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.
5-Azacitidine (AZA) therapy is used in high-risk myelodysplastic syndrome (MDS) patients who often show abnormalities in their immunophenotype. We explored the potential impact of AZA on these ...immunophenotypic abnormalities in serial bone marrow studies performed in 81 patients from five centers. We compared the immunophenotypic features before and after therapy with AZA, established definitions consistent with flow cytometry immunophenotyping (FCI) improvement, and explored its clinical significance. After a median of 6 cycles of AZA, 41% of patients showed a FCI improvement and this finding associated with best possible clinical response (
P
< 0.001). FCI improvement also correlated with hematological improvement (HI) (53/78 patients; 68%), independently of their eligibility for stem cell transplantation. Among patients who achieved a HI after 6 cycles of AZA, the probability of maintaining this response at 12 cycles of AZA was twice as large (67%) for those patients who also achieved a FCI improvement after 6 cycles of AZA as compared to patients who did not (33%,
P
< 0.01). These findings support that monitoring of the immunophenotypic abnormalities during therapy with AZA may assist in redefining the quality of response in patients with MDS.
Analysis of donor chimerism is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for ...monitoring of minimal residual disease. We prospectively investigated the predictive value of donor chimerism analyses in sorted CD34(+) peripheral blood cells in 90 patients with acute leukemia and myelodysplastic syndrome. The cumulative incidence of relapse after four years was significantly increased in cases with decreasing or incomplete CD34(+) donor chimerism (57% vs. 18%, p=0.0001). Multivariate analysis confirmed decreasing CD34(+) donor chimerism as an independent predictor of relapse and inferior survival. The interval between a decrease of CD34(+) chimerism of less than 80% and hematologic relapse was 61 days (range 0-567). Monitoring of CD34(+) donor chimerism in the peripheral blood allows prediction of imminent relapse after allogeneic stem cell transplantation even when a disease-specific marker is lacking.
Gemtuzumab ozogamicin (GO) has been associated with an increased risk of liver sinusoidal obstruction syndrome (SOS) when applied within 3 months of allogeneic hematopoietic cell transplantation ...(HCT). We hypothesized that GO might be safe and effective as part of a reduced-intensity conditioning regimen as salvage therapy of CD33+ acute myeloid leukemia.
Thirty-one patients with acute myeloid leukemia which relapsed following conventional therapy (n=15), autologous (n=3), or allogeneic (n=13) HCT were included in a prospective phase I/II trial. The preparative regimen contained 6 and 3 mg/m(2) of GO on days -21 and -14 before transplantation, leading to a reduction of marrow blasts in 18 patients (58%). Eight patients received further cytoreductive chemotherapy before conditioning therapy was initiated. Fludarabine-based reduced-intensity (n=11) or nonmyelablative (n=16) conditioning and peripheral blood stem cell infusion from related (n=6) or unrelated (n=21) donors could be done in 27 patients during cytopenia.
Primary engraftment occurred in all evaluable patients. Only one case of reversible hepatic sinusoidal obstruction syndrome was documented. Non-relapse mortality until day 100 was 22% (n=6). The probabilities of overall and disease-free survival at 24 months were 39% and 35%, respectively. Relapse of leukemia occurring between 2 and 24 months after transplantation (median, 8 months) was the major reason for treatment failure and death.
These data suggest that GO can be combined with reduced-intensity conditioning even after previous autologous or allogeneic HCT.
Both number and origin (donor vs. host) of dendritic cells (DC) are associated with acute graft-versus-host disease (aGvHD), relapse and graft failure after human allogeneic hematopoietic cell ...transplantation (aHCT).
We prospectively and simultaneously investigated skin and blood DC subtypes, their donor/recipient origin, and the correlation of DC reconstitution kinetics with treatment, clinical outcome, and incidence of aGvHD in patients undergoing aHCT.
A significant reduction of skin and a marked decrease of blood DC were observed in patients compared to healthy volunteers. A dominant donor chimerism of migratory Langerhans cells (LC) and dermal-dendritic-cells (DDC) was detected even early after transplantation, and developed independently from chemotherapy regimen, graft manipulation or time point after transplantation. Before start of the therapy patients showed significantly decreased numbers of peripheral blood CD123+ preDC2, whereas CD11c+ preDC1 numbers appeared to be diminished, but were statistically indistinguishable from controls. Host derived pB preDC were virtually absent following aHCT. After a further reduction in cell number around day 56 both preDC subtypes reconstituted and stabilized to pretransplant numbers by day 112. Occurrence of aGvHD and its treatment diminished numbers of both preDC subtypes. Furthermore conditioning therapy with Alemtuzumab apparently affected reconstitution of both preDC subsets negatively.
Given that induction of GvHD in humans is as host DC dependent as in mouse models, investigation of DC chimerism and number at different sites and especially in GvHD target organs might provide important insights into the pathogenesis of the main obstacle of aHCT.
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