untitled h1
11.7.2 protocol completion/sample destruction

Once primary research objectives for the protocol are achieved, researchers can request access to remaining samples, providing they have both approval of the Principal Investigator of the original protocol under which the samples or data were collected and either an IRB approved protocol and patient consent or the IRB Authorization Form stipulating that the activity is exempt from IRB review (see attached authorization form from the NCI IRB).  
Samples, and associated data, can only be permanently archived if the subject has provided informed consent. If researchers have samples remaining once they have completed all studies associated with the protocol, they must be returned to the Preclinical Service laboratory. The Preclinical Service staff will report to the Principal Investigators any destroyed samples, if samples become unsalvageable because of environmental factors (ex. broken freezer or lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a researcher. The Principal Investigators will annually report this information to the IRB.  
Abbreviated Title: RIST using Unrelated Donors CC Protocol Number: 07-C-0195 11.8