ALBERT

Beschreibung: This study finds significant positive associations between the diversity of soil fungi and surface air temperature in the maritime Antarctic, one of the most rapidly warming regions on Earth. Nature Climate Change 6 182 doi: 10.1038/nclimate2806

Beschreibung: Lake Baikal, Siberia, is the most biodiverse freshwater lake on Earth. However, despite decades of painstaking limnological research on Baikal, broad spatial data on nutrient (nitrogen (N), phosphorus (P), silica (Si)) concentrations and temperature are sparse, as is our understanding of the bottom-up factors that limit phytoplankton in the lake. Earlier studies have suggested both N and P as limiting nutrients in Baikal, but the evidence, mostly based on elemental ratios, is limited and somewhat conflicting. We present experimental evidence that N and P co-limit phytoplankton productivity in some areas of Baikal during summer, along with the results of a comprehensive spatial survey of surface temperature, nutrients and chlorophyll a (Chl a ) in Lake Baikal that support the experimental finding of colimitation. Surface water incubations from two trophically contrasting locations revealed co-limitation by N and P, as well as a positive effect of temperature (fluorescence after 5 d was ∼10% higher at 15°C than at 10°C). In a linear model of the survey data (26 sampling locations), N, P, and their interaction (N × P) were all significant predictors of Chl a concentration, indicating that either N or P (or both) may limit summer phytoplankton, depending on location. In contrast to the incubation experiments, temperature was not a significant predictor of Chl a concentration across the 26 sites we sampled. Lake Baikal is undergoing rapid warming and increased nutrient loading, which may boost phytoplankton productivity in the lake; however, the magnitude of this response will depend on ratios of soluble N and P inputs.

Beschreibung: NM-HCT from related donors who share at least one HLA haplotype with the recipient is a treatment option for patients with hematologic malignancies who do not have suitable HLA-matched related or unrelated donors. We have shown that addition of cyclophosphamide pre-transplant (29 mg/kg) and post-transplant (50 mg/kg on day+3 or days+3 and +4) to a standard nonmyeloablative conditioning regimen of fludarabine and TBI combined with tacrolimus and MMF prophylaxis of GvHD is an effective means of achieving complete engraftment of donor T-cells and granulocytes with low non-relapse mortality and an incidence and severity of acute and chronic GvHD which does not differ from studies of NM-HCT using HLA-matched donors. In a study of 89 patients (FHCRC,N=30; JH,N=59) with advanced myeloid and lymphoid malignancies, patients with relapsed HL had significantly better survival than patients with other diagnoses. Fifteen patients with HL were studied (median follow-up of 17 mo). Patients were heavily pre-treated with a median number of prior cytotoxic therapy regimens of 5 (range: 3–10); 14 patients had failed prior autologous HCT with a median time of 18 mo from auto-HCT to NM-HCT. Donors for 9 patients were HLA-mismatched at ≥4/10 loci. All evaluable patients were complete donor CD3 and CD33 chimeras by day +28 (one patient died on day +28 and was not evaluable). Clinically significant acute GvHD occurred in 9/14 (64%) patients and Grades III/IV GvHD in 3/14 (21%) patients. Extensive chronic GvHD occurred in 5/14 (36%) patients. Two patients (13%) died of non-relapse causes at days +236 and +633 secondary to chronic GvHD. Median failure-free survival (FFS) was 21 mo compared to 6 mo for patients with other lymphoid malignancies (N=23) or myeloid malignancies [(N=51), see Figure]. The hazard of mortality was less among patients with HL compared to those with other lymphoid malignancies [hazard ratio (HR)=0.36 (p=0.05)] yet patients with myeloid malignancies had a similar hazard of mortality compared to those with lymphoid malignancies other than HL [HR=0.88 (p=0.66)]. Difference in FFS between HL and other lymphoid malignancies was not statistically significant [HR=0.54 (p=0.16)], nor was the difference between myeloid and other lymphoid malignancies [HR=1.26 (p=0.44)]. More patients will need to be studied to better demonstrate a graft-versus-lymphoma effect of haploidentical transplantation in relapsed HL. NM-HCT from haploidentical donors may be a good option for such patients who have a limited window of opportunity to proceed to transplant if responsive to salvage chemotherapy. Figure Figure Figure Figure

Beschreibung: Key Points BM donors have a threefold higher risk for life-threatening, serious unexpected, or chronic adverse events vs PBSC donors (0.99% vs 0.31%). Donors receiving granulocyte colony-stimulating factor for PBSC collection had no evidence of increased risk for cancer, autoimmune illness, and stroke.

Beschreibung: We evaluated the utility of allogeneic HCT using nonmyeloablative conditioning as a potential treatment option for 79 patients (pts) with HL who were ineligible for high dose conventional allogeneic HCT and compared outcome based on donor cell source (MRD n=34, URD n=24, Haplo n=21). Conditioning consisted of 2 Gy TBI alone (n=15, MRD) or combined with either 90 mg/m2 (MRD n=19, all URD) or 150 mg/m2 (all Haplo) fludarabine. All haplo recipients also received cyclophosphamide pre (29 mg/kg) and post (50 or 100 mg/kg) HCT. GVHD prophylaxis consisted of mycophenolate mofetil and a calcineurin inhibitor. Pts were heavily pretreated with a median number of 5 (range, 2–10) prior regimens. Most pts failed prior autologous HCT (91%) and radiation therapy (86%). There were no graft rejections. The incidences of acute grades III–IV and extensive chronic GVHD were 15%/47% (MRD), 8%/60% (URD), and 10%/31% (Haplo). There were no statistically significant differences in the ability to discontinue immunosuppression based on donor cell sources. With a median follow up of 20 (range, 4–91) months for living pts; the 18 month overall survivals (OS), progression free survivals (PFS), and incidences of relapse/progressive disease (PD) were 47%, 20%, and 55% (MRD), 74%, 27%, and 65% (URD), and 71%, 60%, and 35% (Haplo), respectively. Nonrelapse mortalities (NRM) were significantly lower for URD (HR 0.16; p=0.03) and Haplo (HR 0.13; p=0.02) recipients compared to MRD recipients. There were also significantly decreased risks of relapse for Haplo recipients compared to MRD (HR 0.35; p=0.03) and URD (HR 0.36; p=0.02) recipients. These data suggest that salvage allogeneic HCT using nonmyeloablative conditioning provides anti-tumor activity in pts with very advanced disease; however, Rel/PD continue to be major problems regardless of stem cell source. Importantly, alternative donor sources are a viable option particularly for those pts who may have a limited window of opportunity to proceed to HCT. Pt Characteristics MRD (n=34) URD (n=24) Haplo (n=21) Median Age (yrs) 33 28 31 Disease Status at HCT CR 11 (32%) 5 (21%) 5 (24%) PR 16 (47%) 8 (33%) 5 (24%) Rel/Ref 7 (21%) 11 (46%) 11 (52%) Disease Bulk 〉 5cm 3 (9%) 3 (13%) 3 (14%) HCT-Comorbidity Index 〉2 21 (62%) 17 (74%) 13 (62%) Regimens 〉 5 16 (47%) 16 (67%) 12 (57%) Failed Prior Auto HCT 30 (88%) 23 (96%) 19 (90%) Median Time Diagnosis - Allo HCT (months) 33 31 32 Median Time Auto-Allo HCT (months) 16 19 17 Outcomes by donor type MRD (n=34) URD (n=24) Haplo (n=21) Median f/u living pts months (range) 15 (4–91) 26 (8–58) 15 (4–49) Acute GVHD grade II–IV, III–IV 53%, 15% 50%, 8% 43%, 10% 18 month extensive chronic GVHD 47% 60% 31% Day 200 NRM 18% 0% 0% 18 month OS 47% 74% 71% NRM 25% 8% 5% Rel/PD 55% 65% 35% PFS 20% 27% 60%

Beschreibung: Key Points Anti-CD45 RIT may replace TBI and simplify BMT-preparative regimens. Anti-CD45 RIT and haploidentical BMT, without TBI, prolongs survival in a murine leukemia model.

Beschreibung: Conflict of interest may arise when 1 physician serves 2 persons whose medical care is interdependent. In hematopoietic cell transplantation (HCT) from unrelated donors and in the setting of solid organ transplantation from living donors, the standard of care is for donors and recipients to be managed by separate physicians to provide unbiased care. However, the practice patterns of evaluation and care of related donors and recipients are not well described. A survey of HCT centers in the United States was conducted by the Donor Health and Safety Working Committee of the Center for International Blood and Marrow Transplant Research to determine the type of provider involved in medical clearance, informed consent, and medical management of hematopoietic cell collection and the relationship of that provider to the HC transplant recipient. The response rate was 40%. In greater than 70% of centers, transplantation physicians were involved or potentially involved in overlapping care of the HC transplant donor and the recipient. These patterns were similar between transplantation teams caring for adult or pediatric donors and recipients. Among responding centers, medical management of recipients and their related donors by the same provider is common, a practice that has the potential for conflict of interest.

Beschreibung: Background: Although a lower relapse risk has been reported after allogeneic BMT with increasing HLA disparity, this potential benefit has been offset by higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). However, it is possible that the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. Patients and methods: We retrospectively analyzed the outcomes of 185 patients with poor-risk hematologic malignancies enrolled on three similar clinical trials of related-donor, haploidentical BMT incorporating high-dose post-transplantation cyclophosphamide (Cy) for GVHD and graft rejection prophylaxis (as published in BBMT2008;14:641–50). Molecular typing was at an allele level for HLA-A, -B, -Cw, and -DRB1 and at an allele group level for -DQB1. All received Cy (14.5 mg/kg IV on days −6, −5), fludarabine (30 mg/m2 IV on days −6 to −2), total body irradiation (200 cGy on day −1), and non-T-cell depleted bone marrow infusion. GVHD prophylaxis consisted of Cy (50 mg/kg IV) either once (on day 3; n = 48) or twice (on days 3, 4; n = 137), mycophenolate mofetil for 35 days, and tacrolimus for up to 6 months, with filgrastim begun after the last dose of Cy. Most patients (median age 50, range 1–71) had advanced disease and 49 (26%) had failed autologous BMT. Diagnoses were MDS (22), CMML (3), acute leukemia or lymphoblastic lymphoma (58), CML (11), CLL (15), multiple myeloma (9), non-Hodgkin lymphoma (42), and Hodgkin lymphoma (25). Results: Median follow-up after BMT is 20 months (range, 2–71 months) in those without events. Nonengraftment attributed to primary graft failure or to residual bone marrow malignancy occurred in 29 of 177 evaluable patients (16%). Cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 31% and 15%, respectively. Cumulative incidences of NRM and relapse or progression at one year were 15% and 50%, respectively. Actuarial event-free survival (EFS) at one year was 35%, with grade II–IV acute GVHD by day 100 associated with a trend toward lower cumulative incidence of relapse (p = 0.08) but a significantly higher cumulative incidence of NRM (p = 0.002) on subgroup analysis. Notably, increasing degrees of HLA mismatch at either class I or class II loci had no significant effect on cumulative incidence of acute or chronic GVHD or NRM. In contrast, the presence of a DRB1 antigen mismatch in the GVH, but not host-versus-graft (HVG), direction was associated with a significantly lower cumulative incidence of relapse (Figure a; p = 0.04) and improved EFS (Figure c; p = 0.009), whereas DQB1 antigen and class II allele mismatch status had no effect. Additionally, the presence of two or more class I allele mismatches (composite of A, B, and Cw) in either direction was associated with a significantly lower cumulative incidence of relapse (Figure b; p = 0.045 for GVH direction, p = 0.01 for HVG direction) and improved EFS (Figure d; p = 0.07 for GVH direction, p = 0.001 for HVG direction). Conclusion: Greater HLA disparity appears to be beneficial after nonmyeloablative, HLA-haploidentical BMT that incorporates high-dose post-transplantation Cy. These results suggest an anti-tumor effect of partially HLA-mismatched BMT that is irrespective of clinically significant GVHD. Potential effectors of anti-tumor immunity include HLA-DRB1 reactive CD4+ T-cells, class I reactive CD8+ T-cells, and/or natural killer cells recognizing missing self. Since most patients have several potential HLA-haploidentical related donors, the results support a strategy of choosing a donor who is incompatible for both HLA-DRB1 antigen and multiple HLA class I alleles. Figure Figure

Beschreibung: Myelodysplastic syndromes (MDS) are a complex and heterogeneous group of hematopoietic stem cell malignancies that are generally incurable outside allo BMT. The toxicities of allo BMT, specifically graft-vs-host disease (GVHD) and end organ toxicity, have limited its use in this traditionally older group of patients (pts) who often have medical co-morbidities. Efforts to apply allo BMT to more pts have focused on reducing the toxicities. Graft manipulation, including TCD, and reduced-intensity conditioning (RIC) regimens have been shown to decrease the upfront mortality of allo BMT; yet improvements in overall survival have been limited due to associated increased post-BMT relapse rates and increased graft failure. Myeloid growth factors have been used commonly, though not systematically, following allo BMT to speed engraftment. Our data, and that of others, suggest that myeloid growth factors may also have anti-tumor properties in MDS by impacting differentiation pathways and/or through their immunomodulatory effects. We developed a clinical trial to determine if the addition of GM-CSF could safely decrease the relapse rate following a TCD allo BMT in pts with high risk MDS. Pts with MDS ≤ 65 undergoing evaluation for a matched sibling allo BMT at the Sidney Kimmel Cancer Center at Johns Hopkins were considered eligible. Pts received a TCD allograft (elutriation and CD34 isolation) following a myeloablative busulfan/cytoxan preparative regimen; GM-CSF @ 250 mcg/m2/day from Day +5 until ANC 〉2000/m3 × 3 days and then 125mcg/m2/day subcutaneously thru Day +60. A total of 43 pts were treated on the protocol with a median age of 56 (range 30 to 65) yrs. Forty pts had poor risk MDS (cytogenetics and IPSS) and 3 pts had AML upon retrospective pathology review. The addition of GM-CSF was well tolerated post-allo BMT with only 1 pt unable to complete the full dose, planned therapy. The overall survival @ 1 and 3 years was 54% and 50% respectively while the event free survival @ 1 and 3 years was 47% and 33% respectively with median follow-up in the surviving group of 37.5 months. Treatment related toxicity was low with a 9% cumulative incidence of grade III/IV aGVHD and a transplant-related mortality (TRM) of 21% (9/43) with 4 deaths related to GVHD, 4 related to engraftment, and 1 secondary to venoocclusive disease. Cumulative incidence of relapse at data analysis was 40% (17/43) with one patient achieving remission after donor lymphocyte infusion. Engraftment failure was seen in only 9% (4/43) of pts. Taken together, ablative preparative regimens followed by TCD allo BMT can safely be used in older MDS pts with the addition of GM-CSF resulting in acceptable engraftment without increased toxicity. Myeloablative conditioning with TCD and prolonged post-transplant GM-CSF produced favorable results in this group of older, high-risk MDS patients. The role of high dose conditioning for alloBMT for MDS is unclear, but the TRM was similar to the low mortality reported with RIC regimens, and the graft failure and relapse rates may be superior.