Anna Locasciulli

Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT

Summary:Over the last 25 years, the numbers of hematopoietic stem cell transplant (SCT) patients have increased rapidly. Infections have been major obstacles for successful transplantation. Thus, infection prevention is very important in transplant recipients. As the results of transplantation have improved, the number of long-term survivors has increased. Vaccination is a potentially important strategy for reducing the risk for vaccine-preventable infections after SCT. The EBMT produced recommendations for vaccination of SCT recipients published in Bone Marrow Transplantation in 1995. This paper updates the previous recommendations based on current knowledge.

Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party

Summary:We have developed a reduced-intensity conditioning regimen for patients with severe aplastic anemia (SAA) undergoing alternative donor transplants, which includes fludarabine (120 mg/m2), cyclophosphamide (1200 mg/m2) and antithymocyte globulin (7.5 mg/kg). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate. We have enrolled 38 SAA patients in this trial: median age of 14 (3–37) years, transplanted from unrelated (n=33) or family mismatched (n=5) donors, with unmanipulated marrow (n=36) or peripheral blood (n=2). Seven patients (18%) had evidence of graft failure, 11% developed grade II–III acute GvHD and 27% developed chronic GvHD. The actuarial 2-year survival is 73%, with a median follow-up of 621 days. Younger patients (⩽14 years) had a lower risk of rejection (5%) and improved actuarial survival (84%). Causes of death were infections (n=3), graft failure (n=2), Epstein–Barr virus lymphoma (n=2) and hemorrhage (n=2). In conclusion, the actuarial 2-year survival is encouraging in young SAA patients receiving a radiation-free conditioning regimen. The significant risk of graft failure in patients 15 years or older may require modification of the conditioning regimen in adults.

Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome

The safety and efficacy of reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) for relapsed lymphomas remains unresolved. We conducted a prospective, multicentered, phase II trial. A total of 170 relapsed/refractory lymphomas received a RIC regimen followed by SCT from sibling donors. The primary study end point was non-relapse mortality (NRM). Histologies were non-Hodgkins lymphomas (NHL) (indolent (LG-NHL), n=63; aggressive (HG-NHL), n=61; mantle cell lymphoma (MCL), n=14) and Hodgkins disease (HD, n=32). Median follow-up was 33 months (range, 12–82). The results show that frequencies were as follows: cumulative NRM at 3 years, 14%; acute and chronic graft-versus-host disease (GVHD) 35 and 52%, respectively; 3-year overall survival (OS), 69% for LG-NHL, 69% for HG-NHL, 45% for MCL and 32% for HD (P=0.058); and 3-year relapse incidence, 29, 31, 35 and 81%, respectively (P<0.001). Relapse risk differed significantly at 3 years between follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) (14 versus 46%, P=0.04). Molecular remission occurred in 94 and 40% (P=0.002) of patients with FL and CLL, respectively. On multivariate analysis, OS was influenced by chemorefractory disease (hazard ratio (HR)=3.6), diagnosis of HD (HR=3.5), and acute GVHD (HR=5.9). RIC allogeneic SCT is a feasible and effective salvage strategy in both indolent and aggressive NHL

Rabbit antithymocyte globulin (r‐ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy

About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte globulin can achieve complete or partial remission after a second IS treatment. Among various second‐line treatments, rabbit ATG (r‐ATG) could represent a safe and effective alternative to horse ALG (h‐ALG). In a multicentre study, 30 patients with SAA (17 males and 13 females, median age 21 years, range 2–67) not responding to a first course with h‐ALG plus cyclosporin (CyA) and granulocyte colony stimulating factor (G‐CSF), were given a second course using r‐ATG (3.5 mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G‐CSF (5 μg/kg subcutaneously from day 1 to 90). The median interval between first and second treatment was 151 d (range 58–361 d). No relevant side‐effects were observed, but one patient died early during treatment because of sepsis. Overall response, defined as transfusion independence, was achieved in 23/30 (77%) patients after a median time of 95 d (range 14–377). Nine patients (30%) achieved complete remission (neutrophils 2.0 × 109/l, haemoglobin 11 g/dl and platelets 100 × 109/l). The overall survival rate was 93% with a median follow‐up of 914 d (range 121–2278). So far, no patient has relapsed. Female gender was significantly associated with a poorer likelihood to respond (P = 0.0006). These data suggest that r‐ATG is a safe and effective alternative to h‐ALG for SAA patients unresponsive to first‐line IS treatment.

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.

Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups

Background Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia. Design and Methods We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells. Results In multivariate Cox analysis negative predictors for survival were: patient’s age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1–19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%). Conclusions This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.

Effectiveness of immunosuppressive therapy in older patients with aplastic anemia

Aplastic anemia is defined as peripheral blood pancytopenia associated with unexplained hypocellularity of the bone marrow without excess of blast cells. If aplastic anemia goes untreated, patients die of bleeding or infections caused by aplasia. Bone marrow transplantation and immunosuppressive treatment have improved outcome, with remission rates of 60% to 80% (1-4). The decision between immunosuppressive therapy and bone marrow transplantation depends largely on the availability of a bone marrow donor. In many centers, the upper age limit for allogeneic bone marrow transplantation in patients with aplastic anemia has been set at 40 to 55 years (5-8). This limit is traditionally less stringent for immunosuppressive treatment (2, 9-14). However, data are scarce, and no study has specifically addressed outcomes in older patients with aplastic anemia. After immunosuppressive treatment, hematologic recovery is slow and often incomplete (15), and clonal transformations, such as myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, or solid tumor, may occur (16-21). As a consequence, fear of life-threatening complications during prolonged aplasia as well as concerns about increased risk for clonal transformations, particularly in older patients, prevail. We sought to 1) determine the outcome of patients 50 years of age or older receiving immunosuppression therapy for aplastic anemia and 2) investigate the response and complication rate among these patients compared with that of younger patients. Methods Design This retrospective cohort study used data from 56 centers reporting to the European Group for Blood and Marrow Transplantation (EBMT) Severe Aplastic Anaemia Working Party between 1974 and 1997. Collected data included demographic information, pretreatment blood values, type of immunosuppressive therapy, date and number of courses of immunosuppressive therapy, response to therapy, date of last known vital status, cause of death, and type and date of late complications for every patient. Follow-up was completed by June 1997. Patients We included 810 patients from the EBMT Registry in whom acquired severe aplastic anemia was diagnosed according to current criteria (22), adequate immunosuppressive therapy (antilymphocyte globulin, cyclosporine, or both) was instituted, and bone marrow transplantation was not performed as second-line treatment. For the purpose of this analysis, patients were separated into three age groups: 50 to 59 years of age (n=115), 60 years of age or older (n=127), and 20 to 49 years of age (n=568). The latter patients served as the reference group. The Severe Aplastic Anaemia Working Party regularly stipulates the definitions for disease and late complications to its participants. No central slide review was performed. Table 1. Characteristics of 810 Patients with Aplastic Anemia Outcome Measures Outcome measures analyzed were overall survival, causes of death, response to immunosuppressive therapy, rate of relapse in responders, and late complications. Late complications were defined as secondary development of a myelodysplastic syndrome, leukemia, paroxysmal nocturnal hemoglobinuria, or solid tumor. Cause of death was classified as related to aplastic anemia or its treatment (bleeding or infection), secondary to late complications, unrelated to aplastic anemia, or unknown. Response to immunosuppressive therapy was defined as reaching complete independence from transfusions. Relapse was defined as dependence on transfusions after 3 months of independence from transfusions. Statistical Analysis Group differences were analyzed by using the Kruskal-Wallis test for continuous variables and the Fisher exact test for categorical variables. Survival probabilities were calculated by using the Kaplan-Meier estimator. Time at risk started at the date of first treatment and ended at the date of an event (response to immunosuppressive therapy, relapse, complication, or death) or the date of last known vital status, whichever came first. We calculated 95% CIs of survival probabilities according to the method of Rothman and Boice. Variables significantly associated with the risk for death were assessed by univariate and multivariate analysis. A two-sided log-rank test was used for comparisons. Because patients were treated at 56 centers, the possibility that center-specific differences in supportive care and patient selection would bias the results cannot be excluded. Therefore, univariate survival comparisons between age groups were made by using the log-rank test stratified on center. Sixty-eight percent of patients were treated at 6 centers (39 to 191 patients per center); 32% of patients were treated at 50 centers (1 to 24 patients per center). Grouping the latter patients led to 7 centers that were used for stratification. Proportional hazards regression analysis was used to assess the effect of known risk factors on survival. Variables considered were sex, age group, disease severity (reflected by neutrophil count at diagnosis), type of treatment (antilymphocyte globulin, cyclosporine, or both), and calendar year (1974 to 1979, 1980 to 1989, or 1990 to 1997). A backward stepwise procedure was used to eliminate nonsignificant variables (cut-off value, P>0.2). To adjust for the inherently increased risk for death with older age, the number of deaths observed after immunosuppressive treatment for aplastic anemia was compared with the expected number of deaths in a general European population matched for sex and age. The standardized mortality ratio (observed deaths/expected deaths) was calculated for each year after treatment. The 95% CI of the standardized mortality ratio was calculated by assuming a Poisson distribution of the number of observed deaths. The changes in risk for events over time were computed for the whole study sample as well as for the three groups separately. Statistical analysis was performed by using the SPSS statistical program (SPSS for Windows, release 6.1, SPSS, Inc., Chicago, Illinois). Role of the Funding Source The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Patients Demographic and disease characteristics of all 810 patients are listed in Table 1. Significant differences were seen among age groups. More female patients were 60 years of age or older, and more men were in the reference group (P<0.001). Fewer cases of viral-associated aplastic anemia were seen in patients 50 to 59 years of age, and no cases were seen in those 60 years of age or older (P=0.008). More patients 60 years of age or older received cyclosporine alone, and more patients in the reference group received antilymphocyte globulin (P<0.001). The proportion of older patients increased continuously over time: Until 1979, 13% of the patients were 50 years of age or older; this proportion increased to 27% from 1980 to 1989 and to 38% since 1990. Hence, the median follow-up was 47 months for surviving patients 50 to 59 years of age and 31 months for patients 60 years of age or older compared with 44 months in reference patients (P<0.001). Severity of disease, as reflected by neutrophil counts at diagnosis and number of courses of immunosuppressive treatment, did not significantly differ among the groups. Multiple interrelations were found among calendar year, type of immunosuppressive therapy, neutrophil count at diagnosis, and age. Calendar year was significantly associated with type of treatment (Table 1). Before 1980, all patients received antilymphocyte globulin alone; since 1990, 51% patients received antilymphocyte globulin and cyclosporine, 31% received antilymphocyte globulin alone, and 18% received cyclosporine alone (P<0.001). Since 1990, however, the type of immunosuppressive therapy was not equally distributed among the age groups (Table 1). Patients 60 years of age or older more often received cyclosporine alone (32%), whereas most patients in the reference group received a combination of antilymphocyte globulin and cyclosporine (61%) (P<0.001). Finally, disease severity was associated with age and calendar year. Before 1980, neutrophil counts less than 0.2 109 cells/L were encountered in 44% of patients in the reference group, 20% of patients 50 to 59 years of age, and none of the patients 60 years of age or older. Since 1990, low neutrophil counts were observed in 19% of patients in the reference group, 15% of patients 50 to 59 years of age, and 55% of patients 60 years of age or older. Survival At the time of last follow-up, 552 of 810 patients (68%) were alive and 258 (32%) had died (survival rate at 5 years, 67% [95% CI, 65% to 69%]). Survival was influenced by age: The older patients were at diagnosis, the lower the survival rate (Table 2). Survival also improved over time; the 5-year survival rate was 52% (CI, 39% to 64%) in patients treated before 1980 compared with 65% (CI, 60% to 69%) in patients treated from 1980 to 1989 and 73% (CI, 66% to 88%) in patients treated since 1990 (P<0.001). This improvement was most pronounced in the reference group (P<0.001) and was not statistically significant in patients 60 years of age or older (Table 2). Table 2. Five-Year Survival by Univariate Analysis Causes of Death Two hundred fifty-eight patients (32%) died. The mortality rate was 39% (45 of 115) for patients 50 to 59 years of age and 43% (55 of 127) for patients 60 years of age or older compared with 28% (158 of 568) for patients in the reference group. The main causes of death were directly related to aplastic anemia: Bleeding or infection occurred in 205 of 258 patients (79%). Thirty of 258 patients (12%) died of late complications, and 23 of 258 patients (9%) died of causes unrelated to aplastic anemia or its treatment. In all three age groups, bleeding or infection was the main cause of death (Table 3). The excess of mortality in older patients was due to aplasia-related d

Bone marrow versus peripheral blood sibling transplants in acquired aplastic anemia: survival advantage for marrow in all age groups

Background Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia. Design and Methods We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells. Results In multivariate Cox analysis negative predictors for survival were: patient’s age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1–19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%). Conclusions This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.

Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission: a study of the european group for blood and marrow transplantation

PURPOSE Advances in bone marrow transplantation (BMT) have consistently improved long-term survival. Therefore, evaluation of late complications such as cataracts is of paramount importance. METHODS AND MATERIALS We analyzed data of 2149 patients from the EBMT registry. A cohort of 1063 patients were evaluable for survival and ophthalmologic status after transplant for acute leukemia (AL) in first or second complete remission. Conditioning therapy included either single-dose total body irradiation (STBI) or fractionated TBI (FTBI) grouped in different dose rates (low: LDR < or = 0.04 Gy/min; high: HDR > 0.04 Gy/min). RESULTS The overall 10-year estimated cataract incidence (ECI) was 50%. It was 60% in the STBI group, 43% in the FTBI group < or = 6 fractions, and 7% in the FTBI group > 6 fractions (p < 10(-4)). It was significantly lower (30%) in the LDR than in the HDR groups (59%;p < 10(-4)). Patients receiving heparin for veno-occlusive disease prophylaxis had fewer cataracts than those who did not (10-year ECI: 33% vs. 53%, respectively;p = 0.04). The 10-year ECI was 65% in the allogeneic vs. 46% in the autologous BMT patients (p = 0.0018). Factors independently associated with an increased risk of cataract were an older age (> 23 years), higher dose rate (> 0.04 Gy/min), allogeneic BMT, and steroid administration (> 100 days). The use of FTBI was associated with a decreased risk of cataract. Heparin administration was a protective factor in patients receiving STBI. In terms of cataract surgery, the unfavorable factors for requiring surgery were: age > 23 yr, STBI, dose rate > 0.04 Gy/min, chronic graft-vs.-host disease (cGvHD), and absence of heparin administration. Among the patients who required cataract surgery (111 out of 257), secondary posterior capsular opacification was observed in 15.7%. CONCLUSION High dose rate and STBI are the main risk factors for cataract development and the need for surgery, and the administration of heparin has a protective role in cataractogenesis.

The role of hepatitis C and B virus infections as risk factors for severe liver complications following allogeneic BMT: a prospective study by the Infectious Disease Working Party of the European Blood and Marrow Transplantation Group

BACKGROUND Severe liver disease, including fulminant hepatic failure and venoocclusive disease can occur after bone marrow transplantation (BMT). The aim of our study was to assess risk factors for veno occlusive disease and severe liver disease occurring within 6 months from BMT. METHODS A total of 193 consecutive patients from 15 BMT Centers were prospectively enrolled between January and June 1995. Data on donors and recipients before and after transplant were collected and included age, gender, alanine aminotransferase (ALT), hepatitis B (HBV), and hepatitis C virus (HCV) markers, hematological disease, status and type of BMT, conditioning regimen and graft versus host disease prophylaxis. Statistical analysis included univariate descriptive and multivariate analysis based on logistic regression on major end-points. RESULTS Forty-three of 193 patients died during the study period, and liver disease was the main cause of death (13 of 43, 30%). Incidence of severe veno occlusive disease was 8%, fulminant hepatic failure 0.5% and 12% of cases had ALT >500 U/L (normal < or =42 U/L). A de novo HBV or HCV infection occurred in 3.2 and 7% of patients respectively. Predictive risk factors for life-threatening liver disease were: unrelated donors (relative risk=5.8, confidence interval=1.7-19.8) and abnormal BMT donor ALT (relative risk=6.3, confidence interval=1. 5- 25.5). CONCLUSIONS This study indicates that ongoing or previous infection with HBV or HCV in donor or recipient is not an absolute contraindication for BMT. However, abnormal ALT levels in BMT donors were a significant predictor of potentially lethal liver complications. The occurrence of de novo HBV or HCV infection did not correlate with severity of liver disease observed in the first 6 months posttransplant. These findings should be carefully evaluated before disregarding HBV or HCV positive siblings with normal transaminase levels in favor of unrelated donors.