Basic characteristics and safety of donation in related and unrelated haematopoietic progenitor cell donors - first 10 years of prospective donor follow-up of Swiss donors.

Since July 2007 prospective life-long follow-up (FU) for unrelated (URD) and related donors (RD) is mandatory in Switzerland and data on every allogeneic haematopoietic progenitor cell (HPC) donation are collected prospectively. We report the real-world experience of HPC donation during a 10-year study period (01.07.2007-30.06.2017) with basic characteristics and FU data. 1105 donors underwent 1155 HPC donation procedures. Eighty percent of first donations performed by 802 (73%) RDs and 303 (27%) URDs were peripheral blood stem cells (PBSC), 20% bone marrow (BM). Male donors were over-represented as URD (60% male vs 40% female). Main differences between RDs and URDs concerned age and pre-existing health disorders. RDs were significantly older at first donation (median age 48 years) compared to URD (34 years, p < 0.0001) and had more pre-existing health problems: 25% vs 9% in URD (p < 0.0001). No fatal complications occurred, collection related severe adverse events (SAE) after first donation were not significantly different between groups (RD 1.2%, URD 0.99%), incidence rates for neoplastic and autoimmune diseases did not exceed the rates of the general population. RDs are a more heterogeneous and potentially more vulnerable group, but if donor evaluation is performed appropriately, HPC donation is still safe.

EXPOSURE OF A SERVICE TECHNICIAN REPAIRING A BIPLANE X-RAY SYSTEM.

While repairing a biplane cardiovascular X-ray system in a hospital, a service technician accidentally activated the system's floor pedal. He continued his work under unnoticed exposure for about 5 min until the system alarm was automatically activated. About 2 h after the exposure, the technician developed an erythema on parts of his left face and neck. The next day, he reported his incident to the competent authorities and was hospitalised in a unit specialised in treating heavily irradiated patients. Frequent blood analysis did not show any signs for a significant exposure to radiation. The Federal Office of Public Health then conducted extensive dose estimations. It could be shown that the dismounted collimator was always in front of the lateral X-ray tube, shielding the technician from the direct beam. The dose estimations came to the following conservative results: an effective dose of 5 mSv, a skin dose of 200 mSv, an eye lens dose of 100 mSv and an extremity dose (arm) of 700 mSv. The cause of the erythema remains unclear since the estimated doses are thought to be too low to induce any visible effect on the skin.

Sensitization and desensitization of burn patients as potential candidates for vascularized composite allotransplantation.

Sensitization describes the acquired ability of the immune system to react to foreign human leukocyte antigens (HLA) by producing antibodies and developing memory cells. In the field of transplantation, recipient preformed HLA antibodies due to previous sensitization have been identified - beneath ABO incompatibility - as a major factor for acute graft rejection. Several reasons for sensitization have largely been studied, such as previous blood transfusions, pregnancies or former transplants. Recent studies indicate that the use of assist devices (e.g. ECMO) or cadaveric skin allotransplantation providing temporary coverage in burn patients may lead to additional sensitization. As vascularized composite allotransplantation (VCA) has become a rapidly advancing therapeutic option for reconstruction of complex tissue defects in burns, it seems even more important to become familiar with immunological principles and to be cautiously aware of both sources of sensitization and therapeutic concepts in burns avoiding sensitization. This may also include emergency VCAs in burn patients as potential strategy for early definitive reconstruction avoiding procedures triggering HLA antibody formation. We hereby provide an overview on current evidence in the field of pre- and peritransplant sensitization, followed by posttransplant strategies of desensitization and their potential impact on future treatments of burn patients.

High-resolution HLA matching in unrelated donor transplantation in Switzerland: differential impact of class I and class II mismatches may reflect selection of nonimmunogenic or weakly immunogenic DRB1/DQB1 disparities.

