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Supplementary Table from Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine

Supplementary Figure from Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine

Not available.

PURPOSE There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10–3 in the VIALE-A trial. METHODS The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10–3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS. RESULTS One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10–3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10–3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10–3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10–3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10–3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001). CONCLUSION Patients who achieved CRc and MRD < 10–3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10–3.

BACKGROUND: IDH2 mutations occur in 8-19% of patients (pts) with AML. ENA is an oral, selective IDH2 inhibitor and AZA is a hypomethylating agent. In a phase 1b/2 trial, combination therapy with ENA + SC AZA significantly improved overall response rate (ORR) and complete remission (CR) rate vs AZA monotherapy (AZA-only) (P = 0.0064 and P = 0.0001, respectively) in pts with newly diagnosed (ND), mutant-IDH2 (m IDH2) AML not eligible for IC (DiNardo, 2020). Injectable AZA has shown to maintain pt-reported health-related quality of life (HRQoL) in ND-AML (Dombret, 2014); the effect of ENA on HRQoL has not been reported. While morphologic responses are associated with improved HRQoL, combining active agents could increase toxicity, which could diminish HRQoL. OBJECTIVE: Assess pt-reported HRQoL outcomes during treatment (Tx) with ENA + AZA and AZA-only in the phase 1b/2 AG-221-AML-005 trial (NCT02677922). METHODS: Adult pts with ECOG PS ≤ 2 and intermediate- or poor-risk cytogenetics were enrolled. In the phase 2 portion, pts were randomized 2:1 to ENA 100-mg QD (continuous) + AZA 75 mg/m 2/day (d) SC × 7d, or to AZA-only, in repeated 28d cycles (C). Pt-reported HRQoL was assessed during Tx using the EORTC QLQ-C30 and EQ-5D-5L instruments, each completed at baseline (BL [C1D1]), on d1 of each Tx cycle, and end of Tx (EOT). The primary HRQoL measures were observed mean changes from BL (CFB) in 5 QLQ-C30 domains-Global Health status (GHS)/QoL, Physical Functioning (PF), Role Functioning (RF), Fatigue, and Dyspnea-each scored from 0-100, with higher scores indicating better QoL or functioning but worse symptomology. Changes in the remaining 10 QLQ-C30 domains, and in the EQ-5D-5L utility index (UI) score (derived via cross-walk to EQ-5D-3L based on UK population weights) and EQ-5D visual analogue scale (VAS) score (0-100) were secondary outcomes. Changes are reported for Tx cycles with ≥ 10 evaluable pts in each Tx arm. Clinically meaningful changes were defined as mean CFB of ≥ 10 points on any QLQ-C30 domain, ≥ 0.08 point on the EQ-5D-5L UI, and ≥ 7 points on the EQ-5D VAS. HRQoL-evaluable pts had an evaluable assessment (≥ 15 items on the QLQ-C30; all 5 EQ-5D-5L items; non-missing EQ-5D VAS) at BL and at ≥ 1 post-BL visit. RESULTS: The HRQoL-evaluable population comprised ~75% of pts randomized to either ENA+AZA (51/68) or AZA-only (25/33); 25 pts were not evaluable due to missing data at BL (n = 16) and/or no post-BL visit (n = 19). QLQ-C30 data were missing for ~20%-30% of eligible pts at almost all post-BL visits through C9D1 (the last visit with ≥ 10 pts in each Tx arm), and for ≥ 50% of pts at the EOT visit; similar rates were observed on the EQ-5D-5L. BL characteristics for HRQoL-evaluable pts were generally comparable between arms and similar to those of the ITT population. At BL, mean QLQ-C30 scores in each Tx arm were meaningfully worse than general population normative scores across the majority of QLQ-C30 domains, including all 5 domains of primary interest, and on the EQ-5D VAS. During early ENA+AZA Tx cycles, observed mean QLQ-C30 scores remained similar to BL in the GHS/QoL and Dyspnea domains, and were worsened from BL in the PF, RF, and Fatigue domains-but reached the threshold for meaningful worsening only in the RF domain and only at C3D1 (Figure). Domain scores then trended toward improvement over time, with clinically meaningful improvements from BL from C4-C9 in the Dyspnea domain, C5-C9 in the GHS/QoL and Fatigue domains (except at C7 for Fatigue), and from C8-C9 in the RF domain; mean scores also improved from BL in the PF domain but were not clinically meaningful at any visit. Similar trends were observed in the AZA-only arm but without the early worsening seen with ENA+AZA (Figure). There were no clinically meaningful or statistically significant differences between Tx arms in mean CFB for any of the primary QLQ-C30 domains through C9. In both Tx arms, mean score CFB in the secondary QLQ-C30 domains, EQ-5D-5L UI, and EQ-5D VAS followed similar trends of improvement over time among pts who remained on Tx. CONCLUSIONS: At BL, these pts with AML reported meaningfully worse HRQoL scores across the majority of the QLQ-C30 domains and the EQ-5D VAS compared with the general population, indicating substantial impairment in HRQoL, functioning, and symptoms. HRQoL scores generally worsened during early ENA+AZA Tx cycles, but then improved with continued Tx, with meaningful improvement across multiple measures during later Tx cycles. Figure 1 Figure 1. Disclosures DiNardo: Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding. Dohner: Pfizer: Research Funding; Roche: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; GEMoaB: Honoraria; Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; Berlin-Chemie: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Abbvie: Honoraria, Research Funding. Zeidan: Agios: Consultancy; AstraZeneca: Consultancy; BioCryst: Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Genentech: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Incyte: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Pfizer: Other: Travel support, Research Funding; Amgen: Consultancy, Research Funding; Ionis: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Astellas: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; Acceleron: Consultancy, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Boehringer Ingelheim: Consultancy, Research Funding; Aprea: Consultancy, Research Funding; Jasper: Consultancy; Epizyme: Consultancy; Jazz: Consultancy; ADC Therapeutics: Research Funding; BeyondSpring: Consultancy; Astex: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Schuh: Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Research Funding; Kite/Gilead: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vyas: Gilead: Honoraria; Jazz: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria; Janssen: Honoraria; AbbVie: Consultancy, Honoraria. Stein: Janssen Pharmaceuticals: Consultancy; Abbvie: Consultancy; Gilead Sciences, Inc.: Consultancy; Blueprint Medicines: Consultancy; Foghorn Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Genentech: Consultancy; Syndax Pharmaceuticals: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Astellas: Consultancy; Novartis: Consultancy. Wei: Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Servier: Consultancy. de Botton: Celgene: Consultancy; Agios: Consultancy, Honoraria; Forma: Consultancy, Honoraria; Astellas: Consultancy; Abbvie: Consultancy; Daiichi: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy. Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lord-Bessen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Martin-Regueira: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lersch: Celgene, a Bristol-Myers Squibb Company: Current Employment. Gong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Guo: Bristol Myers Squibb: Consultancy; Daiichi Sankyo: Consultancy; UCB: Consultancy; Janssen: Consultancy; Gilead: Consultancy; EMD Serono: Consultancy; Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Montesinos: Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Enasidenib; Conventional care Enasidenib; Atenció convencional Enasidenib; Atención convencional This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P

Background: LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 dose escalation study of oral LY3410738 in patients (pts) with R/R IDH1/2m hematologic cancers. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in IDH1/2m R/R AML (NCT04603001). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 114 pts including 108 R/R AML pts received LY3410738 dosed at 5-600 mg QD or 40-300 mg BID. Pts were median 73 years of age (range, 22-92) with a median of 2 prior therapies (range, 1-10); 29% received a prior IDH inhibitor and 58% a prior BCL2 inhibitor. Median time on treatment was 2.3 months (range, 0.1-15). No DLTs or treatment related deaths were observed. Treatment emergent adverse events ≥20% were diarrhea (22%), fatigue (21%), and anemia (20%). Differentiation syndrome was reported in 11 pts (10%); 4 grade 1/2 (4%), 7 grade 3 (6%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Responses were observed in both IDH1m and IDH2m AML (Table). Higher doses were required for IDH2m AML, especially IDH2 R140m pts. Efficacy appears higher in venetoclax naïve pts and limited in IDH inhibitor pre-treated pts. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1m R132, IDH2m R172, and IDH2m R140 mutations. Preliminary efficacy was also seen in all genotypes, in a dose dependent manner. RP2D evaluation is ongoing. Table: Response in R/R AML IDH Inhibitor Naive (N=68) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=13) Prior Venetoclax (n=19) Total (N=32) Low Dosesa (n=5) (High Dosesb) Total (N=13) Low Dosesa (n=9) (High Dosesb) Total (N=23) No prior Venetoclax (n=3) Prior Venetoclax (n=5) No prior Venetoclax (n=6) Prior Venetoclax (n=8) CR+CRh, n (%) 5 (38%) 2 (11%) 7 (22%) - 3 (100%) 2 (40%) 5 (38%) - 2 (33%) - 2 (9%) CR, n (%) 3 (23%) 2 (11%) 5 (16%) - 2 (67%) 2 (40%) 4 (31%) - 2 (33%) - 2 (9%) CRh, n (%) 2 (15%) - 2 (6%) - 1 (33%) - 1 (8%) - - - - CRc (CR+CRh+CRi/CRp), n (%) 6 (46%) 6 (32%) 12 (38%) - 3 (100%) 3 (60%) 6 (46%) - 2 (33%) - 2 (9%) MFLS, n (%) 1 (8%) 3 (16%) 4 (13%) 2 (40%) - - 2 (15%) 1 (11%) - - 1 (4%) IDH Inhibitor Pre-Treated (N=33) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=2) Prior Venetoclax (n=8) Total (N=10) Low Dosesa (n=6) (High Dosesb) Total (N=8) Low Dosesa (n=4) (High Dosesb) Total (N=15) No prior Venetoclax (n=1) Prior Venetoclax (n=1) No prior Venetoclax (n=3) Prior Venetoclax (n=8) CR+CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CR, n (%) - - - - - - - - - - - CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CRc (CR+CRh+CRi/CRp), n (%) - - - - - - - 1 (25%) - 1 (13%) 1 (7%) MLFS, n (%) - - - - - - - - - - - Among the 108 treated R/R AML pts, 101 were efficacy evaluable (42 IDH1 R132, 21 IDH2 R172, 38 IDH2 R140); 68 pts were IDH inhibitor naïve and 33 had received a prior IDH inhibitor treatment. Efficacy evaluable pts are those who had completed the first bone marrow assessment or had discontinued treatment prior to first bone marrow assessment aTotal daily low doses: ≤75 mg Arm A, ≤30 mg Arm B bTotal daily high doses: ≥150 mg Arm A, ≥60 mg Arm B Arm A: not requiring a strong CYP3A4 inhibitor Arm B: requiring a strong CYP3A4 inhibitor Citation Format: Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Maël Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, Eytan M. Stein. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT026.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt. Patients and Methods: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m2 days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally. Results: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18). For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt. For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively. For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients. Conclusions: In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD− status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD− during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients’ MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.

The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol. Methods: a single centre retrospective review of Ph+ve ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008&ndash, 2019 with imatinib plus modified DFCI protocol was conducted. Results: of the 123 patients included, 30 (24.3%) had at least 1 radiology confirmed VTE event from diagnosis to the end of maintenance therapy. 86.7% (26/30) of the VTE events occurred during active treatment. Of all VTE events, the majority (53.3%) were DVT and/or PE while another significant portion were catheter-related (40.0%). Major bleeding was observed in 1 patient on VTE treatment with low molecular weight heparin (LMWH). Conclusion: a high VTE incidence (24.3%) was observed in adults Ph+ve ALL patients treated with imatinib plus an ASNase-free modified DFCI pediatric ALL protocol, suggesting prophylactic anticoagulation should be considered for all adult Ph+ve ALL patients including those treated with ASNase-free regimens.

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

The ultimate goal of treatment for acute myeloid leukemia (AML) is to improve survival, and the best means of doing so is through the induction of morphologic remission, which is historically most reliably achieved with intensive chemotherapy regimens. Older patients with AML are less likely to be candidates for or to benefit from intensive chemotherapy. Patients deemed ineligible for intensive therapy may nevertheless benefit from lower-intensity therapies and from newly available targeted AML treatments. Recently approved lower-intensity treatments for AML include enasidenib, ivosidenib, glasdegib, venetoclax, midostaurin, and gilteritinib, and additional promising agents are in later stages of clinical development. Noncytotoxic agents may result in slower kinetics of therapeutic activity compared to intensive regimens, and although they are generally better tolerated than intensive chemotherapy, bone marrow responses are less frequent and may take longer to achieve. Notably, newer therapies might have been considered ineffective had they been judged solely by 2003 International Working Group response criteria for AML, which were based on experience with intensive regimens in predominantly younger patients. Lower-intensity therapies may require several treatment cycles to induce responses, and failure to achieve rapid morphologic remission may not signal the need for treatment cessation or transition to alternative therapies. Additionally, even in the absence of a conventional complete remission, lower-intensity therapies may provide meaningful clinical benefit, including improved survival and quality of life, by inducing hematologic improvement and transfusion independence. Reviewed here are the mechanisms of activity and response kinetics of lower-intensity AML therapies, as well as the clinical benefits resulting from nontraditional AML responses.

Background: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a disease exhibiting a dynamic mutational landscape over time. Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with AML. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory (R/R) AML and newly diagnosed (ND) AML in adults ≥ 75 years (yrs) of age or with comorbidities precluding intensive induction chemotherapy (IC). In an ongoing phase 1b study (NCT02677922), 23 pts (11 male; median age 76 yrs [range 61-88]) with mIDH1 ND AML received IVO 500 mg daily and subcutaneous azacitidine (AZA) 75 mg/m2 on Days 1-7 in 28-day cycles. As of 19Feb2019, median number of treatment cycles was 15 (range 1-30); 10 pts remained on treatment. Overall response rate (complete remission [CR] + CRi [incomplete neutrophil recovery] + CRp [incomplete platelet recovery] + morphologic leukemia-free state [MLFS]) was 78% (18/23): including CR in 61% (14/23) and CR with partial hematologic recovery (CRh) in 9% (2/23). mIDH1 clearance assessed in bone marrow mononuclear cells (BMMCs) by BEAMing digital PCR (detection limit 0.02-0.04%) was observed in 11/16 pts (69%) with CR/CRh, including 10/14 (71%) with CR. Aim: Characterize clonal evolution and resistance in pts with mIDH1 ND AML treated on study with IVO + AZA. Methods: The secondary efficacy endpoint of CRh was sponsor derived and defined as CR with absolute neutrophil count > 0.5 X 109/L and platelets > 50 X 109/L. Bulk DNA sequencing (DNA-seq, 1400-gene ACE Extended Cancer Panel, 2% variant allele detection limit) was performed on BMMCs and/or peripheral blood mononuclear cells (PBMCs). Single-cell (sc) targeted DNA-seq was performed on PBMCs using a microfluidic platform (Tapestri®) with a 20-gene AML panel capable of detecting rare subclones down to 0.1%. Results: To identify mechanisms of acquired resistance, longitudinal bulk DNA-seq was analyzed for 22/23 pts, including 5 pts with available samples at relapse or disease progression (3 CR and 1 MLFS with morphological relapse; 1 CRh with disease progression). Mutations not detected at baseline but emerging during therapy were categorized into canonical biological pathways (Table). Emerging mutations were observed in 9/22 (41%) pts, including 4 with multiple mutations. 3/22 (14%) pts had emerging IDH2 mutations, with concurrent rise in plasma 2-hydroxyglutarate (2-HG) levels. Within the relapse/progression cases, emerging mutations were observed in 4/5 pts, including 3 where the emerging mutation appeared to be the predominant mutation at relapse/progression (2 CR pts with IDH2 mutations, and 1 CRh pt with a TET2 mutation). To date, from the bulk DNA-seq analysis, no emergence of an IDH1 second-site or receptor tyrosine kinase pathway (FLT3, KRAS, NRAS, PTPN11) mutation has been observed. To further evaluate clonal evolution of clinical response and disease progression, scDNA-seq was performed, with data available for 15 pts (10 CR, 2 CRh, 1 MLFS, and 2 stable disease), including end-of-study time points for 5 relapse/progression pts. In the 2 relapsed pts with an emerging IDH2 mutation observed by bulk DNA-seq, 1 had a minor IDH2 clone present at baseline that expanded independently from IDH1 during therapy (Fig). In a separate case, a subclonal baseline PTPN11 clone evolved to gain both RUNX1 and IDH2 mutations, becoming the predominant clone at relapse. In 2 other cases, scDNA-seq data showed that non-IDH1 clones were selected from baseline clones ancestral (TP53 n = 1) to or emerged separate from mIDH1 (TET2 n = 1). Clonal architecture and evolution from additional pts will be presented. Conclusion: IVO + AZA combination treatment in IC-ineligible ND AML led to deep and durable molecular remissions. Although the dataset is small, IDH2 clones appeared to expand or emerge separate from the IDH1 clone, with no observation of an IDH1 second-site mutation to date. Understanding patterns of emerging mutations/pathways at relapse will allow for comparison with mIDH1 R/R AML and ND AML pts treated with IVO monotherapy. These results underline the importance of mutational testing, particularly at progression to determine optimal salvage therapy. Potential combination or sequential therapies should be evaluated prospectively in future clinical trials. Disclosures Daigle: Agios: Current Employment, Current equity holder in private company. Choe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. DiNardo:Syros: Honoraria; MedImmune: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Stein:Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotheryx: Consultancy; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fathi:Amphivena: Consultancy, Honoraria; Agios: Consultancy, Research Funding; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Takeda: Consultancy; PTC Therapeutics: Consultancy; Novartis: Consultancy; NewLink Genetics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; AbbVie: Consultancy. Döhner:Pfizer: Research Funding; Sunesis: Other, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daichii Sankyo: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy. Patel:France Foundation: Honoraria; DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Tan:AbbVie: Other: Investigator on an AbbVie funded clinical trial; Agios: Research Funding; Janssen: Research Funding; NOHLA Therapeutics: Research Funding; Novartis: Other, Research Funding. Zeidan:Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; ADC Therapeutics: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. De Botton:Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Pierre Fabre: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Honoraria; Bayer: Consultancy, Honoraria; Servier: Consultancy. Stone:Syntrix: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Stemline: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Jazz: Consultancy; Otsuka: Consultancy; Novartis: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Biolinerx: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Daiichi-Sankyo: Consultancy; Agios: Consultancy, Research Funding; Actinium: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Syros: Consultancy; Syndax: Consultancy; Elevate: Consultancy; Gemoab: Consultancy; Janssen: Consultancy. Frattini:BMS: Current Employment, Current equity holder in private company. Franovic:BMS: Current Employment, Current equity holder in private company. Xu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Wu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Vyas:Forty Seven: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau.