Karin Garming-Legert

Improved Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Recent Years. A Single-Center Study

We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.

A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation

To our knowledge, no randomized toxicity studies have been conducted to compare myeloablative conditioning (MAC) and reduced‐intensity conditioning (RIC) in allogeneic haematopoietic stem cell transplantation (HSCT).

Sirolimus and tacrolimus as immune prophylaxis compared to cyclosporine with or without methotrexate in patients undergoing allogeneic haematopoietic stem cell transplantation for non‐malignant disorders

For prevention of graft‐versus‐host disease (GVHD), treatment of 24 haematopoietic stem cell transplantation (HSCT) patients with sirolimus and tacrolimus was compared to treatment of matched controls with cyclosporine‐based regimens. The patients mainly had non‐malignant disorders. Two‐thirds of the donors were unrelated, and bone marrow was the most common source of stem cells. Rejection occurred in four patients in the sirolimus group and three in the control group. Donor chimerism for CD3, CD19 and CD33 was similar in the two groups. The cumulative incidence of grade II acute GVHD was 22% in the sirolimus patients and 17% in the controls (P = 0.78). No patients developed acute GVHD of grades III–IV. The cumulative incidence of chronic GVHD was 25% and 37% in the two groups, respectively (P = 0.40). Two patients in the sirolimus group developed Epstein–Barr virus lymphoma, and none in the controls. Side effects and toxicity were similar in the two groups. There was no transplant‐related mortality at 5 yr in the sirolimus group, as opposed to 8% in the controls (P = 0.47). Survival at 5 yr was 95% and 92%. Thus, sirolimus combined with tacrolimus is a promising immunosuppressive regimen in HSCT, also for non‐malignancies, and its efficacy should be confirmed in prospective clinical trials.

A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation

Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades II–IV (41% vs. 51%; P=0.19) or grades III–IV (13% vs. 7%; P=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; P=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; P<0.01). No significant differences in incidence of oropharyngeal mucositis, time to full donor chimerism, or number of cytomegalovirus infections were seen between the two treatment arms, and transplant-related toxicities were equally distributed. Triglyceride (P=0.005) and cholesterol (P=0.009) levels were higher in tacrolimus/sirolimus patients. Transplant-related mortality (18% vs. 12%; P=0.40) and 5-year overall survival (72% vs. 71%; P=0.71) were similar. Five-year relapse-free survival in patients with malignant diagnoses was 65% in the cyclosporine/methotrexate group and 63% in the tacrolimus/sirolimus group (P=0.73). We conclude that tacrolimus/sirolimus remains a valid and safe alternative to cyclosporine/methotrexate as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation, with comparable transplant-related outcomes. The trial was registered at clinicaltrials.gov identifier: 00993343.

Xerostomia in children and adolescents after stem cell transplantation conditioned with total body irradiation or busulfan.

To study salivary secretion rates and symptoms of xerostomia in children and adolescents conditioned with either radiation therapy or with chemotherapy only in the setting of hematopoietic stem cell transplantation (HSCT). Thirty patients conditioned with 10 Gy single dose TBI (sTBI) and cyclophosphamide (Cy) 60 mg/kg for two days and 35 conditioned busulfan (Bu) and Cy as part of the preparative regimen were included in the study. All patients were treated before 13 years of age, and had survived 2-16 years after HSCT. All patients were interviewed according to a standard questionnaire on symptoms of xerostomia and the unstimulated and stimulated whole salivary secretion rate was determined. The stimulated salivary secretion rates were 0.8±0.5 ml/min in sTBI/Cy group compared to 1.1±0.6 ml/min in the Bu/Cy group (p=0.01). Dysfunction of either unstimulated or stimulated salivary secretion rates were found in 18/30 (60%) in sTBI/Cy group and 9/35 (26%) in Bu/Cy group (p<0.01). There were no differences regarding the number of xerostomia related symptoms in children conditioned with either sTBI/Cy or Bu/Cy. Both unstimulated and stimulated salivary secretion rates were inversely correlated to the total number of complaints of xerostomia. This study shows that children exhibit xerostomia after HSCT irrespective of conditioning with busulfan or sTBI. It is of importance that salivary function is evaluated and that both salivary function as well as the subjective feeling of mouth dryness is evaluated.

Long-term salivary function after conditioning with busulfan, fractionated or single-dose TBI

OBJECTIVES Does conditioning with fractionated total body irradiation (fTBI) or busulfan (Bu) causes less salivary dysfunction compared with single dose (sTBI) after hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS A total of 74 adolescents below 13 years of age received allogeneic HSCT and conditioning with either: sTBI, fTBI or Bu. The unstimulated (USSR) and stimulated (SSSR) whole salivary secretion rates were measured at 15 years of age. RESULTS   Irrespective of conditioning type, there were no significant differences in USSR or SSSR between groups. Girls had a significantly lower SSSR, 0.7 ± 0.3 ml per min compared with 1.1 ± 0.4 ml per min in boys (P < 0.001). A significant correlation between age at HSCT and SSSR at 15 years of age (P = 0.02) in children conditioned with sTBI was found as well as an inverse correlation between the plasma area under curve (AUC) of Bu and SSSR. In the multivariate model, only female sex was significantly correlated with low SSSR at 15 years of age (OR 3.93, 95% CI 1.21-12.79; P = 0.021). CONCLUSION No differences in long-term whole salivary function after HSCT in adolescents receiving conditioning with sTBI, fTBI or Bu were found. Total systemic exposure to Bu was negatively correlated with stimulated salivary secretion.