European LeukemiaNet Risk Research Articles

Real-World Experience of Measurable Residual Disease Response and Prognosis in Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine.

Simple SummaryMore than 90% of patients with acute myeloid leukemia carry aberrant markers that can be detected using flow cytometry. Monitoring low levels of residual disease after treatment (measurable residual disease) is an important biomarker to assess the efficacy of treatment and can identify patients who may eventually relapse. Our retrospective study aimed to determine the potential value of MRD for prognosticating outcomes in AML patients treated with less intensive chemotherapy. In 63 patients with newly diagnosed AML, we found that detectable residual disease by flow cytometry was associated with a higher incidence of relapse, and shorter progression-free and overall survival. We also confirmed that the threshold of measurable disease affecting outcomes is 0.1%. MRD is useful in patients to monitor AML patients treated with less intensive therapy.The prognostic value of measurable residual disease (MRD) by flow cytometry in acute myeloid leukemia (AML) patients treated with non-intensive therapy is relatively unexplored. The clinical value of MRD threshold below 0.1% is also unknown after non-intensive therapy. In this study, MRD to a sensitivity of 0.01% was analyzed in sixty-three patients in remission after azacitidine/venetoclax treatment. Multivariable cox regression analysis identified prognostic factors associated with cumulative incidence of relapse (CIR), progression-free survival (PFS) and overall survival (OS). Patients who achieved MRD < 0.1% had a lower relapse rate than those who were MRD ≥ 0.1% at 18 months (13% versus 57%, p = 0.006). Patients who achieved an MRD-negative CR had longer median PFS and OS (not reached and 26.5 months) than those who were MRD-positive (12.6 and 10.3 months, respectively). MRD < 0.1% was an independent predictor for CIR, PFS, and OS, after adjusting for European Leukemia Net (ELN) risk, complex karyotype, and transplant (HR 5.92, 95% CI 1.34–26.09, p = 0.019 for PFS; HR 2.60, 95% CI 1.02–6.63, p = 0.046 for OS). Only an MRD threshold of 0.1%, and not 0.01%, was predictive for OS. Our results validate the recommended ELN MRD cut-off of 0.1% to discriminate between patients with improved CIR, PFS, and OS after azacitidine/venetoclax therapy.

P509: CLONAL HEMATOPOIESIS-ASSOCIATED MUTATIONS AS MEASURABLE RESIDUAL DISEASE MARKERS IN ACUTE MYELOID LEUKEMIA PATIENTS FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION

Background: Clonal hematopoiesis (CH)-associated mutations (mut) are frequent in acute myeloid leukemia (AML), appear early in leukemogenesis, and often persist in remission after chemotherapy. Following allogeneic hematopoietic stem cell transplantation (HSCT), which replaces the patients’ hematopoiesis, CH mut may present useful measurable residual disease (MRD) markers. Aims: To evaluate patient specific CH-associated mut as MRD markers in AML patients (pts) after allogeneic HSCT. Methods: We analyzed 31 AML pts with CH-associated mut present at diagnosis (DNMT3A: n=17; SRSF2: n=9; IDH2: n=7; ASXL1: n=4; TET2: n=2, and JAK2: n=1), 23 pts had 1, 7 had 2, and 1 patient had 3 CH mut. All received a myeloablative (36%), reduced-intensity (48%), or non-myeloablative (16%) HSCT (median age 58, range 32-72 years). 84% were transplanted in complete remission (CR) or CR with incomplete recovery (CRi). European Leukemia Net (ELN) risk was 23% favorable, 37% intermediate, and 40% adverse. Mut-specific digital droplet PCR assays were developed using a competitive probe-approach. MRDpos was defined as variant allele frequency (VAF) ≥2% for ASXL1 & ≥0.05% for all other analyzed mut. 209 samples with a median of 6 (range 1-13) blood or bone marrow samples per patient were available after HSCT with a median of 1.2 years follow-up time for pts alive. Results: Prior to HSCT, 89% of pts remained CH-associated mut positive in CR/CRi. 11 pts relapsed after HSCT (35%), all with the same CH-associated mut present at diagnosis (median VAF at relapse 15.6, range 0.2-41.2%). Of those, 6 pts had at least 1 MRD sample available prior to relapse. In 5 pts, impeding relapse was predicted by a CH-associated mut MRD conversion with a median VAF of 0.27 (range 0.06-1.0)% at a median of 103 (range 14-199) days prior to relapse. The lead time was longest for a DNMT3A mut patient (199 days) & shortest for a SRSF2 mut patient (14 days). For the patient relapsing without prior CH MRD positivity, the last available sample was taken 169 days before relapse & was CH MRDneg. 20 pts retained remission during follow-up. Of those, 17 pts remained CH MRDneg in all samples (median samples per analyzed mutation 6, range 1-13). 2 pts had 2 MRDpos samples directly after HSCT but became MRDneg in subsequent samples. 1 patient received Enasidenib maintenance after HSCT with fluctuating CH-MRD values after HSCT (SRSF2 & IDH2, VAFs <0.05-0.34% & <0.05-0.14%, respectively). Of the pts with MRD samples within the first year after HSCT available, pts with at least 1 MRDpos sample after HSCT had a significantly higher cumulative incidence of relapse (CIR, P=.008, Figure 1A) & shorter relapse-free survival (RFS, P=.02, Figure 1B). 8 pts had concurrent NPM1 mut (n=4) or RUNX1 mut (n=4), which showed concordant MRD results in 7 pts (4 remained MRDneg, 3 concurrently converted MRDpos). 1 patient suffered a NPM1 MRDneg relapse which was predicted by 2 re-detected CH-associated mut (DNMT3A mut & IDH2 mut, 112 & 199 days prior to relapse, respectively, Figure 1C). Image:Summary/Conclusion: Prior to HSCT most CH-associated mut remain detectable in pts in CR/CRi. However, pts with at least one CH MRDpos sample following allogeneic HSCT had higher CIR & shorter RFS. All relapsing pts were positive for the same CH-associated mut present at diagnosis. 5 of 6 showed increasing VAFs prior to hematologic relapse & the majority of pts retaining remission remained CH MRDneg. While CH-associated mut in chemotherapy treated AML pts have limited MRD value, these mut are feasible MRD markers after HSCT & may inform relapse preventing therapy decisions.

Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study

Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone. This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival. The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13). Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials. None.

Ex Vivo Chemosensitivity Profiling of Acute Myeloid Leukemia and Its Correlation With Clinical Response and Outcome to Chemotherapy.

We evaluated the predictive value of the ex-vivo PharmaFlow PM platform in measuring the pharmacological activity of drug combinations consisting of 20 different chemotherapy regimens (20 Tx) administered in 104 acute myeloid leukemia (AML) patients. The predicted sensitivities of alternative treatments for each patient were ranked in five 20% categories, from resistant to sensitive (Groups 1–5). The complete remission (CR) rates of the five groups were 0%, 12.5%, 38.5%, 50.0%, and 81.3%, respectively. The heat map showed a good relationship between drug sensitivity with CR (Group 4 + 5 vs. Group 1 + 2+3: 77.5% vs. 27.3%, p = 0.002) and the European Leukemia Net risk group (22.6% vs. 63.6%, p = 0.015). The predicted coincidence rate was 90.9% in Group 1 + 2 and 81.3% in Group 5. According to the recommendations of the PharmaFlow PM platform, the CR rate would have increased by about 16.3% in one cycle. The overall survival (OS) was shorter in patients predicted to be resistant (Group 1 + 2 vs. Group 3 + 4+5, p = 0.086). In multivariable analysis, CR after one cycle was an independent prognostic factor for OS [p = 0.001; 95% CI 0.202 (0.080–0.511)], and ex-vivo chemosensitivity was a potential predictive factor for OS [p = 0.078; 95% CI 0.696 (0.465–1.041)]. To conclude, the PharmaFlow PM platform is a rapid and valuable tool for predicting clinical response and outcomes in AML patients.

The Prognostic Significance of C-Reactive Protein to Albumin Ratio in Newly Diagnosed Acute Myeloid Leukaemia Patients.

BackgroundThe ratio of C-reactive protein to albumin (CAR) is an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in several solid tumours and chronic lymphocytic leukaemia (CLL). However, no studies have investigated the prognostic value of the CAR in patients with acute myeloid leukaemia (AML).Objectives and MethodsWe retrospectively analysed 212 newly diagnosed non-M3 AML patients. Using the receiver operating characteristic curve (ROC) method, the optimal cut-off value for CAR was determined. We investigated the correlations of the pretreatment CAR levels with clinical characteristics, treatment response of induction chemotherapy, overall survival (OS) and event-free survival (EFS). We also assessed the prognostic value of the CAR compared with other inflammation-based prognostic parameters by the area under the curve (AUC).ResultsAccording to the ROC curve, the optimal cut-off value of CAR was 1.015. CAR was associated with age, C-reactive protein (CRP) levels, albumin levels, ferritin levels, bone marrow blast percentage, French-American-British (FAB) classification, immunophenotype and 2017 European Leukemia Net (2017 ELN) risk stratification. Importantly, we found that high CAR was a powerful indicator of a lower complete remission (CR) rate (p<0.001), worse OS (p<0.001) and worse EFS (p<0.001). Subgroup analysis showed that a high CAR was associated with shorter OS and EFS in patients with intermediate risk stratification or those aged ≤65 years or those without haematopoietic stem cell transplantation (HSCT). In the multivariate analysis, the CAR was an independent prognostic factor for OS and EFS. Furthermore, the predictive value of CAR for OS is superior to that of CRP, albumin and GPS in de novo AML patients aged ≤65 years old.ConclusionCAR is a simple and effective prognostic marker in patients with AML. It could be an additional prognostic factor that help further precise the current risk stratification of non-M3 AML, particularly for patients in intermediate risk stratification and those aged ≤65 years and those who did not undergo HSCT.

Epidemiology of de novo Acute Myeloid Leukemia in Kuwait per the 2016 WHO Classification

Objective: Acute myeloid leukemia (AML) is a hematological malignancy that arises from the clonal proliferation of immature myeloid cells. Although the number of AML cases has dramatically increased worldwide, information on its prevalence and incidence in Kuwait is lacking. This study reports the incidence of AML and patient demographics in the country from 2014 to 2020, based on the 2016 WHO classification of AML. Subjects and Methods: Data on patients with AML, including acute promyelocytic leukemia (APL), were collected from a clinical cohort with 281 cases analyzed in this study. Results: The overall median age of the population was 47 years with a 1.1:1 male-to-female ratio. Over the study period, the incidence of AML demonstrated a general increasing trend, with the highest and lowest overall incidence occurring in 2018 and 2015, respectively. The frequency of APL in our cohort was 8.9%. Regarding the 2017 European LeukemiaNet (ELN) risk stratification of patients with AML, 37%, 46%, and 17% of patients had a favorable, intermediate, and adverse risk, respectively. A total of 57% of cases achieved complete remission post-induction, and the median overall survival was 37 months. Conclusion: Our study may help predict the future trends of AML in Kuwait to help improve clinical management and patient outcomes.

Acute myeloid leukemia: negative prognostic impact of early blast persistence can be in part overcome by a later remission prior to post-induction therapy.

In acute myeloid leukemia, there is an ongoing debate on the prognostic value of the early bone marrow assessment in patients receiving intensive therapy. In this retrospective study, we analyzed the prognostic impact of the early response in 1,008 patients with newly diagnosed acute myeloid leukemia, who were treated at our institution with intensive chemotherapy followed by consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). We found that early blast persistence has an independent negative prognostic impact on overall survival, event-free survival and relapse-free survival. This negative prognostic impact may only be overcome in patients showing at least a partial remission at the early bone marrow assessment and who subsequently achieve blast clearance by additional induction chemotherapy prior to consolidation therapy with allogeneic HSCT. In accordance, we propose that the time slope of remission is an additional leukemia-related dynamic parameter that reflects chemosensitivity and thus may inform post-induction therapy decision-making. In addition to patient-related factors, European LeukemiaNet risk group, measurable residual disease monitoring and donor availability, this may particularly apply to European LeukemiaNet intermediate-risk patients, for whom a decision between consolidation chemotherapy and allogeneic HSCT remains challenging in many cases.

Stratification of Intermediate-Risk Acute Myeloid Leukemia According to the Expression Level of WT1 mRNA at Diagnosis

IntroductionDespite advances in the genetic analysis of acute myeloid leukemia (AML), Wilms' tumor oncogene 1 (WT1) mRNA remains an important pan-marker of AML. A log reduction in WT1 mRNA expression after chemotherapy is a predictor of prognosis, and WT1 mRNA can be used as a marker of minimal residual disease or relapse. In the 1990s, a high expression level of WT1 mRNA at diagnosis was considered a poor prognostic factor. However, recent analyses have found that WT1 mRNA expression varies with AML type. Since the prognosis is affected by cytogenetic abnormalities and therapeutic intensity, we re-evaluated the clinical significance of WT1 mRNA expression at diagnosis in the context of the European Leukemia Net (ELN) risk classification and treatment.MethodWe retrospectively analyzed 216 patients at five institutions between 2011 and 2020. The expression level of WT1 mRNA was measured for all patients at diagnosis using bone marrow (BM) samples from 191 patients and peripheral blood (PB) samples from 25. WT-1 mRNA expression was measured using real-time quantitative polymerase chain reaction and the measured values were converted in normal logarithm. The median age at diagnosis was 62 (range: 23-93) years. The cytogenetic risk of ELN was classified as favorable (n = 41), intermediate (n = 123), and adverse risk (n = 41). Selected therapeutics were standard chemotherapy (n = 182, 84.3%, including CAG regimen; cytarabine, aclarubicin and G-CSF), hypomethylating agents or low-dose cytarabine (n = 19, 8.8%), and best supportive care (n = 15, 6.9%). Also, 143 patients (66.2%) received one or more courses of standard consolidation chemotherapy and 61 (28.3%) underwent allogeneic hematopoietic stem cell transplantation (allo-HCT). The median observation period was 518 [1-3418] days (Table 1). The overall survival (OS) and event-free survival (EFS) rates were assessed. Relapse or death was defined as an event, and OS was evaluated on the date of death.ResultThe median expression level of WT1 mRNA was 4.68 (range: 1.0-5.72) [log copies/µg RNA, units are omitted thereafter] in BM and 3.66 (range: 1.34-5.20) in PB (Table 1). Favorable-risk AML had the highest WT1 mRNA expression level in BM (4.95, p = 0.0054), whereas there was no difference between the expression levels in intermediate- and adverse-risk AML in BM (4.63 and 4.47, p = 0.711, Fig. 1A). WT1 mRNA expression in PB were 4.04, 3.84, and 3.05 for favorable-, intermediate-, and adverse-risk AML, respectively, and were higher for those with a favorable-risk AML (vs. adverse risk, p = 0.048, Fig. 1B). When WT1 mRNA expression level in BM was compared between the two groups, i.e., <4.0 (BM-WT1 low) vs. ≥4.0 (BM-WT1 high), 2-year EFS rates were 26.8% and 49.7% (p = 0.0035) and 2-year OS rates were 44.9% and 61.5% (p = 0.00053), respectively. When WT1 mRNA expression level in PB was compared between the two groups, i.e., <3.0 (PB-WT1 low) vs. ≥3.0 (PB-WT1 high), 2-year EFS rates were 0% and 51.5% (p = 0.023) and 2-year OS rates were 0% and 73.1% (p = 0.01), respectively. PB- or BM-WT1 low showed a worse prognosis at diagnosis.Since AML prognosis is affected by ELN risk and selected therapeutics, we evaluated 109 intermediate-risk patients who had received at least one course of standard chemotherapy. Fifty of them (45.9%) underwent subsequent allo-HCT. The 2-year EFS rates of PB or BM-WT1 low (n = 25, PB = 2 and BM = 23) vs. PB or BM-WT1 high (n = 84, PB = 23 and BM = 61) were 23.9% and 50.4%, respectively (p = 0.023, Fig. 2A) and the 2-year OS rates were 51.2% and 64.6%, respectively (p = 0.03, Fig. 2B). PB or BM-WT1 low of intermediate-risk AML had a poor prognosis even with standard chemotherapy. Multivariate analysis adjusted for ages, the reduction rate of WT1 mRNA after induction chemotherapy, duration of receiving consolidation chemotherapy, allo-HCT, and PB or BM-WT1 low at diagnosis were independent poor prognosis factors for EFS in intermediate-risk AML (HR: 3.32, 95%CI: 1.29-8.53, p = 0.013). The OS rate of PB or BM-WT1 low also worsened (HR: 2.33, 95%CI: 0.88-6.18, p = 0.089) (Table 2). Whereas, the outcome of adverse-risk AML was not affected by PB or BM-WT1 low/high.ConclusionThe expression level of WT1 mRNA at diagnosis was negatively correlated with prognosis. Favorable-risk AML had higher expressions of WT1 mRNA. PB or BM-WT1 low in intermediate-risk AML was associated with a poor prognosis. In standard-risk AML, WT1 mRNA may be a useful pan-marker to predict prognosis at diagnosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Patients with Acute Myeloid Leukemia on Non-Intensive Therapy: Applicability of the European Leukemia Net Risk Classification

