Abstract 876
Transplantation of bone marrow (BM) from a HLA-matched sibling donor is an effective treatment for severe aplastic anemia (AA) with long-term survival in excess of 80%. In the recent ...years there were two trends in allogeneic stem cell transplantation (SCT) for AA: (1) increasing proportion of transplants performed from matched unrelated donors (MUD) and (2) increasing proportion of transplants using peripheral blood progenitor cells (PBSC) as stem cell source instead of BM. A similar switch to PBSC over BM grafts is reported in leukemia transplants. PBSC grafts for leukemia are associated with higher rates of chronic graft-versus-host disease (cGVHD). This adverse consequence may be offset by lower rates of leukemia relapse in some settings. In contrast, there is no perceived benefit of cGVHD for AA. A recent retrospective analysis of EBMT/CIBMTR reported worse outcome after PBSCT compared to BMT in young patients after HLA-matched sibling (sib) transplantation. The impact of stem cell source on outcome after MUD transplants has not been studied in detail so far.
Some reports on favourable results after MUD SCT prompted the discussion whether MUD SCT should be performed earlier in the treatment algorithm in AA instead of considering it as salvage treatment after failure of immunosuppressive treatment. Therefore we performed a retrospective study on the dataset of the German Registry of Stem Cell Transplantations (DRST) to (1) analyze outcome after MUD compared to sib SCT and (2) to study impact of stem cell source (PBSC vs BM) on both sibling and MUD SCT and (3) to analyze impact of transplant period (1998-2002 vs. 2003-2008).
We analyzed 182 sib SCT and 114 MUD SCT (first transplants only). The interval between diagnosis and transplant was significantly longer for MUD SCT as compared to sib SCT (median 98.5 days vs. 511.5 days; p<0.001 ) suggesting that the majority of sib SCT were performed upfront whereas MUD SCT in the majority of cases was performed after failure of other treatments. Median age was 28.5 years (sib SCT) and 30 years (MUD) years (p=0.41). PBSC were used as stem cell source in 50.5% of sib SCT and 61.4% of MUD (p=0.097). 5-year probability of survival was 84.6% (95%-CI: 79.3-90.3%) after sib SCT and 70.1% (95%-CI. 61.8-79.6%) after MUD (p<0.003). In univariate comparison age at transplant has significant impact on survival: After sib SCT 5-year probability of survival in patients ≤ 30 years vs. > 30 years was 94.5% (95%-CI: 90.0-99.3%) vs. 73.5% (95%-CI: 64.3-84.1%)(p<0.001) . 5-year probability of survival after MUD SCT in patients ≤ 30 years vs. > 30 years was 77.7% (95%-CI: 67.3-89.7%) and 60.6 (95%-CI: 48.2-76.2%) (p=0.044). In the most recent period (2003-2008) 2-year probability of survival was 81.6% (95%-CI: 72.9-91.3%) after sib SCT (n=80) and 75.6 (66.1 – 86.5%) after MUD SCT (n=73) (p=0.34). After sib SCT survival was significantly better with BM as compared to PBSCT (5-yr. prob. 95.3%; 95%-CI: 90.9-99.9%; n=89 vs. 74.1%, 95%-CI: 65.1-84.2%; n=92; p<0.001) and cumulative incidence of chronic GvHD was significantly higher with PBSCT as compared to BM (47.0% vs. 18.4%; p<0.01). Cumulative incidence of acute GvHD II-IV did not differ significantly between BM and PBSC. In contrast, stem cells source did neither significantly affect overall survival nor cumulative incidence of acute or chronic GvHD after MUD. In multivariate analysis of the sib SCT older age (>30 years) and use of PBSC were significant risk factors for mortality (Hazard Ratio (HR) 3.4 (1.2-9.3) and HR 4.0 (1.3-12.2). Other variables in the model (conditioning regimen; GvHD prophylaxis; sex match; time diagnosis to transplant and transplant period) were not significant. For MUD SCT none of these variables were significant in a multivariate model.
These results indicate that BM grafts should be preferred to PBSC in patients undergoing HLA-identical sib SCT for AA. In contrast, no negative impact of stem cell source on outcome after MUD SCT could be demonstrated. Results of MUD SCT substantially improved over time. In the most recent period from 2003- 2008 the probability of survival after MUD and HLA-identical sib SCT was no longer different. So far majority of MUD transplants were performed late after diagnosis, mostly after failure of immunosuppression. Re-assessment of both the indication of MUD SCT for AA and the timing of MUD SCT is warranted.
Supported by the Deutsche José Carreras Leukämie-Stiftung.
No relevant conflicts of interest to declare.
Acute myeloid leukemia bearing a RUNX1 gene mutation (RUNX1+ AML) has been proposed as a provisional entity in the 2016 WHO classification. Clinically, it has been associated with inferior response ...rates and outcome after conventional chemotherapy. Accordingly, RUNX1+ AML is allocated in the unfavorable prognostic category of the 2017 European Leukemia Net classification. Following allogeneic stem cell transplantation (alloSCT), RUNX1 was an unfavorable factor in one study in MDS/secondary AML, while data in de novo AML are scarce.
Here, we present a retrospective study by the EBMT Acute Leukemia Working Party, aiming to elucidate the prognostic value of RUNX1 mutation in patients undergoing alloSCT for AML in first complete remission (CR1).
Adults undergoing alloSCT for AML in CR1 from matched related or unrelated donors between 2013 and 2018 with complete information on conventional cytogenetics and RUNX1 mutational status were selected from the EBMT registry. Variables of interest were overall and leukemia-free survival (OS/LFS), GvHD/relapse free survival (GRFS), cumulative relapse incidence (RI), non-relapse mortality (NRM) and GvHD. Log rank test, Gray test and Cox regression models were used.
128 RUNX+ and 388 RUNX- patients were identified, >80% of both subgroups presenting as de novo AML. As expected, RUNX1+ patients rarely had co-mutations in NPM1 (6% vs. 26%, p=10−3), and showed a positive correlation with ASXL1 mutations (50% vs. 16%, p=10−4). Cytogenetic categories and other mutations (FLT3-ITD, CEBPA) were equally distributed between the two groups, as were age, donor and graft type, CMV, conditioning and T cell depletion (TCD).
Median follow-up was 16.4 (RUNX+) and 19.8 (RUNX-) months. 2y OS/LFS of the entire cohort were 64% 59-69/57% 52-62, with no difference between RUNX1+ and RUNX1- patients either in univariate or multivariate analysis (2y OS: 67.9% 57.3-78.5 vs. 63.1%v57.4-68.7p=0.15; 2y LFS: 57.6% 46.4-68.7 vs. 57% 51.4-62.6, p=0.38, figure 1). RUNX1 mutation neither had any impact among patients with normal karyotype (figure 2). Similarly, no other outcome parameter was influenced by RUNX1 mutational status. Instead, multivariate analysis revealed age and donor type as risk factors for OS, LFS and NRM. Poor cytogenetic was associated with higher RI and inferior LFS/GRFS, in vivo TCD with a lower rate of aGvHD II-IV, cGvHD, and better GRFS. Among patients with available information, FLT3-ITD was an independent risk factor for relapse, LFS and GRFS. RUNX1 did not modify the role of FLT3-ITD.
Within the limits of a retrospective registry analysis, we could not find a negative influence of RUNX1 mutation on outcome after allogeneic SCT in CR1. Hence, transplantation in CR1 might overcome the unfavorable prognostic value of RUNX1 mutation and can be recommended as consolidation treatment in this entity.
Although CD34 progenitors play a crucial role during bone marrow transplantation (BMT), there is only scant knowledge concerning their lineage-restricted mixed chimerism (MCh).
An immunohistochemical ...and fluorescence in situ hybridization study was performed on bone marrow biopsies derived from 11 patients with chronic myelogenous leukemia after sex-mismatched BMT to quantify the CD34 cell population and their expression. After proper identification by a lineage-specific monoclonal antibody, X chromosome- and Y chromosome-specific probes were used for sex typing and for labeling of the locus commercially available detection systems were applied.
After successful engraftment, 241 progenitor cells were identified at days 9 to 586 of the posttransplant period. Overall incidence of MCh was 24% with a tendency to decline after day 100 to 15%. The gene was detectable in only 10% of these precursors and decreased to less than 4% after more than 6 months. Approximately 0.5 to 5.5 years after BMT in six patients, a manifest leukemic relapse occurred, which was accompanied by a conversion of donor-to-host-type progenitors. This phenomenon involved up to 94% of the 303 evaluable CD34 cells and also included a retrieval of the translocation gene in approximately 50% of this population.
The lineage-restricted MCh of progenitors after BMT is in keeping with the assumption that leukemic (bcr/abl ) precursors represent only a fraction of the total host-derived (chimeric) CD34 cells. These residual clonally transformed progenitors survive myeloablative treatment and thus may be the source for a later relapse.
Bone marrow macrophages have been recognized to play a crucial role in the functional network that constitutes the microenvironment. In chronic myelogenous leukemia (CML), neoplastic macrophages are ...presumably responsible for the expansion of the leukemic cell clone. So far, no information is available about a persistence of host-type macrophages after allogeneic bone marrow transplantation (BMT) implicating a lineage-specific mixed chimerism.
Bone marrow trephine biopsies were investigated in eight male and five female patients with CML after BMT after a sex-mismatched host/donor constellation. Techniques included immunophenotyping (CD68) for identification of resident macrophages and a simultaneous genotyping with X- and Y-chromosome-specific DNA-probes (fluorescence in situ hybridization). Normal bone marrow and specimens of CML patients before BMT served as controls.
Contrasting an almost 100% congruence with the genotyping in the controls, a mixed chimerism of the CD68+ macrophages and the other host myeloid cells was found. Until 3 months after BMT, incidence of host-type macrophages ranged from 8% to 10%. This feature was also identifiable in the peculiar subset of pseudo-Gaucher cells (PGCs). The number of host-type macrophages failed to decline significantly during the early posttransplant period, because after almost 4 months these were still detectable. On the other hand, in patients showing an initial-to-manifest leukemic relapse, an insidious conversion of up to 50% from the donor to host-type macrophages and myeloid cells occurred.
The CD68+ resident bone marrow macrophage population including PGCs are involved in the lineage-specific chimerism and minimal residual disease after BMT in CML.
To determine the influence of advanced age on long-term survival after allogeneic bone marrow transplantation (BMT), the probability of survival and the frequency of transplantation-associated ...complications were analysed retrospectively in 20 patients with acute leukaemia (AL) or chronic myeloid leukaemia (CML), who were 40-49 years of age (median 44.5 years) at the time of transplant. The results of this patient group were compared to those of 32 patients aged 30-39 years (median 33.5 years) with AL or CML, who also underwent BMT during the same period of time. The overall actuarial survival of the two age groups was comparable with 44% and 41% at 5.9 and 5.6 years, respectively. Patients with standard risk criteria (i.e. HLA-genotypically identical sibling donor, 1st chronic phase of CML or 1st remission of AL) showed a higher probability of survival in both groups (62% at 5.9 years in older patients and 59% at 5.5 years in younger patients, respectively). In contrast, actuarial survival in patients who underwent BMT at an advanced stage of their disease or with marrow from a partially HLA-compatible donor was significantly inferior (P = 0.04). The cumulative incidence of acute and chronic graft-versus-host disease was low in older patients (27%), who received marrow from an HLA-identical sibling donor. The most frequent cause of death was interstitial pneumonia, occurring in seven of the older patients (35%) and in seven of the younger patients (22%). This difference, however, was not statistically significant. Our results indicate that allogenic marrow transplantation in the fifth decade of life might be associated with a tolerable risk of transplantation-related complications. This treatment modality may therefore be regarded as first-line therapy for patients in 1st remission of AL or first chronic phase of CML, who show a normal performance status. The same applies to older patients in advanced stages of disease, since the results are comparable to those achieved in the younger patient group.
A retrospective immunohistological and morphometric study was performed on bone marrow trephine biopsies derived from 113 patients with Philadelphia chromosome-positive chronic myeloid leukemia ...(Ph(1+)-CML) before and at standardized intervals following allogeneic transplantation (BMT) with full unmanipulated marrow specimens. The purpose of this investigation was to quantify CD34+ progenitor cells and to determine their dynamics during the post-transplant period. Moreover, we tried to correlate their number with corresponding changes in the amount of nucleated erythroid precursors and megakaryocytes including pro- and megakaryoblasts and the fiber content. Monitoring the quantity of precursors after BMT revealed a very rapid recovery in comparison to a control group. However, a more detailed evaluation showed that at day 22 +/- 6 a higher number of progenitor cells was significantly associated with an earlier independence for platelet transfusion and also with a more pronounced growth of erythro- and megakaryopoiesis including their precursor cells. Furthermore, a slight increase in the density of the fibrous matrix (reticulin fibers) was present in these patients that were characterized by a more favorable engraftment. The latter feature sheds some light on the complex pathomechanisms of homing and differentiation of progenitors. In confirmation with in vitro findings, this phenomenon is dependent on proper anchoring sites to the fibrous bone marrow stroma. Finally, the size of a full BM graft exerted a distinctive influence on the number of CD34+ precursors in the early post-transplant period. In conclusion, the present study has validated a number of BM features by focusing on the CD34+ progenitor cells and associated hematopoietic reconstitution including reticulin fibers and precursor cells of the erythroid and megakaryocyte lineage, which are not readily evaluable by fluorescence-activated cell sorting (FACS) analysis.
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