Prospective assessment of bone turnover and clinical bone diseases after allogeneic hematopoietic stem-cell transplantation.

BACKGROUND: Bone complications after hematopoietic stem-cell transplantation (HSCT) are relatively frequent. Evaluation of biomarkers of bone turnover and dual energy x-ray absorptiometry (DEXA) are not known in this context. METHODS: We prospectively evaluated bone mineral density, biomarkers of bone turnover, and the cumulative incidence of bone complications after allogeneic HSCT. One hundred forty-six patients were included. Bone mineral density was measured by DEXA 2-month and 1-year post-HSCT. The markers of bone turnover were serum C-telopeptide (C-TP), 5 tartrate-resistant acid phosphatase (bone resorption), and osteocalcin (bone formation) determined pre-HSCT and 2 months and 1 year thereafter. Potential association between osteoporosis at 2 months, osteoporotic fracture or avascular necrosis and, individual patient's characteristics and biologic markers were tested. RESULTS: C-TP was high before and 2 months after transplant. At 2 months, DEXA detected osteoporosis in more than half the patients tested. Male sex, median age less than or equal to 15 years, and abnormal C-TP before HSCT were risk factors significantly associated with osteoporosis. Three-year cumulative incidences of fractures and avascular necrosis were 8% and 11%, respectively. Children were at higher risk of fracture, whereas corticosteroid treatment duration was a significant risk factor for developing a clinical bone complication post-HSCT. Bone complications and osteoporosis are frequent after HSCT. Bone biologic markers and DEXA showed that subclinical bone abnormalities appeared early post-HSCT. CONCLUSION: The risk factors, age, gender, and C-TP easily available at the time of transplantation were identified. Biphosphonates should probably be given to patients with those risk factors.

Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia.

PURPOSE: This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. PATIENTS AND METHODS: We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). RESULTS: The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. CONCLUSION: Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

Initial liver involvement in acute GVHD is predictive for nonrelapse mortality.

BACKGROUND: Current grading systems in acute graft-versus-host disease (GVHD) are not able to identify patients with poor prognosis at time of onset, because they take into account maximal grade. The aim of this study was to evaluate potential predictors for overall survival at disease onset. METHODS: The study sample was composed of 142 allogeneic hematopoietic stem-cell transplant recipients who developed acute GVHD after a myeloablative conditioning regimen. Factors associated with the risk of nonrelapse mortality (NRM) were analyzed with proportional hazard models. RESULTS: At time of diagnosis, GVHD involved a single organ in the majority of the patients (78%). Initial grade was I in 24%, II or III in 56% of patients. Significant risk factors for NRM were non-HLA matched sibling donor (68% vs. 55%, P=0.05), absence of methotrexate in GVHD prophylaxis (75% vs. 56%, P=0.02), initial liver involvement (80% vs. 56%, P<0.001), time to GVHD more than 24 days (76% vs. 55%, P=0.04), nonhyperacute GVHD (72% vs. 52%, P=0.016), and steroid refractory GVHD (85% vs. 44%, P<0.001). In multivariate analysis, initial liver involvement (hazard ratio 2.45; 95% confidence interval 1.46-4.12) and a non-HLA identical sibling donor (hazard ratio 1.58; 95% confidence interval 1.02-2.43) were independently associated with NRM. CONCLUSION: Initial liver involvement was an important clinical predictor and should be considered in patient management.

Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation.

BACKGROUND: After successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems. DESIGN AND METHODS: The aim of this study was to investigate outcome and risk factors in patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia who underwent allogeneic stem cell transplantation. Between 1981 and 2006, 461 patients with therapy-related myelodysplastic syndrome or acute myeloid, a median age of 40 years and a history of solid tumor (n=163), malignant lymphoma (n=133), or other hematologic diseases (n=57) underwent stem cell transplantation and their data were reported to the European Group for Blood and Marrow Transplantation. RESULTS: The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 31%, respectively. In a multivariate analysis significant factors for relapse were not being in complete remission at the time of transplantation (p=0.002), abnormal cytogenetics (p=0.005), higher patients' age (p=0.03) and therapy-related myelodysplastic syndrome (p=0.04), while higher non-relapse mortality was influenced by higher patients' age. Furthermore, there was a marked reduction in non-relapse mortality per calendar year during the study period (p<0.001). The 3-year relapse-free and overall survival rates were 33% and 35%, respectively. In a multivariate analysis significant higher overall survival rates were seen per calendar year (p<0.001), for younger age (<40 years) and normal cytogenetics (p=0.05). Using age (<40 years), abnormal cytogenetics and not being in complete remission at the time of transplantation as risk factors, three different risk groups with overall survival rates of 62%, 33% and 24% could be easily distinguished. CONCLUSIONS: Allogeneic stem cell transplantation can cure patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia and has markedly improved over time. Non-complete remission, abnormal cytogenetics and higher patients' age are the most significant factors predicting survival.

Influence of bone marrow graft B lymphocyte subsets on outcome after HLA-identical sibling transplants.

The potential role of the infused B cell subset after Hematopoietic Stem Cell Transplantation has not been yet studied. The present study analyzed the impact of B cells on transplant outcome in 254 patients who received a bone marrow graft from a human leucocyte antigen-identical sibling donor. The influence of B lineage-specific hematopoietic progenitor cells (CD34(+) CD19(+)) and B cells (immature and mature B cells, CD34(-) CD19(+)) was also analyzed. All included patients received a myeloablative regimen. The cumulative incidence function of acute graft-versus-host (GvHD) grade II to IV was 48% and was inversely associated with the number of CD34(+) CD19(+). There were no statistically significant associations between B cell subsets and chronic GvHD or survival. The CD34(+) CD19(+) B cell subset remained significantly associated with acute GvHD in multivariate analysis (Relative risk = 0.32, 95% confidence interval: 0.11-0.92, P = 0.035). In conclusion, a higher B lineage-specific hematopoietic progenitor cells (CD34(+) CD19(+)) cell dose is associated with a significant decrease incidence of acute GvHD.

Breakthrough invasive aspergillosis in allogeneic haematopoietic stem cell transplant recipients treated with caspofungin.

During the period January 2004 to April 2007, nine cases of breakthrough invasive aspergillosis occurred among 156 allogeneic haematopoietic stem cell transplant recipients receiving caspofungin therapy, mainly for empirical treatment of persisting fever. Voriconazole salvage therapy induced two complete responses. However, seven patients ultimately died a median of 5 weeks after diagnosis, including five patients with aspergillosis. This high incidence of breakthrough invasive aspergillosis in this patient population receiving caspofungin therapy warrants further investigation.

Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor.

After allogeneic hematopoietic stem cell transplantation (HSCT), early infections represent a major cause of morbidity and mortality but little information has been previously reported on late infections. Late infection incidence and risk factors were retrospectively determined in 196 long-term survivors after HLA matched related HSCT. Patients transplanted for aplastic anemia, chronic myelogenous leukemia (CML), and acute myelogenous leukemia (AML) were included. Median follow-up was 8 years. Thirty patients died beyond the first year, causes of death were relapse (n = 10) and infections (n = 19, associated with graft-versus-host disease [GVHD] in 16 patients). Late severe bacterial (LSB) and fungal infections occurred in 30 and 8 patients, yielding to an 8-year cumulative incidence of 15 (95%CI: 10-20) and 4% (95%CI: 1-6), respectively. The majority of viral infections were hepatitis C (HCV) and VZV (8-year cumulative incidence: 10 (95%CI: 5-14) and 27% (95%CI: 20-34), respectively. Three risk factors for LSB have been identified in multiple Cox analysis: CMV status (positive recipient and negative donor) (hazard ratio [HR]: 2.5, 95%CI: 1.1-5.9, P = .033), irradiation-based conditioning regimen (HR: 3.1, 95%CI: 1.2-7.8, P = .016), and extensive chronic GVHD (cGVHD; HR: 2.9, 95%CI: 1.3-6.9, P = .013). Extensive cGVHD was the only risk factor for non-HCV viral infections in patients transplanted for AML or CML (HR: 2.7, 95%CI: 1.4-5.1, P = .002). After HSCT, patients remain at high risk of infections even late after transplantation, in particular, with the above risk factors, and required a prolonged follow-up.

Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation.

Among 40 allogeneic stem cell transplant recipients who developed symptomatic respiratory syncytial virus infection, including 22 patients with lower respiratory tract infection, 19 received palivizumab (9 of whom had upper respiratory tract disease). Palivizumab did not prevent progression to lower respiratory infection and had no impact on the overall survival rate.

Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome.

We analyzed the factors and outcome of patients with disseminated adenovirus infection (dAdV) after allogeneic hematopoeitic stem cell transplantation (HSCT). Thirty patients with dAdV were identified among 620 allogeneic HSCT recipients. Primary diseases were leukemia (n=17), Fanconi anemia (n=12) or others (n=1). Source of stem cells was unrelated in 28 and related in 2 patients. The graft consisted of peripheral blood (n=3), bone marrow (n=12) and unrelated cord-blood (UCB, n=15). Risk factors for dAdV in unrelated HSCT recipients were previous Fanconi disease (p=0.03) and GVHD (p=0.02) in children, and cord blood source of stem cells (p=0.029) and GVHD (0.024) in adults.

Association of bone marrow natural killer cell dose with neutrophil recovery and chronic graft-versus-host disease after HLA identical sibling bone marrow transplants.

Allogeneic bone marrow (BM) transplant (BMT) outcomes have been correlated with the infused nucleated, CD34(+), and T- cell dose. The potential impact of natural killer (NK) BM infused cell dose has however not been established. We analysed the outcomes of 78 patients receiving an HLA identical BMT. A higher NK cell dose was associated with the speed of neutrophil (P = 0.05) and platelet recovery (P = 0.04). Higher nucleated cells, CD34(+), CD3(+), CD3(+)/4(+), CD3(+)/8(+) and NK cell dose were associated with a lower incidence of chronic GvHD (cGvHD) in univariate analysis. In multivariate analysis, the risk of cGvHD was increased by a lower NK cell dose [hazard ratio (HR) = 2.3 (1.2-4.4) for cell dose <0.9 x 10(6)/kg; P = 0.01] and an older age [HR = 1.4 /10 years (1.1-1.8); P = 0.002]. In addition, a higher CD3(+)/4(+) and NK cell dose were associated with a decreased incidence of viral infections (P = 0.03 and P = 0.06 respectively). No specific cell subpopulation infused dose was associated with survival. In conclusion, a higher BM NK cell dose is associated with an increased speed of neutrophil recovery and a decreased incidence of cGvHD.

Second transplant with two unrelated cord blood units for early graft failure after haematopoietic stem cell transplantation.

Graft failure (GF) can be a fatal complication following haematopoietic stem cell transplantation (HSCT). We report four patients who developed early GF after unrelated HSCT and who subsequently received a double unrelated cord blood transplant (dUCBT) after reduced-intensity conditioning, at a median 15 d after the decision to perform a second transplant. Neutrophil recovery was observed in all four patients between day +15 and +31 with full donor chimaerism of one unit. Acute GVHD grades II-IV was observed in three patients. Three are alive, between 12 and 25 months after dUCBT. In conclusion, dUCBT is a promising procedure to treat early GF.

Increased incidence of cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation.

Six cases of cytomegalovirus retinitis (CMVR) after allogeneic hematopoietic stem cell transplantation were diagnosed between 2002 and 2005 in our center, whereas only one case was diagnosed between 1985 and 2001. Cumulative incidence reaches 2.2%, whereas this complication has been rarely described after hematopoietic stem cell transplantation. We aimed to describe clinical and biologic features of CMVR and search for risk factors associated with CMVR. CMVR was diagnosed on specific funduscopic examination in all patients either on visual symptoms (n=3) or on systematic ophthalmologic examination (n=3). CMVR occurred in the context of unrelated transplantation in patients with profound immune defect and multiple episodes of cytomegalovirus (CMV) reactivation. The combination of a CMV-seropositive recipient and CMV-seronegative donor was the leading risk factor.

Primary Epstein-Barr virus infection with pneumonia transmitted by allogeneic bone marrow after transplantation.

We report a case of primary Epstein-Barr virus infection with lung involvement occurring 1 month after bone marrow transplantation. The transplant recipient had serological test results that were negative for Epstein-Barr virus before transplantation. The virus must have been transmitted by the donor's bone marrow, which was positive for Epstein-Barr virus. The patient recovered after rituximab and corticosteroid therapy.

Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes.

In this multicenter retrospective study, the outcomes of 836 patients with myelodysplastic syndrome (MDS) who underwent transplantation with a human leukocyte antigen (HLA)-identical sibling donor were analyzed according to 2 types of conditioning: reduced-intensity conditioning (RIC) in 215 patients, and standard myeloablative (or high-dose) conditioning (SMC) in 621 patients. In multivariate analysis, the 3-year relapse rate was significantly increased after RIC (hazard ratio [HR], 1.64; 95% confidence interval [95% CI], 1.2-2.2; P = .001), but the 3-year nonrelapse mortality (NRM) rate was decreased in the RIC group (HR, 0.61; 95% CI, 0.41-0.91; P = .015). The 3-year probabilities of progression-free and overall survivals were similar in both groups (39% after SMC vs 33% in RIC; multivariate P = .9; and 45% vs 41%, respectively; P = .8). In conclusion, the lower 3-year NRM after RIC is encouraging, since these patients were older (age > 50 years in 73% RIC vs 28% in SMC, P < .001) and had more adverse pretransplantation variables. However, based on the higher risk of relapse, patients with no contraindications for SMC should not receive RIC outside of prospective randomized trials, which are needed to establish the position of RIC-based transplantation in the treatment of patients with MDS.

Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

The introduction of imatinib mesylate has changed attitudes towards hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Information on the current use and results of HSCT is warranted. Data from 592 teams in 42 European countries described their use of HSCT for CML from 1990 to 2004. Outcomes were analyzed for 13,416 patients, with a median age of 36 years (range 1-71 years); 60% were male. The analysis considered three time cohorts, 1980 to 1990, 1991 to 1999 and 2000 to 2003. Survival, transplant-related mortality and relapse incidence were assessed at 20 years for the first cohort and compared at 2 years between the three cohorts. The numbers of HSCT for CML increased from 540 allogeneic HSCT in 1990 to 1,396 HSCT in 1999 and declined to 802 in 2004. One third of all patients and half of those with a low risk were alive at 20 years. Survival at 2 years has improved from 53% to 61% in the most recent years due to a reduction in transplant-related mortality from 41% to 30% in all patients and from 31% to 17% in low-risk patients. Stage, donor type, time interval, age and donor-recipient sex combination remain the main risk factors; patients with a risk score of 0 or 1 have a survival probability of 80% at 2 years. HSCT remains an important treatment option for patients with CML. The data describe the current status of this option and the outcome a patient can expect today. They provide an objective basis for decision making.

Low-dose thoracoabdominal irradiation for the treatment of refractory chronic graft-versus-host disease.

BACKGROUND: Half of the patients with chronic graft-versus-host disease (GvHD) do not achieve a complete remission with first-line therapy. No clear recommendations are available regarding second-line treatments. METHODS: We retrospectively report our single-center experience of low-dose thoracoabdominal irradiation (1-Gy TAI) in 41 patients with refractory extensive chronic GvHD from 1983 to 2000. Median time from extensive chronic GvHD to TAI was one year (median GvHD episodes before TAI, n = 4). RESULTS: Eighty-two percent of the patients achieved a clinical response at a median of 34 days after TAI (range, 15-180). Best response rates were observed in fasciitis (79%), and oral GvHD lesions (73%). A complete clinical response was achieved in 11 patients by 2 years postTAI. Fifty-seven percent of the patients had at least a 50% reduction of their corticosteroid daily dose by 6 months postTAI. Probability of corticosteroid discontinuation was 38% by 2 years postTAI (95% CI, 23-56%). Two-year chronic GvHD relapse incidence was 34%. Ten-year survival from irradiation was 57% (95% CI, 42-78%); patients with fasciitis, lymphocytes >1.0 x 10/L, and platelets >200 x 10/L had a better outcome. CONCLUSIONS: TAI is a safe and efficient option in patients with refractory chronic GvHD, leading to a significant tapering of systemic corticosteroid dose in most cases.

Numbers of Foxp3-expressing CD4+CD25high T cells do not correlate with the establishment of long-term tolerance after allogeneic stem cell transplantation.

OBJECTIVE: Regulatory CD4 T cells that express high levels of CD25 play a vital role in the maintenance of tolerance to self antigens and are required for the induction of nonresponsiveness to alloantigens. The long-term CD4+CD25high T-cell reconstitution after allogeneic stem cell transplantation is unknown. Here, we evaluated whether recovery of this T-cell subset might be linked to the establishment of full donor/recipient tolerance. METHODS: The frequency of CD4+CD25high T cells was determined by Fluorescence Activated Cell Sorter (FACS) analysis in 31 patients, with a mean follow-up of more than 31 months posttransplant. The expression levels of Foxp3 mRNA were assessed by quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: Patients with or without graft-versus-host disease (GvHD) had significant and persistent CD4 T-cell lymphopenia. The relative frequency of CD25high cells and the expression levels of FoxP3 mRNA within this subset were similar between all patients and healthy controls. No significant difference was found in the number of Foxp3-expressing CD4+CD25high T cells in patients with or without GvHD. Finally, younger age and absence of previous GvHD were significantly linked to CD4+CD25high T-cell recovery. CONCLUSION: The low number of Foxp3-expressing CD4+CD25high T cells in grafted patients is not a specific default of this compartment but a consequence of global CD4 T-cell lymphopenia after allogeneic stem cell transplantation. Moreover, levels of Foxp3 mRNA in the CD25+ T-cell compartment do not allow predicting the development of GvHD in the long term.