Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma in Switzerland, 20 years of experience: 2001-2020.

Despite the high cure rate with initial therapy, approximately 10% of Hodgkin lymphoma (HL) patients are refractory to initial treatment, and up to 30% of patients will relapse after achieving initial complete remission. Despite promising initial results of treatment by immune checkpoint inhibitors, most patients will eventually progress. We analyzed 62 adult patients with relapsed or refractory HL (rrHL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in one of three University Hospitals of Switzerland (Zurich, Basel, and Geneva) between May 2001 and January 2020. The primary endpoint was overall survival (OS). Secondary endpoints were relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence, which were assessed in univariate analysis. The median follow-up was 61 months (interquartile range 59-139). The 2- and 5-year OS was 54% (standard error (SE) ±12) and 50.2% (SE ±13.3), respectively, and the 2- and 5-year RFS was 40.7% (SE ±16.3) and 34.4% (SE ±19.0), respectively. NRM was 23.1% (SE ±2.2) and 27.4% (SE ±2.5) at 2 and 5 years, respectively. The cumulative incidence of relapse was 36.1% (SE ±5.6) at 2 years and 38.2% (SE ±6.6) at 5 years. Our analysis of allo-HSCT outcomes in the context of rrHL shows encouraging OS and RFS rates, with the mortality rate reaching plateau at 50% at 2 years after allo-HSCT. This confirms that allo-HSCT still remains as a potentially curative option for half of patients with rrHL.

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

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.

Pretransplant Genetic Susceptibility: Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA.

Narrowing the gap for hematopoietic stem cell transplantation in the East-Mediterranean/African region: comparison with global HSCT indications and trends.

Hematopoietic Stem Cell Transplantation (HSCT) activity was evaluated in the African (AFR)/EMRO region and compared to the global activity for the years 2006-2013. Data were obtained from 1570 teams in the 6 WHO continental regions. Of these, 29 (1.85%) of all teams were active in 12 of the 68 AFR/EMRO countries. They reported 2.331 (3.3%) of the worldwide 71.036 HSCT, and a transplant rate of 32.8 (TR; HSCT/10 million inhabitants; worldwide 128.5). This reflects still the lowest regional TR despite an increase of 90% since 2006. HSCT activity in AFR/EMRO countries was characterized by a higher use of allogeneic compared to autologous HSCT, an almost exclusive use of family donors, including haploidentical family donors. These findings contrast with the prevalence of autologous over allogeneic HSCT, and a higher frequency of unrelated HSCT in other parts of the world. Of note, the increase by 200% in HSCT for hemoglobinopathies from 2006 to 2013 (72 per year) in the AFR/EMRO region. This reflects the specific role of HSCT for these disease categories with high prevalence and incidence in the AFR/EMRO region. This report provides information for the competent authorities to foster adequate infrastructure. It urges transplant organization to optimize their cooperation.

Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: An analysis by the Acute Leukemia Working Party of the EBMT.

BACKGROUND: Anti-thymocyte globulin (ATG) is widely used to prevent graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (alloPBSCT). The goal of this study was to retrospectively assess the effect of ATG on outcomes in the setting of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). METHODS: In the analysis, 1170 adult patients undergoing alloPBSCT from human leucocyte antigen-matched sibling or unrelated donors in the first complete remission between 2007 and 2016 were included. ATG was used in 429/575 (75%) and 121/595 (20%) patients transplanted from unrelated or sibling donors, respectively. RESULTS: The incidence of chronic GVHD was 35% for patients treated with ATG compared with 52% in those not receiving ATG (p < 0.001), while the rate of extensive chronic GVHD was 16% and 36%, respectively (p < 0.001). The probability of survival free from GVHD and relapse (GRFS) was 42% and 32%, respectively (p = 0.002). In a multivariate model, the use of ATG was associated with reduced risk of overall chronic GVHD (hazard ratio [HR] = 0.52, p < 0.001) and extensive chronic GVHD (HR = 0.46, p < 0.001). It was also associated with better GRFS (HR = 0.77, p = 0.007), despite increased risk of relapse (HR = 1.41, p = 0.02). No significant effect was found with regard to the risk of non-relapse mortality and overall mortality. CONCLUSIONS: The use of ATG for patients with Ph+ ALL undergoing alloPBSCT is associated with reduced risk of chronic GVHD without impact on survival and therefore, could be considered. However, increased risk of relapse suggests the need for strict monitoring of minimal residual diseases and appropriate interventions after transplantation.

Comparable outcomes of haploidentical, 10/10 and 9/10 unrelated donor transplantation in adverse karyotype AML in first complete remission.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most powerful therapy preventing relapse in patients with adverse cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1). In the absence of a matched related donor, potential alternatives include 10/10, 9/10 HLA-matched unrelated (UD) or haploidentical (Haplo) donors. We analyzed clinical outcomes of patients undergoing T-cell repleted Haplo (n = 74), 10/10 UD (n = 433) and 9/10 UD HSCT (n = 123) from 2007 to 2015, reported to the EBMT Registry. Adverse risk AML was defined according to the 2017 ELN cytogenetic risk classification. The 2-year nonrelapse mortality was 19% for Haplo, 18% for 10/10 UD and 18% for 9/10 UD (P = .9). The relapse incidence was not significantly affected by donor source, with a 2-year incidence of 27% for Haplo HSCT, 39% for 10/10 UD and 37% for 9/10 UD SCT (P = .3). We show comparable probabilities of leukemia-free survival (LFS) and overall survival (OS) at 2 years among Haplo HSCT, 10/10 UD SCT and 9/10 UD SCT (53% and 59%, 43% and 50%, 44% and 50%, respectively, P = .5 for both parameters). The type of donor was not significantly associated with either acute or chronic graft-vs.-host disease incidence. Using multivariable Cox model, Haplo HSCT recipients experienced comparable OS and LFS to 10/10 and 9/10 UD. In the present series of adverse cytogenetics AML patients in CR1, Haplo HSCT recipients had comparable outcomes to those of 10/10 and 9/10 UDs, suggesting that all these types of HSCT may be considered a valid option in this high risk population.

Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation (alloHCT) with myeloablative conditioning based on total body irradiation (TBI) is widely used for the treatment of adults with acute lymphoblastic leukemia (ALL). TBI is most frequently administered in combination with either cyclophosphamide (Cy/TBI) or etoposide (Vp/TBI). The goal of this study was to retrospectively compare these two regimens. Adult patients with Ph-negative ALL treated with alloHCT in first or second complete remission who received Cy/TBI (n = 1346) or Vp/TBI (n = 152) conditioning were included in the analysis. In a univariate analysis, as compared to Cy/TBI, the use of Vp/TBI was associated with reduced incidence of relapse (17% vs. 30% at 5 years, P = .007), increased rate of leukemia-free survival (60% vs. 50%, P = .04), and improved "graft versus host disease (GVHD) and relapse-free survival" (GRFS, 43% vs. 33%, P = .04). No significant effect could be observed in terms of the incidence of nonrelapse mortality or acute or chronic GVHD. In a multivariate model, the use of Vp/TBI was associated with reduced risk of relapse (HR = 0.62, P = .04) while the effect on other study end-points was not significant. In conclusion, conditioning regimen based on Vp combined with TBI appears more effective for disease control than the combination of Cy with TBI for adult patients with Ph-negative ALL treated with alloHCT.

Incidence, Risk Factors, and Long-term Outcome of Acute Leukemia Patients With Early Candidemia After Allogeneic Stem Cell Transplantation: A Study by the Acute Leukemia and Infectious Diseases Working Parties of European Society for Blood and Marrow Transplantation.

Background: This study was performed to assess the incidence of and risk factors for Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods: We performed an outcome analysis of 28542 acute leukemia patients who underwent HSCT from 2000 to 2012. There were 347 patients with candidemia by day 100 and 28195 without candidemia or any other type of Candida infection. Results: The incidence of candidemia by day 100 was 1.2% and occurred at a median of 22 days after HSCT. Higher 100-day nonrelapse mortality (NRM; hazards ratio [HR], 3.0, P < .0001) and lower 100-day overall survival (OS; HR, 2.5, P < .0001) were observed in patients with candidemia. The case fatality rate by day 100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were female gender, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft vs host disease. Among the patients alive at day 100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% confidence interval, 5.5 - 5.7) for patients with and without candidemia were 22.5% vs 13.5%, P < .0001 and 45.6% vs. 53.4%, P = .0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day 100 was an independent risk factor for higher NRM (HR, 1.7, P = .001) and lower OS (HR, 1.4, P = .001). Conclusions: The early occurrence of candidemia after HSCT is still associated with higher NRM and lower short- and-long-term OS.

Baseline Characteristics Predicting Very Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Patients With High Cytogenetic Risk Chronic Lymphocytic Leukemia - A Retrospective Analysis From the Chronic Malignancies Working Party of the EBMT.

BACKGROUND: Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population. PATIENTS AND METHODS: Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90.4 months) by Cox regression modeling, and predicted probabilities of NRM and PFS of 2 reference patients with favorable or unfavorable characteristics were plotted. RESULTS: Predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.1-2.5) and partially human leukocyte antigen (HLA)-mismatched unrelated donor (HR, 2.8; 95% CI, 1.5-5.2). The latter variable also predicted a higher risk of 2-year NRM (HR, 4.0; 95% CI, 1.4-11.6) compared with HLA-matched sibling donors. Predicted 2-year NRM and 8-year PFS of a high cytogenetic risk (del(17p) and/or del(11q)) patient in remission with a matched related donor were 12% (95% CI, 3%-22%) and 54% (95% CI, 38%-69%), and for an unresponsive patient with a female partially HLA-matched unrelated donor 37% (95% CI, 12%-62%) and 38% (95% CI, 13%-63%). CONCLUSION: Low predicted NRM and high 8-year PFS in favorable transplant high cytogenetic risk patients compares favorably with outcomes with KI or BCL2i. Taking into account the amount of uncertainty for predicting survival after alloHCT and after sequential administration of KI and BCL2i, alloHCT remains a valid option for younger patients with high cytogenetic risk chronic lymphocytic leukemia with a well-HLA-matched donor.

Individual quality assessment of autografting by probability estimation for clinical endpoints: a prospective validation study from the European group for blood and marrow transplantation.

The aim of supportive autografting is to reduce the side effects from stem cell transplantation and avoid procedure-related health disadvantages for patients at the lowest possible cost and resource expenditure. Economic evaluation of health care is becoming increasingly important. We report clinical and laboratory data collected from 397 consecutive adult patients (173 non-Hodgkin lymphoma, 30 Hodgkin lymphoma, 160 multiple myeloma, 7 autoimmune diseases, and 28 acute leukemia) who underwent their first autologous peripheral blood stem cell transplantation (PBSCT). We considered primary endpoints evaluating health economic efficacy (eg, antibiotic administration, transfusion of blood components, and time in hospital), secondary endpoints evaluating toxicity (in accordance with Common Toxicity Criteria), and tertiary endpoints evaluating safety (ie, the risk of regimen-related death or disease progression within the first year after PBSCT). A time-dependent grading of efficacy is proposed with day 21 for multiple myeloma and day 25 for the other disease categories (depending on the length of the conditioning regimen) as the acceptable maximum time in hospital, which together with antibiotics, antifungal, or transfusion therapy delineates four groups: favorable (≤7 days on antibiotics and no transfusions; ≤21 [25] days in hospital), intermediate (from 7 to 10 days on antibiotics and <3 transfusions, ≤21 to 25 days in hospital or ≥7 days on antibiotics and no transfusions; from 21 to 30 days [25 to 34] in hospital), unfavorable (>7 days on antibiotics, >3 but <6 transfusions; >30/34 days in hospital after transplantation), and very unfavorable (>10 days on antibiotics, >6 transfusions; >30 to 34 days in hospital). The multivariate analysis showed that (1) PBSC harvests of ≥4 × 10(6)/kg CD34 + cells in 1 apheresis procedure were associated with a favorable outcome in all patient categories except acute myelogenous leukemia and acute lymphoblastic leukemia (P = .001), (2) ≥5 × 10(6)/kg CD34 + cells infused predicted better transplantation outcome in all patient categories (P < .0001) except acute myelogenous leukemia and acute lymphoblastic leukemia, (3) 1 or 2 aphereses (P = .001) predicted good outcome, (4) toxicity increased with higher graft volume reinfused (>500 mL) (P = .002), and (5) patients with a central venous catheter during both collection and infusion of PBSC had a more favorable outcome post-PBSCT than peripheral access (P = .007). The type of mobilization regimen did not affect the outcome of auto-PBSCT. The present study identified predictive variables, which may be useful in future individual pretransplantation probability evaluations with the goal to improve supportive care.

Immunological and autoimmune considerations of Autism Spectrum Disorders.

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.

Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

BACKGROUND: Although Hodgkin's lymphoma is a highly curable disease with modern chemotherapy protocols, some patients are primary refractory or relapse after first-line chemotherapy or even after high-dose therapy and autologous stem cell transplantation. We investigated the potential role of allogeneic stem cell transplantation in this setting. DESIGN AND METHODS: In this phase II study 92 patients with relapsed Hodgkin's lymphoma and an HLA-identical sibling, a matched unrelated donor or a one antigen mismatched, unrelated donor were treated with salvage chemotherapy followed by reduced intensity allogeneic transplantation. Fourteen patients showed refractory disease and died from progressive lymphoma with a median overall survival after trial entry of 10 months (range, 6-17). Seventy-eight patients proceeded to allograft (unrelated donors, n=23). Fifty were allografted in complete or partial remission and 28 in stable disease. Fludarabine (150 mg/m(2) iv) and melphalan (140 mg/m(2) iv) were used as the conditioning regimen. Anti-thymocyte globulin was additionally used as graft-versus-host-disease prophylaxis for recipients of grafts from unrelated donors. RESULTS: The non-relapse mortality rate was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. The progression-free survival rate was 47% at 1 year and 18% at 4 years from trial entry. For the allografted population, the progression-free survival rate was 48% at 1 year and 24% at 4 years. Chronic graft-versus-host disease was associated with a lower incidence of relapse. Patients allografted in complete remission had a significantly better outcome. The overall survival rate was 71% at 1 year and 43% at 4 years. CONCLUSIONS: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. The reduced intensity conditioning approach significantly reduced non-relapse mortality; the high relapse rate represents the major remaining challenge in this setting. The HDR-Allo trial was registered in the European Clinical Trials Database (EUDRACT, https://eudract.ema.europa.eu/) with number 02-0036.

Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party.

BACKGROUND: We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed. DESIGN AND METHODS: As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years). RESULTS: With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III-IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4). CONCLUSIONS: This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.

Autologous stem cell transplantation for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is responsive to treatment with immunosuppressives and steroids, but often pursues a relapsing or refractory course resulting in increasing incapacity and reduced survival. Autologous stem cell transplantation (ASCT) following immunoablative chemotherapy is a newer therapy for autoimmune disease of potential use in severe SLE. A retrospective registry survey was carried out by the European Blood and Marrow Transplant and European League Against Rheumatism (EBMT/EULAR) registry. Data was collected from 53 patients with SLE treated by ASCT in 23 centres. Disease duration before ASCT was 59 (2-155) months (median, range), 44 (83%) were female, and median age was 29 (9-52) years. At the time of ASCT a median of seven American College of Rheumatology (ACR) diagnostic criteria for SLE were present (range 2-10) and 33 (62%) had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor in 93% of cases. Ex vivo CD34 stem cell selection was performed in 42% of patients. Conditioning regimens employed cyclophosphamide in 84%, anti-thymocyte globulin in 76% and lymphoid irradiation in 22%. The mean duration of follow-up after ASCT was 26 (0-78) months. Remission of disease activity (SLEDAI < 3) was seen in 33/50 (66%; 95%CI 52-80) evaluable patients by six months, of which 10/31 (32%; 95%CI 15-50) subsequently relapsed after six (3-40) months. Relapse was associated with negative anti-double stranded DNA (anti-dsDNA) antibodies before ASCT (P = 0.007). There were 12 deaths after 1.5 (0-48) months, of which seven (12%; 95%CI 3-21) were related to the procedure. Mortality was associated with a longer disease course before ASCT (P = 0.036). In conclusion, this registry study demonstrates the efficacy of ASCT for remission induction of refractory SLE, although mortality appeared high. The safety of this procedure is likely to be improved by patient selection and choice of conditioning regimen. The return of disease activity in one-third of patients might be reduced by long-term immunosuppressive therapy post-ASCT.