Combining Clinical Features with Genetic Factors Improves Survival Prediction for Adults with Acute Myeloid Leukemia: Validation of a New Score System in 3 Cohorts

Introduction: Risk stratification in acute myeloid leukemia (AML) is continually being refined as we learn more about the molecular pathophysiology of this heterogeneous disease. European LeukemiaNet (ELN) 2017 used widely to stratify the 'genetic' risk of AML, but there are considerable challenges in its application, particularly in centres where molecular genetic testing either not available, or not sufficiently timely for clinical decision making. Up to a third of the study subjects cannot be stratified using a full cytogenetic-molecular model in real-time, real-life setting. There are few attempts to combine clinical features and genetic factors aiming to find a scoring system to improve AML survival prediction. There is only one to our knowledge (Sorror ML et al. 2017). This study has generated an Adapted Genetic Risk (AGR) assessment, and used it in combination with clinical risk parameters to create a novel scoring system which has now been validated using two independent cohorts. Methods: A training cohort from São Paulo (FMUSP, n = 167) of intensively treated AML patients (18-65 years) was assessed using ELN2017 genetic criteria. A comparative validation with our AGR which permits missing cytogenetic or molecular data (Figure 1) split these patients into favorable-risk (FR), intermediate-risk (IR), and adverse-risk (AR). This cohort was also used for Cox Proportional-Hazard Model (CPHM) univariate and multivariate analysis to find clinical parameters that would inform a novel Survival AML Score (SAMLS). Variables which are included in SAMLS had to be either significant in both CPHM models or significant in univariate and crucial for multivariate fitness as measured for the Akaike Information Criterion (AIC). We then applied the AGR strategy and SAMLS to 2 independent test cohorts of intensively treated adult AML patients : Riberao Preto (FMRP, n=145) and Oxford (OUH, n=157). The study was approved by the institutional review boards of the 3 participating centers. Informed consent was obtained from all patients according to the Declaration of Helsinki. Results: Table 1 shows the clinical characteristics for all the 3 cohorts. The median follow-up (FUP) was 72.3, 44.4, and 70.5 months for FMUSP, FMRP, and OUH, respectively. The median Overall Survival (OS) was 12.4, 12.5, and 56.4 months and the 5-year OS were 29.6%, 29.7%, and 49.7% respectively. Both ELN2017 and AGR correlated with significant differences in OS (p-value <0.001) and DFS (ELN p=0.002, AGR p=0.003) in the FMUSP cohort. The ROC c-statistic were 0.68 (ELN) and 0.66 (AGR). AGR was validated in FMRP and OUH cohorts, with statistically significant stratification of OS across the 3 risk groups in both cohorts (FMRP p=0.03, OUH p=0.003); and DFS in FMRP (p = 0.04), but not in OUH (p = 0.7)(Table 2 and Figure 2). Multivariate CPHM model for OS in FMUSP which yielded the smallest AIC were: Age, HR 1.52; Albumin, HR 0.50; WBC, HR 1.37; Haemoglobin, HR 1.48; Platelet count, HR 0.64; and AGR-IR, HR 2.23 and AGR-AR HR, 4.66 (Figure 3). Variables which met SAMLS inclusion criteria are in Table 3. SAMLS stratifies AML as low-risk (LR-AML) (SAMS <=1.5) or high-risk (HR AML) (SAMLS >=2) (Table 3 and Figure 4 C-D), where there is a significant difference in survival in the FMUSP training cohort (p <0.001). The 5-year OS was 55% and 9% for LR and HR AML respectively. The ROC c-statistic for OS in FMUSP using SAMLS was 0.80 (21% bigger than using AGR only). SAMLS risk stratification was validated in both FMRP and OUH cohorts for OS (FMRP p-value 0.003, OUH p-value < 0.001) and DFS (p-value 0.04 OUH only). Prediction accuracy was also increased since ROC c-statistic was 0.65 for OS in FMRP (a 10% increase), and 0.77 in OUH (a 22% increase) (Figure 4). Conclusion: ELN2017 genetic risk score for AML was validated in a cohort from a low-medium income country (LMIC). AGR is a proposed risk evaluation that can be used for AML patients for whom fully genetic testing is not feasible (required for ELN2017) and was as accurate as ELN2017. AGR predicts survival in 3 independent cohorts, from LMIC and developed nation settings. When other biological and clinical factors are added to AGR, we were able to show SAMLS is better to predict overall survival than AGR. Importantly, serum Albumin, a simple and routine test parameter, was an independent predictor of OS for AML in all 3 cohorts. Therefore the use of SAMLS can predict early and late mortality and can impact on treatment decisions. Disclosures Quek: Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. Vyas:Astellas: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau.

