Publications by authors named "Filippo Ballerini"

36 Publications

Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of -ITD in Mutated AML, Irrespectively of -ITD Allelic Burden.

Cancers (Basel) 2020 Dec 24;13(1). Epub 2020 Dec 24.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, 16132 Genova, Italy.

The mutations of and -ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an mutation reduces the negative prognostic impact of -ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the and/or -ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both mut ( < 0.05) and ELN 2017 risk score ( < 0.05) were significant predictors of survival. -mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant -ITD ( = 0.372), irrespective of -ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with mut and question the role of HSCT in 1st CR in mut patients with concomitant -ITD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796342PMC
December 2020

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Italy.

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

Feasibility of Single-Port Laparoscopic Lymph Node Biopsy for Intra-Abdominal Lymphoma: A Case Series.

J Laparoendosc Adv Surg Tech A 2021 Apr 19;31(4):458-461. Epub 2020 Nov 19.

Surgical Clinic Unit I, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Genoa, Italy.

Laparoscopic lymph node biopsy through a multi-port access (MPLB) is a well-established technique for intra-abdominal lymphoma diagnosis. The aim of the current study is to assess the feasibility and the diagnostic accuracy of the single-port laparoscopic lymph node biopsy (SPLB) in intra-abdominal lymphoma. Between October 2016 and February 2019, 15 patients underwent SPLB to rule out or to follow the progression of a lymphoma. The clinical outcome and the pathology reports were analyzed retrospectively. SPLB was completed laparoscopically in all cases. The total number of biopsies performed for each procedure was sometimes multiple (median: 2; range: 1-3). Duration of surgery was 85 ± 32 minutes (range: 75-105 minutes). Length of hospitalization was 1.8 ± 0.7 days (range: 1-3 days). No major postoperative complications occurred. A cutaneous infection managed conservatively was observed in a patient. In 10 patients, SPLB was used to establish a diagnosis whereas in 5 patients it was performed to follow a progression of a lymphoproliferative disease. In 93.3% of the cases, SPLB achieved the correct diagnosis and subsequent therapeutic decisions. SPLB has shown good procedure and postoperative outcomes as well as a high diagnostic yield, comparable to literature data on traditional MPLB. Therefore, our results show that this approach is safe and effective and can be an equally valid option to MPLB to obtain a diagnosis or to follow the progression of a lymphoproliferative disease. Further studies are necessary to support these results before its widespread adoption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/lap.2020.0695DOI Listing
April 2021

Hodgkin's lymphoma: post- autologous transplantation consolidation therapy.

Acta Biomed 2020 05 25;91(S-5):23-29. Epub 2020 May 25.

Onco-Hematology Division, IEO, European Institute of Oncology, IRCCS, Milan, Italy.

A first-line chemotherapy program based on the ABVD regimen is currently considered the golden standard by most hematologists, being able to achieve a cure without any need of subsequent therapies in >70% of patients with advanced-stage Hodgkin's lymphoma (HL). To increase this percentage, efforts in recent decades focused on the development of new therapeutic strategies. A first major effort was the introduction of the BEACOPP chemotherapy regimen, which is able to increase the response rate and to reduce the need of salvage therapies. However, this result did not demonstrate an advantage in terms of overall survival compared to ABVD, mainly due to an excess of non lymphoma-related events in the follow-up phase. Here we describe three clinical cases of young HL patients who had relapsed/refractory disease after the induction chemotherapy. These three clinical cases provide practical and real world evidence in favor of the use of BV in monotherapy as consolidation treatment after autologous stem cells transplantation in patients with relapsed/refractory HL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23750/abm.v91iS-5.9914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944651PMC
May 2020

Prognostic relevance of a blastic plasmacytoid dendritic cell neoplasm-like immunophenotype in cytogenetically normal acute myeloid leukemia patients.

Leuk Lymphoma 2020 07 18;61(7):1695-1701. Epub 2020 Mar 18.

