Candidates For Intensive Chemotherapy Research Articles

The approach of HMA plus VEN with or without BMT for all patients with AML.

Treatment options for acute myeloid leukemia (AML) have expanded over the last 5 years. New regimens are increasing the options for patients who previously may not have been offered any antineoplastic therapy. The use of the hypomethylating agent (HMA) decitabine or azacitidine combined with the BCL2 inhibitor venetoclax (HMA-VEN) has improved overall survival in an older and unfit population compared to HMA therapy alone. Delivering these regimens outside academic centers allows more patients with AML to be treated, though support and collaboration with allogeneic stem cell transplant (SCT) centers should still be considered to determine eligibility and promptly initiate a donor search for potential transplant candidates. Expanding the use of HMA-VEN to younger and fit patients who are also candidates for intensive chemotherapy (IC) is being studied prospectively and is not recommended at this time outside of a clinical trial. Retrospective studies suggest populations that may benefit from HMA-VEN over IC, but this is not yet confirmed prospectively. Utilizing HMA-VEN prior to allogeneic SCT is also under investigation, and some retrospective data show feasibility and the ability to achieve measurable residual disease negativity pretransplant. Upcoming prospective randomized clinical trials aim to answer the comparability or superiority of HMA-VEN vs IC in fit populations and its potential use as a standard pretransplant induction regimen.

Evaluation of ICT01, a γ9δ2 T Cell-Activating Monoclonal Antibody, Combined with Venetoclax and Azacitidine in 1L AML (EVICTION Study)

Background: γ9δ2 T cells are emerging as a novel tumor-infiltrating effector cell that harbors strong cytolytic and pro-inflammatory activities, and whose intratumoral presence is associated with a favorable prognosis across solid and liquid cancer patients (Gentles et al., 2015; Tosolini et al., 2017). ICT01, a first-in-class anti-BTN3AmAb activating γ9δ2 T cells, completed Phase 1 testing in relapsed/refractory (r/r) solid tumors as monotherapy and in combination with pembrolizumab, and as monotherapy in r/r AML and lymphoma (EVICTION-NCT04243499). ICT01 activates circulating γ9δ2 T, CD8 T, and NK cells that leads to tumor infiltration and remodeling of the TME (De Gassart et al., 2021; Wermke et al., 2021) without any dose-limiting toxicities and a good safety profile. Encouraging clinical activity was observed in the hematologic cancer cohort with a 30% DCR on the 10 patients evaluable at week 8 or beyond (Garciaz, SITC 2023) supporting further clinical testing of ICT01 in combination with Venetoclax (VEN) and 5-Azacytidine (AZA), considered the standard of care for patients with newly diagnosed AML who are not candidates for intensive chemotherapy. Both ICT01 + γ9δ2 T cells and VEN/AZA induce killing of AML blasts, while VEN/AZA has been shown to enhance T-cell- and NK-cell-mediated cytotoxicity against AML blasts, suggesting that the combination of ICT01 plus VEN/AZA could lead to greater efficacy. We used preclinical models to demonstrate the ability of VEN/AZA to potentiate the anti-leukemic activity of ICT01-activated γ9δ2 T cells to support the clinical evaluation of ICT01 + VEN/AZA in 1L AML patients eligible to receive VEN/AZA. Results: Preclinical in vitro studies showed that ICT01-mediated activation of g9d2 T cells significantly increased survival against VEN toxicity by >50%, as compared to untreated control (p<0.01). Furthermore, killing assays performed by co-culture of AML blasts and HD-PBMC demonstrated that VEN/AZA enhances the blast killing capacity of ICT01-activated g9d2 T cells. These results were confirmed in vivo in NSG mice engrafted with human AML that were adoptively transferred with human g9d2 T cells and treated with VEN (40mg/kg/day OG)/AZA (2mg/kg/day IP), ICT01 (1mg/kg IV) or the combination. In this model the use of ICT01 together with VEN/AZA significantly delayed tumor growth (p<0.001) and significantly prolonged median survival to 42.5 days (vs 28 and 32.5 days for animals receiving ICT01 or VEN/AZA, respectively) (Figure 1). These results led to the design of the recently initiated Phase 2a arm of EVICTION in 1L AML where ICT01 is given at 10 mg or 75 mg IV Q4W on Day 1 of the 28-day approved regimen of VEN/AZA until toxicity or disease progression. Up to 25 patients will be treated at each dose level, following an interim analysis after 10 pts are treated at each dose. Clinical sites in France, Spain and the USA are participating. Biomarkers include multiparametric flow cytometry analysis of g9d2 T cells and other immune cells, and BTN3A expression in peripheral blood and in bone marrow aspirates at baseline and on Day 21-28. Circulating cytokine levels (including IFNγ, TNFa, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17a and MCP-1) are also assessed with MSD technology. Clinical response is evaluated per AML-specific standards (e.g., Cheson/IWG Criteria), with a target CR rate of >40%. Preliminary safety, biomarker and efficacy data from patients will be presented. Conclusion: Encouraging results obtained in the EVICTION Phase 1 trial and preclinical demonstration of the benefit of using ICT01 plus VEN/AZA allowed the initiation of a Phase 2a expansion cohort to evaluate the clinical benefit of this combination in 1L AML patients.

Functional Ex-Vivo Testing Combined with Machine Learning Predicts Clinical Response to Azacitidine+Venetoclax in AML

Background: The combination of Venetoclax + hypomethylating agents such as Azacitidine (Ven/Aza) has revolutionized the treatment of Acute Myeloid Leukemia (AML). Ven/Aza is currently the standard of care for patients with newly diagnosed AML who are not candidates for intensive chemotherapy (IC), as well as a recurrent therapeutic choice for IC-relapsed/refractory patients. Despite widespread adoption, the predictive biomarkers of Ven/Aza response/resistance available today are not sufficiently conclusive (Griffioen et al. Cancers 2022). In fact, a current hot topic in the field is whether Ven/Aza can also become a frontline therapy for fit patients as an alternative to IC. Several worldwide studies are addressing this issue, including an ongoing clinical trial named “Survival of the Fittest” exploring this concept in the US (NCT04801797). An open question is whether functional ex-vivo testing could become a powerful actionable tool that overcomes limitations presented by genetic and molecular indicators. Aim & Methods: In this study, we utilized an innovative ex-vivo functional platform of Patient Micro Avatars (PMAs) developed at OncoPrecision (García et al, Blood 2022 140 (Supplement 1): 13027-13028) to assess the predictive power for Ven/Aza treatment in a cohort of 11 AML patients. Patient-Derived Cells (PDCs) were obtained from the patients' PBMCs and Ven/Aza activity was assessed using high-throughput flow cytometry. An in-house Machine Learning (ML) tool was developed to identify the optimal variables that predict clinical outcome (Complete Remission: Yes/No). Clusters of predictive Response/Non-Response were defined by analyzing a cohort of >60 previously profiled AML patients and by leveraging the two most predictive populational features generated by the platform that better correlate with clinical outcome from >12,000 combinations of variables. Results: Our findings revealed differential ex-vivo activity of Ven/Aza in AML, with remarkably contrasting outcomes that defined clearly separate clusters of response (Figure - Left Panel). Such ML clustering led to 80% Overall Predictive Power and 100% Positive Predictive Value, meaning that all the patients for whom the platform predicted response achieved complete clinical remission. Moreover, by comparing the performance of other targeted therapies such as Gilteritinib, as well as IC regimens such as AraC-FaraA-IDA, side by side we were able to identify patients for whom Ven/Aza is the optimal regimen (e.g., Patient #169), and others for whom IC or Gilteritinib emerge as more promising therapeutic options (e.g., Patient #170) (Figure - Right Panel). Conclusions: This work presents a groundbreaking approach to predict Aza/Ven responders versus non-responders in AML. Combining the phenotypic outcomes of functional ex-vivo testing with ML tools presents the opportunity to more comprehensively predict response to cutting-edge therapies such as Ven/Aza than traditional genetic testing. This potential is particularly compelling for therapeutic schemes not directly associated with the acquisition of genetic mutations.

Prephase Cyclophosphamide: An Advantageous Bridge to Definitive Therapy

Background Classic Hodgkin lymphoma (cHL) and aggressive non-Hodgkin lymphoma (NHL) account for an estimated 0.5% and 4.1% of all new cancer diagnosis in the US in 2023, respectively. At time of diagnosis, approximately 43% of cHL and 53% of NHL are staged as advanced disease (stage III-IV). While these diseases are considered curable, standard treatments involve intensive combination chemotherapy that may preclude certain patients from receiving optimal therapy. One option to minimize risks is to use prephase cyclophosphamide (pCy) as an initial treatment in aggressive lymphomas. There is however limited data on the utility, adverse effects, and outcomes of this approach. Here we present data on our institutional experience of employing pCy for patients ineligible for intensive chemotherapy. Methods We performed a single institution, retrospective chart review of patients with history of cHL and NHL that received cyclophosphamide (Cy) as an initial chemotherapy during hospitalization. Lymphoma subtype, medical history, baseline bloodwork at time of treatment initiation, outcomes including transplant, relapse data and overall survival were collected. Fifty patients received pCy at 200 mg/m2 with the remaining four receiving 100 mg/m2, 150 mg/m2, or 300 mg/m2 based on provider preference. Corticosteroids, including prednisone, dexamethasone or methylprednisolone, were administered simultaneously with varying duration and dosage. We analyzed hepatic and kidney injury at the time of diagnosis, after initiation of pCy and time to recovery. Acute kidney injury (AKI) was defined as an increase in creatine more than 30% from baseline and hepatic injury was defined based on Common Terminology Criteria for Adverse Events (CTCEA) version 5. Charlson scores for all patients were collected. Results Fifty-four patients received pCy as a bridge to possible definitive therapy. The most common diagnosis was diffuse large B-cell lymphoma (DLBCL) and cHL, with 29 (53.7%) and seven (13%) patients, respectively (Figure 1). The median age was 56 years (18-84) with 21 (39%) patients >65 years. Advanced stage was observed in 49 (90.7%) patients. Four patients required treatment for tumor lysis syndrome (TLS) prior to initiation of pCy. Nineteen (35%) patients had AKI and 15 (28%) patients had hepatic injury at the time of initial presentation. Five patients experienced AKI from pCy with an average time to recovery of 11.2 days. Six patients, with only two having concurrent AKI, had hepatic injury from pCy with an average time to recovery of 8.5 days. PCy allowed 42 (78%) patients to undergo definitive treatment in respect to their lymphoma subtype. Eight (14.8%) patients went on to receive a consolidative autologous transplantation (HSCT) after reaching a remission from definitive therapy. At the time of our analysis, 30 (55%) patients are deceased which includes four patients that underwent HSCT. Of the 30 deceased, 10 patients were transitioned to comfort care during the admission after receiving pCy. Median overall survival is 370.5 days. Conclusion Based on our institutional experience, pCy is a reliable method to salvage patients with aggressive lymphomas that are not candidates for intensive chemotherapy. In our analysis, pCy allowed 78% of patients to receive definitive therapy for their respective lymphoma. In general, patients receiving pCy required hospitalization related to disease burden and pCy represents an effective and cost-efficient bridging strategy to outpatient treatment. Cyclophosphamide has a broad indication across hematologic malignancies and is a well-tolerated chemotherapy with a limited side effect profile. The modest dosing in combination with corticosteroids allows initial disease control and provides the ability to start definitive therapy in a timely manner. Additionally, we feel that pCy should be considered when designing clinical trials in an effort to promote enrollment of the “real-world” patient.

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

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

A Randomized Phase 2 Trial of 28-Day (Arm A) Versus 14-Day (Arm B) Schedule of Venetoclax + Azacitidine in Newly Diagnosed Acute Myeloid Leukemia Patients ≥ 60 Years

Background: Treatment options for older, less fit acute myeloid leukemia (AML) patients continue to be challenging, with toxicities and limited efficacy. The combination therapy of azacitidine (Aza) and the bcl-2 inhibitor venetoclax (Ven) showed superior benefit in response rates and overall survival compared to Aza alone, leading to the combination's FDA approval in newly diagnosed AML patients ≥ 75 years and younger patients ineligible for intensive chemotherapy. While Ven-Aza is a very effective and potent therapy, the 28-day continuous dosing of Ven combined with 7 days of Aza resulted in interrupted dosing or shortened dosing schedules due to persistent cytopenias in more than 50% of treated patients in the VIALE-A trial and subsequent real-world data. Furthermore, investigation of novel agents in combination with Ven-Aza has been challenging due to prolonged cytopenias even when monotherapy with the new agent shows no myelosuppression. Given that Ven-Aza is not curative, successful integration of other agents with this standard of care remains important in AML. The growing knowledge of Ven-Aza toxicities prompted attention to developing a safer dosing regimen while maintaining similar efficacy. Our study will examine the FDA label of 28 days of Ven, versus 14 days, in combination with Aza for newly diagnosed AML patients ≥ 60 years who are not candidates for intensive chemotherapy. The primary objective of this study is to compare complete remission (CR) rates with an abbreviated schedule of Ven (14 days) versus the current package insert approved schedule (28 days). We hypothesize that reducing the dosing duration of Ven would reduce the associated toxicities while maintaining a comparable response rate. Study Design and Methods: This protocol is a sub-study of the Beat AML Master Trial (NCT03013998) in which untreated AML patients age ≥ 60 are assigned an investigational therapy based on cytogenetic and central genomic analysis. Patients are randomized onto Arm A (28-day Ven-Aza schedule) or Arm B (14-day Ven-Aza schedule) stratified by age (60-74 vs. 75+ years). The primary objective is to determine the complete remission (CR) rate of patients treated in each randomized arm for up to 2 cycles. The secondary objectives will include assessments of composite complete remission (CR, CR with hematologic improvement, CR with incomplete count recovery), duration of remission, survival, and incidence of treatment-related and non-related toxicities. Additionally, the overall incidence of febrile neutropenia, grade ≥3 infections, transfusions, days of hospitalization and time to neutrophil recovery will be determined. In both arms of the study, patients will be assessed for response at day 21-28 of cycles 1 and 2. Patients who have marrow remission (< 5% blasts) will wait for count recovery of absolute neutrophil count ≥ 0.5x10 9/L and platelets ≥ 50x10 9/L before initiating the next cycle of therapy. Patients will then be followed for survival. With the exception of the Ven dosing schedule (14 vs. 28 days), the FDA approved package insert for Ven, including dose modifications for concurrent azole therapy, will be followed in both arms. The intent of the analysis is to demonstrate that the 14-day Ven-Aza regimen is at least as effective as the standard 28-day regimen. A total of 166 patients (83 per group) will provide 80% power to detect a 10% non-inferiority margin at the one-sided 5% significance level, assuming that the CR rate is 36% for the 28-day regimen, as observed in VIALE-A, and 25% higher (45%) for the 14-day regimen. In addition to assessing the frequency of adverse events such as cytopenias, safety monitoring will include an assessment of response rates after at least 25% of patients have completed 2 cycles of treatment, with consideration for stopping the study if data suggest the 14-day regimen is inferior to the standard regimen. Correlative studies will include measurement of MRD and a focus on identifying properties of leukemic cells that respond, do not respond and become resistant to therapy.

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study

Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1–21, itraconazole 100 mg twice daily from days 1–21, and azacytidine 100 mg subcutaneously, once daily from days 1–7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25–73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.

Hematopoietic Cell Transplantation in First Remission in AML in Mexico: Very Low Rates Derived from Early Relapses and Lack of Access

Background: Acute myeloid leukemia (AML) is the most frequent indication for allogeneic hematopoietic cell transplantation (alloHCT) in the world. According to international recommendations, intermediate and high-risk patients, <75 years and fit should receive consolidation with alloHCT. The role of autologous HCT in AML is less clear. We previously reported in a multicenter retrospective study a very low HCT rate (8.2%) despite most patients being potential candidates. The HCT rates in Latin America are considerably lower than in US or Europe (63.9 vs. 511.2 and 390.0/10 million). The main objective of this study was to analyze the reasons why the patients that were potential HCT candidates were not transplanted. Methods We included the patients from our previous retrospective multicenter registry that were potential HCT candidates considering: AML diagnosis between January 2013 and December 2017, <66 years, candidates for intensive chemotherapy and with intermediate or high cytogenetic risk. We reviewed the charts to collect information about HCT decisions and the factors associated with access to transplantation. Results We included 301 patients from 10 public centers with a median age of 42 years (14-65), 51.8% were women, 93.2% with an ECOG performance status 0-2 and 91% with an HCT-CI <3. The majority (86.7%) were classified as NOS-AML and 11.6% were secondary AML. Considering cytogenetics: 66.5% had an intermediate risk and 33.5% unfavorable risk. Induction related mortality was: 17.6% and 13.5% were primary refractory. The majority of the patients (80%) were treated in centers with a local transplant progarm. HLA testing was performed in 103 patients (34.2%). The main reasons for not performing the tests were: early relapse or primary refractory in 26.3% and lack of access or financial resources in 26.3%. In 7.5% of the cases, the patient refused to be tested. Age >60 years and HCT-CI >3 were associated with a lower likelihood of undergoing HLA matching (OR 0.2 95% CI 0.04-0.69, p=.006 and OR 0.02 95% CI 0.01-0.46, p<.001, respectively), in contrast with the presence of a local transplant program (OR 3.6 95% CI 1.7-7.71, p<.001). An HLA matched sibling-donor was identified in 45.1%, a haploidentical donor in 32.4% and no donor in 22.5% Only 23.6% of the patients had a HCT consultation and only 36 patients (12%) received HCT as consolidation in first remission: 30 alloHCT and 6 autoHCT. Only 47.9% of the patients receiving a transplant consultation were transplanted; 20/37 relapsed before HCT. The patients with a matched sibling-donor had a higher probability to receive consolidation with HCT when compared to patients with haploidentical or no sibling donor: 50%, 15.2% and 13% (OR 6 95% CI 2.3-15.5, p<.001). All patients without a matched or half-matched sibling donor who underwent transplantation received autoHCT. The median time from diagnosis to HCT consolidation was 7.2 months (2.9-25.1 months). A landmark OS analysis since CR showed a significant benefit from HCT (autoHCT or alloHCT): 3-year OS of 76.9% vs. 37.8%; HR 0.3 (0.1-0.6), p=.001. There was no significant difference between autoHCT and alloHCT with a 3-year OS of 83.3% and 75.4%. Discussion Only 12% of the patients that are potentially candidates are actually receiving HCT in Mexico. HLA testing is performed in only one third of the patients. Lack of access or financial resources and relapses before HLA testing or before HCT are the main reasons. The long-term OS of patients receiving HCT in excellent, however there is a clear bias if with consider the patients that had not the chance to reach the transplant due to early relapses. We have a very big challenge in the region, which is to ensure that the majority of patients who are potential candidates for HCT can access it through timely access to HLA testing and early access to alternative donor HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lower-Intensity CPX-351 + Venetoclax for Patients with Newly Diagnosed Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy: Post Hoc Analysis By Disease Risk Subgroups

Background: CPX-351 (United States: Vyxeos®; European Union/United Kingdom: Vyxeos® liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in patients who are candidates for intensive chemotherapy (IC) and aged ≥1 year in the United States and adults in the European Union/United Kingdom. However, the appropriate dosage of CPX-351 in patients unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit patients with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN. Our analysis evaluates the safety and efficacy of lower-intensity CPX-351 + VEN, based on disease risk classification, in adults with newly diagnosed AML (primarily de novo AML) who are unfit for IC. Methods: This is an open-label, phase 1b study (NCT04038437). Patients who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles of CPX-351 + VEN in the dose-exploration phase or up to 8 similar cycles in the expansion phase. Patients received CPX-351 dose levels of 20 units/m2 (dose level 1; n = 4), 40 units/m2 (dose level 2; n = 7), or 30 units/m2 (dose level 1b [recommended phase 2 dose]; n = 24) intravenously on Days 1 and 3 in combination with VEN 400 mg/day orally on Days 2 to 21 of each 28-day cycle. Patients are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Patients were categorized into disease risk subgroups based on National Comprehensive Cancer Network criteria. Results: This analysis included data from 35 patients enrolled across dose levels as of the data cutoff date of March 23, 2022, including 16 (46%) with favorable/intermediate and 19 (54%) with poor disease risk. Of the patients with favorable/intermediate disease risk, median age was 74 (range: 60, 90); 50% were male; 81% had a diagnosis of de novo AML. Of the patients with poor disease risk, median age was 74 years (range: 59, 89); 68% were male; 74% had a diagnosis of de novo AML; and 42% had mutated TP53. Patients were considered unfit for IC based on age ≥75 years (n = 8 [50%] for favorable/intermediate and n = 9 [47%] for poor disease risk) or ECOG performance status of 2 or 3 or comorbidities (n = 8 [50%]; n = 10 [53%]). Treatment-emergent adverse events (TEAEs) in ≥25% of patients with favorable/intermediate disease risk included febrile neutropenia (38%) and neutropenia (25%) and in those with poor disease risk included nausea (42%), febrile neutropenia (37%), thrombocytopenia (32%) and diarrhea (26%). The majority of patients with favorable/intermediate (94%) or poor (79%) disease risk experienced a grade ≥3 TEAE, primarily myelosuppression. Serious AEs were experienced by 11/16 (69%) and 14/19 (74%) patients, respectively, and the most common serious AE was febrile neutropenia (25% and 37%). There were no deaths in either group on or before Day 30; early mortality by Day 60 was 12% and 11%, respectively. Among patients with an evaluable remission assessment, complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 10/13 (77%) patients with favorable/intermediate and 8/18 (44%) patients with poor disease risk (Table); all patients who achieved CR or CRi did so after Cycle 1. Among evaluable patients with poor disease risk, 1/8 (13%) with and 7/10 (10%) without a TP53 mutation achieved CR. In patients with CR or CRi, MRD negativity was achieved by 7/10 (70%) patients with favorable/intermediate and 7/8 (88%) with poor disease risk; of these, 5 and 4 patients achieved MRD negativity after Cycle 1, respectively. Median (interquartile range) recovery times to neutrophils ≥500/μL and platelets ≥50,000/μL, respectively, were 30 (28, 36) and 21.5 (21, 28) days for patients with favorable/intermediate disease risk in CR or CRi and 32.5 (21, 38) and 21 (21, 28.5) days for those with poor disease risk in CR or CRi. Conclusion: The combination of lower-intensity CPX-351 + VEN demonstrated efficacy in both the favorable/intermediate and poor disease risk subgroups, without excessive myelosuppression. These data also provide further insights into outcomes on CPX-351 combination therapies for the treatment of AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Overview of Acute Myeloid Leukemia in Adults at the Peruvian National Cancer Institute (INEN)

Introduction: Acute myeloid leukemia (AML) 5-year overall survival (OS) previously reported is 16%, which is half of the median 5y OS in the United States. Therefore, to understand this significant disparity we aim to explore the clinical characteristics of AML patients diagnosed and treated at the National Cancer Institute in Peru. Methods: We conducted a retrospective analysis of all newly diagnosed AML patients seen at the National Cancer Institute (INEN) in Lima-Peru between 2015 to 2020. We include patients between 18-60 years old who received induction therapy. Exclusion criteria were acute promyelocytic leukemia, and AML secondary to MDS. Demographic and clinical characteristics were obtained from medical records, and risk stratification was done following the new criteria of the European Leukemia Network 2022. Survival analysis was performed using Kaplan Meier in SPSS. Results: A total of 390 newly diagnosed AML cases met inclusion criteria. The median age at diagnosis was 46 years, and patients were 52.7% male and 47.3% female. According to French American British (FAB) classification, the most common form was M2 (50.9%) followed by M4 (22.8%), M1 (11.9%), M5 (8.7%), and M0 (5.1%). ENL 2022 risk stratification was favorable (22.6%), intermediate (47.1%), adverse (13.9%), and unknown (16.3%). After induction therapy, 32.6% had a complete response (<5% blast in BM), 26.2% partial response, 13.4% no response and 27.8% non-evaluable response. Minimal molecular disease (MRD) was negative in 80.1% (101) of patients who achieved complete response. Response to induction chemotherapy by risk stratification groups is described in Table 1. Median overall survival was 7.2 months [5.8-8.6], and median OS by risk group was 10.1 months for the favorable group, 6.9 and 7 months for the intermediate and adverse respectively (Figure 1). Early death, defined as 60 days from commencing therapy, was 37.3% of all death. During this period, thirty patients went under allogeneic transplant, the median OS was 28.12 months. Conclusion: AML is a lethal disease in Peru, even for patients who are candidates for intensive chemotherapy, overall survival in this young cohort was dismal compared with reported international outcomes. A third of the deaths are within 60 days of starting the induction, which is related to treatment-related mortality and more studies are needed to narrow this outcome. In this Hispanic cohort, the favorable risk group has better outcomes, as expected, but intermediate and adverse groups have no difference in overall survival or response rates, suggesting intrinsic factors are associated and more cytogenetics and molecular studies are needed in Peruvian population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1b Dose Escalation and Expansion Study of SNDX-5613, Azacitidine (AZA) and Venetoclax (VEN) in Newly Diagnosed, Patients ≥ 60 Years with Untreated NPM1-Mutated/ FLT3-Wild Type AML or KMT2A-Rearranged Acute Myeloid Leukemia (AML)

Background: SNDX-5613 is a potent, orally available, small molecule inhibitor of menin, which binds to MLL1, encoded by the KMT2A gene, and MLL1 fusion proteins. Menin expression leads to aberrant gene transcription through its activation of Homeobox-related genes, leading to maturation arrest and leukemogenesis in KMT2A-rearranged and NPM1-mutated leukemias. Inhibition of menin activity significantly blocks the transcriptional signature and subsequently the proliferative capacity of leukemia cells harboring NPM1 mutations or KMT2A rearrangements. SNDX-5613 and its analogs have demonstrated robust single-agent anti-proliferative activity in NPM1-mutated AML cells and AML patient-derived xenograft models. Currently, SNDX-5613 is being explored as a single agent in a phase 1/2 study in patients with NPM1-mutated or KMT2A-rearranged relapsed/refractory AML, mixed phenotypic acute leukemia and acute lymphoblastic leukemia. The primary objective of this study is to determine the safety and recommended dose of SNDX-5613 combined with AZA and VEN in untreated AML patients age ≥ 60 years who are not candidates for intensive chemotherapy. Study Design and Methods: This study is a sub-study of the BeatAML Master Trial (NCT03013998) in which untreated AML patients age ≥ 60 are assigned an investigational therapy based on cytogenetic and central genomic analysis. Patients must specifically harbor an identifiable NPM1 mutation without a concomitant FLT3 mutation or have a KMT2A rearrangement to be eligible. In this phase 1b study, the primary objective is to determine the safety and recommended dose using a standard 3+3 design based on dose-limiting toxicities with 3 dose levels (DL) of SNDX-5613 to be evaluated in combination with VEN/AZA and an anti-fungal (required during induction): 75mg (DL-1), 113mg (DL1), and 163mg (DL2). In continuation phase with anti-fungals not required, SNDX-5613 will be dosed at 113mg (DL-1), 163mg (DL1), or 226mg (DL2) with appropriate dose reductions added for both SNDX-5613 and VEN if continuing on anti-fungals. The secondary objectives are to assess the overall response rate, measurable residual disease (MRD) status, overall survival, transplant rate and duration of remission. During induction cycles, VEN (D1-28) and AZA (D1-7) are dosed per standard of care every cycle. SNDX-5613 is dosed continuously orally twice daily with dose levels listed above. In patients who achieve a morphologic remission (<5% blasts), SNDX-5613 will be held if absolute neutrophil count (ANC) is < 0.5x109/L and/or platelets (PLT) < 50x109/L. Patients can receive up to 3 induction cycles to achieve a composite complete remission (CRc: CR, CRi, CRh). Patients can receive continuation therapy with AZA, VEN and SNDX-5613 once they achieve CRc and after hematologic recovery. Following the determination of a safe and recommended dose in phase 1b, there will be a dose expansion cohort of 12-20 patients following the same schedule as described above (Figure 1) to further evaluate safety, tolerability and correlative biomarkers. Correlative objectives include assessment of SNDX-5613 pharmacokinetics and its correlation with response and toxicities. Additionally, the study will evaluate the impact of MRD, as measured by central flow cytometry and next-generation sequencing of NPM1 mutations. Additional evaluations and biomarkers of potential interest include menin- KMT2A-specific transcriptomic changes, myeloid differentiation/cell subset changes, mechanisms of resistance, and discovery of baseline features (methylation, mutations, etc.) that can impact outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparative Efficacy of Targeted Therapies in Old Unfit Intermediate to High-Risk Patients with Acute Myeloid Leukemia: A Meta-Analysis of Comparative Studies

Introduction: Acute myeloid leukemia (AML) commonly affects the elderly with a median age of 67 years at diagnosis. Elderly AML is associated with high risk factors and adverse cytogenetics contributing to its worse outcomes. Moreover, older patients with AML respond poorly to intensive induction chemotherapy due pre-existing comorbidities. Novel therapies that include Bcl-2 inhibitors (Bcl-2i) and hypomethylating agents (HMA) have been used to treat AML in this patient population with varying degrees of response and success. Often, combination therapy with Bcl-2i and HMA has been used as frontline therapy for older patients or younger unfit patients who are not candidates for intensive chemotherapy. Currently, there are no randomized studies comparing various HMA, Bcl-2i, IDH-targeting agents, and their combinations. We performed a set of meta-analyses to evaluate relative efficacy of these various regimens in the treatment of AML in an old unfit intermediate to high-risk patient population. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; newly diagnosed or relapsed/refractory (R/R) AML; AML in elderly, unfit, intermediate to high-risk patients; comparative studies involving Azacitidine (A), Decitabine (D), Venetoclax (V), Enasidenib (E), and intensive chemotherapy (IC); and comparative studies reporting death rates over 2 year-period. Relative risk (RR) of death was calculated for each regimen. For comparative efficacy of different therapeutic regimens, a frequentists network meta-analysis was conducted using netmeta package and random effects model. For molecular alteration % response across various studies, a proportional meta-analysis was conducted. The pooled proportion with 95% CI was given both for the fixed effects model and the random effects model. Results: Five studies comprising 1,109 participants were included. The RR of death was lowest in A+V<D+V<E+A<A<IC in increasing order. This pattern persisted when the data was analyzed by RR of death at 1, 1.5, and 2 years. While A+V RR of death was the lowest at 1.5 years compared to the rest of the treatment regimens, theirs did not seem to vary much at the different time points. A+V and D+V had a significantly superior RR of death compared to IC, whereas A+V demonstrated also superior RR of death over A. The network meta-analysis ranked A+V as the most favorable regimen for newly diagnosed or R/R AML in an unfit, intermediate to high-risk patients followed by D+V, E+A, A, and IC in a decreasing order. We then analyzed the % CR/CRi rates of A+V across different AML molecular alternations. Those with CR/CRi rates <30%: KRAS, CBL, U2AF1. Alterations with CR/CRi rates 30-49%: JAK2, ETV6, GATA2, ZRSR2, ASXL1, CEBPA, SRSF2, STAG2, WT1. Those with CR/CRi rates of 50-70%: BCOR, BCORL, NF1, TP53, FLT3ITD, TET2, NRAS, DNMT3A, FLT3TKD, PTPN11, RUNX1, SF3B1, IDH2, EZH2. Lastly alterations with CR/CRi rates > 70%: IDH1, NPM1. Conclusions: This network meta-analysis is the first to compare and rank AML targeted therapies in patients with newly diagnosed or R/R AML who are intermediate to high-risk and unfit. It indicates that A+V has better RR of death than A or IC and was ranked as the preferred combination. It also demonstrates that A+V has wide range of activity with demonstrable CR/CRi across various AML molecular alterations.

Higher-Dose Venetoclax with Measurable Residual Disease-Guided Azacitidine Discontinuation in Newly Diagnosed Patients with Acute Myeloid Leukemia: Phase 2 Hiddav Study

Introduction: Venetoclax (ven) with azacitidine (aza) is the standard of care for newly diagnosed acute myeloid leukemia (AML) patients (pts) who are not candidates for intensive chemotherapy (IC). Efforts are needed to further optimize this regimen. In a previous report, measurable residual disease negativity (MRD-) was achieved in 41% of responders; these pts had superior outcomes. We hypothesized ven doses >400mg could be safely administered and would produce deeper remissions. In addition, responding pts continue treatment indefinitely. Given the prognostic significance of MRD-, we hypothesized MRD would identify candidates who could de-intensity therapy. To test these hypotheses, we designed an investigator initiated study in which newly diagnosed older AML pts were given 600mg of ven with aza. Those who achieved MRD- discontinued aza and were maintained on ven alone (High Dose Discontinuation Aza+Ven Study: HiDDAV). Methods: Pts were eligible if they had no prior therapy, were ≥60, ineligible for IC, had adequate organ function and a white blood cell count <25x109/L. Pts were admitted for "induction": dose escalation of ven to 600 mg over a 4 day period (100, 200, 400, 600), continued until day 28, and concomitant aza 75 mg/m2 on d 1-7. Pts without a CR/CRi/MLFS by day 28 either discontinued or repeated an induction cycle, as did those who achieved CR/CRi/MLFS but were MRD+. Up to 3 inductions were permitted for non-responders or MRD+ responders. If pts achieved a response without MRD- after the 3rd induction cycle they moved to MRD+ maintenance: ven 400 mg d 1-28 with aza d 1-7. From the conclusion of the first induction, and continuing with each response assessment, any pt who achieved CR/CRi/MLFS with MRD- went to MRD- maintenance: ven 400 mg d 1-28 and discontinuation of aza. Two MRD assessments were employed: multiparameter flow cytometry (flow) and droplet digital polymerase chain reaction (ddPCR) assays for as many baseline somatic non-DNMT3A/TET2/ASXL1 (DTA) mutations as possible. Full MRD- was defined as MRD- by flow and ddPCR. Results: Baseline data for the 42 pts is summarized in Table 1. Median follow up time is 42 months. 32 pts (76%) had a serious AE (SAE). Common AEs (≥20%) are summarized in Table 2. The most common hematologic AEs ≥ Grade 3 included thrombocytopenia (52%), febrile neutropenia (50%), leukopenia (41%) and neutropenia (38%). 30 day mortality occurred in 5/42 (11.9%), all of whom had refractory disease. The overall response rate was 28/42 (66.7%); 26 (61.9%) had a CR and 2 (4.8%) had MLFS. GCSF was used in 17/28 responders. Of 28 responders, 18 (64.3%) were MRD- by flow. 26/28 (93%) were able to be monitored by ddPCR; the percentage of all baseline non-DTA genes able to be monitored by ddPCR was 70% (45/64). Of pts monitored by ddPCR, 9/26 (35%) achieved MRD-. Full MRD- was achieved in 7/28 (25%). 10 went to transplant. Individual outcomes are summarized in Figure 1. The median duration of response (DOR) was 12.9 months (m) (95% CI=7.4, 17.6), event free survival (EFS) was 7.8 m (95%CI=2.5, 11.2) and OS was 9.8 m (95% CI=6.6, 14.9). MRD- by ddPCR, and full MRD-, did not associate with OS, EFS or DOR. However, MRD- by flow had significantly improved EFS (median 18.7 vs 8.2 m, p=0.047) and DOR (median 16.6 vs 6.7 m, p= 0.037), and a longer OS (19.6 vs 11.2 m, p=0.16) (Figure 2). Aza was discontinued in 12 pts; in 8 this was protocol mandated due to full MRD-, and occurred after a median of 2 cycles. 4 pts chose to stop aza, in violation of the protocol without MRD-, after a median of 4 cycles. The median DOR, EFS and OS for those who stopped aza with and without guidance was 13.9 m (95% CI=7.1, NR) and 12.9 m (95% CI=5.5, NR), 15.4 m (95% CI=8.5, NR) and 14.3 m (95%CI=6.6, NR), and 15.4 m (95% CI=8.5, NR) and 18.8 m (95% CI=6.6, NR), respectively. Conclusions: Higher rates of MRD- were seen with 600mg ven than has been reported with 400mg, and MRD- by flow was associated with improved clinical outcomes. However, DOR, EFS and OS were not improved over what has been reported with ven 400mg. Monitoring MRD by ddPCR was feasible, but in this dataset, this more stringent method of MRD detection did not identify pts with better outcomes. Pts whose aza discontinuation was guided by MRD- did not have improved outcomes compared to pts who discontinued aza without such guidance. Effective methods to de-intensify therapy in appropriate pts remain necessary. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P515: LOWER-INTENSITY CPX-351 + VENETOCLAX FOR PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA WHO ARE UNFIT FOR INTENSIVE CHEMOTHERAPY

Background: CPX-351 (Europe: Vyxeos® liposomal; United States: Vyxeos®) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults in Europe and patients aged ≥1 year in the United States who are candidates for intensive chemotherapy (IC). However, the appropriate dosage of CPX-351 in patients unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit patients with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Aims: Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Patients who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Patients are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 patients enrolled by 15 September 2021, with a data cutoff of 2 December 2021: 4 patients in the DEP at dose level 1 (CPX-351 20 units/m2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 patients in the DEP at dose level 2 (CPX-351 40 units/m2 + VEN 400 mg), and a total of 20 patients in the DEP and EP at dose level 1b (CPX-351 30 units/m2 + VEN 400 mg), which was established as the recommended phase 2 dose. Patients were considered unfit for IC based on age ≥75 years (n=15) or health (Eastern Cooperative Oncology Group performance status of 2 to 3 and/or comorbidities [n=16]). Median age was 74 years (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of patients were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) patients; no nonhematologic grade ≥3 TEAE was reported in >10% of patients. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n=1), worsening lung infection (n=1), and disease progression (n=2). Median (interquartile range) recovery times were 30 days (22, 34.5) to neutrophils ≥500/μL and 21 days (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) patients with an evaluable remission assessment. All 16 of these patients achieved remission (CR or CRi) after the first treatment cycle. MRD negativity was achieved by 12/16 (75%) patients with CR or CRi, primarily after Cycle 1 (Cycle 1: n=8; Cycle 2: n=2; Cycle 3: n=1; Cycle 4: n=1). Survival data are not yet mature. Summary/Conclusion: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of patients.

PB1849: TRIAL IN PROGRESS: PHASE IB/II STUDY OF SIREMADLIN IN COMBINATION WITH VENETOCLAX + AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY

Background: Treatment options for patients with AML who are not candidates for intensive chemotherapy (IC) are limited. The addition of venetoclax to hypomethylating agents demonstrated improved remission rates and survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive (DiNardo CD, N Engl J Med, 2020). Murine double minute-2 (MDM2) is a key negative regulator of tumor protein 53 (p53). Inhibition of the p53-MDM2 interaction results in up-regulation of the tumor-suppressive effect of p53. Siremadlin is a selective inhibitor of the p53-MDM2 interaction. Siremadlin + venetoclax has shown durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Findings from a first-in-human Phase I study with siremadlin demonstrated a tolerable safety profile and preliminary antitumor activity in patients with AML (Stein EM, Clin Cancer Res, 2021; NCT02143635). Preliminary results from the ongoing Phase Ib study exploring siremadlin in combination with venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352). Aims: Here we describe the study design of a Phase Ib/II study to assess the safety and efficacy of the novel combination of siremadlin + venetoclax + azacitidine in patients with AML who are unfit for IC (NCT05155709). Methods: The study will enroll approximately 55 adult patients with AML who are unfit for IC due to older age (≥75 y) or presence of comorbidities (cardiac or pulmonary, Eastern Cooperative Oncology Group performance status of 2 or 3). Patients with prior myelodysplastic syndrome, myelofibrosis, essential thrombocythemia, polycythemia, or therapy-related AML may also be eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated in 2 arms: patients with prior suboptimal response (no complete remission [CR], CR with partial/incomplete hematologic recovery [CRh/CRi], or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax + azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk clinical features that confer a low likelihood of response to venetoclax + hypomethylating agents (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2). The study will consist of a safety run-in (Part 1) and expansion phase (Part 2; Figure). The safety run-in will evaluate safety across 2 siremadlin dose levels (20 or 30 mg) from Day (D)1 to D5 in each 28-d treatment cycle in combination with venetoclax and azacitidine. In Arm 1, pts will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment. In Arm 2, venetoclax will be ramped up over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m2) will be administered from D1–D7 or from D1–D5, and D8 and D9). Upon confirmation of the recommended dose for expansion (RDE, determined for each arm separately), enrollment for the expansion phase (Part 2) will open; patients will be treated with siremadlin at the RDE in combination with venetoclax + azacitidine. The primary endpoints are incidence of dose-limiting toxicities (Arm 1 and Arm 2 separately) and CR rate (Arm 1 only). Secondary endpoints include safety and tolerability; CR rate (Arm 2 only); CR/CRh and CR/CRi rates; duration of CR, CRi, and CRh; overall survival; early mortality; MRD; and pharmacokinetics. Results: None, trial in progress. Image:Summary/Conclusion: None, trial in progress.

Patient, Family Member and Physician Perspectives and Experiences with AML Treatment Decision-Making.

IntroductionTreatment decisions in older adults with acute myeloid leukemia (AML) are challenging, particularly for those who are not candidates for intensive chemotherapy (IC), and the trade-offs patients, their families and physicians consider when choosing a treatment option are not well understood. This qualitative research explored the value of extending survival and the treatment decision-making process from a multi-stakeholder perspective.MethodsOverall, 28 patients with AML (≥ 65 years old, unsuitable for IC), 25 of their relatives and 10 independent physicians from the US, UK and Canada took part in one-on-one, 60-minute qualitative interviews.ResultsAcross all stakeholders, improved health-related quality of life (HRQoL), extended survival and relief of AML symptoms were recognized as most important in AML treatment decision-making. However, extending survival in ‘good health’ was more important than extending survival alone, particularly because of the extra time it gives patients and their relatives together, and allows patients to achieve important goals. Patients’ limited understanding of available treatment options, paired with incorrect perceptions of treatment side effects, impacted their involvement in the treatment decision-making process. Patients and physicians perceived physicians to have the most influence in the decision-making process despite their priorities not always aligning.ConclusionThese findings illustrate the importance of having structured discussions which explicitly assess patients’ goals and their understanding and expectations of treatments and also the need for patient friendly resources about the lived experience of AML and available treatment options. These measures will help to ensure that patients are fully involved in the shared decision-making process.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-022-00200-9.

Lower-intensity CPX-351 + venetoclax for patients with newly diagnosed AML who are unfit for intensive chemotherapy.

7031 Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients (pts) who are candidates for intensive chemotherapy (IC) and aged ≥1 year in the US and adults in Europe. However, the appropriate dosage of CPX-351 in pts unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit pts with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Pts who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Pts are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 pts enrolled by 9/15/2021, with a data cutoff of 12/2/2021: 4 pts in DEP at dose level 1 (CPX-351 20 units/m2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 pts in DEP at dose level 2 (CPX-351 40 units/m2 + VEN 400 mg), and a total of 20 pts in DEP and EP at dose level 1b (CPX-351 30 units/m2 + VEN 400 mg; established as the recommended phase 2 dose). Pts were unfit for IC based on age ≥75 y (n = 15) or health (ECOG PS of 2 to 3 and/or comorbidities [n = 16]). Median age was 74 y (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of pts were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) pts; no nonhematologic grade ≥3 TEAE was reported in &gt; 10% of pts. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n = 1), worsening lung infection (n = 1), and disease progression (n = 2). Median (IQR) recovery times were 30 d (22, 34.5) to neutrophils ≥500/μL and 21 d (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) evaluable pts. All 16 of these pts achieved remission (CR or CRi) after the first cycle. MRD negativity was achieved by 12/16 (75%) pts with CR or CRi, primarily after Cycle 1 (Cycle 1: n = 8; Cycle 2: n = 2; Cycle 3: n = 1; Cycle 4: n = 1). Survival data are not yet mature. Conclusions: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of pts. Clinical trial information: NCT04038437.

Patient and Physician Preferences for Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) in Patients Not Candidates for Intensive Chemotherapy

BackgroundThe number of targeted antileukemic therapies for the treatment of AML has increased over the past decade. However, for patients who are not candidates for high intensive chemotherapy (HIC), a better understanding is needed of what treatment attributes patients and physicians value and how their preferences differ to potentially improve treatment satisfaction.ObjectiveTo understand the impact of treatment attributes on treatment selection, we quantified the preferences of: a) patients newly diagnosed with AML who are not candidates for HIC; and, b) the physicians who treat them.MethodsA discrete choice experiment (DCE) was performed to quantify the extent to which treatment attributes impact patients' and physicians' treatment decisions in various scenarios. A literature review was conducted to identify treatment attributes important to patients with AML. Following the review, one-on-one phone interviews were conducted with patients (United States [US], n=3; United Kingdom [UK], n=3) and physicians (US, n=2; UK, n=2) to finalize the attributes and levels included in the DCE. Patients who were eligible to participate in the online survey were adults with a self-confirmed AML diagnosis, who had not relapsed or been refractory to treatment, had not received a stem cell transplant, and had not received HIC or met one of the following criteria: aged ≥75 years, diagnosis of congestive heart failure, chronic kidney disease, or other types of cancer, or ECOG score of 3 or 4. Physicians included hematologists/ oncologists treating >5 patients with AML over the past year. The web-based DCE included choice cards showing 2 hypothetical treatment profiles with 6 attributes (chance of 2-year overall survival [OS], average quality of life [QoL], risk of serious infections, risk of grade 3/4 nausea, chance of achieving transfusion independence, and duration of hospitalization per year) at varying levels. Participants chose a preferred treatment for each choice card. Conditional logit regression models were used to estimate preference weights and to analyze the impact of treatment attributes on participants' choices.ResultsThe DCE was completed by 77 patients newly diagnosed with AML who had not received HIC (US, n=47; UK, n=30) and 145 physicians (US, n=48; UK, n=52; Canada, n=29; Australia, n=16). Mean patient age was 71.4 years; 51.9% were female. Mean (SD) time since AML diagnosis was 8.3 (8.2) months. Most physicians were hematologists (81.4%) and saw a median of 30 AML patients yearly. For patients, duration of hospitalization (decrease from 6 to 2 weeks/year) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point QoL scale) and chance of 2-year OS (increase from 15% to 40%; Figure). Based on these findings, we estimated that patients were willing to accept a decrease in 2-year OS (from 40% to 15%) or an increase in risk of serious infections (from 5% to 20%) to decrease time spent hospitalized (from 6 to 2 weeks per year). For physicians, chance of 2-year OS (from 15% to 40%) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point scale), risk of serious infections (from 20% to 5%), and risk of grade 3/4 nausea and vomiting (from 20% to 1%; Figure). Based on these findings, we estimated that physicians were willing to accept an increased risk of grade 3/4 nausea and vomiting (from 10% to 20%) in exchange for decreased time in hospital (from 6 to 2 weeks per year) and increased chance of achieving transfusion independence (from 35% to 55%) when other treatment attributes remained stable.ConclusionSignificant differences in treatment attribute importance for patients with newly diagnosed AML who had not received HIC were observed between patients and physicians. Patients most valued treatments that reduced hospitalization duration while physicians most valued treatments that improved chance of 2-year OS. These differences highlight the importance of a shared decision-making process when choosing treatments for patients with AML ineligible for HIC. However, given the variability among individual patients, it may be particularly worthwhile for physicians to initiate a discussion with patients prior to treatment selection to determine what treatment attributes each patient values most. Treatment selection could then be tailored based on attributes most valued by the patient and likely lead to improved treatment satisfaction. [Display omitted] DisclosuresZhou: Astellas Pharma, Inc.: Consultancy. Yang: Astellas Pharma, Inc.: Consultancy. Song: Astellas Pharma, Inc.: Consultancy. Marshall: Astellas Pharma, Inc.: Consultancy; Arthur JE Child Chair: Other: Indirectly related salary support. Griffin: Novartis: Patents & Royalties: Post marketing royalties from midostaurin; Astellas Pharma, Inc.: Consultancy. Saini: Astellas Pharma, Inc.: Consultancy, Honoraria. Shah: Astellas Pharma, Inc.: Current Employment; University of Michigan School of Public Health Department of Health Management and Policy Alumni Board: Other: Chair-Elect.

Heterogeneous Definitions of Secondary Acute Myeloid Leukemia (AML) Yield Distinct Outcomes in Response to First-Line Treatment with Hypomethylating Agents (HMA) and Venetoclax (Ven)

Background:The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML.Methods:Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression.Results:82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS.There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10).Conclusions:Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. [Display omitted] DisclosuresMannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia

AbstractVenetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.