Publications by authors named "Paola Carluccio"

37 Publications

GITMO REGISTRY STUDY ON ALLOGENEIC TRANSPLANTATION IN PATIENTS AGED OVER 60 FROM 2000 TO 2017. IMPROVEMENTS AND CRITICISMS.

Transplant Cell Ther 2021 Nov 21. Epub 2021 Nov 21.

Unit of Haematology and Stem Cell Transplant Centre, "San Camillo" Hospital, Rome, Italy.

Background: Nowadays, allogeneic stem cell transplantation (Allo-SCT) can be offered to patients up to the age of 70-72 years and represents one of the most effective curative treatments for many hematological malignancies.

Objectives: The primary objective of the study is to collect data from the allo-SCTs performed in Italy from 2000 to 2017 in patients over 60 years of age to evaluate the changes in safety and efficacy outcomes as well as their distribution and characteristics over time.

Study Design: The GITMO AlloEld study (ClinicalTrials.gov: NCT04469985) is a retrospective, analysis of the allo-SCTs performed 30 Italian transplant Centers on older patients (≥ 60 years) from 2000 to 2017 (n=1,996).

Results: For the purpose of analysis, patients were grouped into three time periods: time A: 2000-2005, n=256 (12%); time B: 2006-2011, n=584 (29%); and time C: 2012-2017, n=1156 (59%). After a median follow-up of 5.6 years, the 5-year Non Relapse Mortality (NRM) remained stable (time A: 32.8%; time B: 36.2%; and time C: 35.0%, p = 0.5); the Overall Survival (OS) improved (time A: 28.4%; time B: 31.8%; and time C: 37.3%, p = 0.012); and the Cumulative Incidence of Relapse (CIR) reduced (time A: 45.3%; time B: 38.2%; time C: 30.0%, p < 0.0001). The 2-year incidence of extensive cGVHD reduced significantly (time A: 17.2%; time B: 15.8%; and time C: 12.2%, p = 0.004). Considering times A and B together (2000-2011), the 2-year NRM was positively correlated to the HCT-CI score; patients with HCT-CI of 0, 1 or 2, or ≥3 had rates of NRM of 25.2%, 33.9%, and 36.1%, respectively, (p < 0.001). Meanwhile, after 2012, the HCT-CI score was not significantlly predictive of NRM.

Conclusions: The study shows that the transplant procedure in elderly patients became more effective over time. Relapse incidence remains the major problem and strategies to prevent it are under investigation (e.g. post-transplant maintenance). Today, the selection of patients aged over 60 could be improved by combining HCT-CI and frailty assessments to better predict NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.11.006DOI Listing
November 2021

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience.

Front Oncol 2021 6;11:740079. Epub 2021 Sep 6.

UOC Ematologia con Trapianto CSE, AORN "Antonio Cardarelli", Napoli, Italy.

Despite effective treatments, cytomegalovirus (CMV) continues to have a significant impact on morbidity and mortality in allogeneic stem cell transplant (allo-SCT) recipients. This multicenter, retrospective, cohort study aimed to evaluate the reproducibility of the safety and efficacy of commercially available letermovir for CMV prophylaxis in a real-world setting. Endpoints were rates of clinically significant CMV infection (CSCI), defined as CMV disease or CMV viremia reactivation within day +100-+168. 204 adult CMV-seropositive allo-SCT recipients from 17 Italian centres (median age 52 years) were treated with LET 240 mg/day between day 0 and day +28. Overall, 28.9% of patients underwent a haploidentical, 32.4% a matched related, and 27.5% a matched unrelated donor (MUD) transplant. 65.7% were considered at high risk of CSCI and 65.2% had a CMV seropositive donor. Low to mild severe adverse events were observed in 40.7% of patients during treatment [gastrointestinal toxicity (36.3%) and skin rash (10.3%)]. Cumulative incidence of CSCI at day +100 and day +168 was 5.4% and 18.1%, respectively, whereas the Kaplan-Meier event rate was 5.8% (95% CI: 2.4-9.1) and 23.3% (95% CI: 16.3-29.7), respectively. Overall mortality was 6.4% at day +100 and 7.3% at day +168. This real-world experience confirms the efficacy and safety of CMV.
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http://dx.doi.org/10.3389/fonc.2021.740079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489185PMC
September 2021

Long-term quality of life of patients with acute promyelocytic leukemia treated with arsenic trioxide vs chemotherapy.

Blood Adv 2021 11;5(21):4370-4379

Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy.

The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA chemotherapy. The median time since diagnosis of the study sample was 8 years. The 2 largest clinically meaningful differences in the EORTC QLQ-C30 were observed for role functioning (Δ = 8.4; 95% confidence interval [CI], 0.5 to 16.3) and dyspnea (Δ = -8.5; 95% CI, -16.4 to -0.7), favoring patients treated with ATRA-ATO. With regard to the SF-36 results, a clinically relevant better physical component score (Δ = 4.6; 95% CI, 1.3 to 7.8) was observed in patients treated with ATRA-ATO, but this was not the case for the mental component score. The 2 groups showed similar profiles in the scores of the EORTC QLQ-CIPN20 scales and in the prevalence of late comorbidities. Overall, our findings suggest that the greater and more sustained antileukemic efficacy of ATRA-ATO is also associated with better long-term patient-reported outcomes than ATRA chemotherapy. This study was registered at www.clinicaltrials.gov as #NCT03096496.
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http://dx.doi.org/10.1182/bloodadvances.2021004649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579253PMC
November 2021

The Impact of Graft CD3 Cell/Regulatory T Cell Ratio on Acute Graft-versus-Host Disease and Post-Transplantation Outcome: A Prospective Multicenter Study of Patients with Acute Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation.

Transplant Cell Ther 2021 Nov 14;27(11):918.e1-918.e9. Epub 2021 Aug 14.

Hematology and Stem Cell Transplantation Unit, AOUC Policlinico, Bari, Italy; Department of Emergency and Organ Transplantation, Aldo Moro University School of Medicine, Bari, Italy.

Although it is well known that tumor site- or bone marrow-infiltrating regulatory T cells (Tregs) might be correlated with worse outcomes in solid tumors and acute leukemias by promoting immune surveillance escape, their contribution to the immediate post-allogeneic transplantation phase by peripheral blood (PB) allografts remains unclear. Moreover, the Treg content in stem cells harvested from PB has been suggested to be correlated with acute graft versus-host-disease (aGVHD) and immunologic recovery after allogeneic PB stem cell transplantation (allo-PBSCT). This study aimed to investigate the impact of the graft content of Tregs, as graft CD3/Tregs ratio (gCD3/TregsR), on acute GVHD and post-allo-PBSCT outcomes. We prospectively enrolled 94 consecutive patients at 9 Italian centers of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) with acute myelogenous (n = 71; 75%) or lymphoblastic (n = 23; 25%) leukemia in complete remission who underwent matched related donor (n = 35; 37%) or unrelated donor (n = 59; 63%) allo-PBSCT. The median graft CD3 cell, Treg, and gCD3/TregsR values were 196 × 10/kg body weight (range, 17 to 666 × 10/kg), 3 × 10/kg (range, 0.1 to 35 × 10/kg), and 71 (range, 1 to 1883), respectively. The discriminatory power of the gCD3/TregsR value to predict grade ≥II aGVHD was assessed by estimating the area under the receiver operating characteristic (ROC) curve (AUC). Any grade and grade ≥II aGVHD occurred in 24 (26%) and 17 (18%) allo-PBSCT recipients, respectively. By ROC analysis, AUC (0.74; 95% confidence interval [CI], 0.608 to 0.866; P = .002) identified 70 as the optimal gCD3/TregsR cutoff value predicting the appearance of grade ≥II aGVHD with 76% sensitivity and 71% specificity. Patients were subdivided into a high (ROC curve value ≥70) gCD3/TregsR group (HR; n = 48) and a low (ROC curve value <70) gCD3/TregsR group (LR; n = 46). The incidence of grade II-IV aGVHD was lower in the LR group compared with the HR group (9% [4 of 46] versus 27% [13 of 48]) in both univariate analysis (odds ratio [OR], 4.8; 95% CI, 1.44 to 16.17; P = .015) and multivariate analysis (OR, 5.0; 95% CI, 1.34 to 18.93; P = .017), whereas no differences were documented taking into account aGVHD of any grade. The overall survival, disease-free survival, nonrelapse mortality, and relapse rates at 2 and 3 years were 61% and 54%, 62% and 55%, 15% and 23%, and 27% and 30%, respectively. Of note, gCD3/TregsR did not significantly correlate with relapse (P = .135). Taken together, our data from this prospective multicenter study confirm the value of Tregs in preventing aGVHD while maintaining the graft-versus-leukemia effect. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.008DOI Listing
November 2021

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

Transplant Cell Ther 2021 05 16;27(5):406.e1-406.e11. Epub 2021 Feb 16.

Stem Cell Transplant and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.
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http://dx.doi.org/10.1016/j.jtct.2020.11.021DOI Listing
May 2021

The role of ponatinib in adult BCR-ABL1 positive acute lymphoblastic leukemia after allogeneic transplantation: a real-life retrospective multicenter study.

Ann Hematol 2021 Jul 28;100(7):1743-1753. Epub 2021 Mar 28.

Divisione di Ematologia con Trapianto di midollo osseo - Azienda ospedaliero, universitaria Policlinico Vittorio Emanuele, Catania, Italy.

The experience of third-generation tyrosine kinase inhibitor ponatinib treatment in Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph'+ ALL) patients post-allogeneic transplantation is limited. We retrospectively collected data on 25 Ph'+ ALL patients who were started on ponatinib after allogeneic transplantation between July 2015 and July 2019 from nine transplantation centers in Italy. Ponatinib was given in prophylaxis in five (20%), as pre-emptive treatment in seven (28%), and as salvage therapy in thirteen (52%) patients. It was combined with donor leukocyte infusions in ten patients. Half of the patients (12/25) harbored T315I mutation of BCR/ABL1, while in the remaining mutational analysis was negative or not performed. Among the 20 patients who received ponatinib as pre-emptive/salvage treatment, complete molecular response was achieved in 15 (75%) patients. Estimated overall survival at 2-year post-initiation of treatment in the whole cohort was 65% (respectively 60%, 60%, and 78% for the prophylaxis, pre-emptive, and salvage therapy groups). In patients with T315I-positive mutational status, the estimated 2-year survival was 40%. Fourteen patients (56%) experienced toxicity, requiring temporary or definitive suspension of treatment. In conclusion, treatment of Ph'+ ALL patients with ponatinib after transplantation is effective, although the question of adequate drug dose and treatment duration remains unanswered.
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http://dx.doi.org/10.1007/s00277-021-04504-0DOI Listing
July 2021

Nanopore sequencing sheds a light on the gene mutations complexity in acute promyelocytic leukemia.

Leuk Lymphoma 2021 05 8;62(5):1219-1225. Epub 2020 Dec 8.

Department of Emergency and Organ Transplantation (D.E.T.O.) - Hematology and Stem Cell Transplantation Unit, University of Bari 'Aldo Moro', Bari, Italy.

Acute promyelocytic leukemia (APL) patients carry in 27% of cases an activating mutation of the fms-like tyrosine kinase-3 () gene: internal tandem duplication (ITD) or tyrosine kinase domain (TKD) point mutation. The simultaneous presence of both types of mutations, so-called dual mutations, has been reported in 2% of APL, but this circumstance has never been studied. We studied a cohort of 74 APL cases, performing an in-depth analysis of three dual mutant cases. Nanopore sequencing (NS) allowed us to characterize their complex mutational profile, showing the occurrence of multiple activating mutations on different alleles in the leukemic promyelocytes and suggesting a cumulative impact of these events on the constitutive activation of the pathway in APL cells. NS approach not only sheds light on the mutational complexity in APL, but may also be useful to better clarify the mutations landscape in acute myeloid leukemia.
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http://dx.doi.org/10.1080/10428194.2020.1856838DOI Listing
May 2021

After Treatment Decrease of Bone Marrow Tregs and Outcome in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia.

J Immunol Res 2020 4;2020:2134647. Epub 2020 Nov 4.

Hematology and Bone Marrow Transplantation Unit-Azienda Ospedaliero-Universitaria Consorziale Policlinico, Department of Emergency and Organ Transplantation-University of Bari "Aldo Moro", Bari, Italy.

An emerging body of evidence demonstrates that defects in antileukemic effector cells in patients with acute myeloid leukemia (AML) can contribute to the development and/or persistence of the disease. In particular, immune suppressive regulatory T cells (Tregs) may contribute to this defective antileukemic immune response, being recruited by bone marrow leukemic cells to evade immune surveillance. We evaluated Tregs (CD4+/CD45RA-/CD25/CD127), performing multiparametric flow cytometry on freshly collected bone marrow aspirate (BMA), in addition to the usual molecular and cytogenetic work-up in newly diagnosed AML patients to look for any correlation between Tregs and the overall response rate (ORR). We studied 39 AML younger patients (<65 years), all treated with standard induction chemotherapy. ORR (complete remission (CR)+CR with incomplete hematologic recovery (CRi)) was documented in 21 out of 39 patients (54%); two partial responder patients were also recorded. Apart from the expected impact of the molecular-cytogenetic group ( = 0.03) and the NPM mutation ( = 0.05), diagnostic BMA Tregs did not show any correlation with ORR. However, although BMA Tregs did not differ in the study population after treatment, their counts significantly decreased in responder patients ( = 0.039), while no difference was documented in nonresponder ones. This suggested that the removal of Treg cells is able to evoke and enhance anti-AML immune response. However, the role of BMA Tregs in mediating immune system-AML interactions in the diagnostic and posttreatment phase should be confirmed in a greater number of patients.
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http://dx.doi.org/10.1155/2020/2134647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657695PMC
August 2021

Acute promyelocytic leukaemia long-term survivors: higher fatigue and greater overall symptom burden.

BMJ Support Palliat Care 2020 Jul 17. Epub 2020 Jul 17.

Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Roma, Italy

Objective: We aimed to investigate the association of fatigue with severity of other key cancer symptoms, as well as symptom interference with daily activities and outlook on life, in long-term survivors of acute promyelocytic leukaemia (APL).

Methods: The study sample consisted of APL survivors (n=244), with a median time from diagnosis of 14.3 years (IQR=11.1-16.9 years), previously enrolled in a long-term follow-up study. Symptom severity and symptom interference were assessed using the well-validated MD Anderson Symptom Inventory (MDASI). Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire.

Results: Higher fatigue burden was associated with increased affective symptoms, memory problems, drowsiness, sleep disturbances, shortness of breath and pain. Higher levels of fatigue were also associated with higher scores across all interference items of the MDASI. Overall, symptoms interfered most with mood, but among APL survivors with high levels of fatigue, symptoms interfered most with enjoyment of life. Multivariable regression analysis confirmed the independent association between fatigue and all symptom severity items of the MDASI.

Conclusions: The current findings show that long-term APL survivors who report higher fatigue also experience a greater overall symptom burden and a substantial impact on performance of daily activities. Further studies are needed to examine whether interventions aimed at reducing fatigue could also reduce overall symptom burden.
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http://dx.doi.org/10.1136/bmjspcare-2020-002281DOI Listing
July 2020

Antiemetic prophylaxis in patients undergoing hematopoietic stem cell transplantation: a multicenter survey of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) transplant programs.

Ann Hematol 2020 Apr 8;99(4):867-875. Epub 2020 Feb 8.

SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Florence, Italy.

A survey within hematopoietic stem cell transplant (HSCT) centers of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) was performed in order to describe current antiemetic prophylaxis in patients undergoing HSCT. The multicenter survey was performed by a questionnaire, covering the main areas on chemotherapy-induced nausea and vomiting (CINV): antiemetic prophylaxis guidelines used, antiemetic prophylaxis in different conditioning regimens, and methods of CINV evaluation. The survey was carried out in November 2016, and it was repeated 6 months after the publication of the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) specific guidelines on antiemetic prophylaxis in HSCT. The results show a remarkable heterogeneity of prophylaxis among the various centers and a significant difference between the guidelines and the clinical practice. In the main conditioning regimens, the combination of a serotonin receptor antagonist (5-HT-RA) with dexamethasone and neurokin receptor antagonist (NK1-RA), as recommended by MASCC/ESMO guidelines, increased from 0 to 15% (before the publication of the guidelines) to 9-30% (after the publication of the guidelines). This study shows a lack of compliance with specific antiemetic guidelines, resulting mainly in under-prophylaxis. Concerted strategies are required to improve the current CINV prophylaxis, to draft shared common guidelines, and to increase the knowledge and the adherence to the current recommendations for CINV prophylaxis in the specific field of HSCT.
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http://dx.doi.org/10.1007/s00277-020-03945-3DOI Listing
April 2020

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for T Cell Acute Lymphoblastic Leukemia: A Report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

Biol Blood Marrow Transplant 2020 05 9;26(5):936-942. Epub 2020 Jan 9.

Department of Hematology-BMT, Hopital St Antoine, Paris, France.

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.003DOI Listing
May 2020

Droplet digital PCR for the quantification of Alu methylation status in hematological malignancies.

Diagn Pathol 2018 Dec 22;13(1):98. Epub 2018 Dec 22.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, P.zza G. Cesare, 11 70124, Bari, Italy.

Background: Alu repeats, belonging to the Short Interspersed Repetitive Elements (SINEs) class, contain about 25% of CpG sites in the human genome. Alu sequences lie in gene-rich regions, so their methylation is an important transcriptional regulation mechanism. Aberrant Alu methylation has been associated with tumor aggressiveness, and also previously discussed in hematological malignancies, by applying different approaches. Moreover, today different techniques designed to measure global DNA methylation are focused on the methylation level of specific repeat elements. In this work we propose a new method of investigating Alu differential methylation, based on droplet digital PCR (ddPCR) technology.

Methods: Forty-six patients with hematological neoplasms were included in the study: 30 patients affected by chronic lymphocytic leukemia, 7 patients with myelodysplastic syndromes at intermediate/high risk, according with the International Prognostic Scoring System, and 9 patients with myelomonocytic leukemia. Ten healthy donors were included as controls. Acute promyelocytic leukemia-derived NB4 cell line, either untreated or treated with decitabine (DEC) hypomethylating agent, was also analyzed. DNA samples were investigated for Alu methylation level by digestion of genomic DNA with isoschizomers with differential sensitivity to DNA methylation, followed by ddPCR.

Results: Using ddPCR, a significant decrease of the global Alu methylation level in DNA extracted from NB4 cells treated with DEC, as compared to untreated cells, was observed. Moreover, comparing the global Alu methylation levels at diagnosis and after azacytidine (AZA) treatment in MDS patients, a statistically significant decrease of Alu sequences methylation after therapy as compared to diagnosis was evident. We also observed a significant decrease of the Alu methylation level in CLL patients compared to HD, and, finally, for CMML patients, a decrease of Alu sequences methylation was observed in patients harboring the SRSF2 hotspot gene mutation c.284C>D.

Conclusions: In our work, we propose a method to investigate Alu differential methylation based on ddPCR technology. This assay introduces ddPCR as a more sensitive and immediate technique for Alu methylation analysis. To date, this is the first application of ddPCR to study DNA repetitive elements. This approach may be useful to profile patients affected by hematologic malignancies for diagnostic/prognostic purpose.
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http://dx.doi.org/10.1186/s13000-018-0777-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303857PMC
December 2018

Health-related quality of life, symptom burden, and comorbidity in long-term survivors of acute promyelocytic leukemia.

Leukemia 2019 07 20;33(7):1598-1607. Epub 2018 Dec 20.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

The objective of this study was to investigate health-related quality of life (HRQOL), symptom burden, and comorbidity profile in long-term acute promyelocytic leukemia (APL) survivors treated with standard chemotherapy. Overall, 307 long-term APL survivors were invited to participate. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and compared with that of age and sex-matched controls from the general population. Symptom burden was assessed with the MD Anderson Symptom Inventory (MDASI) questionnaire and comorbidity profile was also investigated. Median follow-up time since diagnosis was 14.3 years (interquartile range: 11.1-16.9 years). APL survivors had a statistically and clinically meaningful worse score for the role physical scale of the SF-36 (-9.5; 95% CI, -15.7 to -3.2, P = 0.003) than their peers in the general population. Fatigue was reported as moderate to severe by 29% of patients and 84.4% reported at least one comorbidity. Prevalence of comorbidity in APL survivors was higher than that reported by the general population. Also, marked variations were found in the HRQOL profile by number of comorbidities. Even many years after treatment ends, APL survivors treated with standard chemotherapy do not fully recover as they report HRQOL limitations and a substantial burden of symptoms.
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http://dx.doi.org/10.1038/s41375-018-0325-4DOI Listing
July 2019

Vascular density and inflammatory infiltrate in primary oral squamous cell carcinoma and after allogeneic hematopoietic stem cell transplantation.

Ann Hematol 2019 Apr 5;98(4):979-986. Epub 2018 Dec 5.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Piazza Giulio Cesare, 11, 70124, Bari, Italy.

Hematopoietic stem cell transplantation (HSCT) recipients have been reported to have an increased risk of chronic graft versus host disease (cGVHD) and hematological and solid cancers. Oral manifestations are the first signs of cGVHD observed in the majority of patients, and oropharyngeal cancer is the most frequent secondary malignancy occurred after HSCT. In this study, we have evaluated the inflammatory infiltrate cell content and correlated with the vascular density in patients affected by primary oral squamous cell carcinoma (OSCC) from previous healthy controls and OSCC after cGVHD. Results have demonstrated that patients with OSCC after GVHD show a more consistent inflammatory infiltrate as compared with the OSCC ones. In detail, the inflammatory background composed of CD3-positive T cells, tryptase-positive mast cells, CD31-positive endothelial cells, and CD68-positive macrophages may be more pronounced in the setting of GVHD + OSCC than in the control group. By contrast, CD20-positive B cells and CD1a-positive dendritic cells were more abundant in the latter population. Finally, a positive correlation was found as between vascular density and inflammatory cell infiltration in both GVHD + OSCC and OSCC groups. Overall, these results confirm the role played by immune cells in enhancing tumor progression and angiogenesis and suggest a potential therapeutic strategy involving inhibition of recruitment of immune cells to the tumor microenvironment and blockade of pro-tumoral effects and pro-angiogenic functions.
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http://dx.doi.org/10.1007/s00277-018-3575-3DOI Listing
April 2019

Outcomes of Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Hodgkin Lymphomas: A Retrospective Multicenter Experience by the Rete Ematologica Pugliese (REP).

Clin Lymphoma Myeloma Leuk 2019 01 12;19(1):35-40. Epub 2018 Sep 12.

Haematology, "G.Panico" Hospital, Tricase (LE), Italy.

Background: Hodgkin lymphoma (HL) is a potentially curable disease, and modern therapy is expected to successfully cure more than 80% of the patients. However, patients progressing after intensive treatments, such as autologous stem cell transplantation (SCT), have a very poor outcome. Allogeneic SCT offers the only strategy with a curative potential for these patients. This study reports a retrospective multicenter experience of the Rete Ematologica Pugliese (REP) over the past 17 years, aiming to define the impact of each patient's disease and transplant-related characteristics on outcomes.

Patients And Methods: We retrospectively studied 72 patients with HL who received allogeneic SCT from 2000 to 2017. At the time of allogeneic SCT, 33 (46%) patients had chemosensitive disease, and 39 (54%) were chemo-refractory. All patients received reduced-intensity conditioning, 50% received grafts from a matched sibling donor, and 50% from a matched-unrelated donor.

Results: With a median follow-up of 48 months (range, 3-195 months), 30 patients are alive, and 42 have died. The Kaplan-Meier estimates of overall survival and progression-free survival at 5 years were 35% and 34%, respectively. Following transplantation, 12 (17%) patients died of non-relapse mortality at a median of 90 days (range, 1 day-20 months). The causes of death included infection (n = 7), graft-versus-host disease (n = 3), and multi-organ failure (n = 2).

Conclusions: Allogeneic SCT results extend survival in selected patients with relapsed/refractory HL, showing low treatment-related mortality. Patients with active disease at the time of allogeneic transplantation have poor outcomes. Allogeneic SCT may be an effective salvage strategy for patients who relapse after an autologous SCT.
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http://dx.doi.org/10.1016/j.clml.2018.08.012DOI Listing
January 2019

Impact of Bone Marrow Aspirate Tregs on the Response Rate of Younger Newly Diagnosed Acute Myeloid Leukemia Patients.

J Immunol Res 2018 4;2018:9325261. Epub 2018 Jul 4.

Hematology and Bone Marrow Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Acute myeloid leukemia (AML) is widely considered a distinct clinical entity with a well-defined molecular and genetics-based prognosis. Particularly in a younger patient, the therapeutic approach depends largely on diagnostic risk stratification, which has an impact on the outcome after therapy. We added Treg evaluation to the usual molecular and cytogenetics profile in the AML younger patients' diagnostic bone marrow aspirate (dBMA) in order to search for any correlation between Tregs and overall response (OR) as well as survival (OS) rates. We studied 23 AML young patients, all treated with standard induction chemotherapy: OR (complete remission (CR) + CR incomplete (CRi)) was documented in 10 of 23 patients (44%); there were two partial responder patients. The optimal dBMA Treg cut-off value for predicting response to treatment (≥21/L) was obtained by ROC curve analysis. However, in multivariate analysis, apart from the expected impact of the molecular/cytogenetic risk ( = 0.049) and NPM mutation ( = 0.001), dBMA Tregs ≥ 21/L was not correlated with OR. Actually, higher dBMA Tregs were associated with the good intermediate molecular/cytogenetic risk group ( = 0.02), whose median OS was confirmed to be better as compared with that of the poor risk group (18 versus 5 months, = 0.05) and equal to the dBMA Tregs ≥ 21/L group (5 versus 5 months, = 0.902), respectively. The possible prognostic value of such an immunological player as BMA Tregs in the diagnostic and successive phases of AML needs to be confirmed in larger patient numbers.
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http://dx.doi.org/10.1155/2018/9325261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057333PMC
November 2018

A desensitization protocol for delayed allergy to cytarabine: analysis of two cases.

Postepy Dermatol Alergol 2018 Apr 24;35(2):222-224. Epub 2018 Apr 24.

Department of Emergency and Organ Transplantation, Allergology and Clinical Immunology Section, University of Bari-Aldo Moro, Bari, Italy.

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http://dx.doi.org/10.5114/ada.2018.75249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949556PMC
April 2018

Droplet Digital PCR Is a Robust Tool for Monitoring Minimal Residual Disease in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia.

J Mol Diagn 2018 07 3;20(4):474-482. Epub 2018 Apr 3.

Hematology Section, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. Electronic address:

The breakpoint cluster region-abelson 1 p190 fusion transcript is the most frequent variant observed in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). Qualitative-PCR and real-time quantitative PCR are the currently used methods to monitor minimal residual disease (MRD) in Ph+ ALL patients; for the latter, full standardization and an international quality validation are lacking. Here, we developed a droplet digital PCR (ddPCR) assay for MRD monitoring in p190+ ALL cases. The analytical performance was assessed by the limit-of-detection determination, showing a reliability, sensitivity, and precision of the assay of up to 0.001%. Comparison of results obtained with qualitative PCR and ddPCR in 117 follow-up samples from 16 of 26 Ph+ ALL patients showed discordant results in 27% of cases (32 of 117). Real-time quantitative PCR analysis of 19 ddPCR-positive samples with a low tumor burden failed to provide quantitative results in 63% of cases (12 of 19). These results highlight that in p190+ ALL the ddPCR method has a sufficient analytical performance for very low MRD monitoring and for predicting molecular relapse several months before hematologic relapse. In conclusion, MRD monitoring by ddPCR may better stratify Ph+ ALL patients at risk of disease progression.
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http://dx.doi.org/10.1016/j.jmoldx.2018.03.002DOI Listing
July 2018

FLAG-Ida Regimen as Bridge Therapy to Allotransplantation in Refractory/Relapsed Acute Myeloid Leukemia Patients.

Clin Lymphoma Myeloma Leuk 2017 11 19;17(11):767-773. Epub 2017 Jun 19.

Hematology and Bone Marrow Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Background: Patients with primary refractory or first relapse acute myeloid leukemia (AML) are considered to have worse clinical outcomes after treatment. For these patients, the achievement of complete remission appears crucial for them to be able to undergo allotransplantation, which might be the only possible treatment.

Patients And Methods: We used the FLAG-Ida (fludarabine, cytarabine [cytosine arabinoside], granulocyte colony-stimulating factor, idarubicin) regimen in patients with primary refractory/first relapse AML as a bridge to transplantation. We studied its efficacy in terms of overall response and overall survival to assess which variables (age, lactate dehydrogenase, bone marrow blast count, peripheral blood blast count, platelet count, white blood cell count, de novo or secondary AML, molecular-cytogenetic risk, duration of response, and relapsed or refractory disease) might have an effect on outcome.

Results: We analyzed the data from 108 consecutive adult patients (52 males, 66 females; median age, 49 years; range, 17-72 years) with newly diagnosed AML refractory to standard induction regimens or relapse after first complete remission, who had received the FLAG-Ida protocol as salvage therapy from January 2005 to December 2015. An overall response was achieved in 48 patients (44%). On multivariate analysis, the variables with a positive effect on the response rate were molecular-cytogenetic risk (P = .009), duration of first response in relapsed AML (P = .003), AML status (relapsed or refractory; P = .047), and peripheral blood blast count (P = .016). On multivariate analysis, overall survival was significantly associated with FLAG-Ida response (hazard ratio, 0.343; P = .001) and receipt of allotransplantation (hazard ratio, 0.277; P < .001).

Conclusion: Our data seem to confirm the value of FLAG-Ida in this setting and might suggest its best usage as bridge therapy for patients awaiting allotransplantation.
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http://dx.doi.org/10.1016/j.clml.2017.06.002DOI Listing
November 2017

Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial.

Lancet Haematol 2017 Mar 3;4(3):e127-e136. Epub 2017 Feb 3.

Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy.

Background: In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia.

Methods: EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 10 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33.

Findings: Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4-24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5-211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3-4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ=7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ=0·06, p=0·81).

Interpretation: Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing.

Funding: Associazione QOL-ONE.
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http://dx.doi.org/10.1016/S2352-3026(17)30012-1DOI Listing
March 2017

Azacitidine in the treatment of older patients affected by acute myeloid leukemia: A report by the Rete Ematologica Pugliese (REP).

Leuk Res 2015 Aug 20. Epub 2015 Aug 20.

Hematology and Bone Marrow Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

The optimal treatment of older patients (>65 years) with acute myeloid leukemia (AML) remains challenging in daily clinical practice; a choice has to be made between intensive chemotherapy and best supportive care. To guide physicians, several prognostic factors have been identified and risk scores developed. Recently, the DNA methyltransferase inhibitor azacitidine has become available for use in MDS and AML patients with up to 30% bone marrow blasts. However, limited data are available on the outcome of older unfit AML patients, regardless of their bone marrow blast count. We retrospectively analyzed the outcome of 90 newly diagnosed older unfit AML patients in 9 Institutions from the Apulia Region (REP). Responder patients (evaluation performed after 4 cycles of treatment even in cases of primary failure) showed a better overall survival than non responders (23 vs 6 months, p<.001). ECOG PS≥2 seems to be correlated with OS in multivariate analysis, while neither primary treatment failure (documented after 2 cycles) nor bone marrow blast count were correlated with a worse overall survival either at univariate (22 vs 29 months, p=.ns; 16 vs 19 months, p=.ns) or multivariate analysis. Overall, the results of our retrospective analysis seem to confirm the efficacy of AZA treatment for this unfit AML patients setting, in terms of both CR and OS, regardless of the bone marrow blasts count, while primary treatment failure should not lead to a discontinuation of treatment.
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http://dx.doi.org/10.1016/j.leukres.2015.08.005DOI Listing
August 2015

Overexpression of the LSAMP and TUSC7 genes in acute myeloid leukemia following microdeletion/duplication of chromosome 3.

Cancer Genet 2015 Oct 4;208(10):517-22. Epub 2015 Aug 4.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy. Electronic address:

The 3q13.31 microdeletion syndrome is characterized by developmental delay, postnatal growth above the mean, characteristic facial features, and abnormal male genitalia. Moreover, a frequent deletion in the 3q13.31 chromosome region has been identified in patients who are affected by osteosarcomas. Among the genes located within the deleted region, the involvement of the limbic system-associated membrane protein gene (LSAMP), together with a non-coding RNA tumor suppressor candidate 7 gene (TUSC7), has been suggested. We describe the case of an adult acute myeloid leukemia (AML) patient with a novel chromosomal rearrangement characterized by a 3q13.31 microdeletion and an extra copy of the 3q13.31-q29 chromosomal region translocated to the long arm of the Y chromosome. This karyotypic aberration seems to cause LSAMP and TUSC7 gene expression dysregulation. In conclusion, we report the first case of LSAMP and TUSC7 gene overexpression, possibly due to a position effect in an AML patient bearing a 3q13.31 cryptic deletion.
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http://dx.doi.org/10.1016/j.cancergen.2015.07.006DOI Listing
October 2015

ADAMTS2 gene dysregulation in T/myeloid mixed phenotype acute leukemia.

BMC Cancer 2014 Dec 16;14:963. Epub 2014 Dec 16.

Department of Emergency and Organ Transplantation (D,E,T,O,) - Hematology Section, University of Bari, P,zza G, Cesare, 11 70124 Bari, Italy.

Background: Mixed phenotype acute leukemias (MPAL) include acute leukemias with blasts that express antigens of more than one lineage, with no clear evidence of myeloid or lymphoid lineage differentiation. T/myeloid (T/My) MPAL not otherwise specified (NOS) is a rare leukemia that expresses both T and myeloid antigens, accounting for less than 1% of all leukemias but 89% of T/My MPAL. From a molecular point of view, very limited data are available on T/My MPAL NOS.

Case Presentation: In this report we describe a T/My MPAL NOS case with a complex rearrangement involving chromosomes 5 and 14, resulting in overexpression of the ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2) gene due to its juxtaposition to the T cell receptor delta (TRD) gene segment.

Conclusion: Detailed molecular cytogenetic characterization of the complex rearrangement in the reported T/My MPAL case allowed us to observe ADAMTS2 gene overexpression, identifying a molecular marker that may be useful for monitoring minimal residual disease. To our knowledge, this is the first evidence of gene dysregulation due to a chromosomal rearrangement in T/My MPAL NOS.
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http://dx.doi.org/10.1186/1471-2407-14-963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301820PMC
December 2014

Lymphoid enhancer binding factor-1 (LEF1) expression as a prognostic factor in adult acute promyelocytic leukemia.

Oncotarget 2014 Feb;5(3):649-58

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy.

Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/ β-catenin signaling pathway. High LEF1 expression has been reported as a prognostic marker in hematologic malignancies. We evaluated the prognostic significance of LEF1 expression in 78 adult acute promyelocytic leukemia (APL) patients. APL samples were dichotomized at the median value and divided into: LEF1(low) and LEF1(high). LEF1(high) patients had lower WBC counts at baseline and were less likely to carry a FLT3-ITD than LEF1(low) patients. Early death occurred only in the LEF1(low) group. Moreover, LEF1(low) expression was associated with a high Sanz score. Survival analysis of 61 APL patients < 60 years revealed that the LEF1(high) group had a significantly longer overall survival (OS). Cox analysis for OS confirmed only LEF1 expression as an independent prognostic factor. Of the 17 patients over the age of 60, those in the LEF1(high) group showed a higher median survival. In silico analysis identified 9 differentially expressed, up-modulated genes associated with a high expression of LEF1; the majority of these genes is involved in the regulation of apoptosis. Our study provides evidence that LEF1 expression is an independent prognostic factor in APL, and could be used in patients risk stratification.
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http://dx.doi.org/10.18632/oncotarget.1619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996670PMC
February 2014

Immunophenotypic and molecular features of 'cuplike' acute myeloid leukemias.

Eur J Haematol 2014 Feb;92(2):121-6

Department of Emergency - Section of Haematology, University of Bari, Bari, Italy.

Nuclear invaginations, also referred to as fishmouth or cuplike nuclei, have long been identified in microgranular APL, myelomonocytic and monocytic AMLs. More recently, this typical morphological feature has been associated with NPM1 and FLT3 mutations, as well as with the lack of CD34 and HLA-DR expression. In this study, we retrospectively analyzed the morphologic, immunophenotypic, cytogenetic, and molecular features of 68 patients with AML. A cuplike nuclear invagination was detected in more than 10% of blast cells in 15 (22%) cases. Our data show that a cuplike morphology is associated with FLT3-ITD positivity, as well as with the loss of CD34 and HLA-DR expression. The results were not significantly modified when a higher cutoff of cuplike cells was used. Our results are not sufficient to suggest that cuplike AML could represent a distinct subtype, but further investigations could yield a better characterization of this feature in patients with AML.
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http://dx.doi.org/10.1111/ejh.12217DOI Listing
February 2014

Use of tyrosine kinase inhibitors in a patient with Brugada syndrome and chronic myeloid leukemia.

Int J Hematol 2013 Oct 24;98(4):483-6. Epub 2013 Jul 24.

U.O. Ematologia con Trapianto, D.E.T.O., Universita' degli Studi di Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy,

The treatment and prognosis of chronic myeloid leukemia have dramatically changed since the introduction of tyrosine kinase inhibitors, but although several clinical trials have examined their safety with respect to heart function, no data are yet available about the use of these drugs in patients with Brugada syndrome. We report a case of Brugada syndrome diagnosed during tyrosine kinase inhibitor therapy in a 69-year-old Caucasian male with meningioma and chronic myeloid leukemia. This case report highlights the importance of an integrated approach among hematologists and cardiologists to ensure appropriate treatment with tyrosine kinase inhibitors in patients affected by chronic myeloid leukemia who also suffer from Brugada syndrome.
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http://dx.doi.org/10.1007/s12185-013-1395-8DOI Listing
October 2013

Outcome of allogeneic peripheral blood stem cell transplantation by donor graft CD3+/Tregs ratio: a single-center experience.

Biol Blood Marrow Transplant 2013 Mar 27;19(3):495-9. Epub 2012 Nov 27.

Hematology Section, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11,Bari, Italy.

The therapeutic efficacy of allogeneic peripheral blood stem cell transplantation (PBSCT) for hematological malignancies relies largely on the graft-versus-leukemia (GVL) effects exerted by the donor CD3 cells, but there is a risk of onset of uncontrolled graft-versus-host disease (GVHD). Regulatory T cells (Tregs) (CD4+CD25(high) Foxp3+) are believed to maintain tolerance and to inhibit acute GVHD (aGVHD) after allogeneic PBSCT. Nevertheless, when looking at post-allotransplantation patient outcomes, although the impact of aGVHD on survival is amply documented, so far there is no evidence that the donor graft CD3/Tregs ratio may affect overall survival (OS), nonrelapse mortality (NRM), disease-free survival (DFS), and relapse rates. Our aim was to study the possible impact of the gCD3/Tregs ratio on survival after myeloablative allogeneic PBSCT. We analyzed 74 consecutive patients diagnosed with acute myeloid leukemia (n = 62), acute lymphoblastic leukemia (n = 10), and chronic myeloid leukemia (n = 2) who underwent transplantation with unmanipulated PBSCs from a human leukocyte antigen-identical related donor (n = 48) or a human leukocyte antigen-identical unrelated donor (n = 26). Patients were subdivided into a high gCD3/Tregs ratio (≥36) group (HR group, n = 30) and a low gCD3/Tregs ratio (<36) group (LR group, n = 44). The OS, DFS, NRM, and relapse rates at 3 years were 53%, 51%, 29%, and 34%, respectively. Comparing the LR and HR groups, a statistically significant difference was demonstrated for the 3-year OS, DFS, and NRM rates (65% vs 31%, P = .0001; 67 versus 26%, P = .0001; 5% versus 71%, P < .0001, respectively) but not for relapse (30% vs 25%, P = ns). By multivariate analysis, LR significantly predicted better OS (P = .019), DFS (P = .003), and NRM (P = .05), whereas there was no statistically significant association between LR and relapse (P = .155). Overall, our data may suggest that LR preserves GVL effects but is also protective against aGVHD in allotransplantation patients.
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http://dx.doi.org/10.1016/j.bbmt.2012.11.015DOI Listing
March 2013

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study.

Haematologica 2013 Feb 12;98(2):239-46. Epub 2012 Oct 12.

Institute of Hematology, Catholic University, Rome, Italy.

The objective of this study was to evaluate the clinical features, prognostic factors, and efficacy of treatments in patients with blastic plasmacytoid dendritic cell neoplasm with a leukemic presentation at onset of the disease. In order to do this, a retrospective multicenter study was performed from 2005-2011 in 28 Italian hematology divisions in which 43 cases were collected. Forty-one patients received an induction therapy, consisting of an acute myeloid leukemia-type regimen in 26 patients (60%) and acute lymphoid leukemia/lymphoma-type regimen in 15 patients (35%). Six patients (14%) underwent allogeneic hematopoietic stem cell transplantation. Seventeen patients (41%) achieved a complete remission: seven after acute myeloid leukemia-type treatment and 10 after an acute lymphoid leukemia/lymphoma-type regimen, with a significant advantage for acute lymphoid leukemia/lymphoma-type chemotherapy (P=0.02). Relapse occurred in six of the 17 patients (35%) who achieved complete remission, more frequently after acute lymphoid leukemia/lymphoma-type chemotherapy. The median overall survival was 8.7 months (range, 0.2-32.9). The patients treated with an acute myeloid leukemia-type regimen had an overall survival of 7.1 months (range, 0.2-19.5), whereas that of the patients receiving acute lymphoid leukemia/lymphoma-type chemotherapy was 12.3 months (range, 1-32.9) (P=0.02). The median overall survival of the allogeneic hematopoietic stem cell transplant recipients was 22.7 months (range, 12-32.9), and these patients had a significant survival advantage compared to the non-transplanted patients (median 7.1 months, 0.2-21.3; P=0.03). In conclusion, blastic plasmacytoid dendritic cell neoplasm with bone-marrow involvement is an aggressive subtype of high-risk acute leukemia. The rarity of this disease does not enable prospective clinical trials to identify the better therapeutic strategy, which, at present, is based on clinicians' experience.
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http://dx.doi.org/10.3324/haematol.2012.072645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561431PMC
February 2013
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