Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate risk karyotype in first complete remission

For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long-term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) versus delayed remission (DR) in a cohort of 132 AML patients with an intermediate risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year overall survival (OS) and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, three years after alloSCT the cumulative incidence of relapse (CI-R) was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004), whereas non-relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT

A modified EBMT risk score predicts the outcome of patients with acute myeloid leukemia receiving allogeneic stem cell transplants

The systematic and standardized pre-transplant risk assessment represents an important tool to predict the outcome of patients undergoing allogeneic stem cell transplantation (alloSCT). To investigate the capacity of a modified EBMT (mEBMT) risk score to predict the outcome of patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplants, we retrospectively analyzed 214 patients transplanted at our center between 1995 and 2008. Overall survival (OS) of the whole cohort at 1, 3, and 5 years was 62%, 48%, and 45%, whereas the cumulative incidence of relapse or non-relapse mortality (NRM) was 26%, 33%, and 33% or 19%, 21%, and 22%. In univariate analysis a higher mEBMT risk score was associated with an inferior OS ranging from 69% for patients with a score of 0/1 to 26% for patients with a score of 5/6 at 5 years (p<0.0001) and steadily increasing hazard ratios for each additional score point. Likewise, a higher mEBMT risk score was associated with an increased incidence of relapse (p=0.049). Importantly, the prognostic value of the mEBMT risk score in terms of OS and relapse was maintained in multivariate analysis. Taken together, this indicates that a mEBMT risk score may be used to predict the outcome of patients with AML following alloSCT

Anti-leukemia T cells in AML: TNF-α(+) CD8(+) T cells may escape detection and possibly reflect a stage of functional impairment

Leukemia-associated antigens such as proteinase-3 (PR3) and Wilms' tumor protein-1 (WT-1) are potential targets of T-cell responses, which can be monitored by T-cell assays within vaccination trials and after allogeneic stem cell transplantation (SCT). In chronic myeloid leukemia (CML) an aberrant cytokine profile of antigen-specific T-cells with predominant TNF-{alpha} secretion has previously been described. The aim of this study was to investigate whether these TNF-{alpha}(+)/IFN-{gamma}(-) CD8(+) T-cells can also be observed in AML patients after SCT. Eight HLA-A2(+) AML patients at different time points after SCT were evaluated for HLA-A2-restricted CD8(+) T-cell responses against PR3, WT-1 and influenza-A using pentamer staining and different cytokine-based T-cell assays. Antigen-specific T-cell immune responses against influenza-A and PR3 were observed in 4/8 patients, WT-1-specific T-cells could be detected in 3/8 patients. Interestingly, four different cytokine secretion profiles of antigen-specific T-cells were detected: (1) IFN-{gamma}(+)/TNF-{alpha}(+), (2) IFN-{gamma}(+)/TNF-{alpha}(-), (3) TNF-{alpha}(+)/IFN-{gamma}(-) and (4) IFN-{gamma}(-)/TNF-{alpha}(-). TNF-{alpha}(+)/IFN-{gamma}(-) CD8(+) T-cells are an interesting biological phenomenon which can obviously be observed also in AML patients. This finding has important implications for both T-cell biology and monitoring within immunotherapy trials. The functional characterization of these TNF-{alpha}(+)/IFN-{gamma}(-) CD8(+) T-cells needs further investigations

Cytogenetic risk grouping by the monosomal karyotype classification is superior in predicting the outcome of acute myeloid leukemia undergoing allogeneic stem cell transplantation in complete remission

We retrospectively analyzed the impact of cytogenetic abnormalities grouped according to the monosomal karyotype (MK) classification or the Southwest Oncology/Eastern Cooperative Oncology Group (SWOG/ECOG) definition in 263 patients with acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (alloSCT) in complete remission (CR) at our center. Risk grouping using to the MK criteria shows a highly significant difference in 5-year overall survival (OS) ranging between 67% the most favorable and 32% for the poorest risk group (p=0.001). Although similar precise in predicting OS, the MK scheme better separates patients with respect to relapse incidence as compared to the SWOG/ECOG grouping (p=0.0001 versus p=0.01). Notably, patients displaying non-MK abnormalities (MK-) had a 5-year relapse incidence identical to those cytogenetically normal (CN), i.e. 24%. Multivariate analysis revealed that the MK classification is an independent prognosticator and superior in predicting OS (HR 3.74, p=0.01) and relapse incidence (HR 3.74, p=0.005) as compared to the SWOG/ECOG criteria. Finally, subgroup analysis revealed that the prognostic capacity of the MK classification is highly significant in patients treated with standard myeloablative conditioning (MAC) prior to alloSCT (p=0.0011 for OS, p=0.0007 for relapse). In contrast, the MK grouping failed to predict OS or relapse incidence in patients treated with reduced intensity conditioning (RIC). Taken together, these results indicate that the MK classification is superior in predicting the overall outcome of patients with AML undergoing alloSCT in CR. Furthermore, our data suggest that the genetic risk profile of MK- and CN patients is mostly overlapping in this setting

A modified EBMT risk score and the hematopoietic cell transplantation-specific comorbidity index for pre-transplant risk assessment in adult acute lymphoblastic leukemia

BACKGROUND: Disease stage is the most important prognostic parameter in allogeneic hematopoietic stem cell transplantation (HCT) for acute lymphoblastic leukemia (ALL), but other factors such as donor/host histocompatibility and gender combination, recipient age, performance status and comorbidities need to be considered. Several scoring systems are available to predict outcome in HCT recipients, however their prognostic relevance in ALL is not well defined. DESIGN AND METHODS: In the present study we evaluated a modified EBMT risk score (mEBMT) and the HCT-specific comorbidity index (HCT-CI) in 151 adult ALL patients who received allogeneic HCT from 1995 until 2007 at our center. RESULTS: Disease status was first complete remission (CR1) (47%), CR>1 (21%) or no CR (32%). Overall survival (OS) at 1, 2 and 5 years was 62%, 51% and 40% and non-relapse mortality (NRM) was 21%, 24% and 32%. Median mEBMT was 3 (0-6). Higher mEBMT was associated with inferior OS (hazard ratio per score unit (HR): 1.50, p<0.001), higher NRM (HR: 1.36, p=0.042) and higher relapse mortality (HR: 1.68, p<0.001). Disease stage was the predominant prognostic factor in this score. Comorbidities were present in 71% of patients with mild hepatic disease (29%), moderate pulmonary disease (28%) and infections (23%) being the most common. Median HCT-CI was 1 (0-9). In univariate analysis a trend for inferior OS (HR: 1.08, p=0.20) and higher NRM (HR: 1.14, p=0.11) with increasing HCT-CI was observed but the level of significance was not reached. In additional analyses we found that reduced Karnofsky Performance Status (KPS) was associated with inferior OS (HR: 1.34, p=0.023) and higher relapse mortality (HR: 1.71, p=0.001) when analyzed univariately, however KPS was associated with disease stage and significance was lost in multivariate analysis. CONCLUSIONS: The mEBMT was prognostic in our patient cohort with predominant influence of disease stage, whereas a trend but no significant prognostic value was observed for the HCT-CI

Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome

For patients with refractory acute myeloid leukemia (AML) allogeneic stem cell transplantation (alloSCT) represents the only curative approach. We here analyzed the long-term outcome of 131 consecutive patients with active AML, which was either primary refractory or unresponsive to salvage chemotherapy, transplanted at our center between 1997 and 2013. After a median follow-up of 48 months for the surviving patients, disease-free survival (DFS) at 5 years post alloSCT was 26% (94% CI: 17-35%). Relapses, most of which occurred within the first 2 years from transplant, were the predominant cause of treatment failure affecting 48% (95% CI: 40-58%) of patients, whereas non-relapse mortality was 26% (95% CI: 20-36%) at 5 years and thereafter. A marrow blast count ≥20% before alloSCT was an independent prognosticator associated with an inferior DFS (HR: 1.58, p=0.027), whereas the development of chronic graft-versus-host disease (cGvHD) predicted an improved DFS (HR 0.21, p<0.001) and a decreased relapse incidence (HR: 0.18, p=0.026), respectively. These results indicate that alloSCT represents a curative treatment option in a substantial proportion of patients with refractory AML. A pre-transplant blast count <20% before alloSCT and the development of cGvHD are the most important predictors of long-term disease control

NIH-defined graft-versus-host disease and evidence for a potent graft-versus-leukemia effect in patients with acute lymphoblastic leukemia

BACKGROUND: The prognostic value of the NIH consensus criteria for graft-versus-host disease (GVHD) is not well defined yet. PATIENTS AND METHODS: We analyzed NIH-defined GVHD in 147 acute lymphoblastic leukemia (ALL) patients. RESULTS: The cumulative incidence of classic acute GVHD (aGVHD), late aGVHD and chronic GVHD (cGVHD) was 63%, 12% and 41%, respectively. cGVHD was subclassified as classic versus overlap syndrome in 40% versus 60% of cases. In multivariate Cox regression analysis with GVHD as time-dependent covariate, classic aGVHD grade III/IV had a negative impact on overall survival (OS) due to higher non-relapse mortality. cGVHD of any grade was associated with superior OS, which was due to lower relapse incidence. Classic cGVHD versus overlap syndrome had no differential impact. In 44 patients without GVHD after transplant who received donor lymphocyte infusions (DLI), the cumulative incidence of classic aGVHD, late aGVHD or cGVHD was 60%, 5% and 57%. Occurrence of cGVHD after DLI was associated with improved OS due to lower relapse incidence. CONCLUSIONS: The NIH consensus criteria for GVHD clearly define prognostic subgroups in patients transplanted for ALL. The improved OS in patients developing cGVHD after transplant or DLI gives clear evidence for a potent graft-versus-leukemia effect in this indication

Reduced intensity conditioning prior to allogeneic stem cell transplantation in first complete remission is effective in patients with acute myeloid leukemia and an intermediate-risk karyotype

To evaluate the efficacy of reduced intensity conditioning (RIC) prior to allogeneic stem cell transplantation (alloSCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1), we retrospectively analyzed the outcome of 93 consecutive patients transplanted at our institution either following RIC (n = 37) or standard myeloablative conditioning (MAC) (n = 56) between 1999 and 2007. Projected overall survival (OS) or disease-free survival (DFS) for all patients at 1, 2, and 5 years was 78 or 70%, 65 or 57%, and 61 or 53% in the RIC group versus 73 or 70%, 68 or 62%, and 56 or 54% in the standard MAC group. In the subgroup of patients with an intermediate-risk karyotype projected OS at 1, 2, and 5 years was 86, 68, and 68% following RIC (n = 21) or 75, 69, and 66% following standard MAC (n = 36). Relapse or treatment-related mortality (TRM) was 15 or 17% (RIC group) and 26 or 14% (standard MAC group). Taken together, these data suggest that RIC-alloSCT may induce stable remissions in patients with AML transplanted in CR1. In particular, patients with an intermediate-risk karyotype ineligible to transplantation following standard MAC may benefit from RIC-alloSCT in CR1 at a low TRM