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Stem Cell Transplantation for Diamond-Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT)
Miano, M., Eikema, D. J., de la Fuente, J., Bosman, P., Ghavamzadeh, A., Smiers, F., Sengeløv, H., Yesilipek, A., Formankova, R., Bader, P., et al
Transplantation and cellular therapy. 2021;27(3):274.e1-274.e5
Abstract
Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.
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Upfront Alternative Donor Transplant Versus Immunosuppressive Therapy in Patients with Severe Aplastic Anemia Who Lack Fully HLA Matched Related Donor: Systematic Review and Meta-Analysis of Retrospective Studies. on Behalf of the Severe Aplastic Anemia Working Party of European Group for Blood and Marrow Transplantation (SAAWP of EBMT)
Alotaibi, H., Aljurf, M., de Latour, R., Alfayez, M., Bacigalupo, A., Fakih, R. E., Schrezenmeier, H., Ahmed, S. O., Gluckman, E., Iqbal, S., et al
Transplantation and cellular therapy. 2021
Abstract
Idiopathic aplastic anemia is a rare and life-threatening disorder with hematopoietic stem cell transplant (HSCT) from matched sibling donor (MSD) being the standard treatment strategy for young patients. The use of alternative donor transplant (ADT) from a matched unrelated donor (MUD) or HLA haploidentical donor (HID) is not commonly used in the frontline setting. The aim of this systematic review/meta-analysis is to compare ADT as an upfront, rather than delayed, treatment strategy in the absence of a MSD to immunosuppressive therapy (IST) in severe aplastic anemia (SAA). We searched PUBMED/MEDLINE and EMBASE (1998-2019) for studies that compared the outcomes of ADT with IST as upfront therapy in patients with SAA. We included studies with five patients or more in each arm. Studies that included patients with inherited forms of bone marrow failure syndromes were excluded. The primary outcome was the 5- year overall survival rate. Five studies met the inclusion criteria and were included in this meta-analysis. The pooled 5-year odd ratio (OR) for OS was statistically significant at 0.44 [95% CI 0.23-0.85] in favor of upfront ADT. Additionally, the survival was compared between upfront versus salvage ADT in six studies. The pooled 5-year OR for OS was statistically significant at 0.31 [95% CI 0.15-0.64] in favor of upfront ADT. Although this analysis has some limitations including the retrospective nature of the included studies, the lack of ethnic diversity, the predominantly pediatric population and the relatively suboptimal IST regimen used in some of the studies, it indicated that upfront ADT is a potential alternative treatment option in young and pediatric SAA patients who lack an HLA identical sibling donor, particularly when optimal IST is not available.
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Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group
Bonifazi, F., Sica, S., Angeletti, A., Marktel, S., Prete, A., Iori, A. P., Olivari, D., Rossetti, G., Bertaina, A., Botti, S., et al
Transplantation. 2020
Abstract
Variation in clinical practice affects veno-occlusive disease (VOD) management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). 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 (GITMO) 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 (NIH) 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 EBMT criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favour of prophylactic use of ursodeoxicolic acid (UDCA). As soon as a VOD diagnosis is established, treatment with defibrotide should be started for at least 21d. 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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Oral Dysplastic Complications after HSCT: Single Case Series of Multidisciplinary Evaluation of 80 Patients
Leuci, S., Coppola, N., Blasi, A., Ruoppo, E., Bizzoca, M. E., Lo Muzio, L., Marano, L., Risitano, A. M., Mignogna, M. D.
Life (Basel, Switzerland). 2020;10(10)
Abstract
Oral squamous cell carcinoma (OSCC) is the most common secondary solid malignancy after hematopoietic stem-cell transplantation (HSCT). OSCC following HSCT is frequently preceded by chronic graft-versus-host disease (cGVHD). The aim of this study was to describe a cohort of post-HSCT patients and to evaluate the onset of oral epithelial dysplasia and/or OSCC over time. In this retrospective cohort study, we present a cohort of hematological patients that underwent HSCT. Demographic variables, clinical hematological data, data regarding acute graft-versus-host disease (aGVHD) and cGVHD, and oral clinical features were analyzed. We focused on clinicopathological features of a subgroup of 22 patients with oral cGVHD and OSCC after HSCT. Among 80 included patients, 46 patients (57.5%) developed aGVHD and 39 patients (48.7%) developed cGVHD. Oral mucosa was involved in 17 patients with aGVHD (36.9%) and in 22 patients (56.4%) with cGVHD. Out of a total of 22 oral biopsies, roughly 40% revealed mild to moderate dysplasia, and 32% were OSCC. In the absence of international agreement on the best timing of oral follow-up after HSCT, it is mandatory to establish a close multidisciplinary evaluation in order to prevent the onset of HSCT-related OSCC and to reduce post-transplant mortality due to secondary tumors.
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Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors. A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (Gitmo)
Candoni, A., Rambaldi, A., Fanin, R., Velardi, A., Arcese, W., Ciceri, F., Lazzarotto, D., Lussana, F., Olivieri, J., Grillo, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
PURPOSE We performed a nationwide registry-based analysis to describe the clinical outcome of adults patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a TKI-based treatment. PATIENTS AND RESULTS A total of 441 patients were included in the study. The median age at HSCT was 44 years (range 18-70). All the 441 patients (100%) received TKI before the HSCT (performed between 2005 and 2016). Of these patients, 404 (92%) were in cytologic complete remission (CR), while the remaining 37 (8%) had an 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 cases. The prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (TBI-based in 50%) and included ATG in 51% of cases. With a median follow-up after HSCT of 39.4 months (range: 1-145), the overall survival (OS) probability 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 with CR and MRD-negative at the time of transplant compared with those of patients with CR but MRD-positive (50% OS not reached vs. 36 months, P=0.015; 50% PFS not reached vs. 26 months, P=0.003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5 years OS rate 70%). Conversely, the 37 patients who underwent a HSCT with active Ph+ ALL had a median OS and PFS of 7 and 5 months, respectively. The 5 years cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% vs. 35.4%, P=0.001). The non-relapse mortality (NRM) after 1, 2 and 5 years was 19.1% (95%CI: 15.5-22.9), 20.7% (95%CI: 17-24.7) and 24.1% (95%CI: 20-28.5), respectively. The NRM was significantly lower with a mEBMT risk score of 0-2 compared with mEBMT risk score of ≥ 3 (15% vs. 25%, P=0,016). CONCLUSIONS The median OS for Ph+ ALL patients who underwent a TKI-based treatment followed by an allograft, 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 patients MRD-negative both at HSCT and at 3 months after HSCT (5 year OS 70%).
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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
Bonifazi, F., Solano, C., Wolschke, C., Sessa, M., Patriarca, F., Zallio, F., Nagler, A., Selleri, C., Risitano, A. M., Messina, G., et al
The Lancet. Haematology. 2019;6(2):e89-e99
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Editor's Choice
Abstract
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.
PICO Summary
Population
Patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, undergoing sibling HLA-identical allogeneic peripheral blood stem-cell transplantation.
Intervention
ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG Group, n=83)
Comparison
Standard GVHD prophylaxis without ATLG (non-ATLG group, n=72)
Outcome
Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group. ATLG was descriptively superior to non-ATLG at 24 months for physical function and social function, gastrointestinal side-effects and effect on. Extended follow-up confirmed a lower 5-year cGVHD incidence , no increase in relapses, improved cGRFS, and fewer patients still in immunosuppression 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.
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Impact of t-cell depletion strategies on outcomes following hematopoietic stem cell transplantation for idiopathic aplastic anemia: A study on behalf of the european blood and marrow transplant (ebmt) saa working party
Samarasinghe, S., Clesham, K., Iacobelli, S., Sbianchi, G., Knol, C., Hamladji, R. M., Socie, G., Aljurf, M., Koh, M., Sengeloev, H., et al
American journal of hematology. 2018
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Editor's Choice
Abstract
We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) haemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either ATG (n=1283), alemtuzumab (n=261) or no serotherapy (NS) (n=293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared to no serotherapy (p=0.021 and p=0.003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared to ATG (P=0.012) and no serotherapy (p < 0.001). By multivariate analysis, when compared to ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14-0.47; p<0.001) and chronic GVHD (HR 0.58; 95% CI 0.35 - 0.94; p=0.027). OS was significantly better in ATG and alemtuzumab patients compared with no serotherapy (p=0.010 and p=0.025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared to ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA. This article is protected by copyright. All rights reserved.
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Transplant results in adults with Fanconi anaemia
Bierings, M., Bonfim, C., Peffault De Latour, R., Aljurf, M., Mehta, P. A., Knol, C., Boulad, F., Tbakhi, A., Esquirol, A., McQuaker, G., et al
British Journal of Haematology. 2018;180(1):100-109
Abstract
The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76-87%), acute graft-versus-host disease (GvHD) grade II-IV in 22% (95% CI 16-28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.Copyright © 2017 John Wiley & Sons Ltd.
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Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned
Risitano, A. M., Marotta, S., Calzone, R., Grimaldi, F., Zatterale, A., Riaf Contributors
Haematologica. 2016;101(3):319-27
Abstract
The natural history of Fanconi anemia remains hard to establish because of its rarity and its heterogeneous clinical presentation; since 1994, the Italian Fanconi Anemia Registry has collected clinical, epidemiological and genetic data of Italian Fanconi Anemia patients. This registry includes 180 patients with a confirmed diagnosis of Fanconi anemia who have either been enrolled prospectively, at diagnosis, or later on. After enrollment, follow-up data were periodically collected to assess the clinical course, possible complications and long-term survival; the median follow up was 15.6 years. The main goal of the study was to describe the natural history of Fanconi anemia, focusing on the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation and survival. Typical morphological and/or hematological abnormalities and/or growth retardation were the most common manifestations at diagnosis; the majority of patients (77%) exhibited hematological abnormalities at the initial presentation, and almost all (96%) eventually developed hematological manifestations. More than half of the patients (57%) underwent a bone-marrow transplant. The occurrence of cancer was quite rare at diagnosis, whereas the cumulative incidence of malignancies at 10, 20 and 30 years was 5%, 8% and 22%, respectively, for hematological cancers and 1%, 15% and 32%, respectively, for solid tumors. Overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively; the main causes of death were cancer, complications of the hematological presentation and complications of transplantation. These data clearly confirm the detrimental outcome of Fanconi anemia, with no major improvement in the past decades. Copyright© Ferrata Storti Foundation.