Feasibility of Outpatient Induction Chemotherapy for Adult Patients With Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome
Phase: NA
Conditions: Adult Acute Myeloid Leukemia, Adult Myelodysplastic Syndrome
Sponsor: University of Washington

Cover Page 
 
Outpatient Induction Chemotherapy in Treating 
Patients With Acute Myeloid Leukemia or 
Advanced Myelodysplastic Syndrome 
 
NCT01807091 
 
Study Protocol with Statistical Analysis Plan 
 
Document date: Feb 20, 2019 

7910 
IRO RECD JAN 17 2019 
Fred Hutchinson Cancer Research Center 
University of Washington 
Seattle Cancer Care Alliance 
Current Version: 04/21/2016 
Previous Version: 09/03/2015 
Iitle: Feasibility of Outpatient Induction Chemotherapy for Adult Patients with Acute 
Myeloid Leukemia or Advanced Myelodysplastic Syndrome 
Principal Investigator: 
Pamela S. Becker, M.D., PhD 
Professor of Medicine 
University of Washington 
Campus Box 358056 
850 Republican St. N415 
Seattle, WA 98109 
Tel: 206-616-1589 
Fax: 206-543-3560 
Email: pbecker@u.washington.edu  
Sub-Investigators: 
Frederick R. Appelbaum, M.D. 
Elihu Estey, M.D. 
Paul Hendrie, M.D., PhD 
Bart Scott, M.D. 
Barry Storer, PhD 
Kathleen Shannon Dorcy, PhD 
Andrea Perdue, PA-C 
Wendy Mitsuyama 
Member FHCRC 
Professor of Medicine UW 
Member FHCRC 
Professor of Medicine UW 
Clinical Associate Professor UW 
Assistant Member FHCRC 
Assistant Professor of Medicine UW 
Member FHCRC 
Professor UW 
Director of Research Development SCCA 
Research Nurse FHCRC 
Physician Assistant 
Project Manager 
206-667-4412 
206-288-7176 
206-288-6366 
206-667-1990 
206-667- 6151 
206-667-3648 
206-416-5678 
206-288-6379 
FHCRC IRB Approval 
FEB 20 2019 
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Document Released Date 

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Seattle Cancer Care Alliance Network Investigators 
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Sub Investigators 
Aimee Kohn, MD 
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Table of Contents 
Section 
Page 
Table of Contents 
3 
Study Overview 
4 
1. 
Objectives 
4 
2. 
Background and Study Rationale 
4 
3. 
Eligibility 
5 
3.1. 
Inclusion Criteria 
5 
4. 
Treatment Plan 
6 
4.1. 
Indications for Hospitalization While On Study 
6 
5. 
Study Procedures 
7 
5.1. 
Screening Evaluations 
7 
5.2. 
On Study Evaluations 
7 
6. 
Regulatory and Reporting Requirements 
7 
6.1. 
Adverse Event Monitoring and Reporting 
7 
6.2. 
Data and Safety Monitoring Plan 
8 
7. 
Statistical Considerations 
8 
8. 
References 
10 
9. 
Appendix A 
11 
10. 
Appendix B - Treatment Related Mortality Score 
12 
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Study Overview 
This study will be a pilot trial for the feasibility of outpatient induction chemotherapy for 
diagnosed acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS) 
for those ages >18 years of age. 
1. Objectives 
Assess the feasibility of outpatient induction therapy for acute myeloid leukemia (AML) or 
advanced (MDS) by examining whether: 
1.) >50% of patients treated as outpatients can complete chemotherapy without being 
admitted to hospital. 
2.) <5% of patients die within 14 days of beginning outpatient chemotherapy. 
2. Background and Study Rationale 
Medical practice over the past 20 years has tried to curb health care costs by increasing 
outpatient treatment and care for common medical procedures in patients with mainstream 
conditions. An example of this would be the establishing of "day surgical procedure units". 
Little focus has been on the "outlier healthcare consumer", those patients that make up a 
fraction of the population, but disproportionately consume resources I. Those patients can 
drive up healthcare cost with a rare, life threatening disease. 
