Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes.

This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1-1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.

Alemtuzumab-BEAM as conditioning for allogeneic hematopoietic stem cell transplantation in relapsed/refractory Hodgkin lymphoma: a single-center analysis.

PURPOSE: Treatment of refractory Hodgkin disease deserves specific considerations. Recently, alemtuzumab-BEAM has been introduced in allogeneic hematopoietic stem cell transplantation (HSCT) in these patients. METHODS: We retrospectively analyzed the outcome of 20 patients with relapsed/refractory Hodgkin's lymphoma (HL) who received allogeneic HSCT following conditioning therapy with alemtuzumab-BEAM. RESULTS: Treatment-related toxicity was tolerable. Half of the patients (50 %) had infections. Of these, 50 % were found to have pneumonia or catheter-related infections. In 20 %, an oral mucositis was observed. Acute graft-versus-host disease (GvHD) (≥grade 2) was seen in three patients. Complete remission (CR) could be achieved in 17 patients (85 %), 2 patients had persistent Hodgkin disease, and 1 patient died from infection prior to CR evaluation. Median progression-free survival and overall survival were 17.9 and 67.5 months, respectively. From the 17 CR patients, 8 had a relapse after a median of 10 months. Notably, of the eight patients relapsing after HSCT, all patients received another salvage treatment and four patients are still alive, whereas the other four patients died due to further progress. Six out of the remaining nine patients are still in CR, whereas the other three died from chronic GvHD and multi-organ failure. Overall, seven patients experienced chronic GvHD. CONCLUSION: In summary, alemtuzumab-BEAM is a well-tolerated conditioning therapy for allogeneic HSCT with high response rates in refractory HL.

Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study.

Chronic graft-versus-host disease (GVHD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT). In 2005 the National Institutes of Health (NIH) established new criteria for chronic GVHD based on retrospective data and expert recommendations. We prospectively evaluated the incidence of NIH-defined chronic GVHD and its prognostic impact in 178 consecutive patients. The cumulative incidence of chronic GVHD at 3 years was 64, 48 and 16% for chronic classic GVHD and overlap syndrome. Prior acute GVHD and myeloablative conditioning were significantly associated with increased risk of chronic GVHD. Three-year survival (overall survival (OS)) for late-acute GVHD, chronic classic and overlap chronic GVHD when assigned on day 100 were 69, 83 and 73%. OS was significantly worse for patients with platelet counts below 100 g/l at onset of chronic GVHD (35% versus 86%, P<0.0001) and progressive as compared with de novo and quiescent onset of chronic GVHD (54.5% versus 89.5% versus 84%, P = 0.022 and 0.001). Peak severity of chronic GVHD had no impact on non-relapse mortality (NRM) and OS. Recurrent acute GVHD, platelet counts below 100 g/l at diagnosis of chronic GVHD, progressive onset of chronic GVHD and advanced disease stage prior to HCT were significantly associated with increased NRM. This prospective analysis provides for the first-time data on the incidence rates of NIH-defined chronic GVHD categories and identified risk factors for the occurrence of chronic GVHD. A prognostic value of thrombocytopenia and progressive onset type of chronic GVHD for survival after HCT was observed in NIH-defined chronic GVHD.

What are a patient's current chances of finding a matched unrelated donor? Twenty years' central search experience in a small country.

Between 1988 and 2007, international searches for matched unrelated donors (MUDs) were performed for 1586 Austrian patients. Between 2004 and 2007, a MUD was identified for 76.7% of the patients. Between 1996 and 2003, a donor was identified for 71.3% of the patients, and between 1988 and 1995, only for 53.4% of the patients. Search times of successful searches decreased from 7.7 months in the first period to 1.7 months in the period from 2004 to 2007. However, transplants were not performed in all cases in which a donor was found: only in 61.6% of the patients between 2004 and 2007, in 53.4% between 1996 and 2003 and in 29.6% between 1988 and 1995. Multivariate analysis determined that having a common HLA type was the most important variable impacting on finding a MUD for a patient. Factors that most strongly influence a patient's access to transplant were the patient's European origin and a short time between diagnosis and start of donor search. The strongest factor for both finding a donor and being transplanted was a search being performed during more recent years: patients' chances increased from year to year.

KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation.

Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II-IV) (hazard ratio (HR)=2.23, 95% confidence interval (95% CI): 1.21-4.10, P=0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR=2.37, 95% CI: 1.16-4.84, P=0.018) and in HLA-Bw4(-) (HR=3.20, 95% CI: 1.35-7.60, P=0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II-IV) (HR=0.24, 95% CI: 0.07-0.85, P=0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands.

Regeneration, health status and quality of life after rhG-CSF-stimulated stem cell collection in healthy donors: a cross-sectional study.

Mobilized allogeneic PBPC are increasingly used instead of BM for allogeneic stem cell grafting. Although the short-term safety profile of recombinant human (rh)G-CSF seems acceptable, only minimal data on long-term safety are available. We therefore reviewed data on 171 sibling donors (M/F: 98/73) with respect to side effects of rhG-CSF and PBPC collection and impact on quality of life (QoL) and health status. In a cross-sectional study, we investigated the actual QoL and health status of the donors as well as the need for medical treatment since PBPC donation by a questionnaire that was sent to 151 donors. Ninety-five (64%) of the addressed donors responded to the questionnaire, but only 69 (46%) of them reported on their actual health status and QoL, which was good to very good in the majority of them. Two donors developed malignancies in the post-donation course. In general, PBPC collection after rhG-CSF mobilization was well tolerated by the responding donors. Although the reported events in medical history after PBPC donation do not seem to be associated with rhG-CSF administration or the collection procedure, a lifelong follow-up of donors should be obligatory.

Comorbidity predicts survival in myelodysplastic syndromes or secondary acute myeloid leukaemia after allogeneic stem cell transplantation.

BACKGROUND: Recent data suggest that, among other factors, comorbidity may be an important prognostic variable in patients with myelodysplastic syndromes (MDS) who are eligible for haematopoietic stem cell transplantation (SCT). PATIENTS AND METHODS: We examined the overall survival (OS) and underlying risk factors in 45 adult patients with MDS (n = 38), chronic myelomonocytic leukaemia (n = 1), or secondary acute myeloid leukaemia (AML) arising from MDS (n = 6), who underwent allogeneic SCT at our Institution. RESULTS: With a median follow-up of 37 months, OS for all patients was 23%, post-transplant relapse occurred in 11 patients, and 10 patients died from treatment-related complications. The overall outcome and survival was independent of cytogenetic abnormalities and International Prognostic Scoring System (IPSS). However, we identified comorbidity as defined by the haematopoietic cell transplantation specific comorbidity index (HCT-CI), as a significant adverse prognostic variable in our MDS patients. CONCLUSIONS: Based on these data and similar published data we recommend selecting patients with MDS or secondary AML for SCT according to the presence of comorbidities.

Imaging characteristics of toxoplasmosis encephalitis after bone marrow transplantation: report of two cases and review of the literature.

Toxoplasmosis encephalitis is a severe, but often misdiagnosed complication in patients after bone marrow transplantation (BMT). We describe the unique computed tomography (CT) and magnetic resonance (MR) imaging features of cerebral toxoplasmosis in two bone marrow recipients and compare them to the cases in the literature. To our knowledge, this is the first report analyzing the appearance of cerebral toxoplasmosis on diffusion-weighted MR imaging (DWI).

Impact of HLA class I high-resolution mismatches on chronic graft-versus-host disease and survival of patients given hematopoietic stem cell grafts from unrelated donors.

There is consensus that matching of unrelated donors (URD) and patients for HLA class II alleles improves the outcome of hematopoietic stem cell transplantation (HSCT). However, the significance of HLA class I allelic mismatches for transplant outcome is under discussion and reports on long-term effects like chronic graft-versus-host disease (GVHD) are rare. Thus, we investigated the association of human leukocyte antigen (HLA) class I allele mismatches and outcome in 144 patients given HSCT from URD who were matched for HLA-DRB1, DRB3/4/5, and DQB1 alleles. The risk of chronic GVHD was significantly increased in patients with class I mismatched donors, the mismatch either detected by low- or high-resolution typing. A single HLA class I allele mismatch significantly increased the risk of chronic GVHD in multivariate analysis. Overall survival was significantly reduced in patient/donor pairs with more than one-allele class I mismatch. Thus, selection of unrelated donors for transplantation should be based on high-resolution HLA class I typing.

Bone metabolism in patients more than five years after bone marrow transplantation.

We investigated the bone metabolism of 22 patients (median age 38 years) over 6 years after allogeneic bone marrow transplantation (BMT). Biplanar roentgenograms of the thoracic and lumbar spine were used to diagnose vertebral deformities caused by fractures. The actual bone mineral density (BMD) of the lumbar spine and the femoral neck were measured. Laboratory tests included calcium, phosphate, parathyroid hormone, a marker of bone resorption (beta-crosslaps, CTX), markers of bone formation (osteocalcin, bone-specific alkaline phosphatase), osteoprotegerin (OPG)--antagonist of the osteoclast differentiation factor RANKL, and sex hormone status. One patient had a vertebral fracture. Seven patients (28%) had osteopenia in the lumbar spine while 12 patients (48%) had osteopenia in the femoral neck. Bone resorption was increased in nine patients (43%) and bone formation was increased in four patients (20%). BMT recipients had significantly increased serum levels of OPG (P=0.029). Three women (75%) and four men (25%) were hypogonadal. The data showed that BMD is reduced and bone metabolism is still disturbed more than 6 years after BMT. The RANKL/osteoprotegerin system appears to play an important role in the pathophysiology of late post transplantation osteoporosis.

Early and late gastrointestinal complications after myeloablative and nonmyeloablative allogeneic stem cell transplantation.

Upper and lower gastrointestinal symptoms are major and serious complications after stem cell transplantation. Their main causes are gastrointestinal graft-versus-host disease (GVHD), infections, toxicity, or preexisting gastrointestinal diseases. The clinical presentation of each disease is nonspecific. The diagnostic procedure for this study included physical exam, stool cultures, endoscopy with biopsies, and abdominal computed tomography (CT). The study was designed prospectively with consecutive patients and performed at our institution in a clinical stem cell transplantation setting. Between January 1996 and September 2001, we analyzed 42 consecutive patients who had been admitted at our institution for gastrointestinal complaints after allogeneic stem cell transplantation for hematologic diseases. Diagnostic procedures revealed in decreasing order: GVHD (62%), gastritis/esophagitis (19%), cytomegalovirus (CMV) enteritis (11%), bacterial enteritis (6%), and toxic mucosal damage (2%). CT showed unspecific findings. Gastrointestinal GVHD and infectious colitis accounted for the majority of gastrointestinal complications after allogeneic stem cell transplantation in our patient population. The diagnosis was mainly based on endoscopically obtained biopsies.

Prolonged red cell aplasia after major ABO-incompatible allogeneic hematopoietic stem cell transplantation: removal of persisting isohemagglutinins with Ig-Therasorb immunoadsorption.

Delayed donor red cell engraftment and prolonged red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT). There is an intense debate about the impact on outcome, severity of hemolysis, association with graft-versus-host disease and survival after blood group-incompatible stem cell transplantation. Therefore, therapeutic strategies should be considered to avoid these possible complications. We present five patients, who received allogeneic HSCT from human leukocyte antigen-identical donors for hematological malignancies, which were treated with Ig-Therasorb immunoadsorption (five treatments/week) to remove persisting incompatible isohemagglutinins. After a median of 17 treatments (range 9-25), all the patients became transfusion independent with the presentation of donor's blood group. No side effects occurred during treatment. Ig-Therasorb immunoadsorption seems to be a promising therapeutic method for rapid, efficient and safe elimination for persisting isohemagglutinins for patients with PRCA after allogeneic hematological stem cell transplantation.

Beneficial effect of high-dose chemotherapy in multiple myeloma patients with unfavorable prognostic features.

It has been established that high-dose chemotherapy (HDT) improves the therapeutic outcome of patients with multiple myeloma (MM) as compared with standard-dose therapy (SDT); however, little is known about the impact of HDT on different prognostic groups of MM patients. We therefore compared the survival times of 77 patients with previously untreated MM who were enrolled in HDT regimens with those of 64 similar patients <65 years old, who would be eligible for HDT but were treated by SDT. Overall, HDT was superior to SDT with respect to achievement of complete remissions (28% versus 2%; P <0.0001) and improvement of progression-free survival (PFS) (30.2 versus 21.2 months; P = 0.01) as well as overall survival (OS) (median 54.9 versus 49.4 months; P = 0.048). According to the chromosome 13q14 status as determined by fluorescence in situ hybridization and serum levels of beta(2)-microglobulin (beta(2)M), MM patients were separated into a standard-risk group (normal chromosome 13q14 and beta(2)M 4 mg/l). Among patients of the high-risk group, both PFS (26.4 versus 10.7 months; P = 0.004) and OS times (40 versus 23 months; P = 0.05) were longer in patients receiving HDT compared with patients treated by SDT. In the standard-risk group, PFS and OS times were not significantly different between HDT patients and SDT patients. Results of this retrospective analysis suggest that the beneficial effects of HDT are greater in MM patients with high-risk features than in patients with absence of such poor prognostic indicators.

Influence of human platelet antigen match on the success of stem cell transplantation after myeloablative conditioning.

Mismatches between donor and recipient for human platelet antigens (HPA) may affect the success of transplantation due to: (a) serving as minor histocompa-tibility antigens and therefore render recipients at risk for graft-versus-host disease (GvHD), (b) inhibition of thrombopoiesis due to platelet antibodies. We therefore evaluated the occurrence of GvHD and need of platelet support by prospective analysis of donor-recipient pairs (n=53) for HPA-1, -2, -3, and -5 allotypes and screening for platelet antibodies prior to transplantation and in weekly intervals until day 100 after transplantation. Neither the incidence of GvHD nor the onset of thrombopoiesis, nor the CCI after platelet transfusions, nor the frequency of platelet transfusions was affected by HPA mismatches. Settings of homozygous donors vs heterozygous recipients or homozygous recipients vs heterozygous donors were not associated with any adverse effects on the outcome of the transplantation. Thus, the HPA-match does not affect the success of transplantation.

Successful immunotherapy in early relapse of acute myeloid leukemia after nonmyeloablative allogeneic stem cell transplantation.

We report on a 35-year-old woman who underwent allogeneic stem cell transplantation (SCT) in second complete remission (CR) of acute myeloid leukemia (AML) after reduced-intensity conditioning with fludarabine and 2 Gy of total body irradiation. For graft-versus-host disease (GVHD) prophylaxis, cyclosporin A (CsA) and mycophenolate mofetil (MMF) were given. On day 27 after SCT complete hematological remission and donor chimerism was documented. However, in CD34(+) bone marrow cells 28% of recipient hematopoiesis persisted. On day +59 leukemic relapse occurred. After discontinuation of CsA and onset of GVHD, complete donor chimerism and hematological CR were achieved which has been maintained for 14 months.

Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation.

We assessed long-term outcome in 155 patients who had undergone an allogeneic/syngeneic stem cell transplant (SCT) and were in complete remission for more than 2 years after transplant. Probability of late transplant-related mortality was 6%, and affected only patients with chronic graft-versus-host disease (cGVHD). Thirteen percent of patients experienced relapse. Overall survival projected at 10 and 15 years was 83% and 76%, respectively. Secondary malignancies occurred in two patients, 7.5 and 11 years after SCT. Three female and four male patients parented children 19 to 84 months after SCT. Quality of life (QoL) was assessed in a cross-sectional study by the means of a 30-item questionnaire (QLQ-C30) of the EORTC. The questionnaire was sent to 127 patients remaining alive and answered by 106 patients. Seventy-three percent reported a good to very good QoL within 5 years after SCT and 78% after this time point. However, patients with cGVHD had significant impairment of physical, role and social functioning and only 60% of them were fit for work. These results from long-term survivors show that high cure rates with good to very good QoL can be achieved by allogeneic or syngeneic SCT.

Streptococcus pneumoniae mycotic aortic aneurysm after allogeneic bone marrow transplantation.

BACKGROUND: Streptococcus pneumoniae (SP) is a common cause of community-acquired pneumonia and accounts for up to 30% of all cases of pneumonia. Patients with chronic graft-versus-host-disease (GvHD) after allogeneic bone marrow transplantation (BMT) have a high susceptibility to SP infections. So far, mycotic aneurysm resulting from SP has not been reported after BMT. METHODS: We report on a patient with extensive, chronic GvHD who developed low back pain 22 months after allogeneic BMT. RESULTS: Computed tomography of the abdomen displayed mycotic, saccular aneurysmatic enlargement of the infrarenal aorta, with leakage of contrast medium into the aneurysm. The aneurysm was resected, and the defect was closed with an autologous patch from the internal iliac artery. Bacteriologic samples from the abscess grew SP. The patient recovered uneventfully. CONCLUSIONS: This observation confirms the importance of pneumococcal prophylaxis after BMT and suggests that an aggressive diagnostic approach should always be considered in patients with chronic GvHD, even if they present with nonspecific symptoms.

Autologous blood stem cell transplantation in refractory systemic lupus erythematosus with severe pulmonary impairment: a case report.

For patients with severe forms of autoimmunity, including systemic lupus erythematosus (SLE), purging autoreactive T cells from the immune repertoire by transplanting autologous hematopoietic stem cells (ASCT) is a therapeutic option. We describe an 18-year-old woman with SLE who had been treated with corticosteroids, azathioprine, cyclophosphamide (CYC), and immunopheresis for 4 years, during which time mechanical ventilation for lupus pneumonitis had been repeatedly required. After the patient was conditioned by administration of CYC and antithymocyte globulin, a total of 8.87 x 10(6) purified CD34+ cells per kg of body weight was infused. Hematopoietic regeneration was observed within 9 days. Twenty-one months after ASCT, the patient continues to be in complete clinical remission, with no signs of SLE-related disease activity and without any immunosuppressive medications. Her pulmonary function has returned to normal. Although a longer followup is required for assessment of the durability of response, the patient's course indicates that ASCT may be a way to reinduce tolerance in patients with SLE.

Positron emission tomography with [18F]2-fluoro-D-2-deoxyglucose (FDG-PET) predicts relapse of malignant lymphoma after high-dose therapy with stem cell transplantation.

We have determined the predictive value of [18F]2-fluoro-2-deoxy-glucose (FDG-PET) in patients with Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL) scheduled for high-dose therapy with stem cell transplantation (HDT/SCT). Inclusion criteria were the presence of an FDG-PET scan after chemotherapy (ChT) within 8 weeks prior to HDT/SCT and available follow-up data. Sixteen patients (10 NHL and six HD) were observed during a follow-up period of 4 to 28 months (median 13 months). Before SCT, five patients had a negative PET, three were weakly positive, two moderately positive, and six strongly positive. None of the five patients with a negative PET before HDT/SCT relapsed and two of three patients with a weakly positive scan are still in remission after HDT/SCT. Of eight patients with a moderate or high positive PET before HDT/SCT, seven relapsed and one died of early HDT/SCT related complications (P< 0.01). Three of eight relapsing patients died of lymphoma 5 to 10 months after SCT and in one additional patient not responding to HDT/SCT, the main cause of death was chronic toxicity 4 months after transplantation. After 12 months, in PET-negative patients the overall and relapse-free survival was 100%, in PET-positive patients 55% and 18%, respectively. In NHL, two patients with negative PET, but with an age-adjusted international prognostic index (AaIPI) of 2 and one with AaIPI = 1 are still in remission. In the seven PET-positive subjects, one patient with AaIPI = 0, three with AaIPI = 1, and two with AaIPI = 2 relapsed. We conclude that FDG-PET is accurate in the prediction of relapse prior to HDT/SCT in patients with lymphoma. It provides additional information when compared with the AaIPI.

Deletion of chromosome 13q14 detected by fluorescence in situ hybridization has prognostic impact on survival after high-dose therapy in patients with multiple myeloma.

Interphase cytogenetic analysis of chromosome 13q14 was performed in 28 patients with multiple myeloma (MM) receiving high-dose therapy followed by autologous (n=24) or allogeneic (n=4) stem cell support. Eleven (39%) patients were found to have a deletion of chromosome 13q14. Response rates to high-dose therapy were independent of the chromosome 13 status, but patients with a deletion of 13q14 had a significantly shorter progression-free (p=0.001) and overall survival (p=0.012) than patients with normal chromosome 13q14. Our results indicate that high-dose therapy appears promising in patients with normal chromosome 13, whereas in patients with a deletion of 13q14 innovative therapeutic concepts are warranted.