Pilot Study Evaluating Changes in Physical Function Measures in Stem Cell Transplant Patients at Risk for Steroid Myopathy
Phase: NA
Conditions: Acute Graft Versus Host Disease
Sponsor: M.D. Anderson Cancer Center

2015-0141
Revised February 21, 2017
1
 
 
Pilot Study Evaluating Changes in Physical Function Measures in Stem Cell 
Transplant Patients at Risk for Steroid Myopathy  
 
Principal Investigator: An Ngo-Huang, DO 
Co-Investigators: Rajesh Yadav, MD; Amin Alousi, MD 
Collaborators: Richard Champlin, MD; Eduardo Bruera, MD; Partow Kebriaei, MD; 
Uday Popat, MD; Nina Shah, MD;Ms. Diane Liu, Jimin Wu 
 
 
I.  
BACKGROUND  
 
Allogenic hematopoietic stem cell transplantation (HSCT) is used frequently for treating 
hematologic malignancies [1].  Graft-versus-host disease (GVHD) is one of the major 
complications of HSCT [2,3] and the main cause for transplant-related morbidity and
mortality.  GVHD has been divided into acute and chronic with distinct clinical 
manifestations.  Manifestations of acute GVHD include maculopapular skin rash, 
nausea, vomiting, diarrhea and cholestatic jaundice.   
 
The median occurrence for significant acute GVHD (grade II-IV) is about 40%.  
Moderate to severe acute GVHD occurs in up to 30% of patients despite receiving cells 
from a fully matched human leukocyte antigen (HLA) related or unrelated donor and 
immunosuppressive therapy [4,5,6].  Chronic GVHD is a common late challenge 
associated with HSCT.  Roughly 50% of the patients experience some degree of 
chronic GVHD ranging from 30 to 80%.  Chronic GVHD is a leading cause of late non-
relapse related mortality    
 
With such impact of GVHD on morbidity and mortality, effective prophylaxis of GVHD is 
quite important.  A common approach for such prevention includes prophylactic use of a 
regimen with immunosuppressive agents given after HSCT.  Corticosteroids (typically 
methylprednisolone or prednisone) are the standard therapy for patients with acute 
GVHD grade II-IV.  The starting dose of steroids are generally 2mg/kg for all patients 
with grade II-IV acute GVHD except for isolated upper GI GVHD wherein 1mg/kg is 
commonly the starting dose.  High dose corticosteroids are employed as a front line 
agent to treat this complication [5, 6, 7, 8].  High dose steroid therapy is associated with 
a variety of adverse side effects including avascular necrosis, cataracts, edema, 
gastritis, headaches, hyperglycemia, hypertension, hypokalemia, insomnia, infections, 
mood swings and steroid myopathy [9]. 
 
Steroid myopathy is the most significant complication of such corticosteroid therapy [8, 
10].  Once patients become impaired with significant loss in functional status; outcomes 
are poor with marked increase risk of infections.  Incidence rate of such myopathy has 
been estimated at least at 41% [10].  Although the presentation can be acute, most 
often it is insidious.  
 
To date, research has been infrequent in this common complication of GVHD therapy.  
The only study to address this complication came from our institution [10] in the form of 

2015-0141
Revised February 21, 2017
2
 
 
a retrospective review of 180 patients.  Seventy of these patients met inclusion criteria.  
Twenty nine of these patients were evaluated by physical therapists with manual muscle 
exam (MME) and for functional independence measure (FIM) scores.  With MME data 
missing for 3 patients, 11 patients had scores of 3 out of 5 with MME (movement in full 
range of motion against gravity without resistance) in upper extremities.  Thirteen 
patients had scores of 3 in lower extremities.  These scores constituted myopathy from 
functional perspective.  In 11 and 13 patients, scores of 4 out of 5 with MME (movement 
against moderate resistance) were noted with upper and lower extremities respectively.  
Patients with such strength may be able to ambulate and transfer independently but 
such independence is not guaranteed.  The majority of the patients needed assistance 
with device(s). They also needed some degree of assistance when performing tasks 
including supine to sit transfer (17 out of 29), sit to stand transfer (18 out of 29), and 
walking (22 out of 29).  This study was limited by being retrospective with likely only the 
severe cases referred for evaluation.   
 
To date, despite being a common complication across many different diseases which 
necessitate high-dose steroid treatment, there is no formal definition or disease-severity 
index for patients with steroid myopathy.  A major area of acute GVHD research is to 
develop therapies which minimize exposure to corticosteroids.  These therapies may 
result in comparable GVHD response rates yet are ultimately preferable because of 
reduction in toxicity.  Being able to quantify protection from steroid-myopathy is integral 
to interpreting these studies.  The goal of this protocol is to perform a prospective pilot 
study to define steroid myopathy (definition, measures, incidence, severity) and impact 
on non-relapse mortality in a homogenous population of patients with newly diagnosed 
acute GVHD. 
 
There are very limited studies and limited knowledge of the weakness and subsequent 
functional deficits that develop in patients with steroid myopathy. There are no formal 
tools used to identify or quantify impairments in patients suspected of having steroid 
myopathy.  Steroid myopathy usually affects proximal musculature with preferential 
involvement of lower extremities, especially quadriceps [11].  With such weakness, 
significant functional sequelae include among others, inability to independently sit from 
supine position (only 31%) and stand from sitting position (28%) [10].   
 
The diagnosis of steroid myopathy in HSCT patients was previously based on Manual 
Muscle Exam (MME) and Functional Independence Measure (FIM) [10].  However, 
manual muscle testing is examiner-dependent and can be non-specific.  Tests such as 
the Peripheral Motor Deficits Scale (PMDS), Stepper test, and Ankle/Wrist index and 
Neuropathy Disability Score [12] have been used; however, these tools have not been 
validated and are rarely utilized in clinical or research settings. Laboratory and imaging 
tests cannot reliably diagnose steroid myopathy.  Electromyography is an invasive test 
which cannot be used solely to make such a diagnosis as some of the findings may be 
non-specific.  In addition, it may be too invasive in this setting of patients who have just 
received a stem cell transplant.  The Adult Myopathy Assessment Tool (AMAT) has 
been used in patients with inflammatory myopathies, spinal and bulbar muscular 
atrophy [13], but has not been specifically utilized for steroid myopathy.  This 

2015-0141
Revised February 21, 2017
3
 
 
assessment includes 7 timed functional tasks and 6 endurance tasks, has high inter-
rater and intra-rater reliability and correlation with other physical assessments such gait 
speed, and the physical quality of life.  The Brooke scale was developed to assess 
upper extremity functional performance in Duchenne Muscular Dystrophy patients and 
is easy to apply and interpret [14, 15].  It has also been applied in the rehabilitation 
setting for patients with spinal muscular atrophy [16] Again, none of these tests have 
been studied in patients with steroid myopathy.  
 
No known therapy exists to prevent or to enhance recovery after the development of 
steroid induced myopathy, although rehabilitation measures may improve outcomes of 
these patients [17, 18].  Engaging in treatment for patients who develop steroid 
myopathy is not possible because the not much is known about the time course of the 
weakness that develops.  There are no known tools to assess and measure the 
weakness; and thus, putting together a treatment regimen or even pursing a prospective 
study to implement an intervention becomes a challenge.  A major objective of this 
research is to identify the best tools to capture steroid myopathy incidence and severity. 
An ideal tool should be: 1) easy to perform and measure by multiple disciplines, 2) easy 
to interpret the results, 3) be able to discern post-transplant disability from steroid 
myopathy, and 4) may be used with patients with varying severity of weakness. 
 
Because there are limited diagnostic tools available to formulate a diagnosis of steroid 
myopathy, it is important to study the functional and physical changes that may occur if 
a patient develops steroid myopathy.  It is important to use measures that are widely 
utilized in the literature such as the 6 minute walk test, 5 times sit-to-stand, and manual 
muscle testing, along as ones such as the AMAT and Brooke Scales, which have been 
used in other myopathy settings.  Based on the patterns of physical and functional 
decline measured in this study, we can formulate surrogate markers that will be 
essential in conducting future prospective interventional studies in patients who have 
been diagnosed with or are at risk for developing steroid myopathy.  
 
II. OBJECTIVES 
 
Primary Objective: 
1. To perform a pilot study to estimate the change in six physical and functional tests 
over time in patients with suspected acute graft-versus-host disease (GVHD) who have 
been initiated on treatment with corticosteroids. 
 
Secondary Objectives: 
1. To describe and potentially define steroid myopathy by following the patterns of the 
muscle loss and functional impairment in this population of patients.  
2. To follow steroid myopathy and describe its incidence, its severity, and the impact on 
non-relapse mortality in a homogeneous population of patients with suspected acute 
graft-versus-host disease (GVHD) who have been initiated on treatment with 
corticosteroids at a quaternary institution in the inpatient and outpatient setting. 

2015-0141
Revised February 21, 2017
4
 
 
3. To estimate the adherence to an intermittently supervised exercise program in 
hematopoietic stem cell transplantation (HSCT) patients who are at risk of developing 
steroid myopathy. 
 
 
Hypothesis  There will be a decline in muscle strength and functional measurements 
in patients with suspected graft versus host disease who have been started on 
corticosteroids which will be detected at the Day 28 follow up, and may be more robust 
at the Day 56 follow up.  Steroid myopathy and steroid-myopathy severity is correlated 
with non-relapse mortality in patients with newly diagnosed acute GVHD.   
 
III. STUDY ENDPOINTS: 
  
Primary Endpoints:   
 Physical and functional measurements and the changes in these measures over 
time.  
 
Secondary Endpoints: 
 Physical and occupational therapy is often prescribed for patients who develop 
steroid myopathy.  It is unclear how many adhere to their exercise regimens. We 
will estimate the adherence to the study exercise program, tolerance for specific 
exercises and ability to advance exercises, and completion of study materials. 
 We will also measure the percentage of patients who agree to participate in the 
study as this information will provide us with an estimate of the percentage of 
patients who may participate for future studies and measures. 
 Patient self-reported outcomes in functional status and symptoms over time while 
being followed for GVHD.  
 Overall status of disease and survival at day 180. This includes assessing the 
impact on non-relapse mortality at 6 months post-enrollment.  
 We will assess other variables (age, gender, co-morbidities, type of graft, etc.) 
that may impact incidence of steroid myopathy in this group of patients.   
 Changes in physical and functional measurements in comparison to their 
cumulative steroid dosing.  
 Changes in physical and functional measurements in comparison to the severity 
of GVHD.  
 
IV. ELIGIBILITY CRITERIA: 
Inclusion: 
1) Participants are willing and able to give written informed consent and to comply 
with all of the study visits and procedures.  
2) Age  55years, or with a Sorror co-morbidity index of  3 ]  
3) Post allogenic hematopoietic stem cell transplantation using bone marrow, 
peripheral blood or cord blood; or after pre planned donor lymphocyte infusion.

2015-0141
Revised February 21, 2017
5
 
 
4) Presumptive diagnosis of acute GVHD necessitating high-dose corticosteroid 
treatment (with an approximate starting dose of methylprednisolone equivalent of 
2mg/kg/day).   
5) Within 5 days of receiving corticosteroid treatment  
6) ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2 or 
equivalent Karnofsky score of 60 or higher.  
7) The patient is referred to the study by their stem cell transplant attending 
physician. 
 
 
Exclusion: 
1) Non-English speaking 
2) Patients under 18 years of age 
3) Underlying unstable cardiac or pulmonary disease in the opinion of the 
investigator that limits participant involvement in exercise.  
4) Has a pre-transplant echocardiogram with ejection fraction <45%. 
5) Requires supplemental oxygen to maintain O2 saturation >92% 
6) Musculoskeletal injury that precludes participation in an exercise program 
7) Inability to participate in a structured exercise program 
8) Patients for whom the physician feels is unsafe for an exercise program 
9) Platelets equal to or less than 10,000 or evidence of active bleeding 
10) Patients who are unable to understand or follow through with the exercise 
program 
 
V. STUDY PLAN 
 
Given the pattern of weakness associated with steroid myopathy, we will measure the 
following: 
a) Objective Functional/physical measures: 
a. Manual muscle testing 
i. Measure strength of shoulder abduction, elbow flexion, extension, 
hip flexion, and quadriceps bilaterally. 
ii. Cumulative score out of 50 points total.  
b. Hip flexor and quadriceps strength via handheld dynamometer
i. Reported as strength in pounds 
c. Six minute walk test 
i. Reported as meters 
d. 5x sit to stand  
i. Reported as total time in seconds 
e. Brooke Scale:  
i. Reported as numerically as 1-6.  
1. From arms at side, abduction of arms in full circle until 
touching overhead 
2. Can raise arms above head only flexing the elbow or using 
accessory muscles 

2015-0141
Revised February 21, 2017
6
 
 
3. Cannot raise hands above head, but can raise an 8 ounce 
glass of water to the mouth 
4. Can raise hands to the mouth, but cannot raise an 8 ounce 
glass of water to the mouth 
5. Cannot raise hands to the mouth, but can use hands to hold 
a pen or pick up pennies from the table 
6. Cannot raise hands to the mouth and has no useful function 
of hands 
f. Adult Myopathy Assessment Tool (AMAT)   Only portion of the test 
will be administered:   
i. Reported as summation of the tasks below (total 24 points). 
1. Arm raise (0-3) 
2. Sustained arm raise (0-4) 
3. Sit to stand (0-3) 
4. Sustained hip flexion (0-4) 
5. Sustained knee extension (0-4) 
 
b) Subjective/Patient reported 
a. Self reported Improved (or PROMIS) Health Assessment 
Questionnaire 
b. PROMIS Short Form v1.0  Physical Function 12a.  
c. MD Anderson Symptom Inventory (MDASI) 
d. FACIT-Fatigue Scale 
 
c) Baseline demographics 
a. Pre-transplant comorbidity index (Sorror) 
b. Underlying disease requiring transplantation 
c. Disease stage at the time of transplant 
d. Donor type  
e. Graft Source 
  
d) GVHD-associated measurements at baseline and after initiation of 
corticosteroids at Day 14(+/-5), 28 (+/-5), and 56 (+/-5) 
a. Organ Stage and Grade of GVHD (see Table 1)  
b. Corticosteroid dose at that time and cumulative corticosteroid dose 
through day 56. 
i. Doses of methylprednisolone will be converted to prednisone 
equivalents by multiplying the methylprednisolone dose by 1.25.  
Prednisone doses for each subject will be converted to mg/kg.  The 
cumulative and average corticosteroid doses will be calculated over 
time.  
c. GVHD Response (at days 14, 28, 56) 
d. Body mass index (BMI), albumin, prealbumin levels. Albumin and possibly 
prealbumin levels are collected by the stem cell transplant team whether 

2015-0141
Revised February 21, 2017
7
 
 
the patient is on study or not (standard of care) and are not research-
specific procedures. Prealbumin levels will be recorded if they are 
obtained by the medical team.   
 
e) During the Day 180 post-transplant follow up: 
a. Acute and chronic GVHD assessment, if patient is returning to MDACC 
i. Grade of GVHD, GVHD response 
b. Body mass index (BMI), albumin levels, will be collected from the medical 
record if available. 
c. Non-Relapse Mortality:  non-relapse mortality due to any cause other than 
the underlying malignancy, will be assessed at Day 180 
d. Overall survival:  Overall survival will be computed up to Day 180 
With the exception of the baseline demographic information, physical/functional 
measures, patient reported questionnaires, and GVHD-associated measurements will 
be recorded at the following time points: 
a. Baseline (at the time of screening, consent and enrollment into the study)
b. Day 14 (+/-5) 
c. Day 28 (+/-5) 
d. Day 56 (+/-5) 
 
It will take approximately 15 minutes to perform the physical function tests and it will 
take approximately 20 minutes to complete the patient questionnaires during each 
patient evaluation session. 
 
If a participant remains hospitalized as an inpatient, he or she will continue to participate 
in the exercise program allocated to them and the above measures will be recorded at 
the appropriate time intervals.  The medical indication for hospitalization, discharge 
diagnoses and length of hospital stay will be recorded.  
 
 
 
Table 1: Overall Acute GVHD Response   
Participants will be graded according to the modified Keystone Grading Schema displayed in the table 
below.  
Modified Keystone Grading Schema 
  
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No Rash 
 
Rash <25% 
BSA 
25-50% 
BSA 
>50% 
BSA 
Bullae and
desquamation
Lower 
GI 
Tract 
<500 ml/day 
stool volume 
500-
1000 ml/day 
stool volume 
OR 
Severe 
1001-
1500 ml/day 
stool 
volume 
>1500 ml/ 
day stool 
volume 
Severe 
abdominal 
pain +/- ileus, 
frank blood or 
melena 

2015-0141
Revised February 21, 2017
8
 
 
nausea and 
vomiting 
Liver 
Bilirubin 
 mg/dl 
2.1-3 mg/dl 
3.1-6 mg/dl 
6.1-
15 mg/dl 
>15 mg/dl 
Abbreviations: BSA = body surface area; GI = gastrointestinal (1) 
 
1.  Acute GI GVHD Response Criteria:  Proportion of subjects with CR, PR, MR, NR and Progression 
will be determined over time.  Scoring of CR, PR, MR, Progression and NR will be in comparison to the 
 GVHD Stage (see lower GI tract row of above table).  Response will be based on 
the following response definitions: 
 
Complete Response (CR): a Stage of 0 for the GVHD grading in the lower GI tract with no 
additional intervening therapy for their GVHD. 
 
Partial Response (PR): improvement by at least 1 Stage in GI GVHD symptoms without 
progression in others with no additional intervening therapy for their GVHD.   
 
Mixed Response (MR): improvement in lower GI tract with deterioration in another organ 
manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ.  
 
Progression: deterioration in lower GI tract.   
 
No Response (NR): absence of any improvement or progression as defined above.  Subjects 
receiving secondary therapy (including need to re-
 mg/kg/day of 
prednisone; or methylprednisolone equivalent of 2 mg/kg/day) will be classified as non-
responders. 
2.  Response for All Organs Involved with Acute GVHD:  Proportion of subjects with CR, PR, MR, 
Progression and NR for all organs involved with acute GVHD will be determined over time.  Scoring of 
table of Modified Keystone Grading Schema above).  Response will be based on the following 
response definitions: 
 
Complete Response (CR): a Stage of 0 for the GVHD grading in all evaluable organs with no 
additional intervening therapy for their GVHD. 
 
Partial response (PR): improvement by at least 1 Stage in 1 or more organs involved with GVHD 
symptoms without progression in others with no additional intervening therapy.   
 
Mixed response (MR): improvement in 1 or more organs with deterioration in another organ 
manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ.  
 
Progression: deterioration in at least 1 organ without any improvement in others.   
 
No response (NR): absence of any improvement or progression as defined.  Subjects receiving 
secondary therapy (including need to re-
 mg/kg/day of 
prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) will be classified as non-
responders. 
 
 
 
Patient Recruitment 
Eligible patients with newly diagnosed GVHD will be recruited from the MDACC 
outpatient stem cell transplant clinic and the MDACC inpatient stem cell transplant 
primary service.  The stem cell transplant attending physician will be the primary 
recruiter to the study. Patients will be referred to our research team within 5 days of 
initiating corticosteroids for the presumptive diagnosis of GVHD.  In the event that a 
in no GVHD, but the patient has been on high-dose 
corticosteroids for four or more days, they will still remain on study as they may still be 
at risk for steroid myopathy.  The following screening tests will be performed after 
receiving verbal consent from the patient. Patients will complete the Physical Activity 
Readiness Questionnaire (PAR-Q).  Furthermore, they will undergo baseline physical 

2015-0141
Revised February 21, 2017
9
 
 
functioning tests (walk 10 meters, 5x sit-to-stand test).  Thus, their potential to 
participate in a home-based exercise program will be screened based on subjective 
reports and objective demonstration.  Based on their responses, they will be enrolled 
onto the study or they will be triaged to the study principal investigators for further 
review.  For instance, if they are having on-going cardiopulmonary symptoms, they will 
be re-evaluated by their primary stem cell physician for medical clearance for an 
exercise regimen and if they have musculoskeletal concerns, they will be referred to 
physical medicine and rehabilitation for further evaluation.  
For the PAR-Q screening questions:   
- 
-4, they will be referred back 
to the Stem Cell Transplant attending physician, who will decide to clear the 
patient for exercise, or if they require a cardiology consultation prior to initiating 
exercise. 
- 
Physical Medicine and Rehabilitation faculty who is over-seeing the study.  They 
can potentially evaluate the patient face-to-face during the screening period, or 
will speak with the patient to determine their eligibility to participate in the study.  
- 
In the event that the patient is excluded from the study based on the PAR-Q, the 
patient will either be referred to Physical Medicine and Rehabilitation for a clinical 
consultation to address their impairments or referred to outpatient physical and 
occupational therapy (where they may receive a supervised therapy program).  
  
 
Participants from both inpatient and outpatient who are recruited for this study will 
receive a strengthening and walking program. 
We plan to approach approximately 70 patients to invite them to participate in this study 
with an accrual of 3 new participants per month with an anticipated accrual period of 
approximately 24 months.  
 
When the stem cell transplant team initiates a patient on corticosteroids for newly-
diagnosed GVHD, they will contact our study staff.  Our study staff will meet with the 
patient face-to-face at the stem cell transplant clinic or the Ambulatory Transfusion 
Clinic (ATC).  Follow up visits will also be conducted in the stem cell transplant clinic or 
ATC, as this is where the patients will attend their routinely scheduled clinic 
appointments.  They will be asked a series of questions about their exercise tolerance 
and to screen for any adverse events (script included).  During the follow up face-to-
face visits (Day 14, 28, 56, and 180), we will obtain repeat measures (questionnaires 
and functional measures).  
 
Exercise Regimen 
The American College of Sports Medicine exercise guidelines for cancer survivors 
encourage a combination of 150 minutes of moderate-intensity aerobic activity and two 
to three weekly sessions of strength training, but caution that exercise programs should 

2015-0141
Revised February 21, 2017
10
 
 
be adapted to the needs of each cancer survivor [21]. There are currently no guidelines 
for exercise in patients undergoing treatment for cancer.  Studies show that exercise 
prior to and immediately after HSCT show significant differences strength, endurance, 
functional performance, and quality of life.  [22, 23]. There is also evidence that 
isokinetic strength training can reverse corticosteroid-induced muscle wasting [24].  As 
muscle weakness and deconditioning are frequently seen sequelae after HSCT and as 
steroid myopathy develops, patients are often referred to physical and occupational 
therapy to address the weakness.  Thus, it is important to employ an exercise and 
endurance regimen to preserve strength and to circumvent further functional decline. 
 
The exercise regimen will include an 8-week, home-based strengthening walking 
program. 
 
 MDACC physical medicine and rehabilitation (PM&R) physicians will supervise 
the conduct of the exercise intervention.  
 
 Research staff trained by the PM&R faculty will implement the exercise 
intervention.  
 
 Furthermore, many of these patients receive outpatient physical therapy as 
standard of care.  If the participant is receiving outpatient physical therapy, the 
skilled therapy team will incorporate this exercise regimen in their outpatient 
program and the participant will be encouraged to continue with our exercise 
regimen as their home program. 
 
 The inpatient and outpatient groups will be given the same set of exercises 
(strengthening and walking), instructions for adherence, and follow up 
measurements will be conducted at the standard time intervals as outlined in in 
Section V: 
o Baseline (at the time of screening, consent and enrollment into the study)
o Day 14 (+/-5) 
o Day 28 (+/-5) 
o Day 56 (+/-5) 
o Day 180 post transplant  (+/- 30 days) 
 
a) Resistance/strengthening 
All participants will be instructed to perform resistance/strengthening exercises 
for a 30 minutes period three times a week.  The resistance exercises used in 
this study are designed to engage multiple upper body muscles and lower limb 
muscles.   
 
The exercises consist of seated and standing weight-bearing exercises. The 
patients will start with body-weight based exercises and will graduate to ones 
requiring resistance with the use of exercise bands.  The upper body exercises 
will strength deltoids, scapular stabilizers, triceps and rotator cuff musculature.  
These exercises will include the use of elastic exercise bands. The lower limb 

2015-0141
Revised February 21, 2017
11
 
 
exercises will strengthen the hip flexors, gluteus musculature, quadriceps, and 
gastrocnemius-soleus complex.  These exercises will include (but are not limited 
to) leg lifts, hip abductions, and calf presses.  
 
The participants will be instructed to perform the upper and lower body exercises 
prescribed for a duration of 30 minutes 3 times per week.  Participants will 
perform 1-3 sets of 12 repetitions of each exercise.  Most of the exercises will 
require the use of exercise bands.  Once they are able to perform 3 sets of 12 
repetitions of an exercise, they will graduate to the next level of increasing 
resistance.  The participants will be given a set of three bands which determine 
the level of resistance:  easy, moderate, and hard.  They will record the date, the 
color of elastic exercise band used, the number of repetitions and sets, and their 
perceived intensity of the exercise based on the Borg Rating of Perceived 
 
 
The participants in the strengthening program will be encouraged to complete an 
additional 5 minutes of stretching daily.  They will be provided with a handout 
demonstrating upper and lower body stretches to help alleviate the onset of 
delayed muscle soreness.  
 
All participants will be encouraged to perform stretches before and after their 
strengthening exercises.  We will provide them with diagrams of sample 
stretches they may perform.  
 
 
b) Walking program 
All participants will be instructed to initiate a walking program.  The walking 
program will consist of walking at a comfortable pace for 20 to 30 minutes during 
each walking session.  They will walk at least three times a week.  The goal is to 
achieve a fairly light intensity of exercise (Borg RPE of 8-10) and progress a 
moderate intensity (Borg RPE of 11-12).  Each participant will be provided a 
pedometer and will be instructed to record the number of steps taken each day. 
 
Each participant will meet face-to-face with a member of the research staff.  The 
participant will receive a patient exercise booklet that includes information on 
exercise, research staff contact info, exercise precautions, diagrams on the 
exercises, and the exercise and activity log.  They will also receive a pedometer 
and exercise bands.  Each participant will watch the exercise video clips on a 
computer or have the exercises demonstrated to them. The patient will have the 
opportunity to perform the exercise or request for the exercise to be 
demonstrated again for them.  Thus, every participant receives the same 
education on the exercise regimen.  We can also email them a link for the 
exercise clips to review from home.  Furthermore, they will be instructed on the 
use of the pedometer and for filling out their exercise logs during the initial visit. 
 
 

2015-0141
Revised February 21, 2017
12
 
 
Each participant will be issued an exercise activity log book to record their daily activity:  
record their walking activity (time, intensity, number of steps) and to record the number 
of exercises they are able to complete during each exercise session (time, intensity, 
types of exercises, repetitions).  They will also include if they performed exercises or 
activities not outlined in our study.   
 
 
If participants have internet access and choose to enter their exercise activity online, 
they will be asked to use the Redcap system to log their exercise activity on a daily 
basis. With their consent, participants will receive daily email reminders with a Redcap 
program link to log their aerobic and resistance exercise activity, pedometer steps, and 
to report any barriers or difficulties with their exercises.  Participants will still have the 
option to complete activity logs on paper and the resistance exercise log of individual 
exercises will still remain on paper.  
 
REDCap is a mature, secure web application for building and managing surveys and 
databases. While REDCap can be used to collect virtually any type of data, it is 
specifically geared to support data capture for research studies.  REDCap can 
accommodate complex relationships among tables, allowing large quantities of data to 
be integrated into a single database. Relational databases such as REDCap also allow 
for powerful and flexible queries and reports. These features include more user-friendly 
interfaces, the ability to specify valid ranges for variables, and double-entry systems for 
data, all of which help to maintain data integrity. REDCap provides audit trails for 
tracking data manipulation and user activity, as well as automated export procedures for 
seamless data downloads to Excel, PDF, and common statistical packages (SPSS, 
SAS, Stata, R). We will use the built-in security features of REDCap to restrict user 
access. 
 
Furthermore, to monitor for adherence and to screen for any exercise intolerance or 
exercise barriers, the participants will be counseled face-to-face by our research 
assistant during their follow up visits regarding their progress of their exercise program.  
The research assistant will be provided with a list of screening questions to address 
program.  The research assistant will also implement behavior interventions to 
encourage continued adherence to the exercise program, which will include education 
on the benefits of exercise and physical activity.  There will be one telephone follow up 
during week 6 of enrollment to ensure the participants do not have questions about their 
exercise program. They will receive a reminder to wear the pedometer and to complete 
the daily exercise logs.   
 
The packet includes a list of exercise precautions and also advises the patients to not 
use their exercise resistance bands when their platelet counts are less than 20 K/ul.
 
The participants will also be given the telephone contact information of the research 
staff in case they encounter problems during the exercise intervention period.  In the 

2015-0141
Revised February 21, 2017
13
 
 
event of an acute musculoskeletal injury or cardiopulmonary distress, the patient will be 
managed with an appropriate medical referral.  Participants in the outpatient group who 
are admitted to the hospital for an acute medical concern will also be followed.  They 
will need clearance from their HSCT physician and/or physical medicine and 
rehabilitation physician to continue with their exercise intervention.  They will be 
encouraged to continue with their exercise program (and record their activity) if their 
medical condition allows for it.  Furthermore, patients who develop significant functional 
decline that requires supervision and management from a skilled therapist will be 
referred to inpatient and/or outpatient physical and occupational therapy when 
appropriate.  
 
As current standard-of-care, some of the patients who are seen in the ambulatory 
treatment center (ATC) are referred to outpatient physical therapy for an exercise 
program.  These are usually group sessions for patients who do not required one-on-
one treatment sessions with a physical therapist.  If a participant in our study is enrolled 
in this outpatient ATC physical therapy program, they will still utilize our exercise 
program on their non-therapy days and in some situations, they may perform our 
exercises (aerobic and/or resistance regimens) during their therapy session to fulfill their 
exercise requirement for the day.  Again, the participant will complete their daily log so 
we may track how much exercise they are performing each day.  
 
 
If the patient falls or has an adverse event, they are instructed to call their stem cell 
transplant physician.  These patients receive extensive counseling after their stem cell 
transplant on when and how to contact their stem cell transplant physician and team.  If 
there are questions and concerns about the exercise regimen or intolerance of certain 
exercises, the participant should call our research staff directly.  The Physical Medicine 
and Rehabilitation physicians will be communicating directly with research team on a 
weekly basis to discuss any adverse events or concerns.   
 
It is anticipated that a fully adherent participant would be able to complete 30 minutes of 
exercise daily, five times per week, which equates to approximately 150 minutes of 
exercise per week. 
 
Equipment provided: 
 Notebook for the exercise activity log ($10-20 each x 40) 
 Pedometer:  EKHO One Pedometer 
http://www.amazon.com/Ekho-1277210-EKHO-One-
Pedometer/dp/B002MACRUC/ref=sr_1_2?ie=UTF8&qid=1449008114&sr=8-
2&keywords=ekho+one+pedometer 
 Resistance exercise bands: therabands in 3 different levels of resistance
http://www.amazon.com/Thera-Band-Latex-Exercise-Bands-
YELLOW/dp/B00SX165ZC/ref=pd_sim_328_1?ie=UTF8&dpID=415g8eKmdtL&d
pSrc=sims&preST=_AC_UL160_SR160%2C160_&refRID=1HQKCG0DCF55KP
ZRVKRC 
 

2015-0141
Revised February 21, 2017
14
 
 
 
 
Equipment needed: 
 Handheld dynamometer:  microFET 2 Hoggan Health Industries ($1095) 
http://www.hogganhealth.net/microfet2.php 
 Stop watch 
 
 
The participants will not receive monetary compensation for their participation in this 
study as this is an unfunded pilot study.  The patients are not returning for any follow-up 
visits as they will be seen during their normally scheduled clinic visit. There would be no 
burden of extra re
and incentive for participating in this study is they will receive exercise education and an 
exercise regimen, which will be beneficial in these newly-diagnosed GVHD patients.
 
 
VI. STATISTICS:  
The objective of this study is to estimate change in the six functional/physical measures 
(described in Section VI) over time. The information gained in this study will be used for 
future larger studies.  These measures will be collected at baseline, two weeks, 4 
weeks, and 8 weeks.  
Improved (or PROMIS) Health Assessment Questionnaire, PROMIS Short Form v1.0  
Physical Function 12a, MDASI, FACT-Fatigue, GVHD associated measures and 
corticosteroid dose will also be collected over the same time course.  We plan to 
approach 70 patients (3 patients each month for an approximate period of 24 months of 
accrual).  We expect that about 85% (60 patients) will agree to participate in the study.  
Further if 10 (20%) out of 60 patients drop out early due to developing significant 
weakness, disease progression, or have a prolonged and complicated inpatient hospital 
course, we expect 50 patients to complete the 8 week measures.  With 50 patients, we 
will have an 80% power to detect an effect size of 0.404 in a functional measure change 
from baseline to 8 weeks using a paired t-test with a 0.05 two-sided significance level. 
 
To explore the possible corticosteroid dose effect on the functional measures, graphical 
methods will be used to present data and the cumulative steroid exposure may be 
correlated with functional measures over time in a repeated measures analysis when 
appropriate.  Furthermore, 2-week or 4-week cumulative steroid exposure may be 
compared between 6-month non-relapse deaths and others, provided patients all 
survive past 2 weeks or 4 weeks. 
 
We expect about 20% non-relapse mortality rate at 6 months (NRM6).  With about 10 
non-relapse deaths, we will explore potential difference in baseline and/or the change of 
functional/physical measures between 6-month non-relapse deaths vs others.  With 10 
non-relapse deaths and 40 others, we will have an 80% power to detect an effect size of 
1.011 in the difference of a functional measure at baseline between two groups using a 
two-sample t-test with a 0.05 two-sided significance level.  
 

2015-0141
Revised February 21, 2017
15
 
 
We will also evaluate adherence rates to the exercise regimen and drop-out 
rates/patterns, which is very important for the future larger study planning. 
 
At the end of the study, we will summarize the pattern of the functional/physical 
measure change, pattern of exercise and other secondary measures, using collected 
information from all 50 patients.  Repeated measures analysis or generalized estimating 
equation maybe applied to estimate the magnitude of the measure change over time.  In 
the same model we will also evaluate the correlation between/among different 
measures.  These models incorporate the intra-patient correlation into consideration 
when these measures are recorded multiple times from each patient. 
 
VII. PROTOCOL MONITORING AND SAFETY 
Trained research staff will be performing study assessments and monitoring the patient 
carefully throughout the study period. A study physician will also be available by pager 
to address any concerns, distress, or questions, and will attend to the patient as 
needed.  Regulatory monitoring will be provided by the principal investigator and the 
Institutional Review Board. Patient confidentiality will be ensured by use of patient 
initials, secure storage of clinical data, and anonymous reporting. 
 
Health information will be protected and we will maintain the confidentiality of the data 
obtained from the patient's chart. 
 
Collection of identifiers: We will collect and securely store patients' identifiers (including 
name and medical record number).  Each patient will be assigned a study number that 
will be the only identifier to figure in the analytical file and personal data will not be 
disclosed in any form. The key linking these numbers will be retained in a securely 
locked file by the investigator. 
 
Data Storage: Protection of electronic and paper records will be guaranteed. All 
electronic records will be stored on password-protected institution computers behind the 
institution firewall.  Any paper records will be classified and stored in locked files inside 
a locked office. 
 
Training of personnel: Only MDACC personnel trained in maintaining confidentiality, the 
principle investigators, co-investigators, and research staff will have access to study 
records. 
 
Data sharing: Study data will not be shared with any individuals or entities. The data will 
be kept by the principle investigator in a locked file cabinet. 
 
Final disposition of study records: These data will be used only for this research study. 
Data files will be destroyed within 5 years after publication of the findings. 
 

2015-0141
Revised February 21, 2017
16
 
 
 
 
VIII. REFERENCES 
 
1. Thomas ED. Karnofsky Memorial Lecture. Marrow transplantation for malignant 
diseases. J Clin Oncol 1983; 1: 517 531. 
 
2. Antin JH, Ferrara J. Cytokine dysregulation and acute graft-versus-host disease. 
Blood 1992; 80: 2964 2968. 
 
3. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 
2009 May 2;373(9674):1550-61. PubMed PMID: 19282026. Pubmed Central 
PMCID: 2735047. 
 
4. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD et al. 
Cyclosporine, methotrexate, and prednisone compared with cyclosporine and 
prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med 
1993; 329:1225 1230. 
 
5. Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR et al. A 
retrospective analysis of therapy for acute graft versus-host disease: initial 
treatment. Blood 1990;76: 1464 1472. 
 
6. Ruutu T, Hermans J, van Biezen A, Niederwieser D, Gratwohl A, Apperley JF. 
How should corticosteroids be used in the treatment of acute GVHD? EBMT 
Chronic Leukemia Working Party. European Group for Blood and Marrow 
Transplantation. Bone Marrow Transplant 1998; 22: 614 615. 
 
7. Ruutu T, Niederwieser D, Gratwohl A, Apperley JF. A survey of the prophylaxis 
and treatment of acute GVHD in Europe: a report of the European Group for 
Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party 
of the EBMT. Bone Marrow Transplant 1997; 19: 759 764. 
 
8. Cushing H. The basophil adenomas of the pituitary body and their clinical 
manifestation. Johns Hopkins Med J 1932; 50: 137.  
 
9. Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of 
glucocorticoids. Pharmacol Ther 2002; 96: 23 43. 
 
10. Lee HJ, Oran B, Saliba RM, Couriel DM, Shin K, Massey P, et al. Steroid 
myopathy in patients with acute graft-versus-host disease treated with high-dose 
steroid therapy. Bone marrow transplantation. 2006 Aug;38(4):299-303. PubMed 
PMID: 16819437. 
 

2015-0141
Revised February 21, 2017
17
 
 
11. Khaleeli AA, Edwards RH, Gohil K, McPhail G, Rennie MJ, Round J, et al. 
Corticosteroid myopathy: a clinical and pathological study. Clinical endocrinology. 
1983 Feb;18(2):155-66. PubMed PMID: 6851197. 
 
12. Levin OS, Polunina AG, Demyanova MA, Isaev FV. Steroid myopathy in patients 
with chronic respiratory diseases. Journal of the neurological sciences. 2014 Mar 
15;338(1-2):96-101. PubMed PMID: 24380687. 
 
13. Fernandez-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, et 
al. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular 
atrophy: a randomised placebo-controlled trial. The Lancet Neurology. 2011 
Feb;10(2):140-7. PubMed PMID: 21216197. Pubmed Central PMCID: 3056353.
 
14. Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate JB, Pellegrino RJ. 
Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle & 
nerve. 1981 May-Jun;4(3):186-97. PubMed PMID: 7017401. 
 
15. Mayhew A, Mazzone ES, Eagle M, Duong T, Ash M, Decostre V, et al. 
Development of the Performance of the Upper Limb module for Duchenne 
muscular dystrophy. Developmental medicine and child neurology. 2013 
Nov;55(11):1038-45. PubMed PMID: 23902233. 
 
16. Werlauff U, Vissing J, Steffensen BF. Change in muscle strength over time in 
spinal muscular atrophy types II and III. A long-term follow-up study. 
Neuromuscular disorders : NMD. 2012 Dec;22(12):1069-74. PubMed PMID: 
23127961. 
 
17. Bielefeld P. Actualites sur la myopathie cortisonique. La Revue Med Interne 
1996; 17: 255. 
  
18. Shee CD. Risk factors for hydrocortisone myopathy in acute severe asthma. 
Respir Med 1990; 84: 229 233. 
 
19. Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvao DA, 
Pinto BM, et al. American College of Sports Medicine roundtable on exercise 
guidelines for cancer survivors. Medicine and science in sports and exercise. 
2010 Jul;42(7):1409-26. PubMed PMID: 20559064. 
 
20. Baumann FT, Kraut L, Schule K, Bloch W, Fauser AA. A controlled randomized 
study examining the effects of exercise therapy on patients undergoing 
haematopoietic stem cell transplantation. Bone marrow transplantation. 2010 
Feb;45(2):355-62. PubMed PMID: 19597418. 
 
21. Jarden M, Baadsgaard MT, Hovgaard DJ, Boesen E, Adamsen L. A randomized 
trial on the effect of a multimodal intervention on physical capacity, functional 

2015-0141
Revised February 21, 2017
18
 
 
performance and quality of life in adult patients undergoing allogeneic SCT. Bone 
marrow transplantation. 2009 May;43(9):725-37. PubMed PMID: 19234513.
 
22. Horber FF, Scheidegger JR, Grunig BE, Frey FJ. Evidence that prednisone-
induced myopathy is reversed by physical training. The Journal of clinical 
endocrinology and metabolism. 1985 Jul;61(1):83-8. PubMed PMID: 3998075.