A Phase II Study of the Efficacy and Pharmacogenomics of Cladribine-based Salvage Chemotherapy in Patients With Relapse/Refractory and Secondary Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Myelodysplastic Syndrome
Sponsor: Medical College of Wisconsin

Clinical Protocol 
Date:  August 19, 2020 
Official Title:  A Phase II Study of the Efficacy and Pharmacogenomics of Cladribine-
based Salvage Chemotherapy in Patients With Relapse/Refractory and Secondary 
Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS) 
NCT03150004 
 

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CLINICAL STUDY PROTOCOL 
 
 
Protocol Title 
 
A Phase II Study of the Efficacy and Pharmacogenomics of Cladribine based 
Salvage Chemotherapy in Patients with Relapse/Refractory and secondary Acute 
Myeloid Leukemia (AML) and high risk Myelodysplastic Syndrome (MDS) 
 
Clinical Trials.gov 
Identifier: 
NCT03150004 
 
 
Principal Investigator 
Ehab Atallah, MD 
 
Protocol History 
Original v1, 07/22/2016 
Protocol v2, 05/24/2018 
Protocol v3, 08/19/2020 
 
Proprietary and 
Confidential 
The information in this document is considered privileged and confidential, and may 
not be disclosed to others except to the extent necessary to obtain Institutional 
Review Board approval and informed consent, or as required by federal and state 
laws. Persons to whom this information is disclosed should be informed that this 
information is privileged and confidential and that it should not be further disclosed. 
 
 
 
 
 
 

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Principal Investigator:  
Ehab Atallah, MD  
Associate Professor 
Medical College of Wisconsin  
Department of Medicine 
Division of Hematology and Oncology  
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-4600  
Email: eatallah@mcw.edu 
 
 
Co-investigator: 
Guru Subramanian Guru Murthy, MD  
Assistant professor 
Medical College of Wisconsin  
Department of Medicine 
Division of Hematology and Oncology  
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-4600  
Email: gmurthy@mcw.edu 
 
 
Sub-investigator: 
Alexandra Harrington MD  
Associate Professor of Pathology  
Medical College of Wisconsin  
9200 W Wisconsin Ave,  
Milwaukee, WI 53226 
Telephone: 414-805-6703  
Email: aharrington@mcw.edu 
 
 
Sub-investigator: 
Ulrich Broeckel MD 
Professor of Pharmacology and Pediatrics  
Medical College of Wisconsin 
9200 W Wisconsin Ave,  
Milwaukee, WI 53226 
Telephone: 414-955-2369  
Email: broeckel@mcw.edu 
 
 
 
 
 
 
 
Sub-investigator:  
Sameem Abedin, MD  
Assistant Professor 
Medical College of Wisconsin  
Department of Medicine 
Division of Hematology and Oncology  
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-4600  
Email: sabedin@mcw.edu 
 
 
Sub-investigator:  
Karen-Sue Carlson, MD  
Assistant Professor 
Medical College of Wisconsin  
Department of Medicine 
Division of Hematology and Oncology  
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-4600  
Email:kabarker@mcw.edu 
 
 
Sub-investigator:  
Laura Michaelis, MD  
Associate Professor 
Medical College of Wisconsin  
Department of Medicine 
Division of Hematology and Oncology  
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-4600  
Email: lmichaelis@mcw.edu 
 
 
Pharmacist: 
Angela Urmanski, PharmD, BCOP  
Investigational Drug/Oncology  
Pharmacist  
Froedtert Hospital 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
Telephone:  414-805-3145  
Email: Angela.Urmanski@froedtert.com 
 
 
 

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Biostatistician:  
Aniko Szabo PhD 
Professor 
Division of Biostatistics 
Medical College of Wisconsin 
9200 W Wisconsin Ave,  
Milwaukee, WI 53226  
Email:aszabo@mcw.edu  
 
Mei-Jie Zhang PhD Professor 
Division of Biostatistics 
Medical College of Wisconsin 
9200 W Wisconsin Ave,  
Milwaukee, WI 53226 Email: 
meijie@mcw.edu 
 
 
Laboratory Contact: 
Elizabeth Virlee 
Research Technologist II,  
Pediatrics Section of Genomic Pediatrics 
Department of Pediartics 
Children’s Research Institute and HMGC  
Medical College of Wisconsin 
8701 Watertown Plank Road,  
Milwaukee, WI 53226 
Telephone: 414-955-2361  
Email: evirlee@mcw.edu 
 
 

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PROTOCOL SUMMARY 
 
Title 
A Phase II Study of the Efficacy and Pharmacogenomics of Cladribine based 
Salvage Chemotherapy in Patients with Relapse/Refractory and secondary 
Acute Myeloid Leukemia (AML) and high risk Myelodysplastic Syndrome 
(MDS) 
OnCore Identifier 
IITATALLAHCLAGM-AML 
Principal Investigator 
Ehab Atallah, MD 
Study Sites 
Froedtert & the Medical College of Wisconsin 
Clinical Trial Phase 
Phase II 
Study Disease 
Acute myeloid leukemia (AML) and myelodysplastic syndrome 
Main Eligibility 
Criteria 
 
Inclusion criteria 
1. Age ≥18 years at the time of informed consent. 
2. Morphologically documented primary Acute Myeloid Leukemia (AML) or 
AML secondary to Myelodysplastic Syndrome (MDS) myeloproliferative 
neoplasm (MPN) or therapy related AML (t-AML), as defined by World 
Health Organization (WHO) criteria. Patients with high risk MDS after 
failure of hypomethylating agents are also eligible 
3. Patients must meet one of the following criteria: 
• 
In first or subsequent relapse or refractory status, with or without prior 
hematopoietic stem cell transplant (HSCT) OR 
• 
Patients with MDS or MPN transformed to AML will be eligible even 
if they had not received prior therapy for AML. 
• 
Patients with high risk MDS after failure of hypomethylating agents 
are also eligible 
4. Eastern Cooperative Oncology Group (ECOG) performance score 0–3. 
5. CLAG-M arm only: Patients must meet the following clinical laboratory 
criteria: 
• 
Total bilirubin ≤ 1.5 X the upper limit of the normal range (ULN) (if 
elevated, then complete a direct bilirubin), alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN unless 
related to AML or Gilbert syndrome or hemolysis 
• 
Calculated creatinine clearance ≥30 mL/min 
• 
LVEF ≥ 45% 

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Main Eligibility 
Criteria 
(continued) 
Exclusion Criteria: 
1. Acute Promyelocytic Leukemia. 
2. Pregnant or breast-feeding women. 
3. Participation in clinical trials with other investigational agents not included 
in this trial throughout the duration of this trial. 
Study Rationale 
The optimal treatment regimen for relapsed/refractory AML and high risk 
MDS progressing after hypomethylating agents is unknown. Although 
several chemotherapy options are available, there is no universally accepted 
regimen to date. Cladribine based salvage regimens have been frequently 
used at our center. However, it is uncertain to predict which patients are likely 
to respond to cladribine based salvage or experience treatment related 
toxicities. While studies have demonstrated that achievement of MRD 
negative CR is likely to be associated with a better OS, there is limited 
prospective data evaluating the role of MRD in the setting of 
relapsed/refractory disease.. Through this study, we aim to demonstrate the 
influence of achieving MRD negative CR on survival of patients with 
relapsed/refractory AML/high risk MDS treated with Cladribine based 
salvage therapy. In addition to the conventionally used predictive factors, we 
aim to incorporate pharmacogenomics to assess the efficacy and toxicity of 
therapy. 
Primary Objectives 
To determine the complete remission (CR) rate and achievement of minimal 
residual disease (MRD) negativity after treatment with Cladribine based 
salvage chemotherapy regimen in patients with relapse/refractory AML/high 
risk MDS. 
Secondary Objectives 
1. To determine the progression free survival (PFS) and overall survival 
(OS) of patients treated with a cladribine based  salvage chemotherapy 
regimen. 
2. To study the pharmacogenomics of patients receiving a cladribine based 
salvage and determine its influence on survival, CR rate and MRD 
negativity. 
3. Determination of disease- or patient-related factors that predict MRD 
negativity and survival with a cladribine based salvage regimen. 
Study Design 
This is a prospective phase II clinical study planned to be conducted at the 
Medical College of Wisconsin (MCW). After meeting the study criteria and 
enrollment, patients will be treated with a cladribine based salvage regimen 
and followed at periodic intervals to determine the primary and secondary 
objectives as mentioned above. 

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Study Agent/ 
Intervention 
Description 
Patients will be started on CLAG-M or CLLDAC, which consists of the 
following: 
• 
Cladribine 5mg/m2 IV on days 1–5; 
• 
Cytarabine 2 gm/m2 IV on days 1–5, or 20mg/m2 SC on days 1-10; 
• 
(CLAG-M only) Mitoxantrone 10mg/m2 IV on days 1–3; 
• 
(CLAG-M only) G-CSF at a dose of 300 µg on days 1-5. 
Number of Subjects 
90 patients 
Subject Participation 
Duration 
Patients treatment cycle is 30 days. 
Duration of Follow up 
Patients will be followed for relapse and/or survival every 3 months (+/- 2 
weeks) for up to 4 years from the end of treatment. 
Estimated Time to 
Complete Enrollment: 
August 2027 
Statistical 
Methodology 
Baseline characteristics will be analyzed using descriptive statistics. 
Progression-free survival (PFS) will be calculated from the first day of 
remission after therapy until documentation of another relapse. Overall 
survival (OS) will be calculated from the first day of salvage therapy until 
death. PFS and OS analyses will be done by Kaplan- Meier method with log 
rank test. Multivariate analysis using Cox proportional hazard regression 
method will be used to analyze the determinants of MRD negative CR, OS, 
and PFS. All analyses will be done with a significant p value < 0.05. With an 
expected accrual rate of 10 patients per year, and accrual time of 9 years, we 
anticipate an eventual accrual of 90 patients. With a projected CR rate of 60% 
after treatment and a further anticipated MRD-negative rate of 60%, 36% of 
the study population is anticipated to be in MRD-negative CR. Based on 
binomial proportions, there will be between 23 and 41 MRD-negative patients 
with a 95.3% confidence, and an expected 22 MRD-positive CR patients for 
comparison.  
Safety Assessments 
Analyses will be performed for all patients having received at least one dose 
of study drug. The study will use the common terminology criteria (CTCAE) 
v4.0 for reporting of adverse events. 
Efficacy Assessments 
Assessment of MRD negative CR rate through bone marrow aspirate/biopsy 
and multi-color flow cytometry; Assessment of Pharmacogenomics through 
Affimetry DMET assay 
Unique Aspects of 
this Study 
This is the first study to evaluate the rate of MRD negativity and the role of 
pharmacogenomics in determining treatment outcomes of patients with 
relapsed/refractory AML/high risk MDS treated with cladribine based salvage 
therapy. 
 

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SCHEMA 
 
 
 
 
 
 
1. MRD assessment will be performed on patients achieving CR or CRp. 
2. Patients will be followed for relapse and/or survival every 3 months (+/- 2 weeks) for up to 4 years from the end 
of treatment 
 
 
 
Screening 
Treatment 
Follow-Up 
Consent 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
O 
F 
F 
S 
T 
U 
D 
Y 
Eligibility Criteria 
Pharmacogenomics 
All Screening 
Procedures 
 
CLAG-M 
Or 
CLLDAC 
Response 
assessment1 
 
Disease/ 
Survival 
Status2 

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STUDY CALENDAR 
 
Period/ 
Procedure 
Screening 
Treatment20 
Study Day/Visit Day 
Day – 30 to 
day 0 
(enrollment) 
Day 1 
Day 8 
(+/- 5 
days) 
Day 15 
(+/- 5 
days) 
Day 22 
(+/- 5 
days) 
Day 30/ EOT 
(+/- 5 
days)17 
Follow-up 
q3 months 
for 4 years14 
Informed consent 
x 
AE assessment6 
x 
x 
x 
x 
x 
x 
Concomitant medications 
X2 
x 
x 
x 
x 
x 
Treatment/Drug 
Administration 
CLAG-M or CLLDAC7 
x 
Clinical procedures 
Physical exam 
x 
X19 
x 
x 
x 
x 
Vital signs15 
x 
X19 
x 
x 
x 
x 
Medical history 
x 
X19 
Disease assessment 
x4 
x13 
X18 
ECOG Performance status 
x 
X19 
x 
Minimal Residual Disease 
(MRD) 
x12 
Survival Status 
x 
Laboratory procedures 
CBC w/ Diff and platelet count1 
x3 
x8,19 
x 
x 
x 
x 
X18 
Pharmacogenomics11 
x 
Blood chemistry1, 5 
x3 
x8,19 
x 
x 
x 
x 
 
Pregnancy test (HCG)9 
x 
Bone marrow 
aspiration/biopsy 
x16 
x10, 16 
Imaging procedures 
Cardiac Assessment (ECHO 
or MUGA) 
x3 
1. Must be performed within 7 days prior to enrollment 
2. Capture baseline medications taken within 7 days prior to day 1 and follow concomitant 
medications continuously until day 30. 
3. Any results falling outside of the reference ranges may be repeated at the investigator’s 
discretion. 
4. Capture baseline blast percentage in bone marrow at the diagnosis of relapsed/refractory 
AML or MDS. Assessment is based off the previously completed bone marrow biopsy and 
blast count from recent peripheral blood count. 
5. Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), total 
bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, total protein, albumin, 
glucose, potassium, sodium, chloride, bicarbonate, uric acid, lactate dehydrogenase (LDH), 
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6. AEs will be followed from consent to 30 days’ post last dose. 
7. Treatment will be administered on an inpatient or outpatient (CLLDAC arm only) basis. Refer 
to section 7. 
8. Completed within 24 hours of day 1. 
9. Serum or Urine pregnancy test completed within 14 days prior to enrollment for women of 
child bearing potential. 
10. Repeat BM study should be obtained after the completion of therapy at day 30 or when 
absolute neutrophil count (ANC) recovers to >1000 cells/cu.mm  or when the treating 
physician determines that it is clinically indicated.  If a second cycle of CLLDAC is 
administered, a repeat BM study should be performed at day 30 of cycle 2, or when the 
treating physician determines that it is clinically indicated. 
11. For specimen collection instruction see appendix 3. This sample can be collected after a 
patient consents through day 5.  
12. MRD assessment by flow cytometry will be performed on patients achieving CR or CRp. The 
sample will be collected and processed per institutional guidelines. Refer to section 15.1. 
13. Patients responding to therapy (Refer to sections 13.3 and 14) may be subsequently 
considered for allogeneic stem cell transplantation or further consolidation chemotherapy 
based on the discretion of the treating clinician. Those with PR or no response could be 
given additional chemotherapy at the treating physician’s discretion and patient’s tolerability. 
Refer to sections 13 & 14. Day 30/EOT disease assessment may be delayed at the treating 
physician’s discretion. 
14. Patients will be followed for relapse and/or survival every 3 months (+/- 2 weeks) for up to 4 
years from the end of treatment. 
15. Vital signs: height, weight, blood pressure, pulse rate, respiratory rate, & temperature. 
Height is only required at screening. 
16. If peripheral blasts are present, a bone marrow aspiration/biopsy is not required and should 
be performed at the discretion of the treating physician. 
17. If patient discontinues treatment early and or progresses/relapses then end of treatment 
(EOT) assessments can be completed prior to starting other therapy.  If a patient has 
disease progression/relapse then patient will be followed per follow-up requirements.    
18. Patients will be followed for survival. CBC and Diff can be captured anytime since last follow 
up visit, if possible around time of SoC bone marrow biopsies. Patient do not need to be 
seen by treating physician during the follow-up period. Physician visits to be done only per 
SOC. All disease assessments (i.e. Bone Marrow Biopsies) should be captured on follow up 
CRF. If disease assessment or CBC w/ diff not done as part of routine care, this will not 
result in a protocol deviation. 
19. If patient is consented and enrolled same day, Screening and Day 1 assessments can occur 
on the same day. This will not result in a protocol deviation. 
20. Patients who fail to achieve a CR/CRi after the first 30-day cycle may receive a second cycle 
of CLLDAC, per the discretion of the treating physician.  Patients who receive this second 
cycle should begin cycle 2 no later than 49 days after cycle 1.  If a second CLLDAC cycle is 
administered, the above calendar events will be followed for cycle 2.  
 

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TABLE OF CONTENTS 
PROTOCOL SUMMARY ......................................................................................................... 4 
SCHEMA ................................................................................................................................. 7 
STUDY CALENDAR ............................................................................................................... 8 
LIST OF ABBREVIATIONS ....................................................................................................13 
1.  BACKGROUND ................................................................................................................16 
1.1  Acute Myeloid Leukemia (AML) ....................................................................................16 
1.2  Salvage Chemotherapy and Cladribine ........................................................................16 
1.3  Chemotherapy Overview ...............................................................................................18 
1.4  Response Predictors .....................................................................................................19 
1.5  Minimal (also termed “Measurable”) Residual Disease Monitoring ...........................19 
1.6  Pharmacogenomics .......................................................................................................20 
2.  HYPOTHESIS AND OBJECTIVES ....................................................................................20 
2.1  Primary Objectives .........................................................................................................20 
2.2  Secondary Objectives ....................................................................................................20 
3.  STUDY DESIGN ................................................................................................................21 
3.1  General Description .......................................................................................................21 
3.2  Number of Subjects .......................................................................................................21 
3.3  Primary Endpoint(s) .......................................................................................................21 
3.4  Secondary Endpoint(s) ..................................................................................................21 
3.5  Randomization ...............................................................................................................21 
3.6  Study Completion ..........................................................................................................21 
4.  PATIENT SELECTION ......................................................................................................22 
4.1  Inclusion Criteria ............................................................................................................22 
4.2  Exclusion Criteria ..........................................................................................................24 
5.  STUDY PROCEDURES .....................................................................................................24 
5.1  Study Entry Procedures ................................................................................................24 
5.2  Pretreatment Period .......................................................................................................24 
5.3  Study Procedures during Treatment ............................................................................25 
5.4  End of Treatment ...........................................................................................................26 
5.5  Follow-Up Visits .............................................................................................................26 
6.  STUDY WITHDRAWAL PROCEDURES ...........................................................................27 
7.  TREATMENT PLAN ..........................................................................................................27 

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8.  DOSING DELAYS/DOSE MODIFICATIONS .....................................................................28 
8.1  Dietary Restrictions .......................................................................................................28 
8.2  Prohibited Medications ..................................................................................................28 
9.  PHARMACEUTICAL INFORMATION ...............................................................................28 
9.1  CLADRIBINE ...................................................................................................................28 
9.2  CYTARABINE .................................................................................................................30 
9.3  MITOXANTRONE Product Description .........................................................................33 
9.4  GRANULOCYTE-COLONY STIMULATING FACTOR (FILGRASTIM) ...........................35 
10.  GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ...37 
11.  Chemotherapy KNOWN RISKS .....................................................................................39 
12.  ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENTS (SAE) .............................44 
12.1  Defining and reporting an Adverse Event ..................................................................44 
12.2  Defining and reporting a Serious Adverse Event (SAE) ............................................44 
12.3  Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) ......................46 
12.4  Procedure for Reporting Drug Exposure during Pregnancy and Birth Events ........46 
13.  REPORTING AND DOCUMENTING RESULTS ..............................................................46 
13.1  Evaluable for toxicity ...................................................................................................46 
13.2  Evaluable for objective response ................................................................................46 
13.3  Clinical assessment .....................................................................................................47 
14.  RESPONSE CRITERIA IN ACUTE MYELOID LEUKEMIA .............................................47 
14.1  Duration of Response Duration of overall response .................................................48 
14.2  Evaluation of Safety .....................................................................................................48 
15.  CORRELATIVE STUDIES ...............................................................................................48 
15.1  Correlative #1 ...............................................................................................................48 
15.2  Correlative #2 ...............................................................................................................49 
16.  STUDY ENDPOINTS .......................................................................................................49 
16.1  Primary Endpoint .........................................................................................................49 
16.2  Secondary Endpoints ..................................................................................................49 
17.  STUDY DESIGN ..............................................................................................................50 
17.1  Clinical assessment .....................................................................................................50 
17.2  MRD assessment .........................................................................................................50 
17.3  Pharmacogenomic assessment ..................................................................................51 
17.4  Randomization .............................................................................................................51 
17.5  Stratification Factors ...................................................................................................51 

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18.  DETERMINATION OF SAMPLE SIZE AND ACCRUAL RATE .......................................51 
18.1  Accrual Estimates ........................................................................................................51 
18.2  Sample Size and Power Estimate ...............................................................................51 
18.3  Interim Analyses and Stopping Rules ........................................................................52 
18.4  Analyses Plans .............................................................................................................52 
18.5  Analysis Population .....................................................................................................53 
18.6  Primary Analysis (or Analysis of Primary Endpoints) ...............................................53 
18.7  Secondary Analysis (or Analysis of Secondary Endpoints) .....................................53 
18.8  Other Analyses/Assessments .....................................................................................53 
19.  DATA AND SAFETY MONITORING PLAN (DSMP) .......................................................53 
19.1  Data and Safety Management Overview .....................................................................53 
19.2  Study Team ...................................................................................................................54 
19.3  Quality Assurance ........................................................................................................54 
19.4  Clinical Trials Office .....................................................................................................54 
19.5  DSMC ............................................................................................................................54 
20.  REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ........................55 
20.1  Regulatory Compliance ...............................................................................................55 
20.2  Institutional Review Board ..........................................................................................55 
20.3  Informed Consent Process ..........................................................................................55 
20.4  Protection of Human Subjects Protection from Unnecessary Harm ........................56 
20.5  Investigator Compliance ..............................................................................................56 
20.6  Onsite Audits ................................................................................................................56 
21.  DATA HANDLING AND RECORD KEEPING..................................................................57 
21.1  Overview .......................................................................................................................57 
21.2  Case Report Forms ......................................................................................................57 
21.3  Study Record Retention ..............................................................................................57 
REFERENCES .......................................................................................................................58 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ............................................................62 
APPENDIX 2. PROHIBITED MEDICATIONS .........................................................................63 
APPENDIX 3. SPECIMEN COLLECTION ..............................................................................64 
APPENDIX 4. PREGNANCY FORM ......................................................................................66 
APPENDIX 5. WHO CLASSIFICATION OF ACUTE MYELOID LEUKEMIA ..........................70 
 

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LIST OF ABBREVIATIONS 
 
2-CdA 
Cladribine 
AE 
adverse event 
AML 
Acute myeloid leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BM 
bone marrow 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CLAG-M 
Cladribine, Cytarabine, G-CSF, Mitoxantrone 
CLLDAC 
Cladribine, low dose cytarabine 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 

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DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FC 
flow cytometry 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
FLAG 
Fludarabine, Cytarabine, G-CSF 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
HCT 
Hematocrit 
HDAC 
High-dose Cytarabine 
HGB 
Hemoglobin 
HSCT 
Hematopoietic stem cell transplant 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MCWCC 
Medical College of Wisconsin Cancer Center 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal Residual Disease 
NCI 
National Cancer Institute 

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ORR 
overall response rate 
OS 
overall survival 
PD 
disease progression 
PFS 
progression-free survival 
PO 
per os (by mouth, orally) 
PR 
partial response 
RBC  
red blood cell (count)  
RFS 
Relapse free survival 
RNA 
Ribonucleic acid 
RR-AML 
Relapsed/Refractory AML 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SRC 
Scientific Review Committee 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
t-AML 
therapy related AML 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO 
unanticipated problems involving risks to subjects or others 
WBC 
White blood cell (count) 
WHO 
World Health Organization 

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1 BACKGROUND 
1.1 
Acute Myeloid Leukemia (AML) and high risk myelodysplatic syndrome (MDS) 
 
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by 
clonal expansion of myeloid blasts in peripheral blood, bone marrow and other tissues. In United 
States, it is the most common form of acute leukemia in adults. Most patients with AML are 
older adults with a median age of 67 years and one-third of them being older than 75 years [1]. 
Thus, as the “baby boomer” generation ages, the incidence of AML is on rise. In addition, prior 
chemotherapy and radiation to treat other malignancies contribute to the rising incidence of 
therapy related AML. About 20,000 new AML cases are diagnosed each year in United States 
with more than 10,000 patients dying with this disease. The five-year overall survival of AML is 
about 26% with younger patients having a higher survival rate (more than 50%) than older 
adults (~10% for patients 65–74 years) [2]. Despite achieving a complete remission (CR) rate of 
60-80% with initial induction therapy, more than 50% of AML patients sustain disease relapse 
and 10-40% of patients have primary refractory disease [3, 4]. Patients who do not achieve 
adequate response with initial induction chemotherapy have primary refractory AML. Treatment 
response of patients with relapsed/refractory AML is variable and factors such as age, 
cytogenetics, prior stem cell transplantation and duration of first CR have been proposed as 
important prognostic factors [5]. Factors such as old age and chemotherapy resistance impose 
significant challenges in achieving second complete remission. All patients with AML are best 
managed within the context of an appropriate clinical trial. 
 
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant 
hematopoietic stem cell disorders that are characterized by ineffective blood cell production and 
a variable risk of transformation to acute myeloid leukemia (AML). Hypomethylating agents such 
as decitabine and azacitidine are the current mainstay of therapy for patients with high-risk 
myelodysplastic syndromes (MDS). Unfortunately, when MDS progresses despite these agents, 
the outcomes for these patients remain dismal with a median OS 5.6 months [6]. Management 
of MDS after failure of hypomethylating agents is an area of unmet need for research with no 
standard of care treatments. These patients are often best managed in the context of clinical 
trials.    
 
1.2 
Salvage Chemotherapy and Cladribine based regimens 
 
Several chemotherapy regimens are available for the treatment of patients with 
relapsed/refractory myeloid malignancies. Many of these combinations are dose-intensive and 
have not been directly compared against each other. Hence the choice is primarily based 
upon individual clinical experience. Importantly, a patient's chance of responding to a 
particular regimen is influenced not only by prior exposure to chemotherapy but also by other 
patient- and disease-associated factors. Commonly used regimens in this setting include: 
1. Re-induction with cytarabine and daunorubicin that could produce CR in approximately 
50% of patients with a first remission greater than one year [5, 7]. However, this is often 
limited by the chances of anthracycline induced cardiotoxicity with cumulative exposure 
(as it is also commonly used in initial induction therapy). 
2. High-dose cytarabine (HDAC) regimen using 2 to 3 g/m2 every 12 hours for 8 to 12 doses 
may be effective in 35- 40% of patients’ resistant to conventional dose cytarabine [8]. 
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3. Mitoxantrone, cytarabine with or without etoposide is a commonly used regimen to treat 
RR- AML [9-15]. In a study by Amadori et al. 32 patients with RR-AML were treated with 
salvage MEC therapy (mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 
IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 
6 days) [12]. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) 
died of infection during induction, and nine (28%) had resistant disease. Age greater than 
50 years was the only factor predictive for a significantly lower response rate. The median 
remission duration was 16 weeks and median overall survival was 36 weeks. In another 
series of 47 patients with RR- AML, the combination of mitoxantrone (5 mg/m2 per day for 
five days) and intermediate-dose cytarabine (0.5g/m2 IV every 12 hours for six days) 
resulted in a complete remission rate of 62%, but the median duration of remission was 
only 3.7 months [14]. Ninety-six percent of those achieving CR eventually relapsed. 
4. Fludarabine, cytarabine, plus G-CSF (FLAG) has been reported to have complete 
remission rates of 45 -55% in patients with RR-AML [16,17]. Studies including older adults 
have reported mild nonhematologic toxicity most commonly included mucositis. Median 
survival was over 16 months for those with late relapse (ie, >6 months after stopping 
chemotherapy), but was only three months for those with early relapse or refractory 
disease [16].  
5. Given the aggressive nature of high risk MDS progressing after hypomethylating agents, 
these patients are sometimes managed with AML based chemotherapy regimens, 
especially if they are candidates for allogeneic stem cell transplantation. Many prior 
studies have included both patients with AML and high risk MDS while evaluating the 
efficacy of chemotherapy regimens in this setting as described below. A study by DeWitte 
et al. evaluated the role of idarubicin and cytarabine based chemotherapy in 50 patients 
with MDS and AML (originating from antecedent MDS) [18]. They noted a complete 
remission rate of 54% with this regimen and median OS of 14 months. Another study by 
Ossenkoppele et al. evaluated the efficacy of fludarabine, cytarabine, G-CSF (FLAG) 
chemotherapy in patients with high risk MDS and AML and noted a complete remission 
rate of 71% and OS of 39% at 24 months [19].  A study by Parker et al. investigated the 
efficacy of FLAG-idarubicin chemotherapy in patients with high risk MDS and AML and 
noted complete remission rate of 63% in these patients [20]. 
6. A commonly used salvage chemotherapy regimen for relapsed-refractory AML at our 
center is CLAG-M (cladribine, cytarabine, G-CSF, Mitoxantrone). A phase II study was 
reported by Wierbozwska et al. about this regimen in 2008 [21]. One hundred and 
eighteen patients with RR-AML were included. Sixty-six patients (58%) achieved CR after 
one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC 
>10 g/L and age > 34 years were factors associated with increased risk of treatment 
failure. The probability of 4-year overall survival was 14% (95% CI 4-23%) and 4-year 
disease free survival was 30% for all 66 patients in CR (95% CI 11-49%). Poor karyotype 
was the only factor associated with decreased probability of DFS. A retrospective study by 
Price et al. compared two commonly used regimens in RR-AML - CLAG and MEC [22]. 
The complete response rate (CR) was found to be 37.9% for CLAG (n = 97) and 23.8% for 
MEC (n = 65) (P = 0.048), with a median overall survival of 7.3 and 4.5 months, 
respectively (P = 0.05). In primary refractory disease, CR rate was 45.5% for CLAG and 
22.2% for MEC (P = 0.09), with median overall survival of 11 and 4.5 months, respectively 
(P = 0.07). In patients with relapsed AML, CR rate was 36.8% with CLAG and 25.9% with 
MEC (P = 0.35) and median OS was 6.7 and 6.7 months, respectively (P = 0.87). The 
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accumulation of Ara-C-5′ triphosphate (ara-CTP) that causes cytotoxic effect in leukemic 
blasts. Addition of granulocyte-colony stimulating factor (G- CSF) further improves the 
effects of purine nucleoside analogue in combination with Ara-C by activating the leukemic 
cells and making them susceptible to chemotherapy’s effect. Our center has seen good 
clinical results using this regimen and is often the choice of therapy for RR-AML. 
7. CLAG-M has also been studied in patients with myelodysplastic syndrome who have failed 
hypomethylating agent therapy and progressed to AML [23]. In a retrospective study by 
Jaglal et al. in patients with myelodysplasia who failed azanucleosides and progressed to 
AML, the efficacy of CLAG-M induction (28 patients) was compared against standard 3+7 
induction chemotherapy (24 patients). Response rates and median overall survival were 
64% and 202 days (95% CI 37-367 days) in CLAG-M group versus 29% and 86 days 
(95% CI 36-136) in 3+7 group, respectively. There was no significant difference in the 
mortality or serious adverse effects between the two groups. The combination of 
cladribine, cytarabine, mitoxantrone (in escalating doses) and G-CSF was recently 
evaluated in a phase I/II clinical study by Halpern et al. in patients with relapsed or 
refractory AML and other high-grade myeloid neoplasms (≥10% myeloblasts in blood 
and/or marrow) such as MDS [24]. They reported a response rate (CR, CRi) of 57% 
among 60 patients enrolled in this study. Hence, these studies emphasize the rationale to 
prospectively investigate chemotherapy based strategies in patients with high riks MDS 
progression after hypomethylating agent therapy.Not all patients are “fit” for salvage 
chemotherapy with CLAG-M.  Cladribine, with low dose ara-C (CLLDAC), has shown 
promise in “unfit” AML patients.  Kadia et al studied Cladribine and low-dose cytarabine as 
front-line therapy for elderly patients with AML [25].  This trial enrolled patients who would 
not be considered fit for intensive chemotherapy, with regimens including CLAG-M.  
Impressively, in this difficult to treat patient group, one to two cycles of Cladribine, along 
with low-dose cytarabine, resulted in a CR rate of 58%, with an additional 9% achieving a 
CR with incomplete count recovery.  Total response rate was 68%.  Similarly, the regimen 
with cladribine and low dose cytarabine has been studied in patients with 
relapsed/refractory AML or MDS. A retrospective study by Wisniewski et al. described the 
role of cladribine and low dose cytarabine in patients with relapsed/refractory AML/MDS 
[26]. They reported the outcomes on 16 patients with relapsed/refractory AML/high risk 
MDS/chronic myelomonocytic leukemia (CMML) treated with this regimen and noted that it 
was well tolerated with no treatment related deaths. A complete remission (CR or CRi) 
was achieved in 56% of patients and the median time to response was 1 cycle. Median 
progression-free survival was 8 months, and the median OS reached 10.6 months. 
Although there are no prospective studies that have been reported with this regimen in the 
relapse/refractory setting, the efficacy noted in prior studies warrant prospective evaluation 
of this regimen as being proposed in this study . 
 
1.3 
Chemotherapy Overview 
 
Cladribine is a chlorodinated derivative of adenine which is converted intracellularly to the 
cladribine triphosphate, which is believed to compete with adenine triphosphate in DNA 
synthesis. Cladribine was found to have marked activity against hairy leukemia and was 
approved for this use in the United States in 1993. 
 
For detailed information on cladribine, please see Section 9, Pharmaceutical Information. 
 
 

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Cytarabine 
 
Cytarabine is also known as ara-C (arabinofuranosyl cytidine) or cytosine arabinoside. It kills the 
leukemic cells by interfering with the DNA synthesis. Cytosine normally combines with a 
deoxyribose, to form deoxycytidine, a component of DNA. Cytosine arabinoside is similar to 
human cytosine deoxyribose (deoxycytidine) and gets incorporated into DNA and causes cell 
death. It is one of the oldest and most commonly used drug approved for the treatment of AML. 
 
For detailed information on cytarabine, please see Section 9, Pharmaceutical Information. 
 
Filgrastim (G-CSF) 
 
Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the 
proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology 
and is commonly used to treat neutropenia in patients with malignancy. Rationale for using 
filgrastim in CLAG-M is to stimulate leukemic cells to enter the active phase of cell cycle, 
making them susceptible to chemotherapy’s effect. 
 
For detailed information on filgrastim, please see Section 9, Pharmaceutical Information. 
 
Mitoxantrone 
 
Mitoxantrone is an anthracycline class chemotherapeutic agent with cytotoxic effects. It inhibits 
type II topoisomerase and disrupts DNA synthesis and repair. It has been approved for the 
treatment of AML and is commonly used in combination with various chemotherapeutic agents. 
Mitoxantrone is a cardiotoxic drug and needs adequate left ventricular ejection fraction before 
starting therapy. 
 
For detailed information on Mitoxantrone, please see Section 9, Pharmaceutical Information. 
 
1.4 
Response Predictors 
 
There is no prospective data to identify those patients who would respond well to a cladribine 
based regimen. New strategies, such as minimal residual disease (MRD) monitoring is 
emerging to assess the response to therapy [27,28]. Similarly, pharmacogenomics of the 
chemotherapeutic agents have been used previously to  identify those patients who would have 
a favorable response to therapy [29-32]. In this novel study, we aim to determine the role of 
MRD monitoring and pharmacogenomics assay to predict the response to therapy in patients 
with relapsed refractory AML/high risk MDS planned to be treated with a Cladribine based 
regimen. 
 
1.5 
Minimal (also termed “Measurable”) Residual Disease Monitoring 
 
Relapse results from residual leukemic cells that remain following the achievement of 
morphological "complete" remission. Subclinical levels of residual leukemia are termed minimal 
residual disease (MRD) and can be evaluated using more sensitive assays such as multicolor 
flow cytometry. A large retrospective study by Chen et al. included data from 245 adults with 
AML (of which 81 had RR-AML) who achieved CR, CRp, or CR with incomplete blood count 
recovery (CRi) after induction therapy [28]. They found that the rate of MRD positivity increases 

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from 19% in patients who achieved CR to 54.2% in patients with CRp and 60.9% in patients 
with CRi. Additionally, patients with MRD positive CR had inferior outcomes to therapy as 
compared to patients with MRD negative CR. Even though this study included a large cohort, it 
was retrospective and did not exclusively describe the MRD rates and outcomes in 
relapsed/refractory patients. Hence, it is truly worth exploring prospectively the rate of MRD 
negative CR achieved with Cladribine based salvagechemotherapy and its influence on long-
term outcomes. 
 
1.6 
Pharmacogenomics 
 
Pharmacogenomics is the study of how genes affect a person's response to drugs. This 
relatively new field combines pharmacology and genomics to develop effective, safe 
medications and doses that will be tailored to a person's genetic makeup. Studies have shown 
that patients with AML could have the response and toxicity to chemotherapy predicted using 
pharmacogenomic assay for specific genes [29-32]. A study by Green et al. described the 
association between ABCB1 gene polymorphism and its effect on survival [30]. Patients with 
1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes. 
Both these genotypes were significantly influenced the survival along with age, NPM1 and FLT3 
mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 
2677T/T patients were significantly more susceptible to mitoxantrone, and tended to be more 
susceptible to etoposide and daunorubicin, but not to cytarabine. In another study, Cao et al. 
found that another gene called RRM1 was highly expressed in patient with features indicative of 
a high relapse hazard and RRM1 single nucleotide polymorphism (SNP) rs1042919 and 
promoter SNP rs1561876 were associated with intracellular 1-β-D-arabinofuranosyl-CTP levels, 
response after remission induction therapy, risk of relapse and overall survival in AML patients 
receiving cytarabine and cladribine [32]. In addition to these studies, there is a database 
available to describe the potential genes that could influence the chemotherapeutic drug’s 
course in humans after administration [33]. Hence, this forms a reasonable background to utilize 
this strategy to find the correlation between the patient’s pharmacogenomic profile and the 
response/toxicity to chemotherapy. 
 
2 HYPOTHESIS AND OBJECTIVES 
2.1 
Primary Objectives 
 
To determine the complete remission (CR) rate and achievement of minimal residual disease 
(MRD) negativity after treatment with a salvage cladribine based chemotherapy regimen in 
patients with relapse/refractory AML/high risk MDS. 
 
2.2 
Secondary Objectives 
 
1 To determine the progression free survival (PFS) and overall survival (OS) of patients 
treated with salvage cladribine based chemotherapy in the same patient population. 
 
2 To study the pharmacogenomics of patients receiving salvage cladribine based 
chemotherapy and determine its influence on survival, CR rate and MRD negativity in the 
same patient population. 
 
3 Determination of disease- or patient-related factors that predict MRD negativity and 

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survival after salvage cladribine based chemotherapy. 
 
3 STUDY DESIGN 
3.1 
General Description 
 
This is a prospective, phase II clinical study aimed at determining the efficacy of salvage 
cladribine based chemotherapy in the management of relapse/refractory AML/high risk MDS. 
Study participants will be recruited at the Froedtert & the Medical College of Wisconsin. After 
meeting the study criteria and enrollment, patients will be treated with salvage cladribine based 
chemotherapy and followed at periodic intervals to determine the primary and secondary 
endpoints as mentioned below. 
 
3.2 
Number of Subjects 
 
Ninety subjects will be enrolled in this study. 
 
3.3 
Primary Endpoint(s) 
 
To determine the rate of MRD negative CR in patients with relapsed/refractory AML/high risk 
MDS. 
 
3.4 
Secondary Endpoint(s) 
 
1. Determination of the overall survival (OS) and progression free survival (PFS) in patients 
with relapsed/refractory AML/high risk MDS treated with cladribine based salvage therapy 
 
2. Determination of disease- or patient-related factors that predict MRD negativity and 
survival with cladribine based salvage, including pharmacogenomics. 
 
3. Determination of the role of pharmacogenomics in predicting the development of treatment 
related toxicities with cladribine based salvage therapy. 
 
3.5 
Randomization 
 
Randomization does not apply to this study 
 
3.6 
Study Completion 
 
The study will reach completion approximately 2027. 
 
 

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4 PATIENT SELECTION 
Eligibility Criteria 
 
The written informed consent must be obtained from the patient prior to enrollment and any 
study specific procedures. Patients must have baseline evaluations performed prior to 
enrollment and the first study drug dose. The following criteria apply to all patients enrolled onto 
the study unless otherwise specified. 
 
4.1 
Inclusion Criteria 
 
1. Age ≥18 years at the time of informed consent. 
 
2. Morphologically documented:  
• 
primary acute myeloid leukemia (AML) or  
• 
AML secondary to myelodysplastic syndrome (MDS) or myeloproliferative neoplasm 
(MPN), or  
• 
therapy-related AML (t-AML), as defined by World Health Organization (WHO) criteria 
(Appendix 5).  
• 
Patients with high risk MDS after failure of hypomethylating agents are also eligible. 
 
3. Patients must meet one of the following criteria: 
• 
In first or subsequent relapse or refractory status, with or without prior hematopoietic 
stem cell transplant (HSCT) OR 
• 
Patients with MDS or MPN transformed to AML will be eligible even if they had not 
received prior therapy for AML. 
• 
Patients with high risk MDS after failure of hypomethylating agents 
 
4. Eastern Cooperative Oncology Group (ECOG) performance score 0–3. 
 
5. It is not known what effects this treatment has on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. Non- 
sterilized female patients of reproductive age and male patients should use effective 
methods of contraception through defined periods during and after study treatment as 
specified below. 
 
Female patients must meet one of the following: 
• 
Postmenopausal for at least one year before the screening visit, or 
• 
Surgically sterile, or if they are of childbearing potential, agree to practice two effective 
methods of contraception from the time of signing of the informed consent form 
through 90 days after the last dose of study drug, AND 
• 
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, or 
• 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable contraception methods.) 
 

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Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one 
of the following: 
• 
Practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last study drug dose, OR 
• 
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 
• 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
 
6. Ability to understand a written informed consent document, and the willingness to sign it. 
 
7. Patients must meet the following clinical laboratory criteria:  
 
• 
CLAG-M arm only: For abnormalities in liver function tests, elevation thought to be due 
to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis would not be treated as 
exclusion criteria. 
Organ and Marrow Function Table 
Adequate bone marrow function: 
Absolute neutrophil count 
>1,000/cmm Unless related to AML 
Platelets 
>75,000/cmm Unless related to AML 
Adequate hepatic function: 
Total bilirubin 
≤ 1.5 x the upper limit of the normal range (ULN) 
(if elevated, then complete direct bilirubin). 
AST(SGOT)/ALT 
Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤  3 x ULN 
Adequate renal function: 
Creatinine clearance 
> 30 mL/min 
Cardiac: 
Resting left ventricular ejection fraction 
≥45% 
 
• CLLDAC arm only: 
Organ and Marrow Function Table 
Adequate bone marrow function: 
Absolute neutrophil count 
>1,000/cmm Unless related to AML 
Platelets 
>75,000/cmm Unless related to AML 
 
 
 

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4.2 
Exclusion Criteria 
 
A potential subject who meets any of the following exclusion criteria is ineligible to participate in 
the study. 
 
1. Acute promyelocytic leukemia. 
 
2. Active infection not well controlled by antibacterial or antiviral therapy. 
 
3. Pregnant or breast-feeding women. 
 
4. Participation in clinical trials with other investigational agents not included in this trial, 
throughout the duration of this trial. , participation of follow-up portion of another clinical 
trial will not exclude patient from participation 
 
5 STUDY PROCEDURES 
5.1 
Study Entry Procedures 
 
Required Preregistration Screening Tests and Procedures 
 
The study-specific assessments are detailed in this section and outlined in the Study Calendar. 
Screening assessments unless otherwise specified must be performed within 30 days prior to 
enrollment. Any results falling outside of the reference ranges may be repeated at the 
investigator’s discretion. All on-study visit procedures are allowed a window of ± 5 days unless 
otherwise noted. Treatment or visit delays for public holidays or weather conditions do not 
constitute a protocol violation. 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. 
 
All patients who are consented will be registered in OnCore®, the MCW Cancer Center Clinical 
Trial Management System. The system is password protected and meets HIPAA requirements. 
Once a patient has been consented they will be assigned a screening ID that will be used to 
identify them throughout the study. 
 
5.2 
Pretreatment Period  
 
The screening procedures and assessments must be completed within 30 days (unless 
otherwise specified on the study calendar) of enrollment. 
• 
Informed consent 
• 
Physical examination 
• 
Vital signs 
• 
Medical history 
• 
Disease assessment (Appendix 5) 
• 
ECOG Performance status 
• 
Complete blood count (CBC) with differential and platelet count 

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• 
Blood chemistry assessment, including: 
• 
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), 
total bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, total protein, 
albumin, glucose, potassium, sodium, chloride, bicarbonate, uric acid, lactate 
dehydrogenase (LDH), calculated creatinine clearance (Cockcroft- Gault formula) 
• 
Serum or urine pregnancy test within 14 days prior to enrollment for women of child 
bearing potential 
• 
Cardiac assessment (ECHO or MUGA) 
• 
Serum sample pharmacogenomics (can be collected from consent to day 5) 
• 
Bone marrow aspiration/biopsy- If peripheral blasts are present, a bone marrow 
aspiration/biopsy is not required and should be performed at the discretion of the treating 
physician. 
• 
Adverse events 
• 
Concomitant medications (baseline medications taken within 7 days of Day 1) 
 
5.3 
Study Procedures during Treatment 
 
Patients must meet eligibility criteria on cycle 1 day 1 to be treated. Patients must be enrolled 
prior to treatment. A subject will be considered enrolled onto the study once they have signed 
consent, have successfully met all screening criteria, the eligibility criteria has been reviewed 
and accepted by the PI or a sub-investigator. Any eligibility questions should be directed to Dr. 
Atallah at eatallah@mcw.edu. 
 
Study Procedures, Cycle 1 Day 1* 
• 
Physical examination 
• 
Vital signs 
• 
Medical History 
• 
ECOG Performance status 
• 
Adverse events 
• 
Concomitant medications 
• 
CBC with differential and platelet count (completed within 24 hours of day 1) Blood 
chemistry assessment, including (completed within 24 hours of day 1):  Alkaline 
phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total 
protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, 
LDH, calculated creatinine clearance (Cockcroft- Gault formula) 
*If patient is consented and enrolled on the same day, Screening and Day 1 
assessments can occur on same day. This will not result in a protocol deviation 
 
Study Procedures during Treatment 
 
The following procedures are done days 8, 15, and 22. 
• 
Physical examination 
• 
Vital signs 
• 
Adverse events 

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• 
Concomitant medications 
• 
CBC with differential and platelet count 
• 
Blood chemistry assessment, including:  Alkaline phosphatase, ALT/AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, glucose, potassium, 
sodium, chloride, bicarbonate, uric acid, LDH, calculated creatinine clearance 
(Cockcroft- Gault formula) 
 
5.4 
Day 30/End of Treatment Procedures 
 
To be completed day 30 (+/- 5 days) (unless otherwise specified on the study calendar). If 
patient discontinues treatment early and or progresses/relapses then end of treatment 
(EOT)/day 30 assessments can be completed prior to starting other therapy. 
• 
Disease assessment (Section 14) 
• 
MRD (Section 15.1) 
• 
Physical examination 
• 
Vital signs 
• 
ECOG Performance status 
• 
Adverse events 
• 
Concomitant medications 
• 
CBC with differential and platelet count 
• 
Blood chemistry assessment, including:  Alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, calculated 
creatinine clearance (Cockcroft- Gault formula) 
• 
Repeat bone marrow aspiration/biopsy will be obtained after the completion of 
therapy at day 30 or when absolute neutrophil count (ANC) recovers to >1000 
cells/cu.mm or when the treating physician determines that it is clinically 
indicated. If peripheral blasts are present, a bone marrow aspiration/biopsy is 
not required and should be performed at the discretion of the treating 
physician.  
 
5.5 
Follow-Up Visits 
 
Patients will be followed for relapse and/or survival every 3 months (+/- 2 weeks) for up to 4 
years from the end of treatment. If a patient has disease progression/relapse, then patient will 
be followed per follow-up requirements. The following procedures will be captured at the follow-
up visit(s): 
• 
Disease assessment (Section 14)* Patients do not need to be seen by treating physician 
during the follow-up period. Visits to occur only per SOC. 
• 
CBC with differential and platelet count* at time of SoC Bone Marrow Biopsies, if 
applicable, otherwise as close to follow up window as possible. 
• 
Collected once during each 3-month follow up period. 
*If not done as part of routine care, this will not result in a protocol deviation 
 

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6 STUDY WITHDRAWAL PROCEDURES 
Duration of Therapy 
 
Patients enrolled in the study and treated with therapy will remain in the study up to 4 years 
from the end of therapy. 
 
In the absence of treatment delays due to adverse events, study treatment may continue for the 
protocol specified time frame until: 
• 
Disease progression 
• 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the investigator’s judgment. 
• 
Inter-current illness that prevents further treatment administration 
• 
Patient decides to withdraw from the study 
• 
Significant patient noncompliance with protocol 
• 
Unacceptable adverse event(s) 
 
In the event that a patient withdraws from the study after screening and consenting, additional 
patients will be screened and recruited to match the deficit. 
 
7 TREATMENT PLAN 
Treatment will be administered on an inpatient basis for CLAG-M, and on an inpatient or 
outpatient basis for CLLDAC. 
 
CLAG-M Regimen Description (Cycle = 30 days) 
 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
G-CSF* 
None 
300 µg 
Subcutaneous 
Days 1-5* 
Cladribine* 
Monitor for and 
report infection 
5 mg/m2 
Intravenous 
over 2 hours 
Days 1–5 
Cytarabine* 
Monitor for 
neurologica
l toxicity 
2 gm/m2 
Intravenous 
over 4 hours  
Days 1–5 
Mitoxantrone* 
Monitor for 
cardiovascula
r toxicity 
10 
mg/m2 
Intravenous 
Days 1–3 
* Treatment given per institutional guidelines. Deviations from suggested infusion times above 
will not result in protocol deviations. 
 
G-CSF can be given prior to enrollment per treating physician discretion, but remaining CLAG-M 

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should be given after enrollment. Intrathecal chemotherapy can be given for patients with 
possible CSF involvement.  
 
CLLDAC Regimen Description (Cycle = 30 days) 
 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedul
e 
Cladribine* 
Monitor for and 
report infection 
5 mg/m2 
Intravenous 
over 2 hours 
Days 1–
5 
Cytarabine* 
None 
20 mg/m2 Subcutaneous 
Days 1–
10 
* Treatment given per institutional guidelines. Deviations from suggested infusion times above 
will not result in protocol deviations. 
 
Patients who fail to achieve a CR/CRi after the first 30-day cycle may receive a second cycle of 
CLLDAC, per the discretion of the treating physician.  Patients who receive this second cycle 
should begin cycle 2 no later than 49 days after cycle 1.   
 
8 DOSING DELAYS/DOSE MODIFICATIONS 
Patients must meet eligibility criteria on Day 1 to be treated. Typically, the treatment is given for 
only one cycle. Hence, dose adjustments generally do not apply as subsequent cycles are not 
given in the protocol. In the event that a dose gets delayed, the same dose could be restarted 
within 1-2 days of the missed dose and subsequent doses will be timed accordingly. Dose 
modifications are allowed for safety per treating physician discretion.  
 
Please see dose modification suggestions for each drug in section 9 for treatment days (after 
day 1). Dose modifications are suggestions only.  Please follow institutional guidelines. Failure 
to follow dose modification suggestions will not result in a protocol deviation. 
 
8.1 
Dietary Restrictions 
 
No dietary restrictions are applicable 
 
8.2 
Prohibited Medications 
 
See appendix 2 for prohibited medications 
 
9 PHARMACEUTICAL INFORMATION 
9.1 
CLADRIBINE 
 
Product Description [45,47] 
Cladribine is available in one strength and form: Cladribine 1 mg per mL in 10-mL single-use 

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vials. 
 
Black Box Warning: Acute nephrotoxicity has been observed with high doses of LEUSTATIN (4 
to 9 times the recommended dose for Hairy Cell Leukemia), especially when given 
concomitantly with other nephrotoxic agents/therapies. Avoid nephrotoxic agents. 
 
Classification 
Cladribine is an antineoplastic; antimetabolite and purine antagonist. 
 
Mechanism of Action 
Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of 
action. Although the exact mechanism of action has not been fully determined, evidence shows 
that cladribine is phosphorylated by deoxycytidine kinase to the nucleotide cladribine 
triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is 
incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine 
kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of 
DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, 
which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and 
subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine 
dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, 
cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does 
cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated 
with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase 
(PNP), however no relationship between this binding and a mechanism of action has been 
established. 
 
Metabolism 
Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'- 
triphosphate. 
 
Contraindications 
Hypersensitivity to cladribine; pregnancy. 
 
Side Effects 
See Section 11 (Known Risk List.) Complete and updated adverse event information is available 
in the Investigational Drug Brochure and/or product package insert. 
 
Solution Preparation 
IV Infusion (single daily dose): Prepare per institutional standards in a 500 mL IV Normal Saline 
Bag.  Filter with a 0.22 micron hydrophilic syringe filter prior to adding to infusion bag. 
 
Drug product does not contain anti-microbial preservative or bacteriostatic agent, MUST use 
aseptic technique and take environmental precautions when dispensing. 
 
Dextrose 5% is NOT recommended as a diluent due to the increased degradation of cladribine. 
 
Agent Administration 
IV Infusion (single daily dose): Distribute evenly over ordered time (i.e., 2 h or 24 h). 
 

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Storage Requirements 
Store refrigerated 2° to 8°C (36° to 46°F). Protect from light during storage. 
 
Stability 
When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) protected from light, 
unopened vials of cladribine injection are stable until the expiration date indicated on the 
package. Freezing does not adversely affect the solution. If freezing occurs, thaw naturally to 
room temperature. Do not heat or microwave. Once thawed, the vial of cladribine injection is 
stable until expiry if refrigerated. Do not refreeze. Once diluted, solutions containing cladribine 
injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more 
than eight hours prior to administration. 
 
Nursing Implications Guidelines 
Lab tests: frequent hematologic studies; periodic serum creatinine and liver function tests. 
Closely monitor hematologic status; myelosuppression is common during the first month after 
starting therapy. Monitor for and report signs and symptoms of infection. Note that within the 
first month, fever may occur in the absence of infection. With high doses of cladribine, monitor 
for neurologic toxicity (paraparesis/quadriparesis) and acute nephrotoxicity. 
• 
Hepatic 
o No dosage adjustment [51] 
• 
Renal 
o CrCl 10-50 mL/minute: Administer 75% of dose [51] 
 
 
Handling 
Use disposable gloves and protective clothing when handling the drug. Wash immediately if skin 
contact occurs. 
 
Availability 
This drug is commercially available. 
 
Agent Ordering 
Commercially available. 
 
Agent Accountability 
Commercial Supply 
 
Agent Destruction and Return 
At the conclusion of the study, any unused Cladribine will be destroyed according to institutional 
policies. 
 
9.2 
CYTARABINE 
 
Product Description [45,48] 
Cytarabine is available in vials of 100, 500, 1000 and 2000 mg (20 mg/mL) for intravenous or 
intrathecal infusion generically and under the brand name Cytosar-U. 
 
Classification 

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Cytarabine is an antimetabolite antineoplastic agent. 
 
Mechanism of Action 
Cytarabine acts through direct DNA damage and incorporation into DNA. Cytarabine is cytotoxic 
to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, 
primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking 
the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is 
not completely understood, it appears that cytarabine acts through the inhibition of DNA 
polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has 
also been reported. 
 
Metabolism 
Cytarabine is rapidly metabolised, mainly in the liver, to the inactive metabolite 1-β-D- 
arabinofuranosyluracil. About 70 to 80% of a dose is excreted in the urine within 24 hours; 
approximately 90% as the metabolite and 10% as unchanged cytarabine. 
 
Contraindications 
Cytarabine is contraindicated in patients with a history of drug-induced myelosuppression; 
immunization procedures; pregnancy (particularly during first trimester), lactation. 
 
Side Effects 
See Section 11 (Known Risk List). Complete and updated adverse event information is available 
in the Investigational Drug Brochure and/or product package insert. 
 
Product Description 
Cytarabine for injection USP is available in vials containing 100 mg, 500 mg, 1 g and 2 g 
cytarabine. 
 
Solution Preparation 
Direct: Reconstitute with bacteriostatic water for injection as follows: add 5 mL to the 100-mg 
vial to yield 20 mg/mL; add 10 mL to the 500 mg vial to yield 50 mg/mL. IV Infusion: May be 
further diluted with 100 mL or more of D5W or NS. 
 
Agent Administration 
Direct: Give at a rate of 100 mg or a fraction thereof over three min. IV Infusion: Give over 4 
hours or longer depending on the total volume of IV solution to be infused. 
 
Storage Requirements 
Store at 15°C - 25°C. Keep container in outer carton. Cytarabine should not be stored at 
refrigerated temperatures (2-8°C). 
 
Stability 
Although stability of cytarabine is well retained for 24 hours in intravenous vehicles noted above, 
it is recommended that, as with all intravenous admixtures, dilution should be made just prior to 
administration and the resulting solution used within 24 hours. 
 
Nursing Implications Guidelines for cytarabine (in CLAG-M arm only) 
Inspect patient's mouth before the administration of each dose. Toxicity necessitating dosage 
alterations almost always occurs. Report adverse reactions immediately. 

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Hyperuricemia due to rapid destruction of neoplastic cells may accompany cytarabine therapy. 
A regimen that includes a uricosuric agent such as allopurinol, urine alkalinization, and 
adequate hydration may be started, if the physician orders it. To reduce potential for urate stone 
formation, fluids may be forced in excess of 2 L, if tolerated. Management is at the discretion of 
the physician. 
 
Monitor intake and output ratio and pattern. 
 
Monitor body temperature. Be alert to the most subtle signs of infection, especially low-grade 
fever, and report promptly. 
 
When platelet count falls below 50,000/mm3 and polymorphonuclear leukocytes to below 
1000/mm3, the physician may decide to halt therapy. White blood count nadir is usually reached 
in five to seven days after the therapy has been stopped. Therapy is restarted with appearance 
of bone marrow recovery and when preceding cell counts are reached. Again, this is at the 
discretion of the physician. 
 
Provide good oral hygiene to diminish adverse effects and chance of super infection. Stomatitis 
and cheilosis usually appear five to 10 days into the therapy. 
• 
Hepatic 
o AST/ALT > 3 x ULN 
o Administer 50% of dose; may increase subsequent doses in the absence of 
toxicities (Floyd, 2006) 
o Bilirubin >2 mg/dL: Administer 50% of dose; may increase subsequent doses 
in the absence of toxicities 
 
Administer 50% of dose; may increase subsequent doses in the 
absence of toxicities (Koren, 1992) 
• 
Renal 
o Kintzel [52], 1995 (high-dose cytarabine 1 to 3 g/m2): 
 
CrCl 46 to 60 mL/minute: Administer 60% of dose 
 
CrCl 31 to 45 mL/minute: Administer 50% of dose 
 
CrCl <30 mL/minute: Consider use of alternative drug 
o Smith [53], 1997 (high-dose cytarabine; ≥2 g/m2/dose): 
 
Serum creatinine 1.5 to 1.9 mg/dL or increase (from baseline) of 0.5 to 
1.2 mg/dL: 
• 
Reduce dose to 1 g/m2/dose 
 
Serum creatinine ≥2 mg/dL or increase (from baseline) of >1.2 mg/dL: 
• 
Reduce dose to 0.1 g/m2/day as a continuous infusion 
 
Patients should have a daily creatinine and total bilirubin. The dose of cytarabine will be 
adjusted. The dose of cytarabine should be adjusted if there is a change in the serum creatinine 
or bilirubin during that cycle after the start of therapy. 
 

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Serum Creatinine (mg/dL) 
Serum Total Bilirubin 
Dose (mg/m2) 
< 2 
< 3 
1500 
> 2 
(or an increase of > 0.5 mg/dL from baseline) 
< 3 
750 
> 3 
< 3 
500 
Any 
> 3 
500 
 
Handling 
Use disposable gloves and protective clothing when handling the drug. Wash immediately if skin 
contact occurs. 
 
Availability 
This drug is commercially available. 
 
Agent Ordering  
Commercially available  
 
Agent Accountability  
Commercial supply 
 
Agent Destruction and Return 
At the conclusion of the study, any unused Cytarabine will be destroyed according to 
institutional policies. 
 
9.3 
MITOXANTRONE Product Description [45,50] 
 
Mitoxantrone is available in several generic formulations as a solution for injection (usually 2 
mg/mL). 
 
Black Box Warning: Cardiotoxic drug, extravasation, and secondary malignancy 
• 
Obtain baseline left ventricular ejection fraction (LVEF) 
 
Classification 
Mitoxantrone is an anthracenedione-derived antineoplastic agent. 
 
Mechanism of Action 
Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through 
hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with 
ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for 
uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and 
nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity. 
 
Metabolism 
Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. 
In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as 
either parent drug or metabolite during the 5-day period following drug administration. Of the 

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material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of 
monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The 
pathways leading to the metabolism of Mitoxantrone have not been elucidated. 
 
Weak inducer of CYP450 2E1 
 
Contraindications 
Mitoxantrone Injection, USP is contraindicated in patients who have hypersensitivity to 
mitoxantrone; myelosuppression; are pregnant or lactating. 
 
Cardiotoxic drug consider the benefit-to-risk ratio before starting Mitoxantrone in patients who 
were previously treated with daunorubicin or doxorubicin 
 
Patients with low LVEF are at risk of cardiotoxicity with mitoxantrone. Of note, the LVEF 
threshold for mitoxantrone has only been studied in patients with multiple sclerosis and not 
cancer patients. In accordance with the current ongoing clinical trials in US using mitoxantrone 
(NCT02044796), we have used a LVEF cut-off ≥45% to eligible to receive mitoxantrone. 
 
Side Effects 
See Section 11 (Known Risk List.) Complete and updated adverse event information is available 
in the Investigational Drug Brochure and/or product package insert. 
 
Solution Preparation 
IV Infusion: Withdraw contents of vial and add to at least 50 mL of D5W or NS. Mitoxantrone will 
precipitate if in the same infusion as heparin 
 
Agent Administration 
IV Infusion: Give into the tubing of a freely running IV of D5W or NS and infused over at least 3 
min or longer (i.e., 30–60 min) depending on the total volume of IV solution. If extravasation 
occurs, stop infusion and immediately restart in another vein. 
 
Storage Requirements 
Mitoxantrone Injection, USP should be stored between 15 and 25º Celsius. Like the original 
solutions, the dilutions should also not be frozen. 
 
Stability 
Following preparation of the infusion, the diluted solution should be stored at room temperature 
and used within 24 hours. Any original solution which remains in the vial should be discarded. 
 
Nursing Implications Guidelines 
Monitor IV insertion site. Transient blue skin discoloration may occur at site if extravasation has 
occurred. 
 
The physician may wish to monitor cardiac functioning throughout course of therapy. If so, 
report signs and symptoms of CHF or cardiac arrhythmias. 
 
They physician may choose to order laboratory tests prior to and during the course of treatment. 
If so, monitor levels. 
 
Hepatic 

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o Bilirubin greater than 3.4 
 
Patients were found to have an AUC three times greater than patients 
with normal hepatic function receiving the same dose. 
 
Renal 
o Pharmacokinetics unknown 
 
Extravastation and phlebitis can occur at the infusion site. If it has occurred stop infusion and 
start in another vein. Place ice packs over the area of extravasation and elevate for 15 to 20 
minutes at least 4 times daily for the first 24 hours. If skin is accidentally exposed to 
mitoxantrone rinse with warm water. No antidote 
 
Handling 
Avoid ingestion, inhalation, skin contact, and eye contact. Precautions may include the use of a 
containment cabinet during the weighing, reconstitution and/or solubilization of this 
antineoplastic agent. The use of disposable gloves and respiratory protection is recommended. 
Proper disposal of contaminated vials, syringes, or other materials is required when working 
with this product. If mitoxantrone touches skin, wash immediately with copious amounts of warm 
water. 
 
Availability 
This drug is commercially available. 
 
Agent Ordering  
Commercially available  
 
Agent Accountability  
Commercial supply 
 
Agent Destruction and Return 
At the conclusion of the study, any unused mitoxantrone, will be destroyed according to 
institutional policies. 
 
9.4 
GRANULOCYTE-COLONY STIMULATING FACTOR (FILGRASTIM)  
 
Product Description [45,49] 
Filgrastim is available in ready-to-use syringes or in a small container (vial) of liquid. The doses 
are either 300 mcg (micrograms) or 480 mcg. 
 
Classification 
Filgrastim is a recombinant, non-glycosylated form of the 175 amino acid protein, granulocyte 
colony stimulating factor (G-CSF) that induces the proliferation and maturation of neutrophils. 
 
Mechanism of Action 
Filgrastim binds to the G-CSF receptor and stimulates the production of neutrophils in the bone 
marrow. As a G-CSF analog, it controls proliferation of committed progenitor cells and 
influences their maturation into mature neutrophils. Filgrastim also stimulates the release of 
neutrophils from bone marrow storage pools and reduces their maturation time. Filgrastim acts 
to increase the phagocytic activity of mature neutrophils. In patients receiving cytotoxic 
chemotherapy, Filgrastim can accelerate neutrophil recovery, leading to a reduction in duration 

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of the neutropenic phase. 
 
Metabolism 
The metabolic fate of filgrastim has not been fully determined and it is not known whether the 
drug is metabolized or how it is eliminated from the body. 
 
Contraindications 
Filgrastim is contraindicated in patients with hypersensitivity to Escherichia coli–derived 
proteins. 
 
Side Effects 
See Section 11 (Known Risk List.) Complete and updated adverse event information is available 
in the Investigational Drug Brochure and/or product package insert. 
 
Solution Preparation 
Intermittent/Continuous: May dilute with 10–50 mL D5W to yield 15 mcg/mL or greater. If more 
diluent is used to yield concentrations of 5–15 mcg/mL, 2 mL of 5% human albumin must be 
added for each 50 mL D5W (prior to adding filgrastim) to prevent adsorption to plastic IV 
infusion materials. 
 
Do not dilute with saline at any time because the product may precipitate. 
 
Agent Administration 
• 
Intermittent: Give a single dose over 15–30 min. Continuous: Give a single dose over 
4– 24 h. 
• 
Subcutaneous 
 
Storage Requirements 
Store filgrastim in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not 
freeze. If accidentally frozen, allow the medicine to thaw in the refrigerator. If frozen more than 
once, the medicine should be thrown away. If filgrastim is left at room temperature for more than 
24 hours, it should be discarded. Keep filgrastim out of the reach of children and away from 
pets. 
 
Stability 
Prior to injection, NEUPOGEN may be allowed to reach room temperature for a maximum of 24 
hours. 
 
Nursing Implications Guidelines 
Monitor patients with preexisting cardiac conditions closely. Myocardial infarction and 
arrhythmias have been associated with a small percent of patients receiving filgrastim. 
 
Monitor temperature every four hours. Incidence of infection should be reduced after 
administration of filgrastim. 
 
Assess degree of bone pain if present. Consult physician if nonnarcotic analgesics do not 
provide relief. 
• 
Consider antibiotic, fungal, PCP prophylaxis during neutropenia. Patients should receive 
an oral Quinolone, Fluconazole, and Acyclovir to prevent infection once the ANC drops 

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below 1000. 
• 
Hepatic 
o No dosage adjustments provided  
• 
Renal 
o No dosage adjustment provided 
 
Handling 
Filgrastim should not be vigorously shaken. 
 
Availability 
This drug is commercially available. 
 
Agent Ordering  
Commercially available  
 
Agent Accountability  
Commercial supply 
 
Agent Destruction and Return 
At the conclusion of the study, any unused filgrastim will be destroyed according to institutional 
policies. 
 
10 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE 
GUIDELINES 
Overall recommendations 
1. Antibiotic Prophylaxis [44] 
a. Fungal Prophylaxis 
Consider prophlaxis during neutropenia and continue until resolution of neutropenia per 
institutional guidelines  
b. Bacterial prophylaxis per institutional guidelines 
i. Consider fluoroquinolone prophylaxis 
c. Pneumocytis jirovecii (PCP) 
i. Prophylaxis until CD4 count is greater than 200 cells/mcL 
ii. SMX/TMP (Bactrim) preferred 
1. SMX/TMP  400mg/ 80mg once daily or 
2. SMX/TMP 800mg/ 160mg 3 times per week 
3. SMX/TMP 15 mg/kg IV daily in divided doses 
iii. Atovaquone, dapsone, and pentamidine may be used if intolerant to Bactrim 
d. Herpes simplex virus (HSV) 
i. Provide prophylaxis during treatment and including times with and without 
neutropenia 
1. Acyclovir 400-800 mg PO BID 
2. Tumor lysis prophylaxis: 

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a. Hydration with diuresis 
b. Allopurinol or rasburicase. 
i. Rasburicase should be considered as initial treatment in patients with rapidly 
increasing blast counts, high uric acid, or evidence, or impaired renal function. 
3. Nausea [43], [46] 
a. Moderate emetic risk: 5-HT3 antagonist + steroid 
i. Day 1-5 15 minutes prior to chemotherapy 
1. Ondansetron 16 mg IV 
2. Dexamethasone 12 mg IV 
3. Ondansetron 8 mg PO BID Day 5 @ 2100 for 5 doses 
4. Eye Toxicity 
a. Corticosteroid 2 drops in each eye, 4 times a day for 10 days. The eye drops 
should be applied within one hour of the administration of high dose cytarabine. 
 
Cladribine 
Fever was a frequently observed side effect, especially in neutropenic patients in the first month 
of therapy. Initiate antibiotics as clinically indicated. 
 
Even though it is a rare side effect, patients may experience tumor lysis syndrome. [38] 
 
Cytarabine 
Possible decrease in steady-state digoxin levels 
Decrease therapeutic response of gentamycin and fluorocytosine 
Cytarabine (Ara-C) Syndrome – 6 to 12 hours after administration of drug, Corticosteroids can 
prevent and treat this condition. [39] 
 
Mitxantrone 
Weak inducer of CYP450 2E1 [40] 
 
Usage of Concurrent/Concomitant Medications 
• 
Inactivated Vaccines [42] 
• 
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 
• 
Live Vaccines [42] 
o 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. 
o Risk X: Avoid combination 
 

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11 CHEMOTHERAPY KNOWN RISKS 
Cladribine [38] 
> 10% 
1% to 10% 
< 1%, post-marketing and/or 
case reports 
Central Nervous System 
• fatigue 
• headache 
 
Dermatologic: 
• rash 
 
Gastrointestinal: 
• nausea 
• decreased appetite 
• vomiting 
 
Hematologic and 
Oncologic: 
• neutropenia (grade 4: 
70%; recovery by 
week5) 
• febrile neutropenia 
• anemia (1% to 37%; 
recovery by week 8) 
• bone marrow 
depression 
• thrombocytopenia 
(grade 4: 12%; 
recovery by day 12) 
 
Infection: 
• Month 1 of treatment 
 
Local: 
• injection site reaction 
 
Respiratory: 
• abnormal breath 
sounds 
 
Miscellaneous: 
• fever > 100 or > 104 
Cardiovascular: 
• edema 
• tachycardia 
• phlebitis 
• thrombosis 
 
CNS: 
• dizziness 
 chills 
• malaise 
• insomnia 
 pain 
• anxiety 
• myasthenia 
 
Dermatologic: 
• diaphoresis 
• erythema 
• pruitius 
• hyperhidrosis 
 
Gastrointestinal: 
• diarrhea 
• constipation 
• abdominal pain 
• flatulence 
 
Neuromuscular and 
skeletal: 
• weakness 
• myalgia 
• arthralgia 
Respiratory: 
• cough 
• dyspnea 
• epistaxis 
• rales 
• aplastic anemia 
• bacteremia 
• cellulitis 
• cerebrovascular accident 
• confusion 
• conjunctivitis 
• decreased CD-4 cell count (nadir: 
4 to 6 months) 
• hemolytic anemia 
• hypereosinophilia 
• hypersensitivity reaction 
• impaired consciousness 
• increased serum bilirubin 
• increased serum transaminases 
• lower extremity weakness 
• myelodysplastic syndrome 
• opportunistic infection 
(cytomegalovirus disease, fungal 
infection, herpes virus infection, 
listeriosis, Pneumocystis jirovecii), 
pancytopenia (prolonged), 
pneumonia, polyneuropathy (with 
high doses), progressive 
multifocal leukoencephalopathy, 
pulmonary infiltrates (interstitial), 
quadriparesis (reported at high 
doses) 
• reactivated tuberculosis 
• renal failure 
• renal insufficiency (with high 
doses) 
• septic shock 
• Stevens-Johnson 
• syndrome 
• toxic epidermal 
• necrolysis 
• tumor lysis syndrome 
• urticaria 
 
 
 

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Cytarabine [39] 
Adverse Events with 
high dose cytarabine 
Frequent 
Less Frequent 
Infrequent/Case 
Reports 
Cardiovascular 
• cardiomegaly 
• cardiomyopathy (in 
combination with 
cyclophosphamide) 
CNS 
• cerebellar toxicity 
• coma 
• neurotoxicity (up to 
55% in patients with 
renal impairment) 
• personality change 
• somnolence 
Dermatologic 
• alopecia 
• desquamation 
• rash 
Gastrointestinal 
• ulcer 
• pancreatitis 
• peritonitis 
• pneumatosis 
• cystoides intestinalis 
Hepatic 
• hyperbilirubinemia 
• liver abscess 
• liver damage 
• necrotizing colitis 
Neuromuscular and 
Skeletal 
• Peripheral 
neuropathy (motor 
and sensory) 
Respiratory 
• pulmonary edema 
• syndrome of sudden 
respiratory distress 
CNS 
• fever 
Dermatologic 
• rash 
Gastrointestinal 
• anal 
inflammation 
• anal ulceration 
• anorexia 
• diarrhea 
• mucositis 
• nausea 
• vomiting 
Hematologic 
• myelosuppressio
n 
• neutropenia 
• thrombocytopeni
a 
• anemia 
• bleeding 
• leukopenia 
• megaloblastosis 
• reticulocytes 
decreased 
Hepatic 
• hepatic 
dysfunction 
• transaminases 
increased 
Local 
• thrombophlebitis 
Cardiovascular 
• chest pain 
• pericarditis 
 
CNS 
• dizziness 
• headache 
• neural toxicity 
• neuritis 
Dermatologic 
• alopecia 
• pruritus 
• skin freckling 
• skin ulceration 
• urticaria 
Gastrointestinal 
• abdominal pain 
• bowel necrosis 
• esophageal 
ulceration 
• esophagitis 
• pancreatitis 
• sore throat 
Genitourinary 
• urinary retention 
Hepatic 
• jaundice 
Local 
• injection site 
cellulitis 
Ocular 
• conjunctivitis 
Renal  
• renal dysfunction 
Respiratory 
• dyspnea 
• Acute respiratory 
distress syndrome 
• amylase increased 
• angina 
• aseptic meningitis 
• cardiopulmonary 
arrest (acute) 
• cerebral dysfunction 
• cytarabine 
syndrome (bone 
pain, chest pain, 
conjunctivitis, fever, 
maculopapular rash, 
malaise, myalgia) 
• exanthematous 
pustulosis 
• hepatic sinusoidal 
obstruction 
syndrome (SOS; 
veno-occlusive 
disease) 
• hyperuricemia 
• injection site 
inflammation (SubQ 
injection) 
• injection site pain 
(SubQ injection) 
• interstitial 
pneumonitis 
• lipase increased 
• paralysis 
(intrathecal and IV 
combination 
therapy) 
• reversible posterior 
leukoencephalopath
y syndrome (RPLS) 
• rhabdomyolysis 
• toxic megacolon 

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Miscellaneous 
• sepsis 
Miscellaneous 
• allergic edema 
• anaphylaxis 
• sepsis 
 
Mitoxantrone [40] 
> 10% 
1% to 10% 
< 1%, postmarketing 
and/or case reports 
Cardiovascular 
• edema 
• arrhythmia 
• cardiac function changes 
• ECG 
 
CNS 
• fever 
• pain 
• fatigue 
• headache 
 
Dermatologic 
• alopecia 
• nail bed changes 
• petechiae/bruising 
 
Endocrine & Metabolic 
• menstrual disorder 
• amenorrhea 
• hyperglycemia 
Gastrointestinal 
• nausea 
• vomiting 
• diarrhea 
• mucositis 
• stomatitis 
• anorexia 
• weight gain/loss 
• constipation 
• GI bleeding 
• abdominal pain 
dyspepsia  
Cardiovascular 
• CHF 
• ischemia 
• LVEF decreased 
• hypertension 
 
CNS 
• chills 
• anxiety 
• depression 
• seizure 
 
Dermatologic 
• cutaneous mycosis 
• skin infection 
 
Endocrine/metabolic 
• hypocalcemia 
• hypokalemia 
• hyponatremia 
• menorrhagia 
 
Gastrointestinal 
• aphthosis 
 
Genitourinary 
• impotence 
Hematologic 
• granulocytopenia 
• hemorrhage 
• secondary acute leukemias 
Hepatic 
• Jaundice 
• allergic reaction 
• anaphylactoid reactions 
• anaphylaxis 
• chest pain 
• dehydration 
• extravasation at injection 
site (may result in burning, 
erythema, pain, skin 
discoloration, swelling, or 
tissue necrosis) 
• interstitial pneumonitis 
(with combination 
chemotherapy) 
• hyperuricemia 
• hypotension 
• phlebitis at the infusion site 
• rash 
• sclera discoloration (blue) 
• tachycardia 
• urine discoloration (blue-
green) 
• urticaria 

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Genitourinary 
• urinary tract infection 
• abnormal urine 
 
Hematologic 
• neutropenia 
• leukopenia 
• lymphopenia 
• anemia/hemoglobin 
decreased 
• thrombocytopenia 
• neutropenic fever 
 
Hepatic 
• alkaline phosphatase 
increased 
• transaminases increased 
• GGT increased 
 
Neuromuscular/skeletal 
• weakness 
 
Renal 
• BUN increased 
• creatinine increased 
• hematuria 
 
Respiratory 
• upper respiratory tract 
infection 
• pharyngitis 
• dyspnea 
• cough 
 
Miscellaneous 
• infection 
• sepsis 
• fungal infection 
Neuromuscular/skeletal 
• back pain 
• myalgia 
• arthralgia 
 
Ocular 
• conjunctivitis 
• blurred vision 
 
Renal 
• renal failure 
• proteinuria 
 
Respiratory 
• rhinitis 
• pneumonia 
• sinusitis 
 
Miscellaneous 
• systemic infection 
• diaphoresis 
 
 
 
 

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Granulocyte-Colony Stimulating Factor (Filgrastim) [41] 
> 10% 
1% to 10% 
< 1%, postmarketing 
and/or case reports 
Cardiovascular 
• chest pain 
 
CNS 
• fatigue 
• dizziness 
• pain 
 
Dermatologic 
• skin rash 
 
Endocrine/metabolic 
• increased lactate 
dehydrogenase 
• increased uric acid 
 
Gastrointestinal 
nausea 
 
Hematologic/oncologic 
• thrombocytopenia 
• splenomegaly 
• petechial 
 
Hepatic 
• increased serum alkaline 
phosphatase 
 
Neuromuscular/skeletal 
• ostealgia 
• back pain 
 
Respiratory 
• epistaxis 
• cough 
• dyspnea 
 
Miscellaneous 
• fever 
 
Cardiovascular 
• peripheral edema 
• hypertension 
• cardiac arrhythmia 
• myocardial infarction 
 
CNS 
• headache 
• hypoesthesia 
• insomnia 
• malaise 
• mouth pain 
 
Dermatologic 
• alopecia 
• erythema 
• maculopapular rash 
 
Gastrointestinal 
• vomiting 
• constipation 
• diarrhea 
 
Genitourinary 
• decreased appetite 
• urinary tract infection 
 
Hematologic/oncologic 
• anemia 
• leukocytosis 
 
Hypersensitivity 
• transfusion reaction 
• hypersensitivity reaction 
 
Immunologic 
• antibody development 
 
Infection 
• sepsis 
 
• 
acute calcium 
pyrophosphate 
• 
deposition disease (in 
patients treated for 
cancer) 
• 
anaphylaxis 
• 
calcium pyrophosphate 
deposition disease (in 
patients treated for 
cancer) 
• 
capillary leak syndrome 
• 
cerebral hemorrhage 
• 
decreased bone mineral 
density 
• 
decreased hemoglobin 
• 
euthymia nodosum 
• 
exacerbation of 
• 
psoriasis 
• 
facial edema 
• 
glomerulonephritis 
• 
hematuria 
• 
hemoptysis 
• 
hepatomegaly 
• 
hypersensitivity angiitis 
• 
hypotension 
• 
injection site reaction 
• 
osteoporosis 
• 
proteinuria 
• 
pulmonary alveolar 
hemorrhage 
• 
pulmonary infiltrates 
• 
renal insufficiency 
• 
respiratory distress 
syndrome 
• 
severe sickle cell crisis 
• 
splenic rupture 
• 
Sweet syndrome 
• 
Tachycardia 
• 
Urticarial 
• 
Wheezing 

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Neuromuscular/skeletal 
• arthralgia 
• limb pain 
• muscle spasm 
• musculoskeletal pain 
• weakness 
 
Respiratory 
• bronchitis 
• upper respiratory tract 
infection 
 
 
 
12 ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
12.1 
Defining and reporting an Adverse Event 
 
Definition. Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. 
 
Prior to the trial. Planned hospital admissions or surgical procedures for an illness or disease 
that existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned). 
 
Reporting source. AEs may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures. 
 
For non-serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration. 
 
Signs or symptoms reported as adverse events will be graded and recorded by the investigator, 
according to the CTCAE version 4. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
 
Follow-up of Adverse Events 
 
All adverse events will be followed with appropriate medical management from the date the 
patient signs informed consent until 30 days following the last dose of treatment. 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to adverse event reporting. 
 
12.2 
Defining and reporting a Serious Adverse Event (SAE) 
 
Serious Adverse Event (SAE) means any untoward medical occurrence that at any dose: 
 

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• 
Death. Results in death. 
 
• 
Life threatening. Is life threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 
• 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (excluding initial CLAG-M hospitalization and planned hospitalization). 
 
• 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal 
life functions). 
 
• 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of such 
medical 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; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent. 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; the 
event itself, however, may be of relatively minor medical significance (such as a Grade 3 
headache). This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above, and is usually associated with events that pose a threat to a patient’s 
life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious. For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 
 
Reporting SAEs 
 
Serious AEs must be reported from the date the participant signs Informed consent through 30 
days post last dose or until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es). 
 
For serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration. 
 
Since this is an investigator-initiated study, the principal investigator, also referred to as the 
sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency and to the sponsor-investigator’s IRB when required. 
 

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AEs which are serious must be reported to the Data Safety Monitoring Committee (DSMC) from 
the date the participant signs informed consent through 30 days post last dose on the study. 
 
Reporting to the Data and Safety Monitoring Committee 
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported to the DSMC as soon as possible, but no later than five calendar days of the 
sponsor-investigator’s observation or awareness of the event. 
 
Report Method: The investigator will use email to report SAEs to the DSMC. The SAE report 
must include event term(s), serious criteria, and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to study 
drug administration. Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE version 4 as a guideline whenever possible. 
 
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
12.3 
Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found 
on the Human Research Protection Program website. 
 
12.4 
Procedure for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant, or suspects that she is pregnant, while participating in this study, 
she must inform the investigator immediately and permanently discontinue the study drug. The 
sponsor-investigator must notify the DSMC by email. The pregnancy must be followed for the 
final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately notify the DSMC. Every effort should 
be made to follow the pregnancy for the final pregnancy outcome. 
 
Suggested Pregnancy Reporting Form: 
 
Pregnancy Report Form (a sample is provided in Appendix 4) 
 
13 REPORTING AND DOCUMENTING RESULTS 
13.1 
Evaluable for toxicity 
 
All patients will be evaluable for toxicity from the time of their first study drug treatment. 
 
13.2 
Evaluable for objective response 
 
Only those patients who have measurable disease present at baseline, have received the 
planned cladribine based salvage therapy and have had their disease re-evaluated will be 
considered evaluable for response. These patients will have their response classified according 

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to the definitions stated below. 
 
13.3 
Clinical assessment 
 
Patients will be followed per institutional guidelines for safety assessments. Bone marrow (BM) 
study obtained at the time of diagnosis of relapsed/refractory AML/high risk MDS will be used as 
baseline. Repeat BM study will be obtained after the completion of cladribine based salvage 
therapy when absolute neutrophil count (ANC) recovers to > 1000 cells/cu.mm or at day 30,or 
when the treating physician determines that it is clinically indicated. If peripheral blasts are 
present, a bone marrow aspiration/biopsy is not required and should be performed at the 
discretion of the treating physician. Response to therapy will be assessed according to the 
standard definitions developed by the international working group [34, 35].. Patients responding 
to cladribine based salvage therapy may be subsequently considered for allogeneic stem cell 
transplantation or further consolidation chemotherapy based on the discretion of the treating 
clinician. Those with PR or no response could be given additional chemotherapy at the treating 
physician’s discretion and patient’s tolerability. Hematological toxicity will be assessed 
according to National Cancer Institute Common Terminology Criteria for Adverse Events version 
4.0. MRD assessment and pharmacogenomic assessment is described below in section 15.1 
and 15.2. 
 
14 RESPONSE CRITERIA  
RESPONSE IN AML 
Category 
Definition 
Complete remission (CR) 
Bone marrow blasts <5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; absolute neutrophil count 
>1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); 
independence of red cell transfusions 
CR with incomplete 
recovery (CRi) 
All CR criteria except for residual neutropenia (<1.0 x 109/L 
(1000/µL)) or thrombocytopenia (<100 x 109/L (100,000/µL)) 
Morphologic leukemia-
free state 
Bone marrow blasts <5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; no hematologic recovery 
required 
Partial remission (PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5 to 25 percent; and decrease of pretreatment bone 
marrow blast percentage by at least 50 percent 
Cytogenetic CR 
Reversion to a normal karyotype at the time of morphologic CR (or 
CRi) in cases with an abnormal karyotype at the time of diagnosis; 
based on the evaluation of 20 metaphase cells from bone marrow 
 
 
 

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RESPONSE IN MDS 
 
Complete 
remission 
 
• 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines  
• 
Persistent dysplasia will be noted  
• 
Peripheral blood  
o Hgb ≥ 11 g/dL   
o Platelets ≥ 100 × 109/L   
o Neutrophils ≥ 1.0 × 109/L†  
o Blasts 0%   
Partial 
remission   
All CR criteria if abnormal before treatment except:   
• 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 
5%   
• 
Cellularity and morphology not relevant   
Marrow CR  
• 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over 
pretreatment†  
• 
Peripheral blood: if HI responses, they will be noted in addition to 
marrow CR  
Stable disease   
Failure to achieve at least PR, but no evidence of progression for > 8 wks   
Failure   
Death during treatment or disease progression characterized by worsening 
of cytopenias, increase in percentage of bone marrow blasts, or progression 
to a more advanced MDS FAB subtype than pretreatment   
 
14.1 
Duration of Response Duration of overall response 
 
The overall response duration is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented. The overall CR duration is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively documented. 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time duration from treatment start to 
progression time. 
 
14.2 
Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE v4.0 for reporting of adverse events. 
 
15 CORRELATIVE STUDIES 
15.1 
Correlative #1 
 
MRD assessment: MRD assessment by flow cytometry will be done on patients achieving CR or 
CR with incomplete count recovery or marrow CR, at the Wisconsin Diagnostic Laboratory. The 

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first pulled specimen of the bone marrow aspirate will be used for MRD testing. The test is 
performed using 8-color flow cytometry (FC). Briefly, EDTA-anticoagulated bone marrow 
aspirates are lysed and cell suspensions are prepared for incubation with 8 different, 
fluorochrome-labeled antibodies per tube. Antibodies analyzed across multiple tubes include: 
CD7, CD11b, CD13, CD14, CD15, CD22, CD33, CD34, CD36, CD38, CD45, CD56, CD64, 
CD117, and HLA-DR. At least 200,000 events are collected per tube on a FACS CANTO 
cytometer (BD Biosciences) and analyzed with Paint-A-Gate software (BD Biosciences). Blasts 
are identified using cluster analysis, based on reproducible forward and light scatter properties 
and CD45 staining across tubes, along with identification of other cell populations. Aberrant 
blast immunophenotypes are identified based on comparison with reproducible, known blast 
antigen expression patterns. Comparisons are also made to previous leukemic blast 
immunophenotypes, when available. MRD is defined as at least a 0.01% population of aberrant 
myeloblasts in the absence of morphologic evidence of disease. Contact Dr. Harrington at 
aharrington@mcw.edu with any MRD collection questions. This sample is collected per 
standard of care at Froedtert & Medical College of Wisconsin. 
 
15.2 
Correlative #2 
 
Pharmacogenomic assessment: Genotyping with the DMET Plus array (Drug Metabolizing 
Enzymes and Transporters) will be performed using the DNA extracted from blood through 
Qiagen Blood and Cell Culture DNA extraction kit. This is a high-throughput platform capable of 
analyzing multiple pharmacogenomic variants (1,931variants in 225 genes) and interrogates 
biallelic and triallelic single nucleotide polymorphism (SNPs), copy number variations, and 
insertion/deletions. It uses molecular inversion probes (MIPs) technology and a single-sample 
genotype calling method that compares each marker to an expected signal distribution defined 
by large training sets at Affymetrix. It has been validated as a method of studying 
pharmacogenomics in clinical samples [28, 29]. This analysis will be done at Dr. Ulrich 
Broeckel’s lab in MCW. Genes to be analyzed include those previously described in the 
pharmacogenomics of cladribine (RRM1, RRM2, RRM2B), mitoxantrone (ABCB1, GALNT14) and 
cytarabine (ABCB1, ABCC3, SLCO1B1, CDA, SLC 22A12, SLC29A1, RRM1, RRM2, RRM2B, 
NOS3, ADH1A, DCK, SULT2B1, DCK, GSTM1). 
 
16 STUDY ENDPOINTS 
16.1 
Primary Endpoint 
 
To determine the rate of MRD negative CR in patients with relapsed/refractory AML/high risk 
MDS treated with Cladribine based salvage chemotherapy. 
 
16.2 
Secondary Endpoints 
 
1. Determination of the overall survival (OS) and progression free survival (PFS) in patients 
with relapsed/refractory or secondary AML/high risk MDS treated with Cladribine based 
salvage therapy 
2. Determination of disease- or patient-related factors that predict MRD negativity and survival 
with Cladribine based salvage therapy, including pharmacogenomics. 
3. Determination of the role of pharmacogenomics in predicting the development of treatment 
related toxicities with Cladribine based salvage therapy. 

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17 STUDY DESIGN 
This is a single center non-randomized, single arm prospective study. After obtaining informed 
consent and enrollment in the clinical trial, patients will be treated with cladribine based salvage 
chemotherapy. Patients may either be inpatient or outpatient for CLLDAC salvage therapy.  Baseline 
characteristics such as age, gender, race, disease subtype, date of initial diagnosis, date of 
relapse, interval between diagnosis and relapse, cytogenetics and molecular mutations at 
diagnosis, prior chemotherapy or HSCT, baseline laboratory tests on admission, percentage of 
blasts in peripheral blood and bone marrow at diagnosis and relapse will be obtained. 
Peripheral blood for pharmacogenomics assay will be collected once from consent to day 5. 
CLAG-M  and CLLDAC chemotherapy regimens will be administered as described earlier in the 
protocol. Patients will be assessed subsequently as mentioned below 
 
17.1 
Clinical assessment 
 
Patients will be followed per institutional guidelines for safety assessments. Bone marrow (BM) 
study obtained at the time of diagnosis of relapsed/refractory AML/high risk MDS will be used as 
baseline. Repeat BM study will be obtained after the completion of therapy when absolute 
neutrophil count (ANC) recovers to > 1000 cells/cu.mm or at day 30, or when the treating 
physician determines that it is clinically indicated. If peripheral blasts are present, a bone 
marrow aspiration/biopsy is not required and should be performed at the discretion of the 
treating physician. Response to therapy will be assessed according to the standard definitions 
developed by the international working group [34, 35].. Patients responding to therapy may be 
subsequently considered for allogeneic stem cell transplantation or further consolidation 
chemotherapy based on the discretion of the treating clinician. Those with PR or no response 
could be given additional chemotherapy at the treating physician’s discretion and patient’s 
tolerability. Hematological and extra hematological toxicity will be assessed according to National 
Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. 
 
17.2 
MRD assessment 
 
MRD assessment by flow cytometry will be done on patients achieving CR or CR with incomplete 
count recovery or marrow CR. It is performed using 8-color flow cytometry (FC). Briefly, EDTA-
anticoagulated bone marrow aspirates are lysed and cell suspensions are prepared for incubation 
with 8 different, fluorochrome-labeled antibodies per tube. Antibodies analyzed across multiple 
tubes include: CD7, CD11b, CD13, CD14, CD15, CD22, CD33, CD34, CD36, CD38, CD45, 
CD56, CD64, CD117, and HLA-DR.  At least 200,000 events are collected per tube on a FACS 
CANTO cytometer (BD Biosciences) and analyzed with Paint-A-Gate software (BD 
Biosciences). Blasts are identified using cluster analysis, based on reproducible forward and 
light scatter properties and CD45 staining across tubes, along with identification of other cell 
populations. Aberrant blast immunophenotypes are identified based on comparison with 
reproducible, known blast antigen expression patterns. Comparisons are also made to previous 
leukemic blast immunophenotypes, when available. MRD is defined 
as at least a 0.01% population of aberrant myeloblasts in the absence of morphologic evidence 
of disease. This analysis will be done by pathology at MCW. 
 
 
 

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17.3 
Pharmacogenomic assessment 
 
Genotyping with the DMET Plus array (Drug Metabolizing Enzymes and Transporters) will be 
performed using the DNA extracted from blood through Qiagen Blood and Cell Culture DNA 
extraction kit. This is a high-throughput platform capable of analyzing multiple pharmacogenomic 
variants (1,931variants in 225 genes) and interrogates biallelic and triallelic single nucleotide 
polymorphism (SNPs), copy number variations, and insertion/deletions. It uses molecular 
inversion probes (MIPs) technology and a single-sample genotype calling method that compares 
each marker to an expected signal distribution defined by large training sets at Affymetrix. It has 
been validated as a method of studying pharmacogenomics in clinical samples [15, 16]. This 
analysis will be done at Dr Ulrich Broeckel’s lab in MCW. Genes to be analyzed include those 
previously described in the pharmacogenomics of cladribine (RRM1, RRM2, RRM2B), 
mitoxantrone (ABCB1, GALNT14) and cytarabine (ABCB1, ABCC3, SLCO1B1, CDA, SLC 
22A12, SLC29A1, RRM1, RRM2, RRM2B, NOS3, ADH1A, DCK, SULT2B1, DCK, GSTM1). Any 
leftover blood will be stored for 6 months at Dr. Ulrich Broeckel’s Lab. 
 
17.4 
Randomization 
 
There is no randomization planned for this study as this is single arm. 
 
17.5 
Stratification Factors 
 
There is no preplanned stratification for the institution of treatment or subsequent monitoring. 
However, during final analysis, patients will be stratified into those who achieve MRD negative 
CR, MRD positive CR and did not achieve CR. 
 
18 DETERMINATION OF SAMPLE SIZE AND ACCRUAL RATE 
Sample size of 90 patients was arrived using binomial proportion estimates of the number of 
patients needed to achieve an anticipated MRD negativity of 60% of the total patient population 
who would achieve CR with Cladribine based salvage. Accrual rate of 10 patients per year is 
determined by the Investigator’s personal experience of the number of patients with 
relapsed/refractory AML/high risk MDS at our Institution. 
 
18.1 
Accrual Estimates 
 
With an expected accrual rate of 10 patients per year, and an accrual time of 9 years, we 
anticipate an eventual accrual of 90 patients. If accrual falls short of expectations within the 
study period, the study duration will be extended in order to achieve a target sample size of 90 
patients. 
 
18.2 
Sample Size and Power Estimate 
 
With a projected CR rate of 60% after Cladribine based salvage and a further anticipated MRD-
negative rate of 60%, 36% of the study population is anticipated to be in MRD-negative CR. 
Based on binomial proportions, there will be between 23 and 41 MRD-negative patients with a 
95.3% confidence, and an expected 22 MRD-positive CR patients for comparison. 
 
 

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18.3 
Interim Analyses and Stopping Rules 
 
There is no interim analysis planned for this trial. The study will complete enrollment once the 
target number of patients is recruited and received therapy with Cladribine based salvage. 
 
Stopping Rule 
 
Number of Patients, n 
2 
3 
7 
12 
18 
25 
32 
40 
48 
56 
64 
73 
81 
90 
Boundary, bn 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Example: 5 deaths with 13 enrolled would halt the study, 5 deaths with 20 enrolled would 
continue. 6 deaths with 21 enrolled would halt the study. Stopping Rule applies only to those 
patient deaths that occur while patient is actively receiving study treatment or patient deaths 
believed to be, in the treating physician’s opinion, related to study treatment. 
 
This boundary is equivalent to testing the null hypothesis, after each patient, that the event rate 
is equal to 0.08, using a one-sided level 0.011536 test. 
 
Methods: Sequential boundaries will be used to monitor on-study death rate. The accrual will be 
halted if excessive numbers of deaths are seen, that is, if the number of deaths is equal to or 
exceeds bn out of n patients within 30 days of treatment. This is a Pocock-type stopping 
boundary that yields the probability of crossing the boundary at most [probability of early 
stopping] when the rate of deaths is equal to 8%. 
 
This stopping rule has the following characteristics for actual stopping probability, expected 
accrual and mortality, given these true mortality rates. 
 
True Mortality 
Rate 
Actual probability 
of stopping 
Expected 
Mortality (SD) 
Expected Accrual 
(SD) 
0.08 
0.049 
6.97 (2.44) 
87.03 
(14.23) 
0.1 
0.135 
8.29 (2.58) 
82.95 
(20.37) 
0.2 
0.911 
7.66 (3.30) 
38.33 
(27.20) 
 
18.4 
Analyses Plans 
 
Baseline characteristics will be analyzed using descriptive statistics. The primary objective of 
the rate of MRD negative CR achieved with Cladribine based salvage will be described using 
binomial proportion and confidence intervals. Progression-free survival (PFS) will be calculated 
from the first day of remission after Cladribine based salvage until documentation of another 
relapse. Overall survival (OS) will be calculated from the first day of salvage therapy until death. 
PFS and OS estimates will be done by Kaplan-Meier method. For secondary objectives, the log 
rank test will be used examine the potential significance of patient-related factors. Multivariate 
analysis using Cox proportional hazard regression method will be used to analyze the 

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determinants of MRD negative CR, OS, and PFS. All analyses will be done at a significance 
level of 0.05. Statistical analysis will be supervised by the division of biostatistics at MCW. 
 
18.5 
Analysis Population 
 
All patients who meet the study criteria and enrolled in this trial will be included in the final 
analysis except those who are lost to follow-up or who did not get the planned treatment with 
Cladribine based salvage therapy. 
 
18.6 
Primary Analysis (or Analysis of Primary Endpoints) 
 
Primary end point of the study is to determine the rate of MRD negative CR in patients with 
relapsed/refractory AML/high risk MDS treated with Cladribine based salvage. This will be done 
by identifying the number of patients who attained MRD negative CR amongst all those patients 
who were treated with Cladribine based salvage in this clinical trial. 
 
18.7 
Secondary Analysis (or Analysis of Secondary Endpoints) 
 
1. Determination of the overall survival (OS) and progression free survival (PFS) in patients 
with relapsed/refractory AML/high risk MDS treated with Cladribine based salvage 
therapy will be done using Kaplan-Meier method 
2. Determination of disease- or patient-related factors that predict MRD negativity and 
survival will be done using multivariate analysis. 
3. Pharmacogenomics profile obtained at baseline will be used in predicting MRD negativity, 
and survival. 
 
18.8 
Other Analyses/Assessments 
 
Pharmacogenomics profile obtained at baseline will be used in predicting treatment related 
toxicities 
 
Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the NCI CTCAE v4.0. 
 
Study Results 
 
Results of the study will describe the number of patients achieving MRD negative CR with 
Cladribine based salvage and their OS and PFS. Determinants of MRD negativity, survival and 
toxicity will be reported as multivariate analysis using hazard ratio, 95% confidence interval. 
 
19 DATA AND SAFETY MONITORING PLAN (DSMP) 
19.1 
Data and Safety Management Overview 
 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee(DSMC) and the 
MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 

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investigator-initiated trial will be required to be continuously monitored by the principal 
investigator of the study with regular safety and progress reports submitted to the DSMC. 
 
The DSMP for this study will involve the following entities: 
 
19.2 
Study Team 
 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist and the study biostatistician. While subjects are on treatment, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to 
review study status. This review will include but not be limited to reportable SAEs and UPIRSOs 
and an update of the ongoing study summary that describes study progress in terms of the 
study schema. The appropriateness of further subject enrollment and the specific intervention 
for a next subject enrollment is addressed. All meetings including attendance are documented. 
 
19.3 
Quality Assurance 
 
The MCWCC Clinical Trials Office provides ongoing quality assurance audits. 
• 
Intermediate risk trials are reviewed every year. 
• 
20% of subject files will be selected randomly for review (a maximum of 10 subjects at each 
monitoring time point). Consent/eligibility and objective-based data will be reviewed for those 
files selected. 
• 
One file will be selected randomly for a comprehensive review at each monitoring time point. 
• 
Regulatory documents (IRB submissions, reportable events, etc.) will be reviewed at each 
monitoring time point. 
 
19.4 
Clinical Trials Office 
 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC. 
 
19.5 
DSMC 
 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at 
MCW includes a plan for safety and data monitoring. 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows: 
• 
Review the clinical trial for data integrity and safety 
• 
Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events 
must be reported to the DSMC within 5 calendar days of study staff’s knowledge.) Grade 
4 hematological events are expected and only need routine reporting. 
• 
Review all DSM reports 

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• 
Submit a summary of any recommendations related to study conduct 
• 
Terminate the study if deemed unsafe for patients 
 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee will 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary. 
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
20 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
20.1 Regulatory Compliance 
 
This study will be conducted in compliance with: 
• 
The protocol 
• 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
 
20.2 Institutional Review Board 
 
The protocol, the proposed informed consent form and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the MCW Institutional Review Board. Prior to obtaining MCW approval, the 
protocol must be approved by the Medical College of Wisconsin Cancer Center Scientific 
Review Committee. The initial protocol and all protocol amendments must be approved by the 
IRB prior to implementation. 
 
20.3 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to 
starting intervention/administering study product. 
 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 

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investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study. 
 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff. This confidentiality includes the clinical information relating to 
participating subjects, as well as any genetic or biological testing. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the principal investigator. 
 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects. 
 
20.4 Protection of Human Subjects Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the informed consent process. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits. 
 
Protection of Privacy 
 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they 
will be asked to sign informed consent documents. The original signed document will become 
part of the patient’s medical records, and each patient will receive a copy of the signed 
document. 
 
20.5 Investigator Compliance 
 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies). 
 
20.6 Onsite Audits 
 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency 
standards. 
 
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, 
data capture records and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities. 

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21 DATA HANDLING AND RECORD KEEPING 
21.1 Overview 
 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity: well- 
trained data collectors/recorders to ensure consistency and quality, well-designed data 
collection protocols and ongoing monitoring. In this way, study rigor and validity are maintained. 
Data is protected from physical damage as well as from tampering, loss or theft. This project’s 
data management is a multidisciplinary activity that includes investigators, research 
coordinators and nurses, data mangers, support personnel, biostatisticians and database 
programmers. Quality control will be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly. 
 
21.2 Case Report Forms 
 
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study- 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized 
CRFs, in accordance with the study calendar, using single data entry with a secure access 
account. 
 
All source documentation and data will be available for review/monitoring by the MCWCC 
DSMC and regulatory agencies. 
 
21.3 Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends. 
 
In accordance with FDA regulations, the investigator shall retain records for a period of two 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until two years after the investigation is discontinued and FDA is 
notified. 
 
 
 
 

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Bennett JM, Young ML, Andersen JW et al. Long-term survival in acute myeloid leukemia: 
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Breems DA, Van Putten WL, Huijgens PC et al. Prognostic index for adult patients with 
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Prébet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after 
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Giles F, Verstovsek S, Garcia-Manero G, et al. Validation of the European Prognostic Index 
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Herzig RH, Lazarus HM, Wolff SN, et al. High-dose cytosine arabinoside therapy with and 
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Ho AD, Lipp T, Ehninger G, et al. Combination of mitoxantrone and etoposide in refractory 
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10. Daenen S, Löwenberg B, Sonneveld P, et al. Efficacy of etoposide and mitoxantrone in 
patients with acute myelogenous leukemia refractory to standard induction therapy and 
intermediate-dose cytarabine with amsidine. Dutch Hematology-Oncology Working Group 
for Adults (HOVON). Leukemia 1994; 8:6. 
11. Rowe JM, Mazza JJ, Hines JD, et al. Mitoxantrone and etoposide in patients with relapsed 
and refractory acute nonlymphocytic leukemia. Haematol Blood Transfus 1990; 33:326. 
12. Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and intermediate-dose 
cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid 
leukemia. J Clin Oncol 1991; 9:1210. 
13. Büchner T, Hiddemann W, Wörmann B, et al. Double induction strategy for acute myeloid 
leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard- dose 
cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML 
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14. Bergmann L, Heil G, Denzlinger C, et al. Triple combination of mitoxantrone, topotecan, 
araC (MTC) in relapsed or refractory AML (abstract). Proc ASCO 2002; 21:271a. 
15. Sternberg DW, Aird W, Neuberg D, et al. Treatment of patients with recurrent and primary 
refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose 
cytarabine: a pharmacologically based regimen. Cancer 2000; 88:2037. 
16. Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the 
treatment of poor risk acute myeloid leukemia. Am J Hematol 1998; 58:105. 
17. Jackson G, Taylor P, Smith GM, et al. A multicentre, open, non-comparative phase II study 
of a combination of fludarabine phosphate, cytarabine and granulocyte colony- stimulating 
factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia 
with excess of blasts in transformation. Br J Haematol 2001; 112:127. 
18. de Witte T, Suciu S, Peetermans M, et al. Intensive chemotherapy for poor prognosis 
myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of 
more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the 
European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leukemia 
1995; 9:1805. 
19. Ossenkoppele GJ, Graveland WJ, Sonneveld P, et al. The value of fludarabine in addition 
to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes 
and AML in elderly patients. Blood 2004; 103:2908 
20. Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin 
(FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid 
leukaemia. Br J Haematol 1997; 99:939 
21. Wierzbowska A, Robak T, Pluta A et al. Cladribine combined with high doses of 
arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage 
regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a 
final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80(2):115-26 
22. Price SL, Lancet JE, Georgea TJ et al. Salvage chemotherapy regimens for acute myeloid 
leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens. Leuk 
Res 2011; 35: 301–04. 
23. Jaglal MV, Duong VH, Bello CM et al. Cladribine, cytarabine, filgrastim, and mitoxantrone 
(CLAG-M) compared to standard induction in acute myeloid leukemia from myelodysplastic 
syndrome after azanucleoside failure. Leuk Res. 2014;38(4):443-6 
24. Halpern AB, Othus M, Huebner EM, et al. Phase 1/2 trial of GCLAM with dose-escalated 
mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. Leukemia. 
2018;32(11):2352-2362 
25. Kadia TA, Cortes J, Ravandi F, et al.  Phase II Single-Arm Trial of Cladribine and Low-
Dose Cytarabine Alternating with Decitabine as Frontline Therapy for Older Patients with 
Acute Myeloid Leukemia.  Lancet Haematol. 2018; 5(9): e411-e421. 
26. Wisniewski K, Madry K, Grosicki S et al. High Activity of Cladribine (2-CdA) Combined with 

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Low-Dose Cytarabine in Patients with Acute Myeloid Leukemia or Myelodysplastic 
Syndrome after Azacitidine Failure. Blood 2019; 134 (Supplement_1): 1360. doi: 
https://doi.org/10.1182/blood-2019-123843 
27. Walter RB, Buckley SA, Pagel JM et al. Significance of minimal residual disease before 
myeloablative allogeneic hematopoietic cell transplantation for AML in first and second 
complete remission. Blood. 2013;122(10):1813-21. 
28. Chen X, Xie H, Wood BL et al. Relation of clinical response and minimal residual disease 
and their prognostic impact on outcome in acute myeloid leukemia. J ClinOncol. 
2015;33(11):1258-64 
29. Xiao Q, Deng D, Li H. GSTT1 and GSTM1 polymorphisms predict treatment outcome for 
acute myeloid leukemia: a systematic review and meta-analysis. Ann Hematol. 
2014;93(8):1381-90 
30. Gréen H, Falk IJ, Lotfi K et al. Association of ABCB1 polymorphisms with survival and in 
vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype. 
Pharmacogenomics J. 2012;12(2):111-8. 
31. Drenberg CD, Paugh SW, Pounds SB et al. Inherited variation in OATP1B1 is associated 
with treatment outcome in acute myeloid leukemia. Clin Pharmacol Ther. 2015 Dec 10. doi: 
10.1002/cpt.315. [Epub ahead of print].  
32. Cao X, Mitra AK, Pounds S et al. RRM1 and RRM2 pharmacogenetics: association with 
phenotypes in HapMap cell lines and acute myeloid leukemia patients. Pharmacogenomics. 
2013;14(12):1449-66 
33. The pharmacogenomics knowledge base. https://www.pharmgkb.org. Accessed on March 
2016. 
34. Cheson BD, Bennett JM, Kopecky KJ et al. Revised recommendations of the International 
Working Group for diagnosis, standardization of response criteria, treatment outcomes, and 
reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 
2003;21(24):4642–4649 
35. Cheson BD, Greenberg PL, Bennett JM, et al. . Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood. 2006;108(2):419-425 
36. Fernandez CA, Smith C, Yang W et al. Concordance of DMET plus genotyping results with 
those of orthogonal genotyping methods. Clin Pharmacol Ther. 2012;92(3):360-5 
37. Burmester JK, Sedova M, Shapero MH, Mansfield E. DMET microarray technology for 
pharmacogenomics-based personalized medicine. Methods Mol Biol. 2010; 632:99-124. 
38. Leustatin® [package insert]. Ortho Biotech Products, Raritan, NJ; 2007. 
39. Cytarabine [package insert]. Pfizer Lab, New York, NY; 2011. 
40. Novantrone® [package insert]. EMD Serono Inc., Rockland, MA; 2008. 

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41. Neupogen® [package insert]. Amgen Inc., Thousand Oaks, CA; 2015 
42. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 2.2016) 
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43. National Comprehensive Cancer Network. Antiemesis (Version 2.2016). 
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2016. 
44. National Comprehensive Cancer Network. Prevention and Treatment of Cancer-Related 
Infections (Version 2.2016). 
https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Assessed July 4, 2016. 
45. Froedtert Institutional Guidelines. Extravasation. Assessed June 30, 2016. 
46. Froedtert Institutional Guidelines. CINV Parenteral Guidelines. Assessed June 30, 2016. 
47. Lexicomp Online® , Cladribine: Drug Inforation Lexicomp® , Hudson, Ohio: Lexi-Comp, 
Inc.; June 30, 2016. 
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49. Lexicomp Online® , Filgrastim: Drug Inforation Lexicomp® , Hudson, Ohio: Lexi-Comp, Inc.; 
June 30, 2016. 
50. Lexicomp Online® , Mitoxantrone: Drug Inforation Lexicomp® , Hudson, Ohio: Lexi- Comp, 
Inc.; June 30, 2016. 
51. Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing 
Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of 
Physicians; 2007:98-170. 
52. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for 
altered renal function. Cancer Treat Rev. 1995;21(1):33-64. 
53. Smith GA, Damon LE, Rugo HS, Ries CA, Linker CA. High-dose cytarabine dose 
modification reduces the incidence of neurotoxicity in patients with renal insufficiency. J Clin 
Oncol. 1997;15(2):833-839. 
54. American Cancer Society, Inc. (Feburary 22, 2016). 
http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/leukemia-acute- 
myeloid-myelogenous-classified. Assessed July 22, 2016. 
55. Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in phase 
II trials in oncology. Biometrics 61: 540-545. 
 
 

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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky 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 more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
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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APPENDIX 2. PROHIBITED MEDICATIONS 
Other concomitant AML therapy including but not limited to FLT3 inhibitors, IDH1 or IDH2 inhibitors 
except agents to reduce leukocytosis such as hydroxyurea 
 
 

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APPENDIX 3. SPECIMEN COLLECTION 
Specimen Collection & Handling  
 
Pharmacogenomic collection: 
Collect approximately 10ml of whole blood in an EDTA vacutainer (lavender top) No pre-
processing is required 
 
Specimen Labeling: 
All tubes must be labeled with the patient’s initials, patient study ID#, patient’s date of birth, and 
date/time of specimen collection 
 
Transporting and Storage Requirements: 
For all transportations, a requisition should accompany all samples. A copy of the requisition will 
be retained at the site. Only transport samples Monday thru Friday. Samples can be transported 
at room temperature. Samples should be packed and transported according to IATA 
regulations. 
 
Sample Drop Off Procedure: 
Location: Children’s Hospital-Pediatric TRU 
1. All samples must be in a biohazard sample bag. 
2. Locate a TRU staff member to unlock the door to the sample room for you. 
3. Locate the blue DNL Sample Binder. 
a. On the DNLSample Pickup Log, 
i. 
In the “Sample IN” column, write the sample ID/ attach a sample ID 
sticker, date, and initial. 
ii. 
Fill in one line per sample. 
iii. 
Sample IDs on the blood tubes and sample IDs on the DNL Sample 
Pickup Logmust match. 
b. Replace DNL SampleBinder to the original location. 
4. Place the biohazard bag with samples into the red bin marked “DNL Lab” in 
refrigerator. 
5. The “DNL Lab” bin is checked and any samples are picked up daily from the TRU. 
 
 
 
 

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Specimen Requisition Form 
 
 
A Phase II Study of the Efficacy and Pharmacogenomics of Cladribine based Salvage 
Chemotherapy in Patients with Relapse/Refractory Acute Myeloid Leukemia (AML) 
 
 
 
Patient Information: 
 
Patient initials:   
 
  
Birth Date:   
 
Study ID #:   
 
 
 
 
Pharmacogenomic Sample Information: 
 
Date of Collection 
 
Time of Sample Collection  
 
Physician 
Email    
 
Person Completing Requisition 
Phone Number   
 
 
 
 
 

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APPENDIX 4. PREGNANCY FORM 
Pregnancy occurring in participant in a Clinical Trial of Investigational Medicinal Product, while 
not considered an adverse event or serious adverse event, requires monitoring and follow up. 
 
The investigator must collect pregnancy information for female trial subjects or female partners 
of male trial subjects. This includes subjects who become pregnant while participating in a 
clinical trial or during a stage where the fetus could have been exposed to the investigational 
medicinal product (e.g., if the active substance or one of its metabolites has a long half-life). 
 
Any pregnancy should be reported by the PI to the sponsor using either a study specific or 
generic pregnancy reporting form (see below). 
 
The pregnancy should be followed up by the investigator until delivery. It may be necessary to 
monitor the development of the newborn for an appropriate period post-delivery. Any 
occurrences that result in a Serious Adverse Event should be reported as per the SAE reporting 
procedure. 
 
The below form will be used. 
 
 

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Study Drug: 
Study/Protocol No: 
PATIENT ID 
 
Patient’s Initials 
1. 
2. fam. 
 
 
If applicable 
Centre No.    Patient No 
REPORT TYPE 
Initial 
Follow-Up 
STUDY PREGNANCY FORM 
Page 1 of 3 
1. Country: 
2. LOCAL CASE ID: 
I.    MATERNAL INFORMATION 
3. DATE OF BIRTH 
day 
monthyear 
4. AGE 
yrs./mo. 
5. RACE 
Caucasian 
Oriental 
Black 
Other 
6. HEIGHT 
cm 
7. WEIGHT 
kg 
8. 
Date of Last Menstrual Period 
day 
month 
year 
9. 
Expected Date of Delivery 
day 
month 
year 
10. 
Method of Contraception 
11.   Contraception used as instructed 
yes 
no 
uncertain 
II. 
HISTORY 
12. PATIENT’S PAST MEDICAL HISTORY (include information on familial disorders, known risk factors or 
conditions that may affect the outcome of the pregnancy e.g. alcohol, smoking, other substance 
consumption, hypertension, eclampsia, diabetes including gestational, infections during pregnancy, 
environmental or occupational exposure that may pose a risk factor). 
13. 
PREVIOUS OBSTETRIC HISTORY – provide details on all previous pregnancies below, including abortion or stillbirth (use page 3 if 
needed) 
Gestation week 
Outcome including any abnormalities 
1 
2 
3 
4 
5 
14. 
DRUG INFORMATION – please list the drug(s) first and all other therapies taken prior to or during pregnancy 
Drug Names 
Daily Dose 
Route 
Treatment Dates 
Indication 
(specify week of pregnancy) 
Start 
Stop 
Start 
Stop 
 

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STUDY PREGNANCY FORM 
Page 2 of 3 
2. LOCAL CASE ID: 
III. 
PREGNANCY INFORMATION 
18. 
PRENATAL 
Have any specific tests, e.g. amniocentesis, ultrasound, maternal serum AFP, been performed during the pregnancy so far? 
No 
Yes 
Not known 
If yes, please specify test date and results: 
19. 
PREGNANCY OUTCOME 
Delivery 
Normal 
Forceps/Ventouse 
Caesarean section 
Maternal complications or problems related to birth:  
_ 
 
Abortion 
Therapeutic 
Planned 
Spontaneous 
Please, specify reason and any abnormalities (if known) 
 
Unspecified 
Date of abortion/delivery 
day 
month 
year 
at week   
 
20. 
MATERNAL PREGNANCY ASSOCIATED EVENTS: 
If the mother experiences a serious adverse drug reaction (ADR) during a pregnancy, please complete a SAE form and submit as requested. 
IV. 
CHILD INFORMATION 
21. 
Neonate 
Normal 
Abnormal 
Stillbirth 
please specify any abnormalities:    
 
Sex 
Male 
Female 
Height 
inches 
Weight 
pounds 
Apgar Scores 
1 min. 
5 mins. 
10 mins. 
Head circumference 
inches 
For additional information, please use page 3 (please provide copies of relevant documentation) 
V. 
ASSESSMENT OF PREGNANCY OUTCOME 
22. 
SERIOUSNESS CRITERIA 
Non Serious 
day 
month  year 
day 
month  year 
Mother died 
Stillbirth / Neonate 
died 
Involved or prolonged inpatient hospitalization 
Life-threatening 
Results in persistent or significant disability/incapacity 
Other Seriousness Criteria: 
Congenital anomaly/birth defect 
Other significant medical events 
23. 
ASSESSMENT OF CAUSALITY 
Please indicate the relationship between pregnancy outcome and Novartis study drug 
Not suspected 
Suspected 
INFORMATION SOURCE 
24. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
Signature: 
25. REPORTING DATE BY INVESTIGATOR/PERSON REPORTING 
EVENT 
daymonthyear 
 

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STUDY PREGNANCY FORM 
Page 3 of 3 
2. LOCAL CASE ID: 
FOR ADDITIONAL INFORMATION: 
INFORMATION SOURCE 
32. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
Signature: 
33. REPORTING DATE BY INVESTIGATOR/PERSON REPORTING 
daymonthyear 
PLEASE SEND FORM TO: DSMC 

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APPENDIX 5. WHO CLASSIFICATION OF ACUTE MYELOID LEUKEMIA 
AML with certain genetic abnormalities [54] 
 
• 
AML with a translocation between chromosomes 8 and 21 
• 
AML with a translocation or inversion in chromosome 16 
• 
AML with a translocation between chromosomes 9 and 11 
• 
APL (M3) with a translocation between chromosomes 15 and 17 
• 
AML with a translocation between chromosomes 6 and 9 
• 
AML with a translocation or inversion in chromosome 3 
• 
AML (megakaryoblastic) with a translocation between chromosomes 1 and 22 
 
AML with myelodysplasia-related changes 
 
AML related to previous chemotherapy or radiation 
 
AML not otherwise specified (This includes cases of AML that don’t fall into one of the above 
groups, and is similar to the FAB classification.) 
 
• 
AML with minimal differentiation (M0) 
• 
AML without maturation (M1) 
• 
AML with maturation (M2) 
• 
Acute myelomonocytic leukemia (M4) 
• 
Acute monocytic leukemia (M5) 
• 
Acute erythroid leukemia (M6) 
• 
Acute megakaryoblastic leukemia (M7) 
• 
Acute basophilic leukemia 
• 
Acute panmyelosis with fibrosis 
 
Myeloid sarcoma (also known as granulocytic sarcoma or chloroma)  
 
Myeloid proliferations related to Down syndrome 
 
Undifferentiated and biphenotypic acute leukemias (leukemias that have both lymphocytic 
and myeloid features). Sometimes called ALL with myeloid markers, AML with lymphoid 
markers, or mixed phenotype acute leukemias.