Abstract
In a context of therapeutic revolution in older adults with AML, it is becoming increasingly important to select patients for the various treatment options by taking account of short-term ...efficacy and toxicity as well as long-term survival. Here, the data from three European registries for 1,199 AML patients aged 70 years or older treated with intensive chemotherapy were used to develop a prognostic scoring system. The median follow-up was 50.8 months. In the training set of 636 patients, age, performance status, secondary AML, leukocytosis, and cytogenetics, as well as
NPM1
mutations (without
FLT3
-ITD), were all significantly associated with overall survival, albeit not to the same degree. These factors were used to develop a score that predicts long-term overall survival. Three risk-groups were identified: a lower, intermediate and higher-risk score with predicted 5-year overall survival (OS) probabilities of ≥12% (
n
= 283, 51%; median OS = 18 months), 3–12% (
n
= 226, 41%; median OS = 9 months) and <3% (
n
= 47, 8%; median OS = 3 months), respectively. This scoring system was also significantly associated with complete remission, early death and relapse-free survival; performed similarly in the external validation cohort (
n
= 563) and showed a lower false-positive rate than previously published scores. The European Scoring System ≥70, easy for routine calculation, predicts long-term survival in older AML patients considered for intensive chemotherapy.
Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) leaves few therapeutic options, and mechanisms of immune escape of recurring leukemic cells ...remain poorly understood. Recently, acquired loss of mismatched human leukocyte antigen (HLA) was demonstrated in patients with AML undergoing haploidentical allogeneic HSCT and was suggested not to occur in HLA-matched HSCT. We hypothesized that this mechanism applies to extramedullary AML relapse which occurs frequently after allogeneic HSCT and might also not be restricted to haploidentical HSCT.
DNA from extramedullary AML relapse after HSCT was compared with bone marrow at diagnosis with array comparative genomic hybridization to investigate relapse-specific genomic aberrations in relapsing AML after allogeneic HSCT. Formalin-fixed, paraffin-embedded tissues from the same points of time were assessed for HLA, major histocompatibility complex class I chain-related gene A, and TAP2 immunohistochemistry staining to assess cell surface expression of deleted loci encoded on chromosome 6p.
Array comparative genomic hybridization revealed a partial loss of chromosome 6p in extramedullary myeloid sarcoma relapse of AML after sustained complete remission was achieved through matched related allogeneic HSCT. Among others, a deleted region 6p21.32-p21.33, which included several HLA class I genes, was detected.
These results suggest that the loss of HLA class I haplotype also occurs in AML relapse after HLA-matched related HSCT. Partial loss of several HLA class I genes and subsequent reduced presentation of minor histocompatibility antigens and reduced ligation of activating natural killer-cell receptors may explain the loss of graft-versus-leukemia response and extramedullary AML relapse in tissue with reduced immunologic surveillance.
Study Design
Mutlidisciplinary consensus recommendations for patients suffering from multiple myeloma (MM) involvement of the spinal column by the Spine Section of the German Association of ...Orthopaedic and Trauma Surgeons.
Objective
To provide a comprehensive multidisciplinary diagnostic and therapeutic approach and to summarize the current literature on the management of pathological thoracolumbar vertebral fractures in patients with multiple myeloma.
Methods
Multidisciplinary recommendations using a classical consensus process provided by radiation oncologists, medical oncologists, orthopaedic- and trauma surgeons. A narrative literature review of the current diagnostic and treatment strategies was conducted.
Results
Treatment decision has to be driven by a multidisciplinary team of oncologists, radiotherapists and spine surgeons. When considering surgery in MM patients, differing factors compared to other secondary spinal lesions have to be included into the decision process: probable neurological deterioration, the stage of the disease and prognosis, patient’s general condition, localization and number of the lesions as well as patient’s own wishes or expectations. Aiming to improve quality of life, the major goal of surgical treatment is to preserve mobility by reducing pain, secure neurological function and stability.
Conclusion
The goal of surgery is primarily to improve quality of life by restoring stability and neurological function. Interventions with an increased risk of complications due to MM-associated immunodeficiency must be avoided whenever feasible to allow early systemic treatment. Hence, treatment decisions should be based on a multidisciplinary team that considers patient’s constitution and prognosis.
Lysyl oxidase (LOX) has been described as necessary for premetastatic niche formation in epithelium-derived malignancies and its expression level therefore correlates with risk of metastatic disease ...and overall survival. However, its role in acute myeloid leukemia (AML) has not been sufficiently analyzed.
We investigated LOX plasma expression in 683 AML patients (age 17-60 years) treated within the prospective AML2003 trial (NCT00180102). The optimal cut-off LOX value was determined using a minimal-
-value method dichotomizing patients into a LOX-high group (> 109 ng/mL,
= 272, 40%) and a LOX-low group (≤ 109 ng/mL,
= 411, 60%).
Higher LOX expression was associated with lower peripheral white blood cells, lower serum LDH, and a lower frequency of
-ITD and
mutations at diagnosis. Higher LOX expression was found significantly more frequently in patients with secondary AML and therapy-related AML, in patients with French-American-British M5 subtypes, and in patients with adverse-risk cytogenetics. Comparing patients in the LOX-high group and the LOX-low group revealed a 3-year overall survival (OS) of 47 and 53% (
= 0.022) and 3-year event-free survival (EFS) of 27 and 35% (
= 0.005), respectively. In the LOX-high group significantly more patients had extramedullary AML compared to the LOX-low group (
= 0.037). Combining extramedullary AML and LOX as interacting factors in a multivariate analysis resulted in an independent impact on survival for the LOX-high-extramedullary interaction for OS (HR = 2.25,
= 0.025) and EFS (HR = 2.48,
= 0.008). Furthermore, in patients with extramedullary disease (
= 59) the LOX level predicted survival. Patients within the LOX-low group had an OS of 43% and EFS of 36% as compared to the LOX-high group with an OS of 13% and EFS of 6% (
= 0.002 and
= 0.008, respectively).
We hypothesize LOX expression to be a new potential biomarker to predict outcome in AML, specifically in AML subgroups such as the prognostic heterogeneous group of AML patients with extramedullary disease.
This retrospective study was performed with patient samples registered within the prospective AML2003 trial (NCT00180102). Patients were enrolled between December 2003 and November 2009.
Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Steroid-resistant aGvHD is associated with poor ...outcome, and no commonly accepted salvage therapy is available for its treatment. Here, we report 58 adult patients treated with mesenchymal stromal cells (MSCs) as salvage therapy for steroid-refractory aGvHD. Third-party MSCs expanded in platelet lysate-containing medium were transfused at a median dose of 0.99 × 10(6) cells per kg b.wt. A median of two MSC infusions were administered to each patient. Median time between the onset of aGvHD and the first infusion of MSCs was 12 days (range, 6-62 days). Most patients (79%) had grade IV aGvHD. Five patients showed complete response, five showed very good partial response, 17 showed partial response, and 31 showed no response. The estimated probability of survival after 1 year was 19%, and median survival was 69 days. Overall survival was not significantly different from that of a historical cohort of patients receiving alternative salvage therapy and no MSC infusions. In conclusion, MSC treatment on top of conventional immunosuppression was associated with an overall response rate of 47% but improved outcome in terms of survival remains to be shown.
Abstract 1445
Several recently identified molecular markers, i.e. FLT3-ITD, NPM1 and CEBPA and a number of others, have completely redefined our understanding of disease development in patients with ...acute myeloid leukemia and have already profound effects on risk assessment and treatment in AML. In addition, some of these novel markers, especially NPM1 -mutations, can be very efficiently used to detect minimal residual disease (MRD). In this study we investigated the suitability of NPM1 as MRD-marker, evaluated optimal cut-off points to define molecular relapse and analyzed the impact of MRD and additional risk factors on survival in a large cohort of patients with AML. Methods: The study population consisted of 164 NPM1 -mutant AML patients (pts) (median age 51 yrs. (range, 20–79 yrs.)), having one of the three most common NPM1 -mutations, A (N=139), B (N=16) and D (N=9). The patients were treated in protocols of the Study Alliance Leukemia (SAL) and were prospectively monitored. Consolidation treatment included autologous (N=18) and allogeneic transplantation from HLA-matched related (N=20) and unrelated (N=21) donors. An optimized assay for the sensitive cDNA based detection of the three most common NPM1-mutations using a Real-Time-Q-PCR based on locked-nucleic acid (LNA) containing primers was used. MRD-levels were expressed as percent of ABL1 -copies, which was assessed in all samples to control for sample quality. Results: Of the primary group, 154 patients were available for further analysis, 10 patients did not achieve CR and were excluded. A total of 1671 samples (972 BM; 699 PBL) were analyzed, the median number of samples per patient was 8 (range, 3–59), PBL and BM were analyzed in parallel at 138 time points. Although in general the median NPM1 levels in PBL samples were alsmost one log10 lower, a good qualitative concordance was found between both sources, with 48.6% of the samples being positive and 34.1% negative in both materials, whereas BM was pos. and PBL neg. in 14.5% and PBL pos and BM neg. in 2.9% of the samples, respectively. Using receiver operator characteristic (ROC) curves and regression models, the optimal cut-off value for detection of subsequent clinical relapse was found to be 1% NPM1/ABL1. In a competing risk analysis using Gray’s algorithm, the cumulative incidence of relapse in patients >1% and <=1% at twelve months was 34.8% 95% CI: 18.4–51.2% vs. 7.7% 95% CI: 0–16.1% (p=.0007). We also analyzed, whether the level of MRD at the time of achievement of CR had an impact on outcome. Both, NPM1 -MRD negativity and MRD-values below 1% were associated with significantly improved disease free (DFS) and overall (OS) survival, e.g. median OS in patients with NPM1 >1%: 20.2 months vs. NPM1 <1% not reached (p=.003), median DFS 13.6 months 95% CI: 9.7-35.3 mo vs. 61.1 months 95% CI: 27.3 mo -not reached (p=.0003). Not surprisingly, when we further differentiated the NPM1- positive patients into FLT3-ITD positive and negative, the subgroup of patients with FLT3-ITD andNPM1 >1% was associated with the poorest outcome. Conclusions: Our data clearly support the reported strong predictive value of NPM1 -positivity for the detection of relapse. In addition, our data show that the quality of CR as assessed by molecular methods profoundly affects long term outcome. Taken together, in NPM1 positive patients, MRD should be prospectively monitored to detect impeding relapse and to potentially start preemptive therapy, e.g. treatment with 5-Azacytidine or allo-SCT in eligible patients.
Thiede:AgenDix GmbH: Employment, Equity Ownership. Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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