Long-term survival of adoptively transferred chimeric Ag receptor (CAR) T cells is often limited. Transplantation of hematopoietic stem cells (HSCs) transduced to express CARs could help to overcome ...this problem as CAR-armed HSCs can continuously deliver CAR
multicell lineages (e.g., T cells, NK cells). In dependence on the CAR construct, a variable extent of tonic signaling in CAR T cells was reported; thus, effects of CAR-mediated tonic signaling on the hematopoiesis of CAR-armed HSCs is unclear. To assess the effects of tonic signaling, two CAR constructs were established and analyzed 1) a signaling CAR inducing a solid Ag-independent tonic signaling termed CAR-28/ζ and 2) a nonstimulating control CAR construct lacking intracellular signaling domains termed CAR-Stop. Bone marrow cells from immunocompetent mice were isolated, purified for HSC-containing Lin
cKit
cells or the Lin
cKit
Sca-1
subpopulation (Lin
Sca-1
cKit
), and transduced with both CAR constructs. Subsequently, modified bone marrow cells were transferred into irradiated mice, in which they successfully engrafted and differentiated into hematopoietic progenitors. HSCs expressing the CAR-Stop sustained normal hematopoiesis. In contrast, expression of the CAR-28/ζ led to elimination of mature CAR
T and B cells, suggesting that the CAR-mediated tonic signaling mimics autorecognition via the newly recombined immune receptors in the developing lymphocytes.
While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and ...alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The contribution of the bone marrow microenvironment in myelodysplastic syndrome is controversial. We therefore analyzed the functional properties of primary mesenchymal stromal cells from patients ...with myelodysplastic syndrome in the presence or absence of lenalidomide. Compared to healthy controls, clonality and growth were reduced across all disease stages. Furthermore, differentiation defects and particular expression of adhesion and cell surface molecules (e.g. CD166, CD29, CD146) were detected. Interestingly, the levels of stromal derived factor 1-alpha in patients' cells culture supernatants were almost 2-fold lower (P<0.01) than those in controls and this was paralleled by a reduced induction of migration of CD34(+) hematopoietic cells. Co-cultures of mesenchymal stromal cells from patients with CD34(+) cells from healthy donors resulted in reduced numbers of cobblestone area-forming cells and fewer colony-forming units. Exposure of stromal cells from patients and controls to lenalidomide led to a further reduction of stromal derived factor 1-alpha secretion and cobblestone area formation, respectively. Moreover, lenalidomide pretreatment of mesenchymal stromal cells from patients with low but not high-risk myelodysplastic syndrome was able to rescue impaired erythroid and myeloid colony formation of early hematopoietic progenitors. In conclusion, our analyses support the notion that the stromal microenvironment is involved in the pathophysiology of myelodysplastic syndrome thus representing a potential target for therapeutic interventions.
In newly diagnosed acute myeloid leukemia, immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pre-therapeutic ...risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed acute myeloid leukemia undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based firstline therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months, p=.42) nor in the TriNetX cohort (7.5 vs. 7.2 months, p=.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed acute myeloid leukemia might be a safe option for selected patients, provided that close clinical monitoring is performed.
According to WHO 2008 guidelines, the required percentage of cells manifesting dysplasia in the bone marrow to qualify as significant is 10% or over in one or more hematopoietic cell lineages, but ...this threshold is controversial. No 'normal' values have been established. Therefore, we investigated dyshematopoiesis in bone marrow aspirate squash preparations of 120 healthy bone marrow donors.
Bone marrow squash slides of 120 healthy unrelated bone marrow donors were examined independently by 4 experienced morphologists. Samples were taken from the first aspiration during the harvest. Bone marrow preparation and assessment were performed according to WHO recommendations and ICSH guidelines.
More than 10% dysmyelopoiesis could be detected in 46% of bone marrow aspirate squash preparations with 26% in 2 or more cell lineages and 7% in 3 cell lineages in healthy bone marrow donors. Donors under the age of 30 years exhibited more dysgranulopoietic changes and dysmegakaryopoietic changes (P<0.001) compared to the older donors. Female donors showed more dysgranulopoietic changes than male donors (P = 0.025). The concordance rate between the 4 investigators was modest in dysgranulopoiesis but poor in dyserythropoiesis and dysmegakaryopoiesis.
The poor reliability of the 10% cut off was partly related to the proximity of the current criteria to the observed cut-off mean values of the normal population. These findings question the current WHO threshold of the 10% or over necessary for the percentage of cells manifesting dysplasia to be considered significant, and suggest that either a higher threshold would be more appropriate or different thresholds should be set for each lineage.
We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to ...standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 10
CD34 + cells/kg recipient body-weight (CD34+/kg RBW) after 1st apheresis. A single dose of 240 µg/kg P was injected subcutaneously at 10 p.m. on the day of the 1st apheresis. Thirty-seven allogeneic PBSC donors underwent study treatment. The median CD34+ count in peripheral blood was 15/µl on Day 1 after G-CSF alone, versus 44/µl on Day 2 after G-CSF plus P (p < 0.001). The median yield of CD34+ cells was 1.1 × 10
on Day 1 and 2.8 × 10
on Day 2. In contrast to a median yield of only 1.31 × 10
CD CD34+/kg RBW on Day 1, triggering study inclusion, a median of 3.74 × 10
CD CD34+/kg RBW were collected with G-CSF plus P on Day 2. Of 37 donors, 21 reached the target cell count of >4.5 × 10
CD34+/kg RBW (57%, 95%CI 40-73%). No donor experienced a severe adverse event requiring treatment. In conclusion, P might be considered on a case-by-case basis for healthy allogeneic donors with very poor stem cell mobilization success after G-CSF.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A significant proportion of hematopoietic stem cell transplants are performed with ABO-mismatched donors. The impact of ABO mismatch on outcome following transplantation remains controversial and ...there are no published data regarding the impact of ABO mismatch in acute myeloid leukemia patients receiving haploidentical transplants. Using the European Blood and Marrow Transplant Acute Leukemia Working Group registry we identified 837 patients who underwent haploidentical transplantation. Comparative analysis was performed between patients who received ABO-matched
ABO-mismatched haploidentical transplants for common clinical outcome variables. Our cohort consisted of 522 ABO-matched patients and 315 ABO-mismatched patients including 150 with minor, 127 with major, and 38 with bi-directional ABO mismatching. There were no significant differences between ABO matched and mismatched patients in terms of baseline disease and clinical characteristics. Major ABO mismatching was associated with inferior day 100 engraftment rate whereas multivariate analysis showed that bi-directional mismatching was associated with increased risk of grade II-IV acute graft-
-host disease hazard ratio (HR) 2.387; 95% confidence interval (CI): 1.22-4.66;
=0.01). Non-relapse mortality, relapse incidence, leukemia-free survival, overall survival, and chronic graft-
-host disease rates were comparable between ABO-matched and -mismatched patients. Focused analysis on stem cell source showed that patients with minor mismatching transplanted with bone marrow grafts experienced increased grade II-IV acute graft-
-host disease rates (HR 2.03; 95% CI: 1.00-4.10;
=0.04). Patients with major ABO mismatching and bone marrow grafts had decreased survival (HR=1.82; CI 95%: 1.048 - 3.18;
=0.033). In conclusion, ABO incompatibility has a marginal but significant clinical effect in acute myeloid leukemia patients undergoing haploidentical transplantation.
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