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Summary:Delayed donor red cell engraftment and prolonged red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible myeloablative and nonmyelo-ablative 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.Bone Marrow Transplantation (2003) 32, 1015-1019. doi:10.1038/sj.bmt.1704264 [ABSTRACT FROM AUTHOR]

Background: Autografting of normal stem cells mobilized after chemotherapy is increasingly used in chronic myeloid leukemia (CML). Thus, quantification of possible contamination of progenitor cell apheresis with breakpoint cluster region (bcr)/Abelson murine leukemia (abl)-positive cells is of great clinical interest.Study Design and Methods: Two molecular methods were compared to quantify bcr/abl positivity in leukapheresis components obtained after mobilizing chemotherapy in six patients with CML. To document the efficacy of in vivo purging, the leukapheresis procedures were monitored with interphase fluorescence in situ hybridization (FISH) and quantitative competitive PCR (QC-PCR) as a ratio of bcr/abl:abl.Results: From the first to the last leukapheresis, bcr/abl positivity in FISH increased from a median of 11 percent to 33 percent. For bcr/abl transcripts, a simultaneous increase in consecutive leukapheresis procedures was seen. The median percentage of bcr cells in a bcr/abl:abl ratio was 3.1 percent in the first apheresis. In the last apheresis after the mobilization with mRNA, the QC-PCR showed a median of 19.5 percent. FISH and QC-PCR showed a statistical significant increase of bcr/abl positivity from the first to the last apheresis.Conclusions: Both FISH and QC-PCR were reliable methods of quantifying bcr/abl positivity, and they allowed selection of the optimal apheresis component for autologous transplantation. In both methods, a significant increase in bcr/abl positivity was seen from the first to the last leukapheresis. With FISH, results can be obtained within 24 hours. This method may prevent additional contaminated leukapheresis in case of increasing percentages of bcr/abl-positive cells. [ABSTRACT FROM AUTHOR]

Background: Despite preventive and therapeutical antiviral medication cytomegalovirus (CMV) infection is still a major cause of morbidity and mortality after bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation. Especially CMV-seropositive patients are at high risk for developing CMV infection. The incidence of CMV infection is higher following allogeneic than autologous transplantation. Considering CMV infection as the most significant risk factor for the occurrence of CMV disease early detection is warranted in order to prevent the progression to disease. Methods: Until recently the standard diagnostic method to detect CMV infection in transplant patients has been the pp65 antigen assay, which detects a CMV specific antigen expressed by cells early after infections. Then the polymerase chain reaction was established by Einsele et al. Shortly afterwards followed the application of a quantitative PCR on bone marrow transplantation patients as described by Gerna et al. Results: Sixteen (13%) out of 124 patients developed a positive PCR with a median peak of 37,562 copies/ml a median of 47 days (range, 29-78) posttransplant. All 16 patients underwent allogeneic transplantation. Seven episodes of a positive pp65 antigen assay occurred in 6 allogeneic patients. Seven episodes had a positive antigen and PCR assay, 10 episodes with positve PCR and negative antigen assay, and there was no episode with positive antigen assay and negative PCR. In case of a positve pp65 antigen assay it was preceded by a positive quantitative PCR a median of 11 days and the PCR remained positve for a median for 16 additional days. Three allogeneic patients developed a CMV disease histologically confirmed CMV enteritis. All 3 patients showed positive antigen assay and PCR. One of them recovered fully after antiviral therapy. The other two died during antiviral treatment due to organ toxicity. Conclusions: In conclusion we were able to discern two types of treatment response in our patient population. This observation raises the question what therapy regimen has to be applied on patients that remain PCR positive after 2 weeks of antiviral therapy. Further studies have to address this problem. [ABSTRACT FROM AUTHOR]

