A Phase II Study of the Impact of Clinicogenetic Risk-Stratified Management on Outcomes of Acute Myeloid Leukemia in Older Patients
Overview
- Phase
- Phase 2
- Intervention
- Cytarabine
- Conditions
- Adult Acute Myeloid Leukemia
- Sponsor
- University of Nebraska
- Enrollment
- 75
- Locations
- 1
- Primary Endpoint
- Rate of Complete Remission and Mortality in the Entire Cohort of Older Patients
- Status
- Completed
- Last Updated
- last month
Overview
Brief Summary
Acute myeloid leukemia (AML) is among the most common hematologic malignancies in adults and accounts for approximately 10,000 deaths in the United States every year. AML is commonly diagnosed in sixth or seventh decades of life. The management of AML is complex in older patients because of associated comorbidities, intolerance to high-dose chemotherapy and high-risk tumor biology. In real world practice, over one-third of patients aged 60 years and older do not receive initial chemotherapy for AML, consequently, only 10-20% of patients are alive at 3-5 years. Longer-term survival has not improved significantly in last few decades. Poor survival of older patients with AML may be improved with refined risk-stratification and therapy selection strategies, integration of principles of geriatric medicine, and use of effective but low intensity and novel therapies.
This study will examine the impact of clinicogenetic risk-stratified management on outcomes of acute myeloid leukemia in older participants (≥ 60 years) with newly diagnosed acute myeloid leukemia who receive clinicogenetic risk-stratified therapy allocation. Participants will receive standard of care intensive or low-intensity induction based on cytogenetic and geriatric assessment-based risk stratification. Participants will be evaluated for disease status, survival, quality of life and neurocognitive status for 90 days and then followed for a total of 2 years for survival data.
Detailed Description
Acute myeloid leukemia (AML) is among the most common hematologic malignancies in adults and accounts for approximately 10,000 deaths in the United States every year. AML is commonly diagnosed in sixth or seventh decades of life. The management of AML is complex in older patients because of associated comorbidities, intolerance to high-dose chemotherapy and high-risk tumor biology. The current approach for therapy selection is largely subjective based on chronological age, performance status and/or comorbidities, and does not clearly identify patients who should undergo or forego intensive chemotherapy. The outcomes of older patients with high-risk AML can improve with enhanced risk-stratification and therapy selection strategies, and with the use of low intensity combination chemotherapy in patients who are not fit to receive intensive chemotherapy. Comprehensive geriatric assessment offers a thorough assessment of multiple health domains including comorbidities, polypharmacy, cognitive, nutritional, psychological, functional and social status. Such multidimensional assessment based on geriatric principles is an important tool that can improve risk-stratification and therapy selection in older patients. This approach provides a deeper understanding of the biological age and physical fitness of patients, and anticipated tolerance to chemotherapy. In older patients with AML, previous studies have demonstrated that comprehensive geriatric assessment uncovers significant functional impairments and predicts toxicities and overall survival. Hence, geriatric assessment is considered superior to therapy allocation based on assessment of age and performance status. Up to 75 participants newly diagnosed with AML or AML equivalents, such as myeloid sarcoma, myelodysplastic syndrome in transition to AML or high-grade treatment-related myeloid neoplasm will be enrolled and assigned to one of two groups based on cytogenetic and geriatric assessment-based risk stratification. Group I will receive intensive induction and consolidation therapy. Participants will receive cytarabine and idarubicin or liposome-encapsulated daunorubicin-cytarabine to which gemtuzumab or midostaurin will be added for one course of treatment in the absence of disease progression or unacceptable toxicity. Participants who go into remission will then receive either cytarabine or liposome-encapsulated daunorubicin-cytarabine, depending on induction therapy, for up to 4 or 8 courses in the absence of disease progression or unacceptable toxicity. Group II will receive low-intensity induction and consolidation therapy. Participants will receive oral venetoclax and azacitidine, decitabine or alternate standard of care low-intensity therapies up to four courses in the absence of disease progression or unacceptable toxicity. Participants who achieve complete remission will then receive the above treatments for three or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. All participants are followed up for up to 2 years after completion of treatment. Study objectives include determining the rate of complete remission and mortality at 90 days in participants who receive clinicogenetic risk-stratified therapy allocation, determining the rate of complete remission and mortality in participants who receive intensive versus low-intensity chemotherapy, determining proportion of participants with impairments detected by geriatric assessment, determining the percentage of older participants receiving allogeneic stem cell transplant during the study, and to assessing the overall survival at 1-year for the entire cohort of participants.
Investigators
Eligibility Criteria
Inclusion Criteria
- •New diagnosis of de novo, secondary or treatment-related acute myeloid leukemia (AML), other AML equivalent such as myeloid sarcoma, myelodysplastic syndrome in transformation to AML, or high-grade treatment-related myeloid neoplasm
- •60 years of age or older
- •Karnofsky Performance Status ≥60%
- •Able and willingly give signed informed consent
Exclusion Criteria
- •Acute promyelocytic leukemia (APL). Participants with brief exposure to all-trans retinoic acid (ATRA), arsenic trioxide (ATO) or similar product for suspected APL, who later turn out not to have APL, are eligible.
- •Relapsed or refractory acute myeloid leukemia (AML) requiring salvage therapy
- •Prior exposure to decitabine or azacitidine (exclusion criterion for use of decitabine or azacitidine)
- •Participants requiring urgent initiation of chemotherapy for leukemia-related emergencies such as leukostasis or disseminated intravascular coagulopathy Participants will not be excluded solely based on current or prior use of debulking agent (e.g., hydroxyurea or cyclophosphamide). Prior or current use of leukapheresis will be allowed.
- •Uncontrolled serious infection at enrollment. Infections are considered controlled if appropriate therapy has been instituted and, at enrollment, participants do not have signs of infection progression (e.g., hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection). Persistent fever without other signs or symptoms will not be interpreted as progressing infection.
- •Uncontrolled clinically significant arrhythmia, myocardial ischemia or congestive heart failure within the past 2 weeks, that is considered a contraindication for initiation of chemotherapy by the treating physician
- •Ejection fraction \< 45% will be an exclusion criterion for intensive chemotherapy. These participants may receive low intensity therapy.
- •Clinically significant kidney (e.g., glomerular filtration rate (GFR) ≤ 45ml/minute or creatinine of ≥2 mg/dl) or liver dysfunction \[e.g., aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and/or bilirubin ≥2 times upper limit of normal (ULN)\] at enrollment that may prevent safe use of chemotherapy. These participants may be allowed to receive low-intensity chemotherapy. Participants with elevated bilirubin secondary to Gilbert syndrome will not be excluded.
- •Any other condition that may not allow safe use of chemotherapy based on clinical judgment of treating oncologist
Arms & Interventions
Group I Intensive Induction and Consolidation Therapies
Intensive Induction Therapy: Participants receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin is added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity. Intensive Consolidation Therapy: Participants who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Participants treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Group I Intensive Induction and Consolidation Therapies
Intensive Induction Therapy: Participants receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin is added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity. Intensive Consolidation Therapy: Participants who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Participants treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Idarubicin
Group I Intensive Induction and Consolidation Therapies
Intensive Induction Therapy: Participants receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin is added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity. Intensive Consolidation Therapy: Participants who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Participants treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Group I Intensive Induction and Consolidation Therapies
Intensive Induction Therapy: Participants receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin is added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity. Intensive Consolidation Therapy: Participants who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Participants treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Liposome-encapsulated Daunorubicin-Cytarabine
Group I Intensive Induction and Consolidation Therapies
Intensive Induction Therapy: Participants receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin is added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity. Intensive Consolidation Therapy: Participants who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Participants treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Group I Intensive Induction and Consolidation Therapies
Intensive Induction Therapy: Participants receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin is added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity. Intensive Consolidation Therapy: Participants who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Participants treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: Decitabine
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: Laboratory Biomarker Analysis
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: Quality-of-Life Assessment
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: Questionnaire Administration
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: Azacitidine
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: Venetoclax
Group II Low-intensity Induction and Consolidation Therapies
Low-intensity: Participants receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with fms-like tyrosine kinase 3 (FLT3) inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib. Venetoclax dose varies depending on drug interaction with anti-fungal agents. Given daily continuous for 3 or more months orally. Glasdegib dose is 100 mg oral daily. Decitabine intravenously (IV) over 1 - 3 hours daily for 5 - 10 days. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 - 7. Treatment repeats every 4 - 5 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.
Intervention: glasdegib
Outcomes
Primary Outcomes
Rate of Complete Remission and Mortality in the Entire Cohort of Older Patients
Time Frame: At 90 days
All analyses will be performed based on intent-to-treat principle. The method of inversion will be used to generate an interval estimate for the proportion of 90-day mortality.
Secondary Outcomes
- Mortality at 90 Days(Up to 90 days from diagnosis)
- Rate of Complete Remission (CR) or CR With Incomplete Count Recovery (CRi) and Mortality in Subsets of Older Patients Who Receive Intensive and Low-intensity Chemotherapy(At 90 days)
- To Asses the Impact of Treatment Intensity on Early Mortality in Older Patients, Who Receive Risk Stratified Therapy.(30 and 90 days)
- To Determine Proportion of Patients With Impairments Detected by Geriatric Assessments.(Baseline)