Newly-diagnosed AML Research Articles

FLAG-IDA + venetoclax in newly diagnosed (ND) or relapsed/refractory (RR) AML.

6519 Background: We report the outcomes of a phase 2 study of FLAG-IDA+VEN in AML. Methods: Pts ≥18 with ND or RR AML / MDS-EB2 fit for intensive chemotherapy were eligible. Induction comprised fludarabine 30mg/m2 D2–6, cytarabine 1.5g/m2 D2–6, idarubicin 8 (6 if RR) mg/m2 D4–6 & filgrastim 5mcg/kg D1–7. VEN 400mg was administered D1–14 with CYP3A inhibitor dose adjustment until Jul 2023; following a protocol modification, VEN is now administered D1–7. The primary outcome was ORR (CR + CRh + CRi + MLFS + PR). Secondary outcomes were CRc (CR + CRh + CRi), overall survival (OS), event-free survival (EFS) & duration of response (DOR). Measurable residual disease (MRD) was assessed by flow cytometry. Results: As of Jan 2024, 134 pts have enrolled, 127 (68 ND & 59 RR) evaluable at data cut. Median age was 45 (18 – 73); 19 (15%) age ≥60. 13 (19%), 22 (32%) & 33 (49%) ND pts were ELN22 favorable, intermediate & adverse respectively. There were 7 (10%) secondary (s), including 4 hypomethylating agent failure, & 7 (10%) therapy-related (t) AML. In RR pts, 40 (68%) were in salvage 1 (S1), of whom 32 (54%) were TP53WT. 20 (34%) had prior stem cell transplant (SCT). Median of 2 cycles were given. In ND pts, ORR was 99%, (96% CRc, of whom 89% MRD negative [Table]). Similar responses were seen across ELN groups & s/tAML. At median follow-up (mFU) of 30 months (mo), the mOS, mEFS & mDOR were not reached. The 2yr OS, EFS & DOR were 75% (64 – 88), 68% (56 – 81) & 71% (59 – 85) respectively, with no differences among ELN groups. 57% went to SCT in CR1. 4/4 pts with TP53mut became CRc MRD–, but mDOR was only 8.2 mo (95% CI, 2.2 – NE), resulting in poor mOS (13.5 mo, 95% CI, 8.6 – NE). In RR pts, ORR was 70% (66% CRc, of whom 79% MRD negative [Table]). At mFU 27 mo, the mOS, mEFS & mDOR were 12 (7 – 33), 7 (4 – 23) & 21 (8 – NE) mo respectively. The 2yr OS, EFS & DOR were 40% (28 – 55), 34% (23 – 49) & 49% (35 – 68) respectively. 58% went to SCT. S1+ TP53WT pts had mOS of 34 mo (12 – NE), with 72% going to SCT. 30d & 60d mortality were 0% & 3%. Of the 4 deaths within 60d, 1 was sepsis-related in CR in a ND pt while 3 were disease-related in NR RR pts. The most frequent adverse event was infection. Grade ≥3 infections, gastrointestinal toxicities & bleeding occurred in 102 (80%), 20 (16%) & 9 (7%) pts respectively. The median time to neutrophil >1x109/L & platelet >50x109/L were 27d & 28d for C1, 39d & 67d for C2 & 35d & 50d for C3 respectively. Conclusions: FLAG-IDA+VEN results in high MRD negative response rates, leading to impressive survival outcomes across ELN risk groups in ND AML. It is an effective salvage regimen for RR AML, especially for S1+ TP53WT pts. Clinical trial information: NCT03214562 . [Table: see text]

Outcomes in Patients with Acute Myeloid Leukemia Treated with CLAG (cladribine, cytarabine, filgrastim) and/or Mitoxantrone with Venetoclax

Introduction: CLAG (cladribine, cytarabine, filgrastim) with or without M (mitoxantrone) has anti-leukemic activity in newly diagnosed (ND) and relapsed/refractory (R/R) AML (Wierzbowska et al. 2008, Jaglal et al. 2014, Seiter et al. 2016). Venetoclax (Ven) with hypomethylating agents (HMA), approved for patients (pts) who are not candidates for intensive chemotherapy (IC), is increasingly being employed even for pts who are fit for IC. R/R disease remains a major cause of mortality in fit pts with AML, and thus improved IC regimen is an area of active research. Various combination of IC with Ven are ongoing with promising early findings (DiNardo et al. 2021, Reville et al. 2022). In this study, we examined the outcomes of AML patients treated with CLAG and/or mitoxantrone with Ven, CLAG(M)/Ven. Methods: This was a retrospective study of pts with AML who received CLAG(M)/Ven (Days 2-8) in 2022-2023. Clinical responses were reported using ELN 2022 criteria. Kaplan-Meier analyses were used to estimate overall survival (OS) from the date of CLAG(M)/Ven initiation. Results: This cohort of 19 pts (8M/11F with median age of 60 [23-74] at diagnosis) is comprised of 68.4% (13/19) R/R and 31.6% (6/19) ND AML who had prior MDS directed therapy. There were 57.9% (11/19) with secondary/therapy-related AML and when including de novo AML pts who had mutations highly specific for secondary AML ontogeny, it increased to 78.9% (15/19). Most of the pts (68.4%, 13/19) had adverse risk disease by ELN 2022. Common mutations being TP53 (26.3%, 5/19) followed by IDH1/2 (21.1%), ASXL1 (15.8%), and RUNX1 (15.8%). There were 36.8% (7/19) who had received allogeneic hematopoietic cell transplant (alloHCT) (Table 1). Similar number of pts received CLAG/Ven (47.5%) and CLAG-M/Ven (52.6%). Pts received on average 2.6 lines of treatment prior to CLAG(M)/Ven with 1 pt received 5 prior lines of treatment after AML diagnosis. Most of the pts, 78.9% (15/19), had prior HMA/Ven. The 30-day and 60-day morality was 5.3% (1/19) (disease status unknown at the time of death) and 26.3% (5/19) (disease status: 3 yes, 1 no, 1 unknown), respectively. Among these 5 early deaths within 60 days, 3 were ND AML that were heavily pretreated for prior MDS (average 3 lines of prior therapy) and 2 were R/R AML. All of them had prior HMA/Ven. Eighty percent (4/5) had adverse risk disease and received CLAG-M/Ven. Forty percent (2/5) had TP53 mutation. Objective response rate (ORR) of the entire cohort was 26.3% (5/19) (2 CR, 1 CRi, and 2 MLFS). Among those with evaluable response (n=10), ORR was 50%. Two CR/CRi pts achieved undetectable MRD by flow cytometry. MRD was not tested in the other 3 pts. Notably, ORR was higher in pts who received CLAG/Ven (44.4%, 4/9) compared to CLAG-M/Ven (10%, 1/10). No response in ND AML and 38.5% (5/13) ORR in R/R AML. Of the 47.4% (9/19) nonevaluable pts, 6 had aplastic marrow (2 died while getting induction, 2 transitioned to alloHCT, 1 moved onto next line of treatment, and 1 lost to follow up) and 3 had recovery marrow pending. For pts who achieved a response, 60% (3/5) underwent alloHCT (all of them alive without disease at data cutoff). The median time to count recovery was 42.5 days (27 days to never recovered). Prior HMA/Ven failure, high dose cytarabine failure, and mutations did not significantly impact response in this small cohort. The median OS from the time of CLAG(M)/Ven initiation was 5.5 months with a median follow up of 8.6 months (Figure 1). OS from the date of CLAG(M)/Ven was significantly shorter in pts with TP53 mutation vs. wild-type (2 vs. 11.2 months, p=0.031). Conclusions: Our findings showed the combination regimen CLAG(M)/Ven is feasible in pts with AML. It also provided better characterization in terms of early mortality and survivals in these pts, which can help inform future clinical trial design. ORR was similar to what was previously reported with CLAG(M); however, it is encouraging that those who achieved CR/CRi and had MRD testing also achieved MRD negativity. Outcomes of TP53-mutated subset is dismal suggesting IC-based approach in this setting is limited. Larger cohort and longer follow up is needed to confirm the impact of factors such as specific regimen, mutations, and prior therapies on outcomes.