Department of Oncology and Hematology, Ospedale Policlinico San Martino, Genoa, Italy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a poor prognosis myeloid malignancy characterized by an atypical phenotype (CD123+, CD56+, and CD4+). We reported that BPDCN-like phenotype (CD123+ and either CD56+ or CD4+ or both) confers poor prognosis to acute myeloblastic leukemia (AML) patients with mutated NPM1. Here, we evaluated the incidence and the prognostic relevance of BPDCN-like phenotype in cytogenetically normal AML (CN-AML) patients. From 2006 to 2016, 83 young (age <60 yrs), consecutive, CN-AML patients underwent intensive treatment. Fifteen patients (18%) showed a BPDCN-like phenotype with no difference between -mutated (mut) and -wt patients. It did not significantly affect survival neither in the whole cohort, nor in -wt patients. However, as reported, it conferred a dismal prognosis in -mut AML ( < 0.001), irrespectively of the mutational status for FLT3-ITD. In conclusion we show that BPDCN-like phenotype displays a negative prognostic relevance only in -mutated AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1737685DOI Listing
July 2020

Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes.

JCO Clin Cancer Inform 2019 10;3:1-15

Division of Hematology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.

Purpose: Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points.

Methods: Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact.

Results: The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index.

Conclusion: The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/CCI.19.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873907PMC
October 2019

A simple cytofluorimetric score may optimize testing for biallelic CEBPA mutations in patients with acute myeloid leukemia.

Leuk Res 2019 11 6;86:106223. Epub 2019 Sep 6.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; S. Martino Hospital IRCCS, Genoa, Italy.

Acute myeloid leukemia with biallelic mutation of CEBPA (CEBPA-dm AML) is a distinct good prognosis entity recognized by WHO 2016 classification. However, testing for CEBPA mutation is challenging, due to the intrinsic characteristics of the mutation itself. Indeed, molecular analysis cannot be performed with NGS technique and requires Sanger sequencing. The association of recurrent mutations or translocations with specific immunophenotypic patterns has been already reported in other AML subtypes. The aim of this study was the development of a specific cytofluorimetric score (CEBPA-dm score), in order to distinguish patients who are unlikely to harbor the mutation. To this end, the correlation of CEBPA-dm score with the presence of the mutation was analyzed in 50 consecutive AML patients with normal karyotype and without NPM1 mutation (that is mutually exclusive with CEBPA mutation). One point each was assigned for expression of HLA DR, CD7, CD13, CD15, CD33, CD34 and one point for lack of expression of CD14. OS was not influenced by sex, age and CEBPA-dm score. Multivariate OS analysis showed that CEBPA-dm (p < 0.02) and FLT3-ITD (p < 0.01) were the strongest independent predictors of OS. With a high negative predictive value (100%), CEBPA-dm score < 6 was able to identify patients who are unlikely to have the mutation. Therefore, the application of this simple score might optimize the use of expensive and time-consuming diagnostic and prognostic assessment in the baseline work up of AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2019.106223DOI Listing
November 2019

Dexamethasone, oxaliplatin and cytarabine (R-DHAOx) as salvage and stem cells mobilizing therapy in relapsed/refractory diffuse large B cell lymphomas.

Leuk Lymphoma 2020 01 4;61(1):84-90. Epub 2019 Sep 4.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.

Cisplatin-containing salvage regimens followed by autologous hematopoietic stem cell (HSC) transplantation are the current standard of care for relapsed or refractory (R/R) lymphomas. We retrospectively analyzed efficacy and stem cell mobilizing activity of oxaliplatin, cytarabine, dexamethasone and rituximab (R-DHAOx) in 53 R/R diffuse large B cell lymphomas (DLBCL) treated in our center (median lines 2, range 2-5; median age 59, range 22-79). Hematological toxicity was manageable and no patients experienced renal impairment. After 2 courses the overall response rate was 60% (CR 49%, PR 11%). Median overall survival (OS) was 30.53 months (95% CI 11.5-49.55), 3-year OS 40.5%. Twenty-two eligible patients collected HSC and transplantation was performed in 21/22 patients (95%), after a median of 52 days from last cycle. Our results suggest that in DLBCL R-DHAOx has an excellent stem cell mobilizing capability, response rate comparable to cisplatin-containing regimens and good toxicity profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2019.1658102DOI Listing
January 2020

Performance of serum (1,3)-ß-d-glucan screening for the diagnosis of invasive aspergillosis in neutropenic patients with haematological malignancies.

Mycoses 2018 Sep 13;61(9):650-655. Epub 2018 Jun 13.

Infectious Diseases Unit, Department Health Sciences (DISSAL), Ospedale Policlinico San Martino - IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.

We report our experience with the use of (1,3)-ß-d-glucan (BDG) screening for the diagnosis of invasive aspergillosis (IA) in neutropenic patients with haematological malignancies. The performance of BDG screening was assessed retrospectively in per patient and per sample analyses. Overall, 20 among 167 patients developed IA (12%). In the per patient analysis, BDG showed 60% sensitivity and 78% specificity when the criterion for positivity was the presence of at least one BDG value ≥80 pg/mL. For 2 consecutive positive results, sensitivity decreased to 40%, while specificity increased to 93% and was similar to that of a positive galactomannan (GM; 90%). The highest specificity (97%) was observed for combined positivity of at least one BDG and at least one GM. In the per sample analysis, the specificity of BDG was 100% in the best scenario, 96% in the median scenario and 89% in the worst scenario. BDG became positive before GM in 33% of IA patients with both markers positive (n = 12). Despite good specificity for 2 consecutive positive results, the BDG test offered unsatisfactory performance for the diagnosis of IA due to low sensitivity. The combination of BDG and GM showed the potential for increasing specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/myc.12787DOI Listing
September 2018

Lenalidomide in Pretreated Mantle Cell Lymphoma Patients: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice (the Lenamant Study).

Oncologist 2018 09 19;23(9):1033-1038. Epub 2018 Apr 19.

Institute of Hematology, University of Bologna, Bologna, Italy

Background: Mantle cell lymphoma (MCL) has the worst prognosis of B-cell subtypes owing to its aggressive clinical disease course and incurability with standard chemo-immunotherapy. Options for relapsed MCL are limited, although several single agents have been studied. Lenalidomide is available in Italy for patients with MCL based on a local disposition of the Italian Drug Agency.

Subjects, Materials, And Methods: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use in real practice.

Results: Seventy patients received lenalidomide for 21/28 days with a median of eight cycles. At the end of therapy, there were 22 complete responses (31.4%), 11 partial responses, 6 stable diseases, and 31 progressions, with an overall response rate of 47.1%. Eighteen patients (22.9%) received lenalidomide in combination with either dexamethasone ( = 13) or rituximab ( = 5). Median overall survival (OS) was reached at 33 months and median disease-free survival (DFS) at 20 months: 14/22 patients are in continuous complete response with a median of 26 months. Patients who received lenalidomide alone were compared with patients who received lenalidomide in combination: OS and DFS did not differ. Progression-free survivals are significantly different: at 56 months, 36% in the combination group versus 13% in patients who received lenalidomide alone. Toxicities were manageable, even if 17 of them led to an early drug discontinuation.

Conclusion: Lenalidomide therapy for relapsed MCL patients is effective and tolerable even in a real-life context.

Implication For Practice: Several factors influence treatment choice in relapsed/refractory mantle cell lymphoma (rrMCL), and the therapeutic scenario is continuously evolving. In fact, rrMCL became the first lymphoma for which four novel agents have been approved: temsirolimus, lenalidomide, ibrutinib, and bortezomib. The rrMCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for rrMCL patients is effective and tolerable even in a real-life context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2017-0597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192660PMC
September 2018

A blastic plasmacytoid dendritic cell neoplasm-like phenotype identifies a subgroup of npm1-mutated acute myeloid leukemia patients with worse prognosis.

Am J Hematol 2018 Feb 17;93(2):E33-E35. Epub 2017 Nov 17.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Policlinico San Martino, IRCCS per l'Oncologia, Genoa, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.24956DOI Listing
February 2018

Good tolerability of high dose colistin-based therapy in patients with haematological malignancies.

Infection 2017 Aug 28;45(4):505-511. Epub 2017 Mar 28.

Division of Infectious Diseases, Department of Health Sciences (DISSAL), IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy.

Purpose: Colistin is usually the only drug fully active against multi-drug resistant Gram-negative bacteria, but its nephrotoxicity might limit its use. Recent pharmacokinetic/pharmacodynamic data suggest that high dose of colistin, preceded by a loading dose, are needed to maximize its antibacterial effect. The aim of this study was to determine the safety of high doses colistin, in haematology population.

Methods: A retrospective review of haematology patients who received high dose colistin-based therapy in years 2011-2016 was performed. Nephrotoxicity was assessed using RIFLE criteria.

Results: Thirty patients who received 38 courses of colistin were included in the study. Colistin was always administered together with other antibiotics. Colistin was well tolerated, with one case of neurological toxicity and one of cutaneous reaction. There were 22 (58%) treatment cycles without any nephrotoxicity, even though during 16 of these cycles other nephrotoxic drugs were administered. Severe (injury or failure) renal toxicity occurred during 6 (16%) treatment courses, requiring colistin discontinuation in 2 patients and colistin dose reduction in 1. Poorer renal function at baseline and younger age were the only variables associated with increased renal toxicity (p = 0.011 and p = 0.031, respectively). Overall mortality was 18% (7/38) and 29% (11/38) at 7 and 30 days after the treatment onset.

Conclusions: In adult haematology population, high dose colistin therapy is safe and efficacious, despite high frequency of concomitant nephrotoxic treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s15010-017-1010-7DOI Listing
August 2017

High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk-oriented consolidation: A critical review of a 10-year, single-center experience in younger, non M3 AML patients.

Am J Hematol 2016 08 15;91(8):755-62. Epub 2016 Jun 15.

Hematology Clinic, Department of Internal Medicine (DiMI), University of Genoa, IRCCS AOU S. Martino-IST, Genoa, Italy.

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.24391DOI Listing
August 2016

Mechanisms and Clinical Applications of Genome Instability in Multiple Myeloma.

Biomed Res Int 2015 22;2015:943096. Epub 2015 Oct 22.

Hematology Unit, Department of Internal Medicine (DiMI), University of Genoa, IRCCS AOU San Martino-IST, 1600 Genoa, Italy.

Ongoing genomic instability represents a hallmark of multiple myeloma (MM) cells, which manifests largely as whole chromosome- or translocation-based aneuploidy. Importantly, although it supports tumorigenesis, progression and, response to treatment in MM patients, it remains one of the least understood components of malignant transformation in terms of molecular basis. Therefore these aspects make the comprehension of genomic instability a pioneering strategy for novel therapeutic and clinical speculations to use in the management of MM patients. Here we will review mechanisms mediating genomic instability in MM cells with an emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair, telomere function and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the mechanisms by which genetic aberrations give rise to multiple pathogenic events required for myelomagenesis and conclude with a discussion of the clinical applications of these findings in MM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/943096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633548PMC
August 2016

IL-1β-releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors.

Haematologica 2015 Feb 24;100(2):e42-5. Epub 2014 Oct 24.

IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genova Dipartimento Medicina Sperimentale (DIMES) Università degli Studi di Genova.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2014.110494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803123PMC
February 2015

Liposomal daunorubicin, fludarabine, and cytarabine (FLAD) as bridge therapy to stem cell transplant in relapsed and refractory acute leukemia.

Ann Hematol 2014 Dec 4;93(12):2011-8. Epub 2014 Jul 4.

Division of Clinical Hematology and Division of Hematology and Hematopoietic Stem Cell Transplantation, IRCCS S Martino-IST, Viale Benedetto XV, N 6, 16132, Genova, Italy.

Therapeutic options for patients with relapsed or refractory acute leukemia are still undefined and often unsatisfactory. We report the outcome of 79 patients with relapsed-refractory acute leukemia treated with fludarabine, cytarabine, and liposomal daunorubicin (FLAD regimen) followed by hematopoietic stem cell transplantation (HSCT), when clinically indicated, between May 2000 and January 2013. Forty-one patients had acute myeloid leukemia (AML), and 38 had acute lymphoblastic leukemia (ALL). Two patients with myeloid blast crises of CML and three with lymphoid blast crises were included in the AML and ALL subgroups, respectively. Median age was 48 years (range 13-77). FLAD was well tolerated with negligible, nonhematological toxicity. Six patients (7.5 %) died before response evaluation. Forty-seven patients achieved hematologic complete response (CR). Complete remission rate was 53 and 65 % among AML and ALL patients, respectively. No CR was recorded among 11 refractory AML patients. Twenty-four patients (30 %) underwent HSCT. Nine patients received stem cells from an HLA identical sibling, and 15 from an alternative donor (3 unrelated matched, 12 haploidentical sibling). Median overall survival in AML and ALL patients receiving FLAD therapy was 9 and 8 months, respectively. A 5-year projected OS for patients receiving the whole program (FLAD + HSCT) was 24 % for AML patients (median survival 43 months), 28 % for ALL patients treated in relapse (median survival 15 months), and 0 % for ALL patients treated for refractory disease. In this paper, we show that FLAD seems to be an effective bridge therapy to HSCT for a part of poor prognosis acute leukemia patients. However, prospective studies are needed to confirm our results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-014-2143-8DOI Listing
December 2014

Integrating post induction WT1 quantification and flow-cytometry results improves minimal residual disease stratification in acute myeloid leukemia.

Leuk Res 2013 Dec 23;37(12):1606-11. Epub 2013 Jul 23.

Department of Hematology and Oncology, IRCCS AOU S.Martino-IST, Genova, Italy. Electronic address:

Fifty uniformly treated adult AML patients were analyzed with respect to pre-treatment and post-induction risk factors. Forty-two patients achieving complete hematological remission were assessed for minimal residual disease (MRD) by WT1 gene expression; 34 by flow-cytometry (flow-MRD). Patients who were flow-MRD negative had a better 3-year disease-free (DFS; 79.5% vs. 27.3%; p=.032) compared with patients who were still positive after induction. Interestingly, DFS of flow-MRD positive patients was not related to the amount of flow-detected clone population (≥ or <1%, p=.41) but to WT1 reduction (ΔWT1, 3-year DFS; 46.2% vs. 0% if ΔWT1 was ≥ or < of 1.5 log, p=.001). In AML, combining MRD results provided by WT1 quantification and flow-cytometry improves the reliability of MRD-based prognostic stratification. Similar analyses by further larger studies should be advocated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2013.07.005DOI Listing
December 2013

De novo AML patients with favourable-intermediate karyotype may benefit from the addition of low-dose gemtuzumab ozogamicin (GO) to fludarabine, Ara-C and idarubicin (FLAI): a contribution to the reopened "GO question".

Ann Hematol 2013 Oct 18;92(10):1309-18. Epub 2013 May 18.

Clinical Hematology, IRCCS AOU S. Martino-IST, Genoa, Italy.

We report the final results of a prospective trial testing the combination of fludarabine, Ara-C and idarubicin (FLAI) followed by low-dose gemtuzumab ozogamicin (FLAI-GO) in 85 patients aged 60 years or more with CD33+ acute myeloid leukaemia (AML). Median age was 68 years (60-82); karyotype was unfavourable in 21 patients (24%), intermediate in 63 (74%) and favourable in 1 (2%). There were five therapy-related deaths. Of the 80 evaluable patients, 47 achieved complete response (CR) (58%); CR rates were 65 and 32% in good-intermediate/poor karyotype patients, respectively. Median length of CR was 7 months (3-76). The cumulative incidence of relapse was 84% with an actuarial survival of 50.3% at 1 year and 14.4% at 2 years. The study control population is an unselected consecutive historic cohort of 104 patients treated with the FLAI regimen, who were matched for age and prognostic factors. CR rates after FLAI-GO and FLAI were comparable. However, patients with de novo AML and intermediate-favourable karyotype receiving GO had a significantly lower risk of relapse at 2 years as compared to patients not receiving GO (n = 77) (40 vs 80%, p = 0.01) and significantly better disease-free survival (p = 0.018) and overall survival (p = 0.022).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-013-1780-7DOI Listing
October 2013

Bortezomib as salvage treatment for heavily pretreated relapsed lymphoma patients: a multicenter retrospective study.

Hematol Oncol 2013 Dec 29;31(4):179-82. Epub 2012 Oct 29.

Department of Hematology and Oncology 'L. and A. Seràgnoli', S. Orsola-Malpighi Hospital, University of Bologna, Italy.

Current treatments for non-Hodgkin lymphomas are not optimally effective. Among new agents, bortezomib seems to play a pivotal role in the regulation of several cell pathways involved in the development of lymphomas. After results were obtained with clinical trials, we aimed to observe treatment with bortezomib in everyday clinical practice. We performed a multicenter retrospective analysis to assess the efficacy of bortezomib in heavily pretreated (median number of previous therapies 4, range 2-6) lymphoma patients in an off-label setting. Bortezomib therapy was scheduled for 4-6 cycles (1.3 mg/m(2) biweekly). Data from 50 patients were collected: 22% had a complete remission, 26% obtained a partial response and the remaining 52% was non-responder. According to histotype, we observed an overall response rate (ORR) of 51.6% in mantle cell lymphomas, an ORR of 60% among follicular lymphoma patients, and an ORR of 50% in the indolent nonfollicular lymphomas. None of diffuse large B-cell lymphoma patients obtained a response. Extra-hematological toxicity was really mild, and peripheral neuropathy occurred in only 5 patients; hematological toxicity was grades 3-4 thrombocytopenia in nine patients and grades 3-4 neutropenia in only three patients. In conclusion, treatment with bortezomib as single agent resulted safe and effective in a subset of heavily pretreated lymphoma patients with usually poor outcome. New future hypotheses of investigation are indicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2036DOI Listing
December 2013

Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning.

Biol Blood Marrow Transplant 2013 Jan 29;19(1):117-22. Epub 2012 Aug 29.

Divisione Ematologia e Trapianto di Midollo, IRCCS San Martino, Genova, Italy.

Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18-66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2012.08.014DOI Listing
January 2013

Nucleophosmin gene-based monitoring in de novo cytogenetically normal acute myeloid leukemia with nucleophosmin gene mutations: comparison with cytofluorimetric analysis and study of Wilms tumor gene 1 expression.

Leuk Lymphoma 2012 Nov 21;53(11):2214-7. Epub 2012 May 21.

Department of Hematology and Oncology , IRCCS Azienda Ospedaliera Universitaria S. Martino-IST, Genova, Italy.

