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Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P<0.001). It was negligible in patients older than 70 years reflecting our own transplant policy but also barriers to transplantation (comorbidities and remission status). However, HSCT patients need to survive, be considered eligible both by the referring and the HSCT physicians and have a suitable donor to get transplantation. We, thus, comprehensively analyzed the complete decision-making and outcome of all our AML patients from diagnosis to last followup to decipher how patient allocation and therapy inform the value of HSCT. The role of HSCT in AML is shifting with broad access to different donors including haploidentical ones. Thus, it may (or may not) lead to increased numbers of allogeneic HSCT in AML in adults.

Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, graft-versus-host disease (GvHD) and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation included 479 patients with idiopathic SAA who underwent allo-HSCT in two conventional situations: i) upfront allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GvHD, extensive chronic GvHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (hazard ratio [HR]=4.08; 95% confidence interval [CI]: 1.41-11.83; P=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR=1.04; 95% CI: 1.02-1.06; P<0.001), acute GvHD (HR=1.03; 95% CI: 1.00-1.07; P=0.041), and chronic GvHD (HR=1.04; 95% CI: 1.01-1.08; P=0.032) as the cause of GRFS failure. GRFS after upfront MRD allo-HSCT was very good, notably with early allo-HSCT, confirming that younger patients with an MRD should be transplanted immediately. GRFS was worse in cases of salvage allo-HSCT, most notably in older patients, questioning the utility of allo-HSCT earlier in the disease course.

A cute graft- versus -host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft- versus -host disease. We examined outcome following diagnosis of grade II-IV acute graft- versus -host disease according to time period, and explored effects according to original graft- versus -host disease prophylaxis regimen and maximum overall grade of acute graft- versus -host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grade II-IV acute graft- versus -host disease (n=497 for 1999-2001, n=962 for 2002-2005, n=1,446 for 2006-2010). The median (range) follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the cohort with grade II-IV acute graft- versus -host disease, there was a decrease in the proportion of grade III-IV disease over time with 56%, 47%, and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively ( P <0.001). Considering the total study population, univariate analysis demonstrated significant improvements in overall survival and treatment-related mortality over time, and deaths from organ failure and infection declined. On multivariate analysis, significant improvements in overall survival ( P =0.003) and treatment-related mortality ( P =0.008) were only noted among those originally treated with tacrolimus-based graft- versus -host disease prophylaxis, and these effects were most apparent among those with overall grade II acute graft- versus -host disease. In conclusion, survival has improved over time for tacrolimus-treated transplant recipients with acute graft- versus -host disease., (Copyright© Ferrata Storti Foundation.)

We previously reported that bone marrow grafts from matched sibling donors resulted in best graft-versus-host disease-free, relapse-free survival at 1-year post allogeneic hematopoietic cell transplantation. However, pediatric patients comprised the majority of bone marrow graft recipients in that study. To better define this outcome in adults and pediatric patients at 1- and 2-years post- allogeneic hematopoietic cell transplantation, we pooled data from the University of Minnesota and the Hôpital Saint-Louis in Paris, France (n=1901). Graft-versus-host disease-free, relapse-free survival was defined as the absence of grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease (requiring systemic therapy or extensive stage), relapse and death. In adults, bone marrow from matched sibling donors (n=123) had best graft-versus-host disease-free, relapse-free survival at 1- and 2-years, compared with peripheral blood stem cell from matched sibling donors (n=540) or other graft/donor types. In multivariate analysis, peripheral blood stem cells from matched sibling donors resulted in a 50% increased risk of events contributing to graft-versus-host disease-free, relapse-free survival at 1- and 2-years than bone marrow from matched sibling donors. With limited numbers of peripheral blood stem cell grafts in pediatric patients (n=12), graft-versus-host disease-free, relapse-free survival did not differ between bone marrow and peripheral blood stem cell graft from any donor. While not all patients have a matched sibling donor, graft-versus-host disease-free, relapse-free survival may be improved by the preferential use of bone marrow for adults with malignant diseases. Alternatively, novel graft-versus-host disease prophylaxis regimens are needed to substantially impact graft-versus-host disease-free, relapse-free survival with the use of peripheral blood stem cell., (Copyright© Ferrata Storti Foundation.)

Complement blockade by eculizumab is clinically effective in hemolytic paroxysmal nocturnal hemoglobinuria. However, the response is variable and some patients remain dependent on red blood cell transfusions. In 72 patients with hemolytic paroxysmal nocturnal hemoglobinuria on eculizumab we tested the hypothesis that response may depend on genetic polymorphisms of complement-related genes. We found no correlation between the complement component C3 genotypes and the need for blood transfusions. On the other hand, we found a significant correlation with the HindIII polymorphism of a complement regulatory gene, the complement receptor 1 (CR1) gene. At this locus two co-dominant alleles are known, of which H (common) is associated with high expression, whereas L (rare) is associated with low expression of CR1 on red blood cells. Patients who still needed blood transfusion on eculizumab accounted for 18% of the H/H homozygotes, 33% of the H/L heterozygotes and 68% of the L/L homozygotes (P=0.016). Thus, patients with paroxysmal nocturnal hemoglobinuria who have the L/L genotype are seven times more likely to be sub-optimal responders to eculizumab. Both in vitro and in vivo we found that the CR1 HindIII genotype correlates with the abundance of paroxysmal nocturnal hemoglobinuria red cells that have bound C3, and with the kinetics of C3 binding. These results are consistent with the notion that by affecting C3 binding the CR1 genotype influences the response to eculizumab treatment, and this emerges as a novel example of pharmacogenetics.

The optimal post-remission treatment for acute myeloid leukemia in first complete remission remains uncertain. Previous comparisons of autologous versus allogeneic hematopoietic cell transplantation noted higher relapse, but lower treatment-related mortality though using bone marrow grafts, with treatment-related mortality of 12-20%. Recognizing lower treatment-related mortality using autologous peripheral blood grafts, in an analysis of registry data from the Center for International Blood and Transplant Research, we compared treatment-related mortality, relapse, leukemia-free survival, and overall survival for patients with acute myeloid leukemia in first complete remission (median ages 36-44, range 19-60) receiving myeloablative HLA-matched sibling donor grafts (bone marrow, n=475 or peripheral blood, n=428) versus autologous peripheral blood (n=230). The 5-year cumulative incidence of treatment-related mortality was 19% (95% confidence interval, 16-23%), 20% (17-24%) and 8% (5-12%) for allogeneic bone marrow, allogeneic peripheral blood and autologous peripheral blood stem cell transplant recipients, respectively. The corresponding figures for 5-year cumulative incidence of relapse were 20% (17-24%), 26% (21-30%) and 45% (38-52%), respectively. At 5 years, leukemia-free survival and overall survival rates were similar: allogeneic bone marrow 61% (56-65%) and 64% (59-68%); allogeneic peripheral blood 54% (49-59%) and 59% (54-64%); autologous peripheral blood 47% (40-54%) and 54% (47-60%); P=0.13 and P=0.19, respectively. In multivariate analysis the incidence of treatment-related mortality was lower after autologous peripheral blood transplantation than after allogeneic bone marrow/peripheral blood transplants [relative risk 0.37 (0.20-0.69); P=0.001], but treatment failure (death or relapse) after autologous peripheral blood was significantly more likely [relative risk 1.32 (1.06-1.64); P=0.011]. The 5-year overall survival, however, was similar in patients who received autologous peripheral blood (n=230) [relative risk 1.23 (0.98-1.55); P=0.071] or allogeneic bone marrow/peripheral blood (n=903). In the absence of an HLA-matched sibling donor, autologous peripheral blood may provide acceptable alternative post-remission therapy for patients with acute myeloid leukemia in first complete remission.

Background: Due to increased rates of secondary solid organ cancer in patients with severe aplastic anemia who received an irradiation-based conditioning regimen, we decided some years ago to use the combination of cyclophosphamide and antithymocyte globulin. We report the long-term follow up of patients who underwent hematopoietic stem cell transplantation from an HLA-matched sibling donor after this conditioning regimen., Design and Methods: We analyzed 61 consecutive patients transplanted from June 1991 to February 2010, following conditioning with cyclophosphamide (200 mg/kg) and antithymocyte globulin (2.5 mg/kg/day × 5 days)., Results: Median age was 21 years (range 4-43); 41 of the 61 patients were adults. Median duration of the disease before hematopoietic stem cell transplantation was 93 days. All but 2 patients received bone marrow as the source of stem cells and all but 2 engrafted. Cumulative incidence of acute grade II-IV graft-versus-host disease was 23% (95%CI 13-34) and 18 developed chronic graft-versus-host disease (cumulative incidence 32% at 72 months, 95% CI 20-46). In multivariate analysis, a higher number of infused CD3 cells was associated with an increased risk of developing chronic graft-versus-host disease (P = 0.017). With a median follow up of 73 months (range 8-233), the estimated 6-year overall survival was 87% (95% CI 78-97). At 72 months, the cumulative incidence of avascular necrosis was 21% and 12 patients presented with endocrine dysfunction (cumulative incidence of 19%). Only one patient developed a secondary malignancy (Hodgkin's lymphoma) during follow up., Conclusions: Cyclophosphamide and antithymocyte globulin is an effective conditioning regimen for patients with severe aplastic anemia and is associated with low treatment-related mortality. Long-term complications include avascular necrosis and endocrine dysfunction.

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.

Background: The role of reduced intensity conditioning allogeneic stem transplantation (RICalloSCT) in the management of patients with Hodgkin's lymphoma remains controversial., Design and Methods: To further define its role we have conducted a retrospective analysis of 285 patients with HL who underwent a RICalloSCT in order to identify prognostic factors that predict outcome. Eighty percent of patients had undergone a prior autologous stem cell transplantation and 25% had refractory disease at transplant., Results: Non-relapse mortality was associated with chemorefractory disease, poor performance status, age >45 and transplantation before 2002. For patients with no risk factors the 3-year non-relapse mortality rate was 12.5% compared to 46.2% for patients with 2 or more risk factors. The use of an unrelated donor had no adverse effect on the non-relapse mortality. Acute graft versus host disease (aGVHD) grades II-IV developed in 30% and chronic GVHD in 42%. The development of cGVHD was associated with a lower relapse rate. The disease progression rate at one and five years was 41% and 58.7% respectively and was associated with chemorefractory disease and extent of prior therapy. Donor lymphocyte infusions were administered to 64 patients for active disease of whom 32% showed a clinical response. Eight out of 18 patients receiving donor lymphocyte infusions alone had clinical responses. Progression-free and overall survival were both associated with performance status and disease status at transplant. Patients with neither risk factor had a 3-year PFS and overall survival of 42% and 56% respectively compared to 8% and 25% for patients with one or more risk factors. Relapse within six months of a prior autologous transplant was associated with a higher relapse rate and a lower progression-free., Conclusions: This analysis identifies important clinical parameters that may be useful in predicting the outcome of RICaIICalloSCT in Hodgkin's lymphoma.