Incomplete Blood Count Recovery Research Articles

Clinical outcomes of hypomethylating agents and venetoclax in newly diagnosed unfit and relapsed/refractory paediatric, adolescent and young adult acute myeloid leukaemia patients.

Venetoclax (VEN) combined with hypomethylating agents (HMA) decitabine or azacitidine is used for adult acute myeloid leukaemia (AML), but its application in paediatric, adolescent and young adult (AYA) AML lacks prospective studies. We performed a retrospective chart review of paediatric and AYA AML patients treated with HMA + VEN at Cincinnati Children's Hospital Medical Centre. Twenty-seven patients received 30 HMA + VEN treatment courses for relapsed/refractory (R/R, n = 21) or newly diagnosed (n = 9) AML due to ineligibility for intensive chemotherapy. The R/R cohort had high-risk cytomolecular genetic alterations and prior extensive treatments, with 50% (n = 9) of relapse patients (n = 18) having undergone haematopoietic stem cell transplantation (HSCT). Venetoclax treatment using the 400 mg adult exposure-equivelant dosing (AED) had a median duration of 21 days (range 7-30 days). Grade 3-4 toxicities included neutropenia (90%), anaemia (64%), thrombocytopenia (64%) and febrile neutropenia (44%). The overall complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 73% (77% minimal residual disease [MRD] negativity <0.1%), with 60% undergoing HSCT. Among newly diagnosed patients (n = 9), 89% achieved CR/CRi (78% MRD negativity) and 78% proceeded to HSCT. The R/R cohort (n = 21) showed a 67% CR/CRi rate (71% MRD negativity), with 52% undergoing HSCT. These findings support the safety and efficacy of HMA + VEN in paediatric/AYA AML, indicating it as a viable option for patients unfit for intensive chemotherapy. Further studies are necessary to determine optimal venetoclax dosing, chemotherapy combinations and pharmacokinetics in this population.

Impact of monocytic differentiation on acute myeloid leukemia patients treated with venetoclax and hypomethylating agents.

Although the combination of venetoclax (VEN) and hypomethylating agents (HMAs) results in impressive efficacy in acute myeloid leukemia (AML), there is still a subset of patients who are refractory. We investigated the outcomes of AML patients with monocytic differentiation who were treated with frontline VEN/HMA. A total of 155 patients with newly diagnosed AML treated with frontline VEN/HMA were enrolled in the study. Monocyte-like AML was identified by flow cytometry with typical expression of monocytic markers, and M5 was identified according to French, American, and British category. We compared the outcomes of patients with different characteristics. The rate of complete remission (CR) and CR with incomplete recovery of blood counts (CRi), progression-free survival (PFS), and overall survival (OS) in monocyte-like AML were inferior to those in nonmonocyte-like AML (CR/CRi rates, 26.7% vs. 80.0%, p < 0.001; median PFS, 2.1 vs. 8.8 months, p < 0.001; median OS, 9.2 vs. 19 months, p = 0.013). CR/CRi rate in M5 was lower than that in non-M5 (60.7% vs. 75.5%, p = 0.049). Multivariate analyses showed that monocyte-like AML was associated with lower odds of CR/CRi and higher risk of progression. Our study suggested that newly diagnosed AML with a monocytic immunophenotype had a poor prognosis with VEN/HMA treatment.

Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.

Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.

Evaluation of the toxicity and outcomes of the combination of midostaurin and CLAG-M in patients with FLT3-mutated acute myeloid leukemia (AML): A multi-center retrospective analysis.

6523 Background: FLT3-mutated AML is associated with poor outcomes. Addition of midostaurin (multi-targeted kinase inhibitor) to standard “7+3” with cytarabine and daunorubicin significantly prolongs overall and event-free survival for these patients (Stone 2017). At the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC), the standard regimen for newly diagnosed (ND) and relapsed/refractory (r/r) AML is cladribine, high-dose cytarabine, GCSF, and mitoxantrone (CLAG-M); midostaurin is added if FLT3-mutated (Halpern 2018). There is currently no peer-reviewed literature to support this combination for these patients. The purpose of this study is to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M in FLT3-mutated AML patients and compare the toxicity profile to midostaurin plus 7+3. Methods: This is a retrospective multi-center review conducted at three major cancer centers. Through pharmacy records and/or an institutional AML database, we identified adults with FLT3-mutated AML undergoing (re)induction chemotherapy who received either CLAG-M (UW/FHCC, Swedish) or 7+3 (OHSU, Swedish). The primary outcome was toxicity profile of the combination as measured by rate of adverse events ([AE], CTCAE Version 5.0). Secondary outcomes included disease response per ELN2017 AML working group criteria and 28-day mortality (TRM) (Döhner 2017). Patients treated on a clinical trial and in whom midostaurin was started &gt; 30 days after day 1 of chemotherapy were excluded. Rates of AEs were compared using Fisher’s exact test. Results: Eighty patients treated between 10/2022-12/2023 were included; 35 patients received CLAG-M, and 44 patients 7+3. Baseline characteristics were similar across all institutions, with most patients having adverse or intermediate risk disease. AE rates were similar between the two cohorts, (Table 1) except diarrhea and bleeding events were more common in the 7+3 vs. CLAG-M cohort (p = 0.004 and p = 0.037, respectively). The rate of complete remission (CR) plus CR with incomplete blood count recovery (CRi) did not significantly differ between the two cohorts: CLAG-M, 86% versus 7+3, 70% for 7+3 (p =0.11). No TRM occurred. Conclusions: The toxicity profile of CLAG-M combined with midostaurin is comparable to the combination of 7+3 with midostaurin, and induces high remissions rates in adults with FLT3-mutated AML. [Table: see text]

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial

Venetoclax plus cytarabine and azacitidine in relapsed/refractory AML: An open-label, single-arm, phase 2 study

BackgroundThe outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML. ObjectiveThis phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients. MethodsThirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1–7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis. ResultsThe CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3–4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths. ConclusionThe VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.

Selinexor and Chidamide in Patients with Relapsed/Refractory Acute Myeloid Leukemia Exposed to Venetoclax: A Single-Arm, Phase 2 Study

Background: Novel therapies for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are imperative, particularly those who have experienced relapse or resistance to multiline chemotherapies or venetoclax-based regimens, thereby underscoring the need for more innovative therapies that are both effective and well-tolerated. Chidamide and Selinexor have shown potential synergistic anti-leukemia effects by targeting NF-Κb /c-FLIP signaling via suppressing HDAC1/XPO1 activity. Therefore, the aim of this study was to investigate the activity and tolerability of chidamide combined with selinexor regimen for R/R AML. Methods: We report the findings of a phase 2 study in patients with relapsed/refractory AML that combined chidamide with selinexor. Selinexor was administered orally twice weekly for 4 weeks at a dose of 40/60 mg, depending on the patent's weight (over or under 70 kg). Chidamide was taken orally once a day at a dose of 10mg for 28 days. The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 1 cycles of treatment. The secondary endpoints include safety and survival. Results: Between December 2022 and April 2023, a total of 11 patients, median age 40 years (range, 22-54) were enrolled in the trail (ClinicalTrials.gov number, NCT05951855.). 8 out of 11 (72.7%) patients with R/R AML had received more than three prior lines of treatment. All of patients were previously exposed to venetoclax or hypomethylating agents (HMAs). Key baseline and clinical characteristics are summarized in Table 1. 10(90.9%) patients received the initial dose of 40 mg of selinexor twice a week, while one (9.1%) received 60 mg. Chidamide was administered to all patients at a daily dose of 10 mg daily. Five (45.5%) patients achieved a CRc (with 3 CR and 2 CRi), two (18.1%) achieved Partial remission (PR), and 5 (45.5%) had progressive disease for an overall response rate (ORR) of 63.6%. With a median follow-up of 147 days（range 59-234）, the median event-free survival (EFS) was 75 days and median overall survival (OS) was not yet reached (Figure 1). Among the seven patients who achieved CRc or PR, all proceeded to transplant after responding. One relapsed on day 56 following response and died 20 days later. Another patient died from an infection during the allogeneic hematopoietic stem cell transplantation (allo-HSCT). The remaining 5 patients are currently alive as of July 2023. No dose-limiting toxicities were observed. Common adverse events included neutropenia (72.7%), thrombocytopenia (63.6%), nausea/vomiting (63.6%), fatigue (45.5%), diarrhea (18.1%), bacteremia (9%). Conclusion: In this study, the combination of Selinexor and chidamide was administered as salvage treatment for R/R AML patients, resulting a high response rate and favorable safety profile. This offers a potential way for patients to bridge to transplantation. However, future studies with larger sample sizes and longer follow-up periods are needed to further validate its efficacy.

Decitabine/Cedazuridine (ASTX727) Combined with a Molecularly-Targeted Agent (Venetoclax, Gilteritinib, Ivosidenib, or Enasidenib) As Personalized Maintenance Therapy in Acute Myeloid Leukemia: First Results from a Phase 1b Study

Background: Disease relapse is the major cause of treatment failure and death in acute myeloid leukemia (AML). Currently, oral azacitidine (CC-486) is the only drug approved in the maintenance setting in patients with AML who are unable to complete standard therapy. The ECOG ACRIN E2906 trial suggested an overall survival (OS) benefit with 3-day IV decitabine maintenance. Decitabine/cedazuridine (ASTX727) is an oral formulation of decitabine that achieves systemic exposures as seen with IV decitabine. Multiple small-molecule agents are now available targeting key leukemic drivers (BCL-2, FLT3, and IDH1/IDH2 inhibitors). We developed a multi-arm phase 1b study (NCT05010772) to evaluate an oral maintenance regimen composed of an ASTX727 backbone combined with a molecularly-targeted agent (venetoclax, gilteritinib, ivosidenib, or enasidenib). Methods: Patients ≥ 18 years with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) not currently eligible for stem cell transplantation (SCT) and unable/unwilling to complete standard therapy were eligible. Patients having received either intensive induction (at least 2 cycles of therapy based on intermediate to high dose cytarabine) or low-intensity induction (at least 3 cycles based on low-dose cytarabine or a hypomethylating agent) were permitted. Other inclusion criteria were ECOG ≤ 3, adequate hepatic/renal function, absolute neutrophil count &amp;gt; 0.5 x 10 9/L, and platelets &amp;gt; 50 x 10 9/L. Patients were enrolled in one of five arms per physician choice based on molecular profile. Arm A consisted of ASTX727 35/100 mg PO on D1-3. All other arms combined this ASTX727 backbone with either venetoclax 400 mg (adjusted for azoles) PO on D1-5 (arm B), gilteritinib 120 mg PO on D1-28 (arm C), enasidenib 100 mg PO on D1-28 (arm D), or ivosidenib 500 mg PO on D1-28 (arm E). Treatment was administered in 4-week cycles, up to 24 cycles. Each arm initially consisted of a safety lead-in cohort with predetermined dose reductions for dose-limiting toxicity (DLT) per a 3+3 dose de-escalation design. Prophylactic antibiotics, antifungals, and antivirals were encouraged. The primary objective was safety and tolerability. Secondary objectives included relapse-free survival (RFS) and OS. Patients becoming eligible for SCT were taken off study and censored at the time of SCT for time-to-event endpoints. Results: 23 patients, with a median age of 68 years (range 33-83), have been enrolled (3 on arm A, 19 on arm B, and 1 on arm C). 12 (52%) were enrolled following intensive induction and 11 (48%) after low-intensity induction. 16 (70%) had prior venetoclax. Best response at enrollment was CR in 22 (96%) patients and CRi in 1 (4%). 6/22 (27%) patients with available testing were measurable residual disease (MRD)-positive. 2 (9%) patients had antecedent myelodysplastic/myeloproliferative neoplasms and 1 (4%) had therapy-related AML. ELN 2022 risk was favorable in 10 (43%), intermediate in 3 (13%), and adverse in 10 (43%) patients. The most common grade 3/4 adverse events were neutropenia (96%), thrombocytopenia (74%), anemia (39%), lung infection (22%), hypertension (17%), and neutropenic fever (17%). Cycle 2 dose reductions due to myelosuppression occurred in 5/23 (22%) patients. No DLTs were observed. No deaths occurred on protocol. Two patients died in remission from SCT-related complications after going off maintenance. The current median follow-up time is 5.3 months (m). The median number of cycles given is 3 (1-15). Three relapses have occurred to date (1 in arm A, 2 in arm B). The median RFS for the full cohort is not reached (NR, 1-year 71%). The median OS for the full cohort (figure 1A) is NR (1-year 100%). The median RFS for arms A, B, and C are NR (1-year 67%), NR (1-year 84%), and NR, respectively (figure 1B). The median RFS is 14.5 m (1-year 50%) for patients who received intensive induction and NR (1-year 75%) for those who received low-intensity induction. The median RFS for patients who were MRD-negative and MRD-positive at enrollment were NR (6-month 93%) and NR (6-month 75%), respectively (p=0.50). Of the 6 MRD-positive patients, 2 (33%) cleared their MRD while on maintenance (both patients in arm B). Conclusions: A fully oral, targeted maintenance regimen is feasible in AML. Early results show encouraging RFS and OS. Further enrollment and follow-up are required to better assess the safety and efficacy of these regimens.

Analysis of CD58 As a Predictive Marker of Morphologic Response to Inotuzumab Ozogamicin in Patients with B-Cell Acute Lymphoblastic Leukemia

BACKGROUND Clinical outcomes for B-cell Acute Lymphoblastic Leukemia (B-ALL) have significantly improved in the last decade, owing to the introduction of newer agents such as inotuzumab ozogamicin (INO) and blinatumomab. Both of these antibody-based therapies are effective in adults with relapsed or refractory (R/R) B-ALL and have shown promising results in the frontline setting as well. Given the utility of these therapies, there have been efforts to identify predictive markers for these treatments in B-ALL patients. Recently, CD58 was identified as a modulator of response to blinatumomab due to its role as a CD2 ligand in T-cell activation (Li et al. Sci Adv 2022). This costimulatory relationship between CD58 and CD2 has also been linked to Natural Killer cell mediated lysis, which has been described as a mechanism of action of INO (Fu et al. Signal Transduct Target Ther 2022; Huntington et al. Nat Rev Cancer 2020). In this study, we evaluated the correlation of CD58 expression with achievement of morphologic Complete Remission (CR) or Complete Remission with incomplete blood count recovery (CRi) after treatment with INO. METHODS Retrospective chart review was performed to identify patients in our institution's B-ALL database who received INO between 09/15/2011 and 03/10/2023 with blood or bone marrow samples available for flow cytometry analysis prior to INO infusion. Because all patients had measurable CD58 expression by flow cytometry, mean fluorescence intensity (MFI) was used instead of percent positivity to perform a simple logistic regression analysis to evaluate the relationship between CD58 MFI and achievement of CR/CRi after treatment with INO. We then calculated the odds of achieving CR/CRi by age, molecular risk at diagnosis, and R/R disease status. Two patients lacked diagnostic cytogenetic data. Molecular risk stratification and assessment of morphologic response were performed according to National Comprehensive Cancer Network (NCCN) guidelines. To account CD58 MFI outliers, we then confirmed our results by comparing response rates between patients with a CD58 MFI above our median (CD58 MFI-high) to patients with a CD58 MFI below our median (CD58 MFI-low) using Fisher's exact test. RESULTS We found 34 patients who met our criteria for analysis, 2 of which had previously received INO (Table1). Median Overall Survival (OS) was 21.5 months (range, 1-58) with a median leukemia-free survival (LFS) of 13.5 months (range, 1-52). Response rates after INO were high, including 28 patients (82.4%) achieving CR, 30 patients (88.2%) achieving CR/CRi, and 27 patients (79.4%) achieving Measurable Residual Disease (MRD) negativity. Both patients with a history of prior treatment with INO attained CR with MRD negativity. The chi-square test statistic for our simple logistic regression model was not statistically significant (Figure1, p=0.915). The logistic regression coefficient showed no statistically significant association between CD58 MFI and CR/CRi rates after treatment with INO ( p=0.913). Our model predicted an 88.6% probability of achieving CR/CRi for a CD58 MFI of 8,727.97 (Q1), 88.4% for 11,719.88 (Q2), 88.0% for 19,622.85 (Q3), and 85.7% for 55,217.74 (Q4). There was no statistically significant difference in the odds of achieving CR/CRi in patients with poor molecular risk at diagnosis (OR=0.06, 95% CI [0.01, 1.22]), age &amp;gt;35 years (OR=2.75, 95% CI [0.33, 22.9]), or R/R disease (OR=0.98, 95% CI [0.01, 1.97]). When comparing response rates between CD58 MFI-high and CD58 MFI-low patients, each group contained 15 patients that achieved CR/CRi and 2 patients with refractory disease. This confirmed an equal response rate to INO between CD58 MFI-high and CD58 MFI-low patients ( p=1.000). CONCLUSION Overall, we did not find a statistically significant correlation between CD58 MFI and achievement of CR/CRi. Our study is limited by our small sample size, single-center location, and retrospective design. However, it is important to note the high rates of CR/CRi that were seen, regardless of the intensity of CD58 expression. Further work is needed to evaluate the role of CD58 as a predictive marker for other therapies in B-ALL. These data suggest that INO is likely to remain an effective option for these patients, regardless of the intensity of CD58 expression.

Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Drs. Yifan Zhai and Jie Jin are co-corresponding authors. Introduction Investigational lisaftoclax, a novel BCL-2 inhibitor, has shown antileukemic activities in pts with CLL. For the first time, we present the safety, pharmacokinetics (PK), and efficacy of lisaftoclax alone or combined with azacitidine (AZA) or homoharringtonine (HHT), in adults with AML, MDS, or other myeloid neoplasms. Methods In part one, lisaftoclax was administered orally once daily at an assigned dose (200, 400, 600, or 800 mg) to pts with R/R AML using a “3+3” dose escalation design. In part two, pts with R/R AML, mixed-phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), or chronic myelomonocytic leukemia (CMML) were enrolled in Cohorts A, B, and C; pts with higher-risk MDS (blast cells &amp;gt; 5%; IPSS-R &amp;gt; 3.5) were enrolled in Cohort D; and older (≥ 75 yrs)/unfit pts with TN AML were enrolled in Cohort E. Lisaftoclax was administered orally once daily in either 28- or 14-day cycles (MDS only), depending on the assigned dose level. A daily ramp-up schedule was used to prevent tumor lysis syndrome (TLS).In part two, select lisaftoclax doses were combined with low-dose HHT (1 mg daily on days [d] 1-14; Cohort A) or standard-dose HHT (2 mg/m 2 daily on d1-7; Cohort B) or AZA (75 mg/m 2 daily on d1-7; Cohorts C, D, and E). Dose-limiting toxicity (DLT) was assessed during the first cycle. Results As of July 19, 2023, 115 pts were enrolled, including 89 with AML (64 R/R; 25 TN older/unfit), 22 MDS (7 R/R; 15 TN), 2 MPAL, 1 CMML, and 1 BPDCN. The median (range) age was 62.0 (18-81) years, and 66 (57.4%) were male. A total of 13 pts received lisaftoclax monotherapy, and 102 received combination regimens. DLTs (pneumonia, respiratory failure, and heart failure) were observed in 1 pt in Cohort C, and no TLS was reported. Treatment-emergent adverse events (TEAEs) were observed in all 13 (100%) pts who received lisaftoclax monotherapy, of whom all experienced grade (Gr) 3/4 AEs and 4 (30.8%) experienced serious AEs (SAEs). Common TEAEs (&amp;gt; 30%) included leukopenia, neutropenia, lymphopenia, thrombocytopenia, anemia, diarrhea, hypokalemia, hypocalcemia, and hypomagnesemia. Similarly, TEAEs were reported in 12 (85.7%) pts treated with lisaftoclax combined with HHT, with Gr 3/4 AEs occurring in 12 (85.7%) and SAEs in 2 (14.3%). Common TEAEs (&amp;gt; 30%) included leukopenia, neutropenia, thrombocytopenia, hypokalemia, hypocalcemia, and pneumonia. TEAEs were also observed in 75 (100%) evaluable pts treated with lisaftoclax combined with AZA, with Gr 3/4 AEs occurring in 55 (73.3%) and SAEs in 18 (24.0%). Common TEAEs (&amp;gt; 30%) included leukopenia, neutropenia, thrombocytopenia, anemia, and diarrhea. A total of 40.0% (46/115) of pts discontinued the study because of progressive disease (45.7% [21/46]), lack of clinical benefit (8.7% [4/46]), AEs (17.4% [8/46]), withdrawal (26.1% [12/46], including 4 for transplantation), and investigator's decision (2.2% [1/46]). Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 to 800 mg. Compared to lisaftoclax alone, no significant difference was observed in the PK profile of lisaftoclax when combined with AZA or HHT. In part one, the overall response rate (ORR) and composite remission rate (CRc [complete remission (CR) + CR with incomplete blood count recovery (CRi)]) were each 8.3% (1/12). Lisaftoclax 600 mg was administered for further optimization of the combination regimens, and 800 mg was also explored. In Cohort E (n = 21), among TN AML pts treated with lisaftoclax, ORR and CRc were 71.4% and 47.6%, respectively, and the median (range) time to CR/CRi/MLFS was 1.05 (95% CI, 0.99-NR) months. In Cohort C (n = 36), ORR and CRc were 75.0% and 44.4%, respectively, and the median (range) time to CR/CRi/MLFS was 1.25 (95% CI, 1.02-2.17) months; and median (range) progression-free survival was 10.22 (95% CI, 6.34-NR) months, with a median (range) follow-up time of 3.25 (95% CI, 0.79-14.29) months. In Cohort B, ORR or CRc was 75.0%. In Cohort D, ORR was 70.0% and CR/marrow CR was 60.0% (Table 1). Conclusions Lisaftoclax showed favorable tolerability as monotherapy and when combined with AZA or HHT, exhibiting encouraging clinical efficacy among pts with R/R AML or MDS and older/unfit pts with TN AML. This ongoing trial continues to enroll pts. Internal study (CT.gov) identifier: APG2575AC101 (NCT04501120).

A Phase 2 Study of Lenalidomide in Combination with Mitoxantrone, Etoposide, and Cytarabine (Len plus MEC) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Outcomes for patients with relapsed or refractory acute myeloid leukemia (R/R AML) remain extremely poor. Response rates with salvage chemotherapy regimens, such as mitoxantrone, etoposide, and Cytarabine (MEC), have been associated with a complete remission rate of around 20-30%. We previously reported a phase I study combining Lenalidomide (Len) with MEC salvage chemotherapy, with encouraging response rates in R/R AML compared to other historical standards (DeAngelo et al. AJH 2018). This led to the current phase 2 study (NCT03118466) of Len combined with MEC in R/R AML to evaluate for the efficacy of this combination. Methods: We conducted a phase 2 study of Len plus MEC in adult patients (≥ 18 yrs) with R/R AML after 1 or more cycles of induction chemotherapy. Patients received Len dosed at 50mg/day on days 1-10, and Mitoxantrone 8mg/m2/d, Etoposide 100mg/m2/d and Cytarabine 1000mg/m2/d on days 4 through 8 of induction (Kohrt et al AJH 2010). Patients who achieved a complete remission (CR), complete remission with incomplete blood count recovery (CRi) or incomplete platelet recovery (CRp) could proceed with consolidation chemotherapy or hematopoietic stem cell transplantation at the discretion of the treating physician. The study followed a Simon two-stage design powered to detect improvement to a 45% response rate. The primary objective was to determine the response rate. Secondary objectives included time to neutrophil and platelet count recovery, treatment related mortality, rates of relapse, and overall survival. Results: A total of 40 patients were enrolled and received study treatment. The median age was 56 years (range, 19-70); 58% of the patients were male. 73% of patients had relapsed after initial therapy (29/40) while 27% had primary refractory AML (11/40) after their initial induction chemotherapy. The median number of prior therapies was 2 (range, 1-4). The majority of patients had adverse ELN 2023 risk (n=22; 55%). Recurrent gene mutations in 5 or more patients included DNMT3A (n=8), TET2 (n=7), NRAS (n=6), IDH2 (n=5), and ASXL1 (n=5); 2 patients harbored TP53 mutations. The most frequent grade 3-4 treatment-related toxicities were febrile neutropenia (n = 30; 75%), platelet count decrease (n = 40; 100%), anemia (n = 18; 45%), neutrophil count decrease (n = 14; 34%), blood bilirubin increase (n=6, 14%), and anorexia (n = 5; 12%). Three patients (8%) died during the study treatment period, all secondary to hepatic failure; no other early deaths occurred. Two of these patients had baseline grade 1 bilirubin elevation (no other patients in the study reported baseline bilirubin elevations). Median follow-up was 21 months. The overall response rate was 50% (20/40) where 19 achieved CR while 1 achieved CRi. Of 20 responders, the median time to neutrophil count recovery was 28 days and to platelet recovery was 34 days. The median time to relapse was 22.6 months. The median overall survival (OS) of the entire cohort was 16 months (Figure 1). Conclusions: Len plus MEC was associated with a high response rate and improved OS in patients with R/R AML as compared to historical controls. The overall safety profile was similar to prior MEC chemotherapy trials but several patients did experience early hepatic toxicity. Overall these data support evaluating high-dose Len combined with MEC for patients with R/R AML in a randomized study.

NGS Profile and the Mathematical Prediction Model for Venetoclax Combination Therapy in HM-Screen-Japan 02 Study

[Introduction] Azacitidine and venetoclax combination therapy (Aza/Ven) is a novel strategy for acute myeloid leukemia (AML). Although this regimen is widely used as a first line treatment not only for unfit/elderly patients but also for fit/young patients in the real-world situation, appropriate patient selection is an important issue. HM-SCREEN-Japan 02 (UMIN-CTR UMIN000046371) is a Japanese multicenter prospective observational study to evaluate the clinical utility of targeted sequencing. In this study, we performed the sub-analysis of newly diagnosed AML patients who received Aza/Ven as a 1 st line treatment to elucidate the genetic background of AML. Furthermore, we proposed a novel mathematical model to predict the response of Aza/Ven. [Methods] AmoyDx® Myeloid Blood Cancer Panel for acute myeloid leukemia was used for the targeted sequencing. We performed linear discriminant analysis to predict complete response patients by Aza/Ven based on clinical information before treatment. We utilized three clinical quantities for the analysis: Wilms Tumor-1 (WT1) mRNA expression level, the number of “favorable mutations”, and that of “unfavorable mutations”. Favorable and unfavorable mutations were defined as IDH1, IDH2, NPM1, and CEBPA mutations, and ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and TP53 mutations, respectively, based on the previous reports (NEJM 2019, Blood 2022). The data were standardized and utilized for the linear discriminant analysis. Statistical analyses were performed using R version 4.2.3 software (R Foundation for Statistical Computation, Vienna, Austria). [Results] Total 158 patients were enrolled in our study. Among 48 patients who received Aza/Ven as a 1 st line therapy, NGS analyses were performed prior to treatment in 38 patients. Their median age was 70.5 (39-92) years old. AML with myelodysplasia-related changes was the major subtype (71%) and 37 percent of the cases had high risk cytogenetic abnormalities at diagnosis. After 1 st line Aza/Ven treatment, complete remission (CR)/ CR with incomplete blood count recovery (CRi) was achieved in 63% of the cases while the remaining 37% were non-CR. There was a trend that patients with NPM1 and IDH1/2 mutations achieved CR/CRi, while patients with RUNX1 mutation were not tended to achieve CR (Figure 1). Next, we performed linear discriminant analysis of treatment response using three pretreatment clinical factors. Linear discriminant analysis found a linear combination of prognostic factors that best separates two classes in the group of patients. Thirty-seven patients were employed to determine the discriminant function D, given by D = 0.638 × x − 0.76 × y + 0.68 × z + 0.145. Here x, y, and z represented the WT1 quantity in peripheral blood, the number of “favorable mutations”, and that of “unfavorable mutations” after standardization, respectively. Using this model, 81.1% of cases were correctly classified, and so were 75.7% of cases with leave-one-out cross validation method (Table 1). [Discussions] As previously reported (NEJM 2019, Blood adv 2020), IDH1/2 and NPM1 mutations tended to be sensitive to Aza/Ven in our cohort. However, it would be hard to predict the response of Aza/Ven by a single gene mutation because multiple gene mutations were co-existed in most of the cases (Figure 1) and clinical factors including tumor markers might also affect the outcome. Our mathematical model, involving gene mutations and WT1, could efficiently predict the response of Aza/Ven, which may support the selection of 1 st line treatment. In conclusion, our study revealed the genetic landscape of real-world Aza/Ven therapy and provided a potential prognostic model.

Dose Escalation of HLA-A2-WT1 CD3 T-Cell Bispecific Antibody in a Phase I Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Background: RO7283420 (RG6007) is a 2+1 TCR-like (TCR-L) T-cell bispecific (TCB) antibody targeting CD3 and the RMFPNAPYL peptide of Wilms Tumor 1 (WT1) protein presented by the major histocompatibility complex-I HLA-A*02 on acute myeloid leukemia (AML) blasts and other antigen presenting cells. The pre-clinical evaluation of RO7283420 in our in vivo humanized AML xenografts and ex vivo AML co-culture models showed strong T-cell mediated AML cell killing (Augsberger C, et al. Blood 2021). A Phase 1 dose-escalation (DE) study (NCT04580121) evaluated the safety, tolerability, pharmacokinetics, anti-drug antibodies (ADAs), and anti-leukemic activity of RO7283420 in patients with relapsed/refractory (R/R) AML. Methods: In this open-label, multi-center study, DE was performed using a 3+3 design. Patients received RO7283420 every 3 weeks (Q3W, n=46), or every week (QW, n=4) as intravenous (IV) infusions. Preliminary anti-leukemic activity included response assessment according to European Leukemia Net (ELN) response categories (adapted from Döhner H, et al. Blood 2017). Results: As of 13 April 2023, 50 HLA-A2+ R/R AML patients received at least one dose of RO7283420. Patients had a median age of 65.5 years (range 35-84), presented with ECOG of 0 (56%) or 1 (38%) or 2 (6%), and 58% were male. Median prior line of therapy was 2 (range 1-5). Overall, 58% of patients had relapsed and 42% had primary refractory disease. According to the ELN 2017 risk stratification, patients were of adverse (48%), intermediate (38%) or favorable (8%) risk category, for 6% of patients the risk category missing. The most common genetic abnormalities reported were RUNX1 (21%), ASXL1 (17%), TP53 (10.6%), FLT3-ITD (6.4%) and NPM1 (6.4%) of the 47 patients tested. Median bone marrow blast percentage at baseline was 35% (range 3-90%), while the median of circulating blast was 17% (range 0-88%). Study patients received RO7283420 IV at 13 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.15 mg (flat) to 18 mg Q3W (with a preceding weekly 1/3 mg ‘double step-up’ during Cycle 1) and one QW dose level with 9 mg preceded by a 1/3 mg step-up. Maximum tolerated dose was reached at 1/3/12 mg double step-up Q3W. Explored alternative QW schedule was not tolerable at 1/3/9 mg. The most common (≥20%) adverse events (AEs) were cytokine release syndrome (CRS) occurring in 34 (68%), pneumonia 14 (28%), pyrexia 13 (26%), febrile neutropenia 13 (26%), hyperglycemia 12 (24%), hypokalemia 11 (22%), and nausea 10 (20%) of patients. Eight dose limiting toxicities (DLTs) were reported: five G3 CRS (at 1/3, 2/12, 1/6/12 mg dose levels), G3 stomatitis (at 1/3/12 mg), G3 myositis (at 1/3/18 mg), and G4 thrombocytopenia (at 1/3/18 mg). Eleven patients (22%) experienced Grade 5 AEs with pneumonia, sepsis, and hemophagocytic lymphohistiocytosis (HLH) reported in &amp;gt;1 patient; all Grade 5 events were considered unrelated to RO728342 except 1 (at 1/3/9 mg) of 2 HLH events. IV PK has been overall dose-linear and characterized by a terminal half-life of 29 to 84 hours and a clearance of 58 to 92 mL/h. Preliminary ADA incidence within the study population was 19%. In the dose ranges tested, a trend for study drug exposure-dependent blast reduction was observed in blood, while a clear exposure-response relationship could not be established with BM blast reduction. Furthermore, our preliminary pharmacodynamic analysis identified expansion of naive and memory CD8 T cells in blood and activated CD8+ T cells in bone marrow, in line with the expected mode of action (MoA) of RO7283420. Preliminary efficacy signals were observed with 3 complete responses (CR), including 1 CR with incomplete blood count recovery. Conclusions: RO7283420 is the first TCR-L TCB antibody evaluated in AML. We observed pharmacodynamic evidence of T-cell activation and expansion in the clinic, in line with the expected MoA of TCBs, however, at the explored doses, no clear exposure-response relationship and only a modest clinical activity were observed. The safety profile was shown to be consistent with the other TCBs and R/R AML population. Based on the totality of data, the study was discontinued.

Real-life data of azacitidine-venetoclax combination in acute myeloid leukemia patients: a single center experience

Aims: To evaluate real-life data on the efficacy and safety of Venetoclax (Ven) therapy used in combination with hypomethylating agent (HMA) in patients with acute myeloid leukemia (AML).&#x0D; Methods: The records of newly diagnosed, relapsed or refractory (RR) AML patients over 18 years of age who were planned to be treated with Azacitidine (AZA) combined with Ven because they were not suitable for intensive chemotherapy and patients who received AZA combined with Ven maintenance therapy after achieving remission were retrospectively analyzed. The standard protocol for patients is subcutaneous or intravenous AZA 75 mg/m2 on days 1-7/ every 28 days + oral Ven treatment 100-400 mg/day for 28 days. The treatment response rates, survival times, and side effect profiles of 18 newly diagnosed patients, 12 RR patients, and 4 patients receiving AZA+Ven as maintenance treatment between January 2021 and March 2022 were evaluated.&#x0D; Results: It was found that 8 of the 34 patients (23.5%) who were examined in the present study died before the first response could be evaluated. When the response rates were evaluated, complete response (CR) or complete remission with incomplete blood count recovery (CRi) (CR+CRi) was found to be 61% in the group receiving AZA+Ven in the first line, and CR+CRi was 50% in the group receiving AZA+Ven because of RR AML. In the group receiving AZA+Ven in the first line, the average Overall Survival (OS) was 8.00 months (95% CI: 1.58-14.41), and 7.00 months in the RR group (95% CI: 1.78-12, 21). All patients in the group receiving AZA+Ven for maintenance purposes were alive and the median follow-up period was 12.50±6.02 months in this group (Mean±SD). The most common side effect was neutropenia, and the most common cause of death was disease progression.&#x0D; Conclusion: In AML patients ineligible for intensive treatment due to advanced age or comorbidities, real-life data of AZA+Ven therapy with effective CR+CRi rates and a manageable spectrum of side effects promise hope.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML

AbstractEnasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Comparative Efficacy of Venetoclax-Based Combination Therapies and Other Therapies in Treatment-Naive Patients With Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: A Network Meta-Analysis

ObjectivesThis network meta-analysis (NMA) assessed the efficacy of venetoclax (VEN) + azacitidine (AZA) and VEN + low-dose cytarabine (LDAC) compared with AZA, LDAC, and decitabine monotherapies and best supportive care (BSC) in adults with untreated acute myeloid leukemia ineligible for intensive chemotherapy. MethodsA systematic literature review and feasibility assessment was conducted to select phase III randomized controlled trials for inclusion in the NMA. Complete remission + complete remission with incomplete blood count recovery and overall survival (OS) were compared using a Bayesian fixed-effects NMA. Treatments were ranked using surface under the cumulative ranking curves (SUCRAs) with higher values indicating a higher likelihood of being effective. ResultsA total of 1140 patients across 5 trials were included. VEN + LDAC (SUCRA 91.4%) and VEN + AZA (87.5%) were the highest ranked treatments for complete remission + complete remission with incomplete blood count recovery. VEN + LDAC was associated significantly higher response rates versus AZA (odds ratio 5.64), LDAC (6.39), and BSC (23.28). VEN + AZA was also associated significantly higher response rates than AZA (5.06), LDAC (5.74), and BSC (20.68). In terms of OS, VEN + AZA (SUCRA: 95.2%) and VEN + LDAC (75.9%) were the highest ranked treatments. VEN + AZA was associated with significant improvements in OS compared with AZA (hazard ratio 0.66), LDAC (0.57), and BSC (0.37), and VEN + LDAC was associated with significant improvements in OS compared with LDAC (0.70) and BSC (0.46). ConclusionsVEN + AZA and VEN + LDAC demonstrated improved efficacy compared with alternative therapies among treatment-naive patients with acute myeloid leukemia ineligible for intensive chemotherapy.

Efficacy and safety of venetoclax combined with hypomethylating agents for relapse of acute myeloid leukemia and myelodysplastic syndrome post allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis

BackgroundCurrently, there is no standard treatment for managing relapse in patients with acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after allogeneic hematopoietic cell transplantation. Venetoclax-based therapies have been increasingly used for treating post-transplantation relapse of AML. The aim of this systematic review and meta-analysis was to evaluate the efficacy and adverse events of Venetoclax combined with hypomethylating agents (HMAs) for AML/MDS relapse post-transplantation.MethodsWe searched PubMed, Web of Science, Excerpta Medica Database, Cochrane Library, and Clinical. gov for eligible studies from the inception to February 2022. The Methodological Index for Non-Randomized Studies was used to evaluate the quality of the included literatures. The inverse variance method calculated the pooled proportion and 95% confidence interval (CI).ResultsThis meta-analysis included 10 studies involving a total of 243 patients. The pooled complete response and complete response with incomplete blood count recovery rate of Venetoclax combined with HMAs for post-transplantation relapse in AML/MDS was 32% (95% CI, 26-39%, I2 = 0%), with an overall response rate of 48% (95% CI, 39-56%, I2 = 37%). The 6-month survival rate was 42% (95% CI, 29-55%, I2 = 62%) and the 1-year survival rate was 23% (95% CI, 11-38%, I2 = 78%).ConclusionThis study demonstrated a moderate benefit of Venetoclax in combination with HMAs for patients with relapsed AML/MDS post-transplantation (including those who have received prior HMAs therapy), and may become one of treatment options in the future. Large-scale prospective studies are needed to confirm the potential benefit from venetoclax combined with HMAs.

Gilteritinib plus azacitidine and venetoclax for FLT3-ITD mutated relapsed/refractory acute myeloid leukemia.

e19024 Background: Gilteritinib is a second-generation FLT3 tyrosine kinase inhibitor that has been shown significantly increase the survival of relapsed/refractory (r/r) FLT3-mutated acute myeloid leukemia (AML) patients. We investigated the clinical benefit of gilteritinib plus azacitidine and venetoclax in the treatment of r/r FLT3-ITD mutated AML in the real word. Methods: Gilteritinib was given by oral administration at a dose of 80 or 120mg/d for each cycle. Azacitidine was intravenously administrated at a dose of 75 mg/m2/day d1-7. Venetoclax was given by oral administration at a dose of 100mg/d then ramp-up at 400mg/d, some patients were administrated at a dose of 400mg/d due to prior exposure. The composite complete response (CRc) rate (complete response [CR] and CR with incomplete blood count recovery [CRi]) were assessed, and then the overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) was evaluated. Results: We retrospectively analyzed the outcomes of gilteritinib plus azacitidine and venetoclax in 14 r/r FLT3-ITD mutated AML patients. The CRc rate of the triple therapy was 57.1% (CR, n = 5, 35.7%; CRi, n = 3, 21.4%), in which, all patients achieved minimal residual disease (MRD) negative measured by multi-color flow cytometry. At a median follow-up of 136.5 days, the median OS was 216.0 days, the median EFS was 97.0 days, and the median RFS were 184 days. The common grade 3/4 hematologic adverse events included neutropenia (n = 14, 100.0%), anemia (n = 12, 85.7%), and thrombocytopenia (n = 11, 78.6%). The common grade 3/4 non-hematologic adverse events were pulmonary infection (n = 5, 35.7%), other adverse events were relatively less and milder. Conclusions: In conclusion, the current data demonstrated promising response of the triple therapy in r/r FLT3-ITD mutated AML patients, and the regimen represented a potential option as a bridge to transplant. Prospective studies are warranted to further define the risk or benefit for more patients.

Phase 1b OMNIVERSE trial: Safety and tolerability of oral azacitidine (Oral-AZA) in combination with venetoclax (VEN) for treatment of acute myeloid leukemia.

e19011 Background: Safer and more effective lower-intensity treatment (Tx) options are needed for patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). The combination of VEN, an oral BCL-2 inhibitor, and injectable AZA (Inj AZA), a hypomethylating agent, is indicated in IC-ineligible pts with newly diagnosed (ND) AML and has shown significantly improved response and survival rates vs. Inj AZA alone (DiNardo et al., N Engl J Med 2020). Oral-AZA allows for extended dosing schedules vs. Inj AZA. Methods: OMNIVERSE (NCT04887857) is an ongoing, phase 1b, multicenter, open-label, dose-determination study evaluating Oral-AZA + VEN in pts with relapsed/refractory (R/R; part 1) and ND AML (part 2). This abstract presents data from part 1. Eligible pts are adults with R/R AML (WHO 2016 criteria) not eligible for further IC, with an ECOG performance status of ≤ 2. The Oral-AZA starting dose is 300 mg QD × 14 days (d) per 28d cycle (dose level [DL] −1), which can be de-escalated to 200 mg QD × 14d depending on dose-limiting toxicities (DLTs); VEN 400 mg QD is taken continuously (or 21d per cycle; DL −2). Dosing decisions are guided by a modified toxicity probability interval 2 (mTPI-2) design. The primary endpoint is to evaluate safety/tolerability and establish the maximum tolerated dose (MTD) of Oral-AZA + VEN in R/R AML (starting dose for part 2). Secondary endpoints are to assess preliminary investigator-determined response rates per ELN 2017 AML response criteria (Döhner et al., Blood 2017) for complete remission (CR), CR with partial hematologic recovery, CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, overall response, and measurable residual disease (plus conversion rate). Results: Pt enrollment began in December 2021 and is ongoing; data from part 1 are available for 5 pts (3 female; aged 51–80 years). 3 pts had 1 prior line of Tx and 2 pts had 2. Oral-AZA + VEN was given for 1–12 cycles. Of the 5 pts, 3 reported ≥ 1 any grade (Gr) drug-related adverse event, the most common of which were Gr 1–3 diarrhea (2 pts) and Gr 1–2 nausea (2 pts). Gr 3 febrile neutropenia, which was not deemed drug related, was reported in 4 pts (6 episodes total). In 1 pt, Oral-AZA was reduced to 200 mg QD x 14d from cycle 4 due to Gr 1 diarrhea and VEN to 70 mg QD x 28d from cycle 3 due to co-Tx with a strong CYP3A inhibitor (per protocol). 3 pts died after Tx discontinuation. No DLTs were observed and MTD of Oral-AZA + VEN was determined to be Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d. As of January 2023, 2 pts remained on Tx and best response achieved was CRi in 2 pts and stable disease in 3 pts. Conclusions: These results indicate that a MTD of Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d has a manageable safety profile consistent with known profiles of the 2 agents. Further evaluation in AML is warranted. Clinical trial information: NCT04887857 .

Olutasidenib in post-venetoclax patients with mIDH1 AML.

e19041 Background: Olutasidenib is a potent, selective, oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is FDA approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. Venetoclax (VEN) in combination with a hypomethylating agent (HMA) is standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in IDH1-mutated AML. The sequence of therapy following failure of a VEN-based regimen in IDH1-mutated AML has not been established. We evaluated the efficacy and safety of olutasidenib in a subset of 17 patients from the Phase 2 trial (NCT02719574) previously treated with VEN combination regimens. Methods: Adults with mIDH1 R/R AML received olutasidenib 150 mg twice daily alone (n = 15) or in combination with azacitadine (AZA) (n = 2). The primary endpoint was achievement of a CR/CRh. Secondary endpoints included time to and duration of CR+CRh and rate of transfusion independence (TI). Data cut-off for the analysis was 18 June 2021. Results: Of 17 patients with prior VEN treatment, 5 are ongoing and 12 discontinued due to progressive disease (6), adverse events (4), or withdrawal by subject (2). Median age was 73 (range 65-83). Median time since diagnosis was 19.5 months (1.2-41). Cytogenetic risk class was intermediate in 9, poor in 6, favorable in 1 and unknown in 1. Most patients had relapsed; 6 were refractory to prior treatment. The median number of prior regimens was 2 (range 1-6); 13 had prior HMA, 2 had prior olutasidenib. VEN was generally used for induction. Some patients received VEN in multiple regimens. VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). The best response to olutasidenib was CR/CRh in 5/17 (29.4%), of which 4 (23.5%) were CR. In the 8 patients who previously received the combination of VEN-AZA, 3 (37.5%) patients achieved a CR/CRh. Time to CR/CRh was median 2.1 months (actual: 1, 1.9, 2.1, 2.8 and 2.8). Duration of CR/CRh was median 18.5+ months (4.8, 9.0+, 18.5+, 22.6+, and 28.5+ months as of cut-off date). Other responses included CR with incomplete blood count recovery (CRi) in 2 patients, stable disease (SD) in 2, progressive disease (PD) in 3, not done (ND) in 2, not evaluable (NE) in 1 and not listed in 2. At baseline 14/17 were red blood cell (RBC) dependent, and 4 of the 14 (28%) had a 56-day period of RBC transfusion independence (TI). Ten were platelet dependent at baseline and 5 of the 10 (50%) had a 56-day period of platelet TI while receiving olutasidenib. Conclusions: Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. Clinical trial information: NCT02719574 .