Geriatric Assessment & Genetic Profiling to Personalize Therapy in Older Adults With Acute Myeloid Leukemia

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.

• Cytarabine (Drug), also known as .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453: Given IV
• Decitabine (Drug), also known as 5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine: Given IV
• Idarubicin (Drug), also known as 4-Demethoxydaunomycin, 4-demethoxydaunorubicin, 4-DMDR: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Liposome-encapsulated Daunorubicin-Cytarabine (Drug), also known as CPX-351, Cytarabine-Daunorubicin Liposome for Injection, Liposomal AraC-Daunorubicin CPX-351, Liposomal Cytarabine-Daunorubicin, Liposome-encapsulated Combination of Daunorubicin and Cytarabine, Vyxeos: Given IV
• Quality-of-Life Assessment (Other), also known as Quality of Life Assessment: Ancillary studies
• Questionnaire Administration (Other): Ancillary studies
• Azacitidine (Drug), also known as VIDAZA: Given by infusion
• Venetoclax (Drug), also known as Venclexta, Venclyxto: oral tablet
• glasdegib (Drug), also known as Daurismo: oral tablet

Primary outcomes

• Rate of Complete Remission and Mortality in the Entire Cohort of Older Patients [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

• 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]: 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.
• Mortality at 90 Days [Up to 90 days from diagnosis]: Mortality at 90 days will be calculated from date of diagnosis to date of death due to any cause within 90 days from diagnosis.
• To Asses the Impact of Treatment Intensity on Early Mortality in Older Patients, Who Receive Risk Stratified Therapy. [30 and 90 days]: To asses the impact of treatment intensity on early mortality in older patients, who receive risk stratified therapy at 1-month and 3-month.
• To Determine Proportion of Patients With Impairments Detected by Geriatric Assessments. [Baseline]: To determine proportion of patients with impairments detected by geriatric assessments (Hematopoietic Cell Transplantation Comorbidity Index score (HCL CI >=3), Short Physical Performance Battery (SPPB=9or less), MoCA (Score of 25 or less), Activities of daily living, Instrumental activities of daily living, Depression screen (PHQ-9 >= 10), nutritional screen (MNA<=11)

Sex: All, ages: 60 Years to any

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

Participant flow

Outcome results

• Rate of Complete Remission and Mortality in the Entire Cohort of Older Patients (Primary), Number, percentage of subjects: Entire Cohort 21.9
• 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 (Secondary), Number, percentage of participants: Group I 50; Group II 52.3
• Mortality at 90 Days (Secondary), Number, participants: Group I 1; Group II 15
• To Asses the Impact of Treatment Intensity on Early Mortality in Older Patients, Who Receive Risk Stratified Therapy. (Secondary), Number, percentage of participants: Group I 0; Group II 7.7
• To Determine Proportion of Patients With Impairments Detected by Geriatric Assessments. (Secondary), Number, participants: Group I 0; Group II 40

Adverse events

Time frame: Ongoing from initiation of study drug until 30 days after last administration of study drug, up to 20 weeks

Serious adverse events by term

Other adverse events by term

• Results publication: Bhatt VR, Wichman CS, Koll TT, Fisher AL, Wildes TM, Haddadin M, Berger AM, Armitage JO, Holstein SA, Maness LJ, Gundabolu K. A Phase II Trial of Geriatric Assessment-Guided Selection of Treatment Intensity in Older Adults With AML. Am J Hematol. 2025 Jul;100(7):1163-1172. doi: 10.1002/ajh.27694. Epub 2025 Apr 29. PMID 40298352
• Results publication: Bhatt VR, Wichman C, Koll TT, Fisher AL, Wildes TM, Berger A, Armitage JO, Holstein SA, Maness LJ, Gundabolu K. Longitudinal changes in cognitive and physical function and health-related quality of life in older adults with acute myeloid leukemia. J Geriatr Oncol. 2024 Jan;15(1):101676. doi: 10.1016/j.jgo.2023.101676. Epub 2023 Nov 24. PMID 38000343
• Results publication: Bhatt VR, Wichman C, Al-Kadhimi ZS, Koll TT, Fisher AL, Mahato RI, Hyde RK, Berger A, Armitage JO, Holstein SA, Maness LJ, Gundabolu K. Integrating geriatric assessment and genetic profiling to personalize therapy selection in older adults with acute myeloid leukemia. J Geriatr Oncol. 2022 Jul;13(6):871-874. doi: 10.1016/j.jgo.2022.04.005. Epub 2022 Apr 18. PMID 35450817

• Study Protocol and Statistical Analysis Plan (PDF, 2024-08-29)
• Informed Consent Form (PDF, 2022-03-17)

• Vijaya R Bhatt, MD, Principal investigator, University of Nebraska

NIH grants: P30CA036727