Theis Terwey

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 cell transplantation (HCT) for acute lymphoblastic leukemia, 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 acute lymphoblastic leukemia 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 acute lymphoblastic leukemia 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 one, two and five 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.

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

The systematic and standardized pretransplant 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 European group for blood and marrow transplantation (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 yr 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 yr (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.

Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia.

Little data are available on the relative merits of chimerism and minimal residual disease (MRD) monitoring for relapse prediction after allogeneic hematopoietic stem cell transplantation (HCT). We performed a retrospective analysis of serial chimerism assessments in 101 adult HCT recipients with acute lymphoblastic leukemia (ALL) and of serial MRD assessments in a subgroup of 22 patients. All patients had received myeloablative conditioning. The cumulative incidence of relapse was significantly higher in the patients with increasing mixed chimerism (in-MC) compared with those with complete chimerism, low-level MC, and decreasing MC, but the sensitivity of in-MC detection with regard to relapse prediction was only modest. In contrast, MRD assessment was highly sensitive and specific. Patients with MRD positivity after HCT had the highest incidence of relapse among all prognostic groups analyzed. The median time from MRD positivity to relapse was longer than the median time from detection of in-MC, but in some cases in-MC preceded MRD positivity. We conclude that MRD assessment is a powerful prognostic tool that should be included in the routine post-transplantation monitoring of patients with ALL, but chimerism analysis may provide additional information in some cases. Integration of these tools and clinical judgment should allow optimal decision making with regard to post-transplantation therapeutic interventions.

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 yr post alloSCT was 26% (94% CI: 17–35). Relapses, most of which occurred within the first 2 yr 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 yr 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 pretransplant blast count <20% before alloSCT and the development of cGvHD are the most important predictors of long‐term disease control.

Severe radiotoxicity in an allogeneic transplant recipient with a heterozygous ATM mutation

Patients receiving radiotherapy often experience toxicity of the skin and mucous membranes. While radiotherapy is a mainstay of myeloablative conditioning for allogeneic hematopoietic stem cell transplantation (ASCT), no risk factors for radiotoxicity have been identified in this setting. Here, we report on a patient with excessive radiation‐induced toxicity after ASCT who carried a heterozygous mutation in the Ataxia telangiectasia mutated (ATM) gene. This is the first case to suggest a genetic basis for increased radiotoxicity after myeloablative ASCT.

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT).

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 the MK criteria shows a highly significant difference in 5‐yr overall survival (OS) ranging between 67%, for the most favorable, and 32%, for the poorest risk group (P = 0.001). Although similarly 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 vs. P = 0.01). Notably, patients displaying non‐MK abnormalities (MK−) had a 5‐yr relapse incidence identical to those cytogenetically normal (CN), that is 24%. Multivariate analysis revealed that the MK classification is an independent prognosticator and superior in predicting OS (hazard ratios, 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 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. 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.

Allogeneic hematopoietic stem cell transplantation for adult acute lymphocytic leukemia

Allogeneic hematopoietic stem cell transplantation (alloHCT) is the single most potent treatment modality to prevent relapse in adults with acute lymphocytic leukemia, but its optimal use and timing remains a matter of intense debate and research. There is general agreement that patients with clinical features of high risk for relapse should undergo alloHCT in first complete remission. However, newer studies suggest that even patients without these risk factors may benefit. Monitoring of minimal residual disease may improve risk stratification and may complement or replace conventional risk features. Prognosis in relapsed and refractory patients is dismal, and alloHCT should be performed as soon as possible. AlloHCT also offers the only reasonable chance for cure in Philadelphia chromosome-positive acute lymphocytic leukemia; the role of imatinib is not yet clearly defined. Recent developments in unrelated-donor transplantation and reduced-intensity conditioning allow the beneficial effects of alloHCT to reach a considerably wider patient population.

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-a secretion has previously been described. The aim of this study was to investigate whether these TNF-α+/IFN-γ- 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 in 3/8 patients. Interestingly, four different cytokine secretion profiles of antigen-specific T-cells were detected:1 IFN-γ+/TNF-α+,2 IFN-γ+/TNF-α-,3 TNF-α+/ IFN-γ- and4 IFN-γ-/TNF-α-. TNF-α+/ IFN-γ- 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-α+/ IFN-γ- CD8+ T-cells needs further investigations.

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) vs. 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‐yr overall survival (OS) and disease‐free survival (DFS) of 76% vs. 54% (P = 0.03) and 76% vs. 53% (P = 0.03). Likewise, 3 yr after alloSCT the cumulative incidence of relapse (CI‐R) was significantly lower in the ER subgroup as compared to patients achieving DR, that is, 10% vs. 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.