Unrelated donor searches in Switzerland require high-resolution HLA typing for HLA-A/B/C/DRB1/DRB3,4/DQB1 loci. We evaluated this strategy accepting donors with ⩾9/10 match. Of 802 unrelated donor transplants in 2000-2013, 570 were 10/10 matched, 31 were DRB3/4 mismatched, 261 were single-allele mismatched and 13 had 2 allele mismatches. Of the 261 single-allele disparities, 60 concerned HLA-A/-B, 55 HLA-C and 73 HLA-DRB1/-DQB1 loci. Transplants were reduced intensity conditioning (289, 36%), marrow (187, 23%), EBMT risk score was low in 39, intermediate I in 331, intermediate II in 333 and high in 99 patients. Five-year survival was 48±4%. HLA affected survival in the multivariate model adjusted for risk score. HLA-A/-B and HLA-C mismatches had twice the mortality risks, whereas HLA-DRB1/-DQB1 mismatches were similar to matched transplants. HLA-DRB3/4 mismatches were associated with a nonsignificant increased mortality risk. HLA-DRB3/4 mismatches had higher graft-versus-host disease and transplant-related mortality risks and lower relapse rates compared with matched transplants. We show significant effects of HLA class I, but not HLA class II, mismatches. The lack of impact of DRB1 disparities may be related to the lower immunogenicity of the DRB1*11:01/11:04 and DRB1*14:01/14:54 mismatches, representing 46% of DRB1 incompatibilities. These results support a matching algorithm that prioritizes mismatches considered as more permissive.

Differences in health behaviour between recipients of allogeneic haematopoietic SCT and the general population: a matched control study.

Little is known of health-relevant behaviour among long-term survivors of haematological disorders treated with haematopoietic SCT. This comparative cross-sectional multicentre study aimed (1) to explore the prevalence of selected behaviours in this group and (2) to compare them with those of the general population. Self-reported data of 376 survivors (mean age: 50.4 (s.d. = 12.8); median 7 years postallogeneic SCT (interquartile range (IQR) = 8.9; range 1-33) were compared with controls derived from the Swiss Health Survey 2007 by propensity score matching. Survivors were more physically inactive (26.8% vs 12.5%; P ⩽ 0.001) and consumed fewer portions of vegetables (⩾ 3 pieces: 10% vs 21.6%; P < 0.001), fruits (⩾ 3 pieces: 6.5% vs 10.6%; P < 0.001) and fish (31.2% vs 60.9% weekly fish dish; P < 0.001). More survivors consumed dairy products daily (92.5% vs 62.9%; P < 0.001), used sun protection regularly (94.5% vs 85.3%, P < 0.001) and had received influenza vaccinations in the past year (58.4% vs 21.5%; P < 0.001); fewer survivors smoked (13.4% vs 35.4%; P < 0.001). Survivors' weekly alcohol consumption was lower (median 1.5 servings (IQR 4) vs median 4.5 (IQR 10.3); P < 0.001). Of those taking immunosuppressants, 65.7% were non-adherent. Similar to the general population, survivors experience problems executing several health-enhancing behaviours, warranting corrective interventions.

The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT.

Several T-cell depletion (TCD) techniques are used for haploidentical hematopoietic SCT (HSCT), but direct comparisons are rare. We therefore studied the effect of in vitro TCD with graft engineering (CD34 selection or CD3/CD19 depletion, 74%) or in vivo TCD using alemtuzumab (26%) on outcome, immune reconstitution and infections after haploidentical HSCT. We performed a retrospective multicenter analysis of 72 haploidentical HSCT in Switzerland. Sixty-seven patients (93%) had neutrophil engraftment. The 1-year OS, TRM and relapse incidence were 48 (36-60)%, 20 (11-33)% and 42 (31-57)%, respectively, without differences among the TCD groups. In vivo TCD caused more profound lymphocyte suppression early after HSCT, whereas immune recovery beyond the second month was comparable between the two groups. Despite anti-infective prophylaxis, most patients experienced post-transplant infectious complications (94%). Patients with in vivo TCD had a higher incidence of CMV reactivations (54% vs 28%, P=0.015), but this did not result in a higher TRM. In conclusion, TCD by graft engineering or alemtuzumab are equally effective for haploidentical HSCT.

Risk factors for ICU admission and ICU survival after allogeneic hematopoietic SCT.

A considerable number of patients undergoing allogeneic hematopoietic SCT (HSCT) develop post-transplant complications requiring intensive care unit (ICU) treatment. Whereas the indications and the outcome of ICU admission are well known, the risk factors leading to ICU admission are less well understood. We performed a retrospective single-center study on 250 consecutive HSCT patients analyzing the indications, risk factors and outcome of ICU admission. Of these 250 patients, 33 (13%) were admitted to the ICU. The most common indications for admission to the ICU were pulmonary complications (11, 33%), sepsis (8, 24%), neurological disorders (6, 18%) and cardiovascular problems (2, 6%). Acute GvHD and HLA mismatch were the only significant risk factors for ICU admission in multivariate analysis. Among patients admitted to the ICU, the number of organ failures correlated negatively with survival. Twenty-one (64%) patients died during the ICU stay and the 6-month mortality was 85% (27 out of 33). SAPS II score underestimated the mortality rate. In conclusion, acute GvHD and HLA mismatch were identified as risk factors for ICU admission following allogeneic HSCT. Both, short- and long-term survival of patients admitted to the ICU remains dismal and depends on the number of organ failures.

Heparin-induced thrombocytopenia associated with thrombotic microangiopathy.

Some cases of thrombotic microangiopathy (TMA) are refractory to plasma exchange therapy (PE) with persistence or recurrence of thrombocytopenia. We report two patients suffering from TMA of different aetiologies (associated with disseminated malignancy, typical haemolytic uraemic syndrome) with recurrent or persistent thrombocytopenia despite adequate therapy including PE. Since both patients were exposed to unfractionated heparin, heparin-induced thrombocytopenia (HIT) was suspected as a cause. Pretest probabilities for HIT were intermediate. ELISA for PF4/heparin antibodies was strongly positive in both cases, and HIT was confirmed by heparin-induced platelet activation assay. Anticoagulation with lepirudin was initiated, with subsequent rapid increase of the platelet count. TMA might represent a predisposition for HIT. This could be due to TMA-related platelet activation with increased PF4 release. In TMA patients exposed to heparin and with refractory or rapidly recurrent thrombocytopenia HIT should always be considered as a possible cause.

Lack of recognition of HLA class I mismatches outside α1/α2 domains by CD8+ alloreactive T lymphocytes: the HLA-B44 paradigm.

Transplantation with hematopoietic stem cells (HSC) from a donor with a single human leukocyte antigen (HLA) mismatch can be proposed to those patients lacking an HLA identical sibling donor or an unrelated donor matched for the HLA-A, -B, -C, DRB1, DQB1 loci. Incompatibilities at HLA classes I and II loci are associated with an increased risk of graft-versus-host disease (GVHD) and mortality, although no consensus exists yet on the relative importance of specific allele disparities on clinical outcome. Donor search algorithms are now complicated by the growing number of new HLA alleles, in particular those that differ outside the peptide-binding site of the HLA molecules. We report here an in vitro cellular assay to quantify CD8+CD137+ alloreactive cytotoxic T lymphocytes (CTLs) in a one-way mixed lymphocyte reaction. Two unique combinations with a single HLA mismatch in the HLA-B44 serotype differing by one amino acid in the α3 domain were investigated. We show that the B*44:27 versus B*44:02 mismatch was not recognized by CTLs in both directions. At days 10 and 20, the frequency of CD8+CD137+T cells was comparable to that measured in the autologous stimulation (0.3-3.9%). A B*44:02 versus B*44:03 mismatch was, however, well recognized at day 10 (7.2%) and day 20 (17.8%). This is the first demonstration that a single HLA-B mismatch involving a residue outside the peptide-binding site is not recognized in an in vitro functional assay and may probably be considered as a permissive incompatibility in vivo.

Allo-SCT for multiple myeloma in the era of novel agents: a retrospective study on behalf of Swiss Blood SCT.

Despite the introduction of novel drugs, cure of multiple myeloma remains rare. Allo-SCT can induce long-term remission, but randomized studies in advanced disease are lacking and the influence of novel drugs remains unclear. In our retrospective analysis of all patients with myeloma allografted in Switzerland, 95 patients were transplanted between 1988 and 2011. Most patients were heavily pre-treated, and 53% received novel drugs before transplant. In all, 51% were allografted after relapse or progression. Transplant trends changed over time with an increase in reduced intensity conditioning and unrelated donors. At the time of analysis 47 patients remained alive, with a median follow-up of survivors of 53 months. Acute GVHD II-IV and chronic GVHD (cGVHD) occurred in 49% and 53%, respectively; TRM at 5 years was 18%. Five-year OS and PFS were 51% and 29%, respectively. Patients who received transplant upfront vs after relapse had a significantly better outcome, as well as those who had a related donor and achieved CR post transplant. We found no impact of pre-treatment with novel drugs or cGVHD. Although long-term remission following allo-SCT can be achieved, GVHD and TRM remain major limitations. Our series suggests that benefit is highest when allo-SCT is used early in the disease.

Effects of an outpatient physical exercise program on hematopoietic stem-cell transplantation recipients: a randomized clinical trial.

Patients who undergo hematopoietic SCT (HSCT) often experience physical and psychological problems, even long after treatment has been completed. This study was performed to evaluate the effects of a 12-week outpatient physical exercise (PE) program, incorporating aerobic and strength exercises, as compared with a usual care control condition on patients' physical performance and psychosocial well-being. Patients who had completed HSCT up to 6 months earlier were randomly assigned to a supervised PE program (n=64) or a usual care control group (n=67). Primary outcomes were quantified physical performance and self-reported physical functioning. Secondary outcomes were body composition measurement, quantified walking activity and patient-reported outcomes (physical activity, fatigue and health-related quality of life). Assessments were at baseline, immediately after program completion and at 3-month follow-up. Significant intervention effects were observed at both posttreatment and follow-up on physical performance measures. No other outcomes yielded statistically significant group differences. PE should be considered in the management of HSCT recipients to improve physical performance after discharge from the hospital. Further research is needed to determine how the program can be enhanced so that improved physical performance also translates into improved physical and psychosocial functioning in daily life.

Changes of circulating antibody levels induced by ABO antibody adsorption for ABO-incompatible kidney transplantation.

ABO-incompatible kidney transplantation using immunoadsorption to remove anti-A/B antibodies has become a successful clinical practice. Since the data on the specificity of the ABO columns are controversial, the present study assessed the efficiency and specificity of the ABO immunoadsorption, the effect on total immunoglobulins and antibodies previously induced by vaccination. Anti-A/B antibodies were measured by agglutination and ABO flow cytometry, total IgG/IgM, carbohydrate- and protein-specific antibodies by nephelometry and ELISA. The first immunoadsorption not only efficiently reduced donor-specific anti-A/B IgM (81%) and IgG (56%) but also reduced compatible anti-A/B IgM (59%) and IgG (34%). The measurements of antidonor A/B antibodies by direct agglutination (IgM) or flow cytometry better represented the effective antibody levels than the indirect agglutination test (IgG). The median reduction of total IgM and total IgG levels after a single immunoadsorption was 34% and 18%, respectively. Antibodies against pneumococcus and haemophilus polysaccharide antigens were significantly reduced, whereas antitetanus and antidiphtheria protein antibodies were not affected. Intravenous immunoglobulin administration restored the protective anticarbohydrate antibody levels. In summary, immunoadsorption efficiently removed antidonor A/B antibodies, but was not specific for A/B antigens. Anti-A/B antibody levels as determined by ABO flow cytometry are useful to establish the minimal number of immunoadsorptions needed for successful ABO-incompatible transplantation.

The probability of identifying a 10/10 HLA allele-matched unrelated donor is highly predictable.

Identification of an unrelated HLA allele-matched hematopoietic stem cell (HSC) donor is a costly and time-consuming procedure. To improve search logistics, we have limited the search period to 6 months and have introduced a probability estimate of the chances of identifying a 10/10 HLA allele-matched donor. Probabilities were classified as high (>95%), intermediate (50%) and low (<5% chance) based on allele and haplotype frequencies. By analyzing 350 consecutive searches between 2002 and 2005 (1719 donors tested), the probability estimates turned out to be correct for 96% (high), 88% (low) and 56% (intermediate) patients. For searches with a high probability of success, at least one of the 10 most frequent haplotypes in Caucasoids was found in 69% of the patients, but in only 11% of the patients with a low-probability estimate (P<0.00001). Survival probability at 3 years was significantly higher for HSCT patients classified with a high-probability estimate when compared to patients in the intermediate/low-probability groups (74 vs 51 and 54% respectively, P=0.01). The same difference in survival probabilities was observed when only 10/10 matched unrelated HSCT patients were analyzed. In the intermediate-/low-probability groups, patients with alternative (haploidentical, autologous) or mismatched unrelated donors had similar survival estimates. Probability prediction is therefore feasible in the search process for unrelated donors and can guide the therapeutic strategy.

Favorable long-term outcome of nephrotic syndrome after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The development of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HS-CT) is a rare complication with few long-term outcome data. PATIENTS: Clinical course and long-term outcome of three adult patients and one child with NS after HSCT (total number of transplants n = 533) are presented. RESULTS: The median age at onset of NS was 35 years (range 15 - 56), occurring at a median of 17 months (range 11 - 21) after HSCT. Discontinuation of cyclosporine A (CSA) prior to onset of NS was a consistent feature and occurred a median of 6 months (range 2 - 10 months) prior to the development of NS. The histopathological lesion was membranous nephropathy (n = 3) and membranoproliferative glomerulonephritis Type 1 (n = 1). History of acute or concomitant clinically apparent chronic graft versus host disease (GVHD) was present in all cases except the pediatric patient who had abundant DR-activated cytotoxic T cells without evidence of viral reactivation. Long-term immunosuppression for 11 - 36 months with steroids (n = 1), combined steroids and CSA (n = 2) or CSA alone in steroid-refractory NS (n = 1) resulted in sustained remission of the NS in all patients (12 months - 8 years off immunosuppression). CONCLUSION: NS after HSCT seems to be etiologically related to subclinical or overt chronic GVHD, which flares up after discontinuation of CSA. However, resumption of immunosuppression can reverse NS as well as GVHD and induce favorable sustained long-term remission.

Haematopoietic stem cell transplantation in Switzerland. Report from the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) Registry 1997-2003.

In 1997, the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) initiated a mandatory national registry for all haematopoietic stem cell transplants (HSCT) in Switzerland. As of 2003, information was collected of 2010 patients with a first HSCT (577 allogeneic (29%) and 1433 autologous (71%) HSCT) and 616 additional re-transplants. This included 1167 male and 843 female patients with a median age of 42.4 years (range 0.2-76.6 years). Main indications were leukaemias (592; 29%) lymphoproliferative disorders (1,061; 53%), solid tumours (295; 15%) and non-malignant disorders (62; 3%). At the time of analysis 1,263 patients were alive (63%), 747 had died (37%). Probability of survival, transplant related mortality or relapse at 5 years was 52%, 21%, 36% for allogeneic and 54%, 5%, 60% for autologous HSCT. Outcome depended on indication, donor type, stem cell source and age of patient. HSCT is an established therapy in Switzerland. These data describe current practice and outcome.