A Phase II Study of the Impact of Clinicogenetic Risk-Stratified Management on Outcomes of Acute Myeloid Leukemia in Older Patients
Phase: PHASE2
Conditions: Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Acute Myeloid Leukemia
Sponsor: University of Nebraska

Title: A phase II study of the impact of clinicogenetic risk-stratified management 
on outcomes of acute myeloid leukemia in older patients 
 
 
Principal Investigator:  
Vijaya Raj Bhatt, MD 
 
 
 
 
Professor  
 
 
 
 
Fred & Pamela Buffett Cancer Center 
 
 
 
 
University of Nebraska Medical Center 
 
 
 
 
986805 Nebraska Medical Center 
 
 
 
 
 
Omaha, NE 68198-6805 
 
 
 
 
Phone: 402-559-8008 
Email: vijaya.bhatt@unmc.edu 
 
Secondary Investigators:  
 
 
Lori J. Maness, MD  
Krishna Gundabolu, MD 
Sarah A. Holstein, MD, PhD 
Thuy Koll, MD 
Ann M. Berger, PhD 
James O. Armitage, MD 
 
Statistician: Christopher Wichman, PhD  
 
 
Protocol Version Date:  
Version 1.0, dated 26 Jan2017 
 
 
 
 
Version 2.0, dated 20Apr2017 
 
 
 
 
Version 3.0, dated 29Nov2017 
 
 
 
 
Version 4.0, dated 25Mar2018 
 
 
 
 
Version 5.0, dated 19Dec2018 
  
 
 
Version 6.0, dated 19March2019 
  
 
 
Version 7.0, 29 August 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Title Page   ……………………………………………………………      1 
 
Schema ……………………………………………………………… 
3 
Abstract (no more than 250 words) …………………………………… 4 
 
Section 1.0 
Objectives ……………………………………………… 
5 
 
Section 2.0 
Introduction, including background …………………... 
6 
 
Section 3.0 
Eligibility criteria ………………………………………..   10 
 
Section 4.0 
Randomization/registration procedures ………………….. 11 
Section 5.0 
Treatment plan or research design …………………….....  12 
 
Section 6.0 
Measurement of effect …………………………………….19 
 
Section 7.0 
Study parameters ………………………………………… 21 
 
Section 8.0 
Drug formulation and procurement ……………………..   22 
 
Section 9.0  
Toxicity and adverse event reporting guidelines ………..   37 
 
Section 10.0 Biostatistical considerations including stopping criteria … 41 
 
Section 11.0  Records to be kept ………………………………………   42 
 
Section 12.0 Patient consent form statement ………………………….   43 
 
Section 13.0 References ………………………………………………   45 
Section 14.0 Data collection forms ……………………………………. 52 
Appendix A   2017 ELN risk stratification by genetics*……………….   52 
Appendix B AML with myelodysplasia-related changes ………………53 
Appendix C Eligibility Checklist …………………………………….   54 
Appendix D   Hematopoietic Cell Transplant Comorbidity Index             56 
Appendix E Disease response and treatment failure criteria as per the 
international working group criteria …………………………………….  57 
Appendix F NCI Common Toxicity Criteria Version 4.03 (CTCAE)…58 
Appendix G Assessment of other geriatric syndromes………………..  59 
 
 

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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
*Patients will be risk stratified based on geriatric assessment and cytogenetic risk categories, as 
defined by the 2017 European LeukemiaNet (ELN) criteria (1). Intensive induction used at the 
discretion of treating physician may include combination of infusional cytarabine and idarubicin 
(7+3) (preferred regimen); CPX-351 (liposomal preparation of cytarabine and daunorubicin, 
preferred agent for FDA approved indications) or any other standard of care regimen. Low-
intensity induction used at the discretion of treating physician may include hypomethylating 
agent such as azacitidine or decitabine and venetoclax (preferred regimen); hypomethylating 
agent, or any other standard of care regimen. Enrollment in other clinical trials are permitted. 
Intensive chemotherapy such as 7+3 will be used for fit patients (based on geriatric assessment) 
with good or intermediate risk cytogenetics. CPX-351 will be used for fit patients with prior 
exposure to chemotherapy or radiation, or those with AML with myelodsyplasia-related changes, 
as defined by WHO (2). Patients, who are deemed vulnerable or those with high-risk AML (not 
meeting FDA approved indications for CPX-351) will receive low-intensity therapy. The 
addition of targeted agents namely, FLT3 inhibitor (such as midostaurin (3) or sorafenib (4) in 
FLT3 mutated patients), or gemtuzumab ozogamicin (in non-FLT3 mutated patients) (5) to either 
low-intensity such as hypomethylating agent or intensive chemotherapy such as 7+3 will be 
allowed.  
† EORTC QLQ-C30 indicates European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire C-30, and MOCA indicates Montreal Cognitive Assessment.  
 
 
Risk-stratify using geriatric assessment and cytogenetic 
features* 
-Complete EORTC QLQ-C30 and MOCA at enrollment† 
-Initiate low-intensity or intensive induction  
-Geriatric assessment at 30 +/-14 days and 90 +/-21 days after chemotherapy 
-Assess remission, and 90-day mortality  
-Complete EORTC QLQ-C30 and MOCA at 10+/-3, 30 +/-7 and 90 +/-10 days after chemotherapy† 
New diagnosis of acute myeloid leukemia in patients aged 60 years or older 
Informed consent and registration 

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Abstract:  
Title: A phase II study of the impact of clinicogenetic risk-stratified management on outcomes of 
acute myeloid leukemia in older patients 
Objectives: To determine the rate of complete remission, and mortality at 90 days in the entire 
cohort of older patients (≥60 years) with newly diagnosed acute myeloid leukemia, who receive 
clinicogenetic risk-stratified therapy allocation 
Eligibility: Older patients (≥60 years) with acute myeloid leukemia  
Intervention: Subjects will receive standard of care intensive or low-intensity induction based 
on cytogenetic and geriatric assessment-based risk stratification, as demonstrated in the study 
schema.   
Evaluation: Subjects 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section 1.0 Objectives:  
 
Primary objectives: 
1. To determine the rate of complete remission and 90-day mortality in the entire cohort of 
older patients (≥60 years) with newly diagnosed acute myeloid leukemia (AML), who 
receive clinicogenetic risk-stratified therapy allocation 
 
Secondary objectives: 
1. To determine the rate of complete remission and 90-day mortality in subsets of older 
patients who receive intensive and low-intensity chemotherapy 
2. To assess the impact of baseline functional status (measured by geriatric assessment) on 
mortality in older patients, who receive clinicogenetic risk-stratified therapy allocation  
3. To determine the symptom burden/quality of life, and functional status at diagnosis and 
following initiation of chemotherapy 
4. To determine proportion of patients with impairments detected by geriatric assessment 
5. To calculate the percentage of older patients who receive allogeneic stem cell transplant 
during the study period  
6. To assess overall survival at 1-year for the entire cohort of older patients 
 
 
 
Correlative Objectives 
1. Determine whether expression levels of inflammatory cytokines are regulated by 
miRNAs in patients with AML. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section 2.0 Introduction:  
 
Acute myeloid leukemia (AML) is among the most common hematologic malignancies in adults 
and is commonly diagnosed in sixth or seventh decades of life (6). AML accounts for 
approximately 10,000 deaths in the United States every year (7). Patients with AML are 
categorized into good, intermediate and high-risk AML based on cytogenetic criteria put forth by 
the 2017 European LeukemiaNet (ELN) criteria (1) (Appendix A). 
 
The management of AML is complex in older patients because of associated comorbidities, 
intolerance to high-dose chemotherapy and high-risk tumor biology. For example, in real world 
practice, over one-third of patients aged 60 years and older do not receive initial chemotherapy 
for AML. Consequent to such complexities of AML in older patients and current practice 
patterns, only 10-20% of patients are alive at 3-5 years in real world (8-10). 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. In 2017, FDA approved gemtuzumab ozogamicin (a humanized CD-33 directed 
monoclonal antibody-drug conjugate), CPX-351 (liposomal preparation of anthracycline and 
cytarabine) and midostaurin (FLT3 inhibitor in patients with FLT3 mutated AML) in initial 
management of AML. Gemtuzumab ozogamicin is approved for CD-33 positive AML (blasts 
from AML patients are generally CD33 positive), however, the survival benefit with its use is the 
highest among patients with good risk AML (5). CPX-351(11, 12) is FDA-approved(13) 
(because of survival benefit over 7+3) for patients with prior exposure to chemotherapy or 
radiation, or those with certain genetic markers (AML with myelodsyplasia-related changes, as 
defined by WHO (Appendix B) (2)). The addition of FLT3 inhibitor midostaurin (3) in FLT3 
mutated patients is also associated with survival benefit. In 2018, the FDA approved venetoclax 
(accelerated approval) (inhibits the anti-apoptotic protein BCL-2) and glasdegib (small molecule 
inhibitor of the Hedgehog pathway) for AML. Venetoclax received full FDA approval in 2020 in 
combination with low-dose cytarabine (LDAC) or hypomethylating agents, decitabine or 
azacitidine.(14-16) Glasdegib is approved in combination with LDAC.(17) 
 
2.1 Value of individualized therapy selection 
In older patients with AML, practical and rational therapy selection is crucial to receive 
chemotherapy most likely to benefit an individual patient. Select patients are able to tolerate 
intensive therapy, and achieve high rates of complete remission and long-term survival.(18, 19) 
Such patients are likely to benefit from intensive chemotherapy. Conversely, many older patients 
have significant comorbidities requiring multiple medications, cognitive impairment, or 
malnutrition, and are not physically fit to reap the benefit of intensive chemotherapy.(20-23) The 
use of intensive chemotherapy in such patients may result in significant toxicities, poor quality of 
life, deterioration in physical and neurocognitive status and high early mortality.(24) Such 
patients may be better served with low intensity chemotherapy rather than intensive 
chemotherapy. Hence, individualized therapy selection should balance both anticipated benefits 
and risks of toxicities.  
 
2.2 Current risk-stratification and therapy selection strategies  

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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.(25, 26) Additionally, for many older patients, except 
for those with good-risk cytogenetic, the goal of initial chemotherapy should be to allow eligible 
patients to undergo allogeneic hematopoietic cell transplant because transplant, compared to 
chemotherapy alone, becaue transplant offers a significantly higher possibility of long-term 
disease control in high-risk patients.(27) The benefit of transplant is higher in patients who 
achieve complete remission without significant decline in functional status. The use of intensive 
chemotherapy in older patients may be associated with a risk of functional decline and toxicities 
that may preclude from the safe use of allogeneic transplant.(28, 29) Until recently, low intensity 
chemotherapy options resulted in low rates of complete remission and a small probability of 
undergoing an allogeneic transplant. 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.  
 
2.3 Integration of geriatric assessment in risk-stratified management 
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 is feasible,(20) uncovers  significant 
functional impairments(20) and predicts toxicities and overall survival.(21-23) Hence, geriatric 
assessment is considered superior to therapy allocation based on assessment of age and 
performance status.(6) Geriatric assessment-guided therapy allocation has been demonstrated to 
be feasible in older patients with lung cancer and was shown to reduce toxicities compared to 
therapy allocation based on age and performance status.(30) Based on these rationale, the NCCN 
guidelines(31) and Cancer and Aging Research Group(32) recommend integrating geriatric 
assessment in therapeutic decision-making.  
 
2.4 Impact of leukemia cytogenetics on outcomes of intensive chemotherapy  
Studies in AML have clearly demonstrated the influence of leukemia cytogenetics on the 
probability of complete remission and survival with intensive chemotherapy.(33, 34) Good-risk 
AML in fit older patients is associated with a high complete remission rate (up to 80%(18, 19)) 
and survival (60% at 2 years(19) and 40% at 5 years(18)) when treated with intensive 
chemotherapy such as anthracycline and cytarabine (7+3), hence such patients are good 
candidates for intensive chemotherapy. The outcomes of older patients, who are unfit, or have 
high-risk AML are poor with chemotherapy alone.(35) In these patients, at best, complete 
remission rates are 30-60%, induction mortality is high (10-40% depending on age and 
performance status(24)), and long-term survival is less than 10-20%.(18, 19) Although 
beneficial, allogeneic transplant is not feasible in many older patients, in part because of 
induction mortality and functional decline from intensive chemotherapy.(28, 29) Recently, CPX-
351(11, 12) has demonstrated survival benefit over 7+3 for patients with prior exposure to 
chemotherapy or radiation, or those with certain genetic markers (AML with myelodsyplasia-

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related changes, as defined by WHO (2). For this reason, CPX-351 received FDA approval in 
these subsets of patients.  
 
2.5 Use of hypomethylating agent and other novel combination therapies  
The use of hypomethylating agents such as decitabine therapy for 5 days, or 7-day course 
of azacitidine has been extensively studied in older unfit patients with AML.(25, 36, 37) In these 
studies, hypomethylating agents have improved survival despite a lower probability of complete 
remission with hypomethylating agents.(25, 36, 37) Importantly, hypomethylating agents such as 
decitabine therapy results in comparable remission rate within different risk categories of AML, 
thus indicating that such an approach may be particularly of value in high-risk AML.(36-40) In 
more recent years, venetoclax is approved in combination with low-dose cytarabine (LDAC) or 
hypomethylating agents, decitabine or azacitidine; such combination increases the rates of 
remission as well as survival.(14-16) The use of newer low intensity chemotherapy combinations 
in unfit older patients or those with high-risk AML, with complete remission rate largely 
comparable to intensive chemotherapy, may increase tolerability, and reduce the risk of decline 
in quality of life, and cognitive status. This is particularly important for older patients who 
frequently value maintenance of quality of life and  cognitive status over living with functional 
or cognitive impairment.(41) 
 
2.6 Study Schema and Rationale   
Given the powerful impact of leukemia cytogenetics and functional status determined by 
geriatric assessment on outcomes, we aim to integrate these multidimensional assessments into 
clinicogenetic risk-stratification strategy, as highlighted in the schema of this study (Figure 1). 
While the cytogenetic risk category can provide a probability to achieve complete remission with 
chemotherapy, the findings of geriatric assessment can predict anticipated toxicity risk. Thus, a 
combination of clinical parameters such as level of fitness of patients as measured by geriatric 
assessment, and cytogenetic features of leukemia can provide a strategy to individualize therapy 
selection. The aim of such individualized therapy is to optimize the benefit of chemotherapy in 
patients most likely to benefit from chemotherapy while reducing the risk of serious toxicities 
because of intolerance to chemotherapy.  
 
Figure 1. Risk-stratified management of older patients with AML  
 
EORTC QLQ-C30 
indicates European Organisation for Research and Treatment of Cancer Quality of  Life 
Questionnaire C-30, and MOCA indicates Montreal Cognitive Assessment.  
 
Cytogenetic analysis can delay initiation of therapy, however, prior studies have 
indicated that overall survival is not compromised as a result of delay in time to initiation of 
Risk-stratify using 
geriatric assessment and 
cytogenetic features 
- Complete EORTC QLQ-C30 and 
MOCA at enrollment 
-Initiate low-intensity  or intensive 
induction  
 
-Geriatric assessment at 
about 30 and 90 days 
-Assess remission and 
survival at 90 days 
-Complete EORTC QLQ-
C30 and MOCA at about 
10, 30 and 90 days 

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therapy in stable older patients with AML.(42, 43) Although hypomethylating agent has been 
utilized in patients with high blast count,(38, 44) the time to response to hypomethylating agent 
is generally longer than intensive chemotherapy, hence hypomethylating agent alone may not be 
appropriate in patients with aggressive disease pace (e.g. those with leukostasis).(38-40) Hence, 
patients requiring urgent chemotherapy initiation (in addition to debulking agent such as 
hydroxyurea or cyclophosphamide, or leukapheresis) will be excluded from this study. 
Assessment of quality of life and neurocognitive status at baseline and at 90 days after initiation 
of therapy will determine to which extent these parameters are preserved. 
 
2.7 Inflammatory cytokines 
Inflammatory cytokines can serve as important biomarkers of frailty, quality of life and 
survival. Cytokines such as interleukin-6 are implicated in the development of frailty in older 
adults without any malignancy.(45) In patients with solid malignancies; systemic inflammation 
contributes to growth and progression of cancer,(46, 47) and inflammatory markers correlate 
with quality of life,(48, 49) cognition(50) and survival.(51-56) Inflammatory markers affect 
mortality in patients with hematologic malignancies undergoing allogeneic hematopoietic cell 
transplant.(21, 57) In a study of AML and myelodysplastic syndrome (MDS), interleukin-6 and 8 
correlated with cognition, and IL-6, IL-1RA, and TNF-alpha levels correlated with fatigue.(58) 
Another study of AML patients demonstrated a correlation between TNF-alpha and fatigue.(59) 
These hypothesis-generating studies included only a limited panel of cytokines, both younger 
and older patients, patients with MDS as well (in one study(58)) and did not capture frailty.(58, 
59) Other studies in AML and MDS have demonstrated a correlation between certain cytokines 
and survival.(60-62) In two of the largest study published to date, however, the treatment was 
heterogeneous and different from the current standard of care.(62, 63) The studies included both 
younger and older patients,(62, 63) and in one study, patients with MDS and patients with both 
newly diagnosed and relapsed disease.(62) While these studies lay a strong foundation to 
highlight the potential candidacy of inflammatory cytokines to be biomarkers of frailty, and 
quality of life, further studies are needed in a homogenous study population of older adults with 
AML, who are predominantly treated with chemotherapy used in the contemporary era.  
 
2.8 MicroRNAs 
miRNA-cytokine profiling can provide mechanistic insights of regulatory pathways 
involved in inflammation-mediated frailty in older adults with AML and allow development of 
miRNA-based biomarkers and therapeutic approaches. miRNAs mediate regulation of tumor 
microenvironment, and cytokines and may modulate pathways involved in chemotherapy 
resistance and progression of AML.(64) For example, cytokines such as IL-3, GM-CSF and G-
CSF are predominant regulators of growth and differentiation of myeloid progenitors.(65-67) 
Studies have demonstrated correlation between miRNA signatures and cytogenetic risk-groups, 
and microRNA-expression signatures as prognostic biomarkers in patients with AML with 
normal karyotypes. miRNA-based biomarkers offer an advantage of being more stable over time 
than longer, coding mRNAs used in gene expression profile (GEP) analyses.(68) Current 
research efforts are focused on validation of functional aspects of miRNA expression in AML. 
Expression of 452 genes significantly correlated with the prognostically relevant miRNA-
expression signature. These genes included genes encoding proteins involved in innate 
immunity, such as intracellular sensors of microbial components and cell injury (part of 
“inflammasome” regulating activation of caspase-1 and interleukin-1β). Although the direct 

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involvement of miRNAs in AML has been suggested, their role in the regulation of cytokines 
expression, inflammation-mediated frailty and patient outcomes need further elucidation. Our 
analyses to understand the cytokine network in relation to miRNA could allow the development 
of miRNA-based biomarkers and therapeutic approaches in the future. 
 
Section 3.0 Eligibility Criteria:  
 
Study population will include eligible older patients with histologically confirmed newly 
diagnosed acute myeloid leukemia.  
 
Inclusion criteria: 
1. A new diagnosis of de novo, secondary or treatment-related AML, other AML equivalent 
such as myeloid sarcoma, myelodysplastic syndrome in transformation to AML, or high-
grade treatment-related myeloid neoplasm 
2. Patients aged ≥60 years 
3. Karnofsky Performance Status ≥60% 
4. Subjects  must be able and willingly give signed informed consent 
 
Exclusion criteria: 
1. Acute promyelocytic leukemia (APL). Patients 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 for the study. 
2. Relapsed or refractory AML, who require salvage therapy 
3. Prior exposure to decitabine or azacitidine will be an exclusion criterion for the use of 
decitabine or azacitidine alone. 
4. Patients, who require urgent initiation of chemotherapy (other than debulking agent such 
as hydroxyurea or cyclophosphamide) due to leukemia-related emergencies such as 
leukostasis, or disseminated intravascular coagulopathy. Patients will not be excluded 
solely based on prior use of debulking agent. Prior or current use of leukapheresis will be 
allowed. 
5. Uncontrolled serious infection at the time of enrollment. Infections are considered 
controlled if appropriate therapy has been instituted and, at the time of enrollment, 
patients do not have signs of infection progression. Progression of infection is defined as 
hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs 
or radiographic findings attributable to infection. Persisting fever without other signs or 
symptoms will not be interpreted as progressing infection 
6. Uncontrolled clinically significant arrhythmia, myocardial ischemia or congestive heart 
failure within the past 2 weeks, that is considered by the treating physician as a 
contraindication for initiation of chemotherapy. Discussion with the principal investigator 
is encouraged if further clarification is required. 
7. Ejection fraction <45% will be an exclusion criteria for intensive chemotherapy. Such 
patients may receive low intensity therapy.  
8. Clinically significant kidney (e.g. GFR ≤45ml/minute or Creatinine of ≥2 mg/dl) or liver 
dysfunction (e.g. AST/ALT and/or bilirubin ≥2 times ULN) at the time of enrollment that 
may prevent from safely using chemotherapy. Such patients may be allowed to receive 
low-intensity chemotherapy. Patients with elevated bilirubin secondary to Gilbert 

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syndrome will not be excluded. Discussion with the principal investigator is encouraged 
if further clarification is required. 
9. Any other condition that may not allow safe use of chemotherapy based on the clinical 
judgment of the treating oncologist. 
 
Inclusion of Women and Minorities  
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
Section 4.0 Registration Procedure:  
Subjects, who are referred to the Nebraska Medical Center (NMC)/UNMC or other IRB 
approved participating sites, with histologically confirmed AML may be eligible for this trial.  
 
Screening eligibility based on standard clinical care will be performed by the treating physician 
at the time of initial diagnosis of AML. During the time of diagnosis of AML, a history and 
physical examination is performed, laboratory data obtained, and performance status is assessed. 
Blood and bone marrow studies obtained may include a complete blood count, bone marrow 
aspirate and biopsy with morphologic assessment, flow cytometry, karyotyping, fluorescence in 
situ hybridization (FISH) studies and molecular mutations. Radiologic/imaging evaluations will 
be performed as clinically indicated and is at the discretion of the treating physician. Any 
pathologic specimens obtained at referring institutions will be reviewed for accuracy. The 
subject’s treating physician will make the decision as to eligibility of the candidate based on the 
eligibility criteria listed above, prior to offering consent.  
 
If the subject is screened as potentially eligible, he/she will then be offered the option to 
participate. An informed consent will be signed by the subject after thorough review of the study 
is completed with the physician and his/her designee.  
 
NOTE: Problems related to insurance coverage for UNMC potential subjects or enrolled subjects 
will be reported to the IRB as they are encountered. 
 
Some insurance carrier’s may decline to cover the costs of usual medical care if the subject is 
participating in a clinical trial. The subject will be provided assistance by the research nurse 
coordinator or designated staff in determining if the insurance carrier will decline coverage. 
Insurance carriers may or may not pay for study related expenses. The subject can then decide if 
they wish to participate.  
 
4.1 Eligibility Verification/Registration  
Before patients are enrolled into the study, an eligibility checklist (Appendix C) must be 
completed to verify the subject meets the eligibility criteria. Date of enrollment is defined as the 
date of the start of study treatment/first protocol related intervention. The eligibility check list 
will be maintained in the study file.  
 
All study patients will be registered through the sponsor site (UNMC) by contacting the UNMC 
Project Coordinator. All study personnel from UNMC and non-UNMC IRB approved sites will 
contact the UNMC Research Project Coordinator if a patient appears to meet the eligibility 
criteria. They will email the completed eligibility checklist (Appendix C) and de-identified 

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signed consent form document to the Research Project Coordinator to verify the subject meets 
the eligibility criteria. Once the UNMC Research Project Coordinator confirms that the patient 
meets criteria, and target accrual has not been met, approval for the patient will be given and 
study subject number assigned. A confirmation of registration will be forwarded by the UNMC 
Research Project Coordinator to the site. 
 
In the event of an after-hours potential enrollment (i.e., clinic coast time differences), or an 
immediate need for convenience for the subject, please contact the sponsor PI. 
 
UNMC study personnel will provide the UNMC Fred & Pamela Buffett Cancer Center PRMS 
office and the study project coordinator an electronic copy of the signed and dated consent form 
for each UNMC subject registered to the protocol within 7 days that includes the following 
information:  
 
• Protocol Number  
• Patient Identification: Patient’s name, medical record number  
• Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity  
• Patient zip code/country (if not USA) and  
• primary method of payment information 
 
The UNMC Research Project Coordinator will provide the following listed information to the 
UNMC Fred & Pamela Buffett Cancer Center PRMS office for participating affiliate and non-
UNMC IRB approved sites.  The listed information will be provided to the PRMS office within 
one week of enrollment as applicable:  
o UNMC and Participating Site Protocol Numbers  
o Investigator/Participating Site Identifier (ID)  
o Subject ID: Assigned by UNMC [Site ID followed by, initials and  subject 
number (##-FML initials-###)]  
o Consent Date: Date subject signed consent  
o Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity, patient 
zip code/country 
o Primary method of payment information 
o Re-consent Date: (If applicable)  
o Ineligibility Status: (If known)  
o Off Study Date: (If applicable)  
 
Section 5.0 Treatment Plan:  
This is a phase II trial for patients with AML. Eligible patients will undergo risk-stratification 
based on geriatric assessment and cytogenetic features. Cytogenetic analysis will be done as 
clinically indicated per current standard of care for management of patients with AML. 
 
5.1 Comprehensive Geriatric assessment: Comprehensive geriatric assessment will include 
evaluation of multiple domains (Table 1).  
 

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5.1.1. Comorbidity: Comorbidity burden will be calculated according to the Hematopoietic Cell 
Transplantation Comorbidity Index score (Appendix D).(69) It predicts treatment-related 
mortality and is more sensitive than the Charlson Comorbidity Index in older adults with 
AML.(70) Many patients may not have undergone a pulmonary function test or an 
echocardiogram prior to enrollment. In the absence of a known diagnosis of chronic pulmonary 
obstructive disease or other pulmonary disease, or congestive heart failure, such patients will 
receive a score of 0 for pulmonary comorbidity and congestive heart failure. The use of 
prophylactic antibiotics or fevers thought to be possibly related to tumor fever may not be used 
to assign a score of 1 for infection. A prior diagnosis of solid or lymphoid malignancies but not 
myelodysplastic syndrome or other myeloid malignancies gets a score of 3 for prior malignancy. 
Additional clarification may be obtained from the expert review paper by Sorror (71), who 
designed the tool. 
 
CPX-351 has shown to improve survival over 7+3 among patients who develop AML following 
use of chemotherapy or radiation for prior malignancies. Patients treated with CPX-351 are more 
likely to undergo curative-intent transplant and have lower risk of transplant-related mortality, 
hence for patients with therapy-related AML, the use of CPX-351 is desirable (11, 12). For these 
reasons, patients with therapy-related AML will need an additional score of 2 (not including a 
score for a history of prior malignancies) in the Hematopoietic Cell Transplantation Comorbidity 
Index to be considered vulnerable. 
 
5.1.2 Polypharmacy: The list and the number of medications will be obtained from history and 
physical exam.  
 
5.1.3 Nutritional status: Mini-nutrition assessment short form is a 6-item screening tool used to 
evaluate the risk of malnutrition in frail older adults.(72, 73)  
 
5.1.4 Functional status: Function will be assessed using Katz Index of activities of daily living 
(ADL)(74) and Lawton instrumental activities of daily living (IADL).(75) ADLs are functions of 
bathing, dressing, toileting, transferring, continence and feeding. IADLs are patient’s ability to 
perform complex tasks such as ability to use telephone, shopping, cooking, housekeeping, 
laundry, driving, medication management, and management of finances. Mobility, balance and 
lower extremity strength will be assessed with the Short Physical Performance Battery.(76) 
 
5.1.5. Social support: The Medical Outcomes Study Social Function Scale is a survey 
containing 19 items on emotional/informational, tangible, and affectionate support and positive 
social interaction.(77)               
 
5.1.6 Psychological status: The Patient Health Questionnaire-9 will be used to assess 
depression. It includes nine items that cover the diagnostic criteria for major depressive 
disorder.(78) Although depression is associated with mortality (79), the presence of depression is 
captured by the Hematopoietic Cell Transplantation Comorbidity Index.        
                       
5.1.7 Cognition: Montreal Cognitive Assessment will be used to screen for cognitive 
impairment. It assesses multiple cognitive domains including attention, concentration, executive 

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functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation.(80)  
 
Table 1. Summary of Comprehensive Geriatric Assessment 
Domains 
Instruments 
Comorbidity  
Hematopoietic Cell Transplantation Comorbidity Index 
score 
Polypharmacy 
Patient interview/Medical record 
Nutrition 
Mini Nutritional Assessment-Short Form,* 
Weight loss/body mass index 
Functional status 
     ADL 
     IADL  
     Mobility  
 
Katz ADL Index 
Lawton IADL Index 
Short Physical Performance Battery 
Social Support 
Medical Outcomes Study Social Function Scale  
Depression 
Patient Health Questionnaire-9† 
Cognition   
Montreal Cognitive Assessment 
Geriatric syndromes 
Falls in last 6 months, history of dementia or delirium, 
history of urinary or stool incontinence (Appendix G) 
ADL indicates activities of daily living; IADL indicates instrumental activities of daily living. 
*A score of 11 or less on Mini Nutritional Assessment is considered abnormal.  
†A score of 10 or higher on Patient Health Questionnaire-9 is indicative of major depression. 
 
Physical fitness will be defined based on the abnormalities noted in geriatric assessment into fit 
or vulnerable. Please see table 2 for further details. Table 2 will also be used to identify 
impairments across various domains of geriatric assessment. 
 
Table 2. Definition of Fit and Vulnerable status according to the geriatric assessment 
Geriatric Domains 
Fit: 
presence of 
all criteria 
Vulnerable: 
presence of one 
or more criteria 
Rationale 
Hematopoietic Cell 
Transplantation 
Comorbidity Index 
0-2* 
≥3* 
A higher score predicts worse 
survival in AML.(70, 81, 82)  
Katz ADL Index (0-6) 
6 
5 or less 
Impairment in ADLs correlates 
with poor survival in AML and 
other cancers.(83-85) 
Lawton IADL Index (0-
8) 
8 
7 or less 
Impairment in IADLs correlates 
with poor survival in hematologic 
malignancies.(84, 85) 
Short Physical 
Performance Battery 
10-12 
9 or less 
Impairment correlates with poor 
survival in AML.(23)  
Montreal Cognitive 
Assessment 
≥26 
<25 
Cognitive impairment correlates 
with poor survival in AML.(23) 
ADL indicates activities of daily living; IADL indicates instrumental activities of daily living. 
*Patients with therapy-related AML will need an additional score of 2 (not including a score for 

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a history of prior malignancies) in the Hematopoietic Cell Transplantation Comorbidity Index to 
be considered vulnerable. Please see section 5.1.1 for further details and rationale.  
 
5.2 Risk-stratified therapy selection  
Patients will be risk stratified based on geriatric assessment and cytogenetic risk categories, as 
defined by the 2017 European LeukemiaNet (ELN) criteria (1) (Appendix A and B). Therapy 
will be selected as per the criteria described in the figure 2. 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Therapy Selection.  
 
Intensive induction used at the discretion of treating physician may include combination of 
infusional cytarabine and idarubicin (7+3) (preferred regimen); CPX-351 (liposomal preparation 
of cytarabine and daunorubicin, for FDA approved indications) or any other standard of care 
regimen. Low-intensity induction used at the discretion of treating physician may include 
venetoclax in combination with hypoemthylating agent such as decitabine or azacitidine  
(preferred regimen); venetoclax in combination with low-dose cytarabine; hypomethylating 
agent; glasdegib in combination with low-dose cytarabine; or any other standard of care regimen. 
Given its efficacy, venetoclax in combination with hypoemthylating agent would be the 
preferred low-intensity chemotherapy option.(14, 15) Enrollment in other clinical trials are 
permitted. 
 
Intensive chemotherapy such as 7+3 will be used for fit patients (based on geriatric assessment) 
with good or intermediate risk AML. CPX-351 will be used for fit patients with prior exposure to 
chemotherapy or radiation, or those with AML with myelodsyplasia-related changes, as defined 
by WHO (2). Patients, who are deemed vulnerable or those with high-risk AML (not meeting 
FDA approved indications for CPX-351) will receive low-intensity therapy. At the discretion of 
the treating physician, the addition of targeted agents namely, FLT3 inhibitor (such as 
midostaurin (3), sorafenib (4) or Gilteritinib(86, 87) in FLT3 mutated patients), or gemtuzumab 
ozogamicin (in non-FLT3 mutated patients) (5) to either low-intensity such as hypomethylating 
agent or intensive chemotherapy such as 7+3 will be allowed. 
 
Patients with prior exposure to decitabine or azacitidine may not be treated with decitabine or 
azacitidine alone but may receive other low-intensity or intensive chemotherapy. Patients with 
ejection fraction <45%, or those with significant kidney (e.g. GFR ≤45ml/minute or Creatinine 
of ≥2 mg/dl) or liver dysfunction (e.g. AST/ALT and/or bilirubin ≥2 times ULN) may receive 
low-intensity chemotherapy.  
Geriatric Assessment (table 2) 
Fit                                                     Vulnerable 
 
Genetic markers 
 
           Good             Intermediate risk      High risk              Low-intensity chemotherapy 
              
7+3                                          CPX-351 (if meets FDA approved indication)        
(or intensive chemotherapy)   

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While the study allocates intensive or low-intensity therapies based on risk-stratification, all the 
therapies used in this study are considered standard of care for patients with AML. For the 
purpose of this study, a combination of infusional cytarabine and idarubicin (7+3) is the 
preferred intensive therapy (except in patients meeting the FDA approved indication for CPX-
351), and venetoclax in combination with hypomethylating agent is the preferred low-intensity 
therapy. When possible, patients who receive intensive induction, are encouraged to receive 
intensive consolidation as per the standard of care. A general guidelines for the dosing and dose 
modifications of chemotherapy are presented here, however, final decisions regarding selection 
of specific therapy, dose modification and the use of supportive care will be left to the discretion 
of the treating physician.  
 
5.3 Treatment Schedule 
5.3.1. Intensive induction and consolidation therapy: Infusional cytarabine and idarubicin is 
the preferred intensive induction therapy (except in patients meeting the FDA approved 
indication for CPX-351). Intermediate-dose cytarabine will be used as the standard of care 
consolidation therapy for patients receiving intensive induction therapy (except those treated 
with CPX-351). 
 
 
Drug 
Dose 
Frequency  
Number of 
cycles 
Administration  
Intensive Induction therapy  
Cytarabine 
100-200 mg/m2 
Day 1-7 
1 
IV infusion 
Idarubicin 
12 mg/m2 
Day 1-3 
1 
IV 
Intensive Consolidation therapy 
Cytarabine 
1000-1500 
mg/m2 
Twice daily on 
Days 1, 3, and 5 
2-4, cycles are 
repeated every 4 
weeks 
IV 
 
Intensive induction therapy with cytarabine and idarubicin is given for one cycle. Patients, who 
do not respond, will receive salvage therapy at the discretion of treating physician. Once 
remission is achieved, consolidation therapy will be started. The duration of each cycle of 
consolidation therapy will be approximately 4 weeks but may be prolonged by another 2 weeks 
based on recovery from any toxicities or count recovery in patients with no evidence of disease. 
Patients, who are able to proceed to an allogeneic transplant, or who are not able to tolerate may 
stop consolidation therapy at the discretion of the treating physician. 
 
Drug 
Dose 
Frequency  
Number of 
cycles 
Administration  
Intensive Induction therapy for patients meeting FDA approved indication for CPX-351 
CPX 351 
Daunorubicin 44 
mg/m2 and 
cytarabine 100 
mg/m2 
Days 1, 3, 5 
1 
IV over 90 
minutes  
Intensive Consolidation therapy for patients treated with CPX 351 

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CPX 351 
Daunorubicin 29 
mg/m2 and 
cytarabine 65 
mg/m2 
Days 1, 3 
2 cycles, repeated 
every 5-8 weeks 
IV over 90 
minutes 
 
 
5.3.2 Low-intensity induction and consolidation therapy:   
Venetoclax in combination with hypomethylating agent such as azacitidine or decitabine will be 
the preferred option. 
 
Drug 
Dose 
Frequency  
Number of 
cycles 
Administration  
Azacitidine* 
75 mg/m2 
Day 1-7 
≥3 cycles, repeat 
every 4-5 weeks 
IV 
Decitabine* 
20 mg/m2 
Daily for 5-10 
days 
≥3 cycles, repeat 
every 4-5 weeks 
IV 
Venetoclax 
Variable† 
Daily continuously for ≥3 months 
PO 
 
*The treating physician may select either azacitidine or decitabine. 
†The dose of venetoclax varies depending on drug interaction with antifungal agents. Patients 
who are not on CYP3A inhibitor, dosing includes 100 mg once on day 1, 200 mg once on day 2, 
and 400 mg on days 3 and beyond. Patients on posaconazole or other CYP3A inhibitor require 
dose reduction. For example, a maximum of 70 mg is recommended while on posaconazole, up 
to 100 mg is recommened while on other strong CYP3A inhibitor, and at least 50% dose 
reduction is recommended while on moderate CYP3A inhibitor. 
 
The duration of each cycle of hypomethylating agent will be approximately 4-5 weeks but may 
be prolonged by another 2 weeks based on recovery from any toxicities or count recovery in 
patients with no evidence of disease. Venetoclax doses may also be interrupted for 2 weeks 
based on recovery from any toxicities or count recovery in patients with no evidence of disease. 
Therapy with venetoclax and hypomethylating agent will be continued for 3 or more cycles. 
Patients, who are able to proceed to an allogeneic transplant, or who are not able to tolerate may 
stop therapy at the discretion of the treating physician. Given the focus of the study on early 
mortality, therapy continuation beyond 3 cycles will be left up to the discretion of the treating 
physician. 
 
5.4 Dose modifications  
All the therapies utilized in this study are considered standard of care. Thus, treating oncologists 
are familiar with these drugs and dose modifications.  
 
5.4.1. Intensive therapy: Dose reduction of cytarabine and idarubicin or CPX-351 by up to 50% 
will be allowed for grade 3/4 toxicities, renal or hepatic toxicities at the discretion of the treating 
physician.  
 
5.4.2. Low intensity therapy: Dose reduction of venetoclax or hypomethylating agent by up to 
50% will be allowed for grade 3/4 toxicities at the discretion of the treating physician.  

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5.5 Supportive care: Supportive care will follow the institutional practice of prophylactic 
antimicrobials, antiemetics, blood product transfusions and other supportive care.  
 
5.6 Duration of Study: We estimate that 75 patients will enrolled to this protocol over a 4 year 
period.  
 
5.6.1 Duration of Follow up: The patient will be seen prior to each chemotherapy cycle and as 
clinically indicated. After the completion of chemotherapy, survival data will be recorded for up 
to 2 years.  
 
5.7 Assessment Schedule: CBC and chemistry panel will be performed at each of the follow up 
visits as per the standard of care. Restaging bone marrow aspirate and biopsy will be performed 
as per the standard of care. For patients receiving intensive chemotherapy, restaging bone 
marrow biopsy is performed after the intensive induction chemotherapy when blood counts start 
to recover or after 4-6 weeks of therapy in patients who do not improve blood count. For patients 
receiving low-intensity chemotherapy, restaging bone marrow biopsy is performed after the first 
1-3 cycles of low-intensity chemotherapy. Routine tests performed on bone marrow aspirate and 
biopsy include histopathological examination, flow cytometry, genetic and/or molecular tests.   
 
5.8 Post-trial Assessments: Patients who stop the study drug at any time during the trial for any 
reason will be followed for 30 days after the last day of treatment or until other disease-related 
treatment begins. For all patients, drug-related SAEs and AEs will be followed until baseline, ≤ 
grade 1 levels, death, or until no further improvement is reasonably expected. Survival data and 
data regarding disease status will be collected for up to 2 years. Patients may refuse to participate 
in the post-trial assessments.  
 
5.9 Criteria for Removal from Study:  
Patients will discontinue the study drug for any of the following reasons:  
• Progression of disease  
• If the patient experiences an adverse reaction that, in the opinion of the investigator, 
necessitates the cessation of the study drug, including any unresolved serious adverse 
event.  
• Any patient who suffers a serious systemic allergic response or severe degree of 
intolerance to the study medication will be withdrawn from further study treatment 
• Development of intercurrent medical problems that would make continued protocol 
therapy detrimental to the patient’s safety. 
• The patient chooses to discontinue treatment.  
 
Patients who stop study drug may complete follow-up surveys and assessments at their routine 
clinic visits, if agreed upon by the patients. Data may continue to be collected via chart review, if 
agreed upon by the patients.  
 
Patients will be removed from the study (study withdrawal) for any of the following reasons:  

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• If at any time the constraints of this protocol are detrimental to the patient's wellbeing, or 
if the patient is unable to comply with the requirements of the protocol, the patient will be 
removed from the study. In this event, the reason(s) for withdrawal will be documented.  
• There is concurrent illness or other reasons that would, in the opinion of the investigator, 
affect assessment of clinical status or conduct of the study to a significant degree.  
• The patient chooses to discontinue follow-up.  
 
The reason(s) for study withdrawal will be documented. The reason(s) for withdrawing the 
patient from the treatment portion of the study will be documented in the case report form. If 
available, the following information will be recorded in the case report form: date of disease 
relapse, date of death, cause of death, and autopsy report. 
 
5.10 Correlative studies 
 
The correlative objective for this trial is to determine whether expression levels of inflammatory 
cytokines are regulated by miRNAs in patients with AML. 
 
5.10.1 Specimen collection: The study participants will be offered to optionally co-enroll in IRB 
156-95-FB for correlative study sample collection and biobanking. IRB 156-95-FB is the 
hematologic malignancies tissue bank that collects and stores tissues from patients with 
hematologic malignancies. Please see IRB 156-95-FB for further details.  
 
5.10.2 Cytokine analysis: We will measure levels of inflammatory cytokines including IL-6, IL-
1, IL-2, IL-8, TNF-α, GM-CSF, and CRP in serum obtained at diagnosis. 
5.10.3 miRNA Experiments: We will develop cytokine-miRNA profile by utilizing patient 
samples of known gene sets/pathways. We will determine miRNA signature in patients’ plasma. 
On the basis of pathway predictions combined with expression profile analysis, and 
bioinformatic approaches, we will determine the network of various miRNAs that regulate levels 
of inflammatory cytokines. 
Further details about cytokine analysis and miRNA experiments are provided in the laboratory 
manual.  
6.0 Measurement of Effect:  
6.1 Response criteria: Response criteria and disease progression will be based on definitions 
provided by the International Working Group (Appendix E).(88) However, prior studies have 
demonstrated that multiple cycles of low-intensity therapy such as hypomethylating agent may 
be required to achieve complete remission. (25, 36-40) Hence, patients treated with low-intensity 
therapy may undergo restaging after multiple cycles. The number of cycles of hypomethylating 
agent used prior to restaging will be left to the discretion of the treating physician.  
 
6.2 90-day mortality: Mortality from any causes within the first 90 days from the time of 
diagnosis will count towards 90-day mortality.  
 
6.3 Percentage of patients proceeding to transplant: This will be calculated as the number of 
patients undergoing transplant divided by a total number of patients receiving either intensive 
or low intensity therapy.  

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6.4 Geriatric Assessment: At the time of enrollment, and at about 30 +/-14 days and 90 +/-21 
days, patients will complete geriatric assessment, as discussed previously. 
 
6.5 Symptom burden/Quality of life assessment: At the time of enrollment, 10 +/- 3 days, 30 
+/- 7 days and 90 days +/-10 days, patients will complete European Organisation for Research 
and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30). EORTC 
QLQ-C30 is extensively used in cancer studies,(48) and will be utilized to assess quality of life. 
For non-English speaking patients, any available validated translation (such as Spanish 
version(89, 90)) may be utilized. If no validated translation is available, an interpreter will be 
utilized if needed. 
 
6.6 Assessment of neurocognitive status: At the time of enrollment, 10 +/- 3 days, 30 +/- 7 
days and 90 days +/-10 days, patients will complete Montreal Cognitive Assessment (MOCA) to 
assess neurocognitive status. MOCA is easy to use in clinical practice and has high sensitivity 
and specificity.(80) For non-English speaking patients, any available validated translation (such 
as MOCA in Spanish (91, 92)) may be utilized. If no validated translation is available, an 
interpreter will be utilized if needed.  

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7.0 Study Parameters:  
 
Tests and 
procedures 
At the time 
of 
enrollment 
(day -7 to 
enrollment)  
 4 weeks after 
initiation of 
chemotherapy 
or before 
second cycle 
of 
chemotherapy 
 8 weeks after 
initiation of 
chemotherapy 
or before 
third cycle of 
chemotherapy 
90 days after 
initiation of 
chemotherapy 
or before 
fourth cycle of 
chemotherapy 
Survival data 
History and 
Physical Exam 
X 
 
 
 
Survival, 
disease status 
and transplant 
data will be 
recorded every 
3 months for 
up to 2 years 
in alive 
patients 
Weight, BMI and 
KPS 
X 
 
 
 
Neurocognitive 
assessment 
(MOCA test)g 
X 
X (day 10+/- 3 
and 30+/- 7 
days) 
 
X (day 90 +/- 
10 days) 
Quality 
of 
life 
assessment 
(EORTC 
QLQ-
C30 version 3.0) 
X 
X (day 10 +/- 3 
and 30 +/- 7 
days) 
 
X (day 90+/- 
10 days) 
Disease 
diagnosis 
or 
restaging 
 
 
 
 
Bone marrow 
aspirate and 
biopsyd 
X 
X (consider if 
count recovery, 
and no 
evidence of  
circulating 
disease) 
X (consider if 
complete 
remission is 
not 
documented 
previously) 
X (consider if 
complete 
remission is 
not 
documented 
previously) 
Assessment of 
comorbidities 
 
 
 
 
Geriatric 
assessment 
Xa 
X (30 +/- 14 
days) (if 
feasible)b 
 
X (90 +/- 21 
days) (if 
feasible)b 
Echo, MUGA 
scan or stress 
echo  
Xe 
 
 
 
Laboratory 
studies 
 
 
 
 
CBC 
X 
X 
X 
X 
CMET including 
albumin 
X 
X 
X 
X 
Length of stay 
For  initial diagnosis and chemotherapy only  
 
Adverse event 
monitoringf  
 
Ongoing from initiation of study drug till 30 days 
after last administration of study medicationc 
 

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BMI body mass index; CBC complete blood count; CMET Comprehensive metabolic panel 
(includes sodium, potassium, chloride, bicarbonate, creatinine, BUN, AST, ALT, total protein, 
albumin, bilirubin, alkaline phosphatase, calcium, glucose);KPS Karnofsky performance status; 
MUGA scan multigated acquisition scan   
  
a. Includes assessment indicated in table 1. Medical Outcomes Study Social Function Scale can 
be completed within 48 hours after initiation of chemotherapy.  
b. Repeat geriatric assessment will include Mini Nutritional Assessment-Short Form, 
Weight, body mass index, Katz ADL Index, Lawton IADL Index, Short Physical Performance 
Battery, Patient Health Questionnaire-9 and Montreal Cognitive Assessment. 
c. All grade ≥3 hematological and non-hematological adverse events will be monitored.  Please 
see section 9.0 for AE reporting details.   
d. Routine tests performed on bone marrow aspirate and biopsy include histopathological 
examination, flow cytometry, cytogenetic, fluorescence in situ hybridization and/or molecular 
tests. The specific tests performed will be left to the discretion of the treating physician. In a 
patient with confirmed diagnosis of AML at any time in the past, a repeat bone marrow biopsy is 
not required at enrollment.   
e. As clinically indicated such as in patients planned to undergo intensive chemotherapy. In a 
patient with an echo or MUGA in the recent past (e.g. 6 months), a repeat test is not required at 
enrollment.     
f. Include data on rehospitalization during the study period  
g. Note that version 7.1 original MOCA should be used at time of enrollment visit and day 90 
visit; complete version 7.2 Alternative at day 10 and version 7.3 Alternative at the 4 week (30 
day) visit.     
 
8.0 Drug Formulation and Procurement:  
8.1 Cytarabine 
 8.1.1 Mechanism of Action: Cytarabine inhibits DNA synthesis. Cytarabine gains entry 
into cells by a carrier process, and then must be converted to its active compound, 
aracytidine triphosphate. Cytarabine is a pyrimidine analog and is incorporated into DNA; 
however, the primary action is inhibition of DNA polymerase resulting in decreased DNA 
synthesis and repair. The degree of cytotoxicity correlates linearly with incorporation into 
DNA; therefore, incorporation into the DNA is responsible for drug activity and toxicity. 
Cytarabine is specific for the S phase of the cell cycle (blocks progression from the G1 to 
the S phase). 
 
8.1.2 Clinical Formulation: Commercially available for injection as: 20 mg/mL (5 mL, 50 
mL); 100 mg/mL (20 mL) 
 
8.1.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
Correlative study 
sample collection 
and biobanking 
Patients will be offered to optionally co-enroll in IRB 156-95-FB for biobanking  

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8.1.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
Protect from light. Store intact vials of powder for reconstitution at 20°C to 25°C (68°F to 
77°F); store intact vials of solution at 15°C to 30°C (59°F to 86°F). 
Store in original container. Ph of solution in vial is 7.4. The vials bear an expiration date. 
  
Powder for reconstitution: Reconstituted solutions should be stored at room temperature 
and used within 48 hours. 
For IV infusion: Solutions for IV infusion diluted in D5W or NS are stable for 8 days at 
room temperature, although the manufacturer recommends administration as soon as 
possible after preparation. 
 
Powder for reconstitution: Reconstitute with bacteriostatic water for injection (for standard-
dose). 
 
         Intermittent IV infusion: 
Further dilute the appropriate dose of the injection solution in 100—250 mL of 5% 
Dextrose injection, 5% Dextrose and 0.9% Sodium Chloride injection, 5% Dextrose and 
Lactated Ringer's injection, Ringer's injection, or lactated Ringer's injection. 
  
Continuous IV infusion: 
Further dilute the appropriate dose of the injection solution in 500—1000 mL 5% Dextrose 
injection, 5% Dextrose and 0.9% Sodium Chloride injection, 5% Dextrose and Lactated 
Ringer's injection, Ringer's injection, or lactated Ringer's injection.  
 
 
8.1.5 Administration: Infuse standard dose therapy (100 to 200 mg/m2/day) as a 
continuous infusion. Infuse intermediate or high-dose therapy (1000-1500 mg/m2/day) over 
1 to 3 hours. 
 
8.1.6 Clinical Pharmacology: 
Distribution: Vd: 3 ± 11.9 L/kg; total body water; widely and rapidly since it enters the cells 
readily; crosses blood-brain barrier with CSF levels of 40% to 50% of plasma level  
Protein binding: 13% 
Metabolism: Primarily hepatic; metabolized by deoxycytidine kinase and other nucleotide 
kinases to aracytidine triphosphate (active); about 86% to 96% of dose is metabolized to 
inactive uracil arabinoside (ARA-U) 
Half-life elimination: IV: Initial: 7 to 20 minutes; Terminal: 1 to 3 hours 
Excretion: Urine (~80%; 90% as metabolite ARA-U) within 24 hours  
 
8.1.7 Potential Drug Interactions: 
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. 
Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy 
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. 
Risk X: Avoid combination 

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Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines 
(Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-
appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If 
vaccinated during immunosuppressant therapy, revaccinate at least 3 months after 
immunosuppressant discontinuation. Risk D: Consider therapy modification 
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines 
(Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). 
Management: Avoid use of live organism vaccines with immunosuppressants; live-
attenuated vaccines should not be given for at least 3 months after immunosuppressants. 
Risk X: Avoid combination 
 
8.1.8 Drug toxicities 
Frequency not defined. 
Cardiovascular: Angina pectoris, chest pain, hepatic veno-occlusive disease (also called 
hepatic sinusoidal obstruction syndrome), local thrombophlebitis, pericarditis 
Central nervous system: Aseptic meningitis, cerebral dysfunction, dizziness, headache, 
neuritis, neurotoxicity, paralysis (intrathecal and IV combination therapy), reversible 
posterior leukoencephalopathy syndrome 
Dermatologic: Acute generalized exanthematous pustulosis, alopecia, dermal ulcer, ephelis, 
pruritus, skin rash, urticaria 
Endocrine & metabolic: Hyperuricemia 
Gastrointestinal: Abdominal pain, anal fissure, anal inflammation, anorexia, diarrhea, 
esophageal ulcer, esophagitis, increased serum amylase, increased serum lipase, 
intestinal necrosis, mucositis, nausea, pancreatitis, sore throat, toxic megacolon, 
vomiting 
Genitourinary: Urinary retention 
Hematologic & oncologic: Anemia, bone marrow depression, hemorrhage, leukopenia, 
megaloblastosis, neutropenia (onset: 1 to 7 days; nadir [biphasic]: 7 to 9 days and at 15 
to 24 days; recovery [biphasic]: 9 to 12 days and at 24 to 34 days), reticulocytopenia, 
thrombocytopenia (onset: 5 days; nadir: 12 to 15 days; recovery 15 to 25 days) 
Hepatic: Hepatic insufficiency, increased serum transaminases (acute), jaundice 
Hypersensitivity: Allergic edema, anaphylaxis 
Infection including Sepsis 
Neuromuscular & skeletal: Rhabdomyolysis 
Ophthalmic: Conjunctivitis 
Renal: Renal insufficiency 
Respiratory: Acute respiratory distress, dyspnea, interstitial pneumonitis 
Miscellaneous: Drug toxicity (cytarabine syndrome; chest pain, conjunctivitis, fever, 
maculopapular rash, malaise, myalgia, ostealgia), fever 
Hypersensitivity: Anaphylaxis resulting in acute cardiopulmonary arrest has been reported 
(rare). 
Tumor lysis syndrome and subsequent hyperuricemia may occur. 
 
Adverse events associated with high-dose cytarabine 
Cardiovascular: Cardiomegaly, cardiomyopathy (in combination with cyclophosphamide) 

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Central nervous system: Neurotoxicity (patients with renal impairment), coma, drowsiness, 
neurocerebellar toxicity, peripheral neuropathy (motor and sensory), personality 
changes 
Dermatologic: Alopecia (complete), desquamation, skin rash (severe) 
Gastrointestinal: Gastrointestinal ulcer, necrotizing enterocolitis, pancreatitis, peritonitis, 
pneumatosis cystoides intestinalis 
Hepatic: Hepatic abscess, hepatic injury, hyperbilirubinemia 
Infection including Sepsis 
Ophthalmic: Corneal toxicity, hemorrhagic conjunctivitis 
Respiratory: Acute respiratory distress, pulmonary edema. May present as severe dyspnea 
with a rapid onset and refractory hypoxia with diffuse pulmonary infiltrates, leading to 
respiratory failure; may be fatal. 
 
8.2 Idarubicin 
  
8.2.1 Mechanism of Action: Idarubicin inhibits DNA and RNA synthesis by intercalation 
between DNA base pairs and by steric obstruction. Although the exact mechanism is 
unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair 
(topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and 
fragmentation of DNA. 
 
8.2.2 Clinical Formulation: Commercially available for injection as: 5 mg/5 mL (5 mL); 
10 mg/10 mL (10 mL); 20 mg/20 mL (20 mL) 
 
8.2.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler.  
 
8.2.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
  
Store intact vials of solution refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. 
 
May draw up 1 mg/mL solution into a syringe (for administration) or further dilute in NS 
or D5W. The reconstituted solution is hypotonic and is stable for 72 hours at room 
temperature or 1 week under refrigeration. 
8.2.5 Administration: Administer as slow injection over 10 to 15 minutes into a free-
flowing IV solution of NS or D5W 
 
8.2.6 Clinical Pharmacology: 
Distribution: Vdss: 1,500 L/m2; extensive tissue binding; CSF  
Protein binding: 94-97%  
Metabolism: Hepatic to idarubicinol (active metabolite) 
Half-life elimination:  
22 hours (range: 4 to 48 hours); >45 hours (idarubicinol) 
Excretion: Primarily biliary; urine (8 to 10% as idarubicinol, ~2 to 5% as unchanged drug  
 

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8.2.7 Potential Drug Interactions: 
Cardiac Glycosides: May diminish the cardiotoxic effect of Antineoplastic Agents 
(Anthracycline, Systemic). Antineoplastic Agents (Anthracycline, Systemic) may decrease 
the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may 
be unique from those of the free drug, as liposomal formulation have unique drug 
disposition and toxicity profiles, and liposomes themselves may alter digoxin 
absorption/distribution. Risk C: Monitor therapy 
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. 
Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy 
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Risk 
X: Avoid combination 
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines 
(Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate 
vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during 
immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant 
discontinuation. Risk D: Consider therapy modification 
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 
Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: 
Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines 
should not be given for at least 3 months after immunosuppressants. Risk X: Avoid 
combination 
 
8.2.8 Drug toxicities 
Frequency >10%: 
Cardiovascular: Cardiac failure (dose-related), ECG abnormalities (transient; includes atrial 
premature contractions, S-T wave changes, supraventricular tachycardia, ventricular 
premature contractions; generally asymptomatic and self-limiting) 
Central nervous system: Headache 
Dermatologic: Alopecia (25% to 30%), skin rash (11%), urticaria 
Gastrointestinal: Vomiting (30% to 60%), gastrointestinal hemorrhage (30%), diarrhea (9% 
to 22%), stomatitis (11%), nausea 
Genitourinary: Urine discoloration (darker yellow) 
Hematologic & oncologic: Anemia, bone marrow suppression (nadir: 10 to 15 days; 
recovery: 21 to 28 days; primarily leukopenia, thrombocytopenia 
Hepatic: Increased serum bilirubin, increased serum transaminases 
Miscellaneous: Radiation recall phenomenon 
 
Frequency 1% to 10%: 
Central nervous system: Peripheral neuropathy, seizure 
 
Frequency <1% (Limited to important or life-threatening): Cardiomyopathy, hyperuricemia, 
myocarditis, typhlitis (neutropenic) 
 
Miscellaneous toxicities- Vesicant; may cause severe local tissue damage and necrosis if 
extravasation occurs.  
 

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8.3 CPX-351 (liposomal preparation of daunorubicin and cytarabine) 
 
8.3.1 Mechanism of Action: Liposomal preparation of daunorubicin (anthracycline) and 
cytarabine. Daunorubicin inhibits DNA and RNA synthesis by intercalation between 
DNA base pairs and by steric obstruction. Although the exact mechanism is unclear, it 
appears that direct binding to DNA (intercalation) and inhibition of DNA repair 
(topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and 
fragmentation of DNA. Cytarabine is a pyrimidine analog and is incorporated into 
DNA; however, the primary action is inhibition of DNA polymerase resulting in 
decreased DNA synthesis and repair. 
 
8.3.2 Clinical Formulation: Commercially available for injection as:  44 mg daunorubicin 
and 100 mg cytarabine encapsulated in liposomes as a lyophilized cake in a single-dose 
vial for reconstitution. 
 
8.3.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
8.3.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
 
Calculate the dose based on daunorubicin and individual patient’s BSA. Calculate the 
number of vials based on the daunorubicin dose. Remove the appropriate number of vials 
from the refrigerator and equilibrate to the room temperature for 30 minutes. Then, 
reconstitute each vial with 19 mL of Sterile Water for Injection using a sterile syringe and 
immediately thereafter start a 5-minute timer.  Carefully swirl the contents of the vial for 5 
minutes while gently inverting the vial every 30 seconds. After reconstitution, let rest for 
15 minutes. The reconstituted product should be an opaque, purple, homogeneous 
dispersion, essentially free from visible particulates. After reconstitution (but before final 
dilution), each mL will contain 2.2 mg of daunorubicin and 5 mg of cytarabine. Gently 
invert each vial 5 times prior to withdrawing the reconstituted product for further dilution. 
If the reconstituted product is not diluted into an infusion bag immediately, store in 
refrigerator at 2ºC to 8ºC for up to 4 hours. Aseptically withdraw the calculated volume of 
the reconstituted product from the vial(s) with a sterile syringe and transfer it to an infusion 
bag containing 500 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP. There may be residual product remaining in the vial. Discard unused portion. Gently 
invert the bag to mix the solution. The dilution of the reconstituted product results in a deep 
purple, translucent, homogeneous dispersion, free from visible particulates. If the diluted 
infusion solution is not used immediately, store in refrigerator at 2ºC to 8ºC for up to 4 
hours. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Only 
solutions without visible particles should be used. 
 
8.3.5 Administration: infuse over 90 minutes. 
 
8.3.6 Clinical Pharmacology: 

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Distribution: Daunorubicin 6.6 L; Cytarabine 7.1 L  
 
Metabolism: Upon release from the liposomes, daunorubicin is catalyzed by aldoketo 
reductase and carbonyl reductase to daunorubicinol (active metabolite); cytarabine is 
metabolized by cytidine deaminase to Ara-U (inactive metabolite).  
 
Half-life elimination: 31.5 hours (daunorubicin); 40.4 hours (cytarabine) with >99% of 
drug(s) remaining encapsulated in the liposomes  
 
Excretion: Urine (9% daunorubicin; 71% cytarabine and Ara-U) 
 
8.3.7 Potential Drug Interactions: 
Cardiac Glycosides: May diminish the cardiotoxic effect of Anthracyclines. Anthracyclines 
may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal 
formulations may be unique from those of the free drug, as liposomal formulation have 
unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin 
absorption/distribution. Risk C: Monitor therapy 
 
Clozapine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. 
Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy 
 
 
Vaccines (Inactivated): May diminish the therapeutic effect of Vaccines (Inactivated). 
Management: Vaccine efficacy may be reduced. Risk D: Consider therapy modification 
 
Vaccines (Live): May enhance the adverse/toxic effect of Vaccines (Live). May diminish 
the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism 
vaccines. Risk X: Avoid combination 
 
8.3.8 Drug toxicities 
Frequency >10%: 
Cardiovascular: Edema (51%), cardiac arrhythmia (30%), cardiotoxicity (20%),  
hypotension (20%), hypertension (18%), chest pain (17%) 
Central nervous system: Headache (33%), fatigue (32%), sleep disorder (25%), chills  
(23%), dizziness (18%), delirium (16%), anxiety (14%) 
Dermatologic: Skin rash (54%), pruritus (15%) 
Endocrine & metabolic: Hyponatremia (grades 3/4: 6% to 14%) 
Gastrointestinal: Diarrhea (≤66%), nausea (47%), colitis (≤45%), mucositis (44%),  
constipation (40%), abdominal pain (33%), decreased appetite (29%), vomiting (24%),  
hemorrhoids (11%) 
Hematologic & oncologic: Anemia (100%), neutropenia (100%; grade 4 [prolonged]: 10%  
to 17%), thrombocytopenia (100%; grade 3 [prolonged]: 25% to 28%), hemorrhage (70%;  
grades 3 to 5: 10%), febrile neutropenia (68%; grades 3 to 5: 66%), petechia (11%) 
Hypersensitivity: Transfusion reaction (11%) 
Infection including Bacteremia (24%), fungal infection (18%), sepsis (11%) 

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Local: Injection site reaction (16%; includes catheter and device site) 
Neuromuscular & skeletal: Musculoskeletal pain (38%) 
Ophthalmic: Visual impairment (11%) 
Renal: Renal insufficiency (11%) 
Respiratory: Cough (33%), dyspnea (32%), pneumonia (26%), hypoxia (18%), upper  
respiratory tract infection (18%), pleural effusion (16%) 
Miscellaneous: Fever (17%) 
 
Frequency 1% to 10%: 
Central nervous system: Hallucination (<10%) 
Endocrine & metabolic: Hypokalemia (grades 3/4: 6% to 9%), hypoalbuminemia (grades  
3/4: 2% to 7%), abnormal alanine aminotransferase (grades 3/4: ≤5%) 
Gastrointestinal: Dyspepsia (<10%) 
Hepatic: Hyperbilirubinemia (grades 3/4: 2% to 6%) 
Ophthalmic: Conjunctivitis (<10%), dry eye syndrome (<10%), eye irritation (<10%), eye  
pain (<10%), injected sclera (<10%), ocular hyperemia (<10%), periorbital edema (<10%),  
swelling of eye (<10%) 
Otic: Deafness (<10%) 
Respiratory: Pneumonitis (<10%) 
 
8.4 Decitabine 
  
8.4.1 Mechanism of Action: After phosphorylation, decitabine is incorporated into DNA 
and inhibits DNA methyltransferase causing hypomethylation and subsequent cell death 
(within the S-phase of the cell cycle).  
 
8.4.2 Clinical Formulation: Commercially available for injection as 50 mg single use vial. 
  
8.4.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler.  
 
8.4.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
 
Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). 
Solutions diluted for infusion in NS or D5W may be stored for up to 4 hours prior to 
infusion refrigerated at 2°C to 8°C (36°F to 46°F) if prepared with cold infusion fluids. 
Infusion should begin within 15 minutes of preparation if room temperature infusion 
solutions are utilized. 
 
8.4.5 Administration: infuse over 1 to 3 hours. 
 
8.4.6 Clinical Pharmacology: 
Distribution: ~63 to 89 L/m2  
Metabolism: Possibly via deamination by cytidine deaminase 
Half-life elimination: ~30 to 35 minutes 

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8.4.7 Potential Drug Interactions: 
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. 
Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy 
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Risk 
X: Avoid combination 
 
8.4.8 Drug toxicities 
Frequency >10%:  
Cardiovascular: Peripheral edema (25% to 27%), edema (5% to 18%), heart murmur (16%), 
hypotension (6% to 11%) 
Central nervous system: Fatigue (46%), headache (23% to 28%), insomnia (14% to 28%), 
rigors (22%), dizziness (18% to 21%), chills (16%), pain (5% to 13%), confusion (8% 
to 12%), lethargy (12%), hypoesthesia (11%), anxiety (9% to 11%) 
Dermatologic: Pallor (23%), skin rash (11% to 19%), erythema (5% to 14%), cellulitis (9% 
to 12%), pruritus (9% to 11%) 
Endocrine & metabolic: Hyperglycemia (6% to 33%), hypoalbuminemia (7% to 24%), 
hypomagnesemia (5% to 24%), hypokalemia (12% to 22%), hyponatremia (19%), 
hyperkalemia (13%) 
Gastrointestinal: Nausea (40% to 42%), constipation (30% to 35%), diarrhea (28% to 34%), 
vomiting (16% to 25%), anorexia (≤8% to 23%), decreased appetite (≤8% to 23%), 
abdominal pain (5% to 14%), stomatitis (11% to 12%), dyspepsia (10% to 12%) 
Hematologic & oncologic: Neutropenia (38% to 90%; grades 3/4: 37% to 87%; recovery 28 
to 50 days), thrombocytopenia (27% to 89%; grades 3/4: 24% to 85%), anemia (31% 
to 82%; grades 3/4: 22%), petechia (12% to 39%), febrile neutropenia (20% to 29%; 
grades 3/4: 23%), leukopenia (6% to 28%; grades 3/4: 22%), bruise (9% to 22%), oral 
mucosal petechiae (13%), lymphadenopathy (12%) 
Hepatic: Hyperbilirubinemia (6% to 14%), increased serum alkaline phosphatase (11%)  
Local: Localized tenderness (11%)  
Neuromuscular & skeletal: Arthralgia (17% to 20%), limb pain (18% to 19%), back pain 
(17% to 18%), weakness (15%) 
Respiratory: Cough (27% to 40%), dyspnea (29%), pneumonia (20% to 22%), pharyngitis 
(16%), rales (8% to 14%), epistaxis (13%) 
Miscellaneous: Fever (6% to 53%) 
 
Frequency 5% to 10%: 
Cardiovascular: Tachycardia (8%), chest wall pain (7%), chest pain (≤6% to 7%), chest 
discomfort (≤6% to 7%), facial edema (6%), hypertension (6%), cardiac failure (5%) 
Central nervous system: Depression (9%), falling (8%), malaise (5%), mouth pain (5%) 
Dermatologic: Alopecia (8%), xeroderma (8%), urticaria (6%), catheter site erythema (5%), 
night sweats (5%) 
Endocrine & metabolic: Hyperuricemia (10%), weight loss (9%), increased lactate 
dehydrogenase (8%), dehydration (6% to 8%), hypochloremia (6%), increased serum 
bicarbonate (6%), decreased serum bicarbonate (5%), hypoproteinemia (5%) 
Gastrointestinal: Mucosal inflammation (9%), gingival hemorrhage (8%), hemorrhoids 
(8%), loose stools (7%), tongue ulcer (7%), oral candidiasis (6%), toothache (6%), 

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dysphagia (5% to 6%), abdominal distention (5%), gastroesophageal reflux disease 
(5%), glossalgia (5%), oral mucosa ulcer (lip: 5%) 
Genitourinary: Urinary tract infection (7%), dysuria (6%) 
Hematologic & oncologic: Hematoma (5%), pancytopenia (5%), thrombocythemia (5%) 
Hepatic: Ascites (10%), increased serum AST (10%), decreased serum bilirubin (5%) 
Hypersensitivity: Transfusion reaction (7%) 
Infection including Candidiasis (10%), bacteremia (5% to 8%), staphylococcal infection 
(7%), tooth abscess (5%) 
Local: Catheter infection (8%), catheter pain (5%), swelling at injection site (5%) 
Neuromuscular & skeletal: Myalgia (5% to 9%), muscle spasm (7%), ostealgia (6%), 
musculoskeletal discomfort (≤5% to 6%), musculoskeletal pain (≤5% to 6%), 
crepitations (5%)  
Ophthalmic: Blurred vision (6%) 
Otic: Otalgia (6%) 
Renal: Polyuria (5%) 
Respiratory: Hypoxia (10%), upper respiratory tract infection (10%), abnormal breath 
sounds (5% to 10%), pharyngolaryngeal pain (8%), pulmonary edema (6%), sinusitis 
(5% to 6%), pleural effusion (5%), post nasal drip (5%), sinus congestion (5%) 
 
Frequency <5% (Limited to important or life-threatening): Abscess (peridiverticular), acute 
cardiorespiratory failure, anaphylaxis, atrial fibrillation, cardiomyopathy, catheter site 
hemorrhage, cholecystitis, fungal infection, gastrointestinal hemorrhage, gingival pain, 
hemoptysis, hypersensitivity reaction, intracranial hemorrhage, mental status change, 
myocardial infarction, mycobacterium avium complex, pseudomonal lung infection, 
pulmonary aspergillosis, pulmonary embolism, pulmonary infiltrates, pulmonary mass, 
renal failure, sepsis, splenomegaly, supraventricular tachycardia, Sweet’s syndrome (acute 
febrile neutrophilic dermatosis), urethral bleeding 
 
8.5 Azacitidine 
 
8.5.1 Mechanism of Action: Azacitidine inhibits DNA methyltransferase causing 
hypomethylation and subsequent cell death (within the S-phase of the cell cycle).  
 
8.5.2 Clinical Formulation: Commercially available for injection as 100 mg vial. 
  
8.5.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler.  
 
8.5.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
Infusion must be completed within 1 hour of (vial) reconstitution. 
Wash with soap and water if azacitidine suspension comes in contact with the skin. 
 
8.5.5 Administration: infuse over 10 to 40 min.  
 
8.5.6 Clinical Pharmacology: 

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  Distribution: 76 ± 26 L; does not cross blood-brain barrier  
  Metabolism: Hepatic; hydrolysis to several metabolites  
  Half-life elimination: IV: ~4 hours  
  Excretion: Urine (50% to 85%); feces (<1%) 
 
8.5.7 Potential Drug Interactions: 
         CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. 
Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy 
        Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. 
Risk X: Avoid combination 
 
8.5.8 Drug toxicities 
Frequency >10%:  
Cardiovascular: Peripheral edema (7% to 19%), chest pain (16%) 
Central nervous system: Fatigue (13% to 36%), rigors (26%), headache (22%), dizziness 
(19%), anxiety (5% to 13%), depression (12%), malaise (11%), pain (11%), 
insomnia (9% to 11%) 
Dermatologic: Erythema (7% to 17%), pallor (16%), skin lesion (15%), skin rash (10% to 
14%), pruritus (12%), diaphoresis (11%) 
Endocrine & metabolic: Weight loss (≤16%), pitting edema (15%), hypokalemia (6% to 
13%) 
Gastrointestinal: Nausea (48% to 71%), vomiting (27% to 54%), constipation (34% to 
50%), diarrhea (36%), anorexia (13% to 21%), abdominal pain (11% to 16%), 
abdominal tenderness (12%) 
Hematologic & oncologic: Thrombocytopenia (66% to 70%; grades 3/4: 58%), anemia 
(51% to 70%; grades 3/4: 14%), neutropenia (32% to 66%; grades 3/4: 61%), 
leukopenia (18% to 48%; grades 3/4: 15%), bruise (19% to 31%), petechia (11% to 
24%), febrile neutropenia (14% to 16%; grades 3/4: 13%), bone marrow depression 
(nadir: days 10 to 17; recovery: days 28 to 31) 
Local: Injection site reactions (14% to 29%): Erythema (35% to 43%; more common 
with IV administration), pain (19% to 23%; more common with IV administration), 
bruising (5% to 14%)  
Neuromuscular & skeletal: Weakness (29%), arthralgia (22%), limb pain (20%), back 
pain (19%), myalgia (16%) 
Respiratory: Cough (11% to 30%), dyspnea (5% to 29%), pharyngitis (20%), epistaxis 
(16%), nasopharyngitis (15%), upper respiratory infection (9% to 13%), pneumonia 
(11%), rales (9% to 11%) 
Miscellaneous: Fever (30% to 52%)  
 
Frequency 5% to 10%: 
Cardiovascular: Heart murmur (10%), tachycardia (9%), hypertension (≤9%), 
hypotension (7%), syncope (6%), chest wall pain (5%) 
Central nervous system: Lethargy (7% to 8%), hypoesthesia (5%), postoperative pain 
(5%) 
Dermatologic: Night sweats (9%), cellulitis (8%), rash at injection site (6%), urticaria 
(6%), skin nodules (5%), xeroderma (5%) 

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Gastrointestinal: Gingival hemorrhage (10%), stomatitis (8%), hemorrhoids (7%), 
dyspepsia (6% to 7%), abdominal distention (6%), loose stools (6%), dysphagia 
(5%), tongue ulcer (5%) 
Genitourinary: Urinary tract infection (8% to 9%), dysuria (8%), hematuria (≤6%)  
Hematologic & oncologic: Lymphadenopathy (10%), hematoma (9%), oral mucosal 
petechiae (8%), postprocedural hemorrhage (6%), oral hemorrhage (5%) 
Hypersensitivity: Transfusion reaction (7%) 
Infection: Herpes simplex infection (9%) 
Local: Itching at injection site (7%), hematoma at injection site (6%), induration at 
injection site (5%), injection site granuloma (5%), skin discoloration at injection site 
(5%), swelling at injection site (5%) 
Neuromuscular & skeletal: Muscle cramps (6%) 
Respiratory: Rhinorrhea (10%), wheezing (9%), abnormal breath sounds (8%), nasal 
congestion (6%), pharyngolaryngeal pain (6%), pleural effusion (6%), post nasal 
drip (6%), rhinitis (6%), rhonchi (6%), atelectasis (5%), sinusitis (5%) 
Miscellaneous: Lymphadenopathy (10%), herpes simplex (9%), night sweats (9%), 
transfusion reaction (7%), mouth hemorrhage (5%)  
 
Frequency <5%, postmarketing, and/or case reports: Abscess (limb, perirectal), aggravated bone 
pain, agranulocytosis, anaphylactic shock, atrial fibrillation, azotemia, bacterial infection, 
blastomycosis, bone marrow failure, cardiac failure, catheter site hemorrhage, cellulitis, 
cerebral hemorrhage, cholecystectomy, cholecystitis, congestive cardiomyopathy, decreased 
serum bicarbonate, dehydration, diverticulitis, fibrosis (interstitial and alveolar), 
gastrointestinal hemorrhage, glycosuria, hemophthalmos, hemoptysis, hepatic coma, 
hypersensitivity reaction, hypophosphatemia, increased serum creatinine, injection site 
infection, interstitial pulmonary disease, intracranial hemorrhage, leukemia cutis, melena, 
necrotizing 
fasciitis, 
neutropenic 
sepsis, 
orthostatic 
hypotension, 
pancytopenia, 
pneumonitis, polyuria, pulmonary infiltrates, pyoderma gangrenosum, renal failure, renal 
tubular acidosis, respiratory distress, seizure, sepsis, sepsis syndrome, septic shock, 
splenomegaly, Sweet's syndrome, tissue necrosis at injection site, toxoplasmosis, tumor 
lysis syndrome 
 
8.6 Venetoclax 
 
8.6.1 Mechanism of Action: Venetoclax is a potent, selective, orally bioavailable small-
molecule inhibitor of BCL-2.  
 
8.6.2 Clinical Formulation: Commercially available as 10, 50 and 100 mg tablets.  
 
8.6.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
8.6.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
          
Store at or below 30°C (86°F). 

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8.6.5 Administration:  
 
    Swallow the whole tablet with a meal. Do not crush, chew, or break. 
 
8.6.6 Clinical Pharmacology: 
     Distribution: 256 to 321 L  
   Metabolism: Hepatic, predominantly via CYP3A4/5; the major metabolite is M27 (has BCL-
2 inhibitory activity)  
    Half-life, elimination: ~26 hours  
   Time to peak: 5 to 8 hours 
   Excretion: Feces (>99.9%; ~21% as unchanged drug); Urine (<0.1%) 
 
8.6.7 Potential Drug Interactions: 
    CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine.     
           Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy 
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Venetoclax. Risk X: 
Avoid combination 
CYP3A4 Inducers (Strong): May decrease the serum concentration of Venetoclax. Risk X: 
Avoid combination 
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Venetoclax. 
Management: Reduce the venetoclax dose by at least 50% in patients requiring these 
combinations. Risk D: Consider therapy modification 
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Venetoclax. 
Management: These combinations are contraindicated during venetoclax initiation and 
ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce 
the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Risk 
D: Consider therapy modification 
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with 
Inducers). Risk C: Monitor therapy 
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. 
Risk X: Avoid combination 
Grapefruit Juice: May increase the serum concentration of Venetoclax. Risk X: Avoid  
combination 
Vaccines (Inactivated): Venetoclax may diminish the therapeutic effect of Vaccines 
(Inactivated). Risk C: Monitor therapy 
Vaccines (Live): Venetoclax may enhance the adverse/toxic effect of Vaccines (Live). 
Venetoclax may diminish the therapeutic effect of Vaccines (Live). Management: Avoid 
use of live, attenuated vaccines before, during, or after (prior to B-cell recovery) venetoclax 
treatment. Risk X: Avoid combination 
Warfarin: Venetoclax may increase the serum concentration of Warfarin. Risk C: Monitor  
therapy 
 
8.6.8 Drug toxicities 
Frequency generally >10%: 

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Blood and lymphatic system disorders: Thrombocytopenia, Leucopenia, Lymphopenia, 
Neutropenia, Febrile neutropenia, Anemia, Pancytopenia 
Gastrointestinal disorders: Nausea, Diarrhea, Constipation, Vomiting, Abdominal pain, 
decreased appetite, mucositis, proctitis 
General disorders and administration site conditions: Peripheral edema, fatigue, pyrexia, 
cachexia 
Multiple organ dysfunction syndrome, respiratory failure  
Infections and infestations: Pneumonia, Sepsis, Urinary tract infection, cellulitis, localized 
infection, Device related infection, Upper respiratory tract infection, lower respiratory tract 
infection, candida infection, bacteremia, mucosal infection 
Musculoskeletal and connective tissue disorders: Back pain, myalgia or musculoskeletal 
pain, arthralgia 
Nervous system disorders: Dizziness 
Skin and subcutaneous tissue disorders: Rash 
Respiratory, thoracic and mediastinal disorders: Cough, hypoxia, oropharyngeal pain, 
dyspnea  
Other: Hemorrhage, gastrointestinal hemorrhage, hypotension, hypertension, headache, 
pruritus   
  
Laboratory abnormalities, Hyperglycemia, hypocalcemia, hypoalbuminemia, hypokalemia, 
hyponatremia, hypophosphatemia, hyperphosphatemia, hyperbilirubinemia, 
hypomagnesemia, Blood creatinine increased,  blood bicarbonate decreased, hyperkalemia, 
hyperphosphatemia, Increased serum aspartate aminotransferase or alanine 
aminotransferase 
  
Tumor lysis syndrome (3%) including hyperuricemia 
 
8.7 Glasdegib 
 
8.7.1 Mechanism of Action: Glasdegib binds to and inhibits Smoothened (SMO), a 
transmembrane protein involved in hedgehog signal transduction.  
 
8.7.2 Clinical Formulation: Commercially available as 25 mg and 100 mg tablets. 
  
8.7.3 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler.  
 
8.7.4 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions.  
 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 
86°F). 
 
8.7.5 Administration: Swallow whole tablets without splitting or crushing the tablets. 
 
8.7.6 Clinical Pharmacology: 

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Distribution: 188 L 
Metabolism: Primarily hepatic via CYP3A4, with minor contributions by CYP2C8 and 
UGT1A9 
Half-life elimination: 17.4 hours ± 3.7 hours 
Time to peak: 1.3 to 1.8 hours 
Excretion: Urine: 49% (17% as unchanged drug); Feces: 42% (20% as unchanged drug) 
 
8.7.7 Potential Drug Interactions: 
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates 
(High risk with Inducers). Risk C: Monitor therapy 
CYP3A4 Inducers (Strong): May decrease the serum concentration of Glasdegib. Risk X: 
Avoid combination 
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Glasdegib. 
Management: Consider alternatives to this combination when possible. If the 
combination must be used, monitor closely for evidence of QT interval prolongation and 
other adverse reactions to glasdegib. Risk D: Consider therapy modification 
   Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with  
Inducers). Risk C: Monitor therapy 
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may  
          enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk C:  
          Monitor therapy 
 
8.7.8 Drug toxicities 
Frequency >10%:  
Cardiovascular: Edema (30%), atrial arrhythmia (13%), chest pain (12%) 
Central nervous system: Fatigue (36%), dizziness (18%), headache (12%) 
Dermatologic: Skin rash (20%) 
Endocrine & metabolic: Hyponatremia (11% to 54%), hypomagnesemia (33%), 
hyperkalemia (16%), hypokalemia (15%), weight loss (13%) 
Gastrointestinal: Nausea (29%), decreased appetite (21%), dysgeusia (21%), mucositis 
(21%; grade ≥3: 1%), constipation (20%), abdominal pain (19%), diarrhea (18%), 
vomiting (18%) 
Hematologic & oncologic: Anemia (43%; grade ≥3: 41%), hemorrhage (36%; grade ≥3: 
6%), febrile neutropenia (31%; grade ≥3: 31%), thrombocytopenia (30%; grade ≥3: 
30%), decreased white blood cell count (11%; grade ≥3: 11%) 
Hepatic: Increased serum aspartate aminotransferase (28%), increased serum bilirubin 
(25%), increased serum alanine aminotransferase (24%), increased serum alkaline 
phosphatase (23%) 
Neuromuscular & skeletal: Musculoskeletal pain (30%), increased creatine 
phosphokinase in blood specimen (16%), muscle spasm (15%) 
Renal: Increased serum creatinine (96%), renal insufficiency (19%) 
Respiratory: Dyspnea (23%), pneumonia (19%), cough (18%) 
Miscellaneous: Fever (18%) 
 

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Frequency 1% to 10%: 
Cardiovascular: Prolonged QT interval on ECG (4% to 5%) 
Infection: Sepsis (7%) 
 
Frequency not defined: Endocrine & metabolic: Hypophosphatemia 
 
 
Section 9.0 Toxicity and Adverse Event Reporting Guidelines:  
 
This protocol will comply with monitoring and adverse event reporting requirements of the 
UNMC Fred & Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere to 
the institutional and FDA guidelines for the toxicity reporting.  
 
The reporting is only for “study drug,” from the time of initiation of study drug until 30 days 
after last administration of study medication, or in case of low intensity therapy, 30 days after the 
end of 3rd cycle or last cycle (if stopped prior to the 3rd cycle) of venetoclax-hypomethylating 
combination or low-intensity therapy. Adverse event and serious adverse events will be followed 
until baseline, ≤ grade 1 levels, death, or until no further improvement is reasonably expected. 
Toxicity will be assessed using the revised NCI CTCAE version 4.03 (Appendix F).  
Deaths occurring within 30 days of study treatment regardless of relationship will be reported to 
the UNMC DSMC.  
 
9.1 Definitions:  
9.1.1 Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not the event is 
considered causally related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be considered 
an adverse event if the surgery or procedure is being performed for a pre-existing condition and 
the surgery or procedure has been planned before study entry. However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., the surgery is performed earlier than 
planned), then the deterioration of the condition for which the elective surgery or procedure is 
being done will be considered an adverse event.  
 
Any worsening of a pre-existing condition or illness is considered an adverse event. Laboratory 
abnormalities and changes in vital signs are considered to be adverse events if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, require dose 
modifications and/or if the investigator considers them to be adverse events.  
 
9.1.2 Treatment-emergent Adverse Event  
Treatment-emergent adverse event is defined as any adverse event with onset or worsening from 
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drug is administered, or in case of low intensity therapy, 30 days after the end of 6th cycle or last 
cycle (if stopped prior to the 6th cycle) of decitabine therapy.  
 
9.1.3 Unexpected Adverse Event  
An unexpected adverse event is any adverse drug event that is not listed in the current 
labeling/Investigator’s Brochure. “Unexpected,” as used in this definition, refers to an adverse 
drug experience that has not been previously observed (i.e., included in the labeling) rather than 
from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product.  
 
9.1.4 Serious Adverse Event  
A serious adverse event is one that at any dose (including overdose) and regardless of causality:  
• Results in death  
• Is a serious threat to life, health, safety or welfare-fare of subject1  
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Requires intervention to prevent permanent impairment or damage 
• Results in persistent or significant disability or incapacity2  
• Is a congenital anomaly or birth defect  
• Is another serious important medical event3  
• Is any medical event in an investigational drug study that requires treatment to prevent 
one of the outcomes listed above 
• Seriously jeopardizes the rights, safety, or welfare of subjects  
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it 
were more severe.  
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions.  
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition above 
should also usually be considered serious. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. A new 
diagnosis of cancer during the course of a treatment should be considered as medically important.  
 
9.2 Adverse Event Reporting and Definitions Per University of Nebraska Medical Center, 
IRB and Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee 
(DSMC)  
This protocol will adhere to all institutional guidelines for adverse event reporting. Adverse 
events will be evaluated using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
 
9.2.1 IRB REPORTING  
All internal adverse events (AEs) must be reported to the local IRB promptly per institutional 
human research protection program policies.  

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9.2.2 FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY 
MONITORING COMMITTEE (DSMC) REPORTING  
Grade 4 anemia, thrombocytopenia, neutropenia and leucopenia are routinely expected for 
almost all patients receiving chemotherapy for leukemia; these events will not be included in 
routine reports to the UNMC DSMC.  All other adverse events grade 3 or higher (expected or 
unexpected, at least possibly related to the study drug) will be reported to the University of 
Nebraska Medical Center, Fred & Pamela Buffett Cancer Center Data and Safety Monitoring 
Committee (DSMC) in accordance with the DSMC guidelines. The consenting investigator or 
the site principal investigator will make a determination of whether a grade ≥3 toxicity is related 
to the study drug. 
Deaths occurring within 30 days of the study drug regardless of relationship will be reported to 
the UNMC DSMC. 
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions:  
 
Not related: The subject was not exposed to the study treatment or another cause is obvious.  
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment.  
Possibly related: Study treatment administration and AE occurrence reasonably related in time, 
and the AE is explained equally well by causes other than study treatment, or treatment 
administration and AE occurrence are not reasonably related in time, but the AE is not obviously 
a result of other causes.  
Probably related: Study treatment administration and AE occurrence are reasonably related in 
time, and the AE is more likely explained by study treatment than by other mechanisms.  
Definitely related: The occurrence and timing of the AE are clearly attributable to the study 
treatment.  
 
The reporting is only for the “study drug,” from the time of initiation of study drug until 30 days 
after last administration of the study drug, or in case of low intensity therapy, 30 days after the 
end of 3rd cycle or last cycle (if stopped prior to the 3rd cycle) of venetoclax-hypomethylating 
combination or other low-intensity therapy. The “study drug” refers to the chemotherapy 
regimen planned at the time of initiation of the first cycle of therapy. Addition of a new agent, 
unless pre-planned at the time of initiation of the first cycle of therapy, will constitute a change 
in therapy.  
 
All AEs will be followed until baseline, ≤ grade 1 levels, death, or until no further improvement 
is reasonably expected. AEs judged by the investigator as not related or probably not related to 
the treatment will NOT be followed beyond the 30 days after the final dose of the study drug.  
 
Copies of the AE report will be submitted to the IRB as indicated in Section 9.2.1. Detailed 
policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
 
9.3 Monitoring  

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The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee will review this 
protocol on at least an annual basis. In its initial review, the DSMC will make a recommendation 
for the frequency of DSMC monitoring based on an assessment of risk associated with study-
associated therapy, per the DSMC policy. All adverse events and toxicity reporting will be 
reported to the UNMC Fred & Pamela Buffett Cancer Center Data and Safety Monitoring 
Committee (DSMC).  
 
Various methods will be implemented by the sponsor (UNMC) to exchange information with 
participating sites:  
 
• 
Site Initiation/Orientation  
• 
Regular Teleconferences including group wide progress within the agenda  
• 
Investigator meetings as feasible (remote or on an as needed basis, possibly in 
conjunction with larger meetings)  
• 
Email distributions/reports as needed  
 
9.3.1 Data Monitoring 
For this study, data monitoring is the act of overseeing the progress of a clinical trial, and of 
ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirement(s).  Monitoring is a Quality Control, continuous process during the entire trial. 
 
All participating sites will perform routine data monitoring for this study by each site’s 
institution according to the institution’s internal guidelines and policies.  A copy of the site’s 
monitoring report will be submitted to UNMC project coordinator.  
 
9.4 Auditing  
Auditing is a systematic and independent examination of trial-related activities and documents to 
determine: 
• whether the evaluated trial-related activities were conducted 
•  the data were recorded, analyzed, and accurately reported, according to the protocol, to 
the sponsor's SOPs, GCP, and applicable regulatory requirement(s).  
 
Auditing is a Quality Assurance, one point process during the trial. 
 
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) will 
review this protocol on at least an annual basis.  
 
This study will undergo audit on at least a quarterly basis by the UNMC Fred & Pamela Buffett 
Cancer Center Audit Committee.  
 
Detailed policy and procedures for this section may be reviewed at: 
https://www.unmc.edu/cancercenter/clinical/prms.html. 
 
 
 

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Section 10.0 Statistical Considerations:  
10.1 Study Design: This is a phase II trial that will evaluate the impact of clinicogenetic risk-
stratified management on outcomes of acute myeloid leukemia in older patients. 
 
10.2 Study Population: All patients who receive study drug will be considered evaluable for the 
safety analysis regardless of the duration of treatment. 
 
10.3 Sample size: The study will include a target total of 75 cases of newly diagnosed AML 
(approximately 15-20 cases per year for 4-5 years).  
 
10.4 Sample size justification: An optimal Simon two-stage design (93) was used to test the 
null hypothesis that 60% versus the alternative of 75% will be alive at 3 months. A sample size 
of 67 patients will have a minimum power to detect a difference of 80%, and a significance level 
of 0.05. Accounting for an attrition rate of 10%, a total of 75 patients will be enrolled. PASS 
11(94) software was used to conduct all sample size analyses.  
 
10.5 Data Analysis: 
Data will be descriptively summarized using frequencies and percentages.  A p-value less than 
0.05 will be considered statistically significant unless otherwise specified. All analyses will be 
performed based on intent-to-treat principle. The method of inversion(95) will be used to 
generate an interval estimate for the proportion of 90-day mortality. The association between 
functional status (fit, or vulnerable based on geriatric assessment), and 90-day mortality will be 
explored using a chi-square test (95). The proportion (and associated 95% confidence interval) of 
patients with impairments across various domains of geriatric assessment will be presented.    
 
10.6 Safety endpoint 
All adverse events recorded during the study will be summarized by each subject.  The incidence 
of treatment-emergent adverse events (new or worsening from baseline) will be summarized by 
severity and type of adverse event. Listings of deaths, SAEs, and AEs leading to early 
termination of study treatment or premature withdrawal from study will also be provided. 
 
10.7 Efficacy endpoints 
 
Mortality  
Mortality at 90 days will be calculated as the time from date of diagnosis to date of death due to 
any cause by 90 days from diagnosis.   
 
Quality of life 
Composite scores, as determined by EORTC QLQ-C30 version 3.0, will be utilized to determine 
quality of life status. A generalized linear mixed model will be utilized to evaluate changes in 
quality of life over time. 
 
Neurocognitive status 
Composite scores, as determined by MOCA test, will be utilized to determine neurocognitive 
status.  
 

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Overall survival (OS) 
OS is defined as the time from date of diagnosis to date of death due to any cause.  If a subject is 
not known to have died, survival will be censored at the date of last contact. The Kaplan-Meier 
method will be used to estimate the survival distribution. OS rates at 1 and 2 years will be 
provided as well as 95% CI. 
  
Proportion transplanted 
Included in this comparison are all patients who are enrolled in this study. The percentage of 
patients proceeding to transplant will be calculated for the lower intensity and intensive therapy 
groups along with 95% CI. Groups will be compared with chi-square tests.  
 
Exploratory endpoints and correlative studies 
Descriptive statistics will be used to compare patient characteristics between groups.  Mean, 
standard deviation (SD), median and range will be reported for continuous variables, and they 
will be compared with t-tests or Wilcoxon rank sum test. Frequencies and percentages will be 
used to describe categorical variables, and they will be compared between groups with chi-
square tests.  
 
10.8 Estimated duration of study and accrual goal 
It is expected that 15-20 patients will be enrolled in the trial each year. To meet the accrual goals 
of 75, we require approximately 4-5 years. After accrual is met, we plan to follow the patients for 
up to an additional 2 years to assess survival endpoints. 
 
10.9 Stopping rule 
The therapies used in this study are considered standard of care. A risk stratification strategy is 
considered necessary for therapy allocation even outside of a clinical trial. Significant toxicities 
are frequently observed in clinical practice in this patient population. For example, in one study 
with venetoclax in combination with hypomethylating agent, serious adverse reactions were 
reported in 75-85% of patients.(14, 15)   
 
With this background, the proposed two-stage design (93) has an expected sample size of 39.35 
and a probability of early termination of 0.691 under the conditions specified in the sample size 
justification. After testing the intervention on 27 evaluable patients in the first stage, the trial will 
be halted pending DSMC review if 10 or more patients die within 3 months of diagnosis of 
AML. Patients, who are already enrolled in the study, and are tolerating the study drug may 
continue the drug. If the trial goes on to the second stage, a total of 67 evaluable patients will be 
studied.  If more than 21 patients die by 3 months of diagnosis of AML, the intervention will be 
rejected. For the purpose of stopping rules, patients will be considered evaluable if they receive 
at least one dose of study medication and if alive, maintain study follow-up for at least one 
month after enrolling to the study.     
 
11.0 Records to be Kept:  
Information regarding the actual treatments, adverse effects, radiographic and laboratory 
information, and pathology are to be recorded on appropriate forms. See attached Data forms. 

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Serious adverse events, when noted, will be recorded on site via the standard serious adverse 
events form. 
 
11.1 Quality assurance: Complete records must be maintained in a research chart on each 
patient treated on the protocol. These records should include primary documentation (e.g., lab. 
report slips, imaging reports, pathology reports, physician notes, etc.) which confirm that:  
- The patient met the eligibility criteria.  
- Signed informed consent was obtained prior to treatment.  
- Treatment was given according to protocol (dated notes about doses given & reasons for any 
dose modifications).  
- Toxicity was assessed according to protocol (laboratory report slips, etc.).  
- Response was assessed according to protocol (bone marrow biopsy, lab reports, dated notes on 
clinical assessment, as appropriate).  
 
11.2  Electronic Data Capturing (EDC) System  
For investigator –initiated trials at UNMC, we will be utilizing Forte EDC application. Data will 
be stored electronically for this study on the Forte secure server. Data forms will not differ from 
the paper versions with the exception of an electronic format containing the UNMC Fred & 
Pamela Buffett Cancer Center and Forte logo.  
 
Forte provides for remote data collection that meets FDA 21 CFR Part 11 requirements as well 
as HIPAA and other regulatory requirements designed to enhance data security and protect 
patient confidentiality. Authorized users log into Forte through a secure connection and must 
provide a valid username, password, and database ID. This data may be made available to the 
public at large.  
 
12.0 Patient Consent:  
 
12.1 Human Subjects Research Protection Training  
All personnel involved in this research project will have completed the OHRP-approved 
computer based training course on the Protection of Human Research Subjects. All clinical and 
correlative research included in this application will have approval by the institutional review 
board.  
 
12.2 Study Population  
Patients are from all socio-economic groups and will be entered into the study without bias with 
respect to gender or race. Attempts will be made to recruit minorities. No vulnerable subjects 
will be included in the study.  
 
12.3 Sources of Material  
Pathology material must be reviewed, and the diagnosis confirmed by University Nebraska 
Medical Center pathology department (retrospectively).  
 
12.4 Recruitment and Informed Consent  
Patients with an initial diagnosis of AML seen and evaluated at Nebraska Medicine or IRB 
approved participating sites will be available for recruitment. These patients will be informed of 

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the nature of this study, and will be asked to participate on a voluntary basis after informing them 
of the possible risks and benefits of the study. A number of public registries may be accessible to 
health care providers and prospective subjects as listed below.  
 
National Library of Medicine - http://clinicaltrials.gov (NCT03226418)  
National Cancer Institute - http://www.cancer.gov  (NCI-2017-01285)  
 
12.5 Subject Competency  
Subjects will be eligible to participate in the study only if they are competent to give informed 
consent. A subject that the investigator judges to be incompetent will not be enrolled.  
 
12.6 Process of Informed Consent  
If the patient chooses to be a participant in this study, informed consent will be obtained by the 
investigator. The study and procedures involved including the risks will be explained in detail to 
each subject. It will be clearly explained to the subject that this is a research study and that 
participation is entirely on a voluntary basis. Subjects will be given the option to discuss the 
study with a family member, friend, counselor or, another physician. The participating 
investigators will be available to discuss the study with them.  
 
12.7 Subject/Representative Comprehension  
When the process of informed consent is completed, the subject will be asked to state in his/her 
own words, the purpose of the study, the procedures that will be carried out, potential risk, 
potential benefits to the subject, the alternatives and the right to withdraw from the study. If there 
is any indication that a given subject's comprehension is anything less than accurate, the points 
of confusion will be discussed and clarified.  
 
12.8 Information Purposely Withheld.  
The results of the tests done solely for research purposes will not be disclosed to the subject. No 
other information will be purposely withheld from the subject. 
 
12.9 Potential Benefits of the Proposed Research to the Subjects  
It is hoped that the use of risk-stratified therapy allocation may result in lower early mortality 
rate or lower rates of other toxicities. 
 
12.10 Potential Benefits to Society.  
Information obtained from this study may help other cancer patients by contributing to the 
knowledge of whether the proposed risk-stratified therapy allocation offers potential advantages 
over other strategies currently available.  
 
12.11 Potential Risks  
The use of cytotoxic chemotherapy is associated with numerous potential risks. Chemotherapy is 
considered to be a valid treatment option for patients with AML. Chemotherapy utilized in this 
study are in fact considered standard of care at UNMC and many other cancer centers in the 
United States. It is believed the treatment option outlined in the study will not pose significant 
additional risks compared to conventional treatment that might consist of other chemotherapy 
drugs given alone or in combination. 