BACKGROUNDThe revised genetic risk classification established by the European Leukemia Net (ELN) in 2017 stratifies patients diagnosed with acute myeloid leukemia (AML) into 3 prognostic categories (favourable, intermediate, and adverse) based on cytogenetic and molecular characteristics.The ELN classification is widely accepted in AML patients despite the fact that validation studies were performed in participants who received exclusively first-line treatment with intensive chemotherapy. For this reason, it is not well established whether the ELN risk groups are applicable to patients on non-intensive first-line treatment.OBJECTIVES- To describe and compare baseline characteristics at diagnosis between patients with AML treated with intensive and non-intensive therapy.- To assess whether the ELN prognostic classification is applicable in these subgroups of patients.METHODSWe retrospectively analysed patients with newly diagnosed AML admitted to our center between 2007 and 2020. Patients with acute promyelocytic leukemia (M3), patients younger than 18 years old and/or patients who received exclusively supportive treatment were excluded. Demographic and clinical data, disease characteristics at diagnosis and first-line treatment were collected. Cytogenetic and molecular characteristics were used to classify patients in ELN risk groups.RESULTSOf the total of patients (n=218), one hundred and fifty-six (71.6%) received intensive chemotherapy treatment, while 62 (28.4%) were treated with non-intensive strategies. Idarubicin and cytarabine based schemes regimens (IA) were administered in most patients (98.6%) who received intensive treatment while the rest received fludarabine based regimens. One patient (0.6%) was treated with danurubicin and cytarabine liposome (CPX-351). Fifty-four (87%) patients treated with non-intensive regimens received hypomethylating agents, mostly azacitidine. Five patients (8%) were treated with venetoclax in combination with a hypomethylating agent.Table 1 shows the characteristics at diagnosis in both groups of patients. Patients who received intensive chemotherapy were younger and had higher leukocyte count, LDH values and a higher percentage of blasts in peripheral blood and bone marrow with a median of 40% and 62% blasts respectively. On the other hand, patients under non-intensive treatment more frequently presented a past history of hemopathy and a higher percentage of bone marrow dysplasia.Regarding ELN stratification significant differences were found between both groups. Patients who received aggressive chemotherapy vs patients who did not, were classified in low (28% vs. 7%), intermediate (36% vs. 58%) and high risk (36% vs. 35%) respectively (Figure 1).At the end of the follow-up, 41% of the patients who had received intensive therapy were alive while only 6.5% of the patients who had received non-intensive treatment were alive. Significant differences in survival were observed between both groups (p<0.01); with 1-year overall survival (OS) of 65.8% for intensive therapy group and 49.6% for non-intensive therapy group.In the intensive chemotherapy group, significant differences in survival were observed according to ELN risk stratification (p<0.01), with 5-year OS of 55%, 29% and 23.9% for low, intermediate and high-risk groups respectively. For low-risk patients, median OS was not reached while it was 20 months for the intermediate risk group and 12.2 months for the high-risk group.However, in patients receiving non-intensive therapies, there were no significant differences in survival among different prognostic categories (p=0.06). In this group, 1-year OS was 25%, 57.6% and 40.7% and median OS was 2.1, 14.8 and 10.1 months for low, intermediate and high-risk groups respectively. See Figure 2.CONCLUSIONS:As validated in previous trials, ELN classification constitutes an adequate prognostic marker for patients with newly diagnosed AML treated with intensive chemotherapy. In our series, this classification does not appear to be a good predictor of survival for patients diagnosed with AML who initiated non-intensive treatments. Further validation in prospective studies are needed to better classify this growing subgroup of patients in clinical practice. [Display omitted] DisclosuresMartín-Rojas: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Font Lopez: Pfizer: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Outcomes of Patients with AML Treated with CPX-351 Based on the 2017 ELN Risk Stratification

