8 pharmaceutical information
references

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Mediators of Inflammation, 2013 41. Fernandez-Real JM, Vayreda M, Richart C, et al: Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 86:1154-9, 2001 42. Damas P, Ledoux D, Nys M, et al: Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215:356-62, 1992 43. Veldhoen M, Hocking RJ, Atkins CJ, et al: TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179-89, 2006 44. Bettelli E, Carrier Y, Gao W, et al: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235-8, 2006 45. Wan S, Xia C, Morel L: IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J Immunol 178:271-9, 2007 46. Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033-6, 2003 47. Imamura M, Hashino S, Kobayashi H, et al: Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. Bone Marrow Transplant 13:745-51, 1994 48. Barak V, Levi-Schaffer F, Nisman B, et al: Cytokine dysregulation in chronic graft versus host disease. Leuk Lymphoma 17:169-73, 1995 49. Socie G, Loiseau P, Tamouza R, et al: Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.  
Transplantation 72:699-706, 2001 50. Cavet J, Dickinson AM, Norden J, et al: Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation.  
Blood 98:1594-600, 2001 51. Rose-John S, Scheller J, Elson G, et al: Interleukin-6 biology is coordinated by membranebound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80:227-36, 2006 52. Scheller J, Garbers C, Rose-John S: Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities. Semin Immunol 26:2-12, 2014 53. Mullberg J, Schooltink H, Stoyan T, et al: The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 23:473-80, 1993 54. Jones SA, Horiuchi S, Topley N, et al: The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 15:43-58, 2001 55. Serody JS, Hill GR: The IL-17 differentiation pathway and its role in transplant outcome. Biol Blood Marrow Transplant 18:S56-61, 2012 56. Schaper F, Rose-John S: Interleukin-6: Biology, signaling and strategies of blockade. Cytokine Growth Factor Rev 26:475-87, 2015 57. Givon T, Revel M, Slavin S: Potential use of interleukin-6 in bone marrow transplantation:
effects of recombinant human interleukin-6 after syngeneic and semiallogeneic bone marrow transplantation in mice. Blood 83:1690-7, 1994 58. Chen X, Das R, Komorowski R, et al: Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood 114:891-900, 2009 59. Noguchi D, Wakita D, Ohkuri T, et al: Blockade of IL-6-signaling inhibits the pathogenesis of CD4+ T cell-mediated lethal graft-versus-host reaction against minor histocompatibility antigen. Immunol Lett 136:146-55, 2011 60. Tawara I, Koyama M, Liu C, et al: Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res 17:77-88, 2011 61. Le Huu D, Matsushita T, Jin G, et al: IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease. J Invest Dermatol 132:2752-61, 2012 62. Lee SH, Moon SJ, Park MJ, et al: PIAS3 suppresses acute graft-versus-host disease by modulating effector T and B cell subsets through inhibition of STAT3 activation. Immunol Lett 160:79-88, 2014 63. Radojcic V, Pletneva MA, Yen HR, et al: STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model. J Immunol 184:76474, 2010 64. Lu SX, Alpdogan O, Lin J, et al: STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease. Blood 112:5254-8, 2008 65. Laurence A, Amarnath S, Mariotti J, et al: STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37:209-22, 2012 66. Betts BC, Sagatys EM, Veerapathran A, et al: CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response.  
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results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 67:1516-23, 2008 74. Roddy JV, Haverkos BM, McBride A, et al: Tocilizumab for steroid refractory acute graftversus-host disease. Leuk Lymphoma 57:81-5, 2016 75. Drobyski WR, Pasquini M, Kovatovic K, et al: Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant 17:1862-8, 2011 76. Kennedy GA, Varelias A, Vuckovic S, et al: Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 15:1451-9, 2014 77. Drobyski WR, Szabo A, Zhu F, et al: Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica 103:717-727, 2018 78. Sehn LH, Alyea EP, Weller E, et al: Comparative outcomes of T-cell-depleted and non-T-celldepleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: impact of donor lymphocyte infusion. J Clin Oncol 17:561-8, 1999 79. Soiffer RJ, Lerademacher J, Ho V, et al: Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood 117:6963-70, 2011 80. Alyea EP, Weller E, Fisher DC, et al: Comparable outcome with T-cell-depleted unrelateddonor versus related-donor allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 8:601-7, 2002 81. Holtan SG, DeFor TE, Lazaryan A, et al: Composite end point of graft-versus-host diseasefree, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125:1333-8, 2015 82. Andermann TM, Peled JU, Ho C, et al: The Microbiome and Hematopoietic Cell Transplantation: Past, Present, and Future. Biol Blood Marrow Transplant 24:1322-1340, 2018 83. Holler E, Butzhammer P, Schmid K, et al: Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 20:640-5, 2014 84. Weber D, Jenq RR, Peled JU, et al: Microbiota Disruption Induced by Early Use of BroadSpectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation.  
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Nat Rev Immunol 18:87-88, 2018 89. Wilkinson EM, Ilhan ZE, Herbst-Kralovetz MM: Microbiota-drug interactions: Impact on metabolism and efficacy of therapeutics. Maturitas 112:53-63, 2018 90. Drobyski W SA, Hari P et al.: Results of a Phase II Clinical Trial of Tocilizumab, Tacrolimus and Methotrexate (Toc/Tac/MTX) for the Prevention of Acute Graft Versus Host Disease (GVHD) and Matched Case Control Comparison to Tac/MTX after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant; Abstract 91. 23:S89, 2017 91. Walters W, Hyde ER, Berg-Lyons D, et al: Improved Bacterial 16S rRNA Gene (V4 and V4-5)
and Fungal Internal Transcribed Spacer Marker Gene Primers for Microbial Community Surveys. mSystems 1, 2016 92. Kuczynski J, Stombaugh J, Walters WA, et al: Using QIIME to analyze 16S rRNA gene sequences from microbial communities. Curr Protoc Microbiol Chapter 1:Unit 1E 5, 2012 93. Taur Y, Jenq RR, Perales MA, et al: The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124:1174-82, 2014 94. Bacigalupo A, Ballen K, Rizzo D, et al: Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15:1628-33, 2009 95. Przepiorka D, Weisdorf D, Martin P, et al: 1994 Consensus Conference on Acute GVHD
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8 pharmaceutical information
appendix 1. performance status criteria

| ECOG Performance Status Scale   | Karnofsky Performance Scale                                                                                                                                                             |         |                                                                                |
|---------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|--------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                                            | Percent | Description                                                                    |
| 100                             | Normal, no complaints, no evidence of  disease                                                                                                                                          |         |                                                                                |
| 0                               | Normal activity Fully active, able to carry on all predisease performance without  restriction                                                                                                                                                                                         | 90      | Able to carry on normal activity; minor  signs or symptoms of disease          |
| 1                               | Symptoms, but ambulatory Restricted in physically strenuous  activity, but ambulatory and able to  carry out work of a light or sedentary  nature (e.g., light housework, office  work) | 80      | Normal activity with effort; some signs or  symptoms of disease                |
| 70                              | Cares for self, unable to carry on normal  activity or to do active work                                                                                                                |         |                                                                                |
| 2                               | In bed <50% of the time Ambulatory and capable of all selfcare, but unable to carry out any  work activities Up and about more than 50% of  waking hours.                                                                                                                                                                                         | 60      | Requires occasional assistance, but is  able to care for most of his/her needs |
| 50                              | Requires considerable assistance and  frequent medical care                                                                                                                             |         |                                                                                |
| 40                              | Disabled, requires special care and  assistance                                                                                                                                         |         |                                                                                |
| 3                               | In bed >50% of the time Capable of only limited self-care,  confined to bed or chair more than  50% of waking hours                                                                     | 30      | Severely disabled, hospitalization  indicated Death not imminent               |
| 4                               | 100% bedridden Completely disabled Cannot carry on any self-care Totally confined to bed or chair                                                                                       | 20      | Very sick, hospitalization indicated Death not imminent                        |
| 10                              | Moribund, fatal processes progressing  rapidly                                                                                                                                          |         |                                                                                |
| 5                               | Dead                                                                                                                                                                                    | 0       | Dead                                                                           |
appendix 2. gvhd assessment
acute gvhd assessment staging and

| Staging              |                     |                    |                      |
|----------------------|---------------------|--------------------|----------------------|
| Stage                | Skin                | GI                 | Liver                |
| 1                    | < 25% rash          | Diarrhea > 500ml/d | Bilirubin 2-3mg/dl   |
| or persistent nausea |                     |                    |                      |
| 2                    | 25-50%              | > 1000 ml/d        | Bilirubin 3-6 mg/dl  |
| 3                    | > 50%               | > 1500 ml/d        | Bilirubin 6-15 mg/dl |
| 4                    | Generalized         | Large volume       | Bilirubin > 15 mg/dl |
| erythroderma with    | diarrhea and severe |                    |                      |
| bullae               | abdominal pain ±    |                    |                      |
| ileus                |                     |                    |                      |
appendix 2. gvhd assessment
grading of acute gvhd

| Grade   | Skin       | GI        | Liver   |
|---------|------------|-----------|---------|
| I       | Stage 1-2  | 0         | 0       |
| I       | Stage 3 or | Stage 1   | Stage 1 |
| or      |            |           |         |
| III     | Stage 2-4  | Stage 2-3 |         |
| --      |            |           |         |
| IV      | Stage 4    | ---       | Stage 4 |  
Grading of Chronic GVHD (NIH Criteria)  
| SCORE 0                                                                               | SCORE 1                   | SCORE 2                | SCORE 3                |                    |
|---------------------------------------------------------------------------------------|---------------------------|------------------------|------------------------|--------------------|
| PERFORMANCE                                                                           | □ Asymptomatic and        | - Symptomatic,         | - Symptomatic,         | - Symptomatic,     |
| SCORE:                                                                                | fully active (ECOG        | fully ambulatory,      | ambulatory, capable    | limited self-care, |
| 0; KPS or LPS                                                                         | restricted only in        | of self-care, >50%     | > 50% of waking        |                    |
| 100%)                                                                                 | physically                | of waking hours ou     | hours in bed (ECOG     |                    |
| KPS                                                                                   | ECOG LPS                  | strenuous activity     | of bed (ECOG 2,        | 3-4, KPS or LPS    |
| (COG 1, KPS                                                                           | KPS or LPS 60-            | <60%)                  |                        |                    |
| or LPS 80-90%)                                                                        | 70%)                      |                        |                        |                    |
| SKINT                                                                                 |                           |                        |                        |                    |
| S CORE % BSA                                                                          |                           |                        |                        |                    |
| GV HD features to be scored                                                           | □ No BSA                  | □ 1-18% BSA            | 1 19-50% BSA           | □ >50% BSA         |
| bv BSA:                                                                               | involved                  |                        |                        |                    |
| Check all that apply:                                                                 |                           |                        |                        |                    |
| □ Maculopapular rash/erythema                                                         |                           |                        |                        |                    |
| □ Lichen planus-like features                                                         |                           |                        |                        |                    |
| □ S clerotic features                                                                 |                           |                        |                        |                    |
| □ Fapulosquamous lesions or                                                           |                           |                        |                        |                    |
| ichthyosis                                                                            |                           |                        |                        |                    |
| □ Keratosis pilaris-like GVHD                                                         |                           |                        |                        |                    |
| SKIN FEATURES                                                                         | Check all that apply:     |                        |                        |                    |
| SCORE:                                                                                | □ No sclerotic            | □ Superficial          | □ Deep sclerotic       |                    |
| features                                                                              | sclerotic features        | features               |                        |                    |
| "not hidebound"                                                                       | □ "Hidebound"             |                        |                        |                    |
| (able to pinch)                                                                       | (unable to pinch)         |                        |                        |                    |
| □ Impaired mobility                                                                   |                           |                        |                        |                    |
| □ Ulceration                                                                          |                           |                        |                        |                    |
| Other skin GVHD features (NOT scored by BSA)                                          |                           |                        |                        |                    |
| Check all that apply:                                                                 |                           |                        |                        |                    |
| □ Hyperpigmentation                                                                   |                           |                        |                        |                    |
| □ Hypopigmentation                                                                    |                           |                        |                        |                    |
| □ Poikiloderma                                                                        |                           |                        |                        |                    |
| □ Severe or generalized pruritus                                                      |                           |                        |                        |                    |
| □ Hair involvement                                                                    |                           |                        |                        |                    |
| □ Nail involvement.                                                                   |                           |                        |                        |                    |
| ❏ Abnormality present but explained entirely by non-GVHD documented cause (specify):  |                           |                        |                        |                    |
| MOUTH                                                                                 | ❏ Mild symptoms           |                        |                        |                    |
| ❏ No symptoms                                                                         | □ Moderate                | ❏ Severe symptoms with |                        |                    |
| Lichen planus-like                                                                    | with disease signs        | symptoms with          | disease signs on       |                    |
| features present:                                                                     | but not limiting          | disease signs with     | examination with major |                    |
| Cl Yes                                                                                | partial limitation        |                        |                        |                    |
| oral intake                                                                           | limitation of oral intake |                        |                        |                    |
| E No                                                                                  | significantly             | of oral intake         |                        |                    |
| ❏ ¿ bnormality present but explained entirely by non-GVHD documented cause (specify): |                           |                        |                        |                    |
| IT-Chhabra-Proactive                                                                  | 76                        | Version No.4           |                        |                    |
| Version Date: 09/19/2019                                                              |                           |                        |                        |                    |  
| SCORE 0                                                                              | SCORE 1              | SCORE 2                    | SCORE 3                  |                       |
|--------------------------------------------------------------------------------------|----------------------|----------------------------|--------------------------|-----------------------|
| EYES                                                                                 | ❏ No symptoms        | ❏ Mild dry eye             | □ Moderate dry eye       | ❏ Severe dry eye      |
| symptoms not                                                                         | symptoms partially   | symptoms significantly     |                          |                       |
| Ker atoconjunctivitis                                                                | affecting ADL        | affecting ADL              | affecting ADL (special   |                       |
| sicca (KCS) confirmed                                                                | (requirement of      | (requiring lubricant       | eyeware to relieve pain) |                       |
| by ophthalmologist:                                                                  | eye drops > 3 x per  |                            |                          |                       |
| lubricant eye                                                                        | OR unable to work    |                            |                          |                       |
|                                                                                      | drops < 3 x per      | dy or punctal.             | because of ocular        |                       |
| 1 No                                                                                 | dy)                  | plugs),                    | symptoms OR loss of      |                       |
| WITHOUT new                                                                          |                      |                            |                          |                       |
| ❏ Not examined                                                                       | vision due to KCS    |                            |                          |                       |
| vision impairment                                                                    |                      |                            |                          |                       |
| due to KCS                                                                           |                      |                            |                          |                       |
| ❏ Abnormality present but explained entirely by non-GVHD documented cause (specify): |                      |                            |                          |                       |
| GI Tract.                                                                            | ❏ No symptoms        | □ Symptoms                 | □ Symptoms               | □ Symptoms associated |
| Check all that apply:                                                                | without.             | associated with            | with significant weight. |                       |
| loss* > 15%, requires                                                                |                      |                            |                          |                       |
| ❏ Esophageal web/                                                                    | significant weight   | mild to moderate           |                          |                       |
| loss* (<5%)                                                                          | weight loss*         | nutritional supplement for |                          |                       |
| proximal stricture                                                                   | (5-15%) OR           | most calorie needs OR      |                          |                       |
| for ring                                                                             |                      |                            |                          |                       |
| □ Dysphagia                                                                          | moderate diarrhea    | esophageal dilation OR.    |                          |                       |
| without                                                                              | severe diarrhea with |                            |                          |                       |
| □ Anorexia                                                                           | significant          | significant interference   |                          |                       |
| □ Nausea                                                                             | interference with    | with daily living          |                          |                       |
| □ Vomiting                                                                           | dily living          |                            |                          |                       |
| □ Diarrhea                                                                           |                      |                            |                          |                       |
| ↑ Weight loss >5%*                                                                   |                      |                            |                          |                       |
| □ Failure to thrive                                                                  |                      |                            |                          |                       |
| ❏ Abnormality present but explained entirely by non-GVHD documented cause (specify): |                      |                            |                          |                       |
| LIVER                                                                                | □ Normal total       | □ Normal total             | - Elevated total         | ❏ Elevated total      |
| bilirubin and                                                                        | bilirubin with ALT   | bilirubin but              | bilirubin > 3 mg/dL      |                       |
| AT or AP                                                                             | ≥ to 5 x ULN or      | < 3 mg/dL or               |                          |                       |
| < 3 x ULN                                                                            | AP ≥ 3 x ULN         | ALT > 5 ULN                |                          |                       |
| ❏ Abnormality present but explained entirely by non-GVHD documented cause (specify): |                      |                            |                          |                       |
| LUNGS**                                                                              | □ No symptoms        | □ Mild symptoms            | □ Moderate.              | □ Severe symptoms     |
| Symptom score:                                                                       | (hortness of         | symptoms                   | (shortness of breath  at |                       |
| (shortness of breath                                                                 |                      |                            |                          |                       |
| breath after                                                                         | rest; requiring 02 ) |                            |                          |                       |
| climbing one flight                                                                  | after walking on     |                            |                          |                       |
| of steps)                                                                            | flat ground)         |                            |                          |                       |
| Lung score:                                                                          | □ FEV1≥80%           | □ FEV1 60-79%              | ❏ FEV1 40-59%            | ❏ FEVI ≤39%           |
| % FEV1                                                                               |                      |                            |                          |                       |
| Pul nonary function tests                                                            |                      |                            |                          |                       |
| ❏ Not performed                                                                      |                      |                            |                          |                       |
| ❏ Abnormality present but explained entirely by non-GVHD documented cause (specify): |                      |                            |                          |                       |  
77  
| SCORE 0                                                                               | SCORE 1             | SCORE 2             | SCORE 3                   |                       |
|---------------------------------------------------------------------------------------|---------------------|---------------------|---------------------------|-----------------------|
| JOUNTS AND FASCIA                                                                     |                     | ❏ Mild tightness of | ❏ Tightness of arms or    | ❏ Contractures WITH   |
| symptoms                                                                              | arms or legs,       | legs OR joint       | significant decrease of   |                       |
| P-FOM score                                                                           | normal or mild.     | contractures,       | ROM AND significant       |                       |
| (se: below)                                                                           | decreased range of  | erythema thought    | limitation of ADL         |                       |
| Shoulder (1-7):                                                                       | motion (ROM)        | due to fasciitis,   | (unable to tie shoes,     |                       |
| Eltow (1-7):                                                                          | AND not affecting   | moderate decrease   | button shirts, dress self |                       |
| Wist/finger (1-7):                                                                    | ADL                 | ROM AND mild to     | etc.)                     |                       |
| Ankle (1-4):                                                                          | moderate limitation |                     |                           |                       |
| of ADL                                                                                |                     |                     |                           |                       |
| ❏ ¿!bnormality present but explained entirely by non-GVHD documented cause (specify): |                     |                     |                           |                       |
| GENITAL TRACT                                                                         | □ No signs          | □ Mild signs* and   | ❏ Moderate signs + and    | ❏ Severe signs + with |
| ( See Supplemental figure )                                                           | females with or     | my may have         | or without                |                       |
| [] Not examined                                                                       | without discomfort  | symptoms with       | symptoms                  |                       |
| on exam                                                                               | discomfort on exam  |                     |                           |                       |
| Currently sexually active                                                             |                     |                     |                           |                       |
| [] Yes                                                                                |                     |                     |                           |                       |
| [] No                                                                                 |                     |                     |                           |                       |  
❏ ¿!bnormality present but explained entirely by non-GVHD documented cause (specify):
Other indicators, clinical features or complications related to chronic GVHD (check all that apply and assign a score to severity (0-3) based on functional impact where applicable none - 0.mild -1, moderate -2, severe - 3)
□ Ascites (serositis)
□ Myasthenia Gravis
□ Pericardial Effusion
□ Peripheral Neuropathy
❏ Eosinophilia > 500/μ 1
□ Pleural Effusion(s)
□ Polymyositis
□ Platelets <100,000/ul
[] Nephrotic syndrome,
❏ Weight loss>5%* without GI symptoms  
Overall GVHD Severity
(Opinion of the evaluator)
❏ No GVHD
Mild
□
D
Moderate D
Severe Photographic Range of Motion (P-ROM)
appendix 3 qol measures
grading of acute gvhd

Participant \# _________ Date: _________
IDAS  
  
  
Instructions: Below is a list of feelings, sensations, problems, and experiences that people sometimes have. Read each item to determine how well it describes your recent feelings and experiences. Then select the option that best describes **how much** you have felt or experienced things this way **during the past two weeks, including today**.  
| 1. I was proud of myself………………………………………………………………...      | 1   | 2   | 3   | 4   | 5   |
|----------------------------------------------------------|-----|-----|-----|-----|-----|
| 2. I felt exhausted……………………………………………………………………….          | 1   | 2   | 3   | 4   | 5   |
| 3. I felt depressed……………………………………………………………………….          | 1   | 2   | 3   | 4   | 5   |
| 4. I felt inadequate………………………………………………………………………          | 1   | 2   | 3   | 4   | 5   |
| 5. I slept less than usual…………………………………………………………………      | 1   | 2   | 3   | 4   | 5   |
| 6. I felt fidgety, restless…………………………………………………………………     | 1   | 2   | 3   | 4   | 5   |
| 7. I had thoughts of suicide ……………………………………………………….…     | 1   | 2   | 3   | 4   | 5   |
| 8. I slept more than usual……………………………………………………………….      | 1   | 2   | 3   | 4   | 5   |
| 9. I hurt myself purposely ………………………………                  | 1   | 2   | 3   | 4   | 5   |
| 10. I slept very poorly…………………………………………………………………..       | 1   | 2   | 3   | 4   | 5   |
| 11. I blamed myself for things                           | 1   | 2   | 3   | 4   | 5   |
| 12. I had trouble falling asleep                         | 1   | 2   | 3   | 4   | 5   |
| 13. I felt discouraged about things……………………………………………………… | 1   | 2   | 3   | 4   | 5   |
| 14. I thought about my own death                         | 1   | 2   | 3   | 4   | 5   |
| 15. I thought about hurting myself                       | 1   | 2   | 3   | 4   | 5   |
| 16. I did not have much of an appetite                   | 1   | 2   | 3   | 4   | 5   |  
| 17. I felt like eating less than usual                                                               | 1   | 2            | 3   | 4   | 5   |
|------------------------------------------------------------------------------------------------------|-----|--------------|-----|-----|-----|
| 19. I did not feel much like eating………………………………………………………                                             | 1   | 2            | 3   | 4   | 5   |
| 21. I felt optimistic………………………………………………………………………                                                     | 1   | 2            | 3   | 4   | 5   |
| 23. I felt that I had accomplished a lot                                                             | 1   | 2            | 3   | 4   | 5   |
| 24. I looked forward to things with enjoyment                                                        | 1   | 2            | 3   | 4   | 5   |
| 25. I was furious…………………………………………………………………………                                                        | 1   | 2            | 3   | 4   | 5   |
| 26. I felt hopeful about the future                                                                  | 1   | 2            | 3   | 4   | 5   |
| 27. I felt that I had a lot to look forward to                                                       | 1   | 2            | 3   | 4   | 5   |
| 28. I felt like breaking things   29. I had disturbing thoughts of something bad that happened to me | 1   | 2            | 3   | 4   | 5   |
| 30. Little things made me mad                                                                        | 1   | 2            | 3   | 4   | 5   |
| 31. I felt enraged…………………………………………………………………………                                                       | 1   | 2            | 3   | 4   | 5   |
| 32. I had nightmares that reminded me of something bad that happened                                 | 1   | 2            | 3   | 4   | 5   |
| 33. I lost my temper and yelled at people……………………………………………….                                         | 1   | 2            | 3   | 4   | 5   |
| 34. I felt like I had a lot of interesting things to do.                                             | 1   | 2            | 3   | 4   | 5   |
| 35. I felt like I had a lot of energy                                                                | 1   | 2            | 3   | 4   | 5   |
| 36. I had memories of something scary that happened                                                  | 1   | 2            | 3   | 4   | 5   |
| 37. I felt self-conscious knowing that others were watching me                                       | 1   | 2            | 3   | 4   | 5   |
| 38. I felt a pain in my chest …………………………………………………………….                                               | 1   | 2            | 3   | 4   | 5   |
| 39. I was worried about embarrassing myself socially                                                 | 1   | 2            | 3   | 4   | 5   |
| 40. I felt dizzy or light headed                                                                     | 1   | 2            | 3   | 4   | 5   |
| 41. I cut or burned myself on purpose                                                                | 1   | 2            | 3   | 4   | 5   |
| IIT-Chhabra-Proactive                                                                                | 81  | Version No.4 |     |     |     |  
81  
42. I had little interest in my usual hobbies or activities 1 2 3 4 5  
| 43. I thought that the world would be better off without me…………………………….   | 1   | 2   | 3   | 4   | 5   |
|---------------------------------------------------------------------------|-----|-----|-----|-----|-----|
| 44. I felt much worse in the morning than later in the day                | 1   | 2   | 3   | 4   | 5   |
| 45. I felt drowsy, sleepy…………………………………………………………………                        | 1   | 2   | 3   | 4   | 5   |
| 46. I woke up early and could not get back to sleep…………………………………….        | 1   | 2   | 3   | 4   | 5   |
| 47. I had trouble concentrating                                           | 1   | 2   | 3   | 4   | 5   |
| 48. I had trouble making up my mind                                       | 1   | 2   | 3   | 4   | 5   |
| 49. I talked more slowly than usual                                       | 1   | 2   | 3   | 4   | 5   |
| 50. I had trouble waking up in the morning…………………………………………….              | 1   | 2   | 3   | 4   | 5   |
| 51. I found myself worrying all the time                                  | 1   | 2   | 3   | 4   | 5   |
| 52. I woke up frequently during the night                                 | 1   | 2   | 3   | 4   | 5   |
| 53. It took a lot of effort for me to get going                           | 1   | 2   | 3   | 4   | 5   |
| 54. I woke up much earlier than usual                                     | 1   | 2   | 3   | 4   | 5   |
| 55. I was trembling or shaking…………………………………………………………..                    | 1   | 2   | 3   | 4   | 5   |
| 56. I became anxious in a crowded public setting                          | 1   | 2   | 3   | 4   | 5   |
| 57. I felt faint…………………………………………………………………………….                            | 1   | 2   | 3   | 4   | 5   |
| 58. I found it difficult to make eye contact with people                  | 1   | 2   | 3   | 4   | 5   |
| 59. My heart was racing or pounding                                       | 1   | 2   | 3   | 4   | 5   |
| 60. I got upset thinking about something bad that happened                | 1   | 2   | 3   | 4   | 5   |
| 61. I found it difficult to talk with people I did not know well          | 1   | 2   | 3   | 4   | 5   |
| 62. I had a very dry mouth……………………………………………………                            | 1   | 2   | 3   | 4   | 5   |
| 63. I was short of breath…………………………………………………………………                        | 1   | 2   | 3   | 4   | 5   |  
64. I felt like I was choking…………………………………………………………….. 1 2 3 4 5
appendix 3 qol measures
fsi

Instructions: The following questions ask about fatigue during the **past week**. For each of the following, circle the one number that best indicates how that item applies to you.  
| 1. Rate your level of fatigue on the day you felt most fatigued during the past week.  0 1 2 3 4 5 6 7 8   | 9                | 10   |    |    |    |    |    |    |    |    |    |
|------------------------------------------------------------------------------------------------------------|------------------|------|----|----|----|----|----|----|----|----|----|
| Not at all                                                                                                 | As fatigued as   |      |    |    |    |    |    |    |    |    |    |
| fatigued                                                                                                   | I could be       |      |    |    |    |    |    |    |    |    |    |
| 2. Rate your level of fatigue on the day you felt least fatigued during the past week.  0 1 2 3 4 5 6 7    | 8                | 9    | 10 |    |    |    |    |    |    |    |    |
| Not at all                                                                                                 | As fatigued as I |      |    |    |    |    |    |    |    |    |    |
| fatigued                                                                                                   | could be         |      |    |    |    |    |    |    |    |    |    |
| 3. Rate your level of fatigue on the average in the last week. 0 1 2 3 4 5                                 | 6                | 7    | 8  | 9  | 10 |    |    |    |    |    |    |
| Not at all                                                                                                 | As fatigued as I |      |    |    |    |    |    |    |    |    |    |
| fatigued                                                                                                   | could be         |      |    |    |    |    |    |    |    |    |    |
| 4. Rate your level of fatigue right now.  0 1 2 3                                                          | 4                | 5    | 6  | 7  | 8  | 9  | 10 |    |    |    |    |
| Not at all                                                                                                 | As fatigued as I |      |    |    |    |    |    |    |    |    |    |
| fatigued                                                                                                   | could be         |      |    |    |    |    |    |    |    |    |    |
| 5. Rate how much, in the past week, fatigue interfered with:  No                                           | Extreme          |      |    |    |    |    |    |    |    |    |    |
| interference                                                                                               | interference     |      |    |    |    |    |    |    |    |    |    |
| a. Your general level of activity                                                                          | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| b. Your ability to bathe and dress yourself                                                                | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| c. Your normal work activity (includes both  work outside the home and housework)                          | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| d. Your ability to concentrate                                                                             | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| e. Your relations with other people                                                                        | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| f. Your enjoyment of life                                                                                  | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| g. Your mood                                                                                               | 0                | 1    | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| 6. Indicate how many days, in the past week, you felt fatigued for any part of the day:                    |                  |      |    |    |    |    |    |    |    |    |    |  
0 1 2 3 4 5 6 7 7. Rate **how much of the day**, on average, you felt fatigued in the past week 0 1 2 3 4 5 6 7 8 9 10 None of the day The entire day
appendix 3 qol measures
psqi

Instructions: The following questions relate to your usual sleep habits during the **past month only**. Your answers should indicate the most accurate reply for the majority of days and nights in the past month. Please answer all questions.  
1. During the **past month**, what time have you usually gone to bed at night?
appendix 3 qol measures
bed time

2. During the **past month,** how long (in minutes) has it usually taken you to fall asleep each night?  
NUMBER OF MINUTES ___________
3. During the **past month**, what time have you usually gotten up in the morning?  
GETTING UP TIME ___________
4. During the **past month**, how many hours of actual sleep did you get at night? (This may be different than the number of hours you spent in bed.)
appendix 3 qol measures
hours of sleep per night

For each of the remaining questions, check the one best response. Please answer all questions.  
5. During the **past month**, how often have you had trouble sleeping because you . . .  
a) Cannot get to sleep within 30 minutes  
Not during the past month _____  
Less than once a week _____  
Once or twice a week _____  
Three or more times a week _____  
b) Wake up in the middle of the night or early morning  
Not during the  
past month _____  
Less than  
once a week _____  
Once or twice  
a week _____  
Three or more  
times a week _____  
c) Have to get up to use the bathroom  
Not during the past month _____  
Less than once a week _____  
Once or twice a week _____  
Three or more times a week _____  
d) Cannot breathe comfortably Not during the past month _____
Less than once a week _____
Once or twice a week _____
Three or more times a week _____
e) Cough or snore loudly  
Not during the past month _____  
Less than once a week _____  
Once or twice a week _____  
Three or more times a week _____  
f) Feel too cold  
Not during the  
past month _____  
Less than  
once a week _____  
Once or twice  
a week _____  
Three or more  
times a week _____  
g) Feel too hot h) Had bad dreams  
Not during the past month _____  
Less than once a week _____  
Once or twice a week _____  
Three or more times a week _____  
Not during the  
past month _____  
Less than  
once a week _____  
Once or twice  
a week _____  
Three or more  
times a week _____  
Not during the past month _____  
Less than once a week _____  
Once or twice a week _____  
Three or more times a week _____  
j) Other reason(s), please describe_________________________________________________
__________________________________________________________________________
How often during the past month have you had trouble sleeping because of this?  
Not during the past month _____
Less than once a week _____
Once or twice a week _____
Three or more times a week _____
6. During the **past month**, how would you rate your sleep quality overall?  
Very good __________ Fairly good __________
Fairly bad __________ Very bad __________
i) Have pain 7. During the **past month**, how often have you taken medicine to help you sleep (prescribed or
"over the counter")?  
Not during the past month _____
Less than once a week _____
Once or twice a week _____
Three or more times a week _____
8. During the **past month**, how often have you had trouble staying awake while driving, eating meals, or engaging in social activity?  
Not during the  
 past month _____
Less than once a week _____
Once or twice a week _____
Three or more times a week _____
9. During the **past month**, how much of a problem has it been for you to keep up enough enthusiasm to get things done?  
No problem at all __________
Only a very slight problem __________
Somewhat of a problem __________
A very big problem __________
appendix 3 qol measures
bpi

Instructions: The following questions ask about pain during the **past week**. For each of the following, circle the one number that best indicates how that item applies to you.  
1. Please rate your pain by circling the number that best describes your pain at its **worst** in the last week.  
0 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as you can imagine 2. Please rate your pain by circling the number that best describes your pain at its **least** in the last week.  
0 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as you can imagine 3. Please rate your pain by circling the number that best describes your pain on the **average** in the last week.  
0 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as you can imagine 4. Please rate your pain by circling the number that best describes your pain **right now**.  
0 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as you can imagine  
| 5. Circle the number that describes how, during the past week, pain has interfered with your:  Does not interfere a. General activity 0 1 2 3 4 5 6   | 7   | 8   | 9   | 10   |    |    |    |    |    |    |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------|-----|-----|-----|------|----|----|----|----|----|----|----|
| b. Mood                                                                                                                                               | 0   | 1   | 2   | 3    | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| c. Walking ability                                                                                                                                    | 0   | 1   | 2   | 3    | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| d. Normal work (includes both work outside the  home and housework)                                                                                   | 0   | 1   | 2   | 3    | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| e. Relations with other people                                                                                                                        | 0   | 1   | 2   | 3    | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| f. Sleep                                                                                                                                              | 0   | 1   | 2   | 3    | 4  | 5  | 6  | 7  | 8  | 9  | 10 |
| g. Enjoyment of life                                                                                                                                  | 0   | 1   | 2   | 3    | 4  | 5  | 6  | 7  | 8  | 9  | 10 |  
THESE QUESTIONS NEED ONLY BE ANSWERED ONCE; NO NEED TO ANSWER AT SUBSEQUENT
STUDY FOLLOW-UP VISITS:
Please indicate below what best represents your household income:
_____ <$10,000
_____ $10,001-$25,000 _____ $25,001-$40,000 _____ $40,001-$55,000
_____ $55,001-$70,000
_____ $70,001-$85,000
_____ $85,001-$100,000
_____ > $100,000 Please indicate which education level best describes you: _____ Less than 12 years _____ High School _____ Trade School _____ Some College _____ College Graduate _____ Post-Graduate Degree APPENDIX 4. *GUT MICROBIOME STUDY: STOOL SAMPLE COLLECTION AND*
PROCESSING
sample information management for microbiota
bpi

Each stool sample will be given a unique identifier.  
For example:
Patient 0001 and has sample A and B. Patient 0002 has sample A.  
Sample IDs: MCW_0001-A, MCW_0001-B, MCW_0002-A
As we acquire, aliquot, and store samples, we will not to try to squeeze additional information (metadata), such as date or day of collection or patient initials into the sample ID. Such additional information becomes very difficult to deal with later and statistical software programs can't deal with them well. Please don't name samples things like "Pt 002 Week 3" or "Pt 002 pretransplant" or "Pt JFK (Day -2)". If a patient has more than one transplant, day and week designations are problematic. Another problem with this sort of a sample-naming scheme leads to discrepancies between the target time point (e.g. day 30) and the actual timepoint collected (e.g. day 32)
The following approach is recommended: Keep the names of samples simple and then keep a separate table of sample metadata, as below:
Instructions For Stool Specimen Collection Please place the two gel packs in your freezer in the morning 3 days before your clinic visit.  Specimen can be collected within 2 days of your clinic visit.  
STEP 1. Raise the toilet seat. Place the stool collection frame on the back of the toilet bowl (see Figure 1A).  
All four corners of the collection frame should be supported by the toilet bowl. Remove the lid from the cllection bowl, place collection bowl in frame, and place toilet seat down (Figure 1B).  
  
STEP 2. Deposit your stool directly into the collection container. Try not to urinate into the collection container.  
STEP 3. After collecting your specimen, remove the container from the frame
(Figure 2A). Place the container on a flat surface and firmly press the lid closed (Figure 2B).  
  
STEP 4. Place the closed container into the zip-lock bag provided (see Figure 3) and seal the bag.  
  
STEP 6. Package your specimen immediately, following the instructions below. Write the date and time of collection on the label of the zip-lock bag provided.  There is also a unique ID number pre-printed on the label.  
STEP 7. Place the zip-lock bag containing the specimen container inside the styrofoam box (Figure 4A), along with the two cold packs arranged on the side and on top (Figures 4B and 4C).  
  
STEP 8. Place the lid on the box and place the rubber band provided around the box (Figure 5). You can now place the styrofoam box in the paper bag provided to bring in to clinic.
stool sample collection processing and
sample collection suggested collection days

Inpatient: twice weekly (e.g. Mondays and Thursdays) - once pre-transplant and weekly (+/- 2 days) post-transplant until after neutrophil engraftment.
stool sample collection processing and
tube preparation

Please aliquot into sturdy tubes that can withstand cold temperatures2. Standard urine- or sputum-collection cups crack at freezing temperatures and should not be used.  
If labeling tubes by hand, please use an alcohol-proof marker3. Sharpie, etc. will dissolve in the ethanol used during DNA extraction. If using printed labels, please ensure that they will not peel, crack, or smear at freezing temperatures4, 5.
stool sample collection processing and
aliquoting

Aliquoting should be done as soon as possible after sample is received.  
For solid or semi-solid samples, use a clean disposable spatula6 to transfer stool into cryovials2.  
o Prepare 5 aliquots of ~0.5 mL each. o For more liquid samples, can transfer up to 1 mL material.  
For liquid samples, use transfer pipette7 to prepare 1.5 mL aliquots of material.  
All aliquots should be stored at -80 until shipping.
stool sample collection processing and
shipping address

Attn: Annie Slingerland Z-1419 Memorial Sloan-Kettering Cancer Center 408 East 69th Street New York, NY 10021 United States 646-888-2304
stool sample collection processing and
shipping

Samples should be sent overnight, with enough dry ice to last 2-3 days in the event that delivery is delayed. Please ship only on Monday, Tuesday, or Wednesday to ensure that sample does not sit on loading dock over the weekend.
stool sample collection processing and
after shipping

Please email Annie (slingera@mskcc.org) with tracking number and a shipping manifest
(.xlsx or .csv) detailing for each tube:
o text of written or printed label o unique sample ID (discussed in "Microbiota Data Collection and Management") o unique ID for associated patient (discussed in "Microbiota Data Collection and Management") o date of collection (or day of transplant/conditioning) o preservative added, if any o \# of aliquots made of sample and how many are included in shipment (e.g. 1 of 5; 2 shipped) o If sending more than 20 tubes, please include a map of each tube's location within the grid of the box
stool sample collection processing and
questions?

van den Brink lab tel: 646-888-2317 (ask for Tsoni, Annie, or Melissa) Dr. van den Brink's office & assistants: 646-888-2304.
stool sample collection processing and
suggested materials

1. Outpatient kit:
commode specimen collection system (www.fishersci.com, 02-544-208, $2.75/ea, 60/cs)
(specimen container will need a unique specimen number label)
14 x 9 x 9" corrugated box (www.uline.com, S-4985, $0.66 to $0.94/box, multiples of 25/cs)
8 x 6 x 4.25" foam container (www.uline.com, S-18312, $4.70/ea, 20/cs) (2) cold bricks - 7.5 oz (www.uline.com, S-14294, $0.824/ea, 42/cs)
12 x 15 biohazard zip lock bag (www.ourshippingsupplies.com A-LN4099, $0.18/ea, 1000/cs)
14 x 10 x 15.5" paper shopping bag (www.uline.com, S-9661, $0.345 to $0.38/bag, multiples of 200/cs) outpatient collection directions 2. *Microtubes*, 2ML, w/ screw cap (www.fishersci.com, NC0445483, or www.sarstedt.com 72.694.006,$0.32/ea, 1000/cs)
3. *VWR lab markers*, black ink, fine point (www.vwr.com, 52877-310, $6.19/ea, 10/pack)
4. *Cryo-Clear clear labels,* for 0.5 ml tubes, 0.94" L x 0.5" W
(http://www.usascientific.com/labelsonsheets.aspx, 9125-0238, $3.15/sheet of 119 stickers, 20 sheets/box)
5. *Tough-Spots*, small, colors, for 0.5 ml tubes, 3/8" diameter
(http://www.usascientific.com/labelsonsheets.aspx, 9185-1008, $2.85/sheet of 192 stickers, 20 sheets/box)
6. *Sterile Disposable Spatula*, Double-Ended, with Spoon & Scoop
(https://us.vwr.com/store/product/4531734/vwrdisposable-polypropylene-spatulas, 89097-816, $1.39/ea, 100/pack)
7. *Disposable Graduated Transfer Pipettes*, individually wrapped
(https://www.fishersci.com/shop/products/fisherbrand
-disposable-graduated-transfer-pipettes-5/p-163764, 13-711-20, $0.21/ea, 500/pack)
8. *Feces tube*, 101x16.5mm, sterile (https://www.fishersci.com/us/en/healthcare-products.html, NC0729971, $0.47/ea, 500/case).