Efficacy of conventional-dose cytarabine, idarubicin and thioguanine versus intermediate-dose cytarabine and idarubicin in the induction treatment of acute myeloid leukemia: Long-term results of the prospective randomized nationwide AML-2003 study by the Finnish Leukemia Group.

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.

Long-term outcome after allogeneic stem cell transplantation in multiple myeloma.

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.

Investigation and Management of Bone Mineral Density Following Hematopoietic Cell Transplantation: A Survey of Current Practice by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

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.

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

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.).

A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis.

BACKGROUND: In 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. METHODS: In the current study, the authors performed a long-term follow-up to discover possible late effects of the intensified GVHD prophylaxis. RESULTS: The 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. CONCLUSIONS: Long-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.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program.

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose.

Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study.

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.

Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a randomized study.

We report the long-term results of a prospective randomized study on the use of ursodeoxycholic acid (UDCA) for prevention of hepatic complications after allogeneic stem cell transplantation. Two hundred forty-two patients, 232 with malignant disease, were randomized to receive (n = 123) or not to receive (n = 119) UDCA from the beginning of the conditioning until 90 days post-transplantation. The results were reported after 1-year follow-up. UDCA administration reduced significantly the proportion of patients developing high serum bilirubin levels as well as the incidence of severe acute graft-versus-host disease (GVHD), liver GVHD, and intestinal GVHD. In the UDCA prophylaxis group, nonrelapse mortality (NRM) was lower and overall survival better than in the control group. After a 10-year follow-up, the difference in the survival and NRM in favor of the UDCA-treated group, seen at 1 year, was maintained (survival 48% versus 38%, P = .037; NRM 28% versus 41%, P = .01). A landmark analysis in patients surviving at 1 year post-transplantation showed no significant differences between the study groups in the long-term follow-up in chronic GVHD, relapse rate, NRM, disease-free survival, or overall survival. These long-term results continue to support the useful role of UDCA in the prevention of transplant-related complications in allogeneic transplantation.

Should the standard dimethyl sulfoxide concentration be reduced? Results of a European Group for Blood and Marrow Transplantation prospective noninterventional study on usage and side effects of dimethyl sulfoxide.

BACKGROUND: Dimethyl sulfoxide (DMSO) is essential for the preservation of liquid nitrogen-frozen stem cells, but is associated with toxicity in the transplant recipient. STUDY DESIGN AND METHODS: In this prospective noninterventional study, we describe the use of DMSO in 64 European Blood and Marrow Transplant Group centers undertaking autologous transplantation on patients with myeloma and lymphoma and analyze side effects after return of DMSO-preserved stem cells. RESULTS: While the majority of centers continue to use 10% DMSO, a significant proportion either use lower concentrations, mostly 5 or 7.5%, or wash cells before infusion (some for selected patients only). In contrast, the median dose of DMSO given (20 mL) was much less than the upper limit set by the same institutions (70 mL). In an accompanying statistical analysis of side effects noted after return of DMSO-preserved stem cells, we show that patients in the highest quartile receiving DMSO (mL and mL/kg body weight) had significantly more side effects attributed to DMSO, although this effect was not observed if DMSO was calculated as mL/min. Dividing the myeloma and lymphoma patients each into two equal groups by age we were able to confirm this result in all but young myeloma patients in whom an inversion of the odds ratio was seen, possibly related to the higher dose of melphalan received by young myeloma patients. CONCLUSION: We suggest better standardization of preservation method with reduced DMSO concentration and attention to the dose of DMSO received by patients could help reduce the toxicity and morbidity of the transplant procedure.

The impact of pre-transplantation diabetes and obesity on acute graft-versus-host disease, relapse and death after allogeneic hematopoietic cell transplantation: a study from the EBMT Transplant Complications Working Party.

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.

An international survey to better understand the current incidence, severity, and management of VOD/SOS.

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.

Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation.

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.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study.

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.

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).

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). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score.

Complications of Autologous Stem Cell Transplantation in Multiple Myeloma: Results from the CALM Study.

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.

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial.

BACKGROUND: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome. DESIGN AND METHODS: A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m(2) treosulfan and 5×30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival. RESULTS: All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively. CONCLUSIONS: Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490.

Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial.

BACKGROUND: Most allogeneic haematopoietic stem cell transplants now use peripheral blood progenitor cell transplantation (PBPCT) instead of bone-marrow transplantation (BMT). Long-term data on outcome and late effects of PBPCT compared with BMT are scarce. Here we present long-term data from a randomised study comparing PBPCT with BMT. METHODS: Between February, 1995, and September, 1999, 329 patients with leukaemia received either PBPCT (n=163) or BMT (n=166) from HLA-identical sibling donors after central randomisation accounting for stratification criteria. Follow-up data were collected via questionnaires from 87% (176 of 202; 84 PBPCT, 92 BMT) patients who survived for more than 3 years (median of 9.3 years) after transplantation. Efficacy analyses included all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01020175. FINDINGS: 10-year overall survival was 49.1% for patients who underwent PBPCT and 56.5% for patients who underwent BMT (HR 0.83, 95% CI 0.60-1.15; p=0.27). Leukaemia-free survival was 28.3% with BMT versus 13.0% with PBPCT (0.61, CI 0.32-1.16; p=0.12) for acute lymphoblastic leukaemia; 62.3% with BMT versus 47.1% with PBPCT for acute myeloid leukaemia (0.67, 0.39-1.16; p=0.16); and 40.2% with BMT versus 48.5% with PBPCT for chronic myeloid leukaemia (1.12, 0.73-1.74; p=0.60). More patients developed chronic graft-versus-host disease after PBPCT (n=56, 73%) than after BMT (n=46, 56%; p=0.021), with more frequent involvement of skin, liver, and oral mucosa, and more patients who underwent PBPCT needed immunosuppressive treatment 5 years after transplantation (n=20, 26%) than patients who had BMT (n=10, 12%; p=0.024). Nonetheless, there was no difference in performance status, return to work, incidence of bronchiolitis obliterans, and haematopoietic function between the two groups. 14 cases of secondary malignancies occurred (five after BMT, nine after PBPCT), resulting in a cumulative incidence of 3% and 7% after BMT and PBPCT (p=0.17), respectively. INTERPRETATION: More than 9 years after transplantation, overall and leukaemia-free survival remain similar in patients who underwent BMT and PBPCT. Differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression exist, but do not affect survival, general health status, or late events. FUNDING: No external funding was received.

Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome.

The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI]=13.3%-14.1%). The mean incidence of VOD was significantly lower between 1979-1994 than between 1994-2007 (11.5% [95% CI, 10.9%-12.1%] vs 14.6% [95% CI, 14.0%-15.2%]; P <.05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%-88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome.

Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia.

BACKGROUND: Non-HLA gene polymorphisms have been shown to influence outcome after allogeneic hematopoietic stem cell transplantation. Results were derived from heterogeneous, small populations and their value remains a matter of debate. DESIGN AND METHODS: In this study, we assessed the effect of single nucleotide polymorphisms in genes for interleukin 1 receptor antagonist (IL1RN), interleukin 4 (IL4), interleukin 6 (IL6), interleukin 10 (IL10), interferon (IFNG), tumor necrosis factor (TNF) and the cell surface receptors tumor necrosis factor receptor II (TNFRSFIB), vitamin D receptor (VDR) and estrogen receptor alpha (ESR1) in a homogeneous cohort of 228 HLA identical sibling transplants for chronic myeloid leukemia. Three good predictors of overall survival, identified via statistical methods including Cox regression analysis, were investigated for their effects on transplant-related mortality and relapse. Predictive power was assessed after integration into the established European Group for Blood and Marrow Transplantation (EBMT) risk score. RESULTS: Absence of patient TNFRSFIB 196R, absence of donor IL10 ATA/ACC and presence of donor IL1RN allele 2 genotypes were associated with increased transplantation-related mortality and decreased survival. Application of prediction error and concordance index statistics gave evidence that integration improved the EBMT risk score. CONCLUSIONS: Non-HLA genotypes were associated with survival after allogeneic hematopoietic stem cell transplantation. When three genetic polymorphisms were added into the EBMT risk model they improved the goodness of fit. Non-HLA genotyping could, therefore, be used to improve donor selection algorithms and risk assessment prior to allogeneic hematopoietic stem cell transplantation.