Partial Hematologic Recovery Research Articles

Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10-9), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database.

The potent oral inhibitor of BCL2, venetoclax (VEN), used to treat adults with chronic lymphocytic leukaemia, has been approved in US for the treatment of naïve patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy and recently in Europe, too. However, the drug has been used for years in combination with hypomethylating agents (HMAs) in patients not eligible to other treatment option, according to the so-called off-label use. We collected real-world data about patients treated with VEN + HMAs in the context of a pharmacovigilance project focused on the evaluation of the safety and effectiveness of drugs used for unapproved indication in Italian hospitals. From March to December 2020, 24 patients started treatment with VEN combined with HMAs. 21 patients have been assessed for response. Eleven (52%) patients reached complete remission (CR), and three patients (14%) CR with partial hematological recovery (CRh), with a median duration of response of 4.5 months (range 0.5–12.5). 19 patients experienced at least 1 adverse drug reaction (ADR), mostly serious, including 3 deaths (9% of ADRs; 12.5% of patients) in febrile neutropenia. Hematological toxicities and infections (cytopenia, neutropenia, febrile neutropenia, sepsis), were the most reported ADRs (84.4%). In general, neutropenic fever occurred more frequently in patients treated with decitabine (7 out of 9, 78%) compared to azacitidine (5 out of 15, 33%; p = 0.03), whereas response assessment did not differ based on used HMA (p = 0.1). These results confirm the benefit-risk profile of VEN in a real-world setting of patients with no adequate therapeutic options.

Characterization and Prognosis of Temozolomide-Induced Aplastic Anemia

Introduction: Temozolomide-induced aplastic anemia (TIAA) is a very rare and highly challenging complication of temozolomide (TMZ) chemotherapy. TMZ is a mainstay of therapy in patients with central nervous system (CNS) malignancies. Single-patient case reports and small case series have described variable morbidity and mortality associated with TIAA. However, quantitative evidence describing prognosis, clinical characteristics, and treatment of this entity is absent or very limited.Methods: We performed a 5-center, 22-year observational cohort study of patients with CNS malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. We compared patients who achieved meaningful hematologic recovery [partial hematologic recovery (PHR) or complete hematologic recovery (CHR)] to those who did not recover [refractory disease (RD)]. We used descriptive statistics, T-tests, and chi-square tests to evaluate patient characteristics, outcomes, and laboratory values. Overall time to hematologic recovery and overall survival of patients with PHR, CHR, and RD were estimated using the Kaplan-Meier method and compared using the log-rank test, and a multivariable logistic model evaluated potential predictors of achieving CHR. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery (TABLE 1).Results:Study Population and TIAA Prevalence. Of 3,821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA (FIGURE 1). Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle (TABLE 2).Complications and Outcomes of Hematologic Recovery. 23 patients (67.6%) ultimately achieved a hematologic recovery and the remaining 11 patients (32.4%) had refractory disease. Figure 2A illustrates the time from TIAA diagnosis to PHR and CHR for the cohort. In Kaplan-Meier survival analysis, the median time from TIAA diagnosis to PHR was 84 days and the median time to CHR was 134 days. Patients without recovery were more likely to develop serious complications (TABLE 3), including febrile neutropenia (72.7% vs. 30.4%, P=0.03), major infection (45.5% vs. 8.7%, P=0.02), hospitalization (81.8% vs. 43.5%, P=0.04), and death (100.0% vs. 60.9%, P=0.02). This increased risk of complications in patients not achieving hematologic recovery was observed despite a similar median time from TMZ initiation to TIAA diagnosis in the two groups (45 days vs. 40 days). Figure 2B illustrates the overall survival in the entire cohort and by each hematologic recovery subgroup. In Kaplan-Meier survival analysis, median overall survival from the time of TIAA diagnosis was as follows: entire cohort, 355 days; achieved PHR, 752 days; achieved CHR, 1414 days; refractory disease, 28 days (P<0.0001 for comparison of PHR, CHR, and refractory disease). In a multivariable logistic model, none of the evaluated covariates (age, sex, TMZ dose, body surface area, and use of hematopoietic growth factors) were significantly associated with achieving CHR.Treatment of TIAA and Outcomes of Therapy. 29 patients (85.3%) received hematopoietic growth factors (TABLE 3); no patients were treated with immunosuppression or hematopoietic stem cell transplant. Hematologic recovery rates were numerically higher in patients receiving thrombopoietin receptor agonists vs. those who did not (81.8% vs. 54.2%, P=0.15), but were not higher in patients receiving granulocyte colony stimulating factors vs. those who did not (68.0% vs. 66.7%, P=0.99).Conclusions: TIAA occurs in less than 1% of patients receiving temozolomide for CNS malignancies, occurring rapidly after TMZ initiation, but is highly morbid and often fatal when it occurs, precluding further use of cytotoxic therapy in the vast majority of patients. In the one-third who do not recover, risks of febrile neutropenia, infection, and hospitalization are increased, and overall survival greatly diminished. Hematologic recovery is potentially aided by the use of thrombopoietin receptor agonists, as has been demonstrated in classical autoimmune aplastic anemia. Further study of TIAA treatment is needed for this serious complication of TMZ therapy. [Display omitted] DisclosuresForst: Eli Lilly: Current holder of individual stocks in a privately-held company. Al-Samkari: Rigel: Consultancy; Argenx: Consultancy; Moderna: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

A Phase 1 Study Evaluating ASTX727 (decitabine and cedazuridine) and Venetoclax Combination Therapy in Newly Diagnosed AML Patients Unfit for Intensive Induction Chemotherapy

A Phase 1 Study Evaluating ASTX727 (decitabine and cedazuridine) and Venetoclax Combination Therapy in Newly Diagnosed AML Patients Unfit for Intensive Induction Chemotherapy

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation

AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation

Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)

Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)

OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)

OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)

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.

Response Prediction to Isocitrate Dehydrogenase (IDH) Inhibitors in Patients with IDH1- or IDH2-Mutated Acute Myeloid Leukemia Using Clinical and Genomic Data

Background: Ivosidenib (Servier Pharmaceuticals LLC) and enasidenib (Celgene) are inhibitors of mutant IDH1 and IDH2, respectively, approved for the treatment of relapsed/refractory (R/R) AML with an IDH1 or IDH2 mutation (ivosidenib is also approved for front-line use in patients ≥ 75 years or with comorbidities). While these drugs were approved based on durable complete remission (CR) + CR with partial hematologic recovery (CRh) rate, only 23-43% of patients responded. Thus, there is a need for a biomarker to better predict response. We previously presented a genomic model of response to enasidenib using linear discriminate analysis (Ghazanchyan et al., ASH 2018). In the two-part study presented here, we improved this modeling by adding clinical data, using machine learning-based approaches to model response to both enasidenib and ivosidenib, and generated an independent validation cohort using clinical samples.Methods: In part I, models were generated using data submitted to FDA in the marketing applications for ivosidenib and enasidenib (studies AG120-C-001 [NCT02074839] and AG221-C-001 [NCT01915498], respectively). Analysis inclusion criteria were available genomic data, IDH mutation positivity per the companion diagnostics, and receipt of at least the approved dose of IDH inhibitor. Patients in the ivosidenib cohort had untreated (n=33) or R/R AML (n=173); patients in the enasidenib cohort had R/R AML. Patients achieving a best response of CR or CRh were considered responders; all other patients were considered nonresponders. Genomic data for the ivosidenib cohorts were generated with the Foundation Medicine FoundationOne Heme panel (FMI) in dose escalation (n=38) and Brigham and Women's Hospital Rapid Heme Panel (RHP) in dose expansion (n=168); these cohorts were analyzed separately to account for differences between panels. Genomic data for the enasidenib cohort (n=75) were generated with the FMI panel. Machine learning-based feature selection approaches were used prior to modeling to identify important clinical data variables (i.e., baseline demographics and disease characteristics). Each analysis cohort was split into a training set (80% patients) and a testing set (20% patients). Machine learning modeling was performed with the decision-tree based algorithm XGBoost using repeated stratified cross validation.In part II of the study, we generated an independent validation cohort consisting of patients with IDH-mutated myeloid malignancies treated with ivosidenib or enasidenib at collaborating institutions (n=14). Bone marrow or peripheral blood samples were processed for deep whole exome sequencing to an average coverage of 441X. Custom analysis pipelines for filtering and annotation were developed to harmonize exome and panel data.Results: In part I, separate machine learning models were generated for each cohort using clinical data only, genomic data only, and clinical and genomic data together. Use of clinical and genomic data together, compared with either data type alone, resulted in improved model performance with accuracies of 89-100% in the testing sets. The most important clinical and genomic features for each cohort are shown in Figure 1.In part II, the independent validation cohort, collaborators provided response data and clinical data for variables found to be important in the models. Patient demographics and response rates are shown in Table 1. Mutational profiles for model genes mutated in ≥ 2 patients are shown in Figure 2. The models for CR+CRh response using both clinical and genomic data in the validation cohort had accuracies of 50-75% (66.7% ivosidenib BWH; 50% ivosidenib FMI; and 75% enasidenib). The combined accuracy improved to 80% when restricted to AML cases (excluding CMML and MDS) treated with ivosidenib (using the BWH model) or enasidenib (n=10).Conclusions: This study demonstrates the potential of harnessing machine learning for biomarker discovery to improve response prediction for the treatment of AML. The modeling approaches improved with inclusion of multiple data types, highlighting the importance of multi-faceted approaches for biomarker development in AML. The models presented have encouraging accuracies in a small independent validation cohort, suggesting potential clinical utility of machine learning-based biomarkers for identifying patients likely to respond to IDH inhibitors. [Display omitted] DisclosuresKural: Senseonics: Current equity holder in publicly-traded company; NanoDimensions: Current equity holder in publicly-traded company; Bionano Genomics: Current equity holder in publicly-traded company. Ghiaur: Menarini Richerche: Research Funding; Syros Pharmaceuticals: Consultancy. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lai: Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Astellas: Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynne: Servier Pharmaceuticals: Honoraria; Carisma Therapeutics: Patents & Royalties. OffLabel Disclosure:This presentation references off label use of enasidenib in patients with MDS and CMML.

Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia

Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia

Comparison of Liposomal Daunorubicin and Cytarabine Versus Cladribine and High-Dose Cytarabine-Based Induction Chemotherapy in Secondary Acute Myeloid Leukemia Patients (sAML) or Acute Myeloid Leukemia with Myelodysplastic Related Changes (AML-MRC)

Comparison of Liposomal Daunorubicin and Cytarabine Versus Cladribine and High-Dose Cytarabine-Based Induction Chemotherapy in Secondary Acute Myeloid Leukemia Patients (sAML) or Acute Myeloid Leukemia with Myelodysplastic Related Changes (AML-MRC)

Real World Treatment Patterns and Outcomes of Venetoclax (Ven) and Hypomethylating Agents (HMA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) in the United States

Real World Treatment Patterns and Outcomes of Venetoclax (Ven) and Hypomethylating Agents (HMA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) in the United States

Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy; An Open-Label, Multicenter, Phase 1b Study

Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy; An Open-Label, Multicenter, Phase 1b Study

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Phase 1/2 Study Investigating CC-90011, a Potent, Selective, and Reversible Oral Inhibitor of Lysine-Specific Demethylase 1 (LSD1), Plus Concurrent Venetoclax (VEN) and Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML)

Phase 1/2 Study Investigating CC-90011, a Potent, Selective, and Reversible Oral Inhibitor of Lysine-Specific Demethylase 1 (LSD1), Plus Concurrent Venetoclax (VEN) and Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML)

Characterization and prognosis of temozolomide-induced aplastic anemia in patients with central nervous system malignancies.

Temozolomide-induced aplastic anemia (TIAA) is a rare but highly challenging complication of temozolomide (TMZ) therapy. Evidence describing prognosis, clinical characteristics, and treatment of this entity is very limited. We performed a multicenter, 22-year observational cohort study of patients with central nervous system (CNS) malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery. Of 3821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA. Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle. 23 patients (67.6%) ultimately achieved a hematologic recovery. Patients without recovery were more likely to develop febrile neutropenia (72.7% vs. 30.4%, P = .03), infectious complications (45.5% vs. 8.7%, P = .02), require hospitalization (81.8% vs. 43.5%, P = .04), and die (100.0% vs. 60.9%, P = .02). Median overall survival from TIAA diagnosis was 752 days in patients achieving a partial hematologic recovery versus 28 days in those who did not (P < .0001). 29 patients (85.3%) received one or more hematopoietic growth factors; hematologic recovery rates were higher in patients receiving thrombopoietin receptor agonists (81.8% vs. 60.9%) but were not higher in patients receiving granulocyte colony-stimulating factors. TIAA occurs in <1% of patients receiving TMZ for CNS malignancies, but is highly morbid when it occurs and frequently fatal in the one-third of patients not achieving hematologic recovery. Thrombopoietin receptor agonists may improve the likelihood of a hematologic recovery.

MPN-395: Efficacy and Safety of ≤200 mg Avapritinib in Patients with Advanced Systemic Mastocytosis: Pooled Results from the Phase 1 EXPLORER and Interim Phase 2 PATHFINDER Studies

<h3>Introduction</h3> Systemic mastocytosis (SM), a clonal neoplasm driven by <i>KIT</i> D816V mutation in ~95% of cases, has limited treatment options. We evaluated pooled efficacy and safety of avapritinib, a selective inhibitor of D816V-mutant <i>KIT,</i> in patients with advanced SM (AdvSM) from the phase I/II EXPLORER (NCT02561988) and from interim analysis of the phase II PATHFINDER (NCT03580655) studies. <h3>Methods</h3> Patients included in this <i>post hoc</i> pooled analysis were ≥18 years of age with centrally confirmed diagnosis of AdvSM and treated with once-daily avapritinib at starting doses up to 200 mg. Overall response rate (ORR), defined as complete remission with full (CR) or partial hematologic recovery (CRh), partial remission (PR), or clinical improvement, was evaluated per modified IWG-MRT-ECNM criteria. Other analyses included overall survival (OS), changes from baseline in mast cell disease burden, and safety. <h3>Results</h3> Efficacy of avapritinib was analyzed in 53 ORR-evaluable patients; median age was 67 years (range, 37–85), 32% had an ECOG PS of 2–3, 66% had prior anti-neoplastic therapy, 47% received prior midostaurin, and 94% had a D816V mutation. Responses occurred in 72% (95% CI, 58–83) of patients, with 57% achieving a PR or better (95% CI, 42–70) and 28% with a CR/CRh. Median duration of response was 38.3 months (95% CI, 21.7–NE), and median time to response was 1.9 months (range, 0.3–26.7), with responses deepening over time. Median estimated 12-month OS rate was 84%. Patients achieved ≥50% reductions from baseline in serum tryptase (49/53, 92.5%), marrow mast cell aggregates (46 of 52 evaluable, 88.5%), and blood KIT D816V allele fraction (37 of 52 evaluable, 71.2%). In all AdvSM patients (safety population) receiving the starting avapritinib dose of 200 mg (n=80), common AEs were edema (79%), diarrhea (28%), nausea (24%), and fatigue/asthenia (23%). Decreased platelets (64%), hemoglobin (55%), and neutrophils (54%) from baseline were the most common laboratory abnormalities. Overall, 4 (5%) patients discontinued treatment due to drug-related AEs and 6 (8%) from disease progression. Of 2 (3%) AE-related deaths, neither were treatment-related. <h3>Conclusions</h3> Pooled study results showed ≤200 mg avapritinib induced rapid and deepening clinical responses and had a manageable safety profile.

AML-310: Prognostic Value of CRh in Acute Myeloid Leukemia Treated with Venetoclax and Decitabine

Introduction: Recent FDA approvals of novel therapies and hypomethylating agents/venetoclax (HMA-ven) has transformed AML therapy. CR with partial hematological recovery (CRh), defined as bone marrow blasts 0.5×109/L, and platelet count >50×109/L, was used as a surrogate marker for efficacy due to limited data on HMA-ven. We evaluated the impact of CRh on pts treated with 10-day decitabine and venetoclax (DEC10-VEN, NCT03404193). Method: Patients with newly diagnosed AML aged >60 years or patients with secondary AML and antecedent hematological disorder were included. Decitabine 20 mg/m2 IV for 10 days with oral venetoclax 400 mg daily was administered for induction and decitabine (5 days) with daily venetoclax for consolidation. Responses initially recorded were complete response (CR), CR with incomplete hematologic recovery (CRi), and morphologically leukemia-free state (MLFS), according to ELN 2017 criteria. Pts who achieved CRi and MLFS were re-classified to CRh. Outcomes evaluated were overall survival (OS) and event-free survival (EFS). Full protocol and interim results have been published (DiNardo et al. Lancet Haematol. 2020;7:e724–36) Results: From January 2018 to February 2021, 125 patients (79 [63%] newly diagnosed, 46 [37%] secondary AML) with a median age of 71 yrs (range 48–89) were included. 69 (55%) pts achieved CR, 11 (8%) pts achieved CRh, 14 (11%) pts achieved CRi, 10 (8%) pts achieved MLFS, and 21 (17%) pts were refractory. Of the 11 CRh pts, 8 (73%) patients were previously classified as CRi and 3 (27%) as MLFS. Among pts achieving CR, the median OS was 24.5 mo, and median EFS was 18.0 mo. CRh was achieved with a median of 1 (range 1–3) cycles. Median OS of CRh vs CRi was 16.9 vs 5.8 mo (HR: 0.47, 95% CI: 0.19–1.13, p=.06), and CRh vs MLFS was 16.9 vs 6.2 mo (HR: 0.34, 95% CI: 0.13–0.93, p=.007). Median EFS of pts with CRh vs CRi was 14.1 vs 5.8 mo (HR: 0.49, 95%CI: 0.21–1.14, p=.08); CRh vs MLFS was 14.1 vs 6.2 mo (HR: 0.37, 95% CI: 0.14–1.01, p=.016). Pts achieving CRh had durable remission with a duration of response of 6.0 vs 2.5 mo with CRi and 1 mo with MLFS. Conclusion: In pts with newly diagnosed and secondary AML treated with DEC10-VEN, pts achieving CRh had a trend toward improved OS and EFS compared with CRi or MLFS.

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia

BackgroundUntil recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001).MethodsWe evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC.ResultsMedian OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%).ConclusionFindings in Japanese patients are consistent with those of the overall ADMIRAL study population.