Grundlagen: Nach allogener Stammzelltransplantation tritt häufig eine Graft-versus-Host-Disease (GVHD) auf, die oft mit Gewichtsverlust verbunden ist. Die Ätiologie dieses Gewichtsverlustes ist bislang noch nicht geklärt. Methodik: 13 Patienten mit chronisch extensiver GVHD sowie 13 gematchte gesunde Probanden wurden mittels indirekter Kalorimetrie untersucht, um Ruheenergieumsatz und Substratstoffwechselraten zu bestimmen. Weiters wurden die Serumkonzentrationen von Glukagon. Noradrenalin, TNF-a und IL-6 bestimmt. Ergebnisse: Die Patienten mit chronisch extensiver GVHD wiesen eine Erhöhung des Ruheenergieumsatzes auf (Patienten: 21,8 ± 3,1 kcal/kgKG/d. Probanden: 19,9 ± 2 kcal/kgKG/d: p<0,05). Der respiratorische Quotient (RQ) (Patienten: 0,79 ± 0,04. Probanden: 0,86 ± 0,04; p<0,005) und der non-protein RQ (Patienten: 0,78 ± 0,05, Probanden: 0,87 ± 0,05; p<0,005) der Patienten war erniedrigt. Glukagon (190 ± 87 pg/ml) und Noradrenalin (459 ± 238 ng/ml) konnten über die Norm erhöht nachgewiesen werden, während TNF-a und IL-6 im Normbereich lagen. Schlußfolgerungen: Die Ursache des Gewichtsverlustes der Patienten mit chronisch extensiver GVHD dürfte in der Erhöhung des Ruheenergieumsatzes liegen. Zusätzlich weisen diese Patienten veränderte Oxidationsraten für Fett und Kohlenhydrate auf. Diese metabolischen Veränderungen dürften auf erhöhten Serumkonzentrationen von Glukagon und Noradrenalin basieren. [ABSTRACT FROM AUTHOR]

Background: Patients who relapse after allogeneic stem cell transplantation (SCT) have a poor prognosis. A high proportion of these may be considered unfit for further intensive therapy. Immunotherapy as cessation of immunosuppression in patients with early posttransplam relapse or cell therapy with donor leukocyte infusion (DLI) can be a promising and less toxic therapy. It may enhance the graft versus leukemia efficacy of T cells of donor origin once full chimerism is established. Methods: We analyzed toxicity and efficacy of chemotherapy (CT) or second stem cell transplantation (SCT) and/or immunotherapy defined as stop of immunosuppression (IS) or donor leukocyte infusion (DLI) in 47 patients relapsing with acute leukemia. Ten patients received no treatment and 14 patients were treated with CT only. In 12 patients IS was stopped and 3 of them received additional CT. Five patients received DLI after CT as consolidation and one patient as frontline therapy. Five patients received a second SCT. Results: Median overall survival after relapse was 2 months for the untreated patients, 2 months for patients receiving CT only, 2 months in patients after cessation of IS. 17 months in DLI treated patients and 3 months in patients receiving a second SCT. Fourteen patients achieved remission after relapse. Two with CT (2, 2 months). 3 with SI (3,19, 19+ months), 6 with DLI (3, 8, 9, 14, 20, 36 months) and 3 with second SCT (2, 4, 6 months). Conventional CT was able do reestablish donor hematopoiesis and patients achieving remission showed a significant better survival than patients with refractory disease. Conclusions: Patients who were brought into remission by DLI or cessation of IS had a significant better survival than patients who achieved remission with CT alone or a second SCT. We conclude that a selected group of patients achieving remission with regeneration of donor hematopoiesis following CT might benefit from immunotherapy as consolidation. [ABSTRACT FROM AUTHOR]

Asymmetries of bilaterally symmetrical morphological traits in workers of the ant Formica pratensis Retzius were compared at sites with different levels of metal contamination and between mature and pre-mature colonies. Statistical analyses of the right-minus-left differences revealed that their distributions fit assumptions of fluctuating asymmetry (FA). No direct asymmetry or antisymmetry were present. Mean measurement error accounts for a third of the variation, but the maximum measurement error was 65%. Although significant differences of FAin ants were observed, the inconsistent results render uncovering a clear pattern difficult. Lead, cadmium, and zinc concentrations in the ants decreased with the distance from the contamination source, butno relation was found between FA and the heavy metal levels. Ants from the premature colonies were more asymmetrical than those from mature colonies but accumulated less metals. The use of asymmetry measures in ecotoxicology and biomonitoring is criticized, but should remainwidely applicable if statistical assumptions are complemented by genetic and historical data. [ABSTRACT FROM AUTHOR]

The present study compares the metal levels (Pb, Cd, Cu, Zn, Fe, Mn)in different tissues of workers of the ant species Formica pratensisRetzius, Formica polyctena (Forster), and Camponotus ligniperda (Latreille) collected from a metalpolluted site. In all species, highest metal levels were found in the midgut, followed by the malpighian tubules and the hindgut. Additional target sites were the mandibles and ovarioles for Zn and Pb, Cu, Zn, and Fe, respectively. Among the investigated exocrine glands, highest metal levels were found in the Dufour gland and in the labial gland. The tissue-specific metal accumulation pattern of the three ant species is governed by the degree of site pollution and biased by species-specific properties. In congruence with the environmental pollution at the sampling sites, a general comparison of the tissue metal concentrations between the species revealed highest levels of Pb, Cd, and Zn in F. pratensis. Although F. polyctena and C. ligniperda individuals were taken from the same samplingsite, the tissue metal levels differed substantially from each other. [ABSTRACT FROM AUTHOR]

BACKGROUND Patient outcomes are poor for aggressive B-cell non-Hodgkin’s lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines. METHODS We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety. RESULTS A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P=0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events. CONCLUSIONS Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892. opens in new tab.) [ABSTRACT FROM AUTHOR]

This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ±s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 μg/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients. [ABSTRACT FROM AUTHOR]

The article presents questions and answers related to prophylactic platelet transfusions, the use of platelet additive solution (PAS) and the transfusion of platelets from Rhesus factor positive donors to Rhesus factor negative recipients.

We evaluate how closely diversity patterns of endemic species of vascular plants, beetles, butterflies, molluscs and spiders are correlated with each other, and to what extent similar environmental requirements or survival in common glacial refugia and comparable dispersal limitations account for their existing congruence. Austria. We calculated pairwise correlations among species numbers of the five taxonomic groups in 1405 cells of a 3′ × 5′ raster ( c. 35 km) using the raw data as well as the residuals of regression models that accounted for: (1) environmental variables, (2) environmental variables and the occurrence of potential refugia during the Last Glacial Maximum, or (3) environmental variables, refugia and spatial filters. Pairwise cross-taxonomic group Spearman's rank correlations in the raw data were significantly positive in most cases, but only moderate (0.3 < ρ < 0.5) to weak (ρ < 0.3) throughout. Correlations were closest between plants and beetles, plants and butterflies, and plants and snails, respectively, whereas the distribution of endemic spiders was largely uncorrelated with those of the other groups. Environmental variables explained only a moderate proportion of the variance in endemic richness patterns, and the response of individual groups to environmental gradients was only partly consistent. The inclusion of refugium locations and the spatial filters increased the goodness of model fit for all five taxonomic groups. Moreover, removing the effects of environmental conditions reduced congruence in endemic richness patterns to a lesser extent than did filtering the influence of refugium locations and spatial autocorrelation, except for spiders, which are probably the least dispersal-limited of the five groups. The moderate to weak congruence of endemic richness patterns clearly limits the usefulness of a surrogacy approach for designating areas for the protection of regional endemics. On the other hand, our results suggest that dispersal limitations still shape the distributions of many endemic plant, snail, beetle and butterfly species, even at the regional scale; that is, survival in shared refugia and subsequent restricted spread retain a detectable signal in existing correlations. Concentrating conservation efforts on well-known Pleistocene refugia hence appears to be a reasonable first step towards a strategy for protecting regional endemics of at least the less mobile invertebrate groups. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In this multicenter study, 30 patients undergoing matched related or unrelated allogeneic stem-cell transplantation for leukemia were treated with palifermin, and retrospectively compared to a matched control group. Palifermin recipients transplanted with an unrelated donor showed a significant reduction of severity, incidence and duration of oral mucositis WHO grades 2–4. In addition, in the palifermin group the use of opioid analgesics and the duration of total parenteral nutrition decreased, whether stem cells were used from matched related or unrelated donors. No beneficial influence of palifermin on the incidence and severity of acute GVHD (aGVHD) was apparent. The incidence and duration of febrile neutropenia, documented infections, hematopoietic recovery or overall survival remained unchanged. The most common adverse effects included rash or erythema, generally mild and transient in appearance. Thus, the administration of palifermin was generally well tolerated and safe, and significantly reduced oral mucositis whereas—regardless of donor status—no effect on the incidence and severity of aGVHD was seen.Bone Marrow Transplantation (2008) 42, 275–279; doi:10.1038/bmt.2008.157; published online 26 May 2008 [ABSTRACT FROM AUTHOR]

Background Central nervous system (CNS) relapse in chronic myeloid leukaemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation. The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood–brain barrier. Patients and methods We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukaemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations were found. Both patients received intrathecal liposomal cytarabine (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other, consecutive treatment with dasatinib (70 mg per os twice daily) was started. Results In response to therapy, the clinical symptoms resolved, and the leukaemic cells in the CSF disappeared in both cases. After three months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. Conclusions ‘Anatomic’ resistance against imatinib in the CNS can lead to a myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For systemic treatment and prophylaxis, BCR/ABL kinase inhibitors crossing the blood–brain barrier such as dasatinib should be considered in patients with CNS relapse. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We prospectively monitored 74 consecutive allogeneic and 50 autologous patients after bone marrow/stem cell transplantation from May 1999 to October 2000 at our institution with quantitative CMV PCR and pp65 antigen assay once weekly from conditioning therapy to days 120 and 80 after transplantation, respectively. Written informed consent was obtained from every patient. CMV prophylaxis consisted of acyclovir during transplant. Additionally all patients received only platelet products from CMV-negative donors. In the case of CMV infection preemptive therapy with gancyclovir was applied. In the case of CMV disease high-dose immunoglobulin was given as well. In the allogeneic setting 16 out of 74 (22%) patients developed a positive PCR. Seven episodes of a positive pp65 antigen assay occurred in six allograft recipients. In the autologous setting no positive assay was found during the whole observation period. Additionally, in 6/16 patients a lymphoproliferative assay was performed during CMV infection. Two patients showed a positive (15 and 5.4) and four a negative (2,1.6,1,1.8) stimulation index. Bone Marrow Transplantation (2001) 28, 765–768. [ABSTRACT FROM AUTHOR]

We analyzed toxicity and efficacy of chemotherapy (CT) or second stem cell transplantation (SCT) and/or immunotherapy defined as stop of immunosuppression (IS) or donor leukocyte infusion (DLI) in 47 patients relapsing with acute leukemia. Ten patients received no treatment and 14 patients were treated with CT only. In 12 patients IS was stopped and three of them received additional CT. Five patients received DLI after CT as consolidation and one patient as frontline therapy. Five patients received a second SCT. Median overall survival after relapse was 2 months for the untreated patients, 2 months for patients receiving CT only, 2 months in patients after cessation of IS, 17 months in DLI treated patients and three months in patients receiving a second SCT. Fourteen patients achieved remission after relapse. Two with CT (2, 2 months), three with SI (3, 19, 19+ months), six with DLI (3, 8, 9, 14, 20, 36 months) and three with second SCT (2, 4, 6 months). Conventional CT was able do re-establish donor hematopoiesis and patients achieving remission showed a significantly better survival than patients with refractory disease. Patients who were brought into remission by DLI or cessation of IS had a significantly better survival than patients who achieved remission with CT alone or a second SCT. We conclude that a selected group of patients achieving remission with regeneration of donor hematopoiesis following CT might benefit from immunotherapy as consolidation. [ABSTRACT FROM AUTHOR]

Transplantation with unrelated donor (UD) marrow has been shown to potentially cure patients with leukemia. Between January 1991 and April 1998, 54 patients with leukemia have received an UD BMT at our institution. Five patients received their UD BMT as a second transplant after a preceding autologous or syngeneic BMT and were excluded from further analysis. Forty-nine patients with leukemia (acute leukemia n = 26; CML n = 23) and a median age of 36 years (range 19–51) were analyzed. For conditioning, all patients received a combination of fractionated TBI and CY. GVHD prophylaxis consisted of MTX and CsA in all patients. As of 30 April 1998, 27 of 49 (55%) patients survive after a median observation time of 18 months. The probability of overall survival for standard risk and high risk patients is 54% and 31% (P = 0.05). Probability of transplant-related mortality (TRM) is 27%, 24% in standard risk and 31% in high risk patients (P = 0.44). Patients younger than 40 years (n = 33) had a similar TRM as patients 40 years and older (n = 16). The probability of relapse is 41% for the whole group, 29% for standard risk and 55% for high risk pts (P < 0.05). our data confirm that ud bmt is an effective treatment for patients with leukemia. trm is almost similar to related sibling bmt, most probably due to improvements in hla typing technology, conditioning regimen and supportive patient care. [ABSTRACT FROM AUTHOR]

Between 1982 and 1996, 20 patients (10 male, 10 female) with severe aplastic anemia (SAA) with a median age of 25 years (17–37 years), received grafts from an HLA-identical sibling (n = 17), HLA-identical unrelated donor (n= 2) or identical twin (n= 1). The median time from diagnosis to marrow transplantation (BMT) was 15 months (range 1–96 months). More than half of the patients had received more than 10 units of red blood cells or platelet transfusions prior to BMT. Pretransplant immunosuppression consisted of cyclophosphamide (CY) alone (n= 10), CY in combination with total body irradiation (n= 8), and CY and antithymocyte globulin (n= 2). For graft-versus-host disease (GVHD) prophylaxis methotrexate (MTX) alone (n= 9) or MTX with cyclosporin A (n = 10) were given. One patient died on day 18 after marrow grafting due to infection; all other patients had complete and sustained engraftment (95%). Eight patients developed acute GVHD (42%), nine patients chronic GVHD (53%) including four with extensive disease manifestation. One patient experienced a secondary malignancy 11 years after BMT. Eighteen patients followed for a median of 9.45 years (0.42–14.7 years) have sustained hematological reconstitution and are alive and well with a Karnofsky performance score of at least 90%. Thus, excellent long-term survival and low morbidity make allogeneic or syngeneic BMT the treatment of choice for younger patients with severe aplastic anemia. [ABSTRACT FROM AUTHOR]