Sinusoidal obstruction syndrome (SOS) formerly known as Veno-occlusive disease (VOD) is a potentially fatal complication that occurs mainly after haematopoietic cell transplantation, especially allogeneic transplantation. The liver is the principal organ affected, though other organs, such as the lungs, may also be involved to a lesser extent. The condition is characterised by obstruction of the hepatic venules, leading to sinusoidal congestion, hepatic ischaemia and, in severe cases, fulminant liver failure. Recent refined diagnostic criteria, published by the European Society for Blood and Marrow Transplantation in 2023, provide a more accurate method of detecting SOS/VOD, allowing earlier intervention and better stratification of patients according to the severity of their disease. This article focuses on liver SOS/VOD and discussing key risk factors, new diagnostic methods and therapeutic strategies, with an emphasis on the early use of defibrotide, which remains the reference treatment for severe SOS/VOD.

AbstractThe frequency and severity of hepatic complications during hematopoietic cell transplantation (HCT) markedly decreased in the last decade, thanks to improvements in preventive and therapeutic measures for most frequent complications, as fungal infections, hepatotropic viruses, sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), hepatic graft-versus-host disease (GVHD), and improved management of hepatotoxic drugs and iron overload (Hockenbery et al. 2016).

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.

This international questionnaire survey aimed to explore the current incidence, diagnostic policies, management, and outcomes of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) among healthcare providers involved in the management of these patients. A questionnaire was e-mailed to practitioners with an interest in allogeneic hematopoietic cell transplantation (allo-HCT). Of the respondents, 144 of 215 (67.0%) felt that early detection or diagnosis of VOD/SOS was difficult. Regarding diagnostic criteria, 142 (66.1%) already declared using the 2023 EBMT refined criteria. Most respondents (163/215, 75.8%) found these recent refined EBMT criteria useful for diagnosis, and 193 (89.8%) found the severity criteria easy to use. The major risk factors identified for VOD/SOS were a second allo-HCT (41.4%), pre-existing liver disease (54.9%), and prior use of antibody-drug conjugates (49.8%). Preferences for starting VOD/SOS treatment varied, with 61 (28.4%) preferring initiating therapy at a mild stage, and 122 (56.7%) preferring the moderate stage. In summary, this survey provided valuable insight into the challenges and opportunities of the identification and management of VOD/SOS. By improving current knowledge and increasing collaboration among healthcare professionals, early detection, management, and clinical outcomes for patients with this potentially serious complication can also be improved.

Obesity and diabetes can modulate immune responses, which may impact allogeneic HCT outcomes and GvHD. From the EBMT registry, we included 36,539 adult patients who underwent allogeneic HCT for a hematological malignancy between 2016 and 2020. Of these, 5228 (14%) had obesity (BMI ≥ 30 kg/m2), 1415 (4%) had diabetes (requiring treatment with insulin or oral hypoglycemics), and 688 (2%) had obesity + diabetes pre-transplantation. Compared with patients without diabetes or obesity, the hazard ratio (HR) of grade II–IV acute GvHD was 1.00 (95% confidence interval [CI] 0.94–1.06, p = 0.89) for patients with obesity, 0.95 (CI 0.85–1.07, p = 0.43) for patients with diabetes, and 0.96 (CI 0.82–1.13, p = 0.63) for patients with obesity + diabetes. Non-relapse mortality was higher in patients with obesity (HR 1.08, CI 1.00–1.17, p = 0.047), diabetes (HR 1.40, CI 1.24–1.57, p < 0.001), and obesity + diabetes (HR 1.38, CI 1.16–1.64, p < 0.001). Overall survival after grade II–IV acute GvHD was lower in patients with diabetes (HR 1.46, CI 1.25–1.70, p < 0.001). Pre-transplantation diabetes and obesity did not influence the risk of developing acute GvHD, but pre-transplantation diabetes was associated with poorer survival after acute GvHD.

The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome.

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0–100 days, 101 days–1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4–108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1–7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3–5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. Conclusions: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies.

Objectives AML-2003 study sought to compare the long-term efficacy and safety of IAT and IdAraC-Ida in induction chemotherapy of acute myeloid leukemia (AML) and introduce the results of an integrated genetic and clinical risk classification guided treatment strategy. Methods Patients were randomized to receive either IAT or IdAraC-Ida as the first induction treatment. Intensified postremission strategies were employed based on measurable residual disease (MRD) and risk classification. Structured questionnaire forms were used to gather data prospectively. Results A total of 356 AML patients with a median age of 53 years participated in the study. Long-term overall survival (OS) and relapse-free survival (RFS) were both 49% at 10 years. The median follow-up was 114 months. No significant difference in remission rate, OS or RFS was observed between the two induction treatments. Risk classification according to the protocol, MRD after the first and the last consolidation treatment affected the OS and RFS significantly (p < .001). Conclusions Intensified cytarabine dose in the first induction treatment was not better than IAT in patients with AML. Intensification of postremission treatment in patients with clinical risk factors or MRD seems reasonable, but randomized controlled studies are warranted in the future.

The role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000–2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group ( p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively ( p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group ( p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs.Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement.Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches.Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival.Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients.Novel approaches in treatment include oligonucleotides and complement inhibitors.Indications for these treatments according to different diagnostic criteria are still to be defined.Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders.

Corticosteroids have an established role as the fi rst-line treatment of graft -versus-host disease (GvHD), but their role in the prophylaxis of GvHD is less clear.At present, corticosteroids are included in the prophylaxis regimens only rarely.Studies of adding corticosteroid to the most widely used prophylactic regimen, cyclosporine A and a short course of methotrexate, have yielded confl icting results, possibly due to diff erences in the treatment schedule.In our earlier published randomized prospective study, the addition of methylprednisolone (MP) to cyclosporine and methotrexate resulted in a markedly reduced incidence of acute GvHD.No diff erence was seen in the survival.In long-term follow-up of this study, aft er a median follow-up of 24.5 years in living patients, we observed a marked late non-relapse mortality among the patients not given prophylactic MP, probably due to higher incidence of chronic GvHD in this study arm.At the end of the follow-up, 55% of the patients given MP in the prophylaxis were alive, compared with 20% in the control arm.Th ese fi ndings suggest that the role of corticosteroids in GvHD prophylaxis should be reevaluated.

A survey was carried out among EBMT centers about the use of busulfan for conditioning in allogeneic stem cell transplantation. Of 109 responding centers, 106 used busulfan for conditioning, 102 in conventional myeloablative doses, and 93 in reduced doses (RIC). The route of administration was mostly intravenous, but ~10% of the centers gave the drug orally. The number of doses in i.v. administration varied and was in myeloablative conditioning mostly one (50 centers) or four (43 centers) doses a day. Seventeen of the 106 centers used pharmacokinetics for dose adjustment in myeloablative conditioning, nine in RIC. The details of pharmacokinetic monitoring varied markedly. Three quarters of the centers reported adjusting the dose based on obesity in myeloablative conditioning and about 60% in RIC. The most common method for dose calculation was ideal body weight + 0.25 × (actual body weight − ideal body weight). In conclusion, the present survey showed marked heterogeneity in the current practices of busulfan administration for conditioning. The impact of the heterogeneity is not well known. Due to this and the scarcity of support from controlled clinical studies, no clear guidelines can be presented, but some prevailing policies to be recommended were identified.

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.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). While SOS/VOD may resolve within a few weeks in the majority of patients with mild-to-moderate disease, the most severe forms result in multiorgan dysfunction and are associated with a high mortality rate (>80%). Therefore, careful surveillance may allow early detection of SOS/VOD, particularly as the licensed available drug is proven to be effective and reduce mortality. The aim of this work is to propose an international consensus guideline for the treatment and prevention of SOS/VOD in adult patients, on behalf of an international expert group.

BACKGROUNDIn a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen‐identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP‐) as a part of graft‐versus‐host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP.METHODSIn the current study, the authors performed a long‐term follow‐up to discover possible late effects of the intensified GVHD prophylaxis.RESULTSThe median follow‐up for surviving patients was 24.5 years. In the MP+ group, the overall survival and recurrence‐free survival were higher (P = .021 and P = .028, respectively) and the nonrecurrence mortality was lower (P = .003) than in the MP‐ group. There was a trend toward a lower cumulative incidence and a significantly lower prevalence (P = .031) of chronic GVHD in the MP+ group. There was no difference noted with regard to the rate of disease recurrence or in the incidence of secondary malignancies. Eleven patients in the MP‐ group but none in the MP+ group died >15 years after transplantation. At the end of follow‐up, the overall survival rates in the MP+ and MP‐ groups were 55% and 20%, respectively, and the recurrence‐free survival rates were 49% and 15%, respectively.CONCLUSIONSLong‐term survival was found to be higher among the patients given MP in addition to cyclosporine and methotrexate. There was marked late nonrecurrence mortality observed in the group not given MP. No adverse late effects caused by the addition of corticosteroid were observed. Cancer 2018;124:727‐33. © 2017 American Cancer Society.

Background: We previously demonstrated that the addition of human anti-T lymphocyte globulin (ATLG) to cyclosporine and methotrexate, given to acute leukemia patients in remission undergoing allogeneic hematopoietic stem cell transplantation (HSCT) with peripheral blood stem cells (PBSC) from an HLA-identical sibling donor after a myeloablative conditioning, significantly reduces 2-yr cGVHD incidence (primary endpoint) and severity without increasing disease relapse and infections, improving cGVHD/relapse-free survival (cGRFS). Since very limited information on long-term follow-up has been reported, we extended the observation time of the original study. Methods: Between 2005 and 2012, 161 patients were randomized to receive or not ATLG in addition to cyclosporine and methotrexate. 155 patients were included in the full analysis set. Quality of life (QoL), assessed using EORTC-QLQ-C30 and QLQ-HDC29 questionnaires, was the unpublished secondary endpoint. An extension of follow-up was then performed with the aim of evaluating the long-term outcome. The trial is registered at ClinicalTrials.gov (NCT03042676, NCT00678275). Findings: Global health status (p=0·02), physical function (p=0·014), social function (p=0·047), gastrointestinal side-effects (p=0·008) and impact on family (p=0·032) scored higher in the ATLG arm. Extended follow-up (median 5.9 years) confirmed a lower 5 -yr cGVHD incidence (30·0% vs 69·1%, p<0·001), no increase of relapses (32·4% vs 25·5%, p=0·09), an improved cGRFS (34·4% vs 13·9%, p=0·005), fewer patients still in immunosuppression (9·6% vs 28·3%, p=0·017) in the ATLG arm. 5-yr overall survival, relapse-free survival and non-relapse mortality didn't significantly differ between arms. Interpretation: ATLG improves QoL after HLA identical sibling HSCT with PBSC and its beneficial effect on cGVHD incidence and cGRFS is confirmed even after long-term follow-up. Trial registration number: The trial is registered at ClinicalTrials.gov (NCT03042676, NCT00678275). Funding: NEOVII Biotech provided the study drug and a research grant but did neither have access to data nor decide to submit the manuscript. Declaration of Interest: FB, and NK received speaker-fees and served on the advisory boards for NEOVII Biotech; NK received a research grant from NEOVII Biotech; all the remaining authors declare no competing financial conflict of interest. Ethical Approval: The study was approved by each competent local Ethics Committees, conducted according to the Helsinki declaration.

Recommendations on screening and nutritional support for patients undergoing hematopoietic stem cell transplantation (HSCT) have been presented by international nutritional societies, but nutritional practices remain poorly standardized. Following the general policy of the European Society for Blood and Marrow Transplantation (EBMT) to standardize transplantation procedures, the Complications and Quality of Life Working Party and Nursing Research Group carried out a survey among all EBMT centers about their current nutritional practices. The aim of this study was to better understand current practices, differences from available guidelines, and possible barriers for recommended nutritional therapy. Responses from 90 centers (19%) from 23 countries were received. We observed a marked variability in nutritional care between EBMT centers and a substantial lack of standardized operating procedures in screening patients for malnutrition and management of gastrointestinal GVHD. Furthermore, our study confirmed neutropenic diet as standard of care in most centers as well a preference for parenteral nutritional support over enteral. On the basis of these findings, future EBMT efforts will focus on better implementation of international nutritional guidelines into clinical practice.