We compared the clinical value of minimal residual disease (MRD) monitoring by cytofluorimetric methods, Wilms tumor gene 1 (WT1) expression and the study of nucleophosmin gene (NPM) mutations in a series of 26 patients with NPM-mutated de novo acute myeloid leukemia (NPM-AML) who achieved complete hematological remission after conventional chemotherapy. The relapse risk was significantly lower only in patients achieving a NPM molecular complete response (NPM mol-CR) and confirmed NPM mol-CR (non-detectable NPM mutations in two consecutive marrow samples). The disease-free survival (DFS) of patients achieving a < 4-log or ≥ 4-log reduction in NPM value after induction therapy was 12.6 % and 50%, respectively, at 36 months (p = 0.009). The attainment of a confirmed NPM-CR had a significant influence on overall survival (OS at 36 months was 64.3% and 11.9% in patients obtaining or not obtaining confirmed NPM-CR, respectively, p < 0.03). We confirm that NPM-molecular relapse (NPM-rel) is always followed by hematological relapse (H-rel), but longitudinal studies of NPM mutations may predict an impending H-rel earlier than flow cytometric- or WT1-based methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2012.681658DOI Listing
November 2012

WT1 overexpression at diagnosis may predict favorable outcome in patients with de novo non-M3 acute myeloid leukemia.

Leuk Lymphoma 2011 Oct;52(10):1961-9

Department of Hematology and Oncology, Azienda Ospedaliera Universitaria San Martino, Genova, Italy.

We reviewed the frequency and prognostic significance of FLT3 (fms-like tyrosine kinase receptor-3) and NPM (nucleophosmin) gene mutations and WT1 (Wilms' tumor) and BAALC (brain and acute leukemia, cytoplasmic) gene expression in 100 consecutive patients with intermediate and poor cytogenetic risk de novo acute myeloid leukemia (AML) receiving conventional anthracycline-AraC based therapy. We observed a strict relationship between unfavorable karyotype and BAALC >1000 (p = 0.0001). Multivariate analysis of 81 patients with intermediate karyotype revealed that younger age (p = 0.00009), NPM gene mutation (p = 0.002), and WT1 >75th percentile (>2365) (p = 0.003) were independent, positive factors for complete remission (CR). WT1 expression above 2365 was correlated also to longer event-free survival (EFS) and overall survival (OS) in the same subset of patients (p = 0.003 and p = 0.02, respectively); the same finding occurred in younger patients with AML with intermediate karyotype (p = 0.008 and p = 0.01, respectively). In patients with intermediate karyotype, FLT3 internal tandem duplication (ITD) negatively affected EFS (EFS at 30 months: 30% vs. 6% in FLT3-ITD negative and FLT3 positive patients, respectively; p = 0.01) and OS (OS at 30 months: 38% vs. 20%, p = 0.03). The positive prognostic value of high WT1 expression does not have a clear explanation; it may be implicated either with WT1 anti-oncogenic function, or with the stimulating effect of WT1 oncogene on the leukemic cellular cycle, possibly associated with an enhanced response to chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2011.585673DOI Listing
October 2011

Amphotericin B lipid complex in the management of invasive fungal infections in immunocompromised patients.

Clin Drug Investig 2011 Nov;31(11):745-58

Infectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, Italy.

Invasive fungal infections are associated with a poor outcome and their incidence is rising. Amphotericin B has for a long time been the gold standard for treatment of these infections, but the conventional formulation is associated with a high incidence of adverse events. Lipid formulations of amphotericin, developed to overcome these drawbacks, are now routinely used in clinical practice for the treatment of invasive fungal infections in immunocompromised patients. Amphotericin B lipid complex (ABLC) is prepared from amphotericin complexed to two phospholipids, a process that confers a number of important pharmacodynamic and pharmacokinetic properties compared with conventional amphotericin B. The results of retrospective observational studies and the analysis of databases, including the large Collaborative Exchange of Antifungal Research (CLEAR) database, have shown ABLC to be associated with response rates of up to about 80% in patients with confirmed fungal infections and around 60% in those treated empirically. Intranasal administration of ABLC for prophylaxis of invasive fungal infection in immunocompromised patients is safe and appears to be a promising treatment strategy for the future. ABLC is associated with a substantially lower incidence of nephrotoxicity than conventional amphotericin. Infusion-related reactions also occur less frequently than with conventional amphotericin and can be managed using premedication protocols. When direct and indirect costs are measured, ABLC appears to be less expensive than conventional amphotericin. The number of approved antifungal agents that are effective treatments for invasive fungal infections is increasing. However, lipid formulations of amphotericin, such as ABLC, are effective and well tolerated and remain the standard of care in the treatment of invasive fungal infections. Treatment strategies such as intranasal administration for prophylaxis and combination therapy with newer agents are future directions for these agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2165/11593760-000000000-00000DOI Listing
November 2011

Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.

J Clin Oncol 2009 Oct 31;27(30):5001-7. Epub 2009 Aug 31.

Dipartimento di Ematologia e Scienze Oncologiche Seràgnoli, Istituto di Ematologia Seràgnoli, Università di Bologna, Bologna, Italy.

Purpose: To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM).

Patients And Methods: One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide.

Results: On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events.

Conclusion: In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2009.22.7389DOI Listing
October 2009

The addition of radiotherapy to chemotherapy does not improve outcome of early stage Hodgkin's lymphoma patients: a retrospective long-term follow-up analysis of a regional Italian experience.

Ann Hematol 2009 Sep 3;88(9):855-61. Epub 2009 Feb 3.

Department of Haematology and Oncology, University of Genova, San Martino Hospital, Viale Benedetto XV, N 6, Genova, Italy.

We retrospectively reviewed 139 stage I-II HL patients who were diagnosed and followed up in an Italian northern region (Liguria) from 1995 to 2007, and who received either chemotherapy (CT) alone (mainly doxorubicin, bleomycin, vinblastine, and dacarbazine; ABVD) or a combined modality treatment (chemotherapy + radiotherapy, CT + RT). The two therapeutic groups were comparable for clinical and histologic features. Complete remission rate after CT + RT was higher than what was achieved with CT alone (96% vs. 84%, respectively, p = 0.03). Relapse rate (12%) was the same in both groups and disease-free survival curves were comparable (82% and 83%, p = 0.47). The overall survival of the two therapeutic groups is comparable. No second tumors have been reported among patients receiving chemotherapy alone, whereas a second neoplasia has been diagnosed in four patients (in two cases possibly radiotherapy related) in the CT + RT group (5%, p = 0.09) In conclusion, our retrospective study shows that CT + limited RT is an effective and well-tolerated option for early stage Hodgkin's lymphoma, even if the use of RT is associated with a certain risk of developing a second tumor. However, four to six courses of ABVD can lead to similar, optimal, long-term disease control without exposing patients to the risk of a second neoplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-009-0699-5DOI Listing
September 2009

Molecular analysis of the Imatinib-induced complete cytogenetic response in chronic myelogenous leukemia.

Leuk Lymphoma 2006 Jul;47(7):1348-51

Department of Haematology and Oncology, Azienda Ospedale S.Martino e Cliniche Universitarie Convenzionate, Genova, Italy.

The aim of this study was to elucidate the relationship between clonal and normal haematopoiesis in chronic myelogenous leukemia (CML). Thirteen female patients who reached complete cytogenetic response (CCR) after Imatinib treatment were studied. Although all the study patients exhibited a polyclonal pattern of X inactivation, p210 BCR/ABL transcript remained detectable in all cases by nested RT-PCR. This study also demonstrated the presence of p190 transcript in nine out of 13 study patients. A longer follow-up analysis is needed to clarify the prognostic value of these results. The recent observation that clonal cytogenetic abnormalities may occur in CML patients in polyclonal remission after imatinib suggests that a neoplastic stem cell lacking BCR/ABL rearrangement may acquire further cytogenetic alterations other than Philadelphia chromosome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428190500525607DOI Listing
July 2006