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Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification

Blood ◽

10.1182/blood-2019-129519 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1397-1397

Author(s):

Diego Chacon ◽

Ali Braytee ◽

Yizhou Huang ◽

Julie Thoms ◽

Shruthi Subramanian ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Genetic Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Groups ◽

High Fidelity ◽

Improve Outcome ◽

Acute Myeloid

Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.

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Targeted Intravenous Busulfan and Fludarabine Allogeneic Transplantation Conditioning in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.2290.2290 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2290-2290

Author(s):

Joseph A. Pidala ◽

Jongphil Kim ◽

Claudio Anasetti ◽

Melissa Alsina ◽

Ernesto Ayala ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Large Series ◽

Myelogenous Leukemia ◽

Secondary Aml ◽

Relapsed Disease ◽

Acute Myeloid

Abstract Abstract 2290 Poster Board II-267 Reduced and intermediate intensity conditioning with allogeneic hematopoietic cell transplantation (HCT) offers promise to effectively control hematologic malignancies, while limiting treatment related toxicity and mortality (TRM). We aimed to examine the efficacy of IV targeted Busulfan and Fludarabine (IV-Bu/Flu) in a large series of adults with exclusively acute myelogenous leukemia (AML). One hundred adults (median age 48) with AML (CR1 49, CR2 25, REL1 8, REL2 1, PIF 16, untreated 1) were treated with Busulfan 130-145 mg/m2/day for four days with pharmacokinetic targeting on the final two days to achieve an area under the curve (AUC) of 5300 (+/-10%) μmol*min/L/day and Fludarabine 40mg/m2/day for 4 days, followed by transplantation of G-CSF mobilized peripheral blood stem cells (PBSC) (N=98) or unstimulated bone marrow (BM) (N=2) from allogeneic donors (MRD 38, MUD 38, MMUD 24). Acute GVHD prophylaxis consisted of tacrolimus/methotrexate (N = 77), tacrolimus/mycophenolate mofetil (N = 22), or tacrolimus/sirolimus (N = 1). Median time to neutrophil and platelet engraftment was 16 and 12 days, respectively. Non-relapse mortality was 3% at 100 days, and 15% by 1 year. The cumulative incidence of relapse was 41%. Overall survival (OS) was 59% (95% CI: 48.1 – 67.5) at 1 year, and 42% (95% CI: 30.8-53.3) at 4 years. OS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 52.9%, 40.1%, 41.2%, and 57.5% respectively; none with relapsed disease survived to 4 years (log-rank p = 0.0014). Progression-free survival (PFS) was 53% (95% CI: 42.8 – 62.2) at 1 year, and 32.3% (95% CI: 21.8 – 43.2) at 4 years. PFS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 44.1%, 33.4%, 33.9%, and 33.1%, respectively, while none with relapsed disease at transplant reached this endpoint (p = 0.0264). On multivariable modeling, remission status at HCT (relapsed disease HR 14.85 (95% CI: 2.12 - 104.2), p = 0.007), moderate/severe cGVHD (HR 0.281, 95% CI: 0.10 - 0.76; p = 0.013), and day 90 bone marrow (BM) chimerism ≥ 90% (HR 0.245, 95% CI: 0.08 - 0.79; p = 0.018) predicted overall survival, and day 90 BM chimerism ≥ 90% (HR of 0.18 (95% CI: 0.08 - 0.45), p = 0.0002) predicted PFS. The following were not significantly related with OS or PFS: age, cytogenetics, donor relation, number of induction cycles, aGVHD prophylaxis regimen, maximum aGVHD grade, WBC at diagnosis, time in first CR, or % BM blasts prior to transplant. Day 90 BM chimerism and cGVHD were significantly related with relapse. Maximum grade of aGVHD predicted non-relapse mortality. These data support the low TRM and efficacy of IV-Bu/Flu in a large series of exclusively AML patients, and demonstrate the impact of day 90 bone marrow chimerism as an important prognostic factor. Further efforts to mitigate relapse risk after HCT are warranted, particularly in those with advanced disease at time of transplant. Disclosures: Off Label Use: IV busulfan and fludarabine for the treatment of acute myeloid leukemia. Alsina:Ortho Biotech: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau. Field:PDL BioPharma: Research Funding. Fernandez:Otsuka: Honoraria.

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Lack of Association of Mutations in IDH1, IDH2, DNMT3A with Outcome in Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents (± Histone Deacetylase Inhibitors).

Blood ◽

10.1182/blood.v120.21.2483.2483 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2483-2483

Author(s):

Farhad Ravandi ◽

Keyur P. Patel ◽

Rajyalakshmi Luthra ◽

Sherry A. Pierce ◽

Gautam Borthakur ◽

...

Keyword(s):

Valproic Acid ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Histone Deacetylase ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Hypomethylating Agents ◽

Idh Mutations ◽

Acute Myeloid

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

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Outcome of Acute Myeloid Leukemia AML &High Risk MDS Treated According to the Standard of Care in Community Hospital, Data From Single Center ( 2001–2010)

Blood ◽

10.1182/blood.v120.21.4796.4796 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4796-4796

Author(s):

Ali Al-Ameri ◽

Mohamed Abdelfatah ◽

Zeyad Kanaan ◽

Nairmeen Haller

Keyword(s):

Overall Survival ◽

High Risk ◽

Myeloid Leukemia ◽

Private Insurance ◽

Standard Of Care ◽

P Value ◽

Intermediate Risk ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis ◽

Acute Myeloid

Abstract Abstract 4796 Background: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults causing the highest number of annual deaths secondary to leukemias in the United States. Age, cytogenetics, molecular features are the most important factors in the prognosis, whereby increased age and monosomal karyotypes carry the worst prognosis. The most favorable cytogenetics are patients with normal karyotypes, who can receive standard therapy. Aim: Study the overall survival (OS) of AML/High risk MDS treated according to standard of care at a community teaching hospital. Methods: A retrospective study of AML & High risk MDS patients treated at AGMC, Akron, Ohio USA, during 2002–2010. After IRB approval, we reviewed patient demographics, diagnosis types/subtypes, treatment, and cytogenetics. Patients were classified as low-intermediate risk or high risk according to cytogenetics background using WHO criteria. We also classified patients according to presence of bone marrow fibrosis and health insurance coverage at the time of diagnosis. Overall survival (OS) rates were determined by Kaplan-Meier Survival Analysis. Prognostic factors were evaluated by Log Rank analysis. Results: We were able to classify 98 (75%) pts, with 52 (53%) pts as high risk and 46 (47%) pts as low-intermediate risk. Median age was 55 years (range: 19–90), 43 (45%) pts were older than 75 years. AML pts made up 71%, 45 patients (35%) had complex cytogenetics, and 15% had AML arise from MDS. Median survival overall was 22.4 weeks; 14.4 weeks for high risk and 53.8 weeks for low risk (p<0.01). Median survival for pts greater than 75 years was 11.5 weeks compared to 35.8 weeks for those younger than 75 years (p<0.05). We classified 103 pts according to insurance; 29 pts had private insurance and 74 pts had medicare/Medicaid. Cox regression analysis was performed to examine for the net effect of each of age, insurance, and fibrosis status after controlling for the effect of other variables in the model. Data showed that survival is inversely related to age at diagnosis (p value=.01) while the variables fibrosis status, medicaid/uninsured, and private insurance did not contribute significantly to the model (p value=.97 and.14.34, respectively). Conclusions: No significant differences in OS regarding insurance status or presence of bone marrow fibrosis. This was likely because the majority of pts received standard of care therapy and overall survival, in general, was low in the study population. OS was lowest in high risk patients and those greater than 75 years, and was better in low risk pts and those younger than 75 years respectively. Early referral to a specialized center, or possible clinical trial enrollment may be an alternative way to approach those pts. Disclosures: No relevant conflicts of interest to declare.

