Publications by authors named "Angelo Michele Carella"

90 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

Second allogeneic transplants for multiple myeloma: a report from the EBMT Chronic Malignancies Working Party.

Bone Marrow Transplant 2021 10 11;56(10):2367-2381. Epub 2021 May 11.

Univ. Lille, CHU Lille, INSERM, Infinite, U1286, Lille, France.

The EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30-46%) at 2 years and 25% (17-32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24-46%); Others 9% (0-17%), p < 0.001). There was a significantly higher incidence of acute grade II-IV GvHD in those patients who had also developed GvHD following their initial HLA-identical sibling allo-HCT (HLAid-Sib/HLAid-Sib: 50% (33-67%); Other 22% (8-36%), p = 0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21-40%) vs. 10% (1-20%), P = 0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24-0.67), p < 0.001). In the graft failure group, OS was 41% at 2 years. In summary, a second allo-HCT using a HLA-identical sibling donor, if available, provides the best transplant outcomes for relapsed myeloma in this setting.
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http://dx.doi.org/10.1038/s41409-021-01286-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486670PMC
October 2021

End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA.

Blood Adv 2021 03;5(5):1283-1290

1st Department of Medicine, 1st Faculty of Medicine, Charles University General Hospital, Prague, Czech Republic.

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.
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http://dx.doi.org/10.1182/bloodadvances.2020002690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948296PMC
March 2021

Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group.

Transplantation 2021 04;105(4):686-694

Clinica Medica, Ospedali Riuniti di Ancona, Ancona, Italy.

Variation in clinical practice affects veno-occlusive disease management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation. Disputes about diagnostic criteria, treatment, and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the panel pointed out the need to achieve an early diagnosis, encouraging the adoption of European Society for Blood and Marrow Transplantation criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favor of prophylactic use of ursodeoxycholic acid. As soon as a veno-occlusive disease diagnosis is established, treatment with defibrotide should be started for at least 21 days. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed.
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http://dx.doi.org/10.1097/TP.0000000000003569DOI Listing
April 2021

Impact of donor age and kinship on clinical outcomes after T-cell-replete haploidentical transplantation with PT-Cy.

Blood Adv 2020 08;4(16):3900-3912

Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, Rozzano, Italy.

Donor selection contributes to improve clinical outcomes of T-cell-replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.
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http://dx.doi.org/10.1182/bloodadvances.2020001620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448598PMC
August 2020

Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia.

Am J Hematol 2020 Jul 13. Epub 2020 Jul 13.

Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France and EBMT Paris study office / CEREST-TC, Paris, France.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.
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http://dx.doi.org/10.1002/ajh.25934DOI Listing
July 2020

Effect of the Thiotepa Dose in the TBF Conditioning Regimen in Patients Undergoing Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission: A Report From the EBMT Acute Leukemia Working Party.

Clin Lymphoma Myeloma Leuk 2020 05 27;20(5):296-304. Epub 2020 Jan 27.

Hopital Saint Antoine, Department of Hematology, Paris, France.

Background: Allogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR.

Patients And Methods: In a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months.

Results: On univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups.

Conclusion: T2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.
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http://dx.doi.org/10.1016/j.clml.2020.01.007DOI Listing
May 2020

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO).

Biol Blood Marrow Transplant 2019 12 7;25(12):2388-2397. Epub 2019 Aug 7.

Centro Unico Regionale Trapianto Cellule Staminali e Terapie Cellulari A. Neri, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatment A total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).
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http://dx.doi.org/10.1016/j.bbmt.2019.07.037DOI Listing
December 2019

DNA methylation dynamic of bone marrow hematopoietic stem cells after allogeneic transplantation.

Stem Cell Res Ther 2019 05 20;10(1):138. Epub 2019 May 20.

Laboratory of Preclinical and Translational Research, IRCCS - Referral Cancer Center of Basilicata (CROB), 85028, Rionero in Vulture, Italy.

Background: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. This study aimed to explore global DNA methylation dynamic of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) from donors and their respective recipients affected by acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and Hodgkin lymphoma (HL) during the first year after transplant.

Methods: We measured DNA methylation profile by Illumina HumanMethylationEPIC in BM HSPC of 10 donors (t0) and their matched recipients at different time points after AHSCT, at day + 30 (t1), + 60 (t2), + 120 (t3), + 180 (t4), and + 365 (t5). Differential methylation analysis was performed by using R software and CRAN/Bioconductor packages. Gene set enrichment analysis was carried out on promoter area of significantly differentially methylated genes by clusterProfiler package and the mSigDB genes sets.

Results: Results show significant differences in the global methylation profile between HL and acute leukemias, and between patients with mixed and complete chimerism, with a strong methylation change, with prevailing hyper-methylation, occurring 30 days after AHSCT. Functional analysis of promoter methylation changes identified genes involved in hematopoietic cell activation, differentiation, shaping, and movement. This could be a consequence of donor cell "adaptation" in recipient BM niche. Interestingly, this epigenetic remodeling was reversible, since methylation returns similar to that of donor HSPCs after 1 year. Only for a pool of genes, mainly involved in dynamic shaping and trafficking, the DNA methylation changes acquired after 30 days were maintained for up to 1 year post-transplant. Finally, preliminary data suggest that the methylation profile could be used as predictor of relapse in ALL.

Conclusions: Overall, these data provide insights into the DNA methylation changes of HSPCs after transplantation and a new framework to investigate epigenetics of AHSCT and its outcomes.
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http://dx.doi.org/10.1186/s13287-019-1245-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528331PMC
May 2019

Brentuximab vedotin prior to allogeneic stem cell transplantation increases survival in chemorefractory Hodgkin's lymphoma patients.

Ann Hematol 2019 Jun 14;98(6):1449-1455. Epub 2019 Mar 14.

Haematology, "Policlinico" Hospital, Bari, Italy.

This study reports a retrospective multicenter experience by the Rete Ematologica Pugliese (REP) over the past 16 years, aiming to compare the patients characteristics and outcomes of 21 brentuximab vedotin (BV)-pre-treated patients to 51 patients who received reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT) without prior BV. In total, 72 patients with classical Hodgkin's lymphomas who received allogeneic SCT were retrospectively studied. Prior use of BV had no effect on either engraftment or the incidence and severity of acute graft versus host disease (GVHD). Indeed, a lower incidence of chronic GVHD was observed in the BV group, with a 43% cumulative incidence at 3 years versus 47% in the no BV group, although this was not statistically significant. Despite the low incidence of chronic GVHD, survival was not worse in the BV-treated group: 3-year progression-free survival (PFS) was 53%, 3-year overall survival (OS) was 62%, 3-year non-relapse mortality (NRM) was 24%. In the no BV group, the 3-year PFS was 33%, 3-year OS was 44%, and 3-year NRM was 14%. In chemorefractory patients at the time of transplant, we found a statistically significant difference in PFS between the BV and no BV groups (51% vs. 10%, p = 0.013).
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http://dx.doi.org/10.1007/s00277-019-03662-6DOI Listing
June 2019

Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study.

Lancet Haematol 2019 Feb;6(2):e89-e99

Psy Consult, Hamburg, Germany.

Background: We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension.

Methods: In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov.

Findings: In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups.

Interpretation: The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone.

Funding: Neovii Biotech.
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http://dx.doi.org/10.1016/S2352-3026(18)30214-XDOI Listing
February 2019

Busulfan- or Thiotepa-Based Conditioning in Myelofibrosis: A Phase II Multicenter Randomized Study from the GITMO Group.

Biol Blood Marrow Transplant 2019 05 20;25(5):932-940. Epub 2018 Dec 20.

"Papa Giovanni XXIII" Hospital, Bergamo, Italy; Department of Hematology-Oncology, University of Milano, Milan, Italy.

We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS). Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.064DOI Listing
May 2019

Minimal residual disease and log-reduction of plasma cells are associated with superior response after double autologous stem cell transplant in younger patients with multiple myeloma.

Cytometry B Clin Cytom 2019 05 13;96(3):195-200. Epub 2018 Dec 13.

Department of Hematology and Stem Cell Transplant Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.

Background: Optimization of chemotherapy regimens in the treatment of multiple myeloma (MM) has led to increase the frequency of cases with complete response (CR). Nonetheless, many MM patients still experience relapse, suggesting that CR represents a suboptimal response criteria, and that new therapeutic strategies are needed after single transplant. However, the role of double autologous stem cell transplant (ASCT) as new adjunctive strategy remains to be elucidated. Indeed, we investigated the role of minimal residual disease (MRD) and log-reduction of plasma cells (PCs) as predictors of outcome and in quantifying the degree of tumor reduction after any ASCT.

Methods: MRD and log-reduction were assessed by a six-color flow cytometry (FC) at different time-points: post induction, post first-, and post-second ASCT.

Results: A significant difference was evidenced among the three time points for both log-reduction (P < 0.001) and MRD (P = 0.005). MRD levels after double ASCT were lower than MRD levels achieved after single ASCT (P = 0.005) and after induction (P < 0.001). Frequency of MRD positive patients after double ASCT was significantly lower rather than after the first ASCT (P = 0.008) and after induction (P = 0.004). Interestingly, a significant reduction of PFS was observed in patients with an unfavorable-risk cytogenetic (P < 0.001) and patients with MRD over 0.01% (P = 0.001) as well as log-reduction lower than 2.57 (P = 0.018) after double ASCT.

Conclusions: Our results show that a better clearance of myeloma cells is observed after the double ASCT, and a longer PFS is associated with a lower MRD. © 2018 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21755DOI Listing
May 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

A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial.

Haematologica 2018 05 22;103(5):849-856. Epub 2018 Feb 22.

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy.

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptor and B-cell receptor) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (, and ), was used to classify the 83 cases (43 B-cell receptor and 40 B-cell receptor). The B-cell receptor signature associated with shorter progression-free survival (=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (=0.0014 and =0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. ().
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http://dx.doi.org/10.3324/haematol.2017.184325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927985PMC
May 2018

Comparable survival using a CMV-matched or a mismatched donor for CMV+ patients undergoing T-replete haplo-HSCT with PT-Cy for acute leukemia: a study of behalf of the infectious diseases and acute leukemia working parties of the EBMT.

Bone Marrow Transplant 2018 04 12;53(4):422-430. Epub 2018 Jan 12.

University Hospital Collegium Medicum UMK, Bydgoszcz, Poland.

The role of donor CMV serostatus in the setting of non T-cell depleted haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) has not been specifically addressed so far. Here we analyzed the impact of the donor CMV serological status on the outcome of 983 CMV seropositive (CMV+), acute leukemia patients receiving a first, non T-cell depleted haplo-HSCT registered in the EBMT database. The 1-year NRM was 21.3% (95% CI: 18.4-24.8) and 18.8% (95% CI: 13.8-25.5) in the CMV D+/R+ and D-/R+ pairs, respectively (p = 0.40). Similarly, 1-year OS was 55.1% (95% CI: 50.1-58.0) and 55.7% (95% CI: 48.0-62.8) in the same groups (p = 0.50). The other main outcomes were comparable. No difference in NRM nor OS was observed after stratification for the intensity of conditioning and multivariate anaysis confirmed the lack of significant association with NRM or OS. In conclusion, the choice of a CMV-seronegative donor did not impair early survival of CMV-seropositive patients with acute leukemia after a first, non T-cell depleted haploidentical HSCT and PT-Cy among this series of 983 consecutive patients. Future research may focus on the assessment of the hierarchy of all the donor variables.
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http://dx.doi.org/10.1038/s41409-017-0016-1DOI Listing
April 2018

Italian real life experience with brentuximab vedotin: results of a large observational study on 234 relapsed/refractory Hodgkin's lymphoma.

Oncotarget 2017 Oct 23;8(53):91703-91710. Epub 2017 May 23.

Hematology Unit, Ca' Foncello Hospital, Treviso, Italy.

A large Italian multicenter observational retrospective study was conducted on the use of brentuximab vedotin (BV) for patients with relapsed Hodgkin's lymphoma (HL) to check if clinical trial results are confirmed even in a real life context. 234 CD30+ HL patients were enrolled. Best response was observed after a median of 4 cycles in 140 patients (59.8%): 74 (31.6%) patients obtained a complete response (CR) and 66 (28.2%) achieved a partial response (PR); overall response rate at the end of the treatment was 48.3% (62 CR and 51 PR). The best response rate was higher in the elderly subset: 14 (50%) CR and 5 (17.8%) PR. Disease free survival was 26.3% at 3 years and progression free survival 31.9% at 4.5 years. Duration of response did not differ for who achieved at least PR and then either did or did not undergo consolidative transplant. Overall, the treatment was well tolerated and no death has been linked to BV-induced toxicity. Our report confirms activity in elderly patients, duration of response unrelated to the consolidation with transplant procedure, the relevance of the CR status at first restaging, and the role of BV as a bridge to transplant for chemorefractory patients.
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http://dx.doi.org/10.18632/oncotarget.18114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710959PMC
October 2017

Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma.

J Clin Oncol 2017 Nov 10;35(31):3529-3537. Epub 2017 Aug 10.

Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.

Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.
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http://dx.doi.org/10.1200/JCO.2017.73.3402DOI Listing
November 2017

Italian real-life experience with brentuximab vedotin: results of a large observational study of 40 cases of relapsed/refractory systemic anaplastic large cell lymphoma.

Haematologica 2017 11 3;102(11):1931-1935. Epub 2017 Aug 3.

Sant'Andrea Hospital - Sapienza, Rome, Italy.

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged <30 years at first infusion. The treatment was well tolerated even in this real-life context and no deaths were linked to drug toxicity. Brentuximab vedotin induces clinical responses quite rapidly, i.e. within the first four cycles of treatment in most responders, thus enabling timely use of transplantation. For patients ineligible for transplant or for those in whom a transplant procedure failed, brentuximab vedotin may represent a feasible effective therapeutic option in everyday clinical practice.
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http://dx.doi.org/10.3324/haematol.2017.171355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664397PMC
November 2017

Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study.

Lancet Oncol 2017 08 28;18(8):1076-1088. Epub 2017 Jun 28.

Department of Haematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.

Background: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients.

Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m, cyclophosphamide 750 mg/m, doxorubicin 50 mg/m, and vincristine 1·4 mg/m on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m and doxorubicin 70 mg/m) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m on day 1 or 4 plus intravenous cytarabine 2000 mg/m and dexamethasone 4 mg/m every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m on days 1-3) plus BEAM (intravenous carmustine 300 mg/m on day -7, intravenous cytarabine 200 mg/m twice a day on days -6 to -3, intravenous etoposide 100 mg/m twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018.

Findings: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group.

Interpretation: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis.

Funding: Fondazione Italiana Linfomi.
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http://dx.doi.org/10.1016/S1470-2045(17)30444-8DOI Listing
August 2017

A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up.

Acta Haematol 2017 4;137(1):7-14. Epub 2016 Nov 4.

Program of Innovative Therapy in Oncology and Hematology, Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.
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http://dx.doi.org/10.1159/000449052DOI Listing
February 2017

Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients.

Haematologica 2016 10 28;101(10):1200-1207. Epub 2016 Jul 28.

Department of Hematology and Oncology "L. and A. Seràgnoli", University of Bologna, Italy.

The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR) and 17% (MR) of patients at 2 years; 58% of the enrolled patients achieved a MR at least once, with a sustained MR in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).
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http://dx.doi.org/10.3324/haematol.2016.144949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5046649PMC
October 2016

Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries.

PLoS One 2016 30;11(6):e0157957. Epub 2016 Jun 30.

F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Background: Rituximab is a standard treatment for non-Hodgkin lymphoma. The SABRINA trial (NCT01200758) showed that a subcutaneous (SC) rituximab formulation did not compromise efficacy or safety compared with intravenous (IV) infusion. We aimed to quantify active healthcare professional (HCP) time and patient chair time for rituximab SC and IV, including potential time savings.

Methods: This non-interventional time and motion study was run in eight countries and 30 day oncology units. Rituximab SC data were collected alongside the MabCute trial (NCT01461928); IV data were collected per routine real-world practice. Trained observers recorded active HCP time for pre-specified tasks (stopwatch) and chair time (time of day). A random intercept model was used to analyze active HCP time (by task and for all tasks combined) in the treatment room and drug preparation area, drug administration duration, chair time and patient treatment room time by country and/or across countries. Active HCP and chair time were extrapolated to a patient's first year of treatment (11 rituximab sessions).

Results: Mean active HCP time was 35.0 and 23.7 minutes for IV and SC process, respectively (-32%, p <0.0001). By country, relative reduction in time was 27-58%. Absolute reduction in extrapolated active HCP time (first year of treatment) was 1.1-5.2 hours. Mean chair time was 262.1 minutes for IV, including 180.9 minutes infusion duration, vs. 67.3 minutes for SC, including 8.3 minutes SC injection administration (-74%, p <0.0001). By country, relative reduction was 53-91%. Absolute reduction in extrapolated chair time for the first year of treatment was 3.1-5.5 eight-hour days.

Conclusions: Compared with rituximab IV, rituximab SC was associated with reduced chair time and active HCP time. The latter could be invested in other activities, whereas the former may lead to more available appointments, reducing waiting lists and increasing the efficiency of day oncology units.

Trial Registration: ClinicalTrials.gov NCT01200758.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157957PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928781PMC
July 2017

Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM.

Blood 2016 06 18;127(23):2833-40. Epub 2016 Apr 18.

Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.
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http://dx.doi.org/10.1182/blood-2016-01-694604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900953PMC
June 2016

B-IGEV (bortezomib plus IGEV) versus IGEV before high-dose chemotherapy followed by autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: a randomized, phase II trial of the Fondazione Italiana Linfomi (FIL).

Leuk Lymphoma 2016 10 15;57(10):2375-81. Epub 2016 Feb 15.

a Humanitas Cancer Center , Rozzano , Milan , Italy ;

This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m(2)) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%; p = 0.002) and OS (two-year OS: 100% vs 76%; p < 0.001). Toxicity was overall similar with the two regimens. The addition of bortezomib to IGEV does not improve response in relapsed/refractory HL patients. However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed.
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http://dx.doi.org/10.3109/10428194.2016.1140161DOI Listing
October 2016

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease.

N Engl J Med 2016 Jan;374(1):43-53

From the University Medical Center Hamburg-Eppendorf, Hamburg (N.K., C.W., M.H., F.A.), University Hospital Freiburg, Freiburg (J.F.), University Hospital Tübingen, Tübingen (W.B.), and Psy Consult, Frankfurt (A.V.) - all in Germany; Hospital Clinico Universitario, Valencia (C. Solano), Hospital Ramon y Cajal (J.P.O.) and Hospital Universitario Puerta de Hierro Majadahonda (R.D.), Madrid, Servicio de Hematología, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, (C.F.), Hospital de la Santa Creu i Sant Pau, Barcelona (J.S.), and Hospital Virgen de las Nieves, Granada (M.J.) - all in Spain; S. Orsola-Malpighi University Hospital, University of Bologna, Bologna (G.B., F. Bonifazi), Hematology, DISM, University Udine, Udine (F.P.), Azienda Ospedaliera SS Antonio e Biagio e C. Arrigo, Alessandria (M. Pini), Università Federico II di Napoli, Naples (C. Selleri, A.R.), A.O. Bianchi-Melacrino-Morelli, Reggio Calabria (G. Messina), Ospedale Casa Sollievo della Sofferenza IRCCCS, San Giovanni Rotondo (A.M.C.), Azienda Ospedaliera San Carlo, Potenza (M.C.), Azienda Ospedaliera Careggi, Florence (S.G.), Ospedale Santa Croce, e Carle, Cuneo (N.M.), University of Brescia, Department of Clinical and Experimental Sciences, Brescia (D.R.), University of Pisa, Department of Clinical and Experimental Medicine, Pisa (M. Petrini), Programma di Trapianto Emopoietico Metropolitano, Azienda Policlinico-Vittorio Emanuele, Catania (G. Milone), Policlinico G.B. Rossi, Verona (F. Benedetti), Azienda Ospedaliera, Universitaria Ospedale, Bari (D.P.), Ospedale San Gerardo, Monza (E.T.), Policlinico Modena, Modena (F.N.), and Università di Salerno, Salerno (C. Selleri) - all in Italy; Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel (A.N.); and Helsinki University Hospital, Helsinki (T.R.).

Background: Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling.

Methods: We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease.

Results: After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005).

Conclusions: The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).
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http://dx.doi.org/10.1056/NEJMoa1506002DOI Listing
January 2016
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