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.
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.
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.
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.
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.
Objectives
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).
Methods
We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014.
Results
The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT overall P = 0.0064 for disease‐free survival (DFS), overall P = 0.003 for relapse. Patients with an intermediate‐1 profile have a significantly elevated 5‐yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, hazard ratio (HR) 2.58, P = 0.048. An intermediate‐1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate‐1 patients, the presence of an FLT3 internal tandem duplication (FLT3‐ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3‐ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate‐1 subgroup.
Conclusions
The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate‐1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies.
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.
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.
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.
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.
Introduction: Allogeneic stem cell transplantation (alloSCT) has become an integral part in the therapy of patients with malignancies of the lympho-hematopoietic system. One of the main reasons for ...treatment failure after alloSCT is relapse of the underlying disease, which, in the majority of cases, is associated with a poor prognosis. Adoptive immunotherapy by the use of donor lymphocyte infusions (DLI) was shown to be effective in this setting. However, the conditions and the optimal timing of DLI administration for prophylaxis or treatment of (impending) relapse remains controversial.
Patients and Methods: We retrospectively analyzed 160 consecutive patients (median age: 48 (range: 17-69) years) who received DLI after previous alloSCT performed at our center between 1998 and 2014. Indications for alloSCT were: acute myeloid leukemia (AML) (N=68), acute lymphoblastic leukemia (ALL) (N=49), myelodysplastic syndrome/myeloproliferative neoplasia (MDS/MPN) (N=26), or myeloma/lymphoma (N=17). The disease risk index (DRI) was low (N=1), intermediate (N=101), high (N=43), or very high (N=6) (unknown: N=9). Comorbidities, as specified by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), were low (N=38), intermediate (N=79), or high (N=38) (unknown: N=5). In N=71 patients a 10/10 human leukocyte antigen (HLA) matched-related donor was chosen, whereas N=89 patients were transplanted from an unrelated donor, either matched (N=73) or mismatched (N=16). Conditioning was either myeloablative (MAC) (N=71) or reduced-intensity (RIC) (N=89). The median interval from alloSCT to first DLI was 7.1 (range: 1.0-93.2) months. Indication for DLI was prophylactic (e.g. high-risk of relapse or active disease at the time of alloSCT) (N=28), pre-emptive (e.g. persistent or increasing mixed chimerism/molecular relapse) (N=86), or hematologic relapse (N=46). Pre-treatment before DLI was none/cessation of immunosuppression (N=129), lymphodepleting chemotherapy (N=16), or other (N=15). The median number of DLI units given was 2 (range: 1 - 6) and the median cumulative CD3+ cell dose/kg body weight given was 1.1 x 10E7 (range: 5.0 - 16.0 x 10E7).
Results: The median follow-up of all patients from day of alloSCT was 37.3 (range: 3.0 - 202.6) months, whereas the median follow-up from day of first DLI administration was 21.2 (range: 0.3 - 200.5) months. Overall survival (OS) of the entire cohort at 1, 3, and 5 years after alloSCT was 80.5%, 63.8%, and 57.7%. Calculated from the day of first DLI OS at the same time points was 68.8%, 61.0%, and 55.8%. At five years after alloSCT OS in the group of patients with AML or ALL was significantly lower as compared to patients with MDS/MPN or myeloma/lymphoma, i.e. 52.0% versus 66.2% (p=0.043). Furthermore, OS in the group of patients receiving pre-emptive DLI was virtually identical to patients who received prophylactic DLI, i.e. 70.4% versus 69.8% at 5 years. In contrast, patients with hematologic relapse prior to DLI had an inferior outcome, i.e. an OS of 23.3% at 5 years. In addition to indication for DLI administration, i.e. prophylactic or pre-emptive versus therapeutic, the occurrence of chronic graft-versus-host disease (cGvHD) was the strongest predictor for outcome, i.e. long-term survival.
Conclusions: Taken together, our data indicate that adoptive immunotherapy by the use of DLI is capable of inducing long-term remissions in patients after alloSCT. As pre-emptive and prophylactic treatment yielded virtually identical results, latter may be reserved for selected patients with (very) unfavorable disease characteristics, e.g. AML or ALL with active disease at the time of transplant. The optimal type of pre-treatment needs to be determined by investigating larger patient cohorts.
No relevant conflicts of interest to declare.
Introduction: In acute myeloid leukemia (AML) genetic risk factors are among the strongest predictors for overall outcome. Recently, the European Leukemia Net (ELN) proposed a revised classification ...based on the presence or absence of specific cytogenetic and/or molecular aberrations. Here, we evaluated the prognostic significance of this system in patients with AML undergoing allogeneic stem cell transplantation (alloSCT).
Patients and Methods: A total of 363 patients transplanted at our center between 2004 and 2014 was retrospectively evaluated. According to the ELN classification genetic risk was favorable (N=51), intermediate-1 (N=120), intermediate-2 (N=98), or adverse (N=94). Remission status at the time of alloSCT was first complete remission (CR1) (N=204), CR>1 (N=61), or refractory (N=98). In 107 patients standard myeloablative conditioning (MAC) was used, whereas reduced intensity conditioning (RIC) was applied in 256 patients. Grafts were from either related (N=103) or unrelated (matched: N=191, mismatched: N=69) donors. The median age was 52 (range: 18-75) years.
Results: For the surviving patients the median follow-up was 30 (range: 3-129) months. Whereas in the subgroup of patients aged ≥60 years (N=98) no significant differences in disease-free survival (DFS) or cumulative incidence of relapse (CI-R) between the 4 ELN subgroups were found, the ELN classification was highly predictive for in the subgroups aged <60 years. Patients with an adverse risk karyotype had significantly lower DFS as compared to patients with a favorable or an intermediate risk profile, i.e. 30% versus 56% for favorable, 52% for intermediate-1, or 59% for intermediate-2 (p=0.0064). Correspondingly, the CI-R was highest in patients with an adverse risk profile, i.e. 53% at 5 years. In turn, patients with favorable, intermediate-1, or intermediate-2 risk disease had a CI-R of 15%, 40%, or 21% (p<0.001). In the intermediate-1 subgroup, adverse outcome, i.e. relapse, was predominant in the group of FLT3-ITD positive patients, whereas the CI-R in patients lacking a FLT3-ITD was similar to what was observed in the intermediate-2 subgroup.
Conclusions: Taken together, our data suggest that the ELN classification of genetic risk is suitable for predicting relapse and overall survival of patients with AML aged <60 years undergoing alloSCT. The adverse outcome of patients in the intermediate-2 subgroup may be related to presence of a FLT3-ITD. Therefore, further efforts are needed to improve the clinical results in this particular group.
No relevant conflicts of interest to declare.
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Cytogenetic abnormalities as detected by conventional karyotyping are among the strongest predictors for the long-term outcome of patients (pts) with acute myeloid leukemia (AML). However, up to ...50% of pts are cytogenetically normal (CN) and the screening for mutations of the FLT3 and the NPM1 genes allowed to further dissect this heterogeneous group. Allogeneic stem cell transplantation (alloSCT) has become an integral part of the post-remission therapy for pts with intermediate or high-risk AML in case an HLA-compatible donor is available. Here, we analyzed the impact FLT3 and NPM1 mutations on the outcome of pts with CN-AML who underwent alloSCT at our center between 2006 and 2013.
Follow-up data of all pts were prospectively collected in a computer database and retrospectively analyzed as of June 30th, 2013. 101 pts (46 female, 55 male) with a median age of 54 (range: 18-75) years with CN-AML were included. 71 pts had de novo AML, whereas 30 pts had secondary or therapy-related AML. All pts were treated in a German multicenter AML trial and received at least two courses of induction therapy. The FLT3 and NPM1 mutational status was as follows: 14 pts were FLT3-mutated/NPM1 wild-type, 15 pts were NPM1 mutated/FLT3 wild-type, 22 pts were FLT3-mutated/NPM1 mutated, and 50 pts were wild-type for both FLT3 and NPM1. At alloSCT, 62 pts were in first complete remission (CR1), 16 pts were in CR2, and 23 pts had refractory disease. In 96 pts alloSCT was performed using peripheral blood stem cells (PBSCs), 5 pts received a bone marrow (BM) graft. Conditioning consisted of standard myeloablative conditioning (MAC) (6x2 Gy TBI and 2x60 mg/m2 cyclophosphamide) in 24 pts. 77 pts received reduced intensity conditioning (RIC) (2x4 mg/kg oral busulfan, 6x30 mg/m2 fludarabine and 4x10 mg/kg ATG). A matched related donor was available for 27 pts, whereas 55 pts or 19 pts were transplanted from a matched-unrelated or mismatched unrelated donor.
After a median follow-up of 11 (range: 1-83) months for the surviving pts, 64 pts are alive and in CR. Causes of death were relapse or NRM in 26 pts or 12 pts, respectively. At 1, 3 and 5 years projected overall survival (OS) or disease-free survival (DFS) of the entire cohort was 67% (57-77%), 58% (46-69%), and 54% (42-67%) or 60% (51-71%), 57% (47-68%), or 50% (37-54%). At the same time points the cumulative incidence of relapse (CIR) or non-relapse mortality (CINRM) was 27% (19-38%), 30% (22-43%), and 37% (36-52%) or 12% (6-21%) remaining stable thereafter. Subgroup analysis showed that the presence of a NPM1 mutation in the absence of mutated FLT3 is associated with a significantly lower CIR, i.e. 8%, at 3 years. In the other subgroups the CIR ranges between 32% for pts lacking FLT3 and NPM1 mutations and 37% for pts carrying both mutations (p=0.002). In univariate analysis, pts with refractory disease had a significantly lower DFS (p=0.0002) and a higher relapse incidence (p=0.0001) as compared to pts transplanted in CR. All other factors examined, i.e. AML subtype, stem cell source, type of conditioning, donor/HLA-match were not associated with OS, DFS, or relapse incidence. Notably, there was no correlation between FLT3 or NPM1 mutational status and remission status at the time of alloSCT. OS did not differ significantly between the four subgroups due to an increased NRM in patients with NPM1-mutated CN-AML. Finally, in multivariate analysis only remission status was identified as an independent prognosticator for DFS and relapse incidence, whereas alloSCT from a mismatched unrelated donor predicted a higher NRM.
Taken together, our results indicate that pts with high-risk AML, as defined by the presence of a FLT3-mutation, may achieve durable long-term remissions following either MAC and RIC-alloSCT from related an unrelated donors. In turn, the presence of a mutation of the FLT3 gene may not per se predict a poor outcome in this setting. In contrast, remission status is among the strongest predictors for long-term outcome in patients with CN-AML undergoing alloSCT.
No relevant conflicts of interest to declare.
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