Little research has been done to look at the health care economics of acute myeloid leukemia 
(AML). Commonly today, acute myeloid leukemia (AML) is treated with induction and 
consolidation chemotherapy in an inpatient hospital setting. Feasibility of outpatient 
consolidation chemotherapy has been examined 2, but induction chemotherapy to induce 
remission in an outpatient setting has not been done. 
Research has shown that it is not the LOS (length of stay) fueling the cost of hospital 
admissions, but front loaded costs; the cost that occur during the "early stage of admission 
when resource consumption is most intense" 3. We have already shown that patients can be 
safely early discharged once induction therapy is complete. This can be done without an 
increase in "treatment-related mortality" (TRM) provided the patients are doing well at 
discharge, live in proximity to UW/SCCA, have an outpatient caregiver, and are committed 
to return for outpatient follow-up 4. While we have not quantified the effects of early 
discharge on cost or quality-of-life, it seems likely that these effects are favorable. We have 
also shown that, regardless of neutrophil count, patients can be discharged from the hospital 
after successful treatment of "neutropenic fever" without increase in mortality or admission 
to the ICU 5. We have addressed patient safety and early discharge and now want to look one 
step further. We want to go beyond cost containment of early stage hospital admission and 
take a look at the feasibility of moving induction chemotherapy for AML patients to an 
outpatient treatment setting. 
This protocol is an extension of our early discharge experience. Specifically it will examine 
the feasibility of administering to selected outpatients an induction chemotherapy regimen 
that would usually be administered to inpatients, as will still be the case for most patients. 
Although administration of the regimen requires only 4-7 days, there could be great cost 
savings per patient multiplied by many patients and the same seems highly plausible as 
applied to a patients' quality-of-life. 
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We will use 2 criteria to assess "feasibility". The first is whether an excessively high 
proportion of patients need to be admitted to hospital during administration of chemotherapy 
because of complications such as vomiting, infection etc. The need to admit a high 
proportion of patients would at the very least increase work required by providers. Our 
unpublished experience with outpatient induction is that 15% of a series of 13 patients with 
relapse were admitted prior to completion of therapy. We propose these data as our historical 
control, but any specific number will be arbitrary. Certainly the relevance and utility of 
outpatient therapy would be in doubt were the proportion much above 50%, so we have 
chosen this number. The 2"d and more important criterion is TRM attributable to 
administration of typically inpatient chemotherapy to outpatients. "Attributable" is also 
somewhat nebulous but TRM within 14 days of beginning chemotherapy seems reasonable. 
Current TRM rates for patients receiving chemotherapy as inpatients are <5% 6. Hence it 
would require many patients given chemotherapy as outpatients to be confident that the 
outpatient TRM rate is similarly low. Such hypothesis testing is not our intent. We merely 
intend to enter a maximum of 25 patients stopping early should it become likely that our 2 
criteria for feasibility will not be met. Our statistical section (see section 7.0) provides the 
rationale supporting our stopping rules, briefly stated that the study if 7 of 10 patients are 
hospitalized, or if 3 patients die. 
3. Eligibility 
Our eligibility requirements have been selected to minimize the chance of TRM and, probably, 
the need for admission to hospital during the days of chemotherapy administration. 
3.1. Inclusion Criteria 
1.) Signed Written Informed Consent a.) 
The signed informed consent. 
b.) The benefits / risks of the induction chemotherapy regimen will be reviewed, and a 
second consent may be necessary if the regimen will be administered according to a 
separate protocol. 
2.) AML (APL excepted) or high-risk MDS (10-19% blasts in marrow by morphology or 
flow cytometry or blood). 
3.) Meet the eligibility criteria for the selected inpatient protocol that they will receive as an 
outpatient. 
To receive the treatment as an outpatient they must: 
a.) Treatment-related mortality (TRM) score (ref) <9.21 corresponding to a TRM rate 
of 3% when chemotherapy of similar intensity as proposed here is administered to 
inpatients. 
b.) Ages >18 years of age 
c.) Blast count < 10,000 
d.) Fibrinogen > 200 
e.) Afebrile with clear chest imaging and no signs of active viral, bacterial, fungal 
infection unless determined to be, at the discretion of the investigator, not clinically 
significant in the context of this study. 
f.) Adequate cardiac function as demonstrated by LVEF of 45% or greater, by 
MUGA or echocardiogram. No ongoing cardiac issues such as uncontrolled 
arrhythmias or unstable angina or congestive heart failure. 
g.) Patient must have an outpatient caregiver available. 
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h.) Patient must live within 30 minutes of the treating physician's office during 
outpatient treatment. 
i.) Patient must be willing to return to the treating physician's office for outpatient 
follow-up once outpatient treatment is completed. 
j.) Logistical requirements: 
1. Space available in infusion room. 
2. Outpatient infusion pump available if continuous infusion required. 
3. Case discussed with infusion room nursing staff. 
Note: age and white blood count are already components of the TRM score, but are included 
here for safety purposes 
4. Treatment Plan 
1.) Patients will be treated according to the operative inpatient induction chemotherapy 
regimen for which they will also provide informed consent. 
2.) Treatment must begin on Monday, Tuesday, Wednesday, Thursday, or Friday after 
discussion with the 5th  floor Infusion Room staff 
3.) If treatment includes ara-C at a daily dose of? 1g/m2 patients will receive steroid eye 
drops and prednisone 100 mg daily or its IV equivalent. 
4.) Patients must be followed daily during administration of chemotherapy. Evaluation will 
be until completion of chemotherapy. 
Evaluation will include: 
a.) Daily weight 
b.) Daily CBC and platelet count (ordered as "52D"), chemistries (ordered as S9), 
and uric acid, LDH, Mg, phosphate 
5.) Change in weight of +/- 1.5 kg , hematocrit <24, platelet count < 10, sodium < 130 or > 
145, potassium <3.2 or > 4.8, fever, or development of fever will mandate a call to the 
patient's mid level provider or attending physician. 
6.) Patient will receive prophylactic oral levofloxacin, fluconazole and acyclovir. 
4.1. Indications for Hospitalization While On Study 
1.) Fever (?_101.0 F) 
2.) Infection requiring IV antibiotics. 
3.) Shortness of breath not promptly responsive to red cell transfusion and/or associated with 
new infiltrate on chest X-ray. 
4.) Bleeding not easily halted by platelet transfusion. 
5.) Any grade 3-4 toxicity (NCI Common Toxicity Criteria) other than myelosuppression, 
nausea/vomiting controlled by antiemetics, asymptomatic metabolic abnormalities, or skin 
rash, diarrhea of volume unable to be compensated by oral and IV fluids, pain not controlled 
by analgesics. 
4.2. Mechanism For Care "After Hours" Patients will proceed directly to the local hospital. 
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5. Study Procedures 
All laboratory and radiographic testing mentioned in this protocol will be done as a part of 
standard of care for patients undergoing induction chemotherapy for AML or advanced MDS. 
5.1. Screening Evaluations 
1.) Complete physical examination. 
2.) Medical history: Detailed documentation of disease and treatment history with outcomes 
in standard medical record. 
3.) ECOG performance status. 
4.) Concurrent medical conditions. 
5.) Hematology: CBC with differential and platelet count and peripheral blood smear. 
6.) Serum chemistries: Electrolytes (sodium, potassium, chloride, and bicarbonate), blood 
urea nitrogen (BUN), creatinine, glucose, and liver function tests (aspartate aminotransferase 
(AST) and/or alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, 
DIC panel (includes fibrinogen) 
7.) Initial standard of care diagnostic bone marrow reports, including hematopathology, 
cytogenetics/FISH, and flow cytometry. 
8.) Chest imaging within 7 days of consent. 
9.) MUGA or echocardiogram within 28 days of consent. 
10.) Informed consent. 
5.2. On Study Evaluations 
1.) Daily weights during induction chemotherapy administration. 
2.) Provider (physician or advanced practice provider) visit including elicitation and 
documentation of adverse events as well as symptom-focused physical exam on days 1, 3, and 
5 of induction chemotherapy. 
3.) Hematology: CBC with differential and platelet count daily during induction 
chemotherapy then as standard of care; DIC panel days 1 and 2 of induction chemotherapy 
and then as needed. 
4.) Serum chemistries: Electrolytes (sodium, potassium, chloride, and bicarbonate), BUN, 
creatinine, glucose, and liver function tests (AST, ALT, ALP, total bilirubin, LDH) and 
tumor lysis labs (Ca, Mag, phos, uric acid, LDH) daily during induction chemotherapy. 
5.) Hospitalization and reason for hospitalization during induction will be monitored. 
6.) Mortality during the first 14 days will be monitored. 
6. Regulatory and Reporting Requirements 
6.1. Adverse Event Monitoring and Reporting 
The principal investigator is responsible for monitoring the safety of patients who enroll in 
the study. This protocol will not dictate the choice of chemotherapy regimens. The sole 
research focus of this study is the feasibility of using an outpatient setting for administration 
of chemotherapy for AML or advanced MDS. For purposes of this study, only the following 
AEs will be recorded: 
1.) Reasons for hospitalization during planned outpatient administration of chemotherapy. 
2.) Causes of any deaths that occur within 14 days of start of outpatient chemotherapy 
(expedited reports). 
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6.2. Data and Safety Monitoring Plan 
Ongoing trial oversight is carried out by the principal investigator, Dr. Becker and the primary 
research nurse. These individuals will meet regularly to review recently acquired data, 
and adverse events. Institutional support of trial monitoring is provided in accordance 
with the FHCRC Institutional Data and Safety Monitoring Plan. Under the provisions of this 
plan, the FHCRC research Trials Office coordinates monitoring of data accuracy and 
compliance by consultants, contract research organizations, or FHCRC employees unaffiliated 
with the conduct of the study. Independent monitoring visits occur at specified intervals 
determined by the assessed risk level of the study and the findings of previous visits. 
In addition, protocols are reviewed at least annually by the Protocol and Data Monitoring 
Committee (PDMC) and the Institutional Review Board (IRB). The PDMC reviews accrual, 
adverse events, stopping criteria, and adherence to the data and safety monitoring plan. The 
PHCRC IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects. Approval of both committees is 
necessary to continue the study. 
7. Statistical Considerations 
A maximum of 25 patients will be entered. Stopping earlier would happen under 2 
circumstances: 
1.) Excess probability that patients have to be admitted to hospital during the 4-7 days of 
outpatient chemotherapy. 
2.) Excess probability that patients die during the 14 days after beginning outpatient 
treatment. 
For both 1 and 2 the case for stopping will be evaluated using the program "predictive 
probabilities" freely available from the Statistics Department at MD Anderson Cancer Center 
(https://biostatistics.mdanderson.org/softwaredownload/). In particular stopping will occur 
based on the Bayesian inequality probability Pr[ni> nij] > 0.90 where Pr= probability, ni is 
the posterior probability for rate of admission to the hospital with current management and 
nj the probability of rate of admission with former management. We will assume that it is 
distributed 13(a ,b] where "a" is the number of successes (no admission) and "b" the number 
of failures (admission) with management approach i (current) or management approach j 
(previous). We will assume a prior of 13[25,25] for the previous approach corresponding to a 
50% need for hospital admission with prior outpatient management in 50 patients and a prior 
of13(5,1) with the current approach corresponding to our data indicating that 5 patients have 
been treated as outpatients without need for inpatient admission while 1 has been admitted. 
As patients up to a maximum of 25 are entered on the current approach its prior will be 
updated and compared to the 13[25,25] distribution using the inequality probability 0.90 noted 
above. With this configuration here are the predictive probabilities that the current approach 
(called A) is truly better than the previous approach 13[25,25] denoted B given various 
numbers of successes (no admission during days 4-7) and failures (admission). 
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Successes 
(No admission) 
Failures 
(Admission) 
Predictive Probability A (current) better 
than B (Previous) 
1 
0 
0.95 
0 
1 
0.74 
0 
2 
0.51 
0 
3 
0.31 
0 
4 
0.16 
0 
5 
0.07 
1 
6 
0.05 
1 
5 
0.12 
. 
2 
6 
0.09 
3 
6 
0.15 
3 
7 
0.06 
We would stop accrual should the predictive probability be < 0.10, for example in the 3 
success / 7 failure scenario noted above. In this case 7 patients of 10 patients would have 
been admitted contrasted with the maximum acceptable rate of 4 admitted / 6 not. 
For the death within 14 days endpoint our prior for the current (inpatient) approach will be 
[3[49, 1] corresponding to a 2% (1/50) death rate and will be f3[5, 0] for the outpatient 
approach, corresponding to 0 deaths in the 5 patients who would have met eligibility criteria 
for the proposed protocol. These data will be updated as patients (up to the maximum of 25) 
are enrolled and the resultant beta distribution compared to the [3[49, 1] distribution noted 
above, using the inequality probability 0.9 noted in the section on admission to the hospital. 
With this configuration here are the predictive probabilities that the current approach (called 
A) is truly worse than the previous approach 13[49,  1] denoted B given various numbers of 
successes (no deaths days 1- 14) and failures (deaths days 1- 14). 
Success 
(No death within 14 days) 
Failure 
(death within 14 days) 
Predictive Probability A (current) 
worse than B (Previous) 
1 
0 
0.05 
0 
1 
0.28 
0 
2 
0.97 
1 
2 
0.95 
4 
2 
0.90 
5 
2 
0.88 
21 
3 
0.99 
We would stop accrual should the predictive probability be > 0.90, for example in cases 
where there are 2 failures and < 5 successes, or in any case where there are 3 deaths. 
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8. References 
1. Moroney SD. Understanding Health Care Cost Drivers. National Institute of Health 
Policy. 2003. 
2. Saini L,Minden MD,,Schuh AC, Yee KWL, Schimmer AD, Gupta V, Atenafu EG, 
Murray C, Nixon S, Brandwein JM. Feasibility of outpatient consolidation 
chemotherapy in older versus younger patients with acute myeloid leukemia. Am J 
Hematol. 2012 Mar; 87(3):323-6. 
3. Taheri PA, Butz DA, Greenfield U. Length of Stay Has Minimal Impact on the Cost 
of Hospital Admission. J Am Coll Surg. 2000; 191:123-130. 
4. Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, Appelbaum FR, 
Kantarjian HA, and Estey EH. Prediction of Early Death After Induction Therapy for 
Newly Diagnosed Acute Myeloid Leukemia With Pretreatment Risk Scores: A Novel 
Paradigm for Treatment Assignment. J Clin Oncol. 2011; 29:4417-4423. 
5. Walter RB, Lee SJ, Gardner KM, Chai X, Shannon-Dorcy K, Appelbaum FR, Estey 
EH. Outpatient management following intensive induction chemotherapy for 
myelodysplastic syndromes and acute myeloid leukemia: a pilot study. 
Haematologica. 2011 Jun; 96(6):914-7. 
6. Othus M, Hagop K, Petersdorf S, Ravandi F, Cortes J, Pierce S, Erba H, Faderl S, 
Appelbaum F, Estey E. Declining Rates of Treatment-Related Mortality in Patients 
with Newly Diagnosed Acute Myeloid Leukemia (AML) Given "Intensive" Induction 
Regimens: A Report from the Southwest Oncology Group (SWOG) and MD 
Anderson Cancer Center (MDA). (presented at the oral session at the ASH Annual 
Meeting 2012). 
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9. Appendix A 
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Kamofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about
50  
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
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10. Appendix B 
TREATMENT RELATED MORTALITY SCORE 
Treatment Related Mortality Score 
Patient 
I.D. 
Age Performance 
Status 
Platelet 
Count 
(x1 03/u1) 
Albumin 
(g/dL) 
Secondary 
AML 
(Yes= I ,no=0) 
WBC 
Count 
(x 103/up 
Blast 
Peripheral 
Blood 
(%) 
Creatinine 
(mg/dL) 
* Data collection for calculating the TRM Score 
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