What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML), particularly those involving Venetoclax (a BCL-2 inhibitor) and Low-Dose Cytarabine (a chemotherapy agent), are associated with several side effects. Venetoclax combined with low-dose cytarabine or hypomethylating agents can cause prolonged cytopenias, febrile neutropenia, gastrointestinal issues (nausea, vomiting, diarrhea), fatigue, and edema. There is also a risk of tumor lysis syndrome (TLS), necessitating close monitoring of various blood parameters. Low-dose cytarabine can lead to hematologic toxicities such as neutropenia, thrombocytopenia, and anemia, along with non-hematologic toxicities like nausea, vomiting, and diarrhea.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myeloid Leukemia (AML), particularly for patients ineligible for intensive chemotherapy. Venetoclax, a BCL-2 inhibitor, has been approved in combination with hypomethylating agents (HMAs) such as azacitidine and decitabine. These combinations have shown improved overall survival and response rates in clinical trials. Additionally, Low-Dose Cytarabine (LDAC) is a chemotherapy agent that has been used in combination with Venetoclax in clinical studies, demonstrating efficacy in treatment-naïve AML patients. Other notable FDA-approved drugs for AML include ivosidenib, which is used in combination with HMAs for specific genetic mutations.

What other types of research exist?

Promising novel alternatives for AML treatment in 2024 include: 1) Hypomethylating agents (HMAs) like Azacitidine and Decitabine, which have shown comparable efficacy and are well-tolerated. 2) Gilteritinib, a FLT3 inhibitor, especially for patients with FLT3-ITD mutations. 3) Enasidenib and Ivosidenib for patients with IDH2 and IDH1 mutations, respectively. 4) Immune checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 therapies, which are being explored for their potential benefits in AML.

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Antimetabolite

Venetoclax + Cytarabine for Acute Myeloid Leukemia

Phase 3

Waitlist Available

Research Sponsored by AbbVie

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participant must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hour urine collection

Age > 55 years with no menses for 12 or more months without an alternative medical cause

Must not have

Participants that have acute promyelocytic leukemia (APL)

Chinese subjects are excluded from receiving strong and/or moderate CYP3A inhibitors 7 days prior to the initiation of study treatment through the end of intensive pharmacokinetic (PK) collection (24 hours post dose on Cycle 1 Day 10)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from randomization until the primary analysis cut-off date of february 15 2019; the median follow-up time was 12.0 months (range: 0.2-17.0) in the placebo arm and 12.0 months (range: 0.1-17.6) in the venetoclax arm.

Awards & highlights

Pivotal Trial

Summary

This trial tests if venetoclax with low-dose cytarabine helps untreated AML patients who can't have intensive chemotherapy. Venetoclax works by blocking a protein that keeps cancer cells alive, making it easier to kill them. Venetoclax has been effective in treating leukemia when used with other treatments.

Who is the study for?

This trial is for treatment-naive patients with acute myeloid leukemia who are unfit for intensive chemotherapy. They must be aged ≥75 or 18-74 with certain health conditions, have an ECOG performance status of 0-3, adequate liver and kidney function, a life expectancy of at least 12 weeks, and agree to contraception if applicable. Exclusions include prior malignancies (with some exceptions), known CNS involvement by AML, active hepatitis B/C infections, HIV infection.

What is being tested?

The study aims to determine if venetoclax combined with low-dose cytarabine improves survival compared to low-dose cytarabine and placebo in elderly or less fit patients with AML. Participants will either receive the combination therapy or the standard care (cytarabine plus placebo) to assess effectiveness.

What are the potential side effects?

Venetoclax may cause side effects like diarrhea, nausea, risk of infection due to low white blood cell counts (neutropenia), fatigue, coughing up blood (hemoptysis), and potential tumor lysis syndrome which can affect kidneys. Cytarabine can also lead to fever with low white blood cells (febrile neutropenia), bleeding issues due to reduced platelets.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidneys work well enough, with a creatinine clearance rate of at least 30 mL/min.

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I am over 55 and have not had a period for at least 12 months without another health reason.

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I am 55 or younger, haven't had a period for a year without other causes, and my FSH level is over 40.

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My liver is not working perfectly, and my bilirubin levels are a bit high.

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I have AML and can't undergo intensive chemotherapy.

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I have a heart condition that needed treatment or my heart's pumping ability is reduced.

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My kidney function is low but not severely impaired.

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I have some trouble doing my daily activities but don't need constant care.

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I have had surgery to remove my ovaries or uterus, making me unable to have children.

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I am 75 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been diagnosed with acute promyelocytic leukemia.

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I have not taken strong/moderate CYP3A inhibitors in the last 7 days.

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My heart condition limits my daily activities beyond basic rest.

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My cervical or breast cancer was treated early and effectively.

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I have been treated with venetoclax or am currently in a study with investigational drugs.

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I have been diagnosed with a type of skin cancer that is either basal cell or squamous cell.

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I cannot take medicine by mouth due to a digestive condition.

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I do not have any uncontrolled infections needing treatment.

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I had a blood disorder like myelofibrosis or leukemia before my current AML diagnosis.

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My leukemia has spread to my brain or spinal cord.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ response was assessed at the end of cycle 1 and every 3 cycles thereafter to the end of treatment. median treatment duration at the 15 february 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~response was assessed at the end of cycle 1 and every 3 cycles thereafter to the end of treatment. median treatment duration at the 15 february 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively.

This trial's timeline: 3 weeks for screening, Varies for treatment, and response was assessed at the end of cycle 1 and every 3 cycles thereafter to the end of treatment. median treatment duration at the 15 february 2019 cut-off date was 1.7 months (range: 0.1-14.2) and 3.9 months (range: 0.0-17.1) in each group respectively. for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall Survival (OS)

Secondary study objectives

Change From Baseline in Global Health Status / Quality of Life

Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a

Event-free Survival (EFS)

+14 more

Side effects data

From 2022 Phase 3 trial • 389 Patients • NCT02005471

33%

Neutropenia

11%

SARS-CoV-2 test positive

11%

Sepsis

11%

Abdominal pain

11%

Pneumonia

11%

Rhinovirus infection

11%

COVID-19

11%

Gastroenteritis

11%

Pneumonia pseudomonal

11%

Electrocardiogram QT prolonged

11%

Anaemia

11%

Neutrophil count decreased

11%

Hypokalaemia

11%

Febrile neutropenia

11%

Supraventricular tachycardia

11%

Blood creatinine increased

11%

White blood cell count decreased

11%

Dermatitis

100%

80%

60%

40%

20%

Study treatment Arm

Bendamustine + Rituximab Crossover Substudy

Venetoclax + Rituximab Re-Treatment Substudy

Venetoclax + Rituximab Main Study

Bendamustine + Rituximab Main Study

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: Venetoclax + Low Dose Cytarabine (LDAC)Experimental Treatment2 Interventions

Venetoclax 600 mg orally every day (QD) plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.

Group II: Placebo + LDACPlacebo Group2 Interventions

Matching placebo to venetoclax orally QD plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Venetoclax

2019

Completed Phase 3

~2240

Cytarabine

2016

Completed Phase 3

~3330

0 / 20Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Venetoclax, a BCL-2 inhibitor, promotes apoptosis in AML cells by targeting the BCL-2 protein, which helps cancer cells evade death. Low-Dose Cytarabine (LDAC), a chemotherapy agent, disrupts DNA synthesis, leading to the death of rapidly dividing leukemia cells. This combination is significant for AML patients as it attacks the cancer cells through complementary mechanisms, potentially enhancing treatment efficacy and improving survival rates.

Synergistic effect of chidamide and venetoclax on apoptosis in acute myeloid leukemia cells and its mechanism.Absence of BCL-2 Expression Identifies a Subgroup of AML with Distinct Phenotypic, Molecular, and Clinical Characteristics.Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia.