Publications by authors named "Roberto Massimo Lemoli"

28 Publications

  • Page 1 of 1

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

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

J Laparoendosc Adv Surg Tech A 2020 Nov 19. 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.
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http://dx.doi.org/10.1089/lap.2020.0695DOI Listing
November 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

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

Effects of different doses of erythropoietin in patients with myelodysplastic syndromes: A propensity score-matched analysis.

Cancer Med 2019 12 27;8(18):7567-7576. Epub 2019 Oct 27.

Fondazione Italiana Sindromi Mielodisplastiche (FISM), Bologna, Italy.

Background: Erythropoiesis-stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower "standard doses" (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking.

Methods: A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score-matched analysis to evaluate hematological improvement-erythroid (HI-E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated.

Results: Overall HI-E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion-dependent patients and patients with higher IPSS-R score obtained a higher HI-E rate with HD, although without significant impact on overall survival (OS). Achievement of HI-E resulted in superior OS. At univariate analysis, a higher HI-E rate was observed in transfusion-independent patients (P < .001), with a lower IPSS-R score (P < .001) and lower serum EPO levels (P = .027). Multivariate analysis confirmed that rhEPO doses were not significantly related to HI-E (P = .26). There was no significant difference in OS or progression to leukemia in patients treated with HD vs SD.

Conclusion: SD are substantially equally effective to HD to improve anemia and influencing survival in MDS patients stratified according to similar propensity to be exposed to rhEPO treatment.
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http://dx.doi.org/10.1002/cam4.2638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912022PMC
December 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.
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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

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function.

J Transl Med 2019 08 5;17(1):250. Epub 2019 Aug 5.

Azienda Ospedaliero-Universitaria di Bologna S. Orsola-Malpighi, Bologna, Italy.

Background: Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation.

Methods: We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD.

Results: Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD.

Conclusions: These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation.
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http://dx.doi.org/10.1186/s12967-019-2004-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683529PMC
August 2019

Haploidentical Transplants with Post-Transplant Cyclophosphamide for Relapsed or Refractory Hodgkin Lymphoma: The Role of Comorbidity Index and Pretransplant Positron Emission Tomography.

Biol Blood Marrow Transplant 2018 12 21;24(12):2501-2508. Epub 2018 Jul 21.

Division of Haematology and Bone Marrow Transplantation, Policlinico San Martino, IRCCS Ospedale Policlinico San Martino, Genoa, Italy per l'Oncologia, Genoa, Italy.

Disease relapse remains an unmet medical need for patients with Hodgkin lymphoma (HL) receiving an allogeneic hematopoietic cell transplantation (HCT). With the aim of identifying patients at high risk for post-transplant relapse, we retrospectively reviewed 41 HL patients who had received haploidentical (haplo) nonmyeloablative (NMA) HCT with high dose post-transplant cyclophosphamide (PT-Cy) for graft-versus-host (GVHD) prophylaxis. Primary refractory disease, relapse within 6 months from autologous stem cell transplantation, age, pretransplant chemotherapy, HCT comorbidity index (HCT-CI), sex mismatch, tumor burden and pretransplant fluorodeoxyglucose positron emission tomography (FDG-PET) status, assessed by Deauville score, were analyzed as variables influencing outcomes. All but 1 patient engrafted: median time to neutrophil and platelet recovery was 15 (interquartile range, 13 to 23) days and 19 (interquartile range, 12 to 28) days, respectively. Cumulative incidence of severe (grade III to IV) acute graft-versus-host disease (GVHD) and 3-year moderate-severe chronic GVHD was 2.4% and 11.8%, respectively. The 3-year overall (OS), progression free (PFS), and graft relapse-free survival (GRFS) were 75.6%, 43.9%, and 39%, respectively. On multivariate analysis, 3-year OS was significantly worse in patients with HCT-CI ≥3 (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1 to 21.8; P = .03). Three-year relapse rate, 3-year PFS, and 3-year GRFS were significantly worse in patients with HCT-CI ≥3 (HR, 3.5; 95% CI, 1.3 to 9.3; P = .01; HR, 3.3; 95% CI, 1.2 to 9.0; P = .02; and HR, 4.2; 95% CI, 1.7 to 9.9; P = .001, respectively) and in patients with a Deauville score ≥4 on pretransplant FDG-PET (HR, 4.4; 95% CI, 1.6-12.4; P = .005, HR, 3.8; 95% CI, 1.5 to 9.7; P = .005; and 3.2; 95% CI, 1.3 to 7.9; P = .01, respectively). On univariate analysis, 3-year NRM was significantly worse only in patients with a HCT-CI ≥3 (HR, 17.6; 95% CI, 1.4 to 221.0). Among relapsed or refractory HL patients undergoing haplo NMA HCT with PT-Cy, pretransplant FDG-PET with a Deauville score ≥4 and HCT-CI ≥3 identified patients at high risk of relapse. Moreover, an HCT-CI ≥3 was associated with higher NRM and lower OS.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.025DOI Listing
December 2018

Differential proteomic profile of leukemic CD34+ progenitor cells from chronic myeloid leukemia patients.

Oncotarget 2018 Apr 24;9(31):21758-21769. Epub 2018 Apr 24.

Hematology Unit, Sant'Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML. Our results showed that CP-CML CD34+ progenitors were characterized by significant lower phosphorylation of proteins involved in the regulation of growth and cell survival, such as tyrosine kinases of the Src family and members of STAT family, and by a significant higher phosphorylation of p53 (Ser15), compared to normal CD34+ cells from healthy donors. Consistent with these results, cell cycle analysis demonstrated that CP-CML CD34+ cells were characterized by higher percentage of cells in G0-phase compared to normal CD34+ cells. Analysis of expression profile on proteins involved in the apoptotic machinery revealed that, in addition, CD34+ cells from CP-CML were characterized by a significant lower expression of catalase and higher expression of HSP27 and FADD. In sum, we report that CD34+ cells from CP-CML are characterized by a proteomic and phospho-proteomic profile that promotes quiescence through the inhibition of proliferation and the promotion of survival. This differential signaling activation network may be addressed by novel targeted therapies aimed at eradicating CML stem cells.
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http://dx.doi.org/10.18632/oncotarget.24938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955129PMC
April 2018

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis.

Oncotarget 2017 Oct 27;8(45):79073-79086. Epub 2017 Jun 27.

Division of Cellular Biotechnologies and Hematology, University Sapienza, Roma, Italy.

In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (=0.024), large splenomegaly (=0.017), transfusion dependency (=0.022), platelet count <200×10/l (=0.028), and a time-interval between MF diagnosis and RUX start >2 years (=0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.
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http://dx.doi.org/10.18632/oncotarget.18674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668021PMC
October 2017

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

Molecular and functional characterization of CD133 stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells.

Cytotherapy 2017 12 14;19(12):1447-1461. Epub 2017 Sep 14.

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

Background Aims: Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133 stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated.

Methods: Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133 cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133and LX-2 hepatic stellate cells.

Results: We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133 SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133 SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile.

Discussion: We demonstrated that the interaction between CD133 SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy.
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http://dx.doi.org/10.1016/j.jcyt.2017.08.001DOI Listing
December 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

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

Very low rate of readmission after an early discharge outpatient model for autografting in multiple myeloma patients: an Italian multicenter retrospective study.

Biol Blood Marrow Transplant 2014 Jul 31;20(7):1026-32. Epub 2014 Mar 31.

Clinica di Ematologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.

We analyzed the main modalities and clinical outcomes of the early discharge outpatient model in autologous stem cell transplantation (EDOM-ASCT) for multiple myeloma in Italy. EDOM-ASCT was employed in 382 patients, for a total of 522 procedures, between 1998 and 2012. Our study showed high homogeneity among centers in terms of inclusion criteria, supportive care, and in hospital readmission criteria. Overall, readmissions during the aplastic phase occurred in 98 of 522 transplantations (18.8%). The major extrahematological complication was neutropenic fever in 161 cases (30.8%), which required readmission in 76 cases. The incidence of severe World Health Organization grade 3 to 4 mucositis was 9.6%. By univariate analysis, fever, mucositis, altered renal function at diagnosis, second transplantation, and transplantation performed late in the course of the disease were significantly correlated with readmission, whereas fever, mucositis, altered renal function, and timing of transplantation remained the only independent predictors by multivariate analysis. Overall, transplantation-related mortality was 1.0%. No center effect was observed in this study (P = .36). The safety and low rate of readmission of the EDOM-ASCT in myeloma trial suggest that this strategy could be extended to other transplantation centers if a stringent patient selection and appropriate management are applied.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.027DOI Listing
July 2014

Decreased expression of indoleamine 2,3-dioxygenase 1 in dendritic cells contributes to impaired regulatory T cell development in immune thrombocytopenia.

Ann Hematol 2013 Jan 31;92(1):67-78. Epub 2012 Aug 31.

Institute of Hematology, Department of Hematology and Oncological Sciences L. e A. Seràgnoli, University of Bologna, Bologna, Italy.

Along with their immunogenic role, dendritic cells (DCs) are also critical in maintaining tolerance to self-antigens by inducing regulatory T cells (Tregs) via the expression of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In turn, Tregs modulate the maturation and/or function of DCs. In immune thrombocytopenia (ITP), the interaction between DCs and Tregs has never been investigated although decreased number/function of Tregs as well as altered DCs have been described. Here, we ask whether, in ITP: (1) IDO1 expression/activity is decreased in mature DCs; (2) IDO1-mediated Treg generation is impaired; and (3) DC maturation is abnormally modulated by Tregs. We found that in ITP, DCs show reduced capability of upregulating the expression/activity of IDO1. This finding results in the reduced ability of mature DCs of converting T cells into Tregs. In turn, Tregs are characterized by decreased interleukin-10 production and show lower ability of inhibiting DC maturation. In conclusion, these data point out the role of IDO1 in the impaired regulatory T cell development of ITP patients and suggest that the cross-talk between Tregs and DCs is hampered and plays a pathogenetic role.
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http://dx.doi.org/10.1007/s00277-012-1556-5DOI Listing
January 2013

Autologous stem cell transplantation for acute myeloid leukemia patients in first complete remission: a 10-year follow-up study of 118 patients.

Haematologica 2005 Jan;90(1):139-41

We assessed the impact of unpurged autologous stem cell transplantation (ASCT) on long-term outcome of 118 patients with acute myeloid leukemia (AML) in first complete remission (CR1). With a median follow-up of 95 months, the 10-year overall survival, disease-free survival and relapse risk are, respectively, 54%, 50% and 46%. De novo AML, the presence of a favorable karyotype and intensification of treatment prior to ASCT are independently associated with clinical outcome by multivariate analysis. Thus, a remarkable proportion of AML patients in CR1 can be cured with high-dose therapy and ASCT.
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January 2005

High-dose therapy with autologous transplantation for aggressive non-Hodgkin's lymphoma: the Bologna experience.

Leuk Lymphoma 2004 Feb;45(2):321-6

Institute of Hematology and Medical Oncology L. e A. Seràgnoli, University of Bologna, Italy.

Patients with aggressive non-Hodgkin's lymphoma (NHL) who relapse after initial therapy have a poor prognosis and with standard dose salvage therapy the outlook remains poor. In this work we examine the patient characteristics and outcome of patients with aggressive NHL treated with HDT and autologous transplantation at our Institute from 1982 to 1999. A retrospective analysis was performed examining patient characteristics, prior chemotherapy regimens, pretransplant disease status, HDT regimen, source of stem cells, time for hematopietic recovery, complications of transplantation, response rates, overall survival (OS) and relapse-free survival (RFS). One hundred and thirty-four patients with aggressive NHL were treated with estimated 10-year OS and RFS rates of 50% and 66%, respectively. Disease status (sensitive vs. refractory) pre-HDT was the most powerful predictive parameter for OS and RFS, at both univariate and multivariate analysis. For the entire cohort, transplant-related mortality was only 3.5% without evidence of second malignancies. Our results confirm that HDT with autologous transplantation is associated with a durable RFS in a remarkable proportion of aggressive NHL patients with very low global early and late toxicity. Improved patient selection, transplant timing, ongoing improvements in supportive care, and selected phase III trials should increase outcomes further.
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http://dx.doi.org/10.1080/10428190310001597900DOI Listing
February 2004

High-dose therapy with autologous transplantation for Hodgkin's disease: the Bologna experience.

Haematologica 2003 May;88(5):522-8

Institute of Hematology and Medical Oncology, L.e A. Seragnoli, University of Bologna, Italy.

Background And Objectives: In this work we examine the characteristics and outcome of patients with Hodgkin's disease (HD) treated with high-dose therapy (HDT) and autologous transplantation at our Institute between 1982 to 2000.

Design And Methods: A retrospective analysis was performed examining patients' characteristics, prior chemotherapy regimens, pre-transplant disease status, HDT regimen, source of stem cells, time for hematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and relapse-free survival (RFS).

Results: Ninety-seven patients with HD were treated and had estimated 10-year OS and RFS rates of 32% and 60%, respectively. Disease status (sensitive vs. refractory) before HDT was the most powerful predictive parameter for OS and RFS in both univariate and multivariate analyses. The rate of transplant-related mortality in the whole cohort was only 1% whereas the rate of second malignancies was 3%.

Interpretation And Conclusions: Our results confirm that HDT with autologous transplantation is associated with a durable RFS in a remarkable proportion of HD patients and that the procedure has a very low global early and late toxicity.
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May 2003