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High Expression of Myocyte Enhancer Factor 2C (MEF2C) Is Associated with Adverse Risk Features and Poor Outcome in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽

10.1182/blood.v126.23.2570.2570 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2570-2570

Author(s):

George S. Laszlo ◽

Todd A. Alonzo ◽

Chelsea J. Gudgeon ◽

Kimberly H. Harrington ◽

Alex Kentsis ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Event Free Survival ◽

Free Survival ◽

Expression Levels ◽

Acute Myeloid ◽

Enhancer Factor

Abstract Background: Myocyte enhancer factor 2C (MEF2C) was initially identified as essential transcription factor for cardiac muscle development. However, subsequent studies have indicated that MEF2C plays a much broader biological role, including in the normal hematopoietic system. Recent studies have now identified MEF2C as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML. These findings raised the possibility that MEF2C could serve as marker of poor-risk disease and, therefore, have prognostic significance in AML. To test this hypothesis, we retrospectively quantified MEF2C expression in participants of the AAML0531 trial and correlated expression levels with disease characteristics and clinical outcome. Patients and Methods: AAML0531 (NCT00372593) was a multicenter phase 3 study that determined the addition of gemtuzumab ozogamicin to intensive chemotherapy among 1,022 eligible patients aged <30 yearswith newly diagnosed de novo non-APL AML, excluding those with bone marrow failure syndromes, juvenile myelomonocytic leukemia, or Down syndrome (if ≤3 years of age) between 2006 and 2010. Cryopreserved pretreatment ("diagnostic") specimens from patients enrolled on AAML0531 who consented to the biology studies and had bone marrow samples were available were included in this study. Total RNA from unsorted specimens was extracted, quantified, and subjected to quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) using TaqMan primers to determine expression of MEF2C and, for normalization, the housekeeping gene, β-glucuronidase (GUSB). Patient samples were run in duplicate, and the ΔΔCT method quantified as 2(-ΔΔCT) was used to determine the expression levels of MEF2C relative to GUSB. Results: In all 751 available patient specimens, MEF2C mRNA was detectable and varied >3,000-fold relative to GUSB (0.0091-29.1272 [median: 0.7978]). Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67% vs. 78%, P=0.005). They also had an inferior overall survival (P=0.014; at 5 years: 55±8% vs. 67±4%), inferior event-free survival (P<0.001; at 5 years: 38±7% vs. 54±4%), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P<0.001; at 5 years: 53±9% vs. 35±5%). Of note, exploratory multiple cutpoint analyses for overall and event-free survival indicated that the most statistically significant results were centered around the Q4 cutpoint region, supporting our approach of comparing patients with the highest quartile of relative MEF2C expression with those having lower relative MEF2C expression. Importantly, MEF2C expression was strongly associated with cytogenetic and molecular abnormalities. Specifically, patients with high MEF2C expression less likely had CBF translocations (inv(16): P=0.007, and t(8;21): P<0.001) or normal karyotype AML (P<0.001); conversely, they were more likely to have leukemia with monosomy 7 (P<0.001) and abnormalities involving 11q23 (P<0.001). Furthermore, patients with high MEF2C less likely had a FLT3/ITD (P =0.018) or a mutation in either NPM1 (P=0.010) or CEBPA (P =0.002). Consistently, patients with high MEF2C expression less likely had low-risk disease (16% vs. 46%, P<0.001) and more likely had standard-risk disease (68% vs. 42%, P <0.001) than those with lower MEF2C expression. Indeed, after adjustment for disease risk, age, FAB category, and treatment arm, high MEF2C expression was no longer statistically significantly associated with inferior overall survival (hazard ratio [HR]=0.99 [95% confidence interval: 0.72-1.36], P=0.929), inferior event-free survival (HR: 1.14 [0.86-1.49], P=0.365), or higher relapse risk (HR: 1.32 [0.91-1.92], P=0.137), suggesting that MEF2C cooperates with additional pathogenic abnormalities. Conclusion: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. These findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. Disclosures Walter: AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

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Outcomes By Best Response with Hypomethylating Agent Plus Venetoclax in Adults with Previously Untreated Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-149782 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2292-2292

Author(s):

Virginia Olivia Volpe ◽

Akriti G Jain ◽

Onyee Chan ◽

Eric Padron ◽

David A. Sallman ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Free State ◽

Advisory Committees ◽

Best Response ◽

Baseline Characteristics ◽

Acute Myeloid

Abstract Background: Venetoclax plus hypomethylating agents (HMA) (HMA+VEN) is a standard of care treatment for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. In the phase 3 VIALE-A trial, azacididine (aza)+VEN compared to aza alone demonstrated an improved overall survival of 14.7 months versus 9.6 months, respectively. A common toxicity with HMA+VEN is myelosuppression. The prognostic implications of incomplete count recovery despite leukemia free state after HMA+VEN treatment in AML is unclear. We aimed to compare the outcomes of those who achieved complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) in AML patients treated frontline with HMA+VEN. Methods: Patients seen at Moffitt Cancer Center between 2019 and 2021 diagnosed with AML and treated with frontline HMA+VEN were retrospectively evaluated and included for analysis. Patients were stratified by best response; either CR, CRi, or MLFS. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Results: Of the 102 patients treated with HMA+VEN in the frontline setting, 48% (n=49) had blast clearance with a best response of CR in 27/102 (26.4%), CRi in 16/102 (15.7%), or MLFS in 6/102 (5.9%). The remainder had residual disease. Baseline characteristics were similar among the three response groups (Table 1) as was mutational distribution (Table 2). There was no difference between AML WHO classification subtype (p= .148). Decitabine or aza was used at the discretion of the treating physician did not significantly impact responses (p= .225). In those who achieved CR, 14% had prior therapy related AML compared to 37.5% in CRi and 33.3% in MLFS (p= .314). Antecedent MDS or MPN with transformation to AML was seen in 22.2%, 18.8%, and 66.7% of CR, CRi, and MLFS respectively (p= .029). Of those, 3.7% in CR group had HMA use for prior MDS/MPN compared to 0% in CRi and 50% in MLFS (p= .000). The median relapse free survival was not reached for CR, CRi, and MLFS (Figure 1), it is important to note that 3 of the 6 MLFS patients died without relapse . At median follow up of 23 months, median overall survival (OS) in the CR group was significantly longer, 31 months, compared to 18 months in the CRi group and 8.5 months in the MLFS group (p=0.0415) (Figure 2). Transplant was achieved in 26% of CR and 6.3% of CRi and 0% of MLFS and was not significant among the groups (p = .124). Conclusion: Patients who received frontline HMA+VEN for AML directed therapy and achieved CR/CRi had better survival compared to those who achieved MLFS. Our data suggest that incomplete recovery of blood counts plays a significant role in overall survival regardless of leukemia free state. Further, the data demonstrate significantly higher secondary AML with antecedent MDS or MPN in the MLFS group compared to CR and CRi groups. Of those, prior HMA therapy was also identified as significantly higher in the MLFS group compared to CR and CRi groups which may contribute to the prolonged cytopenias and worse OS. While the limitation to this study is overall small number of patients, it suggests that a goal of CR over CRi or MLFS is desirable for superior OS. In the future, it would be of interest to incorporate the rates of responses and variables that may have an impact such as therapy dose adjustment, time to response, and delays in therapy due to cytopenia. Additional studies identifying dose adjustments or other ways to improve hematologic recovery would be valuable to potentially improve outcomes in this difficult to treat population. Figure 1 Figure 1. Disclosures Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Kura: Research Funding. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽

10.1182/blood.v128.22.1611.1611 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1611-1611 ◽

Cited By ~ 3

Author(s):

Maro Ohanian ◽

Guillermo Garcia-Manero ◽

Elias J. Jabbour ◽

Naval Daver ◽

Gautam Borthakur ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Median Overall Survival ◽

Cell Transplant ◽

Overall Response ◽

Grade 3 ◽

Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.99.99 ◽

2016 ◽

Vol 128 (22) ◽

pp. 99-99 ◽

Cited By ~ 26

Author(s):

Jorge E. Cortes ◽

Florian H. Heidel ◽

Michael Heuser ◽

Walter Fiedler ◽

B. Douglas Smith ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

P Value ◽

Employment Equity ◽

Equity Ownership ◽

Acute Myeloid

Abstract Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.

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Survival Outcome of Patients with Acute Myeloid Leukemia Transformed from Myeloproliferative Neoplasms

Blood ◽

10.1182/blood.v128.22.1940.1940 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1940-1940 ◽

Cited By ~ 5

Author(s):

Dai Chihara ◽

Hagop M. Kantarjian ◽

Kate J Newberry ◽

Farhad Ravandi ◽

Naval G. Daver ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Treatment Strategies ◽

Survival Outcome ◽

Hazard Ratio ◽

Complex Karyotype ◽

Acute Myeloid

Abstract Purpose: Progression to acute myeloid leukemia (AML) from myeloproliferative neoplasms (MPNs) is almost always fatal. To explore the best treatment strategies for this serious complication, we analyzed the survival outcome of patients with MPNs who progressed to AML based on treatment received at our institution. Patients and Methods: A total of 273 patients who were diagnosed with AML secondary to MPNs between 1989 and 2016 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were calculated. Results: The patients progressed to AML from essential thrombocythemia (ET, N=60), polycythemia vera (PV, N=49), primary myelofibrosis (PMF, N=105), post-ET/PV MF (N=37), and MPN-unclassifiable (N=22). The median age of the patients was 67 (range: 28-92). The median time to AML transformation from MPN diagnosis was 64.5 months (range: 0.9-477.7 months). Complex karyotype was seen in 99 patients at the time of transformation (38%). With a median follow up of 16.5 months (range: 2.7-115.7 months), 247 patients had died (88% from AML, 6% from treatment-related mortality, 6% with other cause including infection and GVHD). Ninety-nine patients received hypomethylating including agent (HMA), 71 a high-dose cytarabine regimen, 52 a low-dose cytarabine regimen, 28 other treatments, and 24 patients did not receive any treatment due deterioration of the patientfs condition or patientfs decision. The median PFS and OS after progression to AML were 2.6 months and 7.0 months, respectively. There was no significant improvement in PFS and OS by date of diagnosis (1989 to 2016). Also, complete response (CR) rate and survival outcome were not significantly different by type of treatment (Figure A) or prior MPN subtype. Overall, 46 patients (27 in CR, 14 not in CR, 4 unknown due to the transplant outside) proceeded to allogeneic transplant (allo-SCT), and the median overall survival after transplant was 15.3 months (6.1-29.4 months). Although it was not statistically significant, patients who achieved a CR before allo-SCT had longer OS than those who received allo-SCT without achieving a CR (35.1 vs 8.9 months; Figure B). Complex karyotype was associated with both shorter PFS (Hazard ratio: 2.2, 95%CI: 1.6-2.9) and OS (Hazard ratio: 2.0, 95%CI: 1.5-2.6). Summary: Survival outcome for AML secondary to MPN remains very poor, and there has been no improvement in survival outcome since 1989. Further studies are urgently needed to test new treatment strategies and to detect residual disease post allo-SCT. Considering dismal outcome after transformation, studies are also needed to explore strategies to prevent this fatal complication. Disclosures DiNardo: Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Agios: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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Predictors of Outcomes in Adult Patients with Therapy Related Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation - Twenty Year Experience from a Tertiary Care Centre

Blood ◽

10.1182/blood-2019-128445 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5737-5737

Author(s):

RAM V Nampoothiri ◽

Arjun Law ◽

Wilson Lam ◽

Zeyad Al-Shaibani ◽

David Loach ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Performance Status ◽

Chronic Gvhd ◽

P Value ◽

Hematopoietic Stem ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Related Mortality ◽

Acute Myeloid

Background Therapy related acute myeloid leukemia (t-AML) constitutes a subset of AML that has an increased proportion of high risk cytogenetic and molecular features, poor response to therapy, higher relapse, and decreased overall survival. The incidence ranges from 10-20% across various studies. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure in t-AML, with disease free survival reported up to 30% at 2 years. Most studies on HSCT in t-AML have limited number of patients and are confounded by the inclusion of patients with secondary AML and therapy related myelodysplastic syndromes (t-MDS). We aim to report our 20-year experience of allo-HSCT in t-AML and identify predictors of survival. Patients and Methods We retrospectively reviewed all cases of t-AML who underwent allo-HSCT at our centre from June 1999 to July 2019. We collected data for demographic characteristics, prior malignancy and treatment, latent period before AML, cytogenetic and molecular characteristics of AML, induction treatment received, transplant details (donor details, conditioning regimens, GVHD prophylaxis) as well as post-transplant complications (transplant related mortality, occurrence and severity of acute and chronic GVHD, CMV and EBV reactivations). Primary outcome evaluated was overall survival and secondary outcomes were relapse rate and relapse free survival (RFS). Cox-proportional hazards regression model was used to identify predictors of survival. Results Fifty-two patients underwent allo-HSCT for t-AML during the study period. 58% were male (n=30). Median age at HSCT was 55.5 years (Range 18-70). Baseline characteristics are summarized in Table 1. Complex cytogenetics were present in 23.2% (n=12) patients, while 11q23 rearrangement (MLL-KMT2A), monosomy 7, monosomy 5, and 17p deletion were present in 15.4% (n = 8), 15.4% (n= 8), 7.7% (n = 4) and 7.7% (n=4) patients respectively. Based on the ELN 2017 risk stratification schema, 13.5% (n=7) patients could be considered favorable risk based on cytogenetic and molecular profiles, 36.5% (n=19) intermediate risk, and 57.7% (n=30) in poor risk category. Performance status prior to transplant was ECOG 0/1 in 71.2% (n=37) patients, and 2 in 28.8% (n=15) patients. Myeloablative conditioning was used in 30.8% (n=16) patients, and reduced intensity conditioning in 69.2% (n=36). GVHD prophylaxis was CyclosporineA(CSA)/Methotrexate in 23.1% (n=12), Alemtuzumab/CSA in 21.2% (n=11), ATG/CSA/PTCy in 28.8% (n=15), and other regimens in 26.9% (n=14) patients. Transplant related mortality (death before day+100) was 21.1% (n=11). Acute and chronic GVHD (any grade) occurred in 61.5% (n = 32) and 28.8% (n=15) patients respectively. Eleven patients (21.2%) relapsed with a median RFS of 8 months (Range 0.17-158). Median OS of the whole cohort was 8.9 months (0.17-158 months). No patient had a relapse of their primary malignancy during follow up. RFS at 12 and 24 months were 46% and 28% while OS at 1 and 2 years was 46% and 30%, respectively. Significant predictors of reduced OS (Figure 1a,b,c) after day+100 of HSCT by Cox-regression were ECOG performance status 2 (Hazard ratio - 6.1; p value 0.003), GVHD prophylaxis with CSA/methotrexate (HR - 4.5; p value 0.01), and haploidentical donor transplantation (HR - 34; p value - 0.002). Cytogenetics were a predictor of OS in univariate analysis but not in multivariate regression analysis. No difference in OS was found between patients who underwent HSCT 2010 or prior versus after 2010. Conclusions Patients with favorable cytogenetic profile, better performance status, and an HLA matched donor may have better outcomes after allo-HSCT in therapy related AML. Patients with unfavorable cytogenetic risk profiles may require more intense therapy or post-transplant maintenance therapy to prevent relapse. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria.

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