ELN Risk Research Articles

Effect of change in ECOG performance status at diagnosis and relapse in patients with acute myeloid leukemia.

e19007 Background: ECOG performance status (PS) is often utilized in treatment decision-making for patients with acute myeloid leukemia (AML). Patients with relapsed or refractory (R/R) disease have a particularly poor prognosis and require complex treatment decisions that weight patient preference, disease risk and PS. Currently, limited data exist on changes in performance status from initial diagnosis to the time when R/R AML is found. It would be interesting to characterize whether patients with R/R AML have worse performance status due to progression of disease or stable or improved performance status after initial therapy. Given there are additional factors such as induction chemotherapy that impact performance status at R/R disease, we were also interested in characterizing the association of PS in R/R AML with short and long term survival. Methods: We utilized an institutional database from University of Washington/Fred Hutchinson Cancer Center to retrospectively identify patients with AML or other high-grade myeloid neoplasms (≥10% blasts) who received both induction and salvage chemotherapy between January 1, 2008 through December 1, 2021. Patients with missing performance status at R/R were excluded. Salvage treatment was divided into high (cytarabine greater than 1g/m2/dose), intermediate (7+3 or similar), or reduced intensity (i.e., hypomethylating agents). The McNemar test was used for matched-pair analysis of PS at two timepoints. The Kaplan-Meier method was used for overall survival (OS). Univariate and multivariable linear regression models were used to evaluate associations with 4 week survival. All statistical analyses were performed using R 4.2.1 (2022). Results: Of the patients identified (n = 614), only patients with PS documented at R/R (n = 51) were included in the analysis (baseline characteristics in Table 1). No significant change was identified in PS at diagnosis versus R/R (PS≤1 66.7% vs 70.6%, p = 0.80). Better performance status (PS≤1) at R/R was correlated with improved OS (11.4 months vs 2.33 months, p = 0.003). The 4-week unadjusted mortality rate was 8.5% for patients with PS≤1, and 33.3% for patients with PS > 1 (p = 0.04). Poor performance status (PS > 1) at R/R was associated with significantly increased 4 week mortality (OR 5.5, 95% CI 1.2-30.9), even after adjustment for age and ELN2017 risk (OR 6.2, 95% CI 1.1-41.3). When OS was further stratified by chemotherapy intensity, patients with PS≤1 (n = 36) treated with high intensity chemotherapy (n = 22) had improved OS (14.1 vs 4.3 months, p = 0.007). Conclusions: PS tends to be stable at R/R disease, and poor PS is associated with very poor survival. Further work is needed to characterize the patients with R/R AML who benefit from intensive re-induction chemotherapy.

First-in-human trial of tocilizumab in combination with a standard induction chemotherapy in newly diagnosed acute myeloid leukemia patients: The phase 1 TOCILAM study.

7028 Background: Numerous studies have pointed out the pathological role of deregulated expression of Interleukin-6 (IL-6) in cancers. In acute myeloid leukemia (AML), IL-6 promotes chemo-resistance and correlates with poor prognosis. One explanation is that AML cells express IL-6 receptor (R) and self-produce IL-6 at once, favouring blast proliferation and survival. Therefore, IL-6 blockade may represent a new promising therapeutic strategy for AML. Here, we have tested Tocilizumab (Toci), an anti-IL-6R antibody, in combination with a standard AML induction chemotherapy. Methods: This was a monocentric Phase 1 study testing three escalating doses of Toci (4, 6 and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (Idarubicine 8 mg/m² d1 to d5 + cytarabine 100 mg/m² d1 to d7). All adults ( > = 18 yo) with a newly diagnosed (excluding patients (pts) with a favorable risk according to ELN-2017 classification if < 60 yo) or a relapsed/refractory AML were eligible. The main objective was to determine the maximum tolerated dose of Toci for further phase 2/3 studies. Patients had to be included 2 by 2, according to a continual reassessment method while targeting a related-experimental drug toxicity level < 30%. A maximum of 12 pts had to be included. Toxicity was evaluated using NCI version5 criteria. Responses were evaluated according to ELN-2017 criteria between d30/d45 of induction. Also, IL-6 and Toci plasma levels were assessed. All pts gave informed consent and the trial was registered at Clinical trials under NCT04547062. Results: Between Dec/2020 and Dec/2022, 12 pts were treated, including 2 pts at 4 mg/Kg, 2 at 6 mg/kg and 8 at 8 mg/kg of Toci. The median age was 66 yo (range: 56-73), all pts had a newly diagnosed AML, ELN risk was intermediate: 25%; unfavorable: 75%. No dose limiting toxicity related to Toci was documented. Two pts died during induction, 1 of infection and 1 of cerebral haemorrhage. Complete remission (CR) rate for evaluable pts was 90% (n = 9/10). After induction, 7 received a consolidation and 7 were allo-transplanted. With a median follow-up of 600d, 4 patients have relapsed and 7 have died, 1-y OS and LFS were estimated at 43% (21-88%) and 39% (19-82%), respectively. Dosages of IL-6 (pg/mL) showed a significant increase after Toci injection (median 23,2 (2.6-53.5) vs 202,9 (21.1-6189.2) after 8d and 481,5 (53.8-7327.4) after 15d), suggesting a good saturation of the targets (IL6-R) on AML cells and a potential anti-leukemic effect. Median dosages of Toci (µg/ml) were higher 8d and 15d after injection at L2 (34.8; 17.2) and L3 (38.5; 12.9) compared to L 1 (10.9; 1.4). Conclusions: The combination of Toci to a standard AML intensive induction appears to be very safe providing both high CR rate and the expected biological effect. We now recommend a dose of 8 mg/kg of Toci given at d8 of induction for further phase 2/3 studies. Clinical trial information: NCT04547062 .

Addition of venetoclax to FLAI induction chemotherapy (VFLAI) improves survival in patients with intermediate and high-risk AML vs FLAI and 3+7: A GIMEMA Italian cooperative analysis.

7013 Background: Venetoclax combined with intensive chemotherapy proved to be safe with promising activity. The GIMEMA AML1718 trial (NCT03455504) was based on the administration of venetoclax-FLAI (fludarabine, idarubicin, cytarabine) to intermediate/high-risk ELN2017 AML. Methods: To investigate the potential advantage of the addition of venetoclax, patient-level data from GIMEMA AML1718 (V-FLAI group, n=57) were compared to “3+7”-like induction (AML1310, Venditti et al. 2019, 3+7 group, n=445), and to FLAI real-life experience (Guolo et al. 2016, FLAI group, n=155) using a propensity score matching. In the model, we included the following variables: age at diagnosis, gender, ELN2017 risk classification and allogenic transplant rate. For determining adequate balance, the diagnostic method employed was the standardized mean difference, visualized through a Love plot; a standardized bias score less than 0.2 was used as a criterion. The final weighted sample sizes are 183 (3+7), 54 (V-FLAI) and 155 (FLAI). Weights were calculated with a multinomial logistic regression model. The Odds Ratio (OR) were estimated using logit models. Survival curves were compared by standard and pairwise Log-rank test. Results: FLAI, V-FLAI and 3+7 cohorts differed in terms of age (median: 52 vs 54 vs 49 years, respectively, p<0.001), in terms of risk category (p< .001) - since the low risk was not represented both in V-FLAI and FLAI trials -, in terms of transplant rate (45% vs 49% vs 27%, p<0.001) and female sex (43% vs 35% vs 48%, p=0.15). Being more recent, AML1718 had a shorter median follow-up (10.5 vs 75.8 vs 104.8 months). The matching weights produced the best balance, with SMDs <0.18 for all variables. After weighting, the CR rate observed in the V-FLAI group was higher than FLAI and 3+7, as well as MRD-negativity rate. In terms of Odds Ratio (OR) the probability of achieving CR in V-FLAI and FLAI patients was significantly higher compared to 3+7 patients (p=0.01 and p=0.03, respectively). Conversely, V-FLAI and FLAI did not differ in their probability to achieve CR (p=0.34). Concerning MRD, the OR associated to V-FLAI group was significantly higher (namely, a higher probability of MRD-negativity) of that associated to both FLAI and 3+7 treatments (p=0.005 vs FLAI; p=0.001 vs 3+7). Looking at survival outcomes at 12 months, upon weighting, DFS estimate of the V-FLAI group was higher than “3+7” and FLAI (p=0.048). Conclusions: VFLAI resulted in a deeper disease response as compared to other regimens. These results highlight the potential benefit of venetoclax added to intensive induction chemotherapy and suggest the role of fludarabine-based regimens as a backbone for high-risk disease. [Table: see text]

Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles

BackgroundIncreasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets.MethodsWhile unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available.ResultsUnsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients.ConclusionsDynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18–86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel’s C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as “very adverse”. In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

Verification of prognostic expression biomarkers is improved by examining enriched leukemic blasts rather than mononuclear cells from acute myeloid leukemia patients

BackgroundStudies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers.MethodsTo assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes.ResultsBlast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations (CEP70, COMMD7, DNMT3B, ECE1, LNX2, NEGR1, PIK3C2B, SEMA4D, SMAD2, TAF8, ZNF444). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes (CEP70, DNMT3B, ECE1, and PIK3CB) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells.ConclusionsThis study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts.

A Successful Bridge Therapy Combining Hypomethylating Agents with Venetoclax for Adult Patients with Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia

Recently, the combination of VEN-HMA has been shown to achieve durable responses in patients with both newly diagnosed (ND) and R/R-AML. We retrospectively evaluated the post-allo-HCT outcomes of 50 patients who received VEN-HMA therapy. In total, 10 were ND and 40 were R/R and, at the time of HCT, the median age was 53 years. In the ND- and R/R-AML groups, the percentage of patients who achieved CR/CRi or MLFS was 90% and 92.5%, respectively. In all, after a median follow-up of 13.7 months, the probabilities of overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) at 1 year were 63.7%, 59.3%, 28.5%, and 12.2%, respectively. In addition, the cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and moderate-severe chronic GVHD at 1 year were 28.4% and 37.4%, respectively. In multivariate analysis, the factors associated with a statistically significant impact on OS were VEN-HMA cycle (p = 0.021), ELN risk group (p = 0.041), and the response to VEN-HMA therapy before allo-HCT (p = 0.003). Although 80% of our patients had R/R-AML and 30% underwent a second allo-HCT, our data still suggest that allo-HCT following VEN-HMA therapy is a safe and effective treatment option.

Clinical Implications of the FLT3-ITD Allelic Ratio in Acute Myeloid Leukemia in the Context of an Allogeneic Stem Cell Transplantation.

Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients' outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed 118 patients (median age at diagnosis 58.3, range 14.3-82.3 years) harboring FLT3-ITD, of whom 94 patients were consolidated with an allogeneic HSCT and included in outcome analyses. A high FLT3-ITD allelic ratio was associated with a higher white blood cell count, higher blood and bone marrow blasts, and worse ELN2017 risk at diagnosis. Patients with a high FLT3-ITD allelic ratio more often had NPM1 mutations, while patients with a low allelic ratio more often had FLT3-TKD mutations. Patients with a high FLT3-ITD allelic ratio were less likely to achieve a measurable residual disease (MRD)-negative remission prior to allogeneic HSCT and had a trend for a shorter time to relapse. However, there was no distinct cumulative incidence of relapse, non-relapse mortality, or overall survival according to the FLT3-ITD allelic ratio in transplanted patients. While co-mutated FLT3-TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high FLT3-ITD allelic ratio, comparative studies are needed to evaluate which FLT3-ITD mutated patients benefit from which consolidation strategy.

Mitochondrial gene expression signature predicts prognosis of pediatric acute myeloid leukemia patients.

Gene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance. Children with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset. In 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrell's c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset. We identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.

The trace that is valuable: serum copper and copper to zinc ratio for survival prediction in younger patients with newly diagnosed acute myeloid leukaemia

PurposeNo data on predicting the survival of AML patients based on the level of trace elements in the serum have been presented to date. The aims of this prospective cohort study were as follows: (i) to evaluate the serum Cu and Zn levels in people from Northeast China, (ii) to assess the association between the serum Cu level (SCL) and Cu to Zn ratio (SCZR) and clinical and nutrition data, and (iii) to investigate the predictive values of the SCL and SCZR in newly diagnosed de novo AML patients.MethodsA total of 105 newly diagnosed AML patients and 82 healthy controls were recruited. The serum Cu and Zn levels were determined by inductively coupled plasma spectrometry. The associations of SCL and SCZR with the survival of these AML patients were assessed by Cox proportional hazards models.ResultsBoth SCL and SCZR were positively related to the blast percentage of bone marrow and C-reactive protein, negatively related to albumin level and CEBPA double mutation and were significantly associated with worse overall survival and disease-free survival. Meanwhile, patients with higher SCL had worse CTCAE levels, and patients with higher SCZR showed less complete remission during the first course of induction chemotherapy. Moreover, higher SCZR was positively associated with ELN risk stratification, and was negatively associated with haemoglobin level and prognostic nutritional index (PNI).ConclusionThe SCL and SCZR are associated with long-term survival in patients with newly diagnosed AML undergoing intensive induction and may serve as important predictive biomarkers.

Real-life challenges using personalized prognostic scoring systems in acute myeloid leukemia.

Personalized medicine is a challenge for patients with acute myeloid leukemia (AML). The identification of several genetic mutations in several AML trials led to the creation of a personalized prognostic scoring algorithm known as the Knowledge Bank (KB). In this study, we assessed the prognostic value of this algorithm on a cohort of 167 real life AML patients. We compared KB predicted outcomes to real-life outcomes. For patients younger than 60-year-old, OS was similar in favorable and intermediate ELN risk category. However, KB algorithm failed to predict OS for younger patients in the adverse ELN risk category and for patients older than 60 years old in the favorable ELN risk category. These discrepancies may be explained by the emergence of several new therapeutic options as well as the improvement of allogeneic stem cell transplantation (aHSCT) outcomes and supportive cares. Personalized medicine is a major challenge and predictions models are powerful tools to predict patient's outcome. However, the addition of new therapeutic options in the field of AML requires a prospective validation of these scoring systems to include recent therapeutic innovations.

Prognostic Impact of the 2022 European Leukemia Net Risk Classification in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction: For most acute myeloid leukemia (AML) patients (pts) an allogeneic stem cell transplantation (HSCT) offers the highest chance of cure. Recently, the European LeukemiaNet (ELN) published updated recommendations on the risk classification in AML pts. In addition to the risk at diagnosis, which is now based on cytogenetics and the mutation status of several genes, a dynamic adjustment according to the measurable residual disease (MRD) status in favorable (fav) and intermediate (int) risk pts at informative time points - such as prior to an allogeneic HSCT - was recommended. A validation of the new ELN2022 risk classification has not been reported. Methods: We retrospectively analyzed 522 AML pts who received an allogeneic HSCT between 2000 and 2021 in first complete remission (CR, 54%), second CR (11%), CR with incomplete count recovery (CRi, 13%), or relapsed/refractory (22%) at our center. Median age at HSCT was 59 (range 16-76) years (y), 53% of pts were younger than 60 y. Conditioning regimens were myeloablative (27%), reduced-intensity (23%) or non-myeloablative (50%). At diagnosis, cytogenetics, and the mutation status of CEBPA, NPM1, and FLT3-ITD were assessed. Using next-generation sequencing we analyzed a panel of 54 recurrently mutated genes in myeloid malignancies (MiSeq platform, Illumina). In pts with material available in remission prior to HSCT, the MRD status based on NPM1mutations, BAALC, MN1, and WT1 expression was evaluated as published previously (Jentzsch 2021). MRD positivity (MRDpos) was defined as positivity of any of the analyzed markers. Median follow up after HSCT was 3.0 y. Results: ELN2022 risk at diagnosis was 22% fav, 26% int, and 52% adverse (adv). Older pts (≥ 60 y at HSCT) had significantly worse ELN2022 genetic risk (P<.001). Comparing the ELN2017 and the new ELN2022, 83% (fav), 70% (int), and 90% (adv) of pts kept their allocation, while 15% and 2% of fav ELN2017 risk pts changed to int and adv ELN2022, 30% of int ELN2017 risk pts changed to adv ELN2022 & 1% and 10% of adv ELN2017 risk pts changed to fav and int ELN2022. Analyzing the c-statistic (area under the curves [AUC]) produced by the ELN2017 and ELN2022 for relapse (AUC2017 = 0.64 vs AUC2022 = 0.64, P=.21) and overall survival (OS) prediction (AUC2017 = 0.60 vsAUC2022 = 0.57, P=.06), the ELN2022 did not perform significantly better. However, the ELN2022 risk at diagnosis impacted cumulative incidence of relapse/progression (CIR, P<.001) and OS (P<.001, Figure 1), which was especially seen in pts < 60 y (CIR P<.001, OFS P<.001), but less so in pts ≥ 60 y at HSCT (CIR P=.002, OS P=.10). At diagnosis, outcomes did not differ significantly with respect to the specific genetic abnormality defining the ELN2022 fav or the ELN2022 int risk. Also a high or low FLT3-ITD allelic ratio (0.5 cut) within the ELN2022 int risk did not result in distinct outcomes (CIR P=.13, OS P=.30). In contrast, within pts harboring adv ELN2022 risk, CIR (P=.05) and OS (P<.001) significantly differed according to the presence of specific genetic abnormalities; i.e. a complex karyotype (at 3 y: CIR 59%, OS 30%), other adverse cytogenetic aberrations (at 3 y: CIR 50%, OS 54%), adverse-risk gene mutation (i.e.ASXL1, RUNX1, or TP53, at 3 y: CIR 47%, OS 58%), or secondary AML-like gene mutations (at 3 y: CIR 30%, OS 73%). When we adjusted fav and int risk pts according to the MRD status at HSCT as proposed by the ELN2022 recommendations, 49% of fav risk pts at diagnosis had persisting MRD and were reclassified as int risk at HSCT while 53% of int risk pts at diagnosis were MRD negative and reclassified as fav risk at HSCT. Outcomes of MRD-adjusted fav risk pts improved (at 3 y: CIR 12%, OS 75%), while that of MRD-adjusted int risk pts (at 3 y: CIR 53%, OS 49%) was similar to that of adv risk pts transplanted in morphologic CR/CRi (at 3 y: CIR 47%, OS 54%). Conclusion: In the context of an allogeneic HSCT, the proposed risk assessments by the ELN2022 significantly impacted outcomes at diagnosis as well as after adjustment according to MRD status prior to HSCT of AML pts. However, it did not perform significantly better than the previous ELN2017 risk stratification. The FLT3-ITD allelic ratio did not significantly impacted outcomes within the ELN2022 int risk, justifying the removal from the risk stratification. Noteworthy, in pts receiving allogeneic HSCT, secondary AML-like gene mutations did not associate with adverse outcomes when no other adverse-risk characteristics were present. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Revised Prognostic Index for Patients with Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms in First Relapse

Introduction: Though many patients with acute myeloid leukemia (AML) will achieve a first complete remission (CR1), most patients will relapse. A previous analysis from HOVON on 667 consecutive AML patients in first relapse identified four key predictors for achieving a second CR (CR2), which improved overall survival (OS): age at relapse, CR1 duration, cytogenetic risk, and prior receipt of hematopoietic cell transplant (HCT), thereby developing a scoring system to aid in therapeutic decision making (Breems, JCO 2005). Since this original publication, other predictors of relapse have emerged, most notably measurable residual disease (MRD), and cytogenetic/molecular risk stratification has been refined in the form of ELN2017 (Dohner, Blood 2017). We hypothesize that incorporation of MRD and ELN2017 categorization into a risk stratification model will improve our ability to predict CR2 likelihood and OS after relapse. Methods: Eligible patients included those ≥18 years (yrs) old who received treatment (tx) at our center for AML or other high-grade myeloid neoplasms (≥10% marrow/peripheral blasts at diagnosis) between January 2008 and July 2019, who later relapsed. Using our IRB-approved institutional AML database, we obtained the following demographic and outcome parameters: age; gender; new diagnosis (ND) type (AML vs. other; de novo vs. secondary); ECOG performance status; TRM score; ELN2017 risk; CR1 date; CR1 details [CR vs. CR with incomplete hematologic recovery (CRi) and MRD status]; initial tx intensity [low being hypomethylating agents (HMA); intermediate being 7+3 or similar; high being FLAG-ida/CLAG-M or similar]; cycles to CR1; prior HMA before relapse; prior HCT before relapse; relapse date; relapse salvage tx type and intensity; response to salvage (CR vs. CRi + MRD status); CR2 date; subsequent HCT; and death date or date of last contact. We fit multivariable (MV) models for OS after first relapse (Cox) and CR2 after first relapse (logistic). A score for each respective outcome was developed by rounding the coefficients from the models. C-statistics (Cox) and area under the receiver operating characteristic curve (AUC; logistic) were also calculated. Results: We identified 315 eligible patients who achieved CR1 and relapsed. Among these, 266 received subsequent tx and were included in our analysis: the median age at relapse was 63 yrs (range 20-85); 40% (n=106) were female; 56% (n=148) received high-intensity tx for ND; 47% (n=125) had secondary AML at ND; 28% (n=75) had received prior HCT before relapse; 36% (n=95) had received prior HMA before relapse. For initial tx of first relapse, 52% (n=138) received high-intensity tx; 5% (n=13) received HCT; 12% (n=31) received intermediate-intensity tx; and 32% (n=84) received low-intensity tx. Overall, 60% (n=160) achieved a subsequent CR2. Significant covariates in the CR2 MV model were CRi following ND tx (odds ratio [OR] 0.85; 95% confidence interval [CI] 0.73-0.99), ≥2 cycles to CR1 (OR 0.86; CI 0.75-0.99), CR1 7-18 m (OR 1.22; CI 1.07-1.38), CR1>18 m (OR 1.31; CI 1.12-1.53), post-relapse HCT (OR 1.43; CI 1.1-1.86), and low-intensity tx post-relapse (OR 0.77; CI 0.68-0.87). Significant covariates leading to improved OS in the MV model were CR1 duration of 7-18 m (hazard ratio [HR] 0.5; 95% CI 0.36-0.69), CR1 duration >18 m (HR 0.36; CI 0.24-0.55); and post-relapse HCT (HR 0.49; CI 0.26-0.91). We derived scoring systems from these MV models (Table 1). A positive score indicates a favorable prognosis (median OS of 13.6 m); a score of 0 (median OS 6.5 m) or below (median OS 5.6 m) indicates a poor prognosis (Figure 1). When the Breems scoring system for OS was applied to our dataset, the C-statistic was 0.55; our score improved to a C-statistic of 0.61. The AUC for the CR2 score from our model was 0.69. Conclusions: The Breems system was not well-calibrated to our dataset, underscoring the need to develop an updated scoring model for OS and CR2 in relapsed AML patients. Surprisingly, factors such as CR1 MRD status and ELN2017 risk did not appear to be significant in MV analyses. Efforts are underway to update this dataset to include additional contemporary patients; we hope to enhance the prognostic scoring algorithm by capturing the effect of specific mutational profiling (e.g. TP53, FLT3, and others). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Allogeneic Stem Cell Transplant Outcomes in Patients Treated with Hypomethylating Agent Plus Venetoclax Compared to CPX-351

Introduction: Hypomethylating agent in combination with venetoclax (HMA+Ven) was approved for treatment of newly diagnosed acute myeloid leukemia (AML) after a phase III trial showed 66.4% CR/CRi rates and 17.8 mos median duration of response. However, these results were seen in patients 75 years and older or those who were considered unfit for intensive chemotherapy (IC). These CR rates are superior compared to what was historically reported with IC. Post-remission treatment for most fit patients with intermediate and adverse risk AML involves allogeneic stem cell transplantation (alloSCT) which offers the highest chance of maintaining long-term remission. Many fit patients still receive IC for the purpose of inducing remission. Our aim was to study the post-transplant outcomes of patients who were treated with HMA+Ven compared to CPX-351 along with the factors that help choose between IC and HMA+Ven for fit patients that are transplant candidates. Methods: A retrospective review of patients with newly diagnosed AML treated with CPX-351 or HMA+Ven at Moffitt Cancer Center was performed. Patients who were treated with either CPX-351 or HMA+Ven as front line therapy and then proceeded to alloSCT were included in this analysis. Chi square was used to compare baseline characteristics. Survival estimates were calculated using the Kaplan-Meier method from date of transplant to the date of death or date of last follow up. Results: Out of the total 147 patients that received CPX-351, 65 (44.2%) underwent alloSCT. In contrast, from the 216 patients treated with upfront HMA+Ven, only 21 (9.7%) patients proceeded to alloSCT (p<0.00001). The median age at diagnosis for the CPX-351 treated patients was significantly different from the HMA+Ven patients (65 vs 70 years; p=0.003). There was no difference in gender or race between the two groups. Table 1 describes the baseline and disease characteristics of the two cohorts. More patients with AML-MRC were treated with CPX-351 than HMA+Ven (87.7 vs 66.7%; p<0.001). There were no differences in the distribution of patients in the two groups based on cytogenetic risk, ELN risk or ECOG performance status. Table 2 describes the transplant variables. There were no differences in the type of donor or timing of transplant between the two groups. No patients in the HMA+Ven group underwent myeloablative conditioning (MAC), while 20% of patients in the CPX-351 cohort underwent MAC prior to transplant (p=0.032). Looking at disease state prior to transplant, we saw that more patients in the HMA+Ven group were in CRi (38.1 vs 6.2%; p= <0.001). There were no significant differences based on the Sorror score, hence the co-morbidities between the two cohorts were not significantly different. A higher number of patients with TP53 mutations were treated with HMA+Ven prior to transplant (27.8 vs 7.9%; p=0.047) and greater number of patients with DNMT3A mutations were treated with CPX-351 (30.2% vs 0; p=0.005). There was no significant difference between post-transplant relapse rates between the CPX-351 and HMA+Ven cohorts (12/65, 18.5% vs 5/21, 23.8%; p=0.592). At a median follow up of 18 months, the median OS for both groups was not reached. The 12-month OS probability was 71.4% for patients treated with upfront CPX-351 compared to 69.6% for upfront HMA+Ven (p=0.977). At a median follow up of 16 months, the relapse free survival was also not reached for both groups. The 12-month post-transplant RFS was 80.8% for CPX-351 vs 74.3% for HMA+Ven (p=0.548; Figure 1). The 1-year NRM was not significantly different between the two groups either (13/52, 25%, 2/19, 10.5% respectively; p=0.271) Conclusion: In this analysis a greater number of patients proceeded to alloSCT after achieving remission with CPX-351 compared to HMA+Ven for newly diagnosed AML. Patients who were treated with HMA+Ven tended to be older than those who received CPX-351. However, there were no differences in the ELN risk, OS, RFS or rate of relapse between the two cohorts. This study is limited by the small number of patients however provides an important conclusion, noting no difference in post-transplant OS and RFS for patients who are fit to proceed to a transplant if treated with HMA+Ven or CPX-351. A prospective study with larger numbers of patients is needed to confirm these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Therapy-Related AML: Clinical/Biological Features and Long-Term Outcome in a Cohort of 1133 Adult AML Patients

Introduction: Therapy-related acute myeloid leukemia (t-AML) affects approximately 7% of AML patients and exhibits adverse genetic features that are assumably caused by increased DNA damage after antecedent radiation/chemotherapy. There is an ongoing medical need for a better understanding of differences between patients with t-AML and de novo AML. Here, we assess clinical and biological characteristics of patients with t-AML and compare long-term survival with de novo AML in a large cohort of AML patients. Methods: 225 t-AML patients who were newly diagnosed between 1995-2018 were retrospectively analyzed and compared to a cohort of 908 patients with de novo AML. Mann-Whitney U- and Chi square test were used to assess differences in baseline characteristics between subgroups. Kaplan Meier procedure was applied to calculate overall survival (OS). Cox regression was used to identify hazard ratios (HR) of independent prognostic risk factors. Non-relapse mortality (NRM) and risk of relapse (RR) were calculated by the cause-specific hazard method. Results: As compared to de novo AML, t-AML patients were older (61 vs. 55 years, p<0.001), had increased comorbidity and a higher frequency of adverse genetic alterations (e.g. monosomal or complex karyotypes, -5/-5q, -7, t(v;11)(v;23)). Prior to t-AML, solid cancer was diagnosed in 61% of patients (138/225), whereas 31% had hematologic malignancies (69/225) and 8% had autoimmune diseases (18/225). Previous malignancies had been treated with combined radiochemotherapy in 33% (75/225), chemotherapy in 27% (60/225), radiation therapy in 22% (50/225), immunosuppressive therapy (Cyclophosphamide, Mitoxantrone, Methotrexate, Azathioprine) in 7% (16/225), radio-iodine therapy in 4% (9/225) or multiple preceding cytotoxic therapies in 7% (15/225). Median latency period between cytotoxic therapy and t-AML was 5.8 years. In intensively treated t-AML patients (172/225), median OS was 13.7 months as compared to 39.4 months in de novo AML (823/908, p<0.001). The substantial difference in median OS particularly applied to patients <60 years with a 5-year OS of 31% in t-AML (96/225) as compared to 51% in de novo AML (562/908, p<0.001). In patients ≥60 years, there was a tendency towards better OS in de novo AML, however, this did not reach statistical significance (p=0.066). Interestingly, OS in patients receiving intensive therapy for t-AML was comparable with de novo AML within the favorable genetic risk groups (APL p=0.927, ELN-favorable p=0.714). In contrast, a significant difference in favor of de novo AML was observed within the ELN-intermediate (p=0.009) and ELN-adverse (p=0.016) risk groups, which was most likely caused by age differences between these groups. However, there was no age difference within the favorable ELN risk group (p=0.878). Considering only patients who received non-intensive therapy, OS (p=0.394), age (p=0.087), ECOG status (p=0.123) and ELN risk group (p=0.098) did not differ significantly between t-AML (53/225) and de novo AML (85/908). Multivariate analysis (including several covariates such as age, ELN risk, ECOG and CCI) did not confirm t-AML per se as an independent risk factor for OS (p=0.081), RR (p=0.982) or NRM (p=0.320) in intensively treated patients. Interestingly, OS was particularly favorable after radio-iodine therapy as compared to other treatment modalities (p=0.042) and highly unfavorable after pretreatment with multiple cytotoxic therapies (p=0.009). Multivariate analysis revealed ECOG score >1 (HR 2.3, p=0.002), adverse ELN risk (HR 1.7, p=0.003), BMI <18,5 kg/m2 (HR 2.7, p=0.029), diabetes (HR 2.0, p=0.029) and intensive treatment (HR 0.3, p<0.001) as independent prognostic factors in t-AML. Conclusion: Our data indicate that inferior OS in t-AML as compared to de novo AML rather results from an accumulation of adverse genetic alterations and patient-associated risk factors than from t-AML itself. Thus, our study strongly supports the current view that risk stratification in t-AML (including indication for allo-HSCT) should align with strategies used in de novo AML patients (based on genetic features), both in the case of intensive and non-intensive therapy. Regarding the new International Consensus Classification of AML, our data are in accordance with the classification of t-AML as a "diagnostic qualifier" within the different AML subgroups rather than a separate subcategory.

Racial Disparities in the Treatment of Acute Myeloid Leukemia. ELN Risk Stratification Analysis of Overall Survival According to Race

Introduction and background: Acute myeloid leukemia (AML) is a rare disease that critically disrupts the function of the bone marrow. Genetic mutations and cytogenetic changes are the main culprits of this process. As the bone marrow fails to perform its usual activity, blood production is crucially affected. Patients with AML need immediate access to medical facilities to treat such an acute disease. It has been postulated that a black population may have worse outcomes in AML. The less favorable outcome may result from miscellaneous factors, with social-economical disparities being the most important. In light of the systemic racism in health care and society in general, minorities may have less access to prime health care centers. Many studies suggest racial differences in survival among whites and black populations. But few have compared outcomes based on the ELN genetic risk stratification. It's important to realize that uneven outcomes may also result from more adverse genetic profiles in specific subgroups. In our study, we analyzed the results of the treatment of AML in a single American institution separated by race and ELN risk. Material and Methods: In this study, we retrospectively evaluated the outcomes of all patients with AML at our institution. We collected the data from patients treated with AML from June 2020 to June 2022. The most relevant information collected were: self-declared race, age, blood counts, cytogenetics, Next Generation Sequence information, Charlson Comorbidity Index(CCI), type of treatment, the best response to therapy, time to progression, and overall survival. We evaluated a total of 39 patients. Seventeen individuals were classified as adverse risk and twenty-two as an intermediate or good risk. Overall survival and statistical analysis were performed in all patients, and a special subanalysis was also done in the adverse risk group. Twenty-two patients self-declared as whites and 17 as black. Results: Among all ELN risk groups(figure 2), the estimated mean time until death was 417.21 days for blacks and 476.81 days for whites. At 400 days, the probability of survival was approximately 0.40 (or 40%) for blacks and 0.55 (or 55%) for whites. As the p-value (0.996) was greater than 0.05, we concluded that there was insignificant evidence of a difference in survival times for whites and blacks in all ELN risk groups. In a subanalysis of the ELN adverse risk population(figure 1), the estimated mean time until death was 326.00 days for non-whites and 285.96 days for whites. At 200 days, the probability of survival was approximately 0.68 (or 68%) for blacks and 0.43 (or 43%) for whites. As the p-value (0.187) was greater than 0.05, we again concluded that there was insignificant evidence of a difference in survival times for whites and blacks, even in adverse risk ELN subgroups. Conclusions and recommendations: Our study has identified no statistical difference in survival between whites and blacks in our single university institution population. Moreover, the evaluation in the adverse risk patients showed that at 200 days, the probability of survival in blacks is numerically higher than in whites. These results contradict the idea that a white population tends to have better outcomes than a black population regarding AML. The study's obvious limitation is the small sample population and the short follow-up period. Given equal access to care, as in our institution, outcomes were similar regardless of race. Further studies should be performed to evaluate the differences in outcomes among black and whites to validate our findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Real-World Single-Institution Experience with Hypomethylating Agents Plus BCL-2 Inhibitor for the Treatment of Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disease of myeloid progenitor cells resulting from alterations in cell differentiation, proliferation, and renewal. Treatment for young patients and those with favorable-to-intermediate risk remains a combination of cytarabine and anthracycline, while the optimal regimen for the elderly has yet to be established. First-line and salvage combination hypomethylating agents azacitidine or decitabine with BCL-2 inhibitor venetoclax (HMA+Ven) has shown promise for these patients and are becoming standard therapy. We present a cohort from our institution treated with HMA+Ven vs traditional therapy. We hypothesize HMA+Ven leads to improved overall survival (OS) and complete remission with or without count recovery (CR/CRi) compared to traditional therapy in the elderly and those with unfavorable risk as defined by the European LeukemiaNet (ELN-2017) risk stratification. Methods: 232 AML patients from Baylor St. Lukes Medical Center, and Michael E DeBakey VA Medical Center from 8/26/1997 to 7/31/2021 were reviewed. These patients were stratified by HMA+Ven vs. other standard treatment. Differential survival among groups was measured by Kaplan-Meier method. The independent effect of HMA+Ven against multiple intervening variables was evaluated by Cox proportional regression analysis. Chi-square and t-test detected potential intervening variables with impact on outcome. SAS software was used for analysis. Results: Those treated with HMA+Ven comprised 28 out of 227 patients (12.3%). Average age of patients was 65 (26-80) in the HMA+Ven group and 61.3 (20-93) in the other treatment group (p=0.05). Age, ELN-2017 risk stratification, and HMA+Ven treatment were predictors for survival (Table 1). OS in our cohort favors HMA+Ven vs other treatment (Fig. 1, 348 days vs 261 days, p=0.0004). Overall survival in the elderly population of interest favors HMA+Ven (270 days vs 135 days, p<0.0001). CR/CRi was superior for HMA+Ven in those age >60 (55% vs 24.7%, p=0.006) as well as those age >70 (55% vs 15.2% p=0.007). OS for those with adverse ELN-2017 stratification favors HMA+Ven (352 days vs 164 days, p=.002). Interestingly, overall survival trends for those with active smoking history favors HMA+Ven (p<0.0001). Lastly we found CR/CRi favors HMA+Ven for those with RUNX1 gene mutation (75% vs 25%, p=0.01). Conclusion: HMA+Ven demonstrated superior response in our elderly patients and those with unfavorable risk through OS as well as CR/CRi, compared to those treated with traditional therapy. This held true across all ELN-2017 risk categories when examined by cox regression models (Table 1) and was most notable in the adverse risk subgroup. The mechanism by which smoking may enhance HMA+Ven survival is uncharacterized and warrants investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Persistence of Mutations in Complete Remission Including DNMT3A, TET2 and ASXL1 Mutations Is Associated with Worse Prognosis in Patients with Acute Myeloid Leukemia Treated in ALFA 0702 Study

Background: Only few studies have validated the use of molecular minimal measurable residual disease evaluation using error-corrected NGS (NGS-MRD). The prognostic relevance of detection of isolated DNMT3A, TET2 or ASXL1 (DTA) mutations post-induction remains controversial. Benchmarking of NGS-MRD with respect to other molecular MRD tools (such as WT1 expression and NPM1 mutation) has yet to be conducted. Material and methods: All patients included in the ALFA-0702 study who reached cytological complete remission (CR) or CR with incomplete platelets recovery after one induction course and with available material were included (n=189). Standard NGS sequencing of 67 genes was performed at diagnosis. Error-corrected NGS was performed on post-induction bone marrow samples using a custom panel including all mutations identified at diagnosis (n=735 mutations in 51 genes). Median sequencing depth in CR was 24695x after UMI deduplication. A threshold of 0.1% VAF was set as cut-off value for NGS-MRD detection for all targets. WT1 expression data in CR were available in 100 patients with initial WT1 over-expression. NPM1-MRD was evaluated in 67 patients by error-corrected NGS. For this evaluation, one alternative read was considered sufficient to define positivity. Leukemia free survival (LFS) and overall survival (OS) probabilities were evaluated since CR. Results: Median age at diagnosis was 46 years. ELN2017 risk was favorable in 52 (27%) patients, intermediate in 75 (40%) and unfavorable in 60 (32%). With a median follow-up from CR of 47 months, median LFS and OS was 35 and 41 months respectively. At diagnosis, gene mutations were detected in 181 (95%) patients. The median number of mutations per patient was 4 (range 1-10). Ninety-one patients had no target detected (NGS-MRD neg) and ninety had at least one target detected (NGS-MRD pos) including 42 patients with detection of DTA mutations only (DTA-MRD). NGS-MRD pos patients were significantly older (p=0.0018) than NGS-MRD neg patients and harbored a higher median number of mutations at diagnosis (4 vs 3, p=0.0021). There were no significant differences in terms of demographics and clinical presentation (age, WBC, number of mutation) between patients with DTA-MRD and non-DTA-MRD patients. In univariable analyses, NGS-MRD pos was associated with a lower probability of LFS (4-years LFS: 44% vs 68%, p= 6e-04) and OS (4-years OS: 57% vs 81%, p= 9e-04). There was no impact of the initial number of mutations on LFS nor OS. There were no significant differences in LFS and OS between DTA-MRD and non-DTA-MRD patients (figure 1). When adjusting analysis on ELN2017 status, MRD-NGS pos remained associated with shorter LFS (HR 2.15[1.34-3.44] , p=0.001) and OS (HR 2.41[1.38-4.20] p=0.002). As a continuous variable, the number of mutations detected in CR was associated with shorter LFS and OS. Specifically, detection of ≥2 mutations predicted poorer LFS (HR, p=3e-05) and OS (HR, p=4 e-05), compared with detection of only 1 mutation (figure 2). Sixteen patients were positive for WT1 MRD evaluation, and 84 were negative (WT1 neg). Among the WT1 neg patients 37 were NGS-MRD pos and 47 were NGS-MRD neg. When adjusting for both ELN17 and WT1 expression in CR, there was no significant impact of MRD-NGS positivity on LFS (HR=1.62 [0.85 - 3.09]) nor OS (HR=1.28 [0.59 - 2.74]) In the 67 patients with NPM1 mutation, 41 patients had NPM1 undetectable MRD (including 21 NGS-MRD pos and 20 NGS-MRD neg) and 26 had detectable NPM1-MRD (including 16 NGS-MRD pos and 10 NGS-MRD neg). When adjusting for both ELN status and NPM1-MRD, NGS-MRD pos was associated with a non-significant trend towards lower LFS (HR=2.34[0.96-5.71] p=0.063). Discussion and conclusions: In the homogeneously treated ALFA-0702 population, MRD-NGS positivity after the first induction course predicts shorter LFS and OS independently of ELN17 risk stratification. Detection of a higher number of mutations in CR is associated with a worse prognosis. Contrary to previous studies accruing older patients treated less intensively persistence of DTA mutations has similar prognostic relevance than non-DTA mutations. Future studies will be necessary to determine the superiority or addivitity of NGS-MRD with respect to available molecular MRD tools. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of 5-Day Vs. 10-Day Decitabine in Combination with Venetoclax in Newly Diagnosed AML Patients Ineligible for Induction Chemotherapy

BACKGROUND. Standard dosing of decitabine 20mg/m 2 daily given over 5 days in combination with the Bcl-2 inhibitor venetoclax (5-day DEC/VEN), in elderly or chemotherapy ineligible patients with Acute Myeloid Leukemia (AML), induces both a high rate of complete remission (CR/CRi rate 71%) and prolonged survival (median OS 14.2 months). (DiNardo CD et al. Blood. 2019) Extending the duration of decitabine treatment to 10-days (10-day DEC/VEN) may increase efficacy of the combination. In a phase 2 study of newly diagnosed chemotherapy ineligible AML patients aged ≥ 60 years, 10-day DEC/VEN led to a high CR/CRi rate of 89%, with 67% of these being negative for measurable residual disease and a median OS of 18 months. (DiNardo, CD et al. Leukemia. 2020). As a prospective clinical trial comparing efficacy of the different dosing schedule of decitabine in combination with venetoclax is unlikely to be performed, we conducted a single center retrospective analysis comparing 5-day and 10-day DEC/VEN outcomes. METHODS. We retrospectively studied patients with newly diagnosed AML receiving either 5-day or 10-day DEC/VEN between January 2016 to May 2022 at City of Hope National Medical Center. Patients receiving prior AML therapies including hypomethylating agents were excluded. Responses were evaluated per the ELN criteria (Dohner, H et al. Blood. 2017) Measurable residual disease (MRD) flow cytometry was performed at the University of Washington. Patient characteristics were summarized by frequency and associations between overall response and patient and disease characteristics were tested by Fisher's exact test. Overall Survival (OS) was evaluated by the Kaplan-Meier method and the difference between groups was determined by log-rank test. All statistical analyses were performed using R software. RESULTS. 139 patients were included: 48% (n=67) treated with 5-day decitabine and 52% (n=72) treated with 10-day decitabine. The baseline characteristics of the patients are summarized in table 1. At baseline, 5-day decitabine + venetoclax treated patients were older with a median of age of 73 vs. 70 years (p=0.01). The 5-day and 10-day groups were otherwise well balanced with no significant difference in AML type, ELN risk or adverse molecular features. Rates of CR/CRi, CR/CRi, MRD negativity, and the percentage of responders proceeding to allogeneic stem cell transplant were similar between regimens (Table 1). There was also no difference in 8-week mortality (p = 0.44). With a median follow-up of 12 months for responding patients, the median OS (figure 1) and RFS for 5-day and 10-day DEC/VEN were 14 vs. 27 months, p=0.091 and 12.9 vs. 14.3 months, p= 0.75 respectively. In subgroup analysis, patients without therapy- related AML (non-tAML) receiving the 10-day-regimen had a longer median OS (42.5 vs. 14.6 months, p= 0.03). No other subgroups, including those with high-risk molecular (eg.TP53) or cytogenetic risk factors (e.g. complex karyotype) demonstrated a significant difference between the 5 and 10-day DEC/VEN regimen. CONCLUSION. Among newly diagnosed AML patients receiving venetoclax in combination with either 5-day or 10-day decitabine, there was no significant difference in response (CR/CRi or MRD negativity) or survival outcomes (OS or RFS). Although a significant difference was not observed, 10-day DEC/VEN led to an increased median OS, which may reach significance with more patients and longer follow-up. Additionally, the 10-day DEC/VEN regimen may benefit certain subpopulations; it demonstrated longer median OS in patients without t-AML. Further analysis to confirm a survival benefit among patients without t-AML receiving either 5-day or 10-day DEC/ VEN is needed and will be presented at ASH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Application of a Validated Composite Comorbidity Score Measuring Both Fitness and Cytogenetic Risk to Assess Outcomes in 1L AML Patients Who Received Venetoclax Plus Azacitidine in Viale-A

Background: Approximately half of adults with acute myeloid leukemia (AML) are unable to receive standard intensive chemotherapy (IC) due to older age or comorbidities (Griffiths et al. Leuk Res. 2020;91:106339). Although age is prognostic, several factors define patient fitness, such as comorbidities and cytogenetic risk. A better determination is needed to assess patient fitness for AML treatment regimens as there is no currently defined standard. The AML composite model (AML-CM) is a validated system used to determine fitness for transplant and potentially other intensive regimens. The randomized double-blind phase 3 VIALE-A trial demonstrated that in older adults who were unfit for IC based on modified Ferrara criteria, venetoclax (VEN), an oral BCL-2 inhibitor, combined with azacitidine (AZA) increased median overall survival (mOS) to 14.7 mo compared with 9.6 mo with placebo (PBO)+AZA. However, the Ferrara criteria contain limited patient characteristics to ascertain fitness for IC. Therefore, we aimed to assess the benefit of VEN+AZA vs PBO+AZA in patients with differential fitness and disease biology across the spectrum of AML-CM score. Methods: VIALE-A (NCT02993523) evaluated the efficacy of VEN+AZA compared to PBO+AZA in patients with treatment-naive AML who were ineligible for IC due to age or comorbidities. Patients (N = 431) were randomized 2:1 to receive VEN+AZA or PBO+AZA, respectively. AML-CM score was determined retrospectively based on age, comorbidities, and cytogenetic risks (Sorror et al. JAMA Onc. 2017;3:1675). Patients in each treatment arm were stratified into 3 risk groups by AML-CM scores: group A, score 1 - 4 (patients who could potentially benefit from IC); group B, score 5 - 9 (patients with decreased benefit from IC); and group C, score ≥10 (patients who could potentially benefit from a clinical trial or palliative care). Results: Of 431 patients enrolled to VIALE-A, 380 were categorized by AML-CM score and 51 could not be categorized due to missing data. Missing data included ELN risk, obesity, hepatic comorbidities, and hypoalbuminemia. Some patients with missing data were included in the analysis group if that data would not have impacted AML-CM group assignment. The proportion of patients in AML-CM groups A, B, and C, respectively, was 22 (9%), 172 (68%), and 59 (23%) in the VEN-AZA arm and 10 (8%), 92 (72%), and 25 (20%) in the PBO-AZA arm. Patients with higher AML-CM scores generally had poor prognostic disease characteristics, adverse ELN risk, decreased pulmonary function, and other comorbidities (Table). Composite complete remission (CRc [CR + CRi]) rates (groups A/B/C) were 17 (77%)/116 (67%)/34 (58%) with VEN-AZA, and 5 (50%)/24 (26%)/7 (28%) with PBO-AZA (Table). The median time to first CRc response in the VEN-AZA arm was 1.2 mo for group A, 1.3 mo for group B, and 1.1 mo for group C. In the PBO-AZA arm, the median time to first CRc was 4.2 mo, 3.0 mo, and 2.6 mo for groups A, B, and C, respectively (Table). The median duration of CRc across groups A, B, and C was 25.1 mo, 17.1 mo, 17.8 mo, respectively, in the VEN-AZA arm and 9.4 mo, 13.5 mo, and 8.5 mo in the PBO+AZA arm (Table). The mOS was 38.8 mo, 14.2 mo, and 10.2 mo in groups A, B, and C, respectively, in the VEN+AZA arm, and 17.7 mo, 8.6 mo, and 6.6 mo, respectively, in the PBO+AZA arm (Table). Early deaths within 30 days in groups A, B, and C, respectively, were 0 (0%), 9 (5%), and 8 (14%) in the VEN-AZA arm, and 0 (0%), 2 (2%), and 3 (12%) in the PBO+AZA arm. Of 22 deaths across both treatment arms in all AML-CM groups, there was 1 death within 30 days (VEN+AZA, group B) that was due to disease progression, and 21 deaths within 30 days that were due to adverse events. Conclusion: Based on the AML-CM score, most patients enrolled in VIALE-A were considered to have decreased benefit from IC, and nearly a quarter of patients evaluated were determined to be the frailest. Under this scoring system, patients in VIALE-A treated with VEN+AZA had higher CRc rates and prolonged duration of CRc and OS compared with those treated with PBO+AZA across all 3 AML-CM groupings. Notably, patients who scored >10 on the AML-CM scale, for whom the recommended treatment is enrollment in clinical trials and/or palliative care, had improved outcomes with VEN+AZA compared with PBO+AZA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal