Use Of Intensive Induction Chemotherapy Research Articles

Selinexor in Combination with Hypomethylating Agent (HMA) in Patients with Refractory/Relapsed Acute Myeloid Leukemia (AML) Previously Exposed to Venetoclax: A Retrospective Study

Background Acute myeloid leukemia (AML) is a heterogeneous hematologic tumor with varied clinical manifestations. Venetoclax combination regimens have shown promising results as a first-line treatment for AML. However, for patients who fail venetoclax treatment, the prognosis remains poor, necessitating the exploration of new therapeutic approaches. Selinexor, a selective inhibitor of XPO1, has shown potential as a therapeutic strategy to overcome resistance to conventional chemotherapy for AML. Here, we report the safety and efficacy data from a real-world study of selinexor + HMA in patients with refractory/relapsed (R/R) AML previously exposed to venetoclax. Methods We conducted a monocentric retrospective analysis on adult patients with unfit R/R AML or those with comorbidities preventing the use of intensive induction chemotherapy. The patients received selinexor-based combinations between May 2021 and December 2022. AML genetic risk stratification and response criteria were assessed according to the 2022 European Leukemia Net (ELN) consensus. The selinexor + HMA regimen consisted of selinexor 40 mg twice weekly for 3 weeks orally, and either decitabine (DAC, 10 mg/dfor 7-10 days intravenously) or azacytidine (AZA, 75 mg/m 2/d for 7 days subcutaneously, halved for patients over 60 years). Supportive treatments and dose adjustments were administered based on individual clinical indications. Some patients underwent allogeneic hematopoietic stem-cell transplantation. Results A total of 12 patients with R/R AML treated with selinexor-based combinations were considered in this study, including 7 patients with refractory AML and 5 patients with relapsed AML (one with post-transplant recurrence). The median age of the patients was 36 years (range 18-68 years). All patients had intermediate or adverse ELN genetic risk. All patients had previously received venetoclax-based combinations, and 58% (7/12) had been treated with HMAs. The overall response rate (ORR) was 66.7% (8/12) with a combined CR rate (CRc) of 50% (6/12). Among the 6 patients with CRc, 3 (50%) achieved negative minimal residual disease (MRD,≤1*10 -3). CRc was 42.9% (3/7) in patients previously exposed to HMA-based therapy and 100% in patients without exposure history. The most common grade 3 or 4 adverse events were neutropenia (83.3%) and thrombocytopenia (58%), with the median recovery time of 14 (8-21) and 16 (8-24) days, respectively. Common non-hematologic toxicities included infection (66.7%) and gastrointestinal reactions (66.7%). As of Jun 20, 2023, with a median follow-up of 11.3 months (range 0.7-19.5 months), 50% (6/12) of the patients died due to disease progression or severe infections. 66.7% (8/12) of the patients received transplants after achieving remission. The median overall survival (OS) was significantly longer in the transplantation group compared to the non-transplantation group (p=0.009) (Figure.1a). Patients without previous HMA exposure seemed to have a better efficacy benefit from the X+HMA combination regimen, although the difference was not statistically significant due to the llimited sample size (Figure.1b). Conclusion The real-life study demonstrated that the combination of selinexor and HMAs is a viable and safe option for patients with unfit R/R AML who were previously exposed to venetoclax. X+HMA salvage therapy followed by transplantation showed durable survival benefits in R/R AML patients, especially those without prior HMA exposure, suggesting a potential efficacy advantage.

Preclinical Efficacy of the Menin-KMT2A Inhibitor JNJ-75276617 in Combination with Venetoclax and Azacitidine in AML

Background: JNJ-75276617 is a highly selective and orally bioavailable small molecule targeting the menin- histone-lysine N-methyltransferase 2A (KMT2A) protein-protein interaction. Pharmacologic disruption of this interaction was previously shown to induce differentiation and block progression of KMT2A-r or NPM1c acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (ALL) in preclinical models (Kwon, ASH 2022). Small-molecule inhibitors including JNJ-75276617 are being explored clinically as a treatment for KMT2A- and NPM1-altered leukemias, which represent an area of high unmet medical need. Hypomethylating agents (e.g. azacitidine, decitabine) in combination with venetoclax have significantly improved clinical outcomes for AML patients and have become a preferred frontline treatment for AML patients ≥75 years of age, or who have comorbidities that preclude use of intensive induction chemotherapy. Although promising responses are seen in the frontline setting, unfortunately many patients relapse highlighting the need for better therapies and more effective combinations. JNJ-75276617 was previously shown to inhibit HOX/Meis1 stemness genes and induce differentiation genes in KMT2A- or NPM1-altered leukemic cells. Here, we evaluated whether JNJ-75276617, which induces differentiation followed by cell death, could enhance the mechanisms of action triggered by venetoclax plus azacitidine, which primarily drives apoptosis by displacing anti-apoptotic proteins. Results: JNJ-75276617 exhibited synergistic effects with venetoclax alone or in combination with azacitidine in AML cells bearing KMT2A-r in vitro. Proliferation assays in KMT2A-r MOLM-13 AML cells showed that doublet combination of JNJ-75276617 plus venetoclax induced a synergistic antiproliferative effect in vitro that was significantly increased when compared to JNJ-75276617 or venetoclax monotherapy. The triplet combination of JNJ-75276617 plus azacitidine and venetoclax further induced a synergistic antiproliferative effect that was significantly increased when compared to JNJ-75276617 monotherapy or the doublet combination of venetoclax plus azacitidine. In the disseminated KMT2A-r MOLM-13 model in mice, monotherapy treatment with JNJ-75276617 at 10 mg/kg and azacitidine at 2 mg/kg induced a significant ILS of 35% each compared to the vehicle control group (p<0.0001 each), while 6% ILS was observed for mice treated with 100 mg/kg venetoclax (p=0.0076). The combination of azacitidine plus venetoclax, resulted in a significant ILS of 53% compared to the vehicle control (p<0.0001). Doublet combination treatment with either JNJ-75276617 plus azacitidine or plus venetoclax resulted in a significant ILS of 106% or 256%, respectively, as compared to the vehicle control (p<0.0001 each). The JNJ-75276617 triplet combination with azacitidine plus venetoclax induced a significant ILS of 277%, as compared to the vehicle control group (p<0.0001). These results further showed that either the doublet combinations of JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination provided a superior increase in survival as compared with the clinical standard regimen of azacitidine plus venetoclax (p<0.0001 each). In a disseminated NPM1c model (OCI-AML3), JNJ-75276617 doublet or triplet combination with azacitidine and venetoclax also yielded superior survival versus the standard azacitidine plus venetoclax regimen, however triplet efficacy seemed most strongly driven by JNJ-75276617. Conclusions: These studies suggest that the doublet combinations of either JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination could potentially provide a beneficial treatment option for KMT2A- or NPM1-altered AML, and support the recently initiated clinical trial investigating JNJ-75276617 in combination with AML-directed therapies, including venetoclax and azacitidine (NCT05453903). JNJ-75276617 is also being clinically investigated as a monotherapy for R/R acute leukemia (NCT04811560).

Survival and Outcomes after Relapse in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients Treated with Venetoclax-Based Chemotherapy

Background Venetoclax (bcl-2 inhibitor) was first approved in 2018 for use in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in older patients, or those who have comorbidities that preclude use of intensive induction chemotherapy. However, AML is also known to evolve and undergo clonal selection when treated with venetoclax, leading to treatment failure. Mechanisms for adaptive resistance include kinase activation (e.g. FLT3-ITD), clones that acquire biallelic silencing of TP53, and monocytic AML cells that upregulate MCL1 to evade BCL2 blockade. Other issues with venetoclax-based regimens include prolonged cytopenias and increased risk of infection. Our aim was to investigate survival after relapse, subsequent responses to second- line agents, and pattern of infections in patients treated with first-line venetoclax-based combination therapies. Methods This was a retrospective study of patients who received venetoclax-based regimens for untreated AML or myelodysplastic syndrome with excess blasts (MDS-EB) at LAC+USC Medical Center and Norris Cancer Center in Los Angeles, CA from January 1, 2018 to June 30, 2022. The electronic medical record was reviewed for demographics, disease characteristics, clinical history, transplant status, and survival. Results 61 patients received frontline venetoclax-based regimens for untreated AML or MDS-EB with a mean age of 65 (range 22-84); 36% were female, 44% non-Hispanic white and 31% were Hispanic/Latino. 41% had AML-MRC (myelodysplasia-related changes), 36% had De Novo AML, 16% had therapy-related AML, and 7% had MDS-EB. The majority (70%) were adverse risk group per ELN 2017 and 46% had complex cytogenetics. 58 patients had available myeloid mutation panel at time of diagnosis. The most common mutations (median allele frequencies) were: TP53=33% (0.45), ASXL1=17% (0.37), NPM1=16% (0.39), IDH2=9% (0.42), IDH1=7% (0.29), FLT3-ITD=5% (0.51). 70% received venetoclax with decitabine, 21% received venetoclax with azacitidine, and 2% received venetoclax with LDAC. Median number of cycles was 3 (1-16). 10 patients underwent allogeneic stem cell transplant. Out of 61 patients, 12 (20%) had primary refractory disease and 23 (38%) relapsed on frontline venetoclax. 49% of these relapsed/refractory patients received salvage chemotherapy. The median time to relapse and number of cycles prior to relapse was 6.3 months (1.6-17.4) and 4 (1-12) respectively. There was no correlation between cytogenetics and genetic variables and risk of relapse. Only 3 (19%) out of 16 patients and 3 (27%) out of 11 patients who received second- and third-line treatment achieved CRi respectively. Myeloid mutation panel was available for 12 patients at time of relapse. Most common mutations were FLT3-ITD/TKD (n=5), TP53 (n=3) and NPM1 (n=3). Six patients acquired new mutations at the time of relapse: FLT3-ITD (n=2), TP53 (n=1), WT1 (n=2) and ETV6 (n=1). Median time from relapse to death was 3 months (1-23). Median overall survival was 10.2 months. Median survival in responder compared to non-responders after cycle 1 and cycle 2 was 16.8 vs. 5.3 months (p <0.001) and 19.4 months vs. 7.4 months (p=0.031) respectively. Median survival in patients with relapse compared to non-relapse was 12.1 vs 6 months (p=0.187). 40 (66%) patients died; major causes of death were disease progression (50%), bleeding (10%) and infection (25%). 28% patients died in intensive care unit. 9 patients had fungal infections; most common were aspergillosis (n=5) and mucormycosis (n=2). Conclusions Venetoclax-based regimens are effective options for untreated AML in elderly patients. Response to first and second cycle of combination treatment predict survival. Although we observed clonal evolution in relapsed patients, it did not affect their survival. FLT3-ITD was a commonly acquired mutation at time of relapse, thus patients received salvage with targeted agents. Also, as patients relapse, the chance of attaining CR/CRi with subsequent lines of treatment is less than 30% and risk of invasive fungal infection was approximately 15%. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ivosidenib in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy.

7053 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) occur in ̃3% of patients (pts) with MDS and are associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for m IDH1 R/R AML and m IDH1 newly diagnosed AML in pts ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human study of IVO in pts with m IDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received IVO 500 mg once daily (QD). Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate (ORR) of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to IVO in m IDH1 R/R MDS and the study was amended to enroll additional pts. We report updated results. Methods: This substudy of the single-arm, open-label study of IVO evaluated pts with R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Other key eligibility criteria included: high disease burden based on IPSS or IPSS-R risk at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and no prior IDH1 inhibitor therapy. Pts received IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 pts with R/R MDS were enrolled: 5 (31%) pts remained on treatment and free from leukemic transformation; 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). AEs are summarized in the Table. 2 pts each experienced differentiation syndrome (grade 2) and QTcF prolongation (grade 1 and 2). 7/16 pts achieved complete response (CR, 44%; 95% CI, 20%, 70%), 1 achieved partial response (6%), and 5 achieved marrow CR (31%), resulting in an ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) pts. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 pts experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 pts (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Additional translational data are being analyzed. Conclusions: In pts with m IDH1 R/R MDS, IVO monotherapy was tolerable and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for pts with m IDH1 R/R MDS. Clinical trial information: NCT02074839. [Table: see text]

Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia

Venetoclax is a potent oral, highly selective small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 protein approved for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma in treatment-naive patients (in combination with obinutuzumab) or for patients with relapsed/refractory CLL (in combination with rituximab). Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine, is also approved in the United States for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy. Clinical studies of patients with CLL or AML report both hematologic (e.g., neutropenia) and nonhematologic (e.g., gastrointestinal disorders and tumor lysis syndrome) adverse events associated with administration of venetoclax. It is therefore essential to provide information on the appropriate management of venetoclax-associated side effects. This article discusses the efficacy and safety of venetoclax administration and presents strategies specifically for the management of neutropenia and certain nonhematologic adverse events in patients receiving venetoclax for the treatment of AML and CLL.

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

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

Ivosidenib (IVO) in Combination with Azacitidine (AZA) in Newly Diagnosed (ND) Older Patients with IDH1 R132-Mutated Acute Myeloid Leukemia (AML) Induces High Response Rates: A Phase 2 Sub-Study of the Beat AML Master Trial

Ivosidenib (IVO) in Combination with Azacitidine (AZA) in Newly Diagnosed (ND) Older Patients with IDH1 R132-Mutated Acute Myeloid Leukemia (AML) Induces High Response Rates: A Phase 2 Sub-Study of the Beat AML Master Trial

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Enasidenib in Combination with Venetoclax in IDH2-Mutated Myeloid Malignancies: Preliminary Results of the Phase Ib/II Enaven-AML Trial

Enasidenib in Combination with Venetoclax in IDH2-Mutated Myeloid Malignancies: Preliminary Results of the Phase Ib/II Enaven-AML Trial

Venetoclax (Venclexta)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses venetoclax (Venclexta), 10 mg, 50 mg, and 100 mg oral tablets. Indication: In combination with azacitidine or low-dose cytarabine for the treatment of patients with newly diagnosed AML who are 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

MDS-335: Ivosidenib (IVO) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome (R/R MDS): Updated Enrollment for the MDS Sub-Study

Context: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of patients with MDS and are associated with increased transformation to acute myeloid leukemia (AML). IVO is an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme and is FDA-approved for mIDH1 R/R AML and mIDH1 newly diagnosed AML in patients ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human, phase 1 study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839), 12 patients with R/R MDS, with median age 72.5 years (range 52–78), received IVO 500 mg once daily (QD). All patients received prior MDS treatment. Investigator-assessed ORR (CR + PR + marrow CR, per IWG 2006) was 75% (95% CI 43–95), with median duration of response of 21.4 months (95% CI 2.3–NE). Nine (75%) patients were transfusion-independent for ≥56 days during treatment. No dose-limiting toxicities or adverse events leading to treatment discontinuation were reported among patients with MDS. Based on these encouraging data, the FDA granted Breakthrough Therapy Designation to IVO in mIDH1 MDS; the study was amended to enroll additional patients with mIDH1 R/R MDS. Objective: To evaluate safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Design: A sub-study of the single-arm, open-label, phase 1 dose escalation and expansion study of IVO in mIDH1 advanced hematologic malignancies, evaluating patients with R/R MDS. Patients must have R/R disease after prior standard therapy; high disease burden based on cytopenia and/or transfusion dependence at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and be amenable to bone marrow aspirate and/or core biopsy at specified study timepoints. Patients with documented AML are not eligible. IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: Study is open; enrollment of ~23 patients from the US and France planned. Results not yet available. Conclusions: This sub-study will provide additional insights into safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of treatment with IVO in patients with mIDH1 R/R MDS. Funding: Agios; Servier.

Venetoclax (Venclexta)

&#x0D; CADTH recommends that Venclexta in combination with low-dose cytarabine (LDAC) should not be reimbursed by public drug plans for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.&#x0D; Evidence from 1 clinical trial demonstrated that treatment with Venclexta plus LDAC did not improve overall survival compared to treatment with LDAC alone. No conclusions could be drawn for other important outcomes including remission rates, transfusion independence, event-free survival, quality of life, and symptoms.&#x0D; Patients identified a need for treatments that can maintain remission, improve quality of life and symptoms (fatigue), and that have fewer side effects. It is unclear whether Venclexta plus LDAC meets these needs.&#x0D; Economic evidence suggests that Venclexta plus LDAC is not cost-effective at a willingness-to-pay threshold of $50,000 per quality-adjusted life-year (QALY), even at a 100% reduction in the price of Venclexta.&#x0D; Based on public list prices, the 3-year budget impact is $70,006,541. This estimate is larger than the value identified by drug plans as feasible for adoption.&#x0D;

Venetoclax (Venclexta)

&#x0D; CADTH recommends that Venclexta in combination with azacitidine should be reimbursed for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, only if certain conditions are met.&#x0D; Venclexta plus azacitidine should only be reimbursed if prescribed by clinicians who have expertise in managing patients with AML and are familiar with the toxicity profile of this regimen, and if the costs of Venclexta and azacitidine are reduced.&#x0D; Venclexta plus azacitidine should only be covered to treat adult patients who are considered ineligible for standard intensive induction chemotherapy and have not been treated with venetoclax or chemotherapy for myelodysplastic syndrome.&#x0D;

Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study

Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study

Polatuzumab Vedotin Plus Venetoclax with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Primary Efficacy Analysis of a Phase Ib/II Study

Polatuzumab Vedotin Plus Venetoclax with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Primary Efficacy Analysis of a Phase Ib/II Study

Safety, Efficacy, and Patient-Reported Outcomes of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome: A Phase 1b Study

Safety, Efficacy, and Patient-Reported Outcomes of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome: A Phase 1b Study

A Multicenter, Retrospective Study of Accelerated Venetoclax Ramp-up in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

A Multicenter, Retrospective Study of Accelerated Venetoclax Ramp-up in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Ivosidenib (AG-120) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome: Updated Enrollment of a Phase 1 Dose Escalation and Expansion Study

Ivosidenib (AG-120) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome: Updated Enrollment of a Phase 1 Dose Escalation and Expansion Study

AGILE: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adult Patients with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation

AGILE: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adult Patients with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation