Publications by authors named "Fabio Guolo"

30 Publications

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Overall survival of myelodysplastic syndrome patients after azacitidine discontinuation and applicability of the North American MDS Consortium scoring system in clinical practice.

Cancer 2021 Mar 19. Epub 2021 Mar 19.

Fondazione Italiana Sindromi Mielodisplastiche-ETS, Bologna, Italy.

Background: Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome.

Methods: The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting.

Results: At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients.

Conclusions: Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.
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http://dx.doi.org/10.1002/cncr.33472DOI Listing
March 2021

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

Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes.

Cancers (Basel) 2020 Nov 25;12(12). Epub 2020 Nov 25.

Department of Experimental Medicine (DIMES) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, 16132 Genova, Italy.

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.
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http://dx.doi.org/10.3390/cancers12123504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760325PMC
November 2020

Full donor chimerism after allogeneic hematopoietic stem cells transplant for myelofibrosis: The role of the conditioning regimen.

Am J Hematol 2021 02 30;96(2):234-240. Epub 2020 Nov 30.

UO Ematologia e Trapianto di Midollo Osseo, IRCCS Ospedale Policlinico San Martino Genova, Genova, Italy.

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P < .001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P < .001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P = .004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival.
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http://dx.doi.org/10.1002/ajh.26042DOI Listing
February 2021

The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs.

Haematologica 2020 10 1;105(10):2420-2431. Epub 2020 Oct 1.

University of Genoa, DiMI; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia.
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http://dx.doi.org/10.3324/haematol.2019.224956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556675PMC
October 2020

CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program.

Blood Cancer J 2020 10 6;10(10):96. Epub 2020 Oct 6.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.
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http://dx.doi.org/10.1038/s41408-020-00361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538937PMC
October 2020

Amino acid depletion triggered by ʟ-asparaginase sensitizes MM cells to carfilzomib by inducing mitochondria ROS-mediated cell death.

Blood Adv 2020 09;4(18):4312-4326

Clinic of Hematology, Department of Internal Medicine, University of Genoa, Genoa, Italy.

Metabolic reprogramming is emerging as a cancer vulnerability that could be therapeutically exploitable using different approaches, including amino acid depletion for those tumors that rely on exogenous amino acids for their maintenance. ʟ-Asparaginase (ASNase) has contributed to a significant improvement in acute lymphoblastic leukemia outcomes; however, toxicity and resistance limit its clinical use in other tumors. Here, we report that, in multiple myeloma (MM) cells, the DNA methylation status is significantly associated with reduced expression of ASNase-related gene signatures, thus suggesting ASNase sensitivity for this tumor. Therefore, we tested the effects of ASNase purified from Erwinia chrysanthemi (Erw-ASNase), combined with the next-generation proteasome inhibitor (PI) carfilzomib. We observed an impressive synergistic effect on MM cells, whereas normal peripheral blood mononuclear cells were not affected. Importantly, this effect was associated with increased reactive oxygen species (ROS) generation, compounded mitochondrial damage, and Nrf2 upregulation, regardless of the c-Myc oncogenic-specific program. Furthermore, the cotreatment resulted in genomic instability and DNA repair mechanism impairment via increased mitochondrial oxidative stress, which further enhanced its antitumor activity. Interestingly, carfilzomib-resistant cells were found to be highly dependent on amino acid starvation, as reflected by their higher sensitivity to Erw-ASNase treatment compared with isogenic cells. Overall, by affecting several cellular programs, Erw-ASNase makes MM cells more vulnerable to carfilzomib, providing proof of concept for clinical use of this combination as a novel strategy to enhance PI sensitivity in MM patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509874PMC
September 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.
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http://dx.doi.org/10.1080/10428194.2020.1737685DOI Listing
July 2020

Harnessing NK Cells for Cancer Treatment.

Front Immunol 2019 6;10:2836. Epub 2019 Dec 6.

Department of Experimental Medicine, University of Genoa, Genova, Italy.

In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NK cells are innate lymphocytes with an array of functional competences, including anti-cancer, anti-viral, and anti-graft-vs.-host disease potential. The intriguing idea of harnessing such potent innate immune system effectors for cancer treatment led to the development of clinical trials based on the adoptive therapy of NK cells or on the use of monoclonal antibodies targeting the main NK cell immune checkpoints. Indeed, checkpoint immunotherapy that targets inhibitory receptors of T cells, reversing their functional blocking, marked a breakthrough in anticancer therapy, opening new approaches for cancer immunotherapy and resulted in extensive research on immune checkpoints. However, the clinical efficacy of T cell-based immunotherapy presents a series of limitations, including the inability of T cells to recognize and kill HLA-I tumor cells. For these reasons, new strategies for cancer immunotherapy are now focusing on NK cells. Blockade with NK cell checkpoint inhibitors that reverse their functional block may overcome the limitations of T cell-based immunotherapy, mainly against HLA-I tumor targets. Here, we discuss recent anti-tumor approaches based on mAb-mediated blocking of immune checkpoints (either restricted to NK cells or shared with T cells), used either as a single agent or in combination with other compounds, that have demonstrated promising clinical responses in both solid tumors and hematological malignancies.
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http://dx.doi.org/10.3389/fimmu.2019.02836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908847PMC
November 2020

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

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

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.

Haematologica 2018 01 12;103(1):80-90. Epub 2017 Oct 12.

Chair of Hematology, Department of Internal Medicine (DiMI), University of Genova, Italy

Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34 blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both and In contrast, low SIRT6 levels observed in normal CD34 hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia.
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http://dx.doi.org/10.3324/haematol.2017.176248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777193PMC
January 2018

Impact of HLA Disparity in Haploidentical Bone Marrow Transplantation Followed by High-Dose Cyclophosphamide.

Biol Blood Marrow Transplant 2018 01 9;24(1):119-126. Epub 2017 Oct 9.

U.O. Ematologia, Ospedale Policlinico San Martino, Genova, Italy.

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor-recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.002DOI Listing
January 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.
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http://dx.doi.org/10.1007/s15010-017-1010-7DOI Listing
August 2017

Intesive fludarabine-high dose cytarabine-idarubicin combination as induction therapy with risk-adapted consolidation may improve treatment efficacy in younger Acute Myeloid Leukemia (AML) patients: Rationales, evidences and future perspectives.

Biosci Trends 2017 Mar 24;11(1):110-114. Epub 2017 Jan 24.

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

Acute Myeloid Leukemia (AML) is the commonest form of leukemia in the adults, with an incidence of 3-4 cases per 100,000 people/year. After the first description of the effective cytarabine + antracycline (3+7) induction regimen, in the last 3 decades, no effective targeted drug has been included in the standard treatment of AML. Many efforts of modifying 3+7 adding a third drug or increasing the dose of anthracycline, cytarabine or both did not lead to substantial improvements, mainly due to increased toxicity. Many in vitro and in vivo evidences suggested that fludarabine may increase efficacy of cytarabine through a synergistic effect. Considering the continuous improvements in supportive care and management of infectious complications the feasibility of more intensive induction strategies have increased and a renewed interest in fludarabine-containing induction strategies arose. The recent MRC AML 15 trial has shown that a fludarabine-containing induction, FLAG-Ida, resulted superior to conventional 3+7 in terms of complete remission rates, relapse incidence and survival, although only a minority of patients could complete the whole planned consolidation program due to an excessive hematological toxicity. Our group recently published a 10-year experience with a fludarabine-containing induction that slightly differed from the MRC one and resulted in good efficacy and higher feasibility. In this commentary we review the major evidences supporting the employ of a fludarabine-containing induction in AML, and discuss the future perspectives.
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http://dx.doi.org/10.5582/bst.2016.01221DOI Listing
March 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.
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http://dx.doi.org/10.1002/ajh.24391DOI Listing
August 2016

Chronic graft versus host disease as a weapon for treating chronic myelomonocytic leukemia.

Leuk Res 2016 Apr 22;43:49-50. Epub 2016 Jan 22.

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

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http://dx.doi.org/10.1016/j.leukres.2016.01.005DOI Listing
April 2016

Combined assessment of WT1 and BAALC gene expression at diagnosis may improve leukemia-free survival prediction in patients with myelodysplastic syndromes.

Leuk Res 2015 Aug 27;39(8):866-73. Epub 2015 Apr 27.

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

Several genes with relevant pathogenetic and prognostic value have been identified in patients with myelodysplastic syndromes. Overexpression of WT1 at diagnosis has been associated with increased progression to acute myeloid leukemia and reduced leukemia free survival. Conversely, few data are available on the prognostic value of BAALC gene overexpression in AML and MDS patients. We evaluated the prognostic value of the combined expression of WT1 and BAALC genes at diagnosis in 86 MDS patients who had been stratified according to IPSS and R-IPSS scoring systems. Our results suggest that in the whole group of patients, low levels of both WT1 and BAALC were associated with a favorable outcome (3-year LFS 74.5%, median not reached), whereas patients presenting high expression levels of both genes had the worst prognosis (3-year LFS 0%, median 12 months, p<0.001). More specifically, molecular profiling was especially useful for intermediate 1 and intermediate-2/high risk groups. This study suggests that evaluating WT1 and BAALC gene expression at diagnosis may improve standard risk stratification and possibly refine the therapeutic approach for MDS patients.
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http://dx.doi.org/10.1016/j.leukres.2015.04.011DOI Listing
August 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.
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http://dx.doi.org/10.1007/s00277-014-2143-8DOI Listing
December 2014

Safety and efficacy of (90) yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study.

Br J Haematol 2014 Mar 17;164(5):710-6. Epub 2013 Dec 17.

U.O. Ematologia 1, IRCCS AOU San Martino-IST, Genova, Italy.

(90) Yttrium ((90) Y)-Ibritumomab-Tiuxetan combines the targeting advantage of a monoclonal antibody with the radiosensitivity of Follicular Lymphoma (FL). Previous studies showed that 90Y-IT is safe and effective in relapsed/refractory indolent FL, irrespective of prior treatment with rituximab. This multicentre trial aimed to evaluate the safety and the efficacy of "upfront" single-agent ((90) Y)-Ibritumomab-Tiuxetan in advanced-stage FL. The primary objective was the incidence of responses in terms of complete (CR) and partial remission (PR). Fifty patients with stage II "bulky", III or IV FL received a single treatment course with ((90) Y)-Ibritumomab-Tiuxetan as initial therapy. The median age was 60 years. Bone marrow involvement (<25%) was observed in 24 patients (48%) and 7 (14%) had an elevated lactate dehydrogenase level. The overall response (ORR) and CR rates were 94% and 86%, respectively with a median follow-up of 38·8 months. The median progression-free survival (PFS) was not reached, whereas the 3-year estimated PFS and overall survival (OS) rate was 63·4% and 90%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 30% and 26% of patients respectively; none experienced grade 3/4 non-haematological toxicity. No cases of secondary haematological malignancies were observed. ((90) Y)-Ibritumomab-Tiuxetan was demonstrated to be highly effective and safe as first-line treatment for advanced-stage FL.
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http://dx.doi.org/10.1111/bjh.12695DOI Listing
March 2014

Management of early stage chronic myeloid leukemia: state-of-the-art approach and future perspectives.

Curr Cancer Drug Targets 2013 Sep;13(7):749-54

Divisione di Ematologia 1, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, Largo Rosanna Benzi, 10 -16132 Genova, Italy.

Tyrosin kinase inhibitors (TKI), have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to an impressive increase in overall survival rates and allowing many CML patients to achieve a close-to-normal life expectancy. Unfortunately, there is growing evidence that these drugs are not curative, about 30-35% of the patients who receive imatinib become resistant or discontinue the drug because of side effects; moreover, 15% of all patients become resistant to all TKIs, a condition which represents the biggest challenge in CML treatment. Recent progresses in CML stem cell biology have identified new agents and therapeutic strategies that can be used to target the CML stem cell compartment. These studies have opened new perspectives and have highlighted key strategies for treating, and possibly curing, CML in the upcoming years.
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http://dx.doi.org/10.2174/15680096113139990087DOI Listing
September 2013

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.
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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).
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http://dx.doi.org/10.1007/s00277-013-1780-7DOI Listing
October 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.
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http://dx.doi.org/10.3109/10428194.2012.681658DOI Listing
November 2012