Clinical trial NCT02269267
Conditions: Leukemia, Myeloid, Chronic
Sponsor: Medical College of Wisconsin
Start date: 2014-12-18; Completion date: 2022-04-06
Enrollment: 173 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a non-randomized, prospective, single-group longitudinal study. The purpose of this study is to improve the decision making process used by physicians and patients when they are considering stopping their Tyrosine Kinase Inhibitor (TKI) medication.

Detailed description:
This is a non-randomized, prospective, single-group longitudinal study. The overall objective is to improve decision making for TKI discontinuation in eligible chronic myelogenous leukemia (CML) patients. Patients with CML on treatment with imatinib, dasatinib, nilotinib, or bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (\> 4 log reduction) molecular response (\>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) \< 0.01%, for at least two years. The study will closely monitor patients using standard real-time Quantitative Polymerase Chain Reaction (RQ-PCR) testing for molecular recurrence, testing them monthly for six months, then every other month until 24 months, and then quarterly until 36 months. Concurrently, the study will assess a wide range of patient-reported outcomes (PROs) before stopping TKIs and after discontinuation in conjunction with Polymerase Chain Reaction (PCR) testing, though at fewer time points, utilizing online and/or phone questionnaires. Patients who have molecular CML recurrence based on RQ-PCR will restart imatinib, dasatinib, nilotinib, or bosutinib and will continue to be monitored for disease status and health status until the end of the study.

Arms: arm 1: Patients with CML on treatment with imatinib, dasatinib, nilotinib, or bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (\> 4 log reduction) molecular response (\>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) \< 0.01%, for at least two years.
Interventions: intervention 1: Imatinib (Stopping their TKI) intervention 2: Dasatinib (Stopping their TKI) intervention 3: Nilotinib (Stopping their TKI) intervention 4: Bosutinib (Stopping their TKI)
Intervention descriptions: intervention 1: Patients with CML on treatment with imatinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (\> 4 log reduction) molecular response (\>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) \< 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. intervention 2: Patients with CML on treatment with dasatinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (\> 4 log reduction) molecular response (\>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) \< 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. intervention 3: Patients with CML on treatment with nilotinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (\> 4 log reduction) molecular response (\>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) \< 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. intervention 4: Patients with CML on treatment with bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (\> 4 log reduction) molecular response (\>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) \< 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires.

Protocol documents:
Prot_SAP_000.pdf: 
Study Title:  The Life After Stopping Tyrosine Kinase Inhibitors Study (The LAST Study) 
Clinical Trials.gov Number:  NCT02269267 
Protocol Date:  January 23, 2017 


Medical College of Wisconsin 
Clinical Trial Protocol 
 
 
Protocol Version:  23 January, 2017 
 
The Life After Stopping Tyrosine Kinase Inhibitors Study 
(The LAST study) 
Principal Investigators 
Ehab Atallah, MD (Medical College of Wisconsin) 
Kathryn Flynn, PhD (Medical College of Wisconsin) 
 
Executive committee 
Mary Horowitz, MD MS (Medical College of Wisconsin) 
Mei-Jie Zhang, PhD (Medical College of Wisconsin) 
Kevin Weinfurt, PhD (Duke Clinical Research Institute) 
Charles A Schiffer, MD (Barbara Ann Karmanos Cancer Institute of Wayne State University) 
Jerald Radich, MD (Fred Hutchinson Cancer Research Center) 
 
Steering Committee 
Michael Deininger, MD PhD (Huntsman Cancer Institute at the University of Utah) 
H. Jean Khoury, MD (Winship Cancer Institute of Emory University) 
Richard Larson, MD (University of Chicago Comprehensive Cancer Center) 
Michael Mauro, MD (Memorial Sloan Kettering Cancer Center) 
Joseph Moore, MD (Duke University Cancer Institute) 
Vivian Oehler, MD (Fred Hutchinson Cancer Research Center) 
Javier Pinilla-Ibarz, MD PhD (H. Lee Moffitt Cancer Center) 
Ellen K. Ritchie, M.D. (Weill Medical College of Cornell University) 
Richard Silver, MD (Weill Medical College of Cornell University) 
Neil Shah, MD PhD (UCSF Helen Diller Family Comprehensive Cancer Center) 
Martha Wadleigh, MD (Dana-Farber Cancer Institute) 
Jorge Cortes, MD (University of Texas MD Anderson Cancer Center) 
 
Amendment 6 Version Date: 23 January, 2017 
 
Protocol Version Summary 
Original Protocol v. 1.0 October 17, 2014 
Amendment 1 v. 2.0 December 10, 2014 
Amendment 2 v. 3.0 December 31, 2014 
Amendment 3 v. 4.0 April 14, 2015 
Amendment 4 v. 5.0 September 10, 2015 
Amendment 5 v. 6.0 November 11, 2016 
 
Phase: II 
 
Confidentiality Statement 
This protocol may not be used, published or otherwise disclosed  


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without the written consent of the Medical College of Wisconsin 
 
Principal Investigators 
 
Ehab Atallah, MD 
Associate Professor of Medicine 
Division of Hematology/Oncology 
Medical College of Wisconsin and Froedtert Hospital 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
Telephone number: 414.805.4600 
E-mail: eatallah@mcw.edu 
 
Kathryn Flynn, PhD 
Associate Professor of Medicine 
Division of General Internal Medicine 
Department of Medicine 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Telephone number: 414.955.8847 
Email: kflynn@mcw.edu 
 
Executive committee 
 
Mary Horowitz, MD MS 
Professor of Medicine 
Medical College and Wisconsin and Froedtert Hospital 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
Telephone number: 414.805.0699 
Email: marymh@mcw.edu 
 
Mei-Jie Zhang, PhD 
Professor 
Medical College of Wisconsin 
Division of Biostatistics 
Institute for Health and Society 


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PO Box 26509 
Milwaukee, WI 53226 
Telephone number: 414.456.8280 
Email: meijie@mcw.edu 
 
Kevin Weinfurt, PhD 
 (Duke Clinical Research Institute) 
Professor in Psychiatry and Behavioral Sciences 
Duke University School of Medicine 
PO Box 17969 
Durham, NC 27705 
Telephone number: 919.668.8101 
Email: kevin.weinfurt@duke.edu 
 
Charles A Schiffer, MD 
Professor of Oncology and Medicine 
Wayne State University of Medicine 
Barbara Ann Karmanos Cancer Institute of Wayne State University 
4100 John R 
Detroit, MI 48201 
Telephone number: 800.527.6266 
Email: schiffer@karmanos.org 
 
Jerald Radich, MD 
Full Member, Clinical Research Division 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave. N., D4-100 
Seattle, WA 98109-1024 
Telephone number: 206.667.4118 
Email: jradich@fhcrc.org 
 
 
 
 
 
 


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Steering Committee 
 
Jorge Cortes, MD  
Professor of Medicine and Internist 
Department of Leukemia,  
Division of Cancer Medicine 
1515 Holcombe Blvd 
Univeristy of Texas 
MD Anderson Cancer Center 
Houston, TX 77030 
Telephone number: 713-794-5783 
Email: jcortes@mdanderson.org 
 
Michael Deininger, MD PhD 
M.M. Wintrobe Professor of Medicine 
University of Utah 
Huntsman Cancer Institute 
30 North 1900 East, Room 5C402 
Salt Lake City, UT 84132-2408 
Telephone number: 801.585.3229 
Email: Michael.Deininger@hci.utah.edu 
 
H. Jean Khoury, MD, FACP  
(Winship Cancer Institute of Emory University) 
Professor of Hematology and Medical Oncology 
Department of Hematology and Medical Oncology 
Emory University School of Medicine 
Winship Cancer Institute 
1365-C Clifton Road, Suite C-1152 
Atlanta, GA 30322 
Telephone number: 404.778.3932 
Email: hkoury@emory.edu 
 
 
 


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Richard Larson, MD  
(University of Chicago Comprehensive Cancer Center) 
Professor of Medicine 
Section of Hematology/Oncology 
University of Chicago 
5841 S. Maryland Avenue, MC 2115 
Chicago, IL 60637 
Telephone: 773.702.4400 
Email: rlarson@medicine.bsd.uchicago.edu 
 
Michael Mauro, MD  
(Memorial Sloan Kettering Cancer Center) 
Leader, Myeloproliferative Neoplasms Program 
Memorial Hospital 
1275 York Avenue 
New York, NY 10065 
Telephone number: 212.639.3107 
Email: maurom@mskcc.org 
 
Joseph Moore, MD  
(Duke University Cancer Institute) 
Professor of Medicine 
Duke University 
DUMC 3872 
Durham, NC 27710 
Telephone number: 919.684.8964 
Email: moore035@mc.duke.edu 
 
Vivian Oehler, MD  
(Fred Hutchinson Cancer Research Center) 
Assistant Professor 
University of Washington Medical Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave. N., D4-100 
Seattle, WA 98109-1024 


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Telephone number: 206.667.5000 
Email: voehler@uw.edu 
 
Javier Pinilla-Ibarz, MD PhD  
(H. Lee Moffitt Cancer Center) 
Department of Malignant Hematology 
Moffitt Cancer Center 
Associate Professor of Oncologic Sciences 
University of South Florida 
12902 Magnolia Drive 
Tampa, FL 33612-9416 
Telephone number: 888.860.2778 
Email: Javier.Pinilla@moffitt.org 
 
Ellen K Ritchie, MD  
(Weill Medical College of Cornell University) 
Associate Professor of Medicine 
Division of Hematology and Oncology 
Department of Medicine 
525 East 68th Street 
Payson Pavilion, 3 
New York, NY 10065 
Telephone number: 646.962.2700 
Email: ritchie@med.cornell.edu 
 
Neil Shah, MD PhD 
(UCSF Helen Diller Family Comprehensive Cancer Center) 
Associate Professor of Department of Medicine (Hematology/Oncology) 
University of California San Francisco 
Box 1270, UCSF 
San Francisco, CA 94143-1270 
Telephone number: 415.514.0269 
Email: nshah@medicine.ucsf.edu 
 
 
 


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Richard Silver, MD  
(Weill Medical College of Cornell University) 
Professor of Medicine 
Division of Hematology and Oncology 
Department of Medicine 
1305 York Avenue, Box 403 
New York, NY 10021 
Telephone number: 646.962.2255 
Email: rtsilve@med.cornell.edu 
 
Martha Wadleigh, MD  
(Dana-Farber Cancer Institute) 
Assistant Professor of Medicine 
Division of Hematologic Malignancies 
Department of Medical Oncology 
Harvard Medical School 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215-5450 
Telephone number: 617.632.3712 
Email: mwadleigh@partners.org 


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The LAST Study Support Unit Address and Contact Information 
Site Activation 
Patient 
Enrollments 
OnCore CTSM 
Management 
PRO Management 
PCR core lab 
 
Email: 
LASTstudy@mcw.edu 
 
Paulette Jacobs 
Phone: 414-805-4594 
Fax: 414-805-0596 
 
 
 
 
 
 
 
Email: 
LASTstudy@mcw.edu 
Fax: 414-805-0596 
 
Arielle Baim 
Phone: 414-805-8745 
 
Jessica Guhl 
Phone: 414-805-8746 
 
Hayden Krause 
Phone: 414-805-8753 
 
Alex Hinman 
Phone: 414-805-9001 
 
 
 
Email: 
LASTstudy@mcw.edu 
 
 
 
 
 
Email: 
LASTstudypro@mcw.edu 
 
Judith Myers 
Phone: 414-955-5658 
Fax: 414-955-6689 
 
 
Email: molab@fhcrc.org 
 
 
Molecular Oncology 
1100 Fairview Avenue 
North, D2-281 
Seattle, WA  98109  
Phone: (206) 667-2592 
FAX: (206) 667-6092 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please email all general questions to LASTstudy@mcw.edu 
Please notify us of all  SAEs and SAEs questions via email at  LASTstudy@mcw.edu 
Send all mailings to the following address: 
MCW Clinical Trials Office 
Attn: Paulette Jacobs 
9200 W. Wisconsin Ave 
Milwaukee, WI 53226 


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Schedule of Trial Procedures 
 
Year 1 
Year 2 
Year 3 
Long 
Term 
Follow 
Up 
Month (30 days)a 
Se 
D1f 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 14 16 18 20 22 24 27 30 33 36 
Eligibility criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Medical history 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examj 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
Stop TKI 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RQ-PCRb 
x  
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
PRO assessmentsc 
x 
 
x 
x 
x 
x 
x 
x 
  
 x 
 
  
  
x 
  
  
x 
  
  
x 
 
x 
 
x 
 
Digital PCRd 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
AE assessmenth 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
a. Months after stopping TKI (±4 days for visits month 1-6) (±7 days for visits months 7-36) 
b. During screening, RQ-PCR for BCR-ABL will be performed twice at least 21 days apart to confirm that BCR-ABL is <0.01% (MR4) at the Core Lab. During 
follow up, if BCR-ABL is ≥ 0.01% for the first time, then PCR testing would be repeated monthly for 3 months. If MMR is lost restart TKI. If no loss of MMR 
then resume regular schedule of PCR evaluations. i.e. if patient is in first 6 months of study check RQ-PCR monthly, if in month 7-24 then check RQ-PCR 
q 2 months, if in third year then check RQ-PCR q 3 months. For patients who restart TKI therapy, RQ-PCR will be performed approximately every 3 
months at Core Lab until the patient BCR-ABL is <0.01% (MR4) two consecutive times. Once a patient has two consecutive core lab BCR-ABL < 0.01% 
(MR4), the patient will have their RQ-PCR processed locally approximately every 3 months for the remainder of the study.   
c. PROs will also be collected twice during the screening period. Refer to section 5.3.2 for patients who restart their TKI.  
d. Digital PCR will be performed on the same schedule as RQ-PCR as long as BCR-ABL remains undetectable by RQ-PCR. For patients who restart the 
TKI, the digital PCR will no longer be performed 
e. Screening within 42 days prior to enrollment 
f. Day 1 of stopping TKI 
g. Baseline data will include age, sex, date of diagnosis, baseline BCR-ABL transcript level, Sokal risk score (see appendix 4) and its components (spleen 
size, platelet count, the percentage of blasts in the peripheral blood), basophil %, history of prescribed TKIs including any dose reductions or held dosing, 
time to MR3, time to undetectable BCR-ABL by PCR, duration undetectable BCR-ABL by PCR. 


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h. AEs will be followed throughout the study from the time of Informed Consent until restarting TKI.  See Section 10.1.2 for AE reporting guidelines 
i. Patients will be followed for survival after study completion every 6 months.  
j. Once a patient restarts their TKI, physical exams will be performed at the discretion of the treating physician. 
 


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Schema 
Consent
PCR 1
And 
PRO 1
Note:  this 
can occur 
on the 
same day 
as consent
BCR-ABL
<0.01%
BCR-ABL ≥ 
0.01%
Screen 
Fail
BCR-ABL 
<0.01%
BCR-ABL ≥ 
0.01%
Stop TKI
BCR-ABL <0.01%
Continue Monitoring Phase
Monthly for the 1st 6 months, Every 2 months for the next 18 months, 
and every 3 months for the 3rd year
BCR-ABL ≥ 
0.01% and 
<0.1%
Screen 
Fail
MMR lost
(BCR-ABL ≥  
0.1%)
Screening Phase (42 days)
Monitoring Phase-Treatment Free Remission Phase 
Follow-up 
Phase
More Frequent BCR-Abl Testing 
Recheck monthly for 3 consecutive months.  Then 
resume regular schedule (i.e. If patient is in first 6 
months of monitoring phase check monthly, if patient is in 
months 7-24  of monitoring phase check every 2 months, if in 
3rd year check every 3 months)
PCR 2  
And
 PRO 2
O
N
C
O
R
E
 
R
E
G
I
S
T
R
A
T
I
O
N
E
N
D
 
O
F
 
S
T
U
D
Y
3 
Years
42 
Days
Screening
Restart TKI
(if TKI is restarted within the 3 year timeframe 
of the study, the patient’s PCR will continue 
to be monitored centrally for up to 3 years 
from enrollment or until patients BCR-ABL is 
<0.01% on two consecutive occasions, 
whichever comes first)
Follow-up 
Until End of 
Study
Follow-up 
Until End of 
Study
F
O
L
L
O
W
 
U
P
E
N
R
O
L
L
M
E
N
T
 
 


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List of Abbreviations and Glossary of Terms 
Abbreviation 
Term 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
AP 
Accelerated phase 
AST 
Aspartate aminotransferase 
BC 
Blast crisis 
CBC 
Complete blood count 
CCyR 
Complete cytogenetic response 
CML 
Chronic myelogenous leukemia 
CMR 
Complete molecular response 
CR 
Complete remission  
eCRF 
Electronic case report forms 
CTMS 
Clinical Trials Management System 
CTO 
Clinical trials office 
DCR 
Death in CR 
DSMC 
Data safety monitoring committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
Hb 
HCT 
Hemoglobin 
Hematopoetic stem cell transplantation 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IRB 
IS 
Institutional review board 
International standardized ratio 
MCW 
Medical College of Wisconsin 
MR 
Molecular response 
MMR 
Major molecular response 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PCR 
Polymerase chain reaction 
PO 
Per os; by mouth (orally) 
PR 
Partial remission 
PRO 
Patient reported outcomes 
PROMIS 
Patient Reported Outcomes Measurement Information System 
QA 
Quality assurance 
QOL 
Quality of life 
RFS 
Relapse free survival 
SAE 
Serious adverse event 
TKI 
Tyrosine kinase inhibitors 
US 
United States 
WBC 
White blood cell 


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Protocol Summary 
Study Title:  The Life After Stopping Tyrosine Kinase Inhibitors Study (The LAST study) 
Phase: II 
Number of Patients:  173 
Number of Sites:       14 
STUDY OBJECTIVES 
Primary Objectives: 
1. Proportion of patients with CML who develop molecular recurrence after discontinuing 
tyrosine kinase inhibitors (TKIs). Molecular recurrence defined as loss of MMR (> 0.1% BCR-
ABLIS) 
2. Compare the patient-reported health status of patients before and after stopping TKIs.  
Secondary Objectives: 
1. To prospectively determine whether there are disease, patient-related, or treatment-related 
factors that predict molecular recurrence including sex, age, type of TKI, time to undetectable 
BCR-ABL by PCR, duration undetectable BCR-ABL by PCR, Sokal risk at diagnosis, and 
BCR-ABL transcript levels measured by digital PCR. 
2. Develop a risk scoring system to predict the patient’s risk of molecular recurrence after 
stopping TKI  
3. Assess whether specific time points are more important for clinical prediction of recurrence 
and develop an optimal follow up schedule. 
4. Describe the patient-reported health status of patients after resuming TKIs in patients who 
restart TKIs. 
Overview of Study Design 
This is a non-randomized, prospective, single-group longitudinal study. The overall objective is to 
improve decision making for TKI discontinuation in eligible CML patients. Patients with CML on 
treatment with imatinib, dasatinib, nilotinib, or bosutinib and in confirmed deep molecular response 
will stop their TKI. Confirmed deep molecular response is defined as BCR-ABL < 0.01% (>MR4 i.e. > 
4 log reduction) for at least 2 years. The study will closely monitor patients using standard RQ-PCR 
testing for molecular recurrence, testing them monthly for 6 months, then every other month until 24 
months, and then quarterly until 36 months. Concurrently, the study will assess a wide range of 
patient reported outcomes (PROs) before stopping TKIs and after discontinuation in conjunction with 
PCR testing, though at fewer time points. Patients who have molecular CML recurrence based on 


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RQ-PCR will restart imatinib, dasatinib, nilotinib, or bosutinib and will continue to be monitored for 
disease status and patient-reported health status until the end of the study. 
  
Study population:  
 Inclusion Criteria:  
1. Age 18 or older at time of study entry 
2. Willing and able to give informed consent 
3. Diagnosed with CML in chronic phase and have either the b3a2 (e14a2) or b2a2 (e13a2) 
variants that give rise to the p210 BCR-ABL protein  
4. Currently taking imatinib, dasatinib, nilotinib or bosutinib 
5. Patient has been on TKI therapy for at least 3 years 
6. Documented BCR-ABL <0.01% (>MR4 i.e. >4 log reduction) or undetectable BCR-ABL by 
PCR for at least 2 years according to the patient’s local lab 
7. Documented BCR-ABL <0.01% (>MR4 i.e. >4 log reduction) or undetectable BCR-ABL at 
least 3 times prior to screening according to the patient’s local lab 
8. Two (2) Screening PCRs have been completed and both results are < 0.01% (>MR4 i.e > 4 
log reduction) by central lab 
9. Has been on any number of TKIs, but has not been resistant to any TKI (changes made for 
intolerance are allowed)  
10. Patient has been compliant with therapy per treating physician 
 
Exclusion Criteria: 
1. Prior hematopoietic stem cell transplantation 
2. Poor compliance with taking TKI  
3. Unable to comply with lab appointments schedule and PRO assessments 
4. Life expectancy less than 36 months 
5. Patients who have been resistant to previous TKI therapy are not eligible 
6. Pregnant or lactating women 
 
Duration of Study: 60 months 
 
 
 
 
 
 
 


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Table of Contents 
 
The Life After Stopping Tyrosine Kinase Inhibitors Study .................................................................................. 1 
Schedule of Trial Procedures ................................................................................................................................................ 9 
Schema ............................................................................................................................................................................................... 11 
List of Abbreviations and Glossary of Terms .................................................................................................................... 12 
Protocol Summary ...................................................................................................................................................................... 13 
1. 
Background and Study Rationale ............................................................................................................................ 17 
1.1 
Background .................................................................................................................................................... 17 
1.2 
Chronic myeloid leukemia is treatable with TKIs ........................................................................... 17 
1.3 
Financial impact of TKI therapy ............................................................................................................. 18 
1.4 
TKIs are associated with reduced quality of life ............................................................................. 18 
1.5 
Some patients may not need to continue taking TKIs forever ................................................. 18 
2. 
Study Objectives ................................................................................................................................................................ 21 
3. 
Study Design ........................................................................................................................................................................ 21 
4. 
Study Population ................................................................................................................................................................ 22 
5. 
Procedures............................................................................................................................................................................. 23 
5.1 
Recruitment Sites and Feasibility ......................................................................................................... 23 
5.2 
Screening, registration and enrollment: ............................................................................................ 23 
5.2.1 
Pre-Screening ................................................................................................................................................... 23 
5.2.2 
Screening and Registration ........................................................................................................................ 23 
5.2.3 
Enrollment ........................................................................................................................................................... 24 
5.3 
Monitoring phase ......................................................................................................................................... 24 
5.3.1 
Assessment of BCR-ABL ............................................................................................................................ 24 
5.3.1.1     Assessment of BCR-ABL for GeneXpert Validation ....................................................................... 25 
5.3.2 
Assessment of PROs .................................................................................................................................... 25 
5.4 
Patient Retention and Prevention of Missing Data ........................................................................ 26 
5.5 
Follow up and end of study ..................................................................................................................... 26 
6. 
Measures ................................................................................................................................................................................. 26 
6.1 
Measurement of BCR-ABL ....................................................................................................................... 26 
6.2 
Measurement of PROs ............................................................................................................................... 27 
7. 
Statistical Analysis ........................................................................................................................................................... 27 
7.1 
Data Management and Analyses ........................................................................................................... 27 
7.2 
Analysis for predicting recurrence in patients with CML who discontinue TKIs ............. 27 


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7.3 
Analysis for patient-reported health status ...................................................................................... 28 
7.4 
Managing Missing PRO Data ................................................................................................................... 29 
7.5 
Required Sample Size ................................................................................................................................ 29 
8. 
Study Organization and Administration .............................................................................................................. 31 
8.1 
Multi-Site Management ........................................................................................................ 31 
8.2 
Site Activation ...................................................................................................................... 32 
8.3 
Ongoing Study Management: ............................................................................................. 32 
8.4 
Ongoing Communication with Participating Institution Research Staff ......................... 33 
8.5 
Trial Monitoring/Quality Assurance ................................................................................... 33 
8.5.1 
Trial Monitoring ................................................................................................................................................. 33 
8.5.2 
Quality Assurance ........................................................................................................................................... 33 
9. 
Regulatory .............................................................................................................................................................................. 33 
9.1 
Informed Consent ........................................................................................................................................ 33 
9.2 
Institutional Review ..................................................................................................................................... 34 
10. Adverse Events/Serious Adverse Events Reporting Guidelines ................................................................... 34 
10.1 Adverse Events ............................................................................................................................................. 34 
10.1.1 
Definition .............................................................................................................................................................. 34 
10.1.2 
Reporting ............................................................................................................................................................. 34 
10.2 Serious Adverse Events ............................................................................................................................ 34 
10.2.1 
Definition .............................................................................................................................................................. 34 
10.2.2 
Procedures for Reporting Serious Adverse Events ........................................................................ 35 
11. Data and Safety Monitoring ............................................................................................................................................. 35 
11.1 Study Enrollment Hold Criteria .............................................................................................................. 35 
12. References ............................................................................................................................................................................. 37 
13. Appendices ............................................................................................................................................................................ 41 
Appendix 1: PRO Measurement ........................................................................................................................ 42 
Appendix 2: Specimen Collection & Handling ............................................................................................ 59 
     Appendix 3:  ECOG Status 
 
 
 
 
 
 
 
 
   
      61 
Appendix 4: Sokal risk score (42) ..................................................................................................................... 62 
Appendix 5: Local Lab Draw  and PRO Permission Request Form ................................................... 63 
Appendix 6: GeneXpert Validation tests ........................................................................................................ 64 
 
 
 


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1. Background and Study Rationale 
1.1 
Background 
Tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid 
leukemia (CML), leading to an unforeseen increase in prevalence. Current recommendations are to continue 
therapy indefinitely, sometimes despite significant side effects. Moreover, the costs of TKI therapy are 
substantial and place a financial burden on the US health care system. Small, single-armed studies from 
Europe and Australia suggest that some patients with CML in a TKI-induced complete molecular response (MR 
4.5) maintain this response after discontinuation of TKIs. Given uncertainty about the patient characteristics 
associated with maintenance of MR 4.5 versus recurrence of active leukemia, patients and physicians have 
little basis on which to make the decision to discontinue TKI therapy. Furthermore the impact of discontinuation 
on patients’ experiences of symptoms and the factors driving a patient’s choice about discontinuation have not 
been studied. The Life After Stopping Tyrosine Kinase Inhibitors (LAST) Study will provide answers to these 
practical questions in a comprehensive, outcome-based approach, thereby generating a rational basis for 
decision making. With annual costs of $100,000 per patient (1), an estimated prevalence of 70,000 patients in 
2010 (2), and with an estimated 36% of patients in stable MR 4.5 (3), a discontinuation rate of 50% could lead 
to savings of over $500 million to the US health care system in the first year, even with increased monitoring 
costs and a 50% recurrence rate. Prevalence of CML continues to rise – 180,000 patients are expected by 
2050 (2) – increasing the public health relevance of this important issue. 
 
1.2 
Chronic myeloid leukemia is treatable with TKIs 
CML is caused by the BCR-ABL tyrosine kinase, the product of the t(9;22) translocation visible as the 
Philadelphia chromosome (Ph). This fusion gene confers a proliferative advantage to the cells acquiring this 
translocation. Prior to the introduction of imatinib (Gleevec®) in 2001, the only cure for CML was hematopoetic 
stem cell transplantation, and the median survival of all patients was 4-5 years (4). Since the introduction of 
imatinib, about 87% of patients are expected to be alive at 8 years of follow up (5). Several other TKIs were 
subsequently developed and FDA-approved for the treatment of CML patients, including nilotinib (6) and 
dasatinib (7). As first line therapies, these have been compared head-to-head with imatinib in two phase 3 
studies and found to induce faster cytogenetic and molecular responses than imatinib, although it is not known 
whether this translates into improved long-term survival (8, 9). Response to TKIs usually proceeds in an 
orderly fashion: first normalization of blood counts and spleen size, followed by the disappearance of Ph-
positive metaphases (complete cytogenetic response). Deeper responses at the molecular level are measured 
by reductions of the BCR-ABL transcripts in the blood or marrow to very low or undetectable levels using real-
time quantitative polymerase chain reaction (RQ-PCR) (10, 11). Molecular response (MR) is reported as % 
BCR-ABL/control gene, with ABL1 being the most commonly used control gene. For BCR-ABL to be 
considered undetectable, adequate amplification of a quality control gene is needed to ensure that the 


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measurement is sufficiently sensitive. MR 3.0 is a 3.0 log reduction in BCR-ABL transcripts and is equivalent to 
BCR-ABL ≤ 0.1%. MR 4.0 is BCR-ABL ≤0.01%, MR 4.5 is BCR-ABL ≤0.0032%, and MR 5.0 is BCR-ABL 
≤0.001%.  
 
1.3 
Financial impact of TKI therapy 
This study has the potential to reduce national expenditures associated with treatment with TKIs. In early 2013, 
over 100 experts in CML, including many of the co-investigators on this study, called for a reduction in the 
prices of TKIs to allow greater access to the drugs for more patients and to “maintain sound long-term 
healthcare policies” in light of the $2.7 trillion spent on health care in the U.S. in 2011(1). As outlined above, 
savings could top half a billion dollars in the U.S. if half of eligible CML patients discontinued TKIs, even after 
accounting for recurrence and increased costs of monitoring for patients off therapy. Moreover, the cost 
savings to patients themselves should not be underestimated. Most patients in the U.S. pay at least some of 
their medications costs out of pocket; some pay a very large proportion of those costs out of pocket. 
 
 
1.4 
TKIs are associated with reduced quality of life 
Imatinib was a significant improvement over previous CML treatments in terms of survival and toxicity (12, 13). 
Even so, imatinib and other TKIs are associated with diminished patient-reported health status due to multiple 
side effects of the treatment. While there are relatively few (<10) studies on health status outcomes, patients 
consistently report increased fatigue and depression, difficulties with sleep, and high symptom burden 
particularly nausea, diarrhea, pain, fluid retention (puffy face), and skin problems (14), especially as compared 
to peers without cancer (15). Of particular concern is that patients and physicians may not value health-related 
quality of life in the same way, further limiting which data are collected in research studies and thus our 
understanding of the patient’s experience. A European study found that while both patients and physicians 
ranked fatigue as their first concern, other symptoms and concerns were ranked quite differently (16). The 
issues ranked substantially higher by patients were mostly symptoms – dry mouth, trouble concentrating or 
remembering, frequent urination, skin problems, and drowsiness, whereas the issues ranked substantially 
higher by physicians were psychosocial concerns such as interference with daily activities or worry about the 
treatment schedule. Furthermore, deleterious side effects have been recognized only with longer follow-up, for 
example, pulmonary hypertension in patients on dasatinib (17) and peripheral arterial occlusive disease in 
patients on nilotinib (18). These and other side effects are thought to be related to the inhibition of kinases 
other than the BCR-ABL kinase (19).  
 
1.5 
Some patients may not need to continue taking TKIs forever 
Current guidelines for the treatment of CML recommend continuation of treatment with TKIs as long as patients 
are responding and tolerating the drug (20, 21). The French STIM trial (Stop Imatinib) stopped imatinib in 100 
patients who had sustained MR5 for at least 2 years and monitored them closely (22). Patients who had 


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molecular recurrence restarted imatinib therapy. Molecular recurrence was defined as loss of MR5 confirmed 
by a second rising level. With a median follow up of 50 months, 39 patients had maintained their molecular 
remission and 61 patients had molecular recurrence. Of those 61 patients, all responded to TKI rechallenge; 
no patient experienced disease progression or died from their disease (22). Similar results have been shown in 
five other small, non-US studies (23-27). These studies have varied with regard to sample size, definition of 
recurrence, and TKI therapy before discontinuation. In the TWISTER study conducted in Australia (24), 40 
patients with sustained CMR stopped imatinib and were monitored frequently. Treatment was restarted at loss 
of MMR or two consecutive samples at any level. With a median follow up of 42 months, 18 (45%) of patients 
had not met the study definition of relapse. In all patients who relapsed, the first sample which tested positive 
was at a level below loss of MMR. Eight patients lost MMR prior to starting therapy. Of note 5 of the 18 patients 
who did not meet the pre-specified definition of relapse had detectable levels of BCR-ABL in the blood on one 
or two occasions, but have not relapsed. All patients who restarted imatinib responded, with all patients having 
at least one undetectable PCR measurement. No patients progressed to accelerated phase or blast crisis and 
no patients relapsed. Based on the observation that some patients have a low level detectable disease but 
have no evidence of disease progression, the A-STIM trial (According to Stop Imatinib) was designed where 
patients restart TKI therapy at loss of MMR and not when there was detectable disease.  In the A-STIM trial 
patients with chronic phase CML who had been in CMR and/or had weakly positive samples prior to enrollment 
were eligible (23). In that study, 80 patients were enrolled and stopped their TKI. The median duration of CMR 
prior to study enrollment was 41 months, and 52% had unstable CMR. With a median follow up of 31 months, 
29 patients (36%) lost MMR. Of the patients who lost MMR, only 4 patients lost MMR after 6 months and only 
one patient lost MMR after 12 months. Overall, 45 patients (51%) lost CMR according to the STIM criteria. Of 
those, 29 lost MMR for a cumulative incidence of 65% at 24 months for loss of MMR in patients with loss of 
CMR. Treatment was resumed in 29 patients after loss of MMR and in 2 patients after loss of CMR. With a 
median follow up of 17 months after treatment restart, 23 patients regained CMR and 8 patients are in MMR. 
One patient progressed to lymphoid blast crisis. That patient had a long history of CML, was treated with 
interferon for 4 years, then stopped therapy for intolerance. Seven years later she was started on imatinib, and 
three years later, imatinib was stopped. CMR was lost 9 months later and MMR was lost one month after. She 
was started on imatinib and regained CMR, but 8 months later developed lymphoid blast crisis. The authors of 
the study do not think this was attributed to the design of the study as she lost both CMR and MMR at the 
same time. In addition, this is consistent with previous data of patients who develop sudden blast crisis while 
on imatinib(28).  In the KIDS study (Korean imatinib discontinuation study), 78 patients with CML who had 
undetectable BCR-ABL by RQ PCR for at least 2 years and had been on imatinib therapy for at least 3 years 
discontinued imatinib. Patients who relapsed (defined as loss of MMR on 2 consecutive assessments) 
resumed TKI. With a median follow up of 14 months, 13 patients lost MMR at 12 months. Of those, 9 restarted 
imatinib therapy and achieved CMR at a median of 7.5 months. Interestingly none of the patients who had prior 
HCT relapsed. None of the patients progressed to accelerated phase or blast crisis. In the study by Rea et al, 


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patients on second generation TKIs (2G-TKI) i.e. dasatinib and nilotinib were enrolled on the study and 
stopped TKI therapy. Of the 34 patients who had at least 6 months of follow up, 25 patients (74%) received 
2G-TKI upfront or for intolerance and 9 (26%) received 2G-TKI due to suboptimal response/resistance to 
imatinib. The probability of stable MMR was 67% vs 33% for patients who were on 2G-TKI upfront/intolerance 
vs. suboptimal response/resistance respectively. None of the patients progressed to accelerated phase or blast 
crisis. More recently, the Euro-SKI study interim analysis results were presented(29). In that study, patients 
with CML and sustained deep molecular response defined as BCR-ABL <0.01% (MR4 )  for at least one year 
were enrolled in the study. The planned interim analysis of the first 200 patients completing 6 months of follow 
up was presented. Both duration of CML therapy and duration of deep molecular response were associated 
with prognostic significance. However, there was no prognostic significance for depth of response at 
discontinuation when comparing patients at MR4 vs MR4.5 vs. MR5. Based on this data, this protocol will include 
patients in confirmed deep molecular response defined as BCR-ABL <0.01% (MR4 i.e. > 4 log reduction).  
Taken together, these results are compelling, but the evidence base is not sufficient for a large-scale change in 
the standard of care for CML patients in the US. Indeed, CML experts recommend that discontinuation be 
performed on clinical trials only (22, 30, 31). 
 
Table (1) Previously reported stopping TKI studies 
 
 
# 
TKI 
Prior 
IFN 
N (%) 
Median 
F/U 
(months) 
Definition of 
Relapse 
Relapse 
N (%) 
Relapse 
in first 6 
months N 
(%) 
Latest 
relapse 
(months) 
STIM1(22) 
100 
I 
51 (51) 
50 
detectable BCR-
ABL on 2 
consecutive tests 
with at least 1 log 
increase between 
the 2 or loss of 
MMR once 
61 (61) 
58 (95)¥ 
22 
STIM2(27)* 
124 
I 
0 
12 
48 (39) 
45 (94) 
12 
TWISTER(24) 40 
I 
21 (52) 
42 
detectable BCR-
ABL on 2 
consecutive tests 
at any level or loss 
of MMR once 
22 (52) 
15 (68) 
27 
KIDS(26)**^ 
78 
I 
NR 
14 
loss of MMR on 2 
consecutive tests 
 16 (21) 
NR 
NR 
A-STIM(23)^ 
80 
I 
40 (52) 
31 
Loss of MMR 
once 
29 (36) 
25 (31) 
17  
2G-TKI(25)^ 
34 
D or N 
25 (74) 
14 
Loss of MMR 
once 
15 (44) 
NR 
29 
*No prior therapy with IFN, **21 patients had prior HCT, ^Restarting with loss of MMR only, ¥ 7 months, NR: 
Not reported, I: imatinib, D: dasatinib, N: nilotinib, NR: Not reported, MMR: Major molecular response, F/U: 
Follow up, 2G-TKI: Second generation TKI, IFN: Interferon 


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2. Study Objectives 
Primary Objectives: 
1. Proportion of patients with CML who develop molecular recurrence after discontinuing tyrosine kinase 
inhibitors (TKIs). Molecular recurrence defined as loss of MMR (> 0.1% BCR-ABLIS) 
2. Compare the patient-reported health status of patients before and after stopping TKIs.  
Secondary Objectives: 
1. To prospectively determine whether there are disease, patient-related, or treatment-related factors that 
predict molecular recurrence including sex, age, type of TKI, time to undetectable BCR-ABL by PCR, 
duration undetectable BCR-ABL by PCR, Sokal risk at diagnosis, and BCR-ABL transcript levels 
measured by digital PCR. 
2. Develop a risk scoring system to predict the patient’s risk of molecular recurrence after stopping TKI  
3. Assess whether specific time points are more important for clinical prediction of recurrence and develop 
an optimal follow up schedule. 
4. Describe the patient-reported health status of patients after resuming TKIs in patients who restart TKIs. 
 
3. Study Design 
This is a non-randomized, prospective, single-group longitudinal study. The overall objective is to improve 
decision making for TKI discontinuation in eligible CML patients. Patients with CML on treatment with imatinib, 
dasatinib, nilotinib, or bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed 
deep molecular response is defined as BCR-ABL < 0.01%, (> MR4 i.e. > 4 log reduction) for at least 2 years. 
The study will closely monitor patients using standard RQ-PCR testing for molecular recurrence, testing them 
monthly for 6 months, then every other month until 24 months, and then quarterly until 36 months. 
Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in 
conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. 
Patients who have molecular CML recurrence based on RQ-PCR will restart imatinib, dasatinib, nilotinib, or 
bosutinib and will continue to be monitored for disease status and health status until the end of the study.  
 
Number of Patients: 173 patients 
 
Duration of Study: 60 months 
Number of sites: 14 sites and 2 affiliate sites, all in the US 
 
 
 
 
 
 
 
 


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4. Study Population  
Inclusion Criteria:  
1. Age 18 or older at time of study entry 
2. Willing and able to give informed consent 
3. Diagnosed with CML in chronic phase and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that 
give rise to the p210 BCR-ABL protein  
4. Currently taking imatinib, dasatinib, nilotinib or bosutinib 
5. Patient has been on TKI therapy for at least 3 years 
6. Documented BCR-ABL <0.01% (>MR4 i.e. >4 log reduction) or undetectable BCR-ABL by PCR for at 
least 2 years according to the patient’s local lab 
7. Documented BCR-ABL <0.01% (>MR4 i.e. >4 log reduction) or undetectable BCR-ABL  at least 3 times 
prior to screening according to the patient’s local lab 
8. Two (2) Screening PCRs have been completed and both results are < 0.01% (>MR4 i.e > 4 log 
reduction) by central lab 
9. Has been on any number of TKIs, but has not been resistant to any TKI (changes made for intolerance 
are allowed)  
10. Patient has been compliant with therapy per treating physician 
 
Exclusion Criteria: 
1. Prior hematopoietic stem cell transplantation 
2. Poor compliance with taking TKI  
3. Unable to comply with lab appointments schedule and PRO assessments 
4. Life expectancy less than 36 months 
5. Patients who have been resistant to previous TKI therapy are not eligible 
6. Pregnant or lactating women 
 
 
 
 
 
 
 
 
 
 


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5. Procedures 
5.1 
Recruitment Sites and Feasibility 
To achieve a geographically diverse sample and reach our needed sample size, 14 sites and 2 affiliate sites 
are included for recruitment as outlined in Table 2.  
 
Table 2. Recruitment Sites and Locations 
Site 
Location 
Medical College of Wisconsin Cancer Center 
Milwaukee, WI 
University of Chicago Comprehensive Cancer Center 
Affiliate Site: University of Chicago at Silver Cross 
Chicago, IL 
New Lenox, IL 
Huntsman Cancer Institute at University of Utah 
Salt Lake City, UT 
Dana-Farber Cancer Institute 
Affiliate Site: Dana-Farber Beth Israel 
Boston, MA 
Boston, MA 
Winship Cancer Institute of Emory University 
Atlanta, GA 
Karmanos Cancer Institute of Wayne State University 
Detroit, MI 
Duke University Cancer Institute 
Durham, NC 
Fred Hutchinson Cancer Research Center & Seattle Cancer Care Alliance 
Seattle, WA 
Memorial Sloan Kettering Cancer Center 
New York, NY 
Moffitt Cancer Center 
Tampa, FL 
Weill Medical College of Cornell University 
New York, NY 
UCSF Helen Diller Family Comprehensive Cancer Center 
San Francisco, CA 
The University of Texas MD Anderson Cancer Center 
Houston, TX 
Roswell Park Cancer Institute 
Buffalo, NY 
 
5.2 
Screening, registration and enrollment:  
5.2.1 Pre-Screening 
A log of all potential patients will be kept by each site, including individuals who decide not to participate in or 
who are found to be ineligible for the study.  
5.2.2 Screening and Registration 
Screening will be performed for potential study patients after they have consented to trial participation.  If a 
patient is screened - regardless of whether or not they are registered to the study – their details should be 
entered into the MCW Oncore CTMS.  Patients will receive a screening ID that will be used to identify the 
patient throughout the study. At this time patients will be considered registered on the study.  
 


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Documentation of both the informed consent process and that the process occurred prior to a subject’s entry 
into this study is recorded in the subject’s source documents. The original consent form, signed and dated by 
the subject and by the person consenting the subject prior to the subject’s entry into the study, must be 
maintained in the investigator’s study files at each participating institution. 
 
Patients in screening will be assessed by the PCR Core Lab twice, at least 21 days apart, to confirm that the 
BCR-ABL is < 0.01% (>MR4 i.e. > 4 log reduction). Concurrently; patients will take the PRO questionnaires 
described in Appendix 1 to record their baseline health status.  
 
Participating Sites will upload all de-identified source documents with patient study IDs confirming patient 
eligibility into Oncore CTMS. The coordinating center will review all documents and confirm eligibility. 
5.2.3 Enrollment 
Patients will be considered enrolled in the study once the coordinating site has confirmed that all screening 
eligibility criteria have been met; then the TKI will be stopped within 7 days of enrollment. 
 
5.3 
Monitoring phase 
After patients are enrolled and stop their TKI, the monitoring phase starts. Patients will have both BCR-ABL 
assessments and PRO assessments as clarified below (sections 5.3.1 and 5.3.2). The monitoring phase will 
last for 3 years.  
 
Patients’ study participation may be terminated for any of the following reasons: 
• 
Death 
• 
Medically significant event  
• 
Physician discretion 
• 
Withdrawal of consent 
• 
Patient non-compliance with study procedures 
• 
Patient is lost to follow up 
5.3.1 Assessment of BCR-ABL  
Enrolled patients will have blood draws for RQ-PCR at their local study site laboratory every month for the first 
6 months, every 2 months for the next 18 months (until 24 months), and every 3 months for the third year. 
Patients may be able to get some labs drawn closer to their home. Site will need to complete Appendix 5 if 
they want permission to send patients to a lab closer to home. Sites local IRB should be consulted as well to 
determine local IRB reporting requirements.  All samples will be shipped to the PCR Core Lab. Specimen 
Collection and Handling instructions are detailed in Appendix 2. The PCR Core Lab will perform RQ-PCR and 
digital testing of peripheral blood. Digital PCR will be used for research questions only, with results available to 


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clinicians only upon conclusion of the study. Thus therapy decisions will be made based on RQ-PCR only, per 
existing treatment guidelines. During the monitoring phase, if BCR-ABL ≥0.01% for the first time, then PCR 
testing would be repeated monthly for 3 months. If BCR-ABL ≥0.1% (loss of MMR) restart TKI. If no loss of 
MMR then resume regular schedule of PCR evaluations. i.e. if patient is in first 6 months of study check RQ-
PCR monthly, if in month 7-24 then check RQ-PCR q 2 months, if in third year then check RQ-PCR q 3 
months. If BCR-ABL ≥0.1% at any time point, patients will restart TKI therapy. For patients who restart TKI 
therapy, RQ-PCR will be performed at the central lab approximately every 3 months from the date of restarting 
their TKI, for a total of 3 years from enrollment or until BCR-ABL is < 0.01% twice, whichever comes first. All 
PCR Core Lab results will be entered into Oncore CTMS to facilitate secure sharing of data with the 
Coordinating Center. Following that, BCR-ABL results will be collected locally approximately every 3 months 
for the duration of the study.  These local Lab results will be entered into Oncore CTMS to facilitate secure 
sharing of data with the Coordinating Center.  It may be expected that patients who had been tolerating their 
previous TKI will resume that drug, but the study will not restrict them from starting a different TKI; this decision 
will be left to the patient and his or her physician.  
5.3.1.1  Assessment of BCR-ABL for GeneXpert Validation  
Enrolled patients will have blood draws for their RQ-PCR and Digital PCR that will be shipped to the PCR Core 
Lab at the time points described in sections 5.3.1.  Aliquots of these samples will be taken by the PCR Core 
Lab for GeneXpert Validation tests.  Please see appendix 6 for validation test information. 
5.3.2 Assessment of PROs 
Baseline assessment of on-therapy PROs will be collected twice before enrollment during screening then for 
the duration of the study, at months 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 30, and 36. Because side effects associated 
with TKIs are expected to diminish in 1-3 months after discontinuation, PRO data will be collected more 
frequently in the first 6 months of the study. Prior to each scheduled visit, an MCW study coordinator will email 
the local study coordinator with a link to access a secure platform hosted by MCW using the REDCap platform. 
For all patients PRO assessments will primarily be administered at the time of blood draws. Ideally, the site 
coordinator would meet with the patient at the time of blood draws and administer the survey on an electronic 
tablet provided by the study (though the assessment can also be completed in other ways if necessary, see 
section 5.4. on Prevention of Missing Data).  
 
For patients who restart their TKI, PRO data will be collected approximately every 3 months for the first 12 
months after restarting and then approximately every 6 months until end of study, ideally in conjunction with 
the PCR blood draws. No protocol deviations need be filed if at least 4 PRO assessments are collected within 
the first 18 months after TKI restart date. Note that PRO assessments must be collected at least 1 month 
apart. 
  


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5.4 
Patient Retention and Prevention of Missing Data 
For participants who do not complete their PRO assessment at the clinic, the local site coordinator will either 1) 
email the REDCap link to the participant to complete the assessment online at home, 2) access the 
assessment in REDCap and read them to the participant over the phone, reporting the participant’s responses 
directly into the online system, or 3) give the participant a paper version of the assessment and then upload the 
completed assessment to OnCore.  
Every effort will be made to limit study drop out over the 3-year study follow-up. It is expected that patients will 
want to remain in the study because otherwise they will not have access to the same increased frequency of 
monitoring. A MCW project coordinator will monitor the collection of biologic data through OnCore in 
collaboration with the PCR Core Lab to make sure that expected data is being delivered. A MCW project 
coordinator will monitor the PRO data collection through REDCap, so that local study coordinators can follow 
up with patients in real time each week if they have missed assessments. If patients have missed more than 
two assessments of either type (PCR test or PRO assessment), the site PI might be contacted to recruit their 
assistance in following-up with the participant.  
5.5 
Follow up and end of study 
After completion of the monitoring phase, patients will be followed for survival every 6 months and for 
transformation to accelerated phase or blast crisis.  The RQ-PCRs will be performed by the patient’s physician 
according to standard of care.  
 
6. Measures 
6.1 
Measurement of BCR-ABL 
The Core Lab will use standard molecular RQ-PCR monitoring in all patients on the IS scale. All samples with 
undetectable BCR-ABL will also be examined using digital PCR, which is a more sensitive nanofluidic PCR 
system (Fluidigm Corporation, South San Francisco, CA) with an increased sensitivity of > 2 log beyond the 
standard PCR assay [26, 27]. Digital PCR will follow the same schedule as RQ-PCR monitoring unless CML 
recurs, then only RQ-PCR testing will be used henceforth. In the digital assay, detection sensitivity is 
augmented by sample partitioning prior to PCR, such that multiple PCR reactions are performed 
simultaneously in hundreds of replicates. For example, if a mixture containing 1 molecule of BCR-ABL within 
100,000 molecules of control gene is partitioned into 1,000 independent chambers, the chamber containing the 
single BCR-ABL molecule now only contains ~100 molecules of control gene. This 1,000-fold increase in 
relative concentration theoretically allows for a 1,000-fold improvement in the detection sensitivity of PCR 
reactions, thereby facilitating rare copy detection in patient samples. Digital PCR uses the Poisson distribution 
to calculate BCR-ABL and ABL1 control gene transcript levels.  
 
 


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6.2 
Measurement of PROs 
The PROMIS measurement system will be used for self-reported health status. PROMIS is the NIH’s initiative 
to standardize measurement of PROs in clinical research across all chronic conditions. Where PROMIS 
measures are not available to assess CML-specific symptoms, the EORTC QLQ-CML Symptom Burden scale, 
which covers abdominal pain, dry mouth, skin problems, headaches, joint pain or swelling, eye problems, etc 
will be used (32). The full battery of items is expected to take fewer than 25 minutes to complete based on our 
past experience with these measures. The content of the PROs is provided in Appendix 1; specific wording 
changes may be made in response to feedback from the Patient Advisory Panel. In a longer baseline 
assessment (~30 minutes) sociodemographic characteristics will be collected as well as monthly out of pocket 
expenses for TKIs. In the 3-month assessment, additional questions about medications will be asked. 
 
7. Statistical Analysis  
7.1 
Data Management and Analyses  
All data will be stored securely at the Coordinating Center. Personal health information will be kept separately 
and only key personnel will have access to the identifiers linking clinical and personal data. All variable 
distributions will be reviewed before commencing analysis to identify problematic values. A 2-tailed significance 
level of α=0.05 will be used for all assessments. Statistical analyses will be conducted using SAS 9.3 (SAS 
Institute, Inc). 
 
7.2 
Analysis for predicting recurrence in patients with CML who discontinue TKIs 
In terms of primary objective 1, the clinical outcomes to be examined in this study include the primary event 
of CML molecular recurrence (opposite relapse-free survival [RFS]) and death in complete remission (DCR). 
For the univariate analysis the probabilities of RFS will be calculated using the Kaplan-Meier estimator. 
Probabilities of molecular recurrence and DCR will be generated using cumulative incidence estimates to 
account for competing risks. For secondary objective 1, Cox proportional hazards model(33) and Fine and 
Gray’s subdistribution hazards model (34) and Fine and Gray’s subdistribution hazards model [32] will be used 
to determine the effect of clinical characteristics on RFS and CML recurrence after TKI discontinuation, 
respectively. The baseline clinical risk factors that will be considered in regression analyses include sex, age, 
type of TKI, time to undetectable BCR-ABL by RQ-PCR, duration with undetectable BCR-ABL by RQ-PCR, 
Sokal Risk at diagnosis (see appendix 4), and BCR-ABL transcript levels measured by digital PCR. The 
following analysis plan will be implemented. First, for the continuous variables, including time to undetectable 
BCR-ABL by RQ-PCR, a martingale residual plot will be applied to evaluate the potential threshold cut point(s) 
for the effect on RFS and the maximum partial likelihood method will be used to identify optimal cut point(s). 
Second, univariate probability of RFS, molecular relapse, and DCR with 95% confidence interval (CI) will be 
computed by each clinical risk factor. Third, a Cox regression model building procedure will be used to identity 


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significant risk factors associated with molecular recurrence. The assumption of proportional hazards for each 
factor in the Cox model will be tested using time-dependent covariates. When the test indicates differential 
effects over time (non-proportional hazards), models will be constructed breaking the post-stopping TKI time 
course into two periods, using the maximized partial likelihood method to find the most appropriate breaking 
time point. Following this, the proportionality assumptions will be tested again. Factors that are significant at a 
5% level will be kept in the final model. The potential interactions between all significant risk factors will be 
tested. Fourth, in pursuit of secondary objective 2 and based on the final Cox model, a risk scoring system 
will be developed to predict the patient’s risk of molecular recurrence after stopping TKI. A 3-4 level scoring 
system will be considered as appropriate for the data. For secondary objective 3, we will assess whether 
specific time points are more important for clinical prediction of recurrence within this schedule. At each pre-
scheduled follow-up time, we will calculate the recurrence rate and treatment failure rate (recurrence or DCR) 
with its 95% CI.  The log transfer approach (35) to calculate the CI to force the CI to be within proper range (0, 
1) will be used and based on that make recommendations for the optimal follow-up schedule.  
 
7.3 
Analysis for patient-reported health status 
The components of health status will be analyzed separately (that is, depression separate from fatigue 
separate from GI symptoms, etc), since combining them into a summary score can dilute the effects of the 
individual (and not necessarily related) components and thus mask true change. However, this “battery 
approach” to PRO assessment has the drawback of resulting in multiple, individual component scores and 1) 
raises the possibility of obtaining conflicting results of the different components and 2) creates a potential 
multiple comparisons problem for statistical testing. Pre-specifying the major expected relationships and 
corresponding statistical comparisons minimizes such potential problems. 
 
There are two main objectives for the analysis of PRO measures in this study. The first is to describe what 
happens to patients’ health status after stopping TKI therapy. The second is to describe what happens to the 
health status of patients who then resume therapy because of a CML recurrence (e.g., how quickly and 
strongly do side effects of TKI therapy recur). Both objectives will be pursued in the context of a piecewise 
longitudinal mixed-effects model for each of the PRO endpoints. In this model, each patient’s trajectory over 
time is divided into one “piece” for the assessments up to the point of recurrence and a second “piece” for the 
assessments that follow recurrence. A similar piecewise model in the analysis of PRO endpoints for the HF-
ACTION trial was used(36). This modeling approach offers several advantages: the likelihood-based 
estimation means that all available data from each patient are used; correlations within patients over time are 
addressed; any missing data can be considered ignorable conditional upon the observed data; and the 
piecewise feature allows us to efficiently estimate a single model that can answer multiple questions of interest 
(37). Model construction will include graphical and polynomial tests for nonlinear effects of time, as well as 
more general diagnostics for model assumptions.  


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In terms of the primary objective 2, we hypothesize that, following TKI discontinuation, fatigue, depression, 
sleep disturbance, and GI symptoms will improve by at least 3 points each by 6 months post-discontinuation 
(corresponding to the standardized effect size of 0.3 used in our sample size estimation, see Required Sample 
Size section). These hypotheses will be tested by examining the direction and significance of the coefficient for 
the effect of time in the first “piece” of each PRO domain’s model. Trajectories of the remaining PROs will also 
be described, but there are no a priori hypotheses about how they will change. In terms of our secondary 
objective 4, we will examine each PRO domain’s change after patients resume TKI therapy following CML 
recurrence by examining the coefficients corresponding to the intercept shift and temporal slope in the second 
“piece” of the model (following recurrence). Again, we hypothesize worsening in fatigue, depression sleep 
disturbance, and GI symptoms by at least 3 points each by 6 months post-reintroduction. 
Table 3. Power to Detect differences (Δ) Between Groups (n=165) 
 
Ratio/ 
group 
Δ=20
% 
Δ=25
% 
Δ=30
% 
1 : 1  
75 
90 
97 
1 : 1.5 
73 
89 
97 
1 : 2 
70 
87 
96 
Δ=Difference in CML recurrence after discontinuing TKI therapy 
 
7.4 
Managing Missing PRO Data 
Missing PRO data will be avoided through regular monitoring, as described above (See Patient Retention and 
Prevention of Missing Data). Missing data at the item level will be handled using the following approach. If at 
least 50% of the items per domain were answered, then we will adjust the score to ([Raw sum x number of 
items in the domain] / number of items answered). If fewer than 50% of the items in a domain were answered, 
we will treat the domain as missing. We have chosen the longitudinal mixed effects model to allow the 
inclusion of all cases in our analyses, even those with missing values (38).  
 
7.5 
Required Sample Size 
For predicting CML recurrence, sufficient power to detect differences by patient characteristics is needed. With 
173 patients and assuming 5% loss to follow-up (analysis sample of 165) and a 2-tailed significance level of 
α=0.05, will have 90% power to detect a difference of 25% between groups of equal size (1:1 ratio) in relapse-
free survival (RFS) at 18 months. Using nQuery Advisor, a power analysis with multiple scenarios to detect 
differences in RFS based on plausible differences between groups (based on the STIM trial), as outlined in was 
conducted (Table 3). For developing the risk scoring system, a power analysis with multiple scenarios to identify 
3 risk level groups, namely low, intermediate, and high risk for CML recurrence was conducted. We have 99% 


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power to develop a scoring system to stratify patients into low (20% risk for recurrence), intermediate (50% risk 
for recurrence), and high (80% risk for recurrence). Table 4 shows the power associated with various effect sizes 
in CML recurrence rate for groups of equal size (ratio of 1:1:1) as well another plausible ratio (1:2:3).  
 
 
Table 4. Power to Develop a Risk Scoring System (n=165) 
 
Ratio/ 
group 
CML Recurrence 
Risk 
Power 
1 : 1 : 1 
80% / 50% / 20% 
99 
1 : 2 : 3 
80% / 50% / 20% 
99 
1 : 1 : 1 
80% / 60% / 30% 
99 
1 : 2 : 3 
80% / 60% / 30% 
99 
1 : 1 : 1 
70% / 60% / 30% 
84 
1 : 2 : 3 
70% / 60% / 30% 
80 
1 : 1 : 1 
75% / 60% / 45% 
82 
1 : 2 : 3 
75% / 60% / 45% 
73 
 
For the PRO analysis, we need sufficient power to detect the smallest policy-relevant change in health status, 
which we estimate as an effect size of 0.3, i.e., corresponding to about 1/3 of a standard deviation. (PROMIS 
measures are scored on a standardized 0-100-point scale, where 50 corresponds to the average in the general 
U.S. population with a standard deviation of 10.) We conducted a power analysis using a simulation of a 
piecewise linear mixed model in SAS 9.3. We chose a piecewise model to accommodate CML recurrence and 
reintroduction of TKI therapy (see Analysis Plan for Aim 2). Prior to simulation, the sample size was divided by 
an inflation factor to adjust for potential site clustering effects in PROs (39). We estimated a range of effect 
sizes that a fixed sample size could detect, and for each hypothetical effect size, through simulation, we 
generated many (>1200) random sample datasets based on the following assumptions: 13 PRO assessments 
over 3 years, a median time-to-recurrence of 6 months (40), expected improvement in PROs after TKI 
discontinuation and decline in PROs after CML recurrence/reintroduction of TKI therapy, known variance and 
covariance parameters (36), 4 fixed effects (intercept, time before recurrence, recurrence, and time after 
recurrence), and 2 random effects (random intercept and slope prior to recurrence) to allow baseline and 
monthly change to vary by patient (41). For each generated sample, we fit the piecewise mixed model to the 
data, and collected data on rejection of the null hypothesis of no time effect (that is, no difference in PROs over 
time with TKI discontinuation and reintroduction), and 10% missing data per year to account for dropout and 
missed assessments. To estimate the power associated with a given effect size, we computed the proportion 


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of the successful rejection rate. With >90% power, we need 173 patients to detect a change of 0.3. This 
sample size also provides >85% power to detect a smaller effect size of 0.25.  
 
 
8. Study Organization and Administration 
The LAST study will be conducted using the organizational structure outlined in Figure 1. MCW will serve as 
the coordinating center. Drs. Atallah and Flynn at the MCW Coordinating Center will serve as the principal 
investigators. The executive committee will be comprised of Dr. Horowitz, of MCW’s CIBMTR, Dr. Schiffer from 
Wayne State, Dr. Weinfurt, PI of PROMIS at Duke, Dr. Radich, leader of the PCR Core Lab at Fred Hutchinson 
Cancer Research Center, and Dr. Zhang, lead biostatistician. The MCW Coordinating Center will interface with 
the MCW Cancer Center Data Safety Monitoring Committee (DSMC, see section 11.0), the PCR Core Lab, the 
PRO Core, and the 12 individual Sites (see Table 2). The site investigators will participate on the Steering 
Committee, which will review all aspects of the work at the onset to ensure that our activities are responsive to 
the emerging needs of CML physicians. The Steering Committee will meet quarterly via web-mediated 
conference calls for updates on study progress and annually in-person in conjunction with The American 
Society of Hematology meetings. A Patient Advisory Panel will participate in planning and regular calls to 
review study progress and provide feedback on acceptability to patients.  
 
 
 
 
8.1 
Multi-Site Management 
The Multi-Site Research Program is responsible for oversight of regulatory documentation for each 
Participating Institutions.  Documents should be provided to the Multi-Site Research Program either via the 
Oncore CTMS or LASTstudy@mcw.edu.  See address and contact information: 
 
Multi-Site Research Program (Clinical Trials Office) 
Medical College of Wisconsin/Cancer Center  


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9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
E-mail: LASTstudy@mcw.edu  
 
After the MCW IRB grants initial approval, the multi-site program staff provides regulatory documents to the 
Participating Institutions.   The Participating Institution will receive a letter/packet explaining the required 
regulatory documents.  Required regulatory documents will include: initial approval documents, consent forms, 
site initiation forms, amendments, etc.   
 
Each Participating Institution must receive local IRB approval of both the current protocol and consent prior to 
activation of the study at their site. The Participating Institution may make minor changes to the consent form 
to reflect their institutional standards.  No substantial changes, including changes to the risk language, are 
allowed.  Consent forms and regulatory documents will be reviewed by the Multi-Site Research Program staff 
for content. 
 
The local IRB approval notice and consent is forwarded to the Multi-Site Research Program staff.  Once all of 
MCW administrative requirements are completed, the Multi-Site Research Program staff issues an Activation 
Notice for the Participating Institution and subjects can be enrolled in the study. This Activation includes the 
implementation of Oncore CTMS.  Institutional activation documentation will be sent in a formal letter. 
 
8.2 
Site Activation 
Study Coordinators at each Participating Institution will conduct the Study according to the local policies of the 
IRB Approved Protocol. 
 
The Participating Institution will receive an activation notice and subjects can be enrolled in the study. 
Institutional activation documentation will be sent in a formal letter. 
 
8.3 
Ongoing Study Management: 
• The Multi-Site Research Program will use the OnCore CTMS for collection, management and analysis of data 
from the Participating Institutions. Source documents must be uploaded without unique identifiers as specified 
by HIPAA policies. Study documents must include the subject ID number.  
• De-identified source documents that support the following data points are required to be uploaded in the 
OnCore CTMS shortly after obtaining them: 
• 
All eligibility criteria (including the two screening central lab PCR results)  
• 
TKI stop date and TKI restart date  
• 
Local lab results  


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• 
Additional source specifically requested by MCW staff, on a case-by-case basis, to support data 
entry, deviations, or SAEs 
 
8.4 
Ongoing Communication with Participating Institution Research Staff 
The Participating Institution will receive Oncore CTMS training from the MCW Oncore CTMS Administrator.  
The Coordinating Site will conduct monthly conference calls to discuss any ongoing questions or concerns 
regarding the conduct of the study.  
 
8.5 
Trial Monitoring/Quality Assurance  
8.5.1 Trial Monitoring 
The Multi-Site Research Program will be responsible for ongoing oversight, monitoring, source documentation 
confirmation, protocol compliance, adverse events, etc.  The MCW Principal Investigator will have access to 
the study data for all of the patients entered onto this study. Data storage is carried out according to MCW 
Institutional Policy.  
The MCW Principal Investigator will oversee the conduct of the study. 
 
8.5.2 Quality Assurance 
• The study will be reviewed annually by MCW.  
• 10% of subject files will be selected randomly for review (max 10 subjects at each monitoring timepoint). 
• Consent/eligibility and objective based data will be reviewed for those files selected 
• 1 file will be selected randomly for a comprehensive review at each monitoring timepoint. 
After each review a letter/report will be provided to the study staff and the DSMC after each QA review. 
Necessary corrective action or training will be provided to the staff as needed throughout and following each 
QA review.  Directed audits may be requested at any time by the CCCTO QA Staff, DSMC, Research 
Manager, study staff member, or administrative staff.  
 
9. Regulatory 
The following must be observed to comply with Food and Drug Administration regulations for the conduct and 
monitoring of clinical investigations; they also represent sound research practice: 
9.1 
Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations. 


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9.2 
Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
10. 
Adverse Events/Serious Adverse Events Reporting Guidelines 
10.1 
Adverse Events    
  
10.1.1 Definition  
An Adverse Event (AE) is defined as the presence of a new or the worsening of any pre-existing unfavorable 
and unintended symptoms or medical conditions that occur after consent has been obtained.  
10.1.2 Reporting 
Any AE that the treating physician determines is related to the stopping of the TKI will be reported on the AE 
electronic Case Report Forms (eCRF) in Oncore CTMS.  During the screening phase of the protocol all AEs 
will be recorded on the Baseline AE eCRF but will not need to be followed past the stopping point of the TKI.  
Medical conditions that already existed at the time of informed consent will be recorded in the Baseline AE 
eCRF.  AE monitoring should be continued until restarting TKI or study completion.  SAEs should be followed 
until study completion. 
 
AEs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
10.2 
Serious Adverse Events 
10.2.1 Definition 
A Serious Adverse Event (SAE) is any AE that: 
• 
Results in death. 
• 
Is life-threatening  
• 
Hospitalization or prolongation of an existing hospitalization  
• 
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). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event.  An important medical event that jeopardizes the subject or requires 
medical or surgical intervention to prevent one of the outcomes listed above 


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10.2.2 Procedures for Reporting Serious Adverse Events 
Serious adverse events experienced after signing consent should only be reported to the Medical College of 
Wisconsin if the investigator suspects a causal relationship to stopping the patient’s TKI. All deaths, disease 
transformation to accelerated phase, and blast crisis should be reported immediately despite relationship.  
 
A member of the study staff from each site should complete the SAE eCRF within 24 hours of learning of the 
event and email (LASTstudysae@mcw.edu) or fax (414-805-0596) the completed form signed by the site 
investigator to the Medical College of Wisconsin.  
The initial SAE should be followed until resolution and updated in the SAE eCRF.  Follow-up SAE information 
is sent to the same contacts listed above. Each site is responsible for reporting SAEs to their local Institutional 
Review Board per institutional guidelines.  
11. 
Data and Safety Monitoring  
 
The Medical College of Wisconsin Cancer Center Data Safety Monitoring Committee (DSMC) is responsible 
for monitoring data quality and subject safety for all cancer center investigator initiated clinical trials. A 6 to 8-
member Data and Safety Monitoring Committee will complete a review of protocol-specific data safety 
monitoring reports, to provide recommendations on trial continuation, suspension or termination. The DSMC 
will review these reports no less than bi-annually. A summary of the DSMC activities are as follows  
• 
Review the clinical trials for data integrity and safety  
• 
Review all adverse events requiring expedited reporting as defined per protocol  
• 
Review all DSM reports  
• 
Submit a summary of any recommendations related to study conduct  
• 
Terminate the study if deemed unsafe for patients  
11.1 
Study Enrollment Hold Criteria 
 
In the largest study with imatinib in CML patients, the annual rates of progression to accelerated phase (AP) or 
blast crisis (BC) was 1.5, 2.8, 1.6, 0.9, and 0.5% for years 1, 2, 3, 4, and 5 of therapy, respectively. A total of 
173 patients are expected to be enrolled by end of first year of this study, and adverse events of progression to 
AP or BC will be evaluated at the end of each year. As the rate of disease progression to AP and/or BC is 
about 1.2% per each year, the study will be put on hold if ≥ 3, 6, 9, 12, and 15 patients develop disease 
transformation to AP and/or BC at end of year 1, 2, 3, 4, and 5, cumulatively. In the case of a safety event 
suspending the study, a prompt cumulative examination of all data and circumstances of these events will be 
conducted by the Medical College of Wisconsin DSMC to determine whether the study should be resumed, 
whether the protocol will be revised, or whether the study will be discontinued permanently.  


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Each participating site’s IRB will be notified of any event that triggers postponement of enrollment in this study. 
If the study is suspended for safety reasons and it is deemed appropriate by the sponsor to resume the study, 
approval from the relevant IRBs will be obtained prior to resuming the study at each participating institution. 
 
Decisions regarding ongoing study participation of patients on study will be made on a case by case basis after 
discussion with the participating site’s Principal Investigator and Study Principal Investigator.   
 
 


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12. 
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Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, 
Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim D-W, Larson RA, Lipton JH, Mahon F-
X, Martinelli G, Mayer J, Müller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saußele S, 
Schiffer C, Silver R, Simonsson B, Steegmann J-L, Goldman JM, Hehlmann R. European LeukemiaNet 
recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84. doi: 
10.1182/blood-2013-05-501569. 
21. 
www.nccn.org. Available from: http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. 
22. 
Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini FE, Legros L, Charbonnier A, Guerci A, 
Varet BR, Etienne G, Reiffers J, Rousselot P. Long Term Follow-Up After Imatinib Cessation For Patients 
Indeep Molecular Response: The Update Results Of The STIM1 Study. Blood. 2013;122(21):255. 
23. 
Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gardembas M, Etienne 
G, Rea D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers 
J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon FX. Loss of major molecular response as a trigger for 
restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who 
have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5):424-30. doi: 
10.1200/JCO.2012.48.5797. PubMed PMID: 24323036. 
24. 
Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, 
Filshie RJ, Mills AK, Melo JV, White DL, Grigg AP, Hughes TP. Safety and efficacy of imatinib cessation for 


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CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 
2013;122(4):515-22. doi: 10.1182/blood-2013-02-483750. PubMed PMID: 23704092. 
25. 
Rea D, Rousselot P, Guilhot F, Tulliez M, Nicolini FE, Guerci-Bresler A, Legros L, Gardembas M, 
Giraudier S, Guillerm G, Mahon F-X. Discontinuation of Second Generation (2G) Tyrosine Kinase Inhibitors 
(TKI) in Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) Patients with Stable Undetectable BCR-ABL 
Transcripts. ASH Annual Meeting Abstracts. 2012;120(21):916-. 
26. 
Oh Yj, Choi SY, Lee S-E, Kim S-H, Kim H-J, Kim Y-K, Park JS, Jeong SH, Kim S-H, Zang DY, Oh S, 
Koo DH, Kim H, Do YR, Kwak J-Y, Kim J-A, Kim D-Y, Mun Y-C, Lee WS, Chang MH, Park J, Shin H-J, Kim D. 
Results From The Korean Imatinib Discontinuation Study (KIDS): Updated Data With 14-Month Median Follow 
Up. Blood. 2013;122(21):4003. 
27. 
Mahon FX, Nicolini FE, Noël M-P, Escoffre M, Charbonnier A, Rea D, Dubruille V, Varet BR, Legros L, 
Guerci A, Etienne G, Guilhot F, Dulucq S, Rousselot P, Guilhot J. Preliminary Report Of The STIM2 Study: A 
Multicenter Stop Imatinib Trial For Chronic Phase Chronic Myeloid Leukemia De Novo Patients On Imatinib. 
Blood. 2013;122(21):654. 
28. 
Alimena G, Breccia M, Latagliata R, Carmosino I, Russo E, Biondo F, Diverio D, Mancini M, Nanni M, 
Mandelli F. Sudden blast crisis in patients with Philadelphia chromosome-positive chronic myeloid leukemia 
who achieved complete cytogenetic remission after imatinib therapy. Cancer. 2006;107(5):1008-13. doi: 
10.1002/cncr.22046. PubMed PMID: 16878324. 
29. 
Mahon F-X, Richter J, Guilhot J, Muller MC, Dietz C, Porkka K, Hjorth-Hansen H, Gruber F, 
Panagoitidis P, Ossenkoppele GJ, Mayer J, Almeida A, Machova Polakova K, Ehrencrona H, Kairisto V, 
Berger MG, Olsson stromberg U, Mustjoki S, Hochhaus A, Pfirrmann M, Saussele S. Interim Analysis of a Pan 
European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI study2014 2014-
12-06 00:00:00. 151- p. 
30. 
Sweet K, Oehler V. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is 
this a safe option to consider? ASH Education Program Book. 2013;2013(1):184-8. doi: 10.1182/asheducation-
2013.1.184. 
31. 
Mauro MJ. Striving to achieve safe, permanent treatment discontinuation in chronic myeloid leukemia. 
Leukemia Research. 2013;37(11):1395-403. doi: http://dx.doi.org/10.1016/j.leukres.2013.07.029. 
32. 
Efficace F, Baccarani M, Breccia M, Saussele S, Abel G, Caocci G, Guilhot F, Cocks K, Naeem A, 
Sprangers M, Oerlemans S, Chie W, Castagnetti F, Bombaci F, Sharf G, Cardoni A, Noens L, Pallua S, 
Salvucci M, Nicolatou-Galitis O, Rosti G, Mandelli F. International development of an EORTC questionnaire for 
assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24. Qual 
Life Res. 2013. doi: 10.1007/s11136-013-0523-5. PubMed PMID: 24026634. 
33. 
Cox D. Regression models and life tables (with discussion). Journal of Royal Statistical Society. 
1972;B(34):187-220. 
34. 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of 
the American Statistical Association. 1999;94:496-509. 
35. 
Borgan O, Liestol K. A Note on Confidence Intervals and Bands for the Survival Curve Based on 
Transformations. Scandinavian Journal of Statistics. 1990;17:35-41. 
36. 
Flynn KE, Pina IL, Whellan DJ, Lin L, Blumenthal JA, Ellis SJ, Fine LJ, Howlett JG, Keteyian SJ, 
Kitzman DW, Kraus WE, Miller NH, Schulman KA, Spertus JA, O'Connor CM, Weinfurt KP. Effects of exercise 
training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 
2009;301(14):1451-9. Epub 2009/04/09. doi: 301/14/1451 [pii] 
10.1001/jama.2009.457. PubMed PMID: 19351942. 
37. 
Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data: Springer; 2000. 
38. 
Kraemer HC, Thiemann S. A strategy to use soft data effectively in randomized controlled clinical trials. 
J Consult Clin Psychol. 1989;57(1):148-54. Epub 1989/02/01. PubMed PMID: 2925965. 
39. 
Kerry SM, Bland JM. The intracluster correlation coefficient in cluster randomisation. Bmj. 
1998;316(7142):1455. PubMed PMID: 9572764; PMCID: 1113123. 
40. 
Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet 
B, Etienne G, Reiffers J, Rousselot P, Intergroupe Francais des Leucemies Myeloides C. Discontinuation of 
imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at 


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least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. The lancet oncology. 2010;11(11):1029-
35. Epub 2010/10/23. doi: 10.1016/S1470-2045(10)70233-3. PubMed PMID: 20965785. 
41. 
Weinfurt KP, Castel LD, Li Y, Timbie JW, Glendenning GA, Schulman KA. Health-related quality of life 
among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone 
lesions. Medical care. 2004;42(2):164-75. doi: 10.1097/01.mlr.0000108746.69256.45. PubMed PMID: 
14734954. 
42. 
Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD, 
Cervantes F, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 
1984;63(4):789-99. PubMed PMID: 6584184. 
 
 
 


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13. 
Appendices 
 
 
Appendix 1. PRO Measurement 
Appendix 2.  Specimen Collection and Handling 
Appendix 3. ECOG Status 
Appendix 4. Sokal Risk 
Appendix 5.  Local Lab Draw Permission Request Form 
Appendix 6. GeneXpert Validation  
 
 


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Appendix 1: PRO Measurement 
Instruction 
Part of the purpose of this clinical study is to understand your experiences in your everyday 
life. Next we are going to ask you questions about how you are feeling and functioning. We 
will ask you similar questions many times over the course of the 3-year study.  
 
Please answer the questions as best you can, thinking about your daily life in the past 
7 days, not just your experience having CML or taking a tyrosine kinase inhibitor 
(TKI).  
 
If you have any comments about these questions, please provide them in the textbox 
provided at the end of this set of questions. If you would like a response from the 
researchers please email us at LASTstudyPRO@mcw.edu.  
Domain 
Recall Period 
Item Stem 
Response Options 
New Page 
Location 
  
Are you answering this 
questionnaire in the lab or 
clinic, at home or work, or 
somewhere else? 
1=In the lab or clinic 
2=At home or work 
3=Somewhere else, please specify 
[textbox] 
PROMIS 
Global 1 
  
In general, would you say 
your health is… 
5=Excellent 
4=Very good 
3=Good 
2=Fair 
1=Poor 
PROMIS 
Global 2 
  
In general, would you say 
your quality of life is… 
5=Excellent 
4=Very good 
3=Good 
2=Fair 
1=Poor 
New Page 
PROMIS 
Fatigue 
example 
questions 
In the past 7 days… 
I feel fatigued 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days… 
I have trouble starting things 
because I am tired 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days… 
How run-down did you feel 
on average? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days… 
How fatigued were you on 
average? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
New Page 


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Fatigue 
Context 
  
Thinking about your level of 
fatigue in the past 7 days, 
was anything out of the 
ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
PROMIS 
Depression 
example 
questions 
In the past 7 days... 
I felt worthless 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
In the past 7 days... 
I felt helpless 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
In the past 7 days... 
I felt depressed 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
In the past 7 days... 
I felt hopeless 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
New Page 
Depression 
Context 
  
Thinking about your level of 
depression in the past 7 
days, was anything out of 
the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
PROMIS 
Anxiety 
example 
questions 
In the past 7 days... 
I felt fearful 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
In the past 7 days... 
I found it hard to focus on 
anything other than my 
anxiety 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 


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In the past 7 days... 
My worries overwhelmed me 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
In the past 7 days... 
I felt uneasy 
1, Never2, Rarely3, Sometimes4, 
Often5, Always 
New Page 
Anxiety 
Context 
  
Thinking about your level of 
anxiety in the past 7 days, 
was anything out of the 
ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
PROMIS 
Sleep 
Disturbanc
e example 
questions 
In the past 7 days... 
My sleep quality was 
1, Very poor 
2, Poor 
3, Fair 
4, Good 
5, Very good 
In the past 7 days... 
My sleep was refreshing 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
I had a problem with my 
sleep 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
I had difficulty falling asleep 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
New Page 
Sleep 
Disturbanc
e Context 
  
Thinking about your sleep in 
the past 7 days, was 
anything out of the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 


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PROMIS 
Ability to 
Participate 
in Social 
Roles and 
Activities 
example 
questions 
In the past 7 days... 
I have trouble doing all of 
my regular leisure activities 
with others 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
In the past 7 days... 
I have trouble doing all of 
the family activities that I 
want to do 
1, Never2, Rarely3, Sometimes4, 
Usually5, Always 
In the past 7 days... 
I have trouble doing all of 
my usual work (include work 
at home) 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
In the past 7 days... 
I have trouble doing all of 
the activities with friends 
that I want to do 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
New Page 
Ability to 
Participate 
in Social 
Roles and 
Activities 
Context 
  
Thinking about your work, 
family, and social activities 
in the past 7 days, was 
anything out of the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
PROMIS 
Social 
Isolation 
example 
questions 
  
I feel left out 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
  
I feel that people barely 
know me 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
  
I feel isolated from others 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
  
I feel that people are around 
me but not with me 
1, Never 
2, Rarely 
3, Sometimes 
4, Usually 
5, Always 
New Page 


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Social 
Isolation 
Context 
  
Thinking about your level of 
lonliness, was anything out 
of the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
PROMIS 
Physical 
Function 
example 
questions 
  
Are you able to do chores 
such as vacuuming or yard 
work? 
1, Without any difficulty 
2, With a little difficulty 
3, With some difficulty 
4, With much difficulty 
5, Unable to do 
  
Are you able to go up and 
down stairs at a normal 
pace? 
1, Without any difficulty 
2, With a little difficulty 
3, With some difficulty 
4, With much difficulty 
5, Unable to do 
  
Are you able to go for a walk 
of at least 15 minutes? 
1, Without any difficulty 
2, With a little difficulty 
3, With some difficulty 
4, With much difficulty 
5, Unable to do 
  
Are you able to run errands 
and shop? 
1, Without any difficulty 
2, With a little difficulty 
3, With some difficulty 
4, With much difficulty 
5, Unable to do 
New Page 
Physical 
Function 
Context 
  
Thinking about your physical 
abilities, is anything out of 
the ordinary? 
1=No, this is usual 
2=Things are better than usual 
3=Things are worse than usual 
[If above = 2] 
Please describe how things 
are better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
are worse than usual. 
[textbox] 
New Page 
PROMIS 
Sleep 
Related 
Impairment 
example 
questions 
In the past 7 days… 
I had a hard time getting 
things done because I was 
sleepy 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
When I woke up I felt ready 
to start the day 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 


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In the past 7 days... 
I felt irritable because of 
poor sleep 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
I had trouble staying awake 
during the day 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
New Page 
PROMIS 
Pain 
Interferenc
e example 
questions 
In the past 7 days... 
How much did pain interfere 
with your day to day 
activities? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
How much did pain interfere 
with work around the 
house? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
How much did pain interfere 
with your ability to 
participate in social 
activities? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
In the past 7 days... 
How much did pain interfere 
with your household chores? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very much 
New Page 
PROMIS 
Pain 
Intensity 
In the past 7 days... 
How would you rate your 
pain on average? 
0, No pain 0 
1, 1 
2, 2 
3, 3 
4, 4 
5, 5 
6, 6 
7, 7 
8, 8 
9, 9 
10, Worst imaginable pain 10 
New Page 
Pain 
Context 
  
Thinking about your level of 
pain in the past 7 days, was 
anything out of the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 


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New Page 
PROMIS 
Applied 
Cognition 
General 
Concerns 
example 
questions 
In the past 7 days… 
My thinking has been slow 
1, Never 
2, Rarely (Once) 
3, Sometimes (Two or three times) 
4, Often (About once a day) 
5, Very often (Several times a day) 
In the past 7 days... 
It has seemed like my brain 
was not working as well as 
usual 
1, Never 
2, Rarely (Once) 
3, Sometimes (Two or three times) 
4, Often (About once a day) 
5, Very often (Several times a day) 
In the past 7 days... 
I have had to work harder 
than usual to keep track of 
what I was doing 
1, Never2, Rarely (Once)3, 
Sometimes (Two or three times)4, 
Often (About once a day)5, Very 
often (Several times a day) 
In the past 7 days... 
I have had trouble shifting 
back and forth between 
different activities that 
require thinking 
1, Never 
2, Rarely (Once) 
3, Sometimes (Two or three times) 
4, Often (About once a day) 
5, Very often (Several times a day) 
New Page 
Applied 
Cognition 
General 
Concerns 
Context 
  
Considering your thinking in 
the past 7 days, was 
anything out of the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 
[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
EORTC 
CML 
Symptom 
Burden 
Scale 
During the past week 
Have you had abdominal 
pains or cramps? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had a dry mouth? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had skin problems 
(e.g. color changes, itchy, 
dry or flaking skin)? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had headaches? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had aches or 
pains in your muscles or 
joints? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 


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During the past week 
Have you had hair loss? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you sweated 
excessively? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had acid 
indigestion or heartburn? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you felt drowsy? 
1, Not at all2, A little bit3, Quite a 
bit4, Very much 
During the past week 
Have you experienced any 
swelling in certain parts of 
your body (e.g. ankles, legs 
or around your eyes)? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had to urinate 
frequently? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had problems with 
your eyes (e.g. burning, 
watery, irritated or dry)? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
During the past week 
Have you had muscle 
cramps? 
1, Not at all 
2, A little bit 
3, Quite a bit 
4, Very much 
PROMIS GI 
Symptoms 
- Diarrhea 
In the past 7 days… 
How many days did you 
have loose or watery stools? 
0, No days 
1, 1 day 
2, 2 days 
3, 3-5 days 
4, 6-7 days 
In the past 7 days... 
How often did you feel like 
you needed to empty your 
bowels right away or else 
you would have an 
accident? 
0, Never 
1, One time during the past 7 days 
2, 2-6 times during the past 7 days 
3, Once a day 
4, More than once a day 
PROMIS GI 
Symptoms 
- Nausea 
In the past 7 days… 
How often did you have 
nausea–that is a feeling like 
you could vomit? 
1, Never 
2, Rarely 
3, Sometimes 
4, Often 
5, Always 
Symptoms 
Context 
  
Thinking about any of the 
above symptoms in the past 
7 days, was anything out of 
the ordinary? 
1=No, this was a usual week 
2=Things were better than usual 
3=Things were worse than usual 


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[If above = 2] 
Please describe how things 
were better than usual. 
[textbox] 
[If above = 3] 
Please describe how things 
were worse than usual. 
[textbox] 
New Page 
PROMIS 
Alcohol 
Use 
In the past 30 days… 
Did you drink any type of 
alcoholic beverage? 
1=Yes 
2=No 
In the past 30 days… 
In a typical week, I drank… 
1=1-7 drinks 
2=8-14 drinks 
3=15-21 drinks 
4=22-28 drinks 
5=More than 28 drinks 
PROMIS  
Interest in 
Sexual 
Activity 
In the past 30 days… 
How interested have you 
been in sexual activity? 
1, Not at all2, A little bit3, 
Somewhat4, Quite a bit5, Very 
PROMIS  
Satisfactio
n with Sex 
Life 
In the past 30 days… 
How satisfied have you 
been with your sex life? 
1, Not at all 
2, A little bit 
3, Somewhat 
4, Quite a bit 
5, Very 
PROMIS  
Sexual 
Activity 
Screener 
In the past 30 days… 
Did you have any type of 
sexual activity? 
 
(Examples of sexual activity 
are masturbation, oral sex, 
and sexual intercourse.) 
1=No   
2=Yes 
PROMIS 
Sexual 
Function 
Clinical 
Screener 
In the past 12 months 
Has there ever been a 
period of 3 months or more 
when you had any of the 
following problems or 
concerns?  
 
Please check all that apply. 
1=You wanted to feel more interest 
in sexual activity 
2=You had difficulty with erections 
(penis getting hard or staying hard) 
– MEN ONLY 
2=Your vagina felt too dry – 
WOMEN ONLY 
4=You had pain during or after 
sexual activity 
8=You had difficulty having an 
orgasm 
16=You felt anxious about sexual 
activity 
32=You did not enjoy sexual activity 
64=Some other sexual problem or 
concern ___________ 
128=No sexual problems or 
concerns 


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Thinking about all of the 
questions that you just 
answered about how you 
feel and function, please 
provide any comments or 
questions below. 
[text box] 
New Page 
Instruction 
The next questions are about your background. We will not ask these questions at 
every visit. 
New Page 
Demograph
ic 
questions 
  
What is the zip code where 
you live? 
[number field] 
  
Not including yourself, how 
many people currently live in 
your household? Please 
count people of all ages 
including babies or small 
children. 
Drop down box [Range 0-15] 
  
Please indicate the age of 
the [next] person you live 
with. 
 0-5 years 
 6-15 years 
 16-25 years 
 25-35 years 
 36-45 years 
 46-55 years 
 56-65 years 
 66-75 years 
 over 75 years 
  
What is your marital status? 
1=Married or in a domestic partnership 
or civil union 
2=Widowed 
3=Divorced 
4=Separated 
5=Never married 
6=Other [text box] 
  
Are you of Spanish, 
Hispanic, or Latino descent? 
1=No 
2=Yes 
  
Please check one or more 
categories below to indicate 
what race(s) you consider 
yourself to be. 
1=White 
2=Black or African American 
3=Asian 
4=American Indian or Alaska Native 
5=Native Hawaiian or other Pacific 
Islander 
6=Some other race – Type in race. [text 
box] 


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Socioeconom
ic Status 
  
The next question is about 
the total income of your 
household for the past 12 
months.  Please include 
your income PLUS the 
income of all members living 
in your household.  Please 
count income BEFORE 
TAXES, including income 
from all sources (such as 
wages, salaries, tips, net 
income from a business, 
interest, dividends, child 
support, alimony, and Social 
Security, public assistance, 
pensions, or retirement 
benefits).What was your 
total HOUSEHOLD income 
in the past 12 months? 
1 = Less than $20,0002 = $20,000 to 
$39,9993 = $40,000 to $59,9994 = 
$60,000 to $79,9995 = $80,000 to 
$99,9996 = $100,000 to $199,9997 = 
$200,000 or more 
  
What is the highest degree 
or level of school you have 
completed? 
1=No schooling completed 
2=Nursery school to 5th grade 
3=6th to 8th grade 
4=9th to 12th grade (NO DIPLOMA) 
5=High school graduate or the 
equivalent (GED) 
10=Some college, no degree 
11=Associate's degree 
12=Bachelor’s degree 
13=Master’s degree 
14=Professional or Doctorate degree 
  
Which statement best 
describes your current 
employment status? 
1=Working – as a paid employee 
2=Working – self-employed 
3=Not working – on temporary layoff 
from a job 
4=Not working – looking for work 
5=Not working – retired 
6=Not working – on disability 
7=Not working – other [text box] 
[If working] 
On average, how many 
hours do you work per 
week? 
1=35 hours or more 
2=20-34 hours 
3=10-19 hours 
4=Less than 10 hours 


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[If working] 
In the past 30 days, about 
how many days did you 
miss work because of illness 
or injury?Do not include 
work missed for maternity 
leave. 
[number drop down 0-30] 
In the past 30 days, how 
difficult was it for you to 
meet the monthly payments 
on your bills? 
5=Extremely difficult 
4=Very difficult 
3=Somewhat difficult 
2=Slightly difficult 
1=Not at all difficult 
Health 
Insurance 
  
Do you currently have any 
health insurance? 
 
Include private plans as well 
as government programs 
like Medicare or Medicaid. 
1=No 
2=Yes 
3=I don't know 
[IF above = 2] 
What is your main source of 
health insurance? 
 
(Note: Medicare is a health 
insurance program for 
persons 65 years or over 
and for some disabled 
persons.) 
1=Medicare 
2=Medicaid 
3=A plan provided by an employer 
or union 
4=A plan purchased directly from an 
insurance company, through an 
insurance exchange, or through a 
group such as AARP 
5=TRI-CARE, CHAMPUS or 
CHAMP-VA 
6=I get care from the Department of 
Veterans Affairs (VA) 
7=Other 
[If above = 7] 
Please describe the other 
coverage you have. 
[text box] 
[IF insurance = 
Medicare] 
Which type(s) of Medicare 
coverage do you have? 
 
Check all that apply. 
 
Part A of Medicare covers 
most hospital expenses. 
 
Part B of Medicare covers 
many doctors' expenses 
including doctor visits, and 
the premium is usually 
deducted from your Social 
Security. 
 
Part D of Medicare covers 
prescription drugs, usually 
through a private insurance 
provider. 
1=Part A - Hospital 
2=Part B - Medical 
3=Part D - Prescription drug 
4=I don't know 


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Version: 23 January, 2017                                             The LAST Study 
 
Page 54 
 
[IF above does not equal 
3] 
Do you have a prescription 
drug plan from some other 
source? 
1=No2=Yes3=I don't know 
[IF any insurance] 
Does this plan cover or 
provide help with paying for 
regular prescription drugs? 
1=No 
2=Yes 
3=I don't know 
[If above = 1] 
Do you have a prescription 
drug plan from some other 
source? 
1=No 
2=Yes 
3=I don't know 
[IF no insurance] 
What is the main reason you 
don't have health insurance? 
1=Person in family with health 
insurance lost job or changed 
employers 
2=Employer doesn't offer health 
insurance 
3=Cost is too high 
4=Other 
[IF no insurance] 
Please describe the main 
reason you do not have 
health insurance. 
[text box] 
  
To treat CML, you have 
been prescribed a tyrosine 
kinase inhibitor (TKI) such 
as imatinib, dasatinib, 
nilotinib, or bosutinib.  
 
On average, about how 
much do you pay out of 
pocket for a 30-day supply 
of your TKI? 
 
Do not include money spent 
on premiums for health 
insurance. 
 
Your best guess is fine. 
1=Less than $25 
2=$25-$99 
3=$100-$299 
4=$300-$999 
5=$1000 or more 
4=I don't know 
  
Do you regularly take any 
prescription medications 
other than your TKI? 
1=No 
2=Yes 
3=I don't know 
[IF above = 2] 
Not including your TKI, how 
many prescription 
medications do you regularly 
take each month?  
[number drop down] 


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[IF above = 2] 
On average, about how 
much do you pay out of 
pocket for a 30-day supply 
of your other presciption 
medications (not including 
your TKI)?Do not include 
money spent on premiums 
for health insurance.Your 
best guess is fine. 
1=Less than $252=$25-$993=$100-
$2994=$300-$9995=$1000 or 
more4=I don't know 
[If don't know above] 
Does is amount to less than 
$200 per month, more than 
$400 per month, or what? 
1=Less than $200 per month 
2=$201-$399 per month 
3=More than $400 per month 
4=I really don't know 
  
Please provide any 
comments about health 
insurance or costs that you 
would like to share with the 
researchers. 
[text box] 
Satisfaction 
with Health 
Care 
  
Overall, how satisfied or 
dissatified are you with the 
quality of your health care? 
1=Very satisfied 
2=Somewhat satisfied 
3=Neutral 
4=Somewhat dissatisfied 
5=Very dissatisfied 
  
Overall, how satisfied or 
dissatified are you with the 
cost of your health care? 
1=Very satisfied 
2=Somewhat satisfied 
3=Neutral 
4=Somewhat dissatisfied 
5=Very dissatisfied 
  
Overall, how satisfied or 
dissatified are you with the 
convenience of your health 
care? 
1=Very satisfied 
2=Somewhat satisfied 
3=Neutral 
4=Somewhat dissatisfied 
5=Very dissatisfied 
Trust in 
Provider 
  
Overall, how much trust, if 
any, do you have in your 
usual doctor? 
1=Complete trust 
2=Quite a bit of trust 
3=Some trust 
4=A little bit of trust 
5=No trust 
  
  
What factors were most 
important to you when you 
decided to join this clinical 
study? 
[text box] 
 
New Page 


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Version: 23 January, 2017                                             The LAST Study 
 
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When people take a tyrosine 
kinase inhibitor (TKI) such as 
imatinib, dasatinib, nilotinib, 
or bosutinib, they often have 
side effects from the TKI that 
need to be treated with 
additional prescription 
medications, over-the-
counter medications, or 
supplements.    Before you 
joined the LAST study 3 
months ago and stopped 
taking your TKI, were you 
taking any medications for 
symptoms related to side 
effects from the TKI?    
Include prescription 
medications, over-the-
counter medications, or 
supplements.   
1=Yes 
0=No 
 
 
Since you joined the LAST 
study 3 months ago and 
stopped taking your TKI, are 
you still taking any 
prescription medications for 
symptoms related to side 
effects from the TKI or have 
you stopped taking any 
prescription medications? 
Please check all that apply. 
  
 
 
 
I am still taking prescription 
medication for the following 
symptoms... 
1=Nausea 
2=Diarrhea 
3=Water retention 
4=Sleep problems 
5=Depression 
6=Fatigue 
7=Skin problems 
8=Muscle cramps 
9=Low potassium or magnesium 
7=Other [text box] 
 
 
I stopped taking prescription 
medication for the following 
symptoms... 
1=Nausea 
2=Diarrhea 
3=Water retention 
4=Sleep problems 
5=Depression 
6=Fatigue 
7=Skin problems 
8=Muscle cramps 
9=Low potassium or magnesium 
7=Other [text box] 


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Version: 23 January, 2017                                             The LAST Study 
 
Page 57 
 
 
 
Since you joined the LAST 
study 3 months ago and 
stopped taking your TKI, are 
you still taking any over-the-
counter medications or 
supplements for symptoms 
related to side effects from 
the TKI or have you stopped 
taking any over-the-counter 
medications or 
supplements? 
Please check all that apply. 
  
 
 
I am still taking over-the-
counter medications or 
supplements for the 
following symptoms... 
1=Nausea 
2=Diarrhea 
3=Water retention 
4=Sleep problems 
5=Depression 
6=Fatigue 
7=Skin problems 
8=Muscle cramps 
9=Low potassium or magnesium 
7=Other [text box] 
 
 
I stopped taking over-the-
counter medications or 
supplements for the 
following symptoms... 
1=Nausea 
2=Diarrhea 
3=Water retention 
4=Sleep problems 
5=Depression 
6=Fatigue 
7=Skin problems 
8=Muscle cramps 
9=Low potassium or magnesium 
7=Other [text box] 
 
 
Since you joined the LAST 
study 3 months ago and 
stopped taking your TKI, 
have you started taking any 
new prescription 
medications? 
1=Yes 
0=No 
 
 
Which new prescription 
medications are you taking? 
[Text box] 
 
 
Since you joined the LAST 
study 3 months ago and 
stopped taking your TKI, 
have you started taking any 
new over-the-counter 
medications or 
supplements? 
1=Yes 
0=No 


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Version: 23 January, 2017                                             The LAST Study 
 
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Which new over-the-counter 
medications or supplements 
are you taking? 
[Text box] 
 
 
In your own words, please 
describe your experience 
having to restart a tyrosine 
kinase inhibitor (TKI) 
[Text box] 
 
 


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Version: 23 January, 2017                                             The LAST Study 
 
Page 59 
 
Appendix 2: Specimen Collection & Handling 
 
Specimen Collection 
Peripheral PCR blood sample:   
A minimum of 20 ml of whole blood in an EDTA vacutainer (lavender top). Due to PCR inhibition, the lab does 
not accept heparin as a preservative.  
 
 
 
Specimen Labeling  
All submitted specimens must be labeled with the patient’s initials, patient study ID#, patient’s date of birth and 
date/time of specimen collection.  
 
 
Shipping Requirements 
All specimens must be accompanied by a Specimen Shipping Requisition Form. 
Samples must be received by Molecular Oncology within 48 hours of draw. The Molecular Oncology lab is 
open M-F, 8:00am – 4:30 pm.  Please do not draw samples on Fridays for delivery on Saturday.   
The sample must be placed in a leak proof primary receptacle (ex: vacutainer). 
Multiple primary receptacles must be individually wrapped or separated to prevent contact.  
The primary receptacle must be placed into a leak proof secondary container (ex: resealable biohazard bag) in 
such a way that under normal conditions of transport, they cannot break or leak.   
Absorbent material, such as paper towels or absorbent pads, must be placed in the secondary container with 
sufficient capacity to absorb the entire contents of the primary receptacle(s).  
The secondary container must be placed into an outer shipping container with suitable cushioning material 
(bags or envelopes are not allowed).  The shipping container must be labeled with the universal biohazard 
symbol.  
The outer packaging must be marked with the name, address, and phone number of both the sender and 
recipient.  
All packages shipped via aircraft must display a 2-inch diamond with "UN3373" inside of the diamond.  
 
Send the container via next day delivery at ambient temperature to: 
 
 
 
Molecular Oncology 
 
 
Fred Hutchinson Cancer Research Center 
 
 
1100 Fairview Avenue North, Rm. D2-281 
 
 
Seattle, WA 98109 
 
Please call/email the Molecular Oncology lab as soon as the tracking number is available: (206) 667-2592, 
molab@fhcrc.org.  The Molecular Oncology lab is open M-F, 8:00am – 4:30 pm.  Please do not draw 
samples on Fridays for delivery on Saturday.   
 
 
 
 
 


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Version: 23 January, 2017                                             The LAST Study 
 
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Specimen Shipping Requisition Form 
 
Has The Patient Consented to Research Samples?           YES           NO 
 
Patient Information 
 
Patient Initials:  _________________________________   Birth Date: _______________   Sex: M ___ F___     
 
 
Study ID #: _____________________    
 
 
Check Appropriate Box Below: 
□ Screening #:  __________________ 
□ Month #:  __________________ 
□ Restarted TKI  
 
 
Sample Information 
 
Date of Sample Collection: ____________________    
Time of Sample Collection: ________________ 
 
Eligibility for Screening PCRs only: 
 
 Documented BCR-ABL < 0.1% (> MR4 i.e. >4 log reduction) or undetectable BCR-ABL by PCR for at 
least 2 years according to the patient’s local lab 
 Documented BCR-ABL < 0.1% (> MR4 i.e. >4 log reduction) or undetectable BCR-ABL PCR at least 3 
times prior to screening according to the patient’s local lab 
 Currently taking a TKI (imatinib, dasatinib, nilotinib, or bosutinib)  
 Has not had prior hematopoietic stem cell transplantation 
 Patient has been on a TKI therapy for at least 3 years 
 
Physician Information  
 
Physician’s Full Name:  ___________________________________    NPI # _______________________ 
 
 
Physician’s Phone #:  _________________________________      Fax# __________________________ 
 
 
Physician’s Institution: __________________________________________________________________ 
 
 
Physician’s Address: ____________________________________________________________________ 
 
 
_____________________________________________________________________________________ 
 
 
Person Filling out Requisition: ____________________________   Phone Number___________________ 


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Appendix 3: ECOG Status 
 
 
 
ECOG PERFORMANCE STATUS 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4: Sokal risk score (42) 
 
The score, which is a hazard ratio function, is calculated using the following formula:  
EXP 0.0116 x (age* – 43.4)) + 0.0345 (spleen size** – 7.51) + (0.188 x ((platelets^/ 700)2 – 0.563)) + 
(0.0887 x (blasts# – 2.10)).  
 
Low-risk:  Sokal score < 0.8  
Intermediate-risk: Sokal score 0.8 - 1.2 
High-risk: Sokal score > 1.2 
 
 
 
*Age in years, **spleen size in cm below costal margin, ^109/L, #blast percentage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5: Local Lab Draw and PRO Permission Request Form  
 
This option is not for all patients and careful consideration should be used to ensure proper oversight.  This 
form is to be completed and signed off on by the site PI and coordinating site PI for any site that is requesting 
permission for one of their patients to have blood draws at a location that is not the patient’s study site (study 
site includes: any affiliate sites identified under the sites IRB approval).  This form must be approved and 
signed by both the site PI and the coordinating site PI prior to applicable patient visits. 
 
Patient Initials:  ____________________ Birth Date: _______________   Study ID #:____________     
 
Month # being Requested (Cannot be requested for visits that require MD visits): 
   
_______________________________________________________________________________________ 
 
Reason for request (i.e. distance the patient would need to travel):   
 
________________________________________________________________________________________ 
 
Eligibility: 
 Study site has corresponded with local lab prior to sending patient to ensure that local lab understands 
requirements. 
Local Lab Name: _________________________________ 
 Blood draw billing information has been discussed with the local lab  
 Patient kits have been prepared which include the shipping materials and Shipping Label with 
Appropriate billing information 
 Patient has been instructed on how to complete their electronic PROs and has necessary internet 
access.  They have also confirmed they understand the importance of completing PROs as close to the 
date of the PCR blood draw as possible.   
 PI feels patient has an adequate understanding of the requirements to ensure compliance with the 
scheduled visits  
 
Site Information  
 
Person Filling out Request: ____________________________   Phone Number___________________ 
 
Study Site PI Full Name:  ___________________________________ 
 
PI Phone #:  _________________________________  
    Fax# __________________________ 
 
PI’s Institution: __________________________________________________________________ 
 
By signing below site is agreeing that the above eligibility requirements have been addressed and understands 
that if issues arise approval may be revoked to complete further visits at local lab.  
 
Study Site PI Signature and Date: __________________________________________________ 
 
Final Coordinating Site Decision: 
Coordinating Site PI Signature and Date: ____________________________________________ 


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Appendix 6: GeneXpert Validation tests 
 
Use of BCR-ABL Assays, including GeneXpert BCR-ABL V1 and V2 Assays, in the LAST Trial: 
• 
The use of real time quantitative PCR (RQ-PCR, Q-PCR or RT-Q-PCR) assays for monitoring residual 
disease, as measured by BCR-ABL1 mRNA quantitation as % Ratio (BCR-ABL1/ABL1), is an important 
aspect of evaluating response to drug therapies in patients with Chronic Myelogenous Leukemia 
(CML). 
• 
Although a few specialized academic research laboratories have been able to standardize “standard” 
homebrew BCR-ABL Q-PCR assays within their own labs using the International Scale (IS) developed 
by the World Health Organization (WHO), there is still a need to standardize the methodology and 
reporting of BCR-ABL1 by laboratories in the US and around the world, including in resource poor 
settings in developing countries, in order to improve the care and evaluation of therapeutic treatment 
options of patients with CML. 
• 
Cepheid, a molecular diagnostics company based in Sunnyvale, CA, has developed the GeneXpert Dx 
system and cartridge based assays which standardize and simplify highly accurate and reproducible Q-
PCR assays for the end user by integrating sample preparation, nucleic acid isolation, detection and 
quantification of RNA and DNA targets in a variety of infectious diseases and oncology/hematology 
indications, including BCR-ABL1 testing for CML.   
• 
Cepheid currently has two versions of GeneXpert BCR-ABL Monitoring assays, Version 1 (V1) and 
Version 2 (V2).  These cartridge-based, yet “standard” Q-PCR assays will be evaluated alongside 
“standard” homebrew Q-PCR and investigational digital PCR assays performed in Dr. Jerry Radich’s 
core laboratory facility in the context of the LAST clinical trial.  
It is anticipated that the GeneXpert BCR-ABL Version 2 assay will perform comparably to the other standard 
homebrew BCR-ABL Q-PCR assay(s) being performed on blood samples from the LAST trial, serving as 
evidence of analytical validity in comparison to the gold standard Q-PCR assay run in Dr. Radich’s Core Lab.   
These data, as well as the correlation of  % Ratio (BCR-ABL1/ABL1) by GeneXpert BCR-ABL V2 and the gold 
standard Q-PCR assays with clinical endpoints in the study, such as Time to CML molecular recurrence 
[defined as loss of MMR (> 0.1% BCR-ABL, IS) as assessed by standard Q-PCR], Relapse free survival 
(RFS), and Death in complete remission (DCR),  may provide key evidence to support the claim of the 
GeneXpert BCR-ABL V2 Assay’s clinical validity and utility in monitoring CML disease burden and patient 
response to changes in drug therapy (in this case, discontinuation of therapy), and as such, de-identified study 
data may be shared with Cepheid and subsequently submitted by the company to the FDA to support pre-
market review of the GeneXpert BCR-ABL V2 Assay, allowing widespread use of the assay in laboratories 
throughout the U.S.  Indeed, the FDA has invited Cepheid to submit data for pre-market review that includes a 
clinical cohort with well-characterized clinical outcomes.     
Brief Technical Background and Regulatory Status of GeneXpert BCR-ABL V1 and V2 Assays: 
• 
GeneXpert BCR-ABL Assays utilize standard, but simplified and automated, RT-Q-PCR which is 
performed in the GeneXpert assay cartridge following several off-board sample preparation steps.  
• 
The GeneXpert® BCR-ABL Monitor Assay(s), Version 1 (V1) or Version 2 (V2), can be performed in de-
centralized labs on the Cepheid GeneXpert® Dx System (instrument).   


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• 
Both the V1 and V2 assays are currently considered (in the U.S.) Research Use Only (RUO) in vitro 
diagnostic tests for the simultaneous detection and quantitation of the BCR-ABL1 chromosomal 
translocation mRNA transcripts (type b2a2 or b3a2) and the ABL1 endogenous control mRNA transcript 
in peripheral blood specimens from patients diagnosed with chronic myelogenous leukemia (CML).   
• 
Reporting on International Scale:   
The GeneXpert BCR-ABL Assays (V1 and V2) report BCR-ABL1 mRNA quantitation as % Ratio (BCR-
ABL1/ABL1) on the International Scale (IS) per WHO Standards. 
• 
GeneXpert Assay Regulatory Status, Sensitivity, and Sample requirements 
1. The GeneXpert BCR-ABL Monitor V1 Assay  
• 
Is not FDA cleared but is available in the United States as a RUO in vitro diagnostic 
assay.  This Assay is, however, available for routine clinical use outside the US in those 
countries that accept diagnostics with CE registration.   
• 
Blood sample volume and sensitivity:  This version (V1) of the assay requires a 0.2 ml 
whole blood sample collected in EDTA or PAXgene, and can accurately and 
reproducibly detect and quantify BCR-ABL1/ABL1 % ratios to a 3 log reduction, or 0.1% 
(IS), which defines Major Molecular Response (MMR), per WHO guidelines.  
• 
Due to the improved sensitivity of the BCR ABL V2 assay (please refer to V2 details 
below), Cepheid is not seeking FDA pre-market review for the V1 version of the assay. 
2. The GeneXpert BCR-ABL V2 Assay 
 
• 
Is a RUO in vitro diagnostic assay that is not FDA cleared, but Cepheid intends to submit 
the necessary documentation to FDA to support a pre-market review and, ultimately it is 
hoped, regulatory clearance as an FDA-cleared assay. 
• 
Blood sample volume and sensitivity:  This version (V2) of the assay requires a 4 ml 
whole blood sample collected in EDTA or PAXgene, and can accurately and 
reproducibly detect and quantify BCR-ABL1/ABL1 % ratios to a 4.5-log reduction, or 
0.003% (IS), which defines Complete Molecular Response (CMR), per WHO guidelines. 
GeneXpert Instrument and Cartridges for the LAST study 
• 
Cepheid will supply the Radich Core Laboratory with a GeneXpert 16 module instrument system, as 
well as all BCR-ABL Assay cartridges to support GeneXpert Q-PCR testing of patient samples at the 
same time points for which the standard homebrew Q-PCR assay will be tested.   
• 
All instrumentation and cartridges to support the testing of samples in the study will be provided at no 
cost to the Radich lab or LAST study investigators/NCI.    
• 
Patient de-identified study data and laboratory test results, (“List of Data Elements” as outlined below), 
may be required to be shared directly with Cepheid for analysis to support FDA submission. 
 
 
 


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Version: 23 January, 2017                                             The LAST Study 
 
Page 66 
 
 
The LAST study:  List of Data Elements required  
for potential Cepheid BCR-ABL Monitor Assay submission to FDA  
Note:  All peripheral blood samples tested by RQ-PCR and digital PCR assays will have an aliquot also tested 
in the GeneXpert BCR-ABL Monitor assay performed in the Core Molecular Oncology (Dr. Radich) Lab.  All 
GeneXpert BCR-ABL data, as well as the following data variables, may be required for Cepheid’s US-IVD 
submission to FDA:  
1.  Patient de-identified baseline data/demographic factors 
a. Study ID # 
b. Age/birthdate 
c. Sex 
d. Race 
e. Date of diagnosis 
f. Sokal risk score and its components (spleen size, platelet count, the percentage of blasts in the 
peripheral blood), basophil % 
g. ECOG performance status  
2. Treatment 
a. History of prescribed TKIs including any dose reductions or held dosing  
b. Current TKI at study screening 
c. Duration of treatment on current TKI at study screening and date  
d. Time to MR 3.0 
e. Time to undetectable BCR-ABL by PCR,  
f. Duration undetectable BCR-ABL by PCR 
g. Side effects requiring medical intervention or referral. 
h. For patients in whom MMR is lost after discontinuing TKI, and who must restart TKI:  the type of 
TKI and date of restarting TKI. 
3. Samples -  for each blood sample tested: 
a. Study ID# 
b. Date of Sample Collection 
c. Time of Sample Collection 
4. BCR-ABL levels at screening: 
a. For patients with undetectable BCR-ABL at screening (this category covers all patients who are 
eligible for study enrollment):   
i. Time to undetectable BCR-ABL by PCR 
ii. Duration of undetectable BCR-ABL by PCR 
iii. BCR-ABL transcript levels measured by digital PCR 
b. For patients with detectable BCR-ABL at screening (Screening failures – these patients are not 
eligible for study enrollment):  
i. BCR-ABL transcript levels at screening by PCR 
ii. BCR-ABL transcript levels at screening by digital PCR 
5. BCR-ABL levels for patients on study:   
a. Results of all RQ-PCR and digital PCR testing performed as part of study procedures, including 
i. Both screening visit(s) at least 21 days apart to confirm patient is in MR4; 
ii. On study:  BCR-ABL levels monthly for 6 months, every other month until 24 months, 
and then quarterly until 36 months 
iii. All BCR-ABL RQ-PCR assessments for patients who lose MMR 
iv. After completion of monitoring phase:  as available, BCR-ABL levels every 6 months 
according to physician’s standard of care  
6. Outcomes for each patient after TKI discontinuation: 
a. Time to CML molecular recurrence [defined as loss of MMR (> 0.1% BCR-ABL, IS)] 
b. Relapse free survival (RFS)   
c. Death in complete remission (DCR)