Outcomes of Patients with AML Treated with CPX-351 Based on the 2017 ELN Risk Stratification

Treatment Patterns and Survival Outcomes of Patients with Acute Myeloid Leukemia Who Achieved Remission in the Connect ® Myeloid Disease Registry

Treatment Patterns and Survival Outcomes of Patients with Acute Myeloid Leukemia Who Achieved Remission in the Connect ® Myeloid Disease Registry

Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Comparison of Prognostic Impact between the European Leukemia Net (ELN) 2017 Risk Classification and Pre-Transplant WT1 expression in Patients Receiving Allogeneic Transplantation for Acute Myeloid Leukemia (AML)

Background Although European Leukemia Net (ELN) risk classification was introduced in 2017 and has been applied as an important prediction tool for prognosis, there has been limited data on its value among the patients with allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the prognostic value of ENL 2017 criteria on post-HSCT outcomes and compared it with pre-HSCT measurable residual disease (MRD) status determined by Wilms tumor gene 1 (WT1) expression level.Methods: Patients who underwent HSCT and fulfilled following criteria were eligible in this current study: first HSCT in complete remission (CR) or CR with incomplete hematologic recovery and having bone marrow WT1 expression results before transplant. We found a total of 275 patients between Nov 2017 and July 2020, and we adopted the WT1 cut-off level of 250 copies per 10 4 ABL for defining MRD negative vs positive (Biol Blood Marrow Transplant. 2019;25:1925) .Results: Among 180 patients, , 110 (61%) and 70 (39%) patients were classified as a , intermediated (INT) and adverse (ADV) risk group by ELN 2017 classification. After a median follow-up of 18.3 months (range, 0.4 to 43.2 months), the Kaplan-Meier survival curve could not discriminate overall survival (OS), relapse free survival (RFS), or cumulative incidence of relapse (CIR) between the INT and ADV risk groups (p=0.2, p=0.68, p=0.061, respectively). On the other hand, we found that OS, RFS and CIR were unfavorable in MRD (+) group compared to either MRD negative INT or ADV risk group (35.8 % vs 59.1 % for OS, p=0.05; 24.7% vs 55.9% for RFS, p=0.002; 60.9% vs 20.4 % for CIR, p<0.001). We further divided the groups into 4 subgroups with incorporating pre-HSCT WT1 level: INT MRD(-), INT MRD(+), ADV MRD(-), and ADV MRD(+). Notably, the importance of MRD was more prominent in the INT risk group with showing significant differences in CIR between INT MRD(-) and INT MRD(+) group (p<0.001) in contrast to that observed between ADV MRD(-) and ADV MRD(+) groups (p=0.12). Among the 4 subgroups, patients of INT MRD(+) confers worst prognosis in regards to OS, RFS and CIR, which was even worse than those of ADV MRD(+) group.Conclusions: The ELN 2017 risk classification was not available to predict post-HSCT outcomes in INT and ADV risk group. We found that pre-HSCT MRD rather than ELN 2017 could more likely to predict post-HSCT relapse. The prognostic value of WT1 MRD was more prominent in ELN INT group compared to ADV group. A subset of INT patients had the worst prognosis if their pre-HSCT WT1 MRD remained positive, who they need additional therapeutic strategies to prevent relapse. [Display omitted] DisclosuresKim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Clinical Characteristics and Outcomes of Patients with Newly Diagnosed De Novo Acute Myeloid Leukemia (AML) during the COVID-19 Pandemic

Clinical Characteristics and Outcomes of Patients with Newly Diagnosed De Novo Acute Myeloid Leukemia (AML) during the COVID-19 Pandemic

Day 14 Measurable Residual Disease As a Predictor of Post-Induction Response in Patients with Acute Myeloid Leukemia

INTRODUCTIONSeveral studies have shown that morphological remission at day 14 is a predictor of post-induction response in patients with acute myeloid leukemia (AML) undergoing an intensive treatment. However, the role of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) at day 14 remains unknown. The aim of our study is to explore the role of MRD at day 14 and its association with outcomes of patients with AML undergoing an intensive treatment.METHODSWe conducted a retrospective study in adult patients with newly a diagnosed AML in our center between 2007 and 2020. Adult patients who received intensive chemotherapy, excluding those with an acute promyelocytic leukemia, were included. Bone marrow aspiration was performed at day 14 after induction to assess morphological response and MRD by MFC. Early blast clearance (EBC) was defined as <5% of blasts and negative MRD was defined as <0.1% abnormal cells within mononucleated cells by MFC. Day 14 aspiration findings were compared with clinical data. This study was approved by our Institutional Ethics Committee. Data were analyzed using IBM SPSS Statistics version 24.RESULTSA total of 131 patients were analyzed. Median age was 55.6 years (IQR 42.3-64.2). The most frequent AML subtype was AML with myelodysplasia-related changes (34.4%), followed by NPM1-mutated AML (32.1%). The most commonly used induction regimen was “7+3” (96.2%) (Table 1).On day 14 bone marrow aspiration, median cellularity was 0.5/5 (IQR 0.5-1). 107 patients (81.7%) showed a blast reduction >50% compared to diagnosis and 87 patients (66.4%) had less than 5% of blasts. In this latter group, 28.6% of patients had a positive MRD and 71.4% had a negative MRD. NPM1-mutated AML showed the highest EBC rates while AML with myelodysplasia-related changes had the lowest rates (83.3% versus 55.5%; p=0.04). Furthermore, there were statistically significant differences in EBC rates based on the 2017 European Leukemia Net risk stratification, with 80% of EBC in low risk, 66.6% in intermediate risk and 53.4% in high risk AML (p=0.038). No differences were observed in MRD at day 14 based on AML subtypes or risk stratification.We subsequently analyzed the negative (NPV) and positive predictive values (PPV) of day 14 bone marrow aspiration results by morphology and MFC to predict post-induction results. As a predictor of post-induction CR, day 14 EBC had a NPV of 82% and a PPV of 69%, while day 14 MRD had a NPV of 86% and a PPV of 49%. However, for predicting post-induction MRD, day 14 EBC had a NPV of 49% and a PPV of 15%, while day 14 MRD had a NPV of 71% and PPV of 74%.The correlation between day 14 and post-induction bone marrow aspiration is shown in Table 2. Bivariate analysis showed that achieving CR with negative MRD in post-induction bone marrow aspiration was associated with EBC (p<0.001) and negative MRD (p=0.04) at day 14 bone marrow aspiration. No statistically significances were observed based on marrow cellularity. A multivariate analysis using logistic regression showed that negative MRD by MFC at day 14 was the only independent predictor variable to achieve post-induction CR with negative MRD (OR 4.95% CI 1.0-15.9; p=0.04).CONCLUSIONPatients showing EBC with negative MRD on day 14 bone marrow aspiration are more likely to achieve post-induction CR with negative MRD, with day 14 MRD by MFC being the only independent factor able to predict post-induction CR with negative MRD in our cohort. However, further prospective studies are needed to confirm our findings. [Display omitted] DisclosuresMartín-Rojas: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Epigenetic Phenocopying Expands Molecular Risk Assessment in Acute Myeloid Leukemia (Alliance)

Genetic profiling of leukemic cells forms the basis for risk stratification in acute myeloid leukemia (AML). Genetic markers in AML are used to make recommendations for distinct treatment approaches, such as remission consolidation with chemotherapy rather than stem cell transplant for patients with favorable risk genetics as defined by the current guidelines from the European LeukemiaNet (ELN). Yet, several limitations remain, such as overall rarity of many mutations, hierarchical complexity in cases with multiple mutations, conflicting reports of associations with outcomes for some genetic markers, and the absence of markers with prognostic significance in some patients. We have recently described genome-wide DNA methylation signatures that underlie biological features of AML cells and their utility to classify patients [Giacopelli et al. Genome Res. 2021;31:747]. The additional value of epigenetic information for risk assessment in AML in the context of current genetic and other clinical prognostic markers remains largely unexplored.In this study, we have first developed a targeted approach for assessment of DNA methylation-based signatures and employed it to classify 1,262 patients with de novo AML enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. We successfully classified 87.5% of patients into one of 13 DNA methylation subgroups, termed ‘epitypes’ (Figure 1A,B). We found that epitypes are composed of a majority of patients with a specific genetic alteration (or a unique combination of alterations) in 9 of 13 epitypes. However, we also identified subgroups of patients that lack these highly recurrent alterations, and, instead, represent an epigenetic phenocopy of the dominant genetic feature (epiphenocopy). Epiphenocopies within epitypes were often enriched in specific lower frequency mutations, suggesting convergence of biological function(s) for these rare mutations. Epiphenocopying was also exhibited by patients displaying a DNA methylation signature involving hypomethylation of STAT DNA sequence motifs (termed the STAT hypomethylation signature, SHS) that mimicked FLT3-ITD mutations. Epitype and SHS DNA methylation signatures affected clinical outcomes separately to ELN risk groups (P<0.0001; Figures 1C,D), and FLT3-ITD status (P<0.0001; Figure 1E), respectively.To broadly examine the prognostic power of DNA methylation signatures, we combined methylation-based classifications into a knowledge bank containing a compendium of other prognostic markers. Using a recently developed machine-learning approach [Gerstung et al. Nat Genet. 2017;49(3):332], we found that DNA methylation retained a high degree of importance for clinical outcomes, including overall survival (Figure 1F). Specifically, SHS and 6 epitypes were the most significant features negatively associated with overall survival along with age (P<0.0001; Figure 1G). SHS and epitype were among the most significantly associated features for all other endpoints, such as early death, remission and relapse (P<0.0001) and improved concordance between all predicted to actual outcomes. Finally, we used DNA methylation to reconstruct all 4 genetic features that define the ELN Favorable risk group. We found that patients with epiphenocopies of t(8;21)/inv(16) (CBF-AML), and CEBPA-dm had favorable outcome indistinguishable from that of patients with the respective genetic markers. NPM1-mutated, FLT3-ITD-negative patients displaying SHS-positivity had adverse risk despite lacking FLT3-ITD. Re-classifying patients with CBF-AML and CEBPA-dm epiphenocopies from more unfavorable risk groups into favorable group and excluding KMT2A/MLL-like and SHS-positive patients substantially improves the definition of favorable risk AML (P<0.0001; Figure 1H).Our study demonstrates that DNA methylation signatures advance our understanding of the biology of AML and improve risk stratification through the identification of patients with epiphenocopies that mimic genetic mutations and other biological features. Use of DNA methylation signatures may lead to more effective assignment of patients to existing and novel therapeutic approaches.Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifiers: NCT00048958 (8461), NCT00899223 (9665), and NCT00900224 (20202) [Display omitted] DisclosuresBlachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Blum: Abbvie: Honoraria; AmerisourceBergen: Honoraria; Celyad Oncology: Research Funding; Xencor: Research Funding; Nkarta: Research Funding; Forma Therapeutics: Research Funding; Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria. Stone: Agios Pharmaceuticals Inc, Novartis;: Research Funding; ACI Clinical, Syntrix Pharmaceuticals, Takeda Oncology: Other: Data Safety & Monitoring; AbbVie Inc, Actinium Pharmaceuticals Inc, Aprea Therapeutics, BerGenBio ASA, ElevateBio, Foghorn Therapeutics, GEMoaB, GlaxoSmithKline, Innate Pharma, Syndax Pharmaceuticals Inc, Syros Pharmaceuticals Inc, Takeda Oncology: Other: Advisory Committee. Eisfeld: Karyopharm (spouse): Current Employment. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Harmony Alliance Provides a Machine Learning Researching Tool to Predict the Risk of Relapse after First Remission in AML Patients Treated without Allogeneic Haematopoietic Stem Cell Transplantation

Harmony Alliance Provides a Machine Learning Researching Tool to Predict the Risk of Relapse after First Remission in AML Patients Treated without Allogeneic Haematopoietic Stem Cell Transplantation

Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients

IntroductionA standard therapy for fit older adults (≥60 years) with acute myeloid leukemia (AML) being treated with curative intent consists of induction chemotherapy with cytarabine and an anthracycline followed by 1-4 cycles of shorter course post-remission therapy with cytarabine +/- anthracycline. Historically, HiDAC has been reserved for younger patients due to the high incidence of cytarabine-induced neurotoxicity, febrile neutropenia, and hospital re-admissions in older patients (Mayer et al. 1994). In select older adults (e.g., those with good-risk cytogenetic/molecular abnormalities, or requiring reinduction for persistent AML), the risk/benefit for HiDAC may favor its use. Real world evidence is lacking on the safety of full dose HiDAC (total 18 grams/cycle) in fit older adults in the 60-75 age range.MethodsWe performed a retrospective analysis of AML patients ≥60 years who received at least one cycle of HiDAC, defined as 3g/m2 every 12 hours for 6 doses, either days 1-3 or days 1, 3, 5, as post-remission therapy or primary re-induction (i.e., after failure of primary induction with 7+3 or CPX-351) between July 1, 2014 and May 28, 2021. AML risk was defined by European LeukemiaNet (ELN) guidelines. All patients had daily neurologic exams including prior to each dose of HiDAC and at the beginning of each nursing shift.The primary endpoint was tolerability, defined as average dose per cycle, rate of dose reductions, incidence of febrile neutropenia, cerebellar toxicity, and rate of hospital re-admissions. Secondary endpoints were overall survival (OS), composite complete remission (CCR) for patients treated with HiDAC re-induction, and duration of relapse-free survival (RFS) (from day 1 of treatment) in all patients.ResultsFrom July 2014 to May 2021, 34 patients ≥60-years-old were treated with HiDAC at our center. Median age at HiDAC administration was 64 (60-73) [Table 1]. Approximately half the patients were Hispanic and male and almost all (97%) had ECOG performance scores of 0-1. HiDAC was used as post-remission therapy (following 7+3-type induction in 80%) in 25 patients and as re-induction in 14. Eleven patients (32%) were ELN favorable risk, 8 (25%) were intermediate, and 15 (44%) were poor risk.For post-remission therapy, the average total dose of cytarabine per cycle was 16.6 gm/m2 (6-18 gm/m2) and the median number of cycles was 4 (1-4) [Table 2]; 6 patients (24%) required dose reductions, the most common reason being upcoming allogeneic stem cell transplant (n=4). No cerebellar toxicity was observed. Duration of neutropenia was on average 15 days (7-53) in the re-induction group and 7.5 days (1-29) in the post-remission group, with 23 post-remission patients (92%) receiving granulocyte colony stimulating factors (G-CSF). Eleven hospital readmissions occurred, most commonly (73%) for febrile neutropenia. Early mortality rates were low, with one patient on the post-remission arm and one patient on the re-induction arm dying within 30 and 60 days, respectively, both due to sepsis. Median OS was 15.8 months (95% CI 0-31.8) in patients who received post-remission HiDAC, with 44% of patients still alive with a median follow up of 17.2 months (95% CI 7.2-55.8). Favorable risk patients (n=11) receiving post-remission HiDAC had median OS of 15.8 months (95% CI 0-43.1), while intermediate/poor risk patients (n=14) had median OS of 11.3 months (95% CI 9.3-13.2) [p=0.53]. Median OS was 9.8 months (95% CI 2.5-17.1) in patients who received HiDAC re-induction, with 29% of patients still alive with a median follow up of 28.6 months (95% CI 16.6-39.9) [Table 3]. Five patients (36%) achieved CCR after HiDAC re-induction, all of whom went on to receive post-remission HiDAC. Median RFS was 8.5 months for re-induction and 8.8 months for post-remission patients [Table 3].ConclusionsHiDAC (18 grams) can be safely given to select patients over age 60. Critical to tolerability is rigorous screening of “fitness,” limiting the upper age receiving HiDAC to 75, ensuring adequate renal function and euvolemia, and advances in supportive care. Encouraging survival outcomes were observed in older adults receiving post-remission or re-induction HiDAC, independent of ELN risk. [Display omitted] DisclosuresBradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

Hemopoiesis and Immune Cell Perturbations during Venetoclax Plus Azacytidine Treatment in Acute Myeloid Leukemia

Treatment of acute myeloid leukemia (AML) in elderly is still challenging. Indeed, high-dose chemotherapy followed by hematopoietic stem cell transplantation with myeloablative regimens is not always feasible because patients are often unfit and have several comorbidities; however, they frequently show multiple negative prognostic factors and have a worse overall survival compared to younger adults. Venetoclax, the first-in-class Bcl-2 antagonist and first approved for treatment of chronic lymphocytic leukemia, inhibits the anti-apoptotic functions of Bcl-2 inducing apoptosis and tumor growth arrest. Venetoclax is also used in combination with azacytidine, or decitabine, or low-dose cytarabine for treatment of elderly newly diagnosed AML. However, several mechanisms of resistance have already been described, such as increased expression of other anti-apoptotic proteins by the leukemic clone. In this case series, we investigated hematopoiesis and immune cell perturbations during venetoclax plus azacytidine treatment in elderly AML patients.A total of six AML patients (M/F, 2/4; median age, 71 years old; range, 63-79 years) were retrospectively evaluated at the Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d'Aragona”, Salerno, Italy. Patients received a diagnosis of AML based on the 2016 World Health Organization (WHO) criteria and chemotherapy with azacytidine 75 mg/m 2 daily for 7 days per cycle and venetoclax 70 mg/daily. Two patients were NPM1 mutated (one of them also had mutated IDH1, VAF 27.2%), while all subjects had FLT3 wild type. Based on the 2017 European LeukemiaNet risk classification, two patients had favorable risk and four intermediate. Median follow-up was 10.1 months (range, 4.9-16.6 months), and all patients were in partial or complete remission at the time of writing. Flow cytometry immunophenotype, complete blood counts (CBCs), and WT1 expression levels were performed at diagnosis and after every cycle of therapy as per our institutional guidelines.In our case series, leukemic cells were already decreased after the first cycle of therapy (blasts by flow cytometry + SD, 54.7+39.9% vs 4.2+5.4%, diagnosis vs post I cycle; P = 0.0671; paired t-test performed), while normal granulocytes detected by flow cytometry recovered only after the third cycle of therapy (20.7+23.7% vs 53+6.6%, diagnosis vs post III cycle; P = 0.1396; uncorrected Fisher's mixed model performed). Treated patients also displayed a contextual decreased in WT1 expression levels (normalized WT1 copy number + SD, 1810+2723 copies vs 201+132.9 copies, diagnosis vs post I cycle; P = 0.2660; paired t-test performed). Platelet count tended to increase after the first cycle (P = 0.0680); however, at the end of the second cycle, half of patients were again thrombocytopenic (platelets < 100 x 10 3/µL). Interestingly, percentage of lymphocytes detected by flow cytometry were significantly increased after the second cycle of azacytidine plus venetoclax compared to baseline and after the first cycle of therapy (mean+SD, 13.5+13.3% vs 48+8.7%, diagnosis vs post II cycle; P = 0.0167; and vs 28+11.3%, vs post III cycle; P = 0.0480), likely because an increase in Natural Killer (NK) cell frequency peaking after the second cycle (mean+SD, 19.4+4.4% vs 32.5+15.1%, diagnosis vs post II cycle; P = 0.1383). Moreover, five out of six patients displayed expansion of plasma cells detected by flow cytometry in the bone marrow after the first cycle: in particular, one case patient had expansion of aberrant CD45-/dimCD38++CD138++CD56+CD19- plasma cells, while one subject showed only a transient appearance of clonal plasma cells after the second cycle. No differences in bone marrow monocyte frequencies were described during treatment.Our preliminary results added evidence to efficacy and safety of the combination of venetoclax and azacytidine in treatment of elderly AML in a real-world setting. These drugs might synergistically function on hematopoiesis by inducing apoptosis of neoplastic cells while favoring differentiation of other lineages, as suggested by the expansion of plasma cells, or triggering NK-mediated immunosurveillance. However, prognostic and clinical significance of plasma cell and NK cell expansion in the setting of AML treatment needs to be further explored in larger prospective cohorts. DisclosuresNo relevant conflicts of interest to declare.

Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia

Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia