table 9 additional lab instructions
2007. reference id 33483

89. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, Klickstein LB, Levin J,
Miller K, Reynolds C, Macdonell R, Pasek M, Lee SJ, Ho V, Soiffer R, Antin JH, Ritz J, Alyea E. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108: 756-762, 2006. Reference ID: 30214 90. Zaja F, Bacigalupo A, Patriarca F, Stanzani M, van Lint MT, Fili C, Scime R, Milone G,
Falda M, Vener C, Laszlo D, Alessandrino PE, Narni F, Sica S, Olivieri A, Sperotto A, Bosi A, Bonifazi F, Fanin R. Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant 40: 273-277, 2007. Reference ID: 33392 91. Ratanatharathorn V, Horowitz MM, Logan B, Arora M, Wang D, Uberti JP, Gale RP, Antin JH, Bornhaeuser M, Hale GA, Ringden O, Cairo MS, Gupta V, Cutler C, Anasetti C, Pavletic SZ. Prior therapy with rituximab correlates with less acute graft-versus-host disease and better survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation (PBSCT). Blood 110 (Part 1): 322a, \#1063, 2007.(Abstract)
Reference ID: 34194 92. Ratanatharathorn V, Ayash L, Reynolds C, Silver S, Reddy P, Becker M, Ferrara JL, Uberti JP. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 9: 505-511, 2003.  
Reference ID: 28825 93. Mohty M, Marchetti N, El-Cheikh J, Faucher C, Furst S, Blaise D. Rituximab (RTX) as salvage therapy for refractory chronic graft-versus-host disease (cGVHD). Blood 110 (Part 1): 873A, \#2972, 2007.(Abstract)
Reference ID: 34198 94. Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, Hochberg EP, Wu CJ, Alyea EP,
Cutler C, Ho V, Soiffer RJ, Antin JH, Ritz J. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 105: 2973-2978, 2005.  
Reference ID: 30959 95. Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper N, Amadori S.  
Response to B-cell depleting therapy with rituximab reverts the abnormalities of Tcell subsets in patients with idiopathic thrombocytopenic purpura. Blood 110: 29242930, 2007. Reference ID: 34527 96. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40: 373-383, 1987. Reference ID: 22434 97. Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG,
Storb R. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplant comorbidities. Blood 104: 961-968, 2004. Reference ID: 24482 98. Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM,
Storb R. Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 104: 1550-1558, 2004.  
Reference ID: 24498 99. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B.  
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106: 2912-2919, 2005.  
Reference ID: 28079 100. Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R. Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood 111: 446-452, 2008.  
Reference ID: 33209 101. Ferrebee JW, Thomas ED. Infusions of marrow in the treatment of radiation casualty.  
Cincinnati J Med 41: 515-524, 1960.  
Reference ID: 40 102. Thomas ED, Herman EC, Jr., Greenough WB, III, Hager EB, Cannon JH, Sahler OD,
Ferrebee JW. Irradiation and marrow infusion in leukemia. Arch Intern Med 107: 829-845, 1961.  
Reference ID: 41  
| APPENDIX A   | ELIGIBILITY GUIDELINES FOR DONOR PBSC APHERESIS FOR  TRANSFUSION                          |
|--------------|-------------------------------------------------------------------------------------------|
| APPENDIX B   | THE KARNOFSKY PERFORMANCE STATUS SCALE                                                    |
| APPENDIX C   | ABO INCOMPATIBILITY                                                                       |
| APPENDIX D   | INFECTIOUS DISEASE GUIDELINES                                                             |
| APPENDIX E   | GRAFT-VERSUS-HOST DISEASE DATA COLLECTION FORM                                            |
| APPENDIX F   | ACUTE GRAFT-VERSUS-HOST DISEASE GRADING                                                   |
| APPENDIX G   | CHRONIC GRAFT-VERSUS-HOST DISEASE GRADING                                                 |
| APPENDIX H   | EVALUATION OF DISEASE RESPONSE FOR CLL                                                    |
| APPENDIX I   | STUDY COORDINATOR'S MANUAL INCLUDING PROCEDURE FOR  REPORTING ADVERSE EVENTS              |
| APPENDIX J   | ADVERSE EVENT REPORT                                                                      |
| APPENDIX K   | NOTICE OF DEATH FORM                                                                      |
| APPENDIX L   | PATIENT DEMOGRAPHICS AND REGISTRATION FORM                                                |
| APPENDIX M   | CORE CASE REPORT FORM                                                                     |
| APPENDIX N   | INTRATHECAL THERAPY ADMINISTRATION                                                        |
| APPENDIX O   | HLA MATCHING REQUIREMENTS FOR UNRELATED DONORS AT  THE SCCA/FRED HUTCHINSON ALLIED SYSTEM |
| APPENDIX P   | ADAPTED COMMON TOXICITY CRITERIA                                                          |
| APPENDIX Q   | HCT COMORBIDITY INDEX                                                                     |
| APPENDIX R   | STAGING OF CLL                                                                            |
| APPENDIX S   | WEIGHT/ ADJUSTED BODY WEIGHT FOR DRUG DOSING                                              |
| APPENDIX T   | COORDINATING CENTER FUNCTIONS                                                             |
appendix a eligibility guidelines for
2007. reference id 33483

| IMMUNIZATION                                | DONOR ELIGIBILITY                                                                                        |
|---------------------------------------------|----------------------------------------------------------------------------------------------------------|
| Cholera                                     | No wait                                                                                                  |
| Diphtheria                                  | No wait                                                                                                  |
| Flu                                         | 24 hour wait                                                                                             |
| Gamma globulin                              | No wait unless for hepatitis                                                                             |
| (Immune serum globulin) Hepatitis B vaccine | No wait unless given for hepatitis exposure                                                              |
| Measles (Rubella)                           | 1 month wait                                                                                             |
| Mumps                                       | 2 week wait                                                                                              |
| Polio - Sabin (inj)                         | No wait                                                                                                  |
| Plague                                      | No wait                                                                                                  |
| Rabies                                      | 1 year wait if given as treatment for bite. 2  week wait if given as prophylaxis (DMV's or  zoo workers) |
| Smallpox                                    | 2 week wait                                                                                              |
| Tetanus toxoid                              | No wait                                                                                                  |
| Typhoid                                     | No wait                                                                                                  |
| Typhus                                      | No wait                                                                                                  |
| Yellow Fever                                | 2 week wait                                                                                              |
appendix b
the karnofsky performance status scale

| General                                         |                                                                               | Index                                                                        | Specific criteria   |
|-------------------------------------------------|-------------------------------------------------------------------------------|------------------------------------------------------------------------------|---------------------|
| Able to carry on normal                         | 100                                                                           | Normal, no complaints, no                                                    |                     |
| activity; no special care needed.               | evidence of disease.                                                          |                                                                              |                     |
| 90                                              | Able to carry on normal activity, minor signs  or symptoms of disease.        |                                                                              |                     |
| 80                                              | Normal activity with effort, some signs or  symptoms of disease.              |                                                                              |                     |
| Unable to work, able to live at                 | 70                                                                            | Care for self, unable to carry                                               |                     |
| home and care for most personal                 | on normal activity or to do                                                   |                                                                              |                     |
| needs, varying amount of                        | work.                                                                         |                                                                              |                     |
| assistance needed.                              | 60                                                                            | Requires occasional assistance from others but  able to care for most needs. |                     |
| 50                                              | Requires considerable assistance from others  and frequent medical care.      |                                                                              |                     |
| Unable to care for self, requires               | 40                                                                            | Disabled, requires special                                                   |                     |
| institutional or hospital care or               | care and assistance.                                                          |                                                                              |                     |
| equivalent, disease may be rapidly progressing. | 30                                                                            | Severely disabled, hospitalization indicated,  death not imminent.           |                     |
| 20                                              | Very sick, hospitalization necessary, active  supportive treatment necessary. |                                                                              |                     |
| 10                                              | Moribund                                                                      |                                                                              |                     |
| 0                                               | Dead                                                                          |                                                                              |                     |
appendix c abo incompatibility
red blood cell - incompatibility

Occasional patients may have antibodies directed against red blood cell antigens found on the donor's cells. These are generally ABO or Rh antigens, although incompatibility with other red cell antigens identified by donor-recipient crossmatch may occur. Although the volume of red blood cells (RBC) in most PBMC products will only be 2-5% of the product volume before infusion, the small quantity may cause a hemolytic transfusion reaction. According to the FHCRC policy it is generally acceptable to infuse a volume of about 10ml RBCs per product. If the recipient shows an anti-donor titer of  1:32 or the RBC volume is greater than 10ml (or > 20ml in two products combined) the PBMC components should be RBC depleted by Starch Sedimentation (flowsheet below). *Refer to the Clinical Coordinator's Patient Information Sheet for instructions regarding* management of a specific patient. Post transplant blood component support will be according to Standard Practice Guidelines.  
Timing: Every attempt should be made to infuse red cell depleted PBMC products within 2 hours of depletion.  
Expected Results: Red blood cell depleted PBMC products will contain < 10ml of red blood cells and  90% nucleated cell recovery.
appendix c abo incompatibility
red blood cell - incompatibility

Occasional donors may have antibodies directed against red blood cell antigens (ABO, Rh, or other antigen system) found on the recipient's cells. The risk of hemolysis of recipient red cells immediately after transplant is not of very much clinical import. Due to the high number of lymphocytes in the PBMC inoculum, recipients may be at much greater risk for a delayed type of hemolysis that can be severe. PBMC products contain < 200ml of plasma according to FHCRC
policy and no deleterious effects have been observed so far. However, if donors show an antirecipient titer  1:256, the PBMC component should be plasma depleted (see flowsheet below).  
Refer to the Clinical Coordinator's Patient Information Sheet for instructions regarding management of a specific patient.  
Post transplant blood component support will be according to Standard Practice Guidelines.  
Timing: Every attempt should be made to infuse plasma-depleted PBMC within 2 hours of depletion.  
Expected Results: The plasma depletion should not affect the nucleated cell recovery.
appendix c abo incompatibility
red blood cell - bidirectional

Patients undergoing transplants for bidirectional RBC incompatibility should be managed according to both algorithms shown below. Most red cell depletion techniques also deplete plasma from the PBMC component with no additional cell loss. *Refer to the Clinical Coordinator's Patient* Information Sheet for instructions regarding management of a specific patient. Post transplant blood component support will be according to Standard Practice Guidelines.  
| MAJOR ABO INCOMPATIBLE <20ml RBC total                       |                | Infuse without modification   |                            |
|--------------------------------------------------------------|-----------------|-------------------------------|----------------------------|
|  1:32                                                       |                 |                               |                            |
| Recipient antiDonor titer                                                              | >20ml RBC total |                              | RBC depletion of component |
|  1:16                                                       |                | Infuse without modification   |                            |
| MINOR ABO INCOMPATIBLE  1:256 Plasma depletion of component |                 |                               |                            |
| Donor antiRecipient titer                                                              |  1:128         | Infuse without modification   |                            |
appendix c abo incompatibility
appendix d

INFECTIOUS DISEASE GUIDELINES
Please note that the content of these PDFs is from the Fred Hutchinson Clinical Research Division Standard Practice Manual and does not contain research related procedures.  
Herpes Simplex and Varicella Zoster Virus Prevention and Treatment  
  
CMV Prevention: Surveillance and Preemptive Therapy CMV Prevention  
  
CMV Disease: Diagnosis and Treatment  
  
Antifungal Therapy Guidelines  
  
  
Pneumonia / Pneumocystis Jiroveci Prophylaxis Antibiotic Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic GvHD
Requiring Immunosuppressive Therapy  
  
  
- 72 -
appendix e graft-versus-host disease data
gvhd treatment

Check each agent used to treat GVHD: Date Treatment Started None  
| Cyclosporine                                                | __ __/__ __/__ __ __ __   |    |     |
|-------------------------------------------------------------|---------------------------|----|-----|
| Systemic Corticosteroids                                    | __ __/__ __/__ __ __ __   |    |     |
| Topical Corticosteroids                                     | __ __/__ __/__ __ __ __   |    |     |
| Beclomethasone                                              | __ __/__ __/__ __ __ __   |    |     |
| Rapamycin                                                   | __ __/__ __/__ __ __ __   |    |     |
| MMF                                                         | __ __/__ __/__ __ __ __   |    |     |
| ATG                                                         | __ __/__ __/__ __ __ __   |    |     |
| In Vivo anti-T lymphocyte McAb                              | __ __/__ __/__ __ __ __   |    |     |
| Blinded Randomized Trial                                    | __ __/__ __/__ __ __ __   |    |     |
| Specify_____________________ Other, specify________________ | __ __/__ __/__ __ __ __   |    |     |
| ___________________________                                 |                           |    |     |
| Date of Death:                                              | __ __/__ __/__ __ __ __   |    |     |
| Was an autopsy done?                                        | Yes                       | No |     |
| Was GVHD found at autopsy?                                  | Yes                       | No | N/A |  
If yes:  
  
  
  
Skin Liver Gut GVHD SUMMARY  
| Date of onset:                                                                                                                                                                                                                                | __ __/__ __/__ __ __ __ Day____________   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|
| Overall Grade________________ Skin______________ Liver______________                                                                                                                                                                          | Gut_____________                          |
| Comments______________________________________________________________________ ______________________________________________________________________________ _______________________________________________________________________________ |                                           |
appendix e graft-versus-host disease data
clinical liver

Was skin biopsy done? Yes No  
 Date of skin biopsy: __ __/__ __/__ __ __ __ Results:
Negative Positive GVHD Positive Other Was liver biopsy done? Yes No Date of liver biopsy: __ __/__ __/__ __ __ __ Results:
Negative Positive GVHD
Positive Other Did patient have any GI Biopsy? Yes No Date of biopsy: __ __/__ __/__ __ __ __
Results:
Negative Positive GVHD
Positive Other CLINICAL SKIN
Did patient ever have rash after transplant? Yes No Was rash thought to be due to GVHD? Yes No Date of onset of rash: __ __/__ __/__ __ __ __
Extent of rash on date of first treatment for GVHD: ___________________
Maximum severity of rash:
0 - No rash 1 - Maculopapular rash <25% BSA 2 - Maculopapular rash 25-50% BSA
3 - Generalized erythroderma 4 - Generalized erythroderma with bullous formation and desquamation Date of maximum rash severity: __ __/__ __/__ __ __ __
Bilirubin level on date of first treatment for GVHD: Maximum Bilirubin Date __ __/__ __/__ __ __ __
0 - Bilirubin < 2.0 mg/dl 1 - Bilirubin 2.0 - 3.0 mg/dl 2 - Bilirubin 3.1 - 6.0 mg/dl  
- 74 -
3 - Bilirubin 6.1 - 15.0 mg/dl 4 - Bilirubin >15.0 mg/dl Did patient have other liver process? Yes No VOD
Cyclosporine Toxicity Sepsis Other liver complication CLINICAL GUT
GI consult? Yes No Date of Consult:__ __/__ __/__ __ __ __ Stool volume on date of first treatment for GVHD: ____________
Maximum Daily Stool Output after day 21 0 - 0 - 200 ml 1 - >200 but 1000 ml 2 - >1000 but 1500 ml 3 - >1500 ml 4 - Severe abdominal pain with or without ileus Date of maximum stool output: __ __/__ __/__ __ __ __
Was stool mixed with urine on day of Maximum Stool Output? Yes No If stool volume not measurable, what was maximum number of stools/day? _______
Date of maximum number of stools/day: __ __/__ __/__ __ __ __
Did patient have the following process?  
Frank blood in stool attributed to GVHD
CMV infection of GI tract at time of maximum stool volume Narcotic withdrawal at time of maximum stool volume C. difficile infection at time of maximum stool volume Other GI process Specify___________________________________
appendix e graft-versus-host disease data
appendix f acute graft-versus-host disease

Liver +1 bilirubin (2.0-3.0 mg/100 ml)  
+2 bilirubin (3-5.9 mg/100 ml) +3 bilirubin (6-14.9 mg/100 ml)  
+4 bilirubin > 15 mg/100 ml  
| Skin   | +1                                                                          | a maculopapular eruption involving less than 25% of the body surface   |
|--------|-----------------------------------------------------------------------------|------------------------------------------------------------------------|
| +2     | a maculopapular eruption involving 25-50% of the body surface               |                                                                        |
| +3     | generalized erythroderma                                                    |                                                                        |
| +4     | generalized erythroderma with bullous formation and often with desquamation |                                                                        |
| +2     | bilirubin (3-5.9 mg/100 ml)                                                 |                                                                        |
| +3     | bilirubin (6-14.9 mg/100 ml)                                                |                                                                        |
| +4     | bilirubin > 15 mg/100 ml                                                    |                                                                        |  
Gut Diarrhea is graded +1 to +4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as +1 in severity The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage +2 gut and grade +3 overall Diarrhea
+1  1000 ml of liquid stool/day*( 15ml of stool/kg/day)† +2 >1,000 ml of stool/day*(> 15ml of stool/kg/day)† +3 >1,500 ml of stool/day*(> 20ml of stool/kg/day)† +4 2,000 ml of stool/day*( 25ml of stool/kg/day)†
*In the absence of infectious/medical cause
†For pediatric patients Severity of GVHD
Grade I +1 to +2 skin rash No gut or liver involvement Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
_______________
aFrom "Graft-vs-host disease" Sullivan, Keith M. *Hematopoietic Cell Transplantation* Ed: D. Thomas, K. Blume, S.  
Forman, Blackwell Sciences; 1999, pages 518-519  
| +1 gastrointestinal involvement and/or +1 liver involvement   |
|---------------------------------------------------------------|  
| Grade III   | +2 to +4 gastrointestinal involvement and/or +2 to +4 liver involvement with or without a rash   |
|-------------|--------------------------------------------------------------------------------------------------|
appendix g
chronic graft-versus-host disease grading a

In all cases, concomitant processes (i.e. infections or drug reactions) must be ruled out. Karnofsky or Lansky Clinical Performance scores, 60%, > 15% weight loss, and recurrent infections are usually signs of clinical extensive chronic GVHD. Abnormalities that could indicate chronic GVHD are categorized by organ systems as listed below.  
| Skin         | Erythema, dryness, pruritus, pigmentary changes (i.e. hyperpigmentation,  vitiligo), mottling, papulosquamous plaques, nodules, exfoliation, macularpapular or urticarial rash, scleroderma, morphea (one or several circumscribed,  indurated and shiny lesions)                                                                                                                                                                                                                                                                                             |                                                                                |
|--------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|
| Nails        |                                                                                                                                                                                                                                                                                             | Ridging, onychodystrophy, onycholysis                                          |
| Hair         | Premature graying, (scalp hair, eyelashes, eyebrows), thinning scalp hair,  alopecia, decreased body hair                                                                                                                                                                                   |                                                                                |
| Mouth        | Dryness, burning, gingivitis, mucositis, striae, atrophy, erythema, lichenoid  changes, ulcers, labial atrophy or pigmentary changes, tooth decay, tightness  around the mouth                                                                                                              |                                                                                |
| Eyes         |                                                                                                                                                                                                                                                                                             | Dryness, burning, blurring, gritty eyes, photophobia, pain                     |
| Vagina/vulva | Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid  changes not included                                                                                                                                                                                           |                                                                                |
| Liver        | Elevated liver function tests not due to other causes (alkaline phosphatase  3x  upper limit of normal, AST or ALT 4x upper limit of normal or total serum  bilirubin  2.5; in the absence of chronic GVHD involving other organs, liver  biopsy is required to confirm diagnosis)       |                                                                                |
| Lung         | Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on  exertion, history of recurrent bronchitis or sinusitis                                                                                                                                                   |                                                                                |
| GI           |                                                                                                                                                                                                                                                                                             | Anorexia, nausea, vomiting, weight loss, dysphasia, odynophagia, malabsorption |
| Fasciitis    | Stiffness and tightness with restriction of movement, occasionally with swelling  pain, cramping, erythema and induration, most commonly affecting forearms,  wrists and hands, ankles, legs, and feet, inability to extend wrists without flexing  the fingers or the elbows, contractures |                                                                                |  
| Serositis   | Chest pain or cardiopulmonary comprise due to pericarditis or pleuritis   |                                                                         |
|-------------|---------------------------------------------------------------------------|-------------------------------------------------------------------------|
| Muscle      |                                                                           | Proximal muscle weakness, cramping                                      |
| Skeletal    |                                                                           | Arthralgia of large proximal girdle joints and sometimes smaller joints |
| Laboratory testing sand diagnostic indicators of chronic GVHDa Eye Schirmer's test with a mean value  5mm at 5 minutes, or symptomatic with  values of 6-10mm or keratitis detected by slit lamp examination Liver Elevated liver function tests not due to other causes (see definition of clinical  limited and extensive chronic GVHD) Lung New obstructive lung defect defined as FEV1 < 80% of predicted with either an  FEF 25-75 <65% of predicted or RV >120% of predicted, or a decrease of  FEV1/FVC by > 12% within a period of less than 1 year. A diagnosis of  bronchiolitis obliterans requires negative microbiological tests from  bronchoalveolar lavage and evidence of air trapping by high resolution endexpiratory and end-inspiratory CAT scans o the chest. A thoracoscopic lung  biopsy may be necessary in order to confirm the diagnosis of bronchiolitis  obliterans in patients who have obstructive lung disease without air trapping when  chronic GVHD involving other organs is absent Esophagus Esophageal web formation, stricture or dysmotility demonstrated by barium  swallow, endoscopy or manometry Muscle Elevated CPK or aldolase, EMG findings consistent with myositis Blood Thrombocytopenia (usually 20,000-100,000/l), eosinophilia,  hypogammaglobulinemia, hypergammaglobulinemia, and autoantibodies occur in  some cases             |                                                                           |                                                                         |  
_________________
aFrom Standard Practice Guidelines for "Chronic Graft-versus-Host Disease Classification at the time of presentation" developed by Long Term Follow-Up at the FHCRC
appendix g
grading of chronic graft-versus-host disease

1. Oral abnormalities consistent with chronic GVHD, a positive skin or lip biopsy, and no other manifestations of chronic GVHD
2. Mild liver test abnormalities (alkaline phosphatase  2x upper limit of normal, AST or ALT
3x upper limit of normal and total bilirubin  1.6) with positive skin or lip biopsy, and no other manifestation of chronic GVHD
3. Less than six papulosquamous plaques or limited skin rash or dyspigmentation (< 20% of the body surface), positive skin biopsy, and no other manifestations of chronic GVHD
4. Ocular sicca (Schirmer's test  5mm), positive skin or lip biopsy, and no other manifestations of chronic GVHD
5. Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations of chronic GVHD
appendix g
b. clinical extensive chronic gvhd

1. Involvement of two or more organs with symptoms or signs of chronic GVHD, with biopsy documentation of chronic GVHD in any organ 2. > 15% base line body weight loss not due to other causes, with biopsy documentation of chronic GVHD in any organ 3. Skin involvement more extensive than defined for limited chronic GVHD, confirmed by biopsy 4. Scleroderma or morphea 5. Onycholysis or onychodystrophy thought to represent chronic GVHD, with documentation of chronic GVHD in any organ 6. Decreased range of motion in wrist of ankle extension due to fasciitis caused by chronic GVHD
7. Contractures thought to represent chronic GVHD 8. Bronchiolitis obliterans 9. Positive liver biopsy; abnormal liver function tests not due to other causes with alkaline phosphatase > 2x upper limit of normal, AST or ALT > 3x upper limit of normal, or total bilirubin > 1.6, and documentation of chronic GVHD in any organ 10. Pericarditis or pleuritis not due to other causes 11. Positive upper or lower GI biopsy
appendix h evaluation of disease
b. clinical extensive chronic gvhd

CLL: Modified response criteria based on the NCI-Working Group and the International Workshop Group Joint Formal Criteria for evaluating disease response for CLL. [1-3]
appendix h evaluation of disease
complete remission (cr)

| Imaging studies (Xray, CT, MRI) (nodes, liver, and spleen)   | Normal                |
|--------------------------------------------------------------|-----------------------|
| Peripheral blood by flow cytometry                           | No clonal lymphocytes |  
Bone marrow by morphology No nodules; or if present, nodules are free  
from CLL cells by immunohistochemistry Duration ≥2 months CR with minimal residual disease Stable disease  
| Peripheral blood or bone marrow by flow cytometry                                      | >0 - <1 CLL cells/1000 leukocytes (0.1%)                    |               |
|----------------------------------------------------------------------------------------|-------------------------------------------------------------|---------------|
| Partial Remission (PR):  Both criteria: Absolute lymphocyte count in peripheral blood  | ≥50% decrease3                                              |               |
| Physical exam/Imaging studies (nodes, liver, and/or spleen)                            | ≥50% decrease3,4                                            |               |
| Duration                                                                               | ≥2 months                                                   |               |
| Progressive disease: ≥1 of Physical exam/Imaging studies (nodes, liver, and/or spleen) | ≥50% increase or new                                        |               |
|                                                                                        | Circulating lymphocytes by morphology and/or flow cytometry | ≥50% increase |
| Lymph node Biopsy                                                                      | Richter's transformation                                    |               |  
Did not meet any of the above criteria for complete or partial remission or progression.  
Relapsed disease  
```
Criteria of progression occurring 6 months after achievement of complete or partial remission.
1 Without granulocyte colony stimulating factor support.
2 Without red blood cell transfusions or erythropoietin support.
3 Compared to before starting therapy.
4 Defined by the sum of the products of up to 6 lymph nodes with no increase in the size of any single lymph node (ie, an increase of <25 percent in a
lymph node <2cm is not considered significant) and no new enlarged lymph nodes.

```  
1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institutesponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87: 4990-4997, 1996.  
2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ,
Montserrat E, Rai KR, Kipps TJ, International Workshop on Chronic Lymphocytic Leukemia.  
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the  
- 80 -  
International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer InstituteWorking Group 1996 guidelines [Erratum appears in Blood. 2008 Dec 15;112(13):5259]. Blood 111:
5446-5456, 2008.  
3. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 110: 236-238, 1989.
appendix i study coordinator's manual
i. introduction

The mixed chimerism protocols have been opened to multiple sites to increase the referral base and accrual. Because of this expansion of collaborators, the data collection procedures are being revised. The procedure manual was created to assure consistency of data reporting across the centers and to assure compliance with regulations. General expectations of collaborators are that they will comply with appropriate regulatory requirements, specified protocol requirements, and provide outcome data.  
The manual translates working procedures for study coordination. Its goal is to describe the procedures with sufficient clarity to ensure that all study centers will use the same procedures and follow-up schedules for participant data management and reporting. Changes to the manual and relevant forms will be made as soon as practical and will become effective on receipt of the revised procedures at the study centers, unless otherwise noticed.
appendix i study coordinator's manual
ii. institutional review board review

All research protocols proposed for use that involves human subjects must be reviewed and approved by the Institutional Review Board (IRB) prior to implementation. New protocols will undergo review at the FHCRC IRB and then will be distributed to sites that wish to participate for their IRB's review. For Centers that have a Federal Wide Assurance (FWA), formal collaboration includes submission of a form 310 and a copy of the IRB approved protocol and consent forms to the FHCRC. For sites without a FWA, an FWA form needs to be filed. Once the paperwork is submitted to the Office for Human Research Protection, the approval process can take up to a couple of months, and must be completed before collaboration on a protocol can begin. In addition, all amendments and/or revisions to on-going, approved activities must be submitted for review and approved prior to implementation at an institution. No revisions may be implemented at outside institutions without the prior approval of the FHCRC Principal Investigator. The FHCRC and the local site's IRB must review all protocol activities at least once annually. This must be done within 365 days of the last review regardless of the policies of the institution. A copy of annual renewal approvals must be received for collaboration to continue for the next year.
appendix i study coordinator's manual
iii. registrations

Collaborating Institutions: The principal investigator of the collaborating institution who will register the patient with the FHCRC will identify eligible patients. Registration will include completion of the eligibility checklist/demographic form. This form and a copy of the signed informed consent will be faxed (206-667-5378) prior to treatment initiation. Patients must be registered prior to treatment initiation for valid registration
appendix i study coordinator's manual
iv. reporting adverse events

The following guidelines are the minimum serious adverse event (SAE) reporting guidelines for Category 1 and 2 studies conducted at the Fred Hutchinson Cancer Research Center. Expedited Reporting Requirements
appendix i study coordinator's manual
all unexpected and serious adverse

Definitions Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, medical treatment or procedure and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, medical treatment or procedure whether or not considered related to the medicinal product.  
Life-threatening Adverse Event - Any adverse event that places the patient or subject, in view of the investigator, at immediate risk of death from the reaction. Study toxicities are graded using the NCI Common Toxicity Criteria (where appropriate use the criteria for transplant patients.) All Grade 4 (life-threatening) toxicities occurring between start of conditioning to day 200 that meet expedited reporting requirements must be reported as soon as possible but within at least 10 calendar days of the investigator learning of the event.  
Unexpected Adverse Event - An adverse event, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product). If applicable product information is not available, such as for studies that do not involve pharmaceutical products or devices, an unexpected adverse event is an adverse event that was not described in the study protocol or informed consent.  
Serious Adverse Event (SAE) - Any adverse event occurring that results in any of the following outcomes:
Death - start of conditioning to day 200, regardless of cause, A life-threatening adverse event (see above)
A persistent or significant disability/incapacity, A congenital anomaly Requires intervention to prevent permanent impairment or damage.  
Hospitalization, in general, will not be considered a serious adverse event as approximately half of evaluable MRD patients AND the majority of evaluable URD patients receiving nonmyeloablative transplants were hospitalized. Hospitalization will be considered a serious adverse event if it fulfills the criteria for a serious and unexpected adverse event as described above. To ensure no confusion or misunderstanding exist of the differences between the terms "serious" and "severe," which are not synonymous the following note of clarification is provided:
The term "severe" is often used to describe the intensity (severity) or a specific event (as in mild, moderate or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as
"serious," which is based on patient/event *outcome or action* criteria usually associated with events that pose a threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory obligations.  
Attribution - The FHCRC designation for the determination of whether an adverse event is related to a medical product, treatment or procedure will be as follows:
Related - includes adverse events that are definitely, probably, or possibly related to the medical treatment or procedure.  
Not Related - includes adverse events are doubtfully related or clearly not related to the medical treatment or procedure.  
The FHCRC Serious Adverse Event (SAE) Report Form should be completed for all adverse events that meet the expedited reporting requirements. All available information should be submitted but it is acceptable to fax an incomplete report form at the initial report. A completed report should be faxed as soon as possible but must be received within 10 calendar days. It is the responsibility of the FHCRC Principal Investigator to notify the sponsor, NIH, FDA or other agencies of serious adverse events as required in the protocol. Serious adverse events that do not meet the requirement for expedited reporting (not related to study treatment or expected) will be reported to the IRB as part of the annual renewal of the protocol. FHCRC is acting as the Coordinating Center for this multi-institutional study, and it is the responsibility of the FHCRC Principal Investigator (or designee) to complete the FHCRC Serious Adverse Event Report for all serious adverse events that meet the expedited reporting requirements that are received from the participating sites.  
Procedure for Reporting Serious and Unexpected Adverse Events from Participating Sites Regulations defining the responsibilities for reporting serious and unexpected adverse reactions are defined above. Serious and unexpected adverse events must be reported to the FHCRC Investigator within 10 days of learning of the event. This includes patient deaths (serious, unexpected, and related/possibly related), regardless of cause, occurring start of condition to day 200 post-transplant procedure. The immediate telephone report must be followed by faxed comments to the Trial Coordinator at **(206) 667-5378.** This will be followed by detailed written report (See Appendix J) within 10 working days. The report must include the date and time of onset, severity and duration of the event, the relationship to the study, the treatment given and eventual outcome. Follow-up information to a SAE report must be submitted as soon as the relevant information is available.
appendix i study coordinator's manual
obligation of investigators

All grade 3 or 4 adverse events (or highly unusual grade 2 adverse events), which occur between start of conditioning to day 100 during the study will be recorded on the Case Report Form
(**Appendix M)**. These adverse events which are observed by the Investigator or reported by the patient, whether or not attributed to the study, will be reported on the Case Report Form using the modified (for HSCT) NCI Common Toxicity Criteria (**Appendix P**). Attributes will include a description, date of onset, maximum severity, and assessment of relationship to the study agent or other suspect agent(s). Adverse events will be graded accordingly: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening or debilitating, and 5 = fatal. All Grade 4 (life-threatening) or Grade 5 (fatal) events on the NCI scale meet expedited reporting requirements. Association or relatedness to the study agent will be graded as follows: 1 = unrelated, 2 = unlikely, 3 = possibly, 4 = probably, and 5 = definitely related.
appendix i study coordinator's manual
v. case report forms

Case report forms must be completed for all patients registered onto the protocol and submitted to the FHCRC data coordinating center. The first case report form (day 28) is due on day 50. For outside centers a Staging Form must accompany the form with the patient staging at registration, day 28, day 56, day 84 and day 100. Staging forms should also be completed with each Follow Up Form completed on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly thereafter. For Outside Centers, case report forms are expected to be submitted no later than 30 days following the scheduled follow up date.
appendix i study coordinator's manual
vi. protocol monitoring

As the coordinating center, FHCRC will monitor accrual at the outside institutions. The guidelines below are intended to guide the reviewers in their assessment of items that significantly alter the clinical effectiveness of the treatment or the evaluation of its toxicity.  
A. Registration/Randomization 1. Patient was registered prior to treatment and approval by FHCRC PI occurs prior to randomization.  
2. Information given at registration represents actual data in medical records (stage, diagnosis, cell type, etc.)
B. Informed Consent/IRB Approval Dates 1. The consent was signed prior to registration 2. The consent is in language was approved by the institution's IRB. IRB approval and reapproval are documented including appropriate use of full-board review and proper review of appropriate amendments or revisions 3. Consent was dated and has written witness signature. IRB approval was obtained prior to the patient signing the consent form and start of treatment.  
C. Patient Eligibility 1. Eligibility criteria and exclusion criteria were met 2. Treatment/Intervention Administration 3. Doses were modified according to protocol 4. Accurate documentation of drug administration D. Study Tests/Evaluation 1. Protocol specified laboratory tests or diagnostic studies are available 2. Appropriate record of protocol intervention is documented.  
E. Study Events/Adverse Drug Experience 1. Serious Adverse Evens reported according to protocol specifications F. Follow-Up 1. Disease status assessed according to the required protocol guidelines documenting response to treatment.  
2. Accurate determination of cancer progression
appendix j fred hutchinson cancer
vi. protocol monitoring

FHCRC IR File Number: FHCRC Protocol Number:  
FHCRC Unique Patient # FHCRC/SCCA Other  
Gender: Male Female Age: FHCRC Principal Investigator: Phone Number: Mailstop: Date study staff became aware of event: ______________
Date of Report:
Initial Report Follow-Up Report \# Other Date Serious Adverse Event Started:
Date Ended: Or Ongoing (if ongoing - must submit follow up report)
Adverse Event: Describe the Serious Adverse Event including a summary of all relevant clinical information. (Or attach a MedWatch Form or other SAE reporting form if one has been completed.) Use Page 2, if necessary: Outcomes Attributed to adverse event: (Check all that apply)
Death / / Life-Threatening Hospitalization (initial or prolonged)
Disability Congenital Anomaly Required intervention to prevent permanent impairment/damage Specify Agent(s) and/or Procedure(s) involved in this protocol:
Report Completed by: Date:
The PI has determined that the consent form must be revised: Yes No  
#1  
Pharmaceutical product/medical treatment/procedure  
#2  
Pharmaceutical product/medical treatment/procedure  
Not Related (Unrelated, Unlikely) Not Related (Unrelated, Unlikely) Related (Possible, Probable, Definite) Related (Possible, Probable, Definite) Follow-up Report Required Final Report (PI must sign final report)  
Does this study involve the deliberate transfer of recombinant DNA or DNA or RNA derived from recombinant DNA, into human subjects (human gene transfer)? yes no If yes and the activity involves the SCCA
outpatient clinic, a copy of this Protocol Modification Form and any supporting documents to be reviewed and approved, will be forwarded to the FHCRC's Institutional Biosafety Committee (IBC) by the Protocol Office (Mailstop: LM-230).  
Signature of Principal Investigator Date:  
- 87 -
Page 2
fred hutchinson cancer research center
vi. protocol monitoring

FHCRC IR File Number: FHCRC Protocol Number:  
FHCRC Unique Patient # Date of Report:  
Describe the Serious Adverse Event including a summary of all relevant clinical information.  
  
Patient ID: __________________ Date of Death: ______________ Place of Event: ___________________________________________ Apparent cause of death (Please be specific. Attach hospital summary or death summary when possible): Form completed by: ________________________________Date: ______________
appendix l
1840

Please Fax this completed form to (206)-667-5378 for patient registration.  
Questions regarding eligibility should go to Mohamed Sorror, M.D., 206-667-2765.  
  
  
Patient Diagnosis: ___________________________________ Planned Day 0: _____/______/_____
Ethnicity (choose one): Instruct the research subject to select one *of the following.*
Hispanic *(A person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or* origin, regardless of race. Term "Spanish Origin" can also be used in addition to "Hispanic" or "Latino".  
Not Hispanic or Latino Declined to report Race (check all that apply): Instruct the research subject to select one or more *of the following.*
American Indian/Alaska Native *(A person having origins in any of the original peoples of North, Central, or* South America, and who maintains tribal affiliations or community attachment).  
Asian *(A person having origins in any of the original peoples of the Far East, Southeast, Asia, or the Indian* subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam).  
Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of Hawaii, Guam, Samoa or other Pacific Islands).  
Black/African American *(A person having origins in any of the black racial groups of Africa).*
White *(A person having origins in any of the original peoples of Europe, the Middle East or North Africa).*
Research subject does not know race Declined to report
appendix l
protocol 1840 eligibility inclusion criteria

All of the following questions must be marked "Yes" for the patient to enter the study.  
1. Yes No Patient signed IRB approved consent form. Date: ___________
IRB File Number: Date of IRB Approval:
2. Yes No Patient has a diagnosis of CLL (or small lymphocytic lymphoma) or Diagnosis of CLL that progresses to prolymphocytic leukemia (PLL).  
3. Yes No Patient has at least one of the following:
a.square yes square no .
protocol 1840 eligibility inclusion criteria

a. Yes No Has B-Cell CLL or PLL and failed to meet NCI
Working Group criteria (Appendix H) for complete or partial response after 2 cycles of therapy with a regimen containing fludarabine (or another nucleoside analog, e.g. 2-CDA, pentostatin) or disease relapse within 12 months after completing therapy with a fludarabine (or another nucleoside analog) containing regimen.  
$$\mathrm{\boldmath~0.~}\bigsqcup\mathrm{\boldmath~Ye~}$$  
b. Yes No Has B-Cell CLL or PLL and failed FCR or PCR
combination chemotherapy at any time point.  
$\text{c.}\;\boxed{\phantom{\rule{0.2em}{0ex}}\text{Yes}\;\boxed{\phantom{\rule{0.2em}{0ex}}\text{No}}}$  .
c. Yes No Has B-Cell CLL or PLL and had de novo or acquired "17p deletion" cytogenetic abnormality. Patients should have received induction treatment but could be transplanted in 1st CR.  
4. Yes No Related donor who is genetically phenotypically HLA-identical OR Unrelated donors who are prospectively:
i) Matched for HLA-A,B,C, DRB1 and DQB1 alleles by high resolution typing AND
ii) Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing (See appendix O for other donor selection details).  
| Patient A: ________   | A:_________    | C: _________   | C: _________   | B: _________   | B: _________   |
|-----------------------|----------------|----------------|----------------|----------------|----------------|
| DRB1: ________        | DRB1: ________ | DQB1: ________ | DQB1: ________ |                |                |
| Donor A: _________    | A:_________    | C: _________   | C: _________   | B: _________   | B: _________   |
| DRB1: ________        | DRB1:_______   | DQB1: ________ | DQB1: _______  |                |                |  
iii) Yes No Have a negative anti-donor cytotoxic crossmatch. N/A Cytotoxic crossmatch **not done as patient and donor are**
phenotypically identical by molecular methods.  
iv) Yes No Patient and donor pairs must not be homozygous at a mismatched allele.  
5. Yes No Patient is 18 years of age or older.
a.square yes square no .
exclusion criteria

Each of the following questions must be marked "No" Or "NA" for the patient to enroll in the study.  
12. Patient has organ dysfunction as described below. Please check YES if patient has any of the following.
a.square yes square no .
a.cardiovascular

Yes No Cardiac Ejection Fraction <40%. Ejection fraction is required if age >50 years or there is a history of prior transplant, anthracycline exposure or history of cardiac disease.  
- 92 -  
| 6.   | Yes   | No   | Has active CNS involvement with CLL. For LP requirement, see   |                                                                                                                                                                                                                                                                          |
|------|-------|------|----------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 7.   | Yes   | No   | Patients with active non-hematologic malignancies (except nonmelanoma skin cancers). This exclusion does not apply to patients with non-hematologic  malignancies that do not require therapy                                                                |                                                                                                                                                                                                                                                                          |
| 8.   | Yes   | No   | Patients with a history of non-hematologic malignancies (except nonmelanoma skin cancers) currently in a complete remission, who are less  than 5 years from the time of complete remission, and have a >20% risk  of disease recurrence. This exclusion does not apply to patients with non-hematologic  malignancies that do not require therapy                                                                |                                                                                                                                                                                                                                                                          |
| 9.   | Yes   | No   | NA                                                             | Fertile man or woman unwilling to use contraceptive techniques during  and for 12 months following treatment.                                                                                                                                                            |
| 10.  | Yes   | No   | NA                                                             | Female who is pregnant or breastfeeding.                                                                                                                                                                                                                                 |
|      | 11.   | Yes  | No                                                             | The addition of cytotoxic agents for "cytoreduction" with the  exception of tyrosine kinase inhibitors (such as imatinib mesylate),  cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or  rituxan within three weeks of the initiation of conditioning. |  
Yes No Poorly controlled hypertension despite  
  
multiple antihypertensives.  
b. **Pulmonary:**
Yes No DLCO < 40%, TLC <40%, FEV1 <40% and/or is requiring supplementary continuous oxygen, or severe deficits in pulmonary function testing as defined by pulmonary consultant service. The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules.  
PI Signature: Date:  
c. **Hepatic**  
| Yes   | No   | Patients with clinical or laboratory evidence of liver disease  would be evaluated for the cause of liver disease, its  clinical severity in terms of liver function, and the degree  of portal hypertension. Patients will be excluded if they are  found to have fulminant liver failure, cirrhosis of the liver  with evidence of portal hypertension, hepatic damage with  bridging fibrosis, alcoholic hepatitis, esophageal varices, a  history of bleeding esophageal varices, hepatic  encephalopathy, uncorrectable hepatic synthetic  dysfunction evidenced by prolongation of the prothrombin  time, ascites related to portal hypertension, bacterial or  fungal liver abscess, biliary obstruction, chronic viral  hepatitis with total serum bilirubin >3 mg/dl, or  symptomatic biliary disease.   |
|-------|------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
.  
13. Yes No Performance status:
a. Karnofsky score < 60 (see **Appendix B**) for adult patients  
14. Yes No Infection with HIV
15. Yes No Active bacterial or fungal infections unresponsive to medical therapy.
a.square yes square no .
note the hct-ci score is

| Signature of person completing form:   | Date:   |
|----------------------------------------|---------|
| Signature of Principal Investigator:   | Date:   |  
APPENDIX M  
  
CRFs
appendix o
hla matching requirements for unrelated

Human Leukocyte Antigen (HLA) Terminology. The HLA region consists of genes that encode two classes of HLA molecules. **HLA class I molecules**, HLA-A, -B, and –C, are composed of a single glycoprotein chain that is expressed in association with 2-microglobulin on most tissue cells. **HLA class II** molecules, HLA-DR, -DQ, and –DP, are heterodimers consisting of and glycoprotein chains. HLA class I and HLA class II molecules are highly polymorphic.  
HLA Typing Methods. At the Seattle Cancer Care Alliance Clinical Immunogenetics Laboratory (CIL)
DNA-based methods of HLA-A, B, C, DRB1, DQB1 typing are now performed routinely. **High resolution**
typing is required to define individual alleles and the level of mismatching between donor and recipient.  
High resolution data are reported with four or more digits (e.g., A*0201, A*0205, B*1504, or DRB1*0401).  
A current listing of recognized HLA alleles and their sequences can be found at the Immunogenetics/HLA sequence database **website at** www.anthonynolan.org.uk/HIG/data.html.  
Initial typing reports obtained through the international marrow donor registries may consist of intermediate resolution typing. **Intermediate resolution** defines alleles in groups of related families historically defined as *antigens* by alloantisera. **Intermediate resolution** typing results are reported as two digits (e.g., A*02, B*15, or DRB1*04). In cases where the HLA-A, B and C loci are typed at intermediate resolution and high resolution data are not available, it should be understood that unidentified allele disparity might be present.  
Donor Selection. Final selection of an unrelated donor should be based upon results of **high resolution**
typing of HLA-A, B, C, DRB1, DQB1 alleles. Cross match assay is not required when high resolution typing indicates matching for HLA-A, B, C, DRB1 and DQB1 AND the platelet reactive antibody (PRA) screen is not elevated (defined as ≤10%). A negative cross match test result is required for final donor selection in the following situations: 1) PRA screen is positive (>10%), or 2) high resolution typing indicates mismatching for one or more HLA-A, B, C, DRB1 and DQB1 alleles. A positive anti-donor cytotoxic crossmatch absolutely excludes the donor.  
Donor Selection Criteria. Protocols and treatment plans must specify donor inclusion and exclusion criteria, using terminology indicated below.  
Donor inclusion criteria **must specify** 1) the allowable genetic relationship between the patient and donor (related and/or unrelated), 2) the allowable limits of mismatch, and if applicable 3) any modification of mismatch criteria according to type of disease or patient characteristics.  
Acceptable levels of recipient-donor mismatch for research related treatment protocols or standard treatment plans include the following:
Allele-match for HLA-A, B, C, DRB1 and DQB1.  
Single allele disparity for HLA-A, B, C, or DRB1 or DQB1 Two allele disparities for HLA-A, B, or C. Single allele disparity for HLA-DRB1 and/or a single DQB1 antigen or allele disparity.  
Single antigen plus single allele disparity for HLA-A, B, or C.  
The following levels of patient-donor mismatch should be restricted to research protocols:
Two antigen disparity, either HLA-A plus C or HLA-B plus C.  
Single antigen disparity for HLA-DRB1 with or without DQB1 allele or antigen disparity Combined disparity of class I and class II loci, i.e. disparity for HLA-A, or B, or C, and any additional disparity for DRB1 or DQB1 Donor Exclusion Criteria to be considered for protocols or standard treatment plans include:
Double locus disparity. Two disparities are not allowed when they both involve the same locus, i.e., the patient is A*0101, A*0201 and the donor is A*0102 and A*0205. Recipient and donor homozygous at mismatched locus. Patient and donor pairs homozygous at the mismatched locus are considered a two-locus mismatch, i.e., the patient is A*0101 and the donor is A*0201, and this type of mismatch is not allowed.  
Recipient homozygous at mismatched locus. If the recipient is homozygous at HLA-A, B, or C
and the donor is mismatched at that locus, i.e., patient is A*0101 and donor is A*0101 and A*0201, the risk of rejection is increased. Such a donor should be avoided if there is already an appreciable risk of rejection, i.e., in patients with CML/MDS/Severe Aplastic Anemia (SAA) or those receiving reduced conditioning.  
Relevance of HLA matching for transplantation of unrelated hematopoietic cells:
Human Leukocyte Antigen (HLA) typing of patients and prospective hematopoietic stem cell (HSC) donors is carried out to identify and match for HLA determinants associated with successful HSC transplant outcome. While several preliminary studies (1, 2, 3) suggested the importance of allele level matching in hematopoietic cell transplantation (HCT), recent comprehensive studies confirmed that allele-level typing and matching is necessary to optimize clinical outcome in hematopoietic cell transplantation (4, 5, 6, 7).  
The pervasiveness of occult HLA mismatch was shown by Petersdorf, et al in an analysis of 300 CML/CP
unrelated donor-recipient pairs matched for HLA-A and B by serologic typing, and matched for the DRB1 alleles.(4) The percent of patient-donor pairs found to be matched at the allele level for all 5 loci (HLA-A, B, C, DRB1, DQB1) was only 47% (n=142). High resolution typing demonstrated previously undetected mismatches in 53% (158), indeed 26% (79) pairs were mismatched for multiple alleles. Mismatch of class I HLA was found at one locus in 55 pairs (18%) and at two or more loci in 35 pairs (12%). A single mismatch of class II HLA was  
- 97 -
detected in 24 pairs (8%), whereas 7 pairs (2%) had multiple class II mismatches, and 37 pairs (12%) had multiple mismatches involving both class I and class II. These data show the  
importance of high resolution typing for defining the degree of mismatching between potential unrelated patient-donor pairs.  
The degree of HLA mismatch, as well as the locus of mismatch, influence the development of alloimmune reactions and have significant implications for the outcome of HSC transplants. Studies of patient-donor pairs have shown an increased risk for graft failure with multiple mismatches that involve at least one class I
allele. The incidence of graft failure was 29% in pairs where the mismatch involved more than one class I allele mismatch and 12% for mismatches involving both class I and class II alleles, compared with 2% or less for pairs with either no mismatch or mismatch confined to a single HLA-A, B, C, DRB1 and DQB1 allele. The risk of developing grades III-IV acute GVHD also has been shown to be influenced by the number and class of mismatched alleles. In studies involving primarily Caucasian patient-donor pairs, the highest risk for severe acute GVHD was observed for multiple mismatches involving both class I and class II alleles (2.0 hazard ratio and p=0.02). Pairs with a single class I mismatch did not have a significant increase in acute GVHD compared with matched recipients, but a single class II mismatch or multiple class I mismatches both appeared to confer a higher (though not significant) hazard of severe GVHD. As results of future studies further define risks of mismatches, particularly in nonCaucasian populations, we may be able to delineate more precisely "low risk" from "high risk" mismatches. Until then, the donor selection process should endeavor to identify the best matched donor within the time allowed by the clinical situation.  
References: 1. Petersdorf EW, Longton GM, Anasetti C, Martin PJ, Mickelson EM, Smith AG, Hansen JA. The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation. Blood 1995: 86:1606-1613.  
2. Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, Smith AG, Martin PJ, Hansen JA. Definition of HLA-DQ
as a transplantation antigen. Proc. Natl. Acad. Sci. USA 1996; 93: 15358.  
3. Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, McKinney SK, Smith AG, Martin PJ, Hansen JA. Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. Blood 1997: 89:
1818. 4. Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson EM, Woolfrey AE, Hansen JA.  
Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 1998: 92: 3515. 5. Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H, Yoshida T, Kimura A, Akaza T,
Kamikawaji N, Kodera Y, Takaku F. Importance of HLA-class I allele matching for clinical outcome after unrelated donor hematopoietic stem cell transplantation. New Engl J Med 1998: 339: 1177.  
6. Hansen JA, Yamamoto K, Petersdorf E, Sasazuki T. The role of HLA matching in hematopoietic cell transplantation. Reviews in Immunogenetics 1999: 1: 359. 7. Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, Storer B, Mickelson E, Smith A, Anasetti C. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. New Engl J Med 2001: 345: 1794.  
8. Bodmer JG, Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Hansen JA, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GMTh, Strominger JL, Svejgaard A, Terasaki PI. Nomenclature for factors of the HLA system, 1998. Tissue Antigens 1999: 53: 407.  
9. List of known HLA allele sequences: **www.anthonynolan.org.uk/HIG/data.html**. 10. Information on HLA complex: http://www.ebi.ac.uk/imgt/hla/intro.html.  
References continued:
11. Little AM and Parham P. Polymorphism and evolution of HLA class I and II genes and molecules. Reviews in Immunogenetics 1999: 1: 105.  
12. Schreuder GMTh, Hurley CK, Marsh SGE, Lau M, Maiers M, Kollman C, Noreen H. The HLA Dictionary 2001: A
summary of HLA-A, B, C, DRB1/3/4/5, DQB1 alleles and their association with serologically defined HLA-A, B, C, DR, and DQ antigens. Tissue Antigens 2001: 58: 109-140.  
13. Smith A, McKinney S, Menninger O, Warnock S, Hansen JA. Detection of a novel "nonexpression" HLA-B*15 allele adds to data on the frequency of class I expression variants in a hematopoietic transplant population. Human Immunology 29th Annual ASHI Meeting Abstracts 2003: 64: S159. 14. Hurley CK, Baxter Lowe LA, Logan B, Karanes C, Anasetti C, Weisdorf D, Confer DL. National marrow donor program HLA-matching guidelines for unrelated marrow transplants. Biology of Blood and Marrow Transplantation 2003: 9. 15. Petersdorf, E.W., Anasetti, C., Martin, P.J., Gooley, T., Radich, J., Malkki, M., Woolfrey, A., Smith, A., Mickelson, E., Hansen, J.A. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood, (in press).  
Approved by the Standard Practice Committee January 16, 2002 (Donor Selection Matching Requirements.doc)
HLA_matching_for_URD_selection.doc Approved by the Medical Advisory Committee (Medical Exec. Comm.) April 9, 2002 Approved by the Clinical Sectional Meeting April 16, 2002 Revised by the Standard Practice Committee June 15, 2005 Minor wording change approved by SPC chairperson March 13, 2006
appendix p adapted from common
hla matching requirements for unrelated

| Grade                                                                                                                                          |                                                                                                                              |                                                                                                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|
| Adverse Event                                                                                                                                  | 3                                                                                                                            | 4                                                                                                                       |
| ALLERGY/IMMUNOLOGY Allergic  reaction/hypersensitivity  (including drug fever)                                                                 | Symptomatic bronchospasm, requiring  parenteral medication(s), with or  without urticaria; allergy-related  edema/angioedema | Anaphylaxis                                                                                                             |
| Vasculitis                                                                                                                                     | Requiring steroids                                                                                                           | Ischemic changes or requiring amputation                                                                                |
| Allergy/Immunology - Other                                                                                                                     | Severe                                                                                                                       | Life-threatening or disabling                                                                                           |
| (Specify,_______________) BLOOD/BONE MARROW Bone marrow cellularity Hemolysis (e.g., immune  hemolytic anemia, drug-related  hemolysis, other) | Requiring transfusion and/or medical                                                                                         | Catastrophic consequences of hemolysis                                                                                  |
| intervention (e.g., steroids)                                                                                                                  | (e.g., renal failure, hypotension,  bronchospasm, emergency splenectomy)                                                     |                                                                                                                         |
| For BMT studies, if specified in  the protocol.                                                                                                | >4 u pRBC in 24 hours                                                                                                        | Hemorrhage or hemolysis associated with  life-threatening anemia; medical  intervention required to improve  hemoglobin |
| For pediatric BMT studies, if  specified in the protocol.                                                                                      | >30mL/kg in 24 hours                                                                                                         | Hemorrhage or hemolysis associated with  life-threatening anemia; medical  intervention required to improve  hemoglobin |
| Grade                                                                                                                                          |                                                                                                                              |                                                                                                                         |
| Adverse Event                                                                                                                                  | 3                                                                                                                            | 4                                                                                                                       |
| CARDIOVASCULAR (ARRHYTHMIA) Cardiovascular/Arrhythmia -Other (Specify,  __________) Symptomatic, and requiring                                 | Life-threatening (e.g., arrhythmia                                                                                           |                                                                                                                         |
| treatment of underlying cause                                                                                                                  | associated with CHF, hypotension,  syncope, shock)                                                                           |                                                                                                                         |
| CARDIOVASCULAR (GENERAL) Acute vascular leak  Respiratory compromise or                                                                        | Life-threatening; requiring pressor                                                                                          |                                                                                                                         |
| syndrome                                                                                                                                       | requiring fluids                                                                                                             | support and/or ventilatory/support                                                                                      |
| Cardiacischemia/infarction                                                                                                                                                | Angina without evidence of                                                                                                   | Acute myocardial infarction                                                                                             |
| infarction FHCRC Current Version 1/13/2016 - 100 -                                                                                             |                                                                                                                              |                                                                                                                         |  
| Grade                                                                                                                                                                           |                                                                                                                |                                                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|
| Adverse Event                                                                                                                                                                   | 3                                                                                                              | 4                                                                                                 |
| CARDIOVASCULAR (GENERAL) continued. Cardiac left ventricular  CHF responsive to treatment                                                                                       | Severe or refractory CHF or                                                                                    |                                                                                                   |
| function                                                                                                                                                                        | requiring intubation                                                                                           |                                                                                                   |
| Cardiac troponin I (cTnI)                                                                                                                                                       | Levels consistent with unstable  angina as defined by the  manufacturer                                        | Levels consistent with myocardial  infarction as defined by the  manufacturer                     |
| Cardiac troponin T (cTnT)                                                                                                                                                       |  0.1 - <0.2 ng/mL                                                                                             |  0.2 ng/mL                                                                                       |
| Hypotension                                                                                                                                                                     | Requiring therapy and sustained  medical attention, but resolves  without persisting physiologic  consequences | Shock (associated with acidemia and  impairing vital organ function due to  tissue hypoperfusion) |
| Myocarditis                                                                                                                                                                     | CHF responsive to treatment                                                                                    | Severe or refractory CHF                                                                          |
| Pericardial effusion/                                                                                                                                                           | With physiologic consequences                                                                                  | Tamponade (drainage or pericardial                                                                |
| pericarditis                                                                                                                                                                    | window required)                                                                                               |                                                                                                   |
| Syncope (fainting) is  graded in the  NEUROLOGY category.                                                                                                                       | -                                                                                                              | -                                                                                                 |
| Thrombosis/embolism                                                                                                                                                             | Deep vein thrombosis, requiring                                                                                | Embolic event including pulmonary                                                                 |
| anticoagulant therapy                                                                                                                                                           | embolism                                                                                                       |                                                                                                   |
| Vein/artery operative  injury is graded as  Operative injury of  vein/artery in the  CARDIOVASCULAR  (GENEARL) category. Cardiovascular/General - Other  (Specify, ___________) | Severe                                                                                                         | Life-threatening or disabling                                                                     |  
| Grade                                                                                                                                                                      |                                                                                |                                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------|
| Adverse Event                                                                                                                                                              | 3                                                                              | 4                                                                                                                        |
| COAGULATION DIC (disseminated  intravascular coagulation) Also consider Platelets.  Note: Must have increased  fibrin split products or D-dimer  in order to grade as DIC. | Laboratory findings present                                                    | Laboratory findings and                                                                                                  |
| with no bleeding                                                                                                                                                           | bleeding                                                                       |                                                                                                                          |
| Coagulation - Other                                                                                                                                                        | Severe                                                                         | Life-threatening or disabling                                                                                            |
| (Specify, _______________) CONSTITUTIONAL SYMPTOMS Weight gain associated with  Veno-Occlusive Disease  (VOD) for BMT studies, if  specified in the protocol.  Also consider Ascites Edema,  Pleural effusion (nonmalignant).                                                                                                                                                                            | >10% or as ascites                                                             | >10% or fluid retention  resulting in pulmonary failure                                                                  |
| DERMATOLOGY/SKIN Erythema multiforme (e.g.,  Stevens-Johnson syndrome,  toxic epidermal necrolysis)                                                                        | Severe or requiring IV fluids  (e.g., generalized rash or  painful stomatitis) | Life-threatening (e.g.,  exfoliative or ulcerating  dermatitis or requiring enteral  or parenteral nutritional  support) |  
APPENDIX P (continued)  
Grade  
| Grade                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                              |                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|
| Adverse Event                                                                                                                                                                                                                                                                                                       | 3                                                                                                                                                                            | 4                                                                                  |
| DERMATOLOGY/SKIN continued Rash/desquamation associated  with graft versus host disease  (GVHD) for BMT studies, if  specified in the protocol.                                                                                                                                                                     | Symptomatic generalized  erythroderma or symptomatic  macular, papular or vesicular  eruption, with bullous  formation, or desquamation  covering 50% of body surface  area | Generalized exfoliative  dermatitis or ulcerative  dermatitis or bullous formation |
| GASTROINTESTINAL Ascites(none-malignant)                                                                                                                                                                                                                                                                            | Symptomatic, requiring                                                                                                                                                       | Life-threatening physiologic                                                       |
| therapeutic paracentesis                                                                                                                                                                                                                                                                                            | consequences                                                                                                                                                                 |                                                                                    |
| Colitis                                                                                                                                                                                                                                                                                                             | Abdominal pain, fever, change  in bowel habits with ileus or  peritoneal signs, and  radiographic or biopsy  documentation                                                   | Perforation or requiring surgery  or toxic megacolon                               |
| Also consider  Hemorrhage/bleeding with  grade 3 or 4 thrombocytopenia,  Hemorrhage/bleeding without  grade 3 or 4 thrombocytopenia,  Melena/GI bleeding, Rectal  bleeding/hematochezia,  Hypotension.  Diarrhea associated with graft  versus host disease (GVHD)  for BMT studies, if specified in  the protocol. | >1500mL of diarrhea/day                                                                                                                                                      | Severe abdominal pain with or  without ileus                                       |
| For pediatric BMT studies, if  specified in the protocol.                                                                                                                                                                                                                                                           | >15mL/kg of diarrhea/day                                                                                                                                                     |                                                                                    |
| Also consider  Hemorrhage/bleeding with  grade 3 or 4 thrombocytopenia,  Hemorrhage/bleeding without  FHCRC Current Version 1/13/2016 - 103 -                                                                                                                                                                       |                                                                                                                                                                              |                                                                                    |  
| grade 3 or 4 thrombocytopenia,  Pain, Dehydration,  Hypotension.   |
|--------------------------------------------------------------------|  
APPENDIX P (continued)
Grade  
| Adverse Event                                                                                                                                     | 3                                                                                                                    | 4                                                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|
| GASTROINTESTINAL (continued). Duodenal ulcer (requires  radiographic or endoscopic  documentation)                                                | Uncontrolled by outpatient  medical management; requiring  hospitalization                                           | Perforation or bleeding,  requiring emergency surgery   |
| Gastric ulcer (requires radiographic or  endoscopic documentation)                                                                                | Bleeding without perforation,  uncontrolled by outpatient  medical management; requiring  hospitalization or surgery | Perforation or bleeding,  requiring emergency surgery   |
| Also consider  Hemorrhage/bleeding with  grade 3 or 4 thrombocytopenia,  Hemorrhage/bleeding without  grade 3 or 4 thrombocytopenia. Gastritis    | Uncontrolled by out-patient  medical management; requiring  hospitalization or surgery                               | Life-threatening bleeding,  requiring emergency surgery |
| Also consider  Hemorrhage/bleeding with  grade 3 or 4 thrombocytopenia,  Hemorrhage/bleeding without  grade 3 or 4 thrombocytopenia. Pancreatitis | Abdominal pain with pancreatic                                                                                       | Complicated by shock (acute                             |
| enzyme elevation                                                                                                                                  | circulatory failure)                                                                                                 |                                                         |
| Also consider Hypotension. Note: Amylase is graded in the  METABOLIC/LABORATOR Y category. FHCRC Current Version 1/13/2016                        |                                                                                                                      |                                                         |  
- 105 -  
| Grade                                                                                                                                                                    |                                                                                                                                     |                                                                                                                               |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|
| Adverse Event                                                                                                                                                            | 3                                                                                                                                   | 4                                                                                                                             |
| GASTROINTESTINAL (continued). Mucositis                                                                                                                                  | Painless erythema, edema, or  ulcers preventing swallowing or  requiring hydration or  parenteral (or enteral)  nutritional support | Severe ulceration requiring  prophylactic intubation or  resulting in documented  aspiration pneumonia                        |
| Note: Radiation-related  mucositis is graded as  Mucositis due to radiation. Typhlitis (inflammation of the cecum)                                                       | Abdominal pain, diarrhea,  fever, and radiographic or  biopsy documentation                                                         | Perforation, bleeding or necrosis  or other life-threatening  complication requiring surgical  intervention (e.g., colostomy) |
| Also consider  Hemorrhage/bleeding with  grade 3 or 4 thrombocytopenia,  Hemorrhage/bleeding without  grade 3 or 4 thrombocytopenia,  Hypotension, Febrile  neutropenia. |                                                                                                                                     |                                                                                                                               |  
| APPENDIX P cont'd Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                             |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|----|
| Adverse Event                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | 3                                                           | 4  |
| HEMORRHAGE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Notes: Transfusion in this section refers to pRBC infusion. |    |
| For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                             |    |
| thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to grading  severity by grading the site or type of bleeding.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                             |    |
| If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of  bleeding: NS Hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding  with surgery, Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal  bleeding/hematochezia, Vaginal bleeding. Hemorrhage/bleeding with grade 3 or  4 thrombocytopenia  Requiring transfusion Catastrophic bleeding, requiring  major non-elective intervention Also consider Platelets, Hemoglobin,  Transfusion: platelets, Transfusion:  pRBCs, site or type of bleeding. If  the site is not listed, grade as  Hemorrhage - Other  (Specify site, __________). Note: This adverse event must be  graded for any bleeding with grade 3  or 4 thrombocytopenia. Hemorrhage/bleeding without grade  3 or 4 thrombocytopenia Requiring transfusion Catastrophic bleeding requiring  major non-elective interventionAlso consider Platelets, Hemoglobin,  Transfusion: platelets, Transfusion:  pRBCs, Hemorrhage - Other  (Specify site, ____________). Note: Bleeding in the absence of  grade 3 or 4 thrombocytopenia is  graded here only if the specific site  or type of bleeding is not listed  elsewhere in the HEMORRHAGE  category. Also grade as Other in the  HEMORRHAGE category.  FHCRC Current Version 1/13/2016 - 107 - |                                                             |    |  
APPENDIX P (continued)  
| Grade                                                                                                        |                                                                    |                                                                                              |
|--------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|----------------------------------------------------------------------------------------------|
| Adverse Event                                                                                                | 3                                                                  | 4                                                                                            |
| HEMORRHAGE (continued) CNS hemorrhage/bleeding                                                               | Bleeding noted on CT or other  scan with no clinical  consequences | Hemorrhagic stroke or  hemorrhagic vascular event  (CVA) with neurologic signs  and symptoms |
| Hemoptysis                                                                                                   | Requiring transfusion                                              | Catastrophic bleeding, requiring  major non-elective intervention                            |
| Melena/GI bleeding                                                                                           | Requiring transfusion                                              | Catastrophic bleeding, requiring  major non-elective intervention                            |
| Rectal bleeding/hematochezia                                                                                 | Requiring transfusion                                              | Catastrophic bleeding, requiring  major non-elective intervention                            |
| Vaginal bleeding                                                                                             | Requiring transfusion                                              | Catastrophic bleeding, requiring  major non-elective intervention                            |
| Hemorrhage - Other                                                                                           | Requiring transfusion                                              | Catastrophic bleeding, requiring                                                             |
| (Specify site, _____________)                                                                                | major non-elective intervention                                    |                                                                                              |
| Grade                                                                                                        |                                                                    |                                                                                              |
| Adverse Event                                                                                                | 3                                                                  | 4                                                                                            |
| HEPATIC Bilirubin                                                                                            | >3.0 - 10.0 x ULN                                                  | >10.0 x ULN                                                                                  |
| Bilirubin associated with graft  versus host disease (GVHD)  for BMT studies, if specified in  the protocol. | >6 - <15 mg/100mL                                                  | >15 mg/100mL                                                                                 |  
| Grade                                                                                                                                      |         |                                               |
|--------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------------------------------------------|
| Adverse Event                                                                                                                              | 3       | 4                                             |
| INFECTION/FEBRILE NEUTROPENIA Febrile neutropenia (fever of unknown origin without clinically or  microbiologically documented  infection) | Present | Life-threatening sepsis (e.g., septic  shock) |
| Infection/Febrile Neutropenia - Other                                                                                                      | Severe  | Life-threatening or disabling                 |
| (Specify, _____________)                                                                                                                   |         |                                               |  
APPENDIX P (continued)  
| Adverse Event                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | 3   | 4   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|-----|
| NEUROLOGY Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY  category. CNS cerebrovascular ischemia Transient ischemic event or  Permanent event (e.g., cerebral  attack (TIA) vascular accident) Leukoencephalopathy  Severe increase in SAS; severe  associated radiological findings ventriculomegaly; near total  white matter T2 hyperintensities  or diffuse low attenuation (CT);  focal white matter necrosis  (cystic) Severe increase in SAS; severe  ventriculomegaly; diffuse low  attenuation with calcification  (CT); diffuse white matter  necrosis (MRI) Seizure(s) Seizure(s) in which  Seizures of any type which are  consciousness is altered  prolonged, repetitive, or difficult  to control (e.g., status  epilepticus, intractable epilepsy) Grade Adverse Event 3 4 PULMONARY Adult Respiratory Distress  - Present Syndrome (ARDS) Apnea Present Requiring intubation Carbon monoxide diffusion  >25 - <50% of pretreatment or  <25% of pretreatment or normal  capacity (DLCO) normal value value FEV1 >25 - <50% of pretreatment or  <25% of pretreatment or normal  normal value value Hypoxia Decreased O2 saturation at rest,  Decreased O2 saturation,  requiring supplemental oxygen requiring pressure support  (CPAP) or assisted ventilation |     |     |  
APPENDIX P (Continued)  
| Grade                                                                                                                      |                         |                        |
|----------------------------------------------------------------------------------------------------------------------------|-------------------------|------------------------|
| Adverse Event                                                                                                              | 3                       | 4                      |
| RENAL/GENITOURINARY Creatinine  Note: Adjust to age-appropriate  levels for pediatric patients.                            | >3.0- 6.0 x ULN         | >6.0 x ULN             |
| Renal failure                                                                                                              | Requiring dialysis, but | Requiring dialysis and |
| reversible                                                                                                                 | irreversible            |                        |
| SECONDARY MALIGNANCY Secondary Malignancy - Other (Specify type, _____________)  excludes metastasis from initial  primary | -                       | Present                |
appendix q the hematopoietic cell
hla matching requirements for unrelated

Assign scores appropriately if the patient has any of these comorbidities  
| Patient ___________________________________ (name), UPN______________ Date_____________ Comorbidities Definitions HCT-CI  Actual Lab  scores Values/Comments Arrhythmia Atrial fibrillation or flutter, sick sinus syndrome, and  ventricular arrhythmias requiring treatment in the patient's  past history 1 Cardiac Coronary artery disease†, congestive heart failure,  myocardial infarction in patient's past history or EF of  50% at time of HCT 1 Crohn's disease or ulcerative colitis requiring treatment in  Inflammatory bowel  1 disease the patient's past history Diabetes Requiring treatment with insulin or oral hypoglycemic, but  1 not diet alone, at time of HCT Cerebro-vascular  Transient ischemic attack or cerebro-vascular accident in  1 disease patient's past history Psychiatric  Depression/anxiety requiring psychiatric consult or  1 disturbance treatment at time of HCT Hepatic - mild Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or  1 AST/ALT >ULN-2.5XULN at time of HCT Obesity Patients with a BMI of >35 for adults or with BMI-for-age percentile of ≥ 95th  percentile for children at time of HCT 1 Infection Documented infection or fever of unknown etiology  requiring anti-microbial treatment before, during and after the start of conditioning regimen 1 Rheumatologic SLE, RA, polymyositis, mixed CTD, polymyalgia  2 rheumatica in patient's past history Peptic ulcer Requiring treatment in patient's past history 2 Renal Serum creatinine >2 mg/dl, on dialysis, or prior renal  2 transplantation at time of HCT Moderate pulmonary DLco and/or FEV1 >65%-80% or 2 Dyspnea on slight activity at time of HCT Prior solid tumor Treated at any time point in the patient's past  3 history, excluding non-melanoma skin cancer Heart valve disease At time of HCT excluding mitral valve prolapse 3 Severe pulmonary DLco and/or FEV1 65% or 3 Dyspnea at rest or requiring oxygen at time of HCT Moderate/severe  Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT  3 hepatic >2.5XULN at time of HCT Total  Please provide (KPS): Karnofsky Performance Score = _______% Score =________ Signature of  Provider: _______________FHCRC Current Version 1/13/2016 - 112 -   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
†One or more vessel-coronary artery stenosis, requiring medical treatment, stent, or bypass graft.  
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythmatosis; RA, rheumatoid arthritis; CTD, connective tissue disease; DLco, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; AST, aspartate aminotransferase; ALT, alanine aminotransferase.  
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythmatosis; RA, rheumatoid arthritis; CTD, connective tissue disease; DLco, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
appendix q the hematopoietic cell
appendix r staging of cll

| Binet stage       | Lymph node areas    | Hemoglobin   | Platelet   | Survival   |
|-------------------|---------------------|--------------|------------|------------|
| 11 g/dl          |  100  109 /L      | (years)      |            |            |
| A                 |  3                 | No           | No         | 12         |
| B                 | 3 or >              | No           | No         | 7          |
| C                 |                    | Yes          | Yes        | 2          |
| (or low platelet) | (or low hemoglobin) |              |            |            |  
| Modified Rai staging Rai  Risk category Lymphocytosis   | Lymph node   | Spleen/liver   | Hemoglobin   | Platelet    | Survival   |     |      |
|---------------------------------------------------------|--------------|----------------|--------------|-------------|------------|-----|------|
| stage                                                   | enlargement  | enlargement    | < 11 g/dl    | <100109 /L | (years)    |     |      |
| 0                                                       | Low          | Yes            | No           | No          | No         | No  |  10 |
| I                                                       | Intermediate | Yes            | Yes          | No          | No         | No  |  7  |
| II                                                      | Intermediate | Yes            |             |            | No         | No  |  7  |
| III                                                     | High         | Yes            |             |            | Yes        | No  | 1.5  |
| IV                                                      | High         | Yes            |             |            |           | Yes | 1.5  |
appendix t coordinating center functions
appendix r staging of cll

Outside Center - PI Communication in Hematologic Malignancies I. **Study Management, data analysis, and Data and Safety Monitoring**
a. Study Management:
i. Each local PI is responsible for selection, training and oversight of local study coordinators ii. The Coordinating Center registers subjects on the study and assigns study IDs iii. One copy of the research data is retained by the site. Another data set (identified only by study IDs) is transmitted to the Coordinating Center to create the master data file. All data are kept in locked areas and password protected databases accessible only to study staff iv. The quality of data is monitored in an ongoing fashion with the study team and corrective action plans instituted as necessary b. Data Analysis:
i. Study staff review data for completeness as it is submitted by the sites ii. The study statistician is responsible for data cleaning and the conduct of analyses as outlined in the protocol and grant c. Data Safety and Monitoring:
i. The trial coordinators at collaborating centers or the local PIs will fax an official report of an SAE (as defined by the protocol) to the Coordinating Center within ten days ii. The SAE report is reviewed by the Overall PI. If the SAE meets the FHCRC
criteria for reporting then an official signed report is submitted to the IRB
iii. An independent DSMB will meet at six-month intervals and all outcome data is reviewed including all adverse events and SAEs reported to the Coordinating Center along with those officially reported to the IRB
iv. A report from the DSMB is submitted to the IRB as well as the trial coordinators/local PIs participating in the protocol
appendix t coordinating center functions
ii. protocol and informed consent

a. A master protocol is maintained by the Coordinating Center and distributed to the sites for customization and local IRB review b. All protocol and consent modifications initiated by the Coordinating Center are sent to the Collaborating Sites following approval by the Coordinating Center IRB, for review and approval by the local IRB
c. Changes required by local IRBs are reviewed by the Coordinating Center and approved prior to implementation at local sites  
- 116 -
appendix t coordinating center functions
iii.assurance of local irb ohrp-approved

a. Each site provides their OHRP assurance number and evidence of IRB certification b. Study staff monitor maintenance of institutional assurance and IRB certification
appendix t coordinating center functions
iv.assurance of local irb approvals

a. The Coordinating Center maintains copies of the most current collaborating site Consent Forms and IRB approval documentation b. No site may enroll subjects until the Coordinating Center has received confirmation of local IRB approval c. Each site is responsible for preparation and submission of their continuing reviews.  
Any changes to the protocol or consent form will be communicated to the Coordinating Center d. Sites are required to have active IRB approvals to participate in any study related activities
appendix t coordinating center functions
v. any substantive modification by

a. The Coordinating Center reviews any modifications to consent forms to ensure that site consents do not delete or change the basic or additional elements or alternatives required in the sample consent form VI. **Informed consent is obtained from each subject in compliance with HHS regulations**
a. Subjects must provide written informed consent prior to study participation b. The Coordinating Center verifies eligibility and signed consent prior to assigning a study ID number