐up of 66.4 months, overall survival (OS) and relapse‐free survival (RFS) at 5‐years were 61.4% and 52.4%, respectively. Twenty‐eight selected patients aged >65 had similar outcomes. According to European leukemia net‐2010 classification, the OS and RFS at 5‐years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate‐I, 45.2% and 36.5% in Intermediate‐II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.
Michele Malagola, Caterina Pollara, Nicola Polverelli, Tatiana Zollner, Daria Bettoni, Lisa Gandolfi, Doriana Gramegna, Enrico Morello, Alessandro Turra, Silvia Corbellini,et al.
Frontiers Media SA
CMV infection is a major challenge in allogeneic stem cell transplantation (allo-SCT). The changing landscape in CMV management includes the introduction of letermovir in prophylaxis of high-risk patients and the source of CMV DNA monitoring (plasma—PL vs. whole blood—WB), for pre-emptive therapy (PET) initiation. We report here how our real-life experience in CMV management evolved, following letermovir registration. We focus on: (i) the effects of systematic use of letermovir for CMV prophylaxis in high-risk patients, (ii) the results of a longitudinal comparison of CMV DNAemia monitoring in PL and WB. From December 2018 to April 2020, 60 allo-SCTs have been performed in our center (LET ERA), of whom 45 received letermovir in prophylaxis from day 0 to day + 100, because of recipient positivity of anti CMV IgG. These patients were compared with a cohort of 41 allo-SCTs performed between November 2017 and November 2018 (NO LET ERA). Firstly, the incidence of CMV clinically significant infections, CMV disease, bacterial infections, proven/probable fungal infections, hospital re-admissions after allo-SCT by day + 100 in the two ERA were 8 vs. 44% (p = 0.0006), 2 vs. 12% (p = 0.02), 37 vs. 56% (p = 0.05), 8 vs. 19% (p = 0.09), and 23 vs. 39% (p = 0.09), respectively. By day + 180 these differences were 17 vs. 68% (p < 0.00001), 2 vs. 12% (p = 0.02), 45 vs. 78% (p = 0.09), 8 vs. 22% (p = 0.05), and 40 vs. 66% (p = 0.01), respectively. Secondly, from February to May 2019, we comparatively measured CMV DNA from WB and PL and we confirmed that there is a linear correlation between CMV DNA level in WB and PL (Spearman’s test r = 0.86). Moreover, CMV DNAemia at the time of PET in the 12 patients with a clinically significant CMV infection was higher in WB vs. PL (5.202 vs. 4.981 copies/ml, p = 0.1). Our real-life experience confirms that: (i) letermovir is highly effective, leading to a significant drop in CMV clinically significant infections and CMV-related complications by day + 100 and + 180 after allo-SCT; (ii) WB may be an effective alternative to PL as a source for CMV DNA monitoring, as a linear correlation of DNAemia was confirmed between WB and PL, even if the CMV DNAemia at PET initiation was comparable in the two sources.
Mirko Farina, Simona Bernardi, Lisa Gandolfi, Camilla Zanaglio, Enrico Morello, Alessandro Turra, Tatiana Zollner, Doriana Gramegna, Benedetta Rambaldi, Federica Cattina,et al.
Frontiers Media SA
Background Myelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an in vivo model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes. Case Presentation We report a case of DC-MDS diagnosed 5 years after an allo-SCT from a matched related donor (patient’s sister) in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). The sex-mismatch allowed us to identify the donor cell origin. At the onset, the DC-MDS was characterized by chromosome seven monosomy and NRAS, RUNX1, and BCOR mutations. Because of a familiar history of colorectal neoplasia and the variant allele frequency (VAF) of NRAS mutation at the onset, this mutation was searched on germline DNA in both the donor and the recipient, but the result was negative. Moreover, after transplant (+4 months), the patient developed severe and long-lasting chronic graft-versus-host disease (cGVHD), requiring multiple lines of treatments. Because of the severe immunosuppression, recurrent infections occurred and, lately, the patient died due to septic shock. Conclusion This case report highlights the need, whenever possible, to evaluate the donor origin of the posttransplant myelodysplasia and acute leukemias. The potential key role of the impaired immune surveillance and of long-lasting immunosuppression appears to be emerging in the development of this case of DC-MDS. Finally, this case reminds the importance to investigate the familiar genetic predisposition in donors with a familiar history of neoplasia.
Chiara Cattaneo, Alessandro Busca, Doriana Gramegna, Francesca Farina, Anna Candoni, Monica Piedimonte, Nicola Fracchiolla, Chiara Pagani, Maria Ilaria Del Principe, Maria Chiara Tisi,et al.
Ovid Technologies (Wolters Kluwer Health)
Abstract Invasive fungal diseases (IFDs) remain a major clinical issue in patients with hematological malignancies (HMs). To confirm the efficacy and safety of the new azole isavuconazole (ISV) in a clinical care setting, we planned a multicenter retrospective study; we collected data on all possible/probable/proven IFDs in patients with HMs treated with ISV in 17 centers. Between July 2016 and November 2018, 128 patients were enrolled, and 122 were fully evaluable. ISV was employed as the 1st line therapy in 43 (35%) patients and as a subsequent therapy in 79 (65%) patients. The response rate was 82/122 patients (67.2%); it was similar when using ISV as a 1st or 2nd line treatment (60.5% vs 70.9%, respectively; p = 0.24). In multivariate analysis, both female sex (OR: 2.992; CI: 1.22–7.34) and induction phase of treatment (OR: 3.953; CI: 1.085–14.403) were predictive of a favorable response. At a median follow-up of 5 months, 43 (35.2%) patients were dead; the 1-year overall survival (OS) was 49.9%. In multivariate analysis, the response to ISV (OR: 0.103; CI: 0.041–0.262) and IFD refractoriness to previous antifungals (OR: 3.413; CI: 1.318–8.838) were statistically significant for OS. Adverse events (AEs) were reported in 15/122 patients (12.3%); grade 3–4 AEs were reported in 5 (4%) and led to ISV discontinuation. Our study confirms the safety and tolerability of ISV, also in diseases other than acute leukemia. Phase of hematological disease, gender and refractoriness to previous antifungals are the main predictive factors for the aforementioned response and outcome.
Chiara Cattaneo, Doriana Gramegna, Michele Malagola, Chiara Pagani, Erika Borlenghi, Elisa Cerqui, Angela Passi, Margherita Sciumé, Simona Bernardi, Claudia Crippa,et al.
Informa UK Limited
Abstract We evaluated the impact of invasive pulmonary aspergillosis (IPA) on epidemiology and outcome in acute leukemia (AL), analyzing all acute myeloid (AML) and acute lymphoblastic leukemia (ALL) consecutively admitted to our Institution during a 5-year period of observation. Only AML patients received anti-mold prophylaxis. Among 175 AL patients (136 AML/39 ALL), possible and proven/probable IPA were diagnosed in 28 (16%). Frequency of IPA was similar in AML (16.2%) and in ALL (15.4%). Two-year overall survival (OS) was significantly affected by IPA (no IPA: 69.8% vs IPA: 31.7% p = .002). OS was similar in patients with proven/probable (28.2%) and possible IPA (36.4%) (p = .003 and .065, respectively). When censoring patients at transplant, IPA still affected 2-year survival (49.6% vs 79.2%, p = .02), but only proven/probable IPA was associated with lower survival (34.7%, p = .0003). IPA negatively impacts on long-term survival of leukemia patients; antifungal prophylaxis should be adopted also during induction in ALL and in AML beyond induction therapy.
Mariella D'Adda, Mirko Farina, Francesca Schieppati, Erika Borlenghi, Chiara Bottelli, Elisa Cerqui, Samantha Ferrari, Doriana Gramegna, Chiara Pagani, Angela Passi,et al.
Wiley
Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment‐free remission (TFR).
Erika Borlenghi, Chiara Cattaneo, Francesca Schieppati, Doriana Gramegna, Angela Passi, and Giuseppe Rossi
Informa UK Limited
Acute promyelocytic leukemia (APL) is considered rare in elderly patients mainly because the proportion of patients included in clinical studies was limited due to frequent comorbidities, poor clinical conditions and to their higher vulnerability to drug toxicities causing an increased rate of treatment-related mortality. APL can be cured with current treatment strategies in more than 80% of patients [1,2]; since the biological characteristics of APL in elderly patients are the same than in the younger, using current treatments, APL should be potentially highly curable also in elderly patients [3–6]. In clinical trials patients aged >70 represented only 3–9% of the entire population studied [3]. Therefore, the efficacy and safety of a standard treatment program in this subset of patients are still unclear. Recommendations to reduce the intensity of the chemotherapy combined with all-trans retinoic acid (ATRA) [4–6] or to use alternative less toxic strategies [7,8] have been proposed, but only few reports are available. Herein we report clinical data and treatment results in a cohort of 21 patients aged 70 years consecutively diagnosed between 2000 and 2016, who represented 20% of 95 APL seen in the same period at our Institution. The diagnosis was confirmed by detection of PML-RARalfa molecular rearrangement with RT-PCR. All patients received at least one dose of ATRA which was given as early as APL could be suspected on morphological grounds. Patients were treated with ATRA alone or with a combination of ATRA and idarubicin according to AIDA protocols [2,5]. Schedules and doses were adapted to the single patient based on clinical judgment. Survival was evaluated using the Kaplan–Maier method and compared using log-rank tests. The main clinical characteristics at onset, the risk category according to Sanz score [9] and the treatment administered are shown in Table 1. As to comorbidities, cardiovascular disease was present in nine patients and nine patients had a prior neoplasia, treated either with radiotherapy (rectum carcinoma (n1⁄4 1)), chemotherapy (non-Hodgkin lymphoma (n1⁄4 1)), surgery and radiotherapy (thyroid carcinoma (n1⁄4 1), breast cancer (n1⁄4 1), prostate cancer (n1⁄4 1)) or surgery only (basal cell carcinoma (n1⁄4 1), melanoma (n1⁄4 1), prostate (n1⁄4 1) and bladder (n1⁄4 1) cancer). At APL diagnosis, neoplastic disease was active in one patient with breast carcinoma. Induction treatment consisted of ATRA monotherapy (n1⁄4 6) given at 45mg/sqm/d for a median of 28 days (range 1–45). In 15 patients, idarubicin at reduced dosage, by skipping 1–3 of the four scheduled doses of 12mg/sqm was added to ATRA. There was one early death (4%) due to cerebral hemorrhage. The hematological complete remission (CR) rate was 95.2% and molecular remission rate 85.7%. ATRA-induced differentiation syndrome occurred in seven cases (33%) and was successfully managed according to common guidelines [10]. Ten infectious complications, including sepsis (n1⁄4 4), invasive aspergillosis (n1⁄4 2), Herpes Zoster Virus (HZV) reactivation (n1⁄4 1), Clostridium difficile enteritis (n1⁄4 2) and Cytomegalovirus hepatitis (n1⁄4 1) were observed in five patients. Moreover uncomplicated acute myocardial infarction occurred in one patient, four patients had deep venous thrombosis and two developed transient renal failure, not requiring dialysis. Consolidation was given to 18 of 20 patients: 17 received chemotherapy with (n1⁄4 14) or without (n1⁄4 3) ATRA and one patient ATRA only. Maintenance with ATRA 45mg/sqm/d for 15 days every 3 months plus low dose chemotherapy (methotrexate and 6-mercaptopurine) was administered for 2 years, in 16 patients. During consolidation and maintenance, non-fatal complications, including HZV reactivation (n1⁄4 1), recurrent urinary tract infections (n1⁄4 1), congestive cardiac failure (n1⁄4 1) and fever of unknown origin (n1⁄4 2), were observed. Seven patients relapsed (7/ 20; 35%), two of whom in central nervous system, after a median of 7 months (range 3–63) from CR achievement. Relapse was correlated neither to APL Sanz risk score (two relapses in low risk, three in intermediate risk and two in high risk patients, respectively), nor to the dose of idarubicin received during induction. After a median observation period of 49 months, 12 patients died, only five of them (41.6%) with active APL. One patient died of sepsis during consolidation chemotherapy in second CR and one of
Bruno Fattizzo, Raffaella Pasquale, Monica Carpenedo, Silvia Cantoni, Giuseppe Auteri, Doriana Gramegna, Mariella D’Adda, Mariasanta Napolitano, Dario Consonni, Marco Ruggeri,et al.
Ferrata Storti Foundation (Haematologica)
It is well established that immune thrombocytopenia (ITP) results from increased immune mediated platelet destruction (anti-platelets antibodies, autoreactive T cells, and reduction of regulatory T cells) along with impaired production in the bone marrow.[1][1] The latter has been attributed to both
C. Cattaneo, , R. Di Blasi, C. Skert, A. Candoni, B. Martino, N. Di Renzo, M. Delia, S. Ballanti, F. Marchesi,et al.
Springer Science and Business Media LLC
Giuseppe Rossi, Doriana Gramegna, Francesca Paoloni, Bruno Fattizzo, Francesca Binda, Mariella D’Adda, Mirko Farina, Elisa Lucchini, Francesca Romana Mauro, Flavia Salvi,et al.
American Society of Hematology
TO THE EDITOR:
Cold agglutinin disease (CAD) is a chronic hemolytic disorder caused by anti–red blood cell immunoglobulin M (IgM) autoantibodies most often monoclonal with k light-chain restriction.[1][1],[2][2] The autoantibody reacts at temperatures lower than the body temperature, causing