Composite Complete Remission Research Articles

A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Entospletinib (ENTO) and Decitabine (DEC) Combination Therapy in Older Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Patients with Mutant TP53 or Complex Karyotype Is Associated with Poor Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial

Entospletinib (ENTO) and Decitabine (DEC) Combination Therapy in Older Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Patients with Mutant TP53 or Complex Karyotype Is Associated with Poor Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial

Venetoclax with Azacitidine or Low Dose Cytarabine As an Alternative to Intensive Chemotherapy in Fit Adults during the COVID19 Pandemic: Real World Data from the UK National Health Service

Venetoclax with Azacitidine or Low Dose Cytarabine As an Alternative to Intensive Chemotherapy in Fit Adults during the COVID19 Pandemic: Real World Data from the UK National Health Service

Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service

Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service

Pegcrisantaspase in Combination with Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: A Phase 1 Study

Background:Despite new therapeutic advances, acute myeloid leukemia (AML) still has poor outcomes, especially in patients with relapsed or refractory (R/R) disease with complex karyotype (CK) and/or TP53 mutation. Venetoclax (Ven), an oral BCL-2 inhibitor, in combination with DNA methyltransferase inhibitors (DNMTIs) has been approved by the FDA for treatment of newly diagnosed AML in adults who are unfit for intensive therapy with encouraging results, but the combination has been found to be less effective in patients with R/R AML.AML cells have been shown to be sensitive to extracellular glutamine depletion or manipulation of intracellular glutamine metabolism. Asparaginase converts asparagine and glutamine to aspartate and glutamate, decreasing plasma concentrations of asparagine and glutamine, with anti-leukemia activity. We previously published that crisantaspase produced complete plasma glutamine depletion in patients without dose-limiting toxicities and was associated with anti-leukemic activity in R/R AML (Emadi et al. Cancer Chemother Pharmacol 2018). In preclinical studies, we found that Pegcrisantaspase (PegC), a long-acting crisantaspase, not only had potent single-agent anti-AML activity, but also synergized with Ven in CK-AML cell lines and primary cells in vitro and in vivo (Emadi et al. Leukemia 2021). Ven-PegC targets the mTOR-eIF4E-driven ribosomal translational protein synthesis apparatus in AML. With no standardized treatment and poor outcomes for R/R AML, there is an unmet need for effective treatment options.Trial Design: We present an ongoing, non-randomized, open-label Phase 1 clinical trial evaluating Ven administered orally daily in combination with PegC administered intravenously every 14 days in 28-day treatment cycles in adults patients with R/R AML. The trial consists of two phases: dose escalation (four cohorts) and dose expansion at the final recommended phase 2 doses (RP2Ds).Adult patients with a pathologically confirmed diagnosis of AML whose disease has relapsed or is refractory to at least one line of AML therapy and with adequate organ function and no prior history of pancreatitis or ≥ Grade 3 thrombohemorrhagic events are eligible for this trial. All patients with FLT3, IDH1 or IDH2 mutation must have received at least one line of therapy with an available FLT3/IDH1/IDH2 inhibitor to be eligible for this trial. The study will include CK-AML and TP53-mutated AML.The primary objectives of the trial are to evaluate the safety and tolerability of Ven-PegC and estimate the maximum tolerated doses (MTDs) and/or biologically active doses (e.g. RP2D) of Ven-PegC in patients with R/R AML. The primary endpoints of the trial are incidences of regimen-limiting toxicities (RLTs) and treatment-emergent adverse events (TEAEs). The secondary endpoints include the rates of complete remission (CR) and composite complete remission (CR+CRh+CRi), event-free survival, overall survival, the rate of conversion from transfusion dependence to transfusion independence, and achievement of MRD <0.02% within 2 cycles of treatment with Ven-PegC. If a patient does not achieve at least hematologic improvement within 3 cycles of treatment, the patient will be taken off study. Responding patients can continue with the assigned doses until progression.The study uses a 3+3 design. Up to 24 subjects will be enrolled during dose escalation (in case exactly one RLT occurs in the first three patients enrolled at each of the four dose levels). Another 10 subjects will be enrolled at the final RP2D in an expansion cohort, for a total of 16 patients treated at the RP2D. The study is currently open at the University of Maryland Greenebaum Comprehensive Cancer Center. ClinicalTrials.gov Identifier is NCT04666649. [Display omitted] DisclosuresEmadi: Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Servier: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Secura Bio.: Consultancy; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder.

Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia

Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia

Gilteritinib Can be Safely Combined with Atezolizumab for the Treatment of Relapsed or Refractory FLT3-Mutated AML: Results of a Phase 1 Study

Gilteritinib Can be Safely Combined with Atezolizumab for the Treatment of Relapsed or Refractory FLT3-Mutated AML: Results of a Phase 1 Study

Modified Intensive Induction Treatment for Elderly Acute Myeloid Leukemia Patients Based on Peripheral Blast Clearance Rate: A Phase II Single-Arm Study

BackgroundOutcomes and prognosis of older patients with acute myeloid leukemia (AML) are fairly dismal and poor tolerance to regimens hinders treatment decision-making to expand to the greatest extent. Nevertheless, it is still indicated that a certain proportion of elder patients may benefit from intensive therapies [1], after which the insistent need for algorithms to select elder patients fit for intensive regimens has emerged. Based on the previous achievement, monitoring the peripheral blast clearance rate on the day 5 of induction chemotherapy (D5-PBCR) showed its promising value in younger patients [2]. Along with the increasingly important comprehensive geriatric assessment (CGA), we conducted this trial in fit elderly AML patients to confirm the non-inferior efficacy of modified intensive treatment on the basis of D5-PBCR.Materials and methodsThis multiple-center, single-arm, phase 2 trial of early intervention according to D5-PBCR results with modified “3+7” regimen was performed at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China) and the other two hospitals in Shanghai. Patients aged 60-75 years were assessed via CGA and required to be fit for intensive chemotherapy. Eligible patients had newly diagnosed AML with more than 0·5% blasts detected in the peripheral blood and adequate end-organ function. The initial induction included idarubicin (6 mg/m² for 3 days) and cytarabine (100 mg/m² for 7 days). Peripheral blood specimens were collected before and on day 5 of induction and analyzed by multi-parameter flow cytometry to calculate the D5-PBCR. D5-PRCR (+) patients received extra IDA (6 mg/m² for 2 days) starting from induction day 6 with the absence of contraindications. Responders received another “2+5” regimens and at least two cycles of mediate dose cytarabine or even allogeneic stem cell transplantation, if eligible. The primary endpoint was composite complete remission (CR/CRi), and secondary endpoints were overall survival, event-free survival, early mortality, minimal residual disease after one cycle of induction, drug toxicity, and safety. The trial was registered in the Chinese Clinical Trial Register (ChiCTR-OPC-16008955).ResultsBetween March 30, 2016, and June 30, 2021, a total of 120 eligible patients were enrolled in the trial (Fig.1). Fifty-nine (49.2%) patients were D5-PBCR (+), of which seventeen patients were ineligible for extra idarubicin due to severe infection or unstable hemodynamic parameters and one patient was lost to follow-up. None of the patients in the D5-PBCR (-) group discontinued induction due to adverse events, and three patients were lost to follow-up. The composite complete remission rate after one course of induction for all patients was 62.6% (62/99), with 65.5% (38/58) and 58.5% (24/41) for D5-PBCR (-) and D5-PBCR (+) groups, respectively (P=0.497). At a median follow-up of 24.3 months (95% CI 10.4-38.2), median overall survival (OS) was 20.0 months (95% CI 15.2-24.8) and 13.6 months (95% CI 9.8-17.4), and the median event-free survival (EFS) was 7.8 months (95% CI 2.5-13.1) and 6.6 months (95% CI 4.3-8.9), respectively (Fig.2). Neither the OS nor EFS showed significant differences between the two groups. The total 30-day mortality rate of the two cohorts was 6.8% (7/103). The median platelet recovery time (PLT>50×109/L) after induction therapy in CR/CRi was different between patients with D5-PBCR(-) and D5-PBCR(+) (22 days vs 26 days, P=0.000, Fig.2F). There was a trend but no significant difference in the recovery time of neutrophils (ANC>0.5×109/L) in two cohorts (21 days vs 23 days, P=0.025, Fig.2E). The incidence of adverse events during the first induction was comparable between the two groups and key adverse events of grade ≥3 included pneumonia(37%), sepsis (7%), and γ-glutamyl transpeptidase(GGT) increase (6%) in the entire cohort(Table.1).Conclusion:“3+7” regimen modified by the composition of D5-PBCR and CGA was safe and tolerable in fit older patients with AML. The efficacy and safety of induction were non-inferior compared with the results of existing trials, along with a relatively lower dose of IDA. We considered there may be reserved probability for combining other emerging drugs to challenge higher remission rate in fit AML with additional investigation.Keywords: acute myeloid leukemia; elderly; induction therapy; non-inferior; flow cytometry; D5-PBCR. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Venetoclax Plus Decitabine for Young Adults with Newly Diagnosed ELN Adverse-Risk Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase 2 Trial

Background:The standard of induction therapy for fit patients(pts) with acute myeloid leukemia (AML) has not changed much since 1973, when the 7+3 regimen of cytarabine and anthracycline was born. This combination of agents produces complete remission (CR) in about 60-80% of younger adults and in 40-60% of older adults (60 years) depending on genetic risk group. However, compared with AML in favorable- and intermediate-risk categories, induction therapy for fit AML pts in adverse-risk category had significantly lower CR rates and dismal outcome. Recently, combination therapy with venetoclax and azacitidine or decitabine for the treatment of older pts with de novo AML unsuitable for intensive chemotherapy, has resulted in response rates of 60-70%. Currently, the role of venetoclax in combination with azacitidine or decitabine in young adults with newly diagnosed ELN adverse-risk AML remains unclear. This study aims to evaluate the safety and efficacy of venetoclax plus decitabine as induction therapy in young adults with newly diagnosed ELN adverse-risk AML.Methods:This is an interim analysis of an ongoing phase 2 clinical trial (NCT04752527) of a planned 42 untreated ELN adverse-risk AML pts 18-59. The fast next-generation sequencing (NGS) for the most commonly mutated genes in AML using Oncomine TM myeloid research assay on Ion S5 and Chef platform (Thermo Fisher) was completed within 72 hours, which could screen for the ELN adverse-risk features in AML pts together with multiplex RT-PCR and fluorescence in situ hybridization (FISH). In cycle 1, pts receive decitabine 20mg/m 2 on d1-5 and venetoclax escalated from 100mg to 200mg to 400mg until 28-day cycle is finished. For pts with high FLT3-ITD allelic ratio, sorafenib was optional administered at a dose of 400mg orally twice daily. Bone marrow assessments were performed on d28 before subsequent cycle. Pts who achieve composite complete remission (defined as complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with partial hematological recovery [CRh], and morphologic leukemia free state [MLFS]) receive 1 or 2 cycles of consolidation with high dose of cytarabine followed by allogeneic hematopoietic stem cell transplantation. Non-responders or pts who achieve partial remission (PR) receive 1 additional cycle of combination of venetoclax plus decitabine. The primary objective is to determine the composite complete remission rate (CR+CRi+CRh+MLFS). The endpoint is to show that venetoclax plus decitabine is superior to historical control (HC) of cytarabine combined with idarubicin (12 mg/m 2) in young adults with newly diagnosed ELN adverse-risk AML.Results:From February 1, 2021 to July 31, 2021, a total of 104 newly-diagnosed AML pts underwent screening, and 30 pts were classified as ELN adverse-risk category by NGS (within 72 hours) together with multiplex RT-PCR and FISH. Totally, 19 pts with ELN adverse-risk were enrolled, comprising 14 males and 5 females. 2 (10%) pts had secondary AML (sAML). Median age was 38 years (range, 19-57 years). The baseline patient characteristics are summarized in Table 1. Outcome data were updated as of July 2021, for a median follow-up of 2.7 months. Among 14 evaluable pts, 4 (28.6%) achieved a CR, 5 (35.7%) achieved a CRh and 5 (35.7%) had a PR in cycle 1. Individual pts data of this study (n = 14) was compared to a HC, combining individual pts data of AML with adverse-risk from the SZ3202 registry (n = 42) and the pts treated with IA (IDA:12 mg/m 2) in the same period (n = 18). The venetoclax plus decitabine cohort demonstrated higher rates of CR than the HC cohort, with an observed CR/CRh rate of 64.3%, compared with 38.3% (Figure 1).The regimen was well tolerated, with 4- and 8-week mortality rates of 0% and 0%, respectively. The most frequent nonhematologic adverse events of any grade were neutropenic fever (n=6) and pneumonia (n=3). With a median follow-up of 2.7 months, the median remission duration and overall survival (OS) have not been reached. Tumor lysis syndrome occurred in one patient and resolved with medical management.Conclusions:Preliminary results indicate that venetoclax plus decitabine is an effective, lower-intensity regimen that is well tolerated for young adults with newly diagnosed ELN adverse-risk AML, producing high rates of CR, low rates of infections, and low rates of early death. Recruitment of young adults with newly diagnosed ELN adverse-risk AML pts for this trial is ongoing. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Real World Prospective Observational Multicenter Trial of Venetoclax-Based Therapy for Patients with AML Reveals Unique Patterns of Patient Selection and Treatment Utilization - Revive Study

Real World Prospective Observational Multicenter Trial of Venetoclax-Based Therapy for Patients with AML Reveals Unique Patterns of Patient Selection and Treatment Utilization - Revive Study

Outcome with Intensive Chemotherapy Compared to Hypomethylating Agent- Based Induction in Patients Aged 70 Years or Older with Newly Diagnosed Favorable Risk Acute Myeloid Leukemia

Outcome with Intensive Chemotherapy Compared to Hypomethylating Agent- Based Induction in Patients Aged 70 Years or Older with Newly Diagnosed Favorable Risk Acute Myeloid Leukemia

Comparative Effectiveness of Venetoclax Combinations Vs Other Therapies Among Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from the AML Real World Evidence (ARC) Initiative

Comparative Effectiveness of Venetoclax Combinations Vs Other Therapies Among Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from the AML Real World Evidence (ARC) Initiative

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

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

Novel Combination Therapy of Venetoclax and Ruxolitinib in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

Novel Combination Therapy of Venetoclax and Ruxolitinib in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

A Real World Study of Venetoclax Combined with Azacitidine in 64 Chinese Patients Newly Diagnosed Acute Myeloid Leukemia

Background: Venetoclax combined with azacitidine has been demonstrated to have a favorable overall response rate and tolerable safety in acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy.Methods: This study retrospectively recruited 64 Adults (≥18 years) with newly diagnosed AML ineligible for intensive chemotherapy who had received at least one cycle of treatment with venetoclax plus azacitidine. The primary endpoint was overall survival (OS). Secondary endpoints were remission rates. Safety was evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.Results: The median age of the enrolled patients was 69 years. The median OS for the cohort was 15.5 months, with 21.2 months for complete responders as opposed to 13.3 months for those who did not achieve a complete response. 39 (60.9%) patients achieved composite complete remission (completeremission (CR) + CR with incomplete count recovery (CRi)) and 7/64 (10.9%) achieved morphologic leukemia-free state (MLFS) with a median follow-up time of 14.7 months. The median CR+CRi duration was 10.9 months. It is noteworthy that 43/64 (67.2%) patients achieved the best response after one cycle with a median time of 1.2 months. Normal karyotype (P=0.015) was significantly associated with extended OS in multivariate analysis, while higher white blood cell count (P=0.032), lower platelet count (p=0.018) and antifungal drug combination (P=0.013) were predictors of shortened OS in univariate analysis. Common grade 3/4 Adverse Events (AEs) included infection (68%) and hematological AEs consisting of neutropenia (93%), anemia (90%), leukopenia (86%), thrombocytopenia (77%) and febrile neutropenia (52%). The median neutropenia duration was 16 days.Conclusions: The novel venetoclax-azacitidine combination regimen showed prolonged survival period, promising efficacy, sound and rapid response, and superior tolerance in Chinese patients newly diagnosed AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Time Spent at Home Among Older Adults with AML Treated with Hypomethylating Agents and Venetoclax

IntroductionThe prognosis for older adults with acute myeloid leukemia (AML) is poor. Of approximately 12,000 adults age ≥ 60 diagnosed with AML in the U.S. annually, less than 40% survive 1 year from diagnosis. Prior research has shown that adults with AML feel time at home is a critical consideration in treatment selection. However, to date, no study has adequately described the amount of time older adults can expect to spend at home following initiation of AML therapy. In this study, we aimed to (1) quantify this time and (2) assess the impact of venetoclax (VEN) combination therapy on time at home for older adults with AML.MethodsWe queried records from University of North Carolina Health to identify individuals age ≥ 60 newly diagnosed with AML from 2015 to 2020. First-line AML therapy was identified, and those receiving azacitidine (AZA) and/or VEN were included. Dates of diagnosis, first remission, death, last follow up, and all oncology clinic / emergency department (ED) / inpatient encounters were captured. Patients with incomplete records were excluded.The primary outcome was proportion of days at home (PDH). PDH was calculated for each patient by subtracting the number of care days (days hospitalized or seen in an ED / oncology clinic / infusion center) from the total days of follow up, divided by total days of follow up. Overall survival (OS) was calculated via the Kaplan-Meier method. Covariates including demographics and disease risk (per European Leukemia Net 2017) were captured.PDH was evaluated via summary statistics for the full cohort and stratified by each categorical variable, both for the full follow up period and on a month-by-month basis among survivors. Associations between PDH and covariates were further assessed via linear regression with adjustment for length of follow up, with significance assessed via Wald Chi-square test.ResultsFrom 2015-2020, 137 older adults receiving first-line AZA and/or VEN were identified. 24 were excluded due to incomplete records. Among the remaining 113, mean age was 76 (range 60-99), 80.4% were white, and 43.4% were female. Most received AZA+VEN (51.3%) followed by AZA monotherapy (39.0%) and other VEN-containing combinations (9.7%). The majority had adverse-risk AML (61.3%). Baseline covariates including age and ELN risk were similar across therapy groups.Over the full follow up period, mean PDH was 0.58 (95% confidence interval 0.54-0.63) with a median of 0.63. PDH was similar among those with adverse-risk (mean 0.55, CI 0.49-0.61) and intermediate-risk AML (0.64, CI 0.56-0.72). PDH did not differ among therapy groups: AZA+VEN (0.60, CI 0.54-0.66), AZA alone (0.57, CI 0.49-0.66), and other VEN-containing regimens (0.54, CI 0.40-0.69). When adjusted for length of follow up, no covariate had a significant association with PDH (all p > 0.05).When evaluated month-by-month, the proportion of days at home rose over time among survivors. For example, of patients who survived the full month, mean PDH was 0.51 (CI 0.47-54, n = 105) in month 1 following diagnosis and 0.77 (CI 0.72-0.82, n = 57) in month 6. Figure 1 summarizes person-days at home or engaged in care for 12 months following diagnosis (including contributions from those who did not survive the full month).34.5% of patients achieved composite complete remission, with higher rates among those receiving AZA+VEN (51.7%) than AZA alone (13.6%) (OR 6.8, p = 0.0002). Median OS was 0.64 years (CI 0.32 - 0.91) and was similar across therapy groups.ConclusionBurden of care for older adults with AML treated with first-line AZA or VEN is high. These individuals spend nearly half (cohort mean 42%) of days following diagnosis engaged in oncology care. In randomized studies, the addition of VEN to AZA improves OS and increases remission rates though results in higher rates of neutropenic fever. Although this study may be underpowered to detect small differences, the superior remission rates with AZA+VEN did not translate to more days at home, perhaps due to increased admissions for neutropenic fever and office/infusion visits.Given the importance of time at home to older adults with AML identified in prior research, these data provide new information to support shared decision making regarding treatment options. Future prospective trials should evaluate burden of care, including time at home, as an endpoint. While awaiting these data, larger analyses of the impact of treatment regimen on burden of care would be useful. [Display omitted] DisclosuresBryant: Carevive: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Servier Pharmaceuticals: Honoraria, Speakers Bureau. Coombs: Alexion Pharmaceuticals: Research Funding; Machaon Diagnostics: Research Funding. Foster: Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bellicum Pharmaceuticals: Research Funding.

AML-091: Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib

<h3>Context:</h3> Findings from the phase 1/2 CHRYSALIS trial and the phase 3 ADMIRAL trial demonstrated the safety and efficacy of the <i>FLT3</i> inhibitor gilteritinib in patients with FLT3-mutated (<i>FLT3^Mut</i>⁺) relapsed/refractory (R/R) AML. The efficacy of gilteritinib after prior tyrosine kinase inhibitor (TKI) therapy in these patients is unclear. <h3>Objective:</h3> Determine whether prior TKI therapy affected response and survival in <i>FLT3^Mut</i>⁺ R/R AML patients treated with gilteritinib. <h3>Design:</h3> A retrospective analysis of the CHRYSALIS and ADMIRAL trials. <h3>Patients:</h3> We retrospectively analyzed outcomes in patients with R/R AML previously treated with TKIs (midostaurin/sorafenib), before receiving 120 or 200 mg gilteritinib. <h3>Main Outcomes Measures:</h3> Treatment response and overall survival (OS) in patients who previously received or did not receive treatment with TKIs. <h3>Results:</h3> Of the 145 FLT3-mutation-enriched patients who received 120- or 200-mg gilteritinib in the CHRYSALIS trial, 33 (23%; 120 mg, n=15; 200 mg, n=18) had received a prior TKI (all sorafenib). Rates of composite complete remission (CRc) in patients who received prior TKIs (42%) and those who did not (43%) were similar. Among patients who received prior TKIs, rates of CRc were 53% in the 120 mg group and 33% in the 200 mg group; rates of CRc in patients without prior TKIs were similar across dose groups (44% and 42%, respectively). In the ADMIRAL trial, 31 of 247 (13%) R/R <i>FLT3^Mut</i>⁺ AML patients in the gilteritinib arm and 14 of 124 (11%) patients in the salvage chemotherapy (SC) arm had received prior TKIs. In the gilteritinib arm, CRc rates were comparable in patients who received (48%) and did not receive prior TKIs (55%); lower CRc rates were observed in the SC arm in both TKI and non-TKI pretreated groups (21% and 22%, respectively). Median OS in patients treated with prior TKIs was 6.5 months with gilteritinib and 4.7 months with SC (HR=0.671 [95% CI: 0.328, 1.376]); in patients without prior TKIs, median OS was 9.6 and 6.0 months, respectively (HR=0.625 [95% CI: 0.474, 0.824]). <h3>Conclusion:</h3> High response rates with gilteritinib were observed in patients with <i>FLT3^Mut</i>⁺ R/R AML who received prior TKIs.

AML-162: Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: Updated Analyses of a Phase 1b Study

<h3>Background/Objective:</h3> To provide updated results from a Phase 1b trial (NCT03625505) of BCL-2 inhibitor venetoclax and FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Ven+Gilt) in patients with relapsed/refractory (R/R) FLT3-mutated (<i>FLT3^Mut</i>⁺) acute myeloid leukemia (AML). <h3>Methods:</h3> Patients with R/R AML <i>FLT3^Mut</i>⁺ received up to Ven 400mg daily with Gilt (80 or 120 mg) daily in 28-day cycles, following Ven ramp-up. Primary endpoint was modified composite complete remission (mCRc) to align with Phase 3 ADMIRAL trial CRc responses. Secondary endpoint was mCRc duration of response (DOR); overall survival (OS), and changes in <i>FLT3</i> allelic burden were exploratory. Adverse events (AEs) were monitored. <h3>Results:</h3> At data cutoff (November 30, 2020), 43 patients (median age 63 yrs) with <i>FLT3^Mut</i>⁺ were enrolled. <i>FLT3</i> internal tandem duplications (ITD) were identified in 86% patients, and 14% had only tyrosine kinase domain (TKD) mutations. Baseline cytogenetic risk was favorable in 5%, 55% intermediate, 31% poor, and 12% had no mitoses/missing data. Median (range) prior lines of therapy were 2 (1–5), and 77% patients had 2 or more prior lines of therapy: 65% received at least one prior FLT3 inhibitor, and 7% received prior Ven; 33% had prior transplant. Grade 3/4 AEs were reported in 98% of patients; grade ≥3 cytopenias occurred in 79% and were predominantly managed by Ven/Gilt dose interruptions. The only grade 3/4 nonhematologic AEs reported in >20% of patients was pneumonia (n=9; 21%) and 1 instance of clinical tumor lysis syndrome. Serious AEs were reported in 74% of patients. Overall, 30- and 60-day mortality rates were 0% and 12%, respectively. AEs led to either Ven or Gilt interruptions in 56% patients, reductions in 7%, and discontinuations in 14%. mCRc was achieved by 86% of <i>FLT3^Mut</i>⁺ efficacy population (36/42) with median time to first response of 1.0 mo (range: 0.7–4.6) and 86% with prior FLT3 tyrosine kinase inhibitor (TKI) exposure (24/28). FLT3 molecular clearance (<10^–2) was observed in 69% of mCRc patients with PCR analyzed at baseline and at least 1 follow-up timepoint (18/26). <h3>Conclusions:</h3> Updated analyses show Ven+Gilt achieved high rates of mCRc in patients with heavily pre-treated and prior TKI-exposed R/R <i>FLT3^Mut</i>⁺AML with encouraging molecular clearance rates. Using similar criteria to previous <i>FLT3^Mut</i>⁺ studies, high mCRc rate with Ven+Gilt suggests strong anti-leukemic activity. Cytopenias were prominent but manageable.