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12.12 Therapeutic Alternatives  
If patients choose not to participate in this study they may elect to receive standard therapy as per 
their primary oncologist, which may include similar or other chemotherapy drugs given alone or 
in combination.  
 
12.13 Risk/Benefit Relationship  
Although there are inherent risks involved because of the use of chemotherapy agents, the risk is 
considered to be acceptable in the setting of cancer given the potential benefit of chemotherapy 
in extending survival or improving quality of life over time.  
 
12.14 Consent Form Documents  
No information will be purposely withheld from the patients. The consent document used in this 
study will include the adult consent document. See attached consent form 
 
Section 13.0 References   
  
1. 
Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. 
Diagnosis and management of AML in adults: 2017 ELN recommendations from an 
international expert panel. Blood. 2017;129(4):424-47. 
2. 
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 
revision to the World Health Organization classification of myeloid neoplasms and acute 
leukemia. Blood. 2016;127(20):2391-405. 
3. 
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. 
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J 
Med. 2017;377(5):454-64. 
4. 
Muppidi MR, Portwood S, Griffiths EA, Thompson JE, Ford LA, Freyer CW, et al. 
Decitabine and Sorafenib Therapy in FLT-3 ITD-Mutant Acute Myeloid Leukemia. Clin 
Lymphoma Myeloma Leuk. 2015;15 Suppl:S73-9. 
5. 
Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN, et al. Effect of 
gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia 
(ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-16. 
6. 
Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic 
syndromes in older adults. J Clin Oncol. 2014;32(24):2541-52. 
7. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-
30. 
8. 
Upadhyay S, Dahal S, Khanal N, Bhatt VR, Silberstein PT. Chemotherapy in Elderly 
Patients with Acute Myeloid Leukemia (AML): Analysis of Socioeconomic Factors Using 
National Cancer Data Base (NCDB). Blood. 2014;124(21):5267. 
9. 
Meyers JL, Yu YF, Davis KL. Medicare Fee-for-Service Enrollees with Acute 
Myelogenous Leukemia: An Analysis of Treatment Patterns and Patient Survival. Blood. 
2011;118(21):505. 
10. 
Alibhai SM, Leach M, Minden MD, Brandwein J. Outcomes and quality of care in acute 
myeloid leukemia over 40 years. Cancer. 2009;115(13):2903-11. 

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11. 
Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. Final results of a 
phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high 
risk (secondary) AML. Journal of Clinical Oncology. 2016;34(15_suppl):7000. 
12. 
Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et al. Phase 
2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs 
cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239-46. 
13. 
FDA News Release. FDA approves first treatment for certain types of poor-prognosis 
acute myeloid leukemia. Accessed on November 12,2017. Available at:  
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm569883.htm  [ 
14. 
DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al. Safety and 
preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with 
previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. 
Lancet Oncol. 2018;19(2):216-28. 
15. 
Venetoclax Prescribing Information. Available at: 
https://www.rxabbvie.com/pdf/venclexta.pdf. Accessed on December 4, 2018. 
16. 
Wei A, Strickland SA, Hou J-Z, Fiedler W, Lin TL, Walter RB, et al. Venetoclax with 
Low-Dose Cytarabine Induces Rapid, Deep, and Durable Responses in Previously Untreated 
Older Adults with AML Ineligible for Intensive Chemotherapy. Blood. 2018;132(Suppl 1):284. 
17. 
Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T, et al. A Phase 2 
Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated 
Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. Blood. 
2016;128(22):99-. 
18. 
Gardin C, Chevret S, Pautas C, Turlure P, Raffoux E, Thomas X, et al. Superior long-
term outcome with idarubicin compared with high-dose daunorubicin in patients with acute 
myeloid leukemia age 50 years and older. J Clin Oncol. 2013;31(3):321-7. 
19. 
Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al. 
High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 
2009;361(13):1235-48. 
20. 
Klepin HD, Geiger AM, Tooze JA, Kritchevsky SB, Williamson JD, Ellis LR, et al. The 
feasibility of inpatient geriatric assessment for older adults receiving induction chemotherapy for 
acute myelogenous leukemia. J Am Geriatr Soc. 2011;59(10):1837-46. 
21. 
Muffly LS, Kocherginsky M, Stock W, Chu Q, Bishop MR, Godley LA, et al. Geriatric 
assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. 
Haematologica. 2014;99(8):1373-9. 
22. 
Tawfik B, Pardee TS, Isom S, Sliesoraitis S, Winter A, Lawrence J, et al. Comorbidity, 
age, and mortality among adults treated intensively for acute myeloid leukemia (AML). J Geriatr 
Oncol. 2016;7(1):24-31. 
23. 
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14.0 Data Collection Forms:  
Attached  
Appendix A. 2017 ELN risk stratification by genetics* 
 
Risk category Genetic abnormality 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow† 
Biallelic mutated CEBPA 
Intermediate 
Mutated NPM1 and FLT3-ITDhigh† 
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-
risk genetic lesions) 
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ 
Cytogenetic abnormalities not classified as favorable or adverse 
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214 
t(v;11q23.3); KMT2A rearranged 
t(9;22)(q34.1;q11.2); BCR-ABL1 
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) 
-5 or del(5q); -7; -17/abn(17p) 
Complex karyotype,§ monosomal karyotype|| 
Wild-type NPM1 and FLT3-ITDhigh† 
Mutated RUNX1⁋ 
Mutated ASXL1⁋ 
Mutated TP53# 
 
†Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5) 
‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations. 
§Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring 
translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); 
AML with BCR-ABL1. 
||Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional 
monosomy or structural chromosome abnormality (excluding core-binding factor AML). 
⁋These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML 
subtypes. 
#TP53 mutations are significantly associated with AML with complex and monosomal karyotype. 
 
*In our study, we will use the results of conventional karyotyping/fluorescence in situ 
hybridization (FISH) for classification of risk categories since molecular mutation panel 
generally take more than 7-10 days to results, however, if certain molecular mutation results (e.g. 
NPM1 and FLT3 ITD mutations) are available at the time of risk categorization and decision-
making regarding low intensity and intensive chemotherapy, the results will be taken into 
consideration. Since allelic ratio is not performed in routine practice, if FLT3 ITD is present, 
patients will be categorized as intermediate risk category. If cytogenetic and/or FISH testing 
cannot be performed despite reasonable attempt because of reasons such as failure to grow 
cells/induce mitosis, lack of suitable specimens, patients will be categorized as intermediate-risk 
AML. Enrollment of such cases should be discussed with the principal investigator.  
 

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Appendix B. AML with myelodysplasia-related changes 
The presence of multilineage dysplasia alone will not classify a case as AML with 
myelodysplasia-related changes when a mutation of NPM1or biallelic mutation of CEBPA is 
present. In cases lacking these mutations, the morphologic detection of multilineage dysplasia 
(defined as the presence of 50% or more dysplastic cells in at least 2 cell lines) remains a poor 
prognostic indicator and is sufficient to make a diagnosis of AML with myelodysplasia-related 
changes. A history of MDS remains as an inclusion criterion for this category as does the 
presence of an MDS-related cytogenetic abnormality with 1 exception: del(9q) has been removed 
as a defining cytogenetic abnormality for AML with myelodysplasia-related changes because of 
its association with NPM1 or biallelic CEBPA mutations and its apparent lack of prognostic 
significance in those settings. The cytogenetic abnormalities that now define AML with 
myelodysplasia-related changes are listed below.  
 
Cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related changes 
when ≥20% PB or BM blasts are present and prior therapy has been excluded 
 
Cytogenetic abnormalities 
Complex karyotype (3 or more abnormalities) 
Unbalanced abnormalities 
 −7/del(7q) 
 del(5q)/t(5q) 
 i(17q)/t(17p) 
 −13/del(13q) 
 del(11q) 
 del(12p)/t(12p) 
 idic(X)(q13) 
Balanced abnormalities 
 t(11;16)(q23.3;p13.3) 
 t(3;21)(q26.2;q22.1) 
 t(1;3)(p36.3;q21.2) 
 t(2;11)(p21;q23.3) 
 t(5;12)(q32;p13.2) 
 t(5;7)(q32;q11.2) 
 t(5;17)(q32;p13.2) 
 t(5;10)(q32;q21.2) 
 t(3;5)(q25.3;q35.1) 
 
 
 

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Appendix C. Eligibility Checklist 
Date Completed: 
 
Protocol #: 179-17  
Institution:  UNMC 
Patient ID: 
Checklist version # 1.0 
Waiver #: 
 
Eligibility Checklist        
        Inclusion criteria 
1. A new diagnosis of de novo, secondary or treatment-related AML, other AML 
equivalent such as myeloid sarcoma, myelodysplastic syndrome in 
transformation to AML, or high-grade treatment-related myeloid neoplasm 
2. Patients aged ≥60 years 
3. Karnofsky Performance Status ≥60% 
4. Subjects  must able and willingly give signed informed consent 
 
All of the above must be yes to be eligible.  
 
Exclusion criteria 
1. Acute promyelocytic leukemia (APL). Patients 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 for the study. 
2. Relapsed or refractory AML, who require salvage therapy 
3. Prior exposure to decitabine or azacitidine will be an exclusion criterion for the 
use of decitabine or azacitidine alone. 
4. Patients, who require urgent initiation of chemotherapy (other than debulking 
agent such as hydroxyurea or cyclophosphamide) due to leukemia-related 
emergencies such as leukostasis, or disseminated intravascular coagulopathy. 
Patients will not be excluded solely based on prior use of debulking agent. Prior 
or current use of leukapheresis will be allowed. 
5. Uncontrolled serious infection at the time of enrollment. Infections are 
considered controlled if appropriate therapy has been instituted and, at the time 
of enrollment, patients do not have signs of infection progression. Progression of 
infection is defined as hemodynamic instability attributable to sepsis, new 
symptoms, worsening physical signs or radiographic findings attributable to 
infection. Persisting fever without other signs or symptoms will not be 
interpreted as progressing infection 
6. Uncontrolled clinically significant arrhythmia, myocardial ischemia or 
congestive heart failure within the past 2 weeks, that is considered by the treating 
physician as a contraindication for initiation of chemotherapy. Discussion with 
the principal investigator is encouraged if further clarification is required. 
7. Ejection fraction <45% will be an exclusion criteria for intensive chemotherapy. 
Such patients may receive low intensity therapy.  
8. Clinically significant kidney (e.g. GFR ≤45ml/minute or Creatinine of ≥2 mg/dl) 
or liver dysfunction (e.g. AST/ALT and/or bilirubin ≥2 times ULN) at the time 
of enrollment that may prevent from safely using chemotherapy. Such patients 
may be allowed to receive low-intensity chemotherapy. Patients with elevated 
bilirubin secondary to Gilbert syndrome will not be excluded. Discussion with 
Yes   No  N/A 
 
[   ]   [   ]   [   ] 1. 
 
 
[   ]   [   ]   [   ] 2. 
[   ]   [   ]   [   ] 3. 
[   ]   [   ]   [   ] 4. 
 
 
 
 
[   ]   [   ]   [   ] 1. 
 
 
[   ]   [   ]   [   ] 2. 
[   ]   [   ]   [   ]3. 
 
[   ]   [   ]   [   ] 4. 
 
 
 
 
[   ]   [   ]   [   ] 5. 
 
 
 
 
 
 
[   ]   [   ]   [   ] 6. 
 
 
 
[   ]   [   ]   [   ] 7. 
 
[   ]   [   ]   [   ] 8. 
 
 
 
 

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the principal investigator is encouraged if further clarification is required. 
9. Any other condition that may not allow safe use of chemotherapy based on the 
clinical judgment of the treating oncologist. 
All of the above must be no to be eligible. 
 
[   ]   [   ]   [   ] 9. 
 
 
Eligibility:      [    ]  Patient satisfies all criteria.  
                       [    ]  Patient not formally eligible, but admitted to study because (state reason);  
             
_________________________________________________________________________________________
_________ 
             Patient Initials:  ______________MR #______________DOB ______________ 
   
ELIGIBILITY reviewed and confirmed  
Site Investigator Signature _______________________Date_____________        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D. Hematopoietic Cell Transplant Comorbidity Index 
 
Many patients may not have undergone a pulmonary function test or an echocardiogram prior to 
enrollment. In the absence of a known diagnosis of chronic pulmonary obstructive disease or 
other pulmonary disease, or congestive heart failure, such patients will receive a score of 0 for 
pulmonary comorbidity and congestive heart failure. The use of prophylactic antibiotics or fevers 
thought to be possibly related to tumor fever may NOT be used to assign a score of 1 for 
infection. A prior diagnosis of solid or lymphoid malignancies but NOT myelodysplastic 
syndrome or other myeloid malignancies get a score of 3 for prior malignancy.  
Patients with therapy-related AML will need an additional score of 2 (NOT including a score for 
a history of prior malignancies) in the Hematopoietic Cell Transplantation Comorbidity Index to 
be considered vulnerable. Please see section 5.1.1 for further details and clarification.  Additional 
clarification may be obtained from the expert review paper by Sorror (71), who designed the 
tool.  
 
 
 
 
 
 
 

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APPENDIX E. Disease response and treatment failure criteria as per the international 
working group criteria 
 
Response criteria  
 
 
Morphologic complete remission: A complete remission designation requires that the patient 
achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 
1,000/microL and platelet count of ≥100,000/microL. Hemoglobin concentration or hematocrit 
has no bearing on remission status, although the patient must be independent of transfusions. 
 
Molecular complete remission or minimal residual disease negative status: Molecular complete 
remission requires achievement of complete remission and absence of any detectable disease by 
molecular and/or multidimensional flow cytometric techniques. 
 
Treatment failure 
 
 
 
 
 
 

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APPENDIX F 
NCI Common Toxicity Criteria Version 4.03 (CTCAE) 
Active Date: June 14, 2010 
Toxicity will be scored using NCI CTC Version 4.03 for toxicity and adverse event 
reporting. A copy of the NCI CTC Version 4.03 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov). All appropriate treatment areas have access to a copy of 
the CTC Version 4.03. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX G. Assessment of other geriatric syndromes 
 
1. Have you had any falls in the last 6 months? 
Yes       No  
Comments regarding falls(ie: specify number of falls)_______________ 
2. Have you had a period of confusion (delirium) in the past? 
Yes 
 
No 
Comments regarding dementia or delirium: ____________________________ 
3. Do you have a history of urine leakage (incontinence)?  
Yes 
 
No 
 
4. Do you have a history of stool leakage (incontinence)? 
Yes 
 
No 
Comments regarding urinary or stool incontinence: ________________________