Three-Day Decitabine Combined with Venetoclax in Patients with Newly Diagnosed or Relapsed/Refractory AML

INTRODUCTION Venetolax (VEN) combined with azacytidine (AZA), decitabine (DEC), and low-dose cytarabine has been the first-line therapy for newly diagnosed (ND) AML patients who are elderly or unfit for intensive chemotherapy. Previous reports shown that ten-day DEC with VEN (DEC 10-VEN) was an effective therapy for newly diagnosed elderly patients. Though higher remission rate in ND AML compared five-day DEC with VEN, DEC 10-VEN induced prolonged myelosuppression. Therefore, optimizing the combination of DEC with VEN is still being explored. In this study, we retrospectively collected and analyzed the clinical data of three-day DEC combined with VEN (DEC 3-VEN) ( Tianjin-Handan regimen) in twelve patients with ND or relapsed/refractory (R/R) AML who were elder or ineligible for intensive chemotherapy to evaluate the efficacy and safety of the regimen. METHODS Retrospectively collected and analyzed the clinical data of twelve ND or R/R AML patients treated with three-day DEC combined with VEN as induction therapy between July 2022 and June 2023 at 4 hospitals in china. The induction regimen consisted of oral Ven (100mg Day 1; 200mg Day 2; 400mg Day 3-9 or 3-14), intravenous DEC (20mg/m²/q8h, days 4-6), sorafenib were administered (600mg days 8-14) in relapsed/refractory patients with FLT3/ITD. The primary objective was composite complete response rate (CR + CRi) and the secondary objectives was safety. RESULTS Until June 2023, twelve patients with de novo or relapsed/refractory AML were treated with three-day DEC combined with VEN as induction therapy. The median age of the twelve patinets was 67 years (range, 32-76), with 58.3% (7/12) male. Seven (58.3%) patients were ND AML, and five patients (41.7%) were R/R AML. The clinical data and treatment information of the patients are shown in table 1. The composite complete response rate (CR + CRi) after one cycle of induction was 100% (CR 10/12, CRi 2/12). For patients who achieved CR or CRi, MRD negative rate was 77.8% (7/9) by flow cytometry. None of patients died during the induction therapy.The median time to recovery of the absolute white blood count (WBC) to ≥1.0 × 10 9/L and the platelet count to ≥20 × 10 9/L after induction was 13 (range: 7-25) and 15 days (range: 0-27), respectively. CONCLUSION: DEC 3-VEN is a highly effective and safe induction therapy for ND and R/R AML patients who are elderly or unfit for intensive chemotherapy. Further study with more patients will be updated. 【Keywords】Venetoclax; decitabine; AML; induction treatment.

Comparing the Efficacy and Safety of Venetoclax Combined with Decitabine Versus Conventional Chemotherapy As Induction Therapy for Young Adults with Newly Diagnosed Acute Myeloid Leukemia - Interim Analysis of a Multicenter, Randomized, Phase 2b Trial

Introduction: Venetoclax in combination with hypomethylating agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for older or unfit AML patients. In a phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DAC) resulted in a 93% of response rate in young adult patients with newly diagnosed (ND) ELN adverse-risk AML. Currently, there is a lack of data on the VEN-DAC regimen in ND young adults with favorable or intermediate risk AML who are fit for intensive chemotherapy. There are also no studies directly comparing the VEN-DAC regimen with intensive chemotherapy in patients with ND AML. Here, we report the results of an interim analysis of a multicenter, randomized, phase 2b trial (NCT05177731) , which explored the efficacy and safety of VEN-DAC versus intensive chemotherapy (idarubicin and cytarabine) in ND AML patients. Methods: Adult patients with newly diagnosed AML aged between 18 and 59 years were enrolled. The diagnosis was made according to the WHO 2016 criteria. Risk stratification was performed according to the 2017 ELN recommendations. Eligible patients were randomized in a 1:1 ratio to the VEN-DAC group (decitabine 20mg/m 2 on days 1-5 and venetoclax at an escalated dose of 100mg, 200mg and 400mg by day 28) or the IA-12 group (idarubicin 12mg/m 2 on days 1-3 and cytarabine 100mg/m 2 on days 1-7). Patients who did not respond to the treatment were allowed to receive another cycle of the original induction regimen. Intermediate-dose cytarabine (2g/m 2, q12h, days 1-3) were applied as consolidation therapy. The primary endpoint was the composite complete remission (CRc, including complete remission, CR and complete remission with incomplete hematologic recovery, CRi). The secondary endpoints included measurable residual disease (MRD) negative remission (defined as <1×10 -3 by flow cytometry), event-free survival (EFS) , overall survival (OS) and adverse events. Results: Since March, 2022, a total of 163 patients with AML were screened and 116 patients were randomized. Sixty patients received the VEN-DAC regimen and 55 patients received the IA-12 regimen. There were no differences in baseline characteristics between the two groups of patients (Table 1). Bythe cut-off date of July 11, 2023, a total of 102 patients have been evaluated, 55 in the VEN-DAC group and 47 in the IA-12 group. The overall CRc rate in the VEN-DAC group was 85.5%, which was comparable to that of the IA-12 group (78.7%, P=0.37). The MRD-negative CR rate in the VEN-DAC group was 67.3%, which was much higher than that in the IA-12 group (53.2%) ( P=0.147). According to univariate analysis, efficacy of the VEN-DAC regimen did not differ from that of the IA-12 regimen with respect to sex, age, initial bone marrow blast count, genetic risk category, and major molecular markers (Figure 1A). Notably, the CRc rate and MRD-negative CR rate were significantly higher in the VEN-DAC group than in the IA-12 group for intermediate-risk and adverse-risk patients, especially those with adverse risk ( P=0.031 for CRc, P=0.029 for MRD-negative CR) (Figure 1A). At median follow-ups of 7.8 months (range, 0.9-16.6), the EFS and OS were not reached in both groups. The median time for platelets to recovery to 20×10 9/L or above in the VEN-DAC group was 12 days after induction in the VEN-DAC group, which was shorter than that in the IA-12 group (21 days) ( P<0.01). In addition, patients in the VEN-DAC group required fewer platelet (5 U vs 7 U, P<0.01) and red blood cell infusions (3 U vs 5 U, P=0.023) during induction as compared with that in the IA-12 group. In addition, the incidence of grade 3 or higher febrile neutropenia (41.8% vs. 83.0%), infection (27.3% vs. 72.3%) and sepsis (5.5% vs. 31.9%) were all significantly lower in the VEN-DAC group than in the IA-12 group ( P<0.01) (Figure 1B). Conclusion: In newly diagnosed young AML patients, venetoclax in combination with decitabine as an induction regimen had comparable efficacy and a higher safety profile compared to IA-12 regimen. In particular, patients with adverse-risk AML showed higher and deeper remission rate in the venetoclax plus decitabine group as compared with the IA-12 group.

Despite High Rates of Remission, Treatment of IDH-Mutant AML with Hypomethylating Agents and Venetoclax Is Associated with Frequent Treatment Delays, Modifications, and Transfusions

Introduction: 25-30% of adult patients with AML have mutations in the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2. Hypomethylating agents (HMA) and venetoclax (Ven) is a widely used combination in induction-ineligible patients with IDH mutations. A subset analysis of VIALE-A data showed composite complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate of 79% and median overall survival (mOS) of 24.5 months with frontline azacitidine and Ven. IDH1-mutant and IDH2-mutant patients had CR/CRi rates of 66.7% and 86.0%, respectively. IDH1-mutant patients had mOS of 15.2 months and IDH2-mutant patients did not reach mOS. We report a single-center retrospective analysis of HMA/Ven in patients with IDH mutations. Methods: This single-center retrospective study examined all patients with IDH mutations who received HMA/Ven from January 1, 2018 to June 30, 2023 at Memorial Sloan Kettering Cancer Center and summarizes their characteristics and outcomes. Demographics, adverse events, treatment course, and laboratory and transfusion data were retrospectively reviewed with institutional IRB approval. Results: Ninety-four patients, 50 with newly diagnosed (ND) AML and 44 with relapsed/refractory (R/R) AML, were identified (Table 1). 32% (n=16) of ND patients and 41% (n=18) of R/R patients had IDH1 mutations and 68% (n=34) of ND patients and 59% (n=26) of R/R patients had IDH2 mutations. With median follow-up of 21.9 months, mOS was 29.2 months (95% CI 17.9, NA) for ND patients and 17.1 months (95% CI 12.1, 34.2) for R/R patients (Figure 1). The CR/CRi rate was 76% (n=38; 30% CR, n=15; 46% CRi, n=23) for ND patients and 52% (n=23; 32% CR, n=14; 20% CRi, n=9) for R/R patients. Patients received median of 3 cycles of HMA/Ven (range 1, 22) and experienced frequent treatment modifications and delays. Of 356 total cycles, 62% (n=218) were modified to have fewer than 28 days of venetoclax, 7 days of azacitidine, or 5 days of decitabine. In addition, 296 cycle holds or delays of at least one week occurred. 66.2% (n=196) of holds or delays were due to cytopenia and 11.5% (n=34) were due to infection. 77% (n=72) of patients had Common Terminology Criteria for Adverse Events (CTCAE) grade 3 pancytopenia and 47% (n=44) had febrile neutropenia. Through 356 cycles spanning 21,386 patient-days, 5,651 complete blood counts (CBCs, mean 15.9 per cycle), 986 red blood cell transfusions, (RBC, mean 2.8 per cycle) and 1,018 platelet transfusions (PLT, mean 2.9 per cycle) were recorded at our center. Additional CBCs or transfusions performed externally were not captured. After CR/CRi, dose adjustments, cycle holds or delays, and cytopenias remained frequent. The 63 patients that achieved CR/CRi underwent 198 cycles, 71% (n=141) of which were modified as above. There were 209 holds or delays (65%, n=136 for cytopenias, 10%, n=21 for infection). Median time between cycles was 7 weeks. Cycles given after CR/CRi frequently resulted in grade 3 cytopenias by CTCAE (neutropenia: 82%, n=163; anemia: 15%, n=29; thrombocytopenia: 37%, n=74). Through 198 cycles spanning 13,463 patient-days, 2,426 CBCs (mean 12.3 per cycle), 141 RBC transfusions, (mean 0.7 per cycle) and 236 PLT transfusions (mean 1.2 per cycle) were performed. At last follow-up, 28% (n=14) of ND AML patients continued HMA/Ven, whereas 28% (n=14) had proceeded to allogeneic stem cell transplantation (alloSCT), 28% (n=14) were relapsed or refractory to HMA/Ven, and 12% (n=6) were deceased. For R/R AML patients, 20% (n=9) continued HMA/Ven but 27% (n=12) had proceeded to alloSCT, 34% (n=15) were relapsed or refractory, and 14% (n=6) were deceased. Of the 68 patients who were no longer receiving HMA/Ven at end of follow-up, only 23.5% (n=16) of patients received an IDH-inhibitor in their next line of therapy, the rest primarily transitioning to alloSCT (38.2%, n=26), chemotherapy (8.8%, n=6), or supportive measures (20.6%, n=14). Conclusion: In a single-center retrospective setting, HMA/Ven is efficacious in achieving CR/CRi in ND and R/R IDH-mutant AML. However, its use, even in CR/CRi, is associated with significant cytopenias and infections that necessitate indefinite and frequent treatment modification, laboratory utilization, and transfusions. A strategy that incorporates HMA/Ven followed by non-myelosuppressive targeted therapy with IDH inhibition as maintenance should be explored to minimize these toxicities.

CLAG-Based Chemotherapy in Previously Untreated AML Patients: 12 Year Follow-up

Introduction: The 7+3 combination of cytarabine plus an anthracycline is the most commonly used induction regimen for AML in the US. There is evidence FLAG-IDA may be superior to 7+3 (Solh et al Leuk Res 2020), and that cladribine is superior to fludarabine (Holowiecki et al JCO 2012). Currently we report the results of CLAG-based chemotherapy in newly-diagnosed AML patients. Methods: This single-center retrospective cohort studied all patients with newly-diagnosed AML who received CLAG-based induction therapy (with or without an anthracycline, depending on cardiac function) between February 2011 and June 2023. Chemotherapy consisted of cladribine 5 mg/m 2 daily times 5 days, cytarabine 2 gm/m 2 over 4 hrs daily times 5 days (given 2 hours after the completion of each cladribine dose), plus G-CSF 300 ug daily during chemotherapy and then based on weight after that. Patients with adequate cardiac function also received 3 days of mitoxantrone 12 mg/m 2 (CLAG-M) or idarubicin 12 mg/m 2 (CLAG-IDA) on days 1-3 or 2-4. Many of these patients were treated prior to the current era of targeted therapies and thus most received chemotherapy without targeted agents. Post-remission therapy was given at the physician's discretion based on the patient's tolerance of induction chemotherapy. Complete response (CR) was defined as less than 5% blasts in the marrow with recovery of ANC >1000/mm 3 and platelets >100,000/mm 3. Lesser responses included CRi, CRp and PR. All others were considered failures or early deaths (within 30 days). This study was approved by the IRB of New York Medical College. Results: We analyzed all 87 newly-diagnosed AML patients that were treated with CLAG-based induction therapy (CLAG alone: 10%, CLAG-IDA: 87%, CLAG-M: 3%). 4 patients with a FLT-3 mutation received a FLT-3 inhibitor concurrently. Post-remission therapy included allo transplant (13%), further CLAG+/- IDA, reduced to 4+2 days (84%), HiDAC (27%), and hypomethylators (36%), in that order of priority. The intensity of the post-remission therapy was matched with the perceived ability of the patient to tolerate it. Many patients received more than one post-remission therapy in sequence. The median age of the cohort was 65 (33-85) years. 59% were male, 47% were smokers, 6% had prior MDS and 13% had therapy-related AML. The median baseline WBC was 9.7 (0.4-392) k/mm 3. 10% of patients were stratified as favorable ELN cytogenetic risk, 45% as intermediate, and 45% as adverse. TP53 mutation was present in 22% patients and FLT3 mutation in 14% patients. CR was obtained in 67% of patients overall and did not differ significantly by age (<60: 65%, 60-70: 70%, >70: 64%). Early deaths (within 30 days) were more common in older patients (<60: 3%, 60-70: 3%, >70: 8%). The CR rate was similar across all cytogenetic risk groups (good risk: 67%, intermediate risk: 68%, poor risk: 62%) and was favorable in patients with a TP53 mutation (68%), as well as those with therapy-related AML (69%). The median overall survival (OS) was 13 months. By cytogenetic risk the median OS was good: not reached, intermediate: 25.6 months and poor: 6.8 months (Figure 1). It should be noted that two patients with good risk cytogenetics who expired included an 80-year-old woman with therapy-related AML after treatment for breast cancer who declined further therapy after cycle 1 and survived 20 months with no further therapy, as well as a second unvaccinated patient who expired due to complications of COVID. Median OS by age was <60: 18 months, 60-70: 25.6 months and >70: 8 months (Figure 2). Median overall survival for patients with TP53 mutation was 5.6 months. Conclusion: CLAG provides an alternative induction regimen to 7+3. Interestingly, in contrast to 7+3, CR rates did not differ significantly by age or cytogenetic risk group. The older patients treated on this trial were a select group that were considered eligible for intensive chemotherapy. Many of the patients on this trial would be treated differently today, with the availability of more targeted therapies. However the relatively high response rates in patient with poor risk cytogenetics and/or TP53 mutation gives fit patients the opportunity of pursuing stem cell transplantation.

Phase Ib/II Study (NCT02488408 / BGBC003) of Bemcentinib Monotherapy or in Combination with Cytarabine or Decitabine in Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): FINAL Results

Background: The standard of care (SOC) in newly-diagnosed (ND) AML patients (pts) unfit for intensive chemotherapy (IC) yields median overall survival (mOS) of 14.7 months. However, beyond 1 st line (1L), pts have limited treatment options and dismal mOS of 2.3 months (4.7 months in pre-venetoclax era), highlighting the need for more effective treatments in 2 nd line (2L) and beyond. Activation of AXL, a receptor tyrosine kinase, is associated with poor prognosis, resistance to chemotherapy and decreased antitumor immune response in AML. Bemcentinib (BEM) is a first-in-class, oral, highly selective AXL inhibitor. Aims: The BGBC003 PhIb/II trial studied the safety and efficacy of BEM as monotherapy in AML (cohort B1) and MDS (cohort B4) and in combination with decitabine (cohort B3) or low-dose cytarabine (LDAC) (cohorts B2 and B5) in ND and relapsed/refractory (R/R) AML pts unfit for IC. Pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted in pts treated with BEM monotherapy in the safety run-in phase (part A). Here, we present final efficacy and safety data, as well as PK/PD analysis from part A. Methods: In part A, 36 pts received BEM monotherapy in a dose escalation manner. In part B (cohorts B1-B5), pts received 3 loading doses at daily 400 mg BEM followed by 200 mg BEM daily. Study endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR) (ORR+unchanged [UC]). Plasma and peripheral blood (PB) samples were used for PK and phospho-AXL (pAXL) analyses. Results: From Oct-14 to Jul-21, 86 pts were enrolled in part B (72 efficacy evaluable), with a median age of 76 years (range 50-86), 77% being R/R at study entry. BEM monotherapy and in combination was well tolerated, with a safety profile comparable to the known safety profile of the combination agents. The ORR was 18% (B1), 0% (B3), 25% (B2+B5), and 19% (B4). The CBR was 45% (B1), 31% (B3), 31% (B2+B5) and 56% (B4). The mOS (months) was 18 (B1), 6.4 (B3), 8.0 (B2+B5) and 9.2 (B4). BEM+LDAC (B2+B5) showed promising survival benefit in ND (mOS 16.5 months, n=5) and R/R pts (mOS 7.8 months, n=27). The PK/PD analysis showed inhibition of the biological target pAXL in PB following monotherapy. BEM showed dose-dependent inhibition of pAXL and downstream targets of pAXL (pAKT, pERK and pNFkB) with EC 50 values of 89-162 ng/mL. Summary/Conclusions: BEM demonstrated on-target effect by inhibition of pAXL and downstream signalling in a concentration-dependant manner. BEM monotherapy and in combination was well tolerated across all cohorts. The overall efficacy observed is comparable with historical data in 2L AML and MDS. Although the shift in 1L SOC in AML during the study limits adequate comparisons, a survival benefit was observed both in ND and R/R AML, warranting further investigation. Keywords: Acute myeloid leukemia, Clinical trial, Receptor tyrosine kinase

Prognostic Impact of Clonality of Myelodysplasia-Related Gene Mutations in AML

Introduction: The 2022 International Consensus Classification (ICC) stresses the importance of molecular- and cytogenetic aberrations over previous medical history. Nine mutations are used to define a subgroup of AML with myelodysplasia related gene mutations (AML-MRGM). On a lower hierarchical level specific cytogenetic changes are used to define a subgroup of AML with myelodysplasia related cytogenetic abnormalities (AML-MRCA). Both groups together with TP53 mutations are categorized within the adverse risk group of the 2022 ELN classification. We evaluated the prognostic implications of clonality of MRGM mutations. Methods: 552 newly-diagnosed adult AML patients (pts.) with a median age of 55 years who received intensive induction chemotherapy followed by consolidation chemotherapy or allogeneic stem cell transplantation and with available genetic and follow-up data were included. Mutations present at diagnosis were identified by Illumina myeloid panel sequencing covering 48 AML-associated genes. Variant allele frequency (VAF) was adjusted for sex for mutations located on the X chromosome (BCOR, STAG2, ZRSR2). The prognostic VAF cutoff was identified by maximally selected rank statistics. We defined AML-MRGM as having at least one MRG mutation, AML-MRCA as having at least one MRCA without MRGM, TP53 mutated patients as having TP53 mutations regardless of the presence of MRGM or MRCA and for the remaining pts. de novo AML and secondary/therapy-related AML according to medical history of the patient. For multivariate analysis value imputation was used for missing values. Results:40 (7.2%) of 552 pts. were TP53 mutated,196 (35.5%) had at least one MRGM, and 47 pts. (8.5%) had MRCA. Among the clinically defined cases 215 pts. (38.9%) had genuine de novo AML and 54 (9.8%) had a previous history of a hematologic malignancy or cytotoxic treatment. The median follow-up was 5.8 years. Overall survival (OS) and relapse free survival (RFS) for de novo AML and secondary AML based on medical history were not significantly different and were therefore grouped together as clinically-defined AML (cdAML). AML-MRGM pts. had a significantly lower complete remission (CR) rate (OR=0.32, 95%CI 0.18-0.56, p<0.001) and shorter OS, but not RFS, compared to cdAML pts. (OS, HR 1.38, 95%CI 1.04-1.83, p=0.02; RFS, HR 1.12, 95%CI 0.84-1.48, p=0.44). AML-MRCA had similar OS and RFS compared to both cdAML and AML-MRGM pts., but a significantly better CR rate than AML-MRGM pts. (OR 5.68, 95%CI 1.64-38.65, p=0.01). Pts. with TP53 mutations had a worse OS and RFS than all other subgroups. A VAF of 45% was identified as a prognostic cutoff by maximally selected rank statistics. Patients with MRGM and VAF ≥ 45% were associated with higher age (p=0.04) and a lower platelet count at diagnosis (p=0.04). A VAF ≥ 45% was identified in 81 pts. (41.3%) and was associated with a significantly worse OS and RFS compared to the 115 pts. (58.7%) with a VAF below 45% (OS, HR 1.70, 95%CI 1.12-2.57, p=0.01; RFS, HR 1.65, 95%CI 1.05-2.57, p=0.03) (Figure 1). Patients with VAF ≥ 45% had an OS and RFS similar to AML-MRCA pts., but significantly shorter OS and RFS than cdAML pts. (OS, HR 1.89, 95%CI 1.32-2.69, p<0.001; RFS, HR 1.52, 95%CI 1.04-2.21, p=0.03). In multivariate analysis the presence of MRGM with a VAF ≥45% was an independent adverse prognostic factor for OS. Conclusion: In the present study, we confirm myelodysplasia-related gene mutations and TP53 mutations as negative prognostic markers in line with the hierarchical significance proposed by ELN. Our study suggests that the presence of MRGM is associated with worse OS especially if it is present at a VAF ≥ 45%, likely representing patients with at least one MRG mutation in the major AML clone.

Myelodysplasia-Related Gene Mutations for NGS-Based MRD Assessment in Acute Myeloid Leukemia

Introduction: Measurable residual disease (MRD) plays an increasing role for treatment management of AML patients. While next-generation-sequencing (NGS) based MRD assessment can be well standardized, there is uncertainty about the type of gene mutations that associate with prognosis and are useful for MRD assessment. The 2022 ELN recommendations assign patients with at least one mutation in the genes ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 or ZRSR2 to the subgroup of myelodysplasia-related gene mutations (MRGM), which is associated with poor prognosis. We aimed to define the prognostic effect of MRD after induction chemotherapy in AML patients with MRGM using MRG mutations for MRD assessment by NGS. Methods: We retrospectively collected bone marrow and peripheral blood samples from AML patients in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after one to two cycles of 7+3-based standard induction chemotherapy (IC) with at least one MRGM detected at diagnosis by myeloid panel sequencing covering 48 AML associated genes. Patients treated with one course of IC were included if they proceeded to allogeneic hematopoietic cell transplantation (alloHCT) already after one cycle. Molecular MRD status was assessed using targeted NGS and bioinformatics error-correction with 0.01% sensitivity as described before using only MRGM as MRD markers. Results: MRD was assessed on 104 adult newly-diagnosed AML patients (median age 58.6) with a total of 166 MRGM, resulting in a median of one MRGM per patient (range 1-4). 43 (41.3%) patients had secondary or therapy-related AML and 20 (19.2%) had myelodysplasia-related cytogenetic abnormalities. 68 (65.4%) patients were MRD positive for at least one MRGM after one (18 patients (17.3%)) or two (86 patients (82.7%)) cycles of intensive chemotherapy, while 36 (34.6%) became MRD negative. Measured variant allele frequencies (VAF) of positive samples ranged from 0.02-43.1% (median VAF 1.34%).MRD positive patients were older and more likely to be male compared to MRD negative patients, while cytogenetic risk, WBC count, Hgb, platelet count and ECOG status at diagnosis were similar to MRD negative patients. 53 (77.9%) MRD positive and 23 (63.9%) MRD negative patients underwent alloHCT in first CR/CRi.Median follow-up was 3.35 years. OS (P = 0.92), RFS (P = 0.99) and CIR (P = 0.98) were similar in MRD positive (at least one MRGM detectable) and negative (no MRGM detectable) patients (Figure 1). OS, RFS and CIR were also similar between MRD positive and negative patients, when MRD negativity was defined by conversion of at least one MRGM to negativity (55 (52.9%) MRD positive, 49 (47.1%) MRD negative), and when ASXL1 was excluded from the analysis. As variants with VAF >5% in CR/CRi samples may indicate clonal hematopoiesis, we excluded all variants with VAF >5% and repeated the analysis with the 88 (84.6%) remaining patients. Again, OS, RFS and CIR were similar for MRD positive and negative patients. We next reasoned that reduction of VAF correlates with the sensitivity of leukemic cells and possibly with depth of remission and long-term outcome. The fold-reduction of VAFs from diagnosis to the time of MRD analysis was calculated for all variants. For patients with several MRGMs, the variant with the largest fold-reduction was considered including undetectable variants. Patients with more or less than a 2-log, 3-log or 4-log reduction (log 10) had similar OS, RFS and CIR, respectively. Evaluating each MRGM individually, only RUNX1-MRD associated with RFS and by trend CIR (comparing MRD positive to negative patients for OS, HR 3.41, 95% CI 0.43-26.82, P = 0.24; RFS, HR 4.37, 95% CI 1.07-17.79, P = 0.04; CIR, HR 3.30, 95% CI 0.79-13.82, P = 0.1). Conclusion: 65.4% of AML-MRGM patients in CR/CRi remained MRD positive when MRGMs were used for MRD assessment by NGS. MRD positivity was associated with age above 60 years and male sex.Using all MRG mutations for MRD assessment at a threshold of 0.01% or by various degrees of log-reduction was not predictive of outcome after intensive induction chemotherapy. This limits the number of potential MRD markers for NGS analysis before alloHCT, although individual markers like RUNX1 may be of prognostic value.

Pivekimab Sunirine (PVEK, IMGN632), a CD123-Targeting Antibody-Drug Conjugate, in Combination with Azacitidine and Venetoclax in Patients with Newly Diagnosed Acute Myeloid Leukemia

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; <0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in > 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, <0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

Impact of KRAS and NRAS mutations on outcomes in acute myeloid leukemia

The prognostic significance of RAS mutations in AML is poorly understood. In this ambispective cohort study of 239 newly-diagnosed AML patients at the University of Maryland, we assessed the median overall survival (mOS) and median event-free survival (mEFS) in RAS wild-type (WT) AML (n = 196), KRAS-mutated AML (n = 11), NRAS-mutated AML (n = 25), and KRAS/NRAS-mutated AML (n = 7). We used propensity score to adjust outcomes. NRAS-mutated AML had a similar response rate to first-line treatment and mOS compared to RAS-WT AML (57 vs. 54%, p = 0.8, 22.7 vs. 14.6 months, p = 0.7). The mOS of KRAS-mutated AML was shorter compared to RAS-WT AML (p = 0.049) and NRAS-mutated AML (p = 0.02). KRAS-mutated AML treated with anthracycline-based first-line regimens had a lower relative mortality compared to treatment with hypomethylating agents with venetoclax (HR <0.01, p = 0.04) and without venetoclax (HR <0.01, p = 0.04). This study demonstrates that KRAS but not NRAS mutations are associated with worse outcomes in AML. NOVELTY STATEMENT What is the new aspect of your work? The clinical significance of RAS mutations remains poorly defined and prior studies have yielded conflicting results. We used causal inferential methods, propensity score modeling, to determine the impact of KRAS and NRAS mutation on survival in newly diagnosed AML patients, independent of other risk factors. Moreover, we analyzed the outcomes of KRAS and NRAS-mutated AML patients receiving first-line therapy with hypomethylating agents and other non-anthracycline-based regimens. We provided a detailed description of RAS-mutated AML, including co-occurring mutations and cytogenetic abnormalities. What is the central finding of your work? KRAS mutations but not NRAS mutations in AML are directly linked to worse outcomes even after controlling for differences in AML type, co-occurring cytogenetic changes, treatment regimens, and comorbidities. KRAS-mutated AML has a higher relative mortality when treated with a hypomethylating agent-based first-line induction regimen compared to treatment with an anthracycline-based regimen. What is (or could be) the specific clinical relevance of your work? Our findings can help refine our genetic profiles of AML, improve prognostic models, and better stratify treatment regimens.

Initial Results from SELECT-AML-1, a Phase 2 Study of Tamibarotene in Combination with Venetoclax and Azacitidine in RARA-Positive Newly Diagnosed AML Patients Ineligible for Standard Induction Chemotherapy

RARA-positive AML is a novel genomically-defined subset with an actionable target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown, Cancer Discovery 2017). Approximately 30% of non-APL AML patients are RARA-positive based on overexpression of the RARA gene in peripheral blood blasts as determined by an RT-PCR based assay (de Botton, ESH 2019). In patients with newly diagnosed (ND) AML ineligible for standard induction chemotherapy, tamibarotene/azacitidine led to a CR/CRi rate of 61% in RARA-positive patients with a rapid onset of response. The combination was well-tolerated with no increase in myelosuppression compared to azacitidine (aza) alone (de Botton, ASH 2020). Responses were observed irrespective of mutations or cytogenetic risk. Approximately one-third of ND AML patients ineligible for standard induction therapy do not respond to venetoclax (ven) and nearly all eventually relapse (DiNardo, NEJM 2020). Translational data suggest that RARA-positive patients are enriched for monocytic features based on a positive Monocytic Expression Score (MES) that may be associated with ven resistance (Fiore, ASH 2020), suggesting that the blood-based RARA biomarker test selects for patients who may respond to tamibarotene and who may also be less likely to respond to ven/aza alone. SELECT-AML-1 (NCT04905407) is a Phase 2, open-label, multi-center study in the US and France comparing the activity of tamibarotene/ven/aza to ven/aza in treatment-naive RARA-positive ND AML patients ineligible for standard induction therapy. The 3-part study includes a safety lead-in of the tamibarotene/ven/aza combination, a randomized efficacy study versus ven/aza, and a salvage arm for ven/aza only patients with primary endpoints of safety, CR/CRi rate, and overall response rate, respectively. Following the safety lead-in, patients will be randomized 1:1 to receive tamibarotene/ven/aza or ven/aza. In the salvage arm, patients randomized to ven/aza only who experience progressive disease, treatment failure, or relapse, will have tamibarotene added to their ven/aza regimen. Patients currently enrolled in the safety lead-in are treated with starting doses of aza at 75 mg/m2 IV/SC daily on Days 1-7, ven on Days 1-28 per the ven USPI/SMPC, followed by tamibarotene at 6 mg twice per day PO on Days 8-28 of each 28-day cycle. Enrollment is ongoing. As of 22 June 2022, six patients have enrolled to date, including four who are response-evaluable. Baseline characteristics of the response-evaluable patients include 75% male; median age 57 (55-74); median bone marrow blasts 55% (39-100%); cytogenetically normal (n=2), inversion 16 (n=1), del 5q and -7 (n=1); and molecular genetic testing normal (n=3), mutations of IDH2, BCOR, SRSF2, CSF3R, RUNX1 (n=1). The MES was high in 3 of 4 (75%) response evaluable patients consistent with a prior report in RARA-positive AML (Fiore, ASH 2020). All 4 response-evaluable patients achieved a best response of CR/CRi (2 CR, 2 CRi). The onset of response was rapid with all patients achieving an initial response after Cycle 1 (2 CR, 1 CRi, 1 MLFS). Median duration of treatment was 68 days (21-110). Two patients discontinued, both in remission, one due to death from neutropenic sepsis and the other by physician decision. The adverse event (AE) profile of the triplet was consistent with reports of ven/aza in AML. AEs experienced by 2 or more patients (all grades/causality) included febrile neutropenia, pneumonia, anxiety, cough, diarrhea, fatigue, decreased appetite, myalgia, decreased neutrophil count, and decreased platelet count. The only serious AE (all causality) occurring in more than one patient was febrile neutropenia. A high response rate was observed in early results of tamibarotene/ven/aza in RARA-positive ND AML patients ineligible for standard induction chemotherapy with 100% (4 of 4) response evaluable patients achieving CR/CRi, 3 of whom may have features of ven-resistance based on high MES. The triplet demonstrated an initial safety profile similar to ven/aza. Data from the safety lead-in will inform triplet dosing for the randomized portion of the study.

Optimizing the Supportive Care of Intensive Chemotherapy in AML : Impact of Vitamin C and D Supplementation in Patients with NPM1 Mutation. a Dataml Registry Study

Background Vitamin (vit) deficiencies are frequently observed in patients (pts) with newly diagnosed AML (ND-AML). A lower level of vit D is associated with a worse prognosis in pts treated with intensive chemotherapy (IC) (Lee HJ, Cancer 2014). Similarly, a pretransplant vit D deficiency is associated with a higher risk of relapse (Radujkovic JCO, 2017). Moreover, preclinical studies demonstrated the antileukemic activity of vit D through the modulation of cell cycle, differenciation and apoptosis even though the clinical translation has not been successful (Cao H, Exp Hematol 2017 ; Paubelle E, Cell Rep 2020). More recent data have highlighted the role of vit C in AML. Vit C is a cofactor and increases the activity of TET2 enzyme, inducing DNA demethylation, stem cell differentiation and antileukemic activity (Agathocleous M, Nature 2017; Cimmino L, Cell 2017). Cases of remission following vit C supplementation have been reported (Foster M, Antioxidants, 2018 ; Das A, Blood Cancer J, 2019) and a small study showed that the addition of vit C to decitabine/AraC/aclarubicin/G-CSF improved outcome compared to DCAG (Zhao H, Leuk Res 2018). Based on these data, we modified our practice by adding vit C and D to the supportive care (SC) of IC. Methods The study population included all pts with ND-AML treated by IC and registered in Toulouse DATAML from 01/2015 to 05/2020. As of March 2018, as part of the SC for AML pts treated by IC and in the absence of contra indication (renal lithiasis, renal insufficiency, G6PD deficiency, hypercalcemia), vit C (1g x 2/d, three times a week ; IV) and vit D (100,000 IU/week ; PO) have been administered from d10 until hematologic recovery of induction and consolidation. The principal objective of this retrospective study was to assess the impact of the vit supplementation on EFS. Secondary objectives were response to induction, early death, OS, RFS, incidence of relapse, vitamin levels during treatment and safety. Results 431 pts were included, 262 without (from 01/2015 to 02/2018 ; control group) and 169 with vit C/D supplementation (03/2018-05/2020 ; vitC/D group). Data were updated on 03/03/2022. The median FU was 45.6 months. Pt characteristics were well balanced except for age, PS and creatinine (Table 1). In the vitC/D group, the median plasma level of vit C was 3.20 mg/L (range, 0.47-15.42) at diagnosis and 4.62 mg/L (range, 0.18-18.1) at time of hematologic recovery from induction (P=0.18). The level of vit D at diagnosis was 16 ng/mL (range, 4-56) and 18 ng/mL (range, 4-42) in the control and vitC/D groups, respectively. Upon recovery from induction, vit D levels significantly increased compared to diagnosis in the vitC/D group (median, 39 ng/ml, range, 5-93 ; P<0.0001). CR/CRi rate was 84.4% (control) and 84% (vitC/D) (P=0.93). Day-30 death rate was 4.2% (control) and 2.4% (vitC/D) (P=0.31). During induction, the rates of grade 3-4 bacterial infections (vitC/D, 27.2% vs control, 35.1%, P=0.086), fungal infections (10.1 vs 18.3%, P=0.019), hemorrhages (1.8 vs 5.7%, P=0.045) or macrophage activation syndrome (1.8 vs 8.8%, P=0.002) were lower in the vitC/D group. Median level of day-21 calcemia was higher in the vitC/D group (2.48 mmol/L vs 2.44, P=0.003). Grade 2 hypercalcemia was observed in only 1 patient of the control group. Allo-SCT was performed in 37 (26.1%) and 75 (33.9%) pts of the vitC/D and control groups, respectively. Median pretransplant vit D levels were significantly higher in the vitC/D group (33 vs 19 ng/mL, P<0.0001). There was no significant difference in EFS (vitC/D, median 13.9 vs 17.4 months, P=0.26), RFS (15.5 vs 23.5, P=0.24) and OS (30.8 vs 34.5, P=0.80) between both groups. However, multivariate analysis for OS showed a significant interaction between vitC/D and NPM1 mutation meaning that vitC/D supplementation was significantly and independently associated with better OS in pts with NPM1 mutations (HR, 0.52 ; 95%CI: 0.30-0.90, P=0.019) but not in NPM1 wildtype pts (HR, 1.01 ; 95%CI: 0.68-1.51, P=0.95). MV analysis for EFS, RFS and CIR did not find any significant interactions. Conclusion Vit C and D supplementation is feasible and safe in AML pts during IC. Normal Vit D levels can be restored before transplant, which may be important. The potential impact of vit C/D supplementation in AML with NPM1 mutations needs further studies and pave the way for exploratory analyses to explain how the VDR pathway and/or vit C activity may interact with the biology of NPM1 mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns and Transfusion Burden Among Newly Diagnosed Older Adults with Acute Myeloid Leukemia

Background: The approval of Venetoclax (VEN; a BCL-2 inhibitor) has changed the treatment paradigm for older/unfit newly-diagnosed AML patients (ND AML) and improved outcomes in the landmark randomized phase 3 clinical trial, VIALE-A. However, real world evidence of population-level clinical benefit is still limited, especially on the impact of transfusion burden and achievement of transfusion independence (TI). Repeated transfusions are associated with significant risks and costs and impair quality of life for patients. This study examined real-world treatment patterns and clinical outcomes focusing on transfusion independence in a contemporary cohort of Medicare beneficiaries with newly diagnosed AML. Methods: This cohort study examined newly diagnosed Medicare beneficiaries (age ≥65 years) with AML using claims from the Centers for Medicare & Medicaid Services, representing 100% of Medicare fee-for-service beneficiaries. The identification period was July 2016-June 2020, with an observational period from January 2016 to December 2020. The first active AML treatment identified in the data was categorized into four different treatment categories; 1) Venetoclax combination (VEN; Venetoclax in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC)), 2) low-intensity treatment (LOW; HMA monotherapy or LDAC), 3) high-intensity chemotherapy (HIGH; patients with an inpatient stay lasting ≥22 days or ≥7 days where a non-specific antineoplastic treatment or cytotoxic chemotherapy was documented), and 4) other targeted therapies (OTHER; ivosidenib, glasdegib, gilteritinib, enasidenib, midostaurin, gemtuzumab ozogamicin). Patients who received any AML therapy prior to the index date except for treatments for myelodysplastic syndromes (e.g., HMAs and lenalidomide) were excluded. Transfusion independence (TI) was defined as a rolling period of no red blood cell (RBC) or platelet (PLT) transfusions for a consecutive 56-days. Results: We identified 5,855 ND AML Medicare beneficiaries, with 734 patients who met eligibility criteria and were categorized as VEN, 2,562 patients as LOW, 1,318 patients as HIGH, and 146 patients as OTHER. The median follow-up duration was 8 months and the median age at diagnosis was 76 years old in all patients. Patients had a mean Charlson Comorbidity Index score of 3, including common comorbidities: 23.4% with congestive heart failure and 27.6% with chronic pulmonary disease. The VEN cohort initiated their first line (1L) treatment on an average of 30 days from their diagnosis. Median duration of 1L therapy was 4.8 months (IQR: 1.9-6.6) in the VEN cohort, 3.1 months (IQR: 1.1-8.1) for the LOW cohort, 1.7 months (IQR: 0.9-1.8) for the HIGH cohort, and 2.1 months (IQR: 1.0-6.1) in the OTHER cohort. The mean daily dose in the VEN cohort over the 1L treatment period was 287 mg (median: 332). 15.4% of VEN patients had overlapping hospitalizations, indicating that patients may initiate Venetoclax at inpatient setting. Within 56-days prior to treatment initiation, 86.4% of VEN cohort had PLT-TI and 54.5% had RBC-TI, and similar proportions of TI were observed in other treatment groups. When evaluating the transfusion status every 56-days on a rolling weekly basis (Figures 1 & 2): a trend of decreased proportion of TI were observed from 56-days prior to the treatment initiation across treatment groups. By weeks 0-7 post-treatment initiation, 49.5% in VEN cohort achieved TI in PLT and 18.0% in RBC, which was lower than the LOW cohort (58.2% were TI in PLT vs. 29.4% in RBC). However, there was an apparent increasing trend of TI rate in both RBC and PLT since the first week after the patients initiating VEN, while the TI rate only slightly increased over time since the treatment initiation in the other treatment group. At weeks 8-15, a higher proportion of patients achieved TI in PLT and RBC in the VEN cohort, compared with the other treatment groups (PLT-TI: 74.2% in VEN, 70.1% in LOW, 40.0% in HIGH, and 57.6% in OTHER; RBC-TI: 52.2% in VEN, 41.9% in LOW, 35.6% in HIGH, and 41.3% in OTHER). At week 12-19, 62.1% in VEN achieved RBC-TI, versus 47.7% in LOW, 44.2% in HIGH, and 48.1% in OTHER. Conclusions: In the Medicare elderly population, ND AML patients treated with VEN had a longer median duration of therapy compared with other treatment groups. A larger proportion of VEN patients were able to achieve transfusion independence over time compared to the other treatment groups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Molecular Characterization of Clinical Response and Relapse in Patients with IDH1m ND-AML Treated with Ivo+AZA in the AGILE Study

Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in approximately 6-10% of patients (pts) with AML. Ivosidenib (IVO), a potent, oral, targeted inhibitor of mIDH1, is FDA approved as monotherapy for the treatment of relapsed/refractory AML and newly-diagnosed AML (ND-AML) in adults >75 years of age or with comorbidities that preclude the use of intensive chemotherapy. In addition, the combination of IVO with azacitidine (AZA) was recently FDA approved in older or unfit AML pts with mIDH1 as a result of the global Phase 3 AGILE trial (NCT03173248). Compared to placebo (PBO) + AZA, the combination of IVO + AZA extended event-free survival (EFS; hazard ratio 0.33, 95% CI [0.16 - 0.69]; P = 0.002), overall survival (OS; median 24.0 months vs. 7.9 months; hazard ratio 0.44; 95% CI [0.27 - 0.73]; P = 0.001), and increased the rates of complete remission or complete remission with partial hematologic recovery (CR/CRh; 52.8% vs. 17.6%). To date, biomarker analysis has shown that IVO+AZA is associated with deep and durable clearance of IDH1m clones with improved clinical responses and EFS/OS in several pt subgroups, including those with mutations in receptor tyrosine kinase (RTK) pathway genes, a subgroup refractory to IVO monotherapy. Aim: To characterize clonal evolution and relapse mechanisms in pts with mIDH1 ND-AML treated with IVO+AZA. Methods: Patients received oral IVO + AZA per study protocol. Next-generation DNA sequencing (DNA-seq) on baseline and longitudinal samples was performed on bone marrow aspirates (BMA), bone marrow mononuclear cells (BMMCs), or peripheral blood mononuclear cells (PBMCs) depending on sample availability using the ACE Extended Cancer Panel (Personalis, Inc); limit of detection (LOD) 2% variant allele frequency (VAF). This analysis was focused on variants in 95 AML-associated genes with known or likely oncogenic potential. Results: Among 72 pts enrolled on the IVO+AZA arm, 46 had both baseline and longitudinal DNA-seq data available, with a median follow-up of 366 days on study (range 16 - 1210). The median number of baseline mutations was 3 (range 1 - 10). Suppression of all baseline non-DTA (DNMT3A / TET2 / ASXL1) mutations to below the LOD ("mutation clearance") was observed in 28 patients, including 22/34 (65%) pts who achieved CR/CRh [Table 1]. To identify potential mechanisms of acquired resistance, on-treatment samples were analyzed for the emergence of mutations not detected at baseline. Overall, emerging mutations were identified in 22/46 (48%) pts (median 2 emerging mutations; range 1-6). 2/46 (4%) pts had emerging mutations in IDH2, but discontinued treatment due to adverse events and stable disease, respectively. No second-site IDH1 mutations were observed across any response category. Longitudinal samples were available for 8/10 (80%) pts who discontinued treatment due to relapse (RL) following an objective response (4 CR, 2 CRh, 1 CRi, 1 MLFS). Emerging mutations were detected in 6/8 (75%) of RL pts [Table 2]. Genes with emerging mutations recurrently associated with RL included ASXL1, FLT3, RUNX1, and TET2 (2 pts each). The IDH1 mutation was not detected at RL in 6/8 (75%) pts. Among the two RLs that occurred in the absence of emerging mutations, one was associated with expansion of a baseline FLT3-ITD subclone, and one was not associated with any new emerging or expanding mutations. To further evaluate clonal evolution and disease progression of these pts, scDNA-seq is being performed and will be presented. Conclusion: IVO+AZA combination therapy leads to deep and durable remissions associated with clearance of mIDH1 and baseline co-mutations. To date, no second-site IDH1 mutations have been observed, but mutations in other genes, including IDH2, can emerge and may provide an opportunity for relapse. Relapses were observed in a subset of responders and were generally associated with expansion or emergence of high-risk mutations occurring independently of mIDH1. Further study is needed to better characterize mechanisms of RL to IVO+AZA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Impact of Clonal Hierarchy of Myelodysplasia-Related Gene Mutations in AML Patients

Introduction: The 2022 ICC classification identifies mutations in nine genes that classify AML with myelodysplasia-related gene mutations (AML-MRG). AML-MRG is associated with an unfavourable prognosis according to the 2022 ELN classification. However, it is unknown whether the clonal hierarchy of those mutations impacts prognosis. Methods: 485 adult newly-diagnosed AML patients (median age 54) with available genetic and follow-up data were included. Mutations present at diagnosis were identified by Illumina myeloid panel sequencing covering 56 AML-associated genes. Patients received standard induction and consolidation chemotherapy or underwent allogeneic hematopoietic cell transplantation (alloHCT). MRG mutations were classified as subclonal if their variant allele frequency (VAF) was ≥ 10% below the mutation with the highest VAF of other co-occuring mutations. Otherwise, MRG mutations were considered part of the dominant clone. Results: 177 (36.5%) patients carried at least one of the nine MRG mutations ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2. The MRG mutation was found in the dominant clone in 134 (75.7%) and in a subclone in 43 patients (24.3%). BCOR, RUNX1, SRSF2, STAG2 and U2AF1 were more likely found in the dominant clone, whereas ASXL1, EZH2, SF3B1 and ZRSR2 were more often found in a subclone. Patients with MRG mutations in the dominant as well as a subclone were significantly older than patients without MRG mutations (p < 0.001 and p = 0.03, respectively). Patients with MRG mutations in the dominant or a subclone and patients without MRG mutations achieved CR/CRi in 80.6%, 83.7% and 87.3%, respectively (p = n.s.). In line with the ELN classification, patients with MRG mutations in the dominant clone had a worse OS than patients without MRG mutations (p = 0.004, HR = 1.505, 95%CI 1.136-1.995); however, patients with MRG mutations in a subclone had a similar OS compared to patients with MRG mutations in the dominant clone and to patients without MRG mutations (Figure 1A). TP53 mutations with ≥10% VAF are defined as AML with mutated TP53 by ICC 2022. 39 (8%) patients carried a TP53 mutation. One third of the cases had a subclonal TP53 mutation. Median TP53 VAF was 39.6% and 15.5% in patients with dominant or subclonal TP53 mutation (p < 0.001). OS was significantly worse in patients with dominant TP53 mutation compared to TP53 wildtype patients (p = 0.002, HR = 2.047, 95%CI 1.276-3.284), whereas OS was similar in patients with subclonal TP53 mutation compared to TP53 wildtype patients (Figure 1B). Conclusion: In our study, 76% of MRG mutations occur in the dominant clone in newly diagnosed AML patients. Dominant MRG mutations have a worse prognosis compared to patients without MRG mutations, while prognosis of subclonal MRG mutations should be evaluated in larger cohorts. AML patients with subclonal TP53 mutation have a similar outcome to patients without TP53 mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-256 A Phase 1 Study of Gilteritinib in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Final Study Results

Gilteritinib, an oral FLT3 inhibitor, demonstrated antileukemic responses in patients with FLT3mut+ relapsed/refractory AML. Present final data from a phase 1 study of once-daily gilteritinib plus intensive chemotherapy in newly diagnosed (ND) AML. This 4-part, open-label study (NCT02236013) assessed gilteritinib dose/schedule and effects of alternative anthracycline treatment. Gilteritinib plus 7+3 induction with idarubicin or daunorubicin, plus ≤3 cycles of high-dose cytarabine and gilteritinib consolidation, and 2 years of single-agent gilteritinib maintenance treatment post consolidation or transplant. Adults with ND AML; FLT3 mutation not required for enrollment (known core binding factor fusions excluded). Safety, tolerability, PK, antileukemic effects. Eighty patients were allocated to gilteritinib (safety analysis set, n=78 [age 23-77 y]; FLT3mut+, n=44 [FLT3-ITD, n=33]). Median follow-up was 37.7 months. On-study HSCT was performed in 27/80 (33.8%) patients (FLT3mut+, 26/44 [59.1%]). Dose-limiting toxicities occurred in 15/78 (19.2%) patients (200-mg/d cohort: neutropenia, n=1; neutropenic colitis, n=1). Maximum tolerated dose was 120 mg/d. Across the study, AEs led to gilteritinib discontinuation in 24.4% of patients. At end-of-treatment, composite complete remission (CRc: complete remission [CR] + CR with incomplete hematologic recovery [CRi] + CR with incomplete platelet recovery [CRp]), CR, CRi, and CRp rates were 79.7%, 54.4%, 21.5%, and 3.8%, respectively, in the overall population and 90.9%, 70.5%, 13.6%, and 6.8% among FLT3mut+ patients. In the overall (n=79) and FLT3mut+ populations (n=44), 60-day mortality rates were 1.3% and 0%, respectively, and median (95% CI) disease-free survival was 15.1 (9.5, 31.9) and 15.1 (4.9, 31.9) months. In the overall (n=69) and FLT3mut+ populations (n=41) receiving ≥80 mg/d, median (95% CI) OS was 38.6 (21.7, NE) and 45.9 (30.8, NE) months, respectively, and the estimated 3-year OS rate was 56.0% and 60.1%. Anthracycline choice did not substantially impact CRc rate or toxicity. In patients who achieved CRc with gilteritinib ≥120 mg/d, mutational clearance of FLT3-ITD (summed FLT3 ITD:wildtype signal ratio ≤10-4) after consolidation was 84.6% (11/13). Gilteritinib plus induction and consolidation chemotherapy was well tolerated and resulted in CR, FLT3-ITD clearance, and long-term survival in patients with ND FLT3mut+ AML, supporting ongoing randomized trials testing this approach against current standards.

AML-440 Prognosis of Molecularly-Defined Secondary Acute Myeloid Leukemia Patients

Mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 were proposed as secondary AML (sAML) defining mutations independent from the patients' history. We evaluated the prognostic impact of molecularly-defined sAML (msAML) patients in the context of the European LeukemiaNet (ELN) risk categories. 459 adult newly-diagnosed AML patients (median age 54) with available genetic and follow-up data were included. Patients received standard induction and consolidation chemotherapy or underwent allogeneic hematopoietic cell transplantation (alloHCT). Patients were classified as de-novo AML (dnAML), msAML carrying ≥ 1 sAML-defining mutations, and clinically-defined secondary AML (csAML) based on previous medical history and cytogenetics. 208 (45%) patients had dnAML, 155 (34%) msAML, and 96 (21%) csAML. 62 msAML patients overlapped with csAML. Of msAML patients, 104 (67%) had 1, 39 (25%) 2, and 12 (8%) 3 or more msAML-defining mutations. The most frequently mutated msAML-defining genes were ASXL1 (n=48, 31%) and SRSF2 (n=44, 28%). The likelihood to reach complete remission (CR) was higher for dnAML compared to msAML patients (92% vs 79%, P =.003), but there was no difference between csAML and msAML patients. The median follow-up of all patients was 5.56 years. The transplantation rate in first CR was similar in dnAML, msAML and csAML patients (33%, 37%, 44%, respectively). Overall survival (OS) was significantly worse in msAML compared to dnAML patients (median OS 3.3 years vs not reached, HR = 1.7, 95%CI 1.2-2.2, P<.001), also when ASXL1 mutated patients were excluded (HR = 1.7, 95%CI 1.2-2.4, P<.001). OS was similar in csAML vs dnAML and in msAML vs csAML patients. In the ELN favorable and intermediate risk groups msAML patients (n=19 and n=52) had a significantly worse OS compared to dnAML patients (n=66 and n=80) (HR=3.1 95%CI 1.5-6.3, P=.001 and HR=2, 95%CI 1.2-3.2, P=.008, respectively). OS was similar in the ELN adverse risk group between msAML (n=79) and dnAML patients (n=31). Accordingly, the ELN risk groups did not stratify OS in msAML patients. msAML-defining mutations identify a subgroup of dnAML patients with poor prognosis and reclassify 10% of all patients in our cohort from favorable/intermediate to the adverse risk group.

P534: AZACITIDINE PLUS VENETOCLAX FOR THE TREATMENT OF RELAPSED AND FIRST-LINE AML PATIENTS

Background: Venetoclax (VEN) belongs to a novel BH3-mimetic class of small molecules that selectively targets BCL-2, activating the apoptosis effectors BAX and BAK to drive mitochondrial outer membrane permeabilization, cytochrome c release and cell death. Combination of VEN and the hypomethylating agent azacitidine (AZA) has deeply changed the paradigm of treatment of newly diagnosed (ND) AML patients ineligible for high dose chemotherapy because of older age or comorbidities. There is scarce evidence for the utilization of VEN-AZA for relapsed or refractory (R/R) AML, a category of patients classically associated with an extremely poor outcome. Aims: The objective of our study was to describe a R/R AML cohorts of AML patients treated with VEN-AZA in our institution and to compare the clinical and molecular characteristics predicting response in R/R AML versus ND AML Methods: This retrospective study included consecutive patients treated with VEN-AZA for R/R AML and ND AML. Patients received AZA at standard dose of 75 mg/m2 QD for seven days and VEN was administrated either at 400 mg or at 100 mg when associated with strong CYP3P450 A3 inhibitors after three days ramp up. Response was determined using the ELN 2017 criteria. The ORR was defined as the combination of complete response (CR), CR with incomplete hematologic recovery (CRi), and morphologic leukemia-free state (MLFS). Results: We compared the outcome of 39 R/R AML and 38 concomitant ND AML patients treated in our institution between Jan. 2020 and Dec. 2021. The median age was 69 (22-86) and 73 (61-81) in the R/R and ND groups, respectively. Thirty-five percent of patients had MRC-AML. Adverse cytogenetics was found in 36% of patients in the R/R group and 59% of patients in the ND group. Most frequent mutations were ASXL1, RUNX1, TET2, IDH1/2 and TP53 found in 33%, 33%, 28%, 24% and 22% of patients, respectively. Overall response rate was lower in R/R AML (37% versus 56%) including 13% CR, 8% CRi, 3% PR and 13% MLFS in the R/R AML group and 32% CR, 13% CRi and 13% MLFS in the ND AML group. Adverse cytogenetics was associated with treatment failure only in the R/R group (Relative Risk=0.10, p=0.005). ASXL1, IDH1/2 and SFSR2 mutations were associated with a trend in a higher response rate in the R/R group. Median overall survival (OS) were 5.9 months in the R/R group and 9.4 months in the ND group. In the R/R group, median OS were 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group (p=0.02). Median leukemia-free survival of responding patient was not different between the two groups (9 months), indicating that VEN-AZA can be efficient as a salvage treatment for selected R/R AML patients. Summary/Conclusion: We described one of the largest series of R/R AML patients treated wiht VEN-AZA. By a doing a direct comparison between R/R AML and ND AML treated concomitantly, we found that adverse cytogenetics was associated with treatment failure only in the R/R group suggesting that this subgroup of patients should not be treated with VEN-AZA. Further analyses including more patients are needed to determine which subgroup may benefit from the VEN-AZA as a salvage treatment.

P492: TAMIBAROTENE IN COMBINATION WITH VENETOCLAX AND AZACITIDINE IN PREVIOUSLY UNTREATED ADULT PATIENTS SELECTED FOR RARA-POSITIVE AML WHO ARE INELIGIBLE FOR STANDARD INDUCTION THERAPY (SELECT AML-1)

Background: RARA-positive (RARA+) AML is a novel genomically defined patient subset with an actionable biological target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown 2017). RARA+ patients can be selected by a blood-based biomarker test, with approximately 30% of newly diagnosed (ND) AML patients being RARA+ (Vigil 2017). As a biologically targeted agent for patients with RARA overexpression, tamibarotene has the potential to provide benefit irrespective of mutation or cytogenetic risk classification. In RARA+ ND AML patients ineligible for standard induction therapy, tamibarotene plus azacitidine (aza) led to a CR/CRi rate of 61% and a rapid onset of response (de Botton 2020). Approximately one-third of patients with ND unfit AML do not respond to front-line standard of care venetoclax (ven)/aza (DiNardo 2020). Translational data suggest RARA positivity enriches for monocytic features reported to be associated with ven resistance (Fiore 2020, Pei 2020). This data suggests the RARA biomarker selects for patients who may respond to tamibarotene and may be less likely to respond to ven/aza. Given that tamibarotene plus aza has been generally well tolerated, with no increase in myelosuppression compared to single agent aza (de Botton 2020), it is anticipated that tamibarotene can be administered safely in combination with ven/aza. Aims: This is a Phase 2, open-label, multi-center study in the U.S. and France comparing the clinical activity of tamibarotene/ven/aza to ven/aza in treatment-naive RARA+ AML patients ineligible for standard induction chemotherapy. The primary objectives are to characterize the safety of the combination and to compare the CR/CRi rate of tamibarotene/ven/aza vs. ven/aza, with secondary objectives to compare CR rate, CR/CRh rate, duration of response, and time to response. The overall response rate using tamibarotene/ven/aza following ven/aza treatment failure will be explored. Clinical activity will be characterized by ELN criteria (Dohner 2017). Methods: This 3-part trial includes a safety lead-in, randomized efficacy study, and salvage arm. Following the safety lead-in, approximately 80 patients will be randomized 1:1 to receive tamibarotene/ven/aza or ven/aza. In the salvage arm, tamibarotene will be added for study patients randomized to ven/aza who experience progressive disease, relapse, or treatment failure. Patients will be treated with aza at 75 mg/m2 IV/SC daily on days 1-7, ven on days 1-28 per VENCLEXA USPI, followed by tamibarotene at 6 mg twice per day by mouth on days 8-28 of each 28-day cycle. Results: Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. Summary/Conclusion: The SELECT AML-1 trial (NCT04905407) opened in July 2021 with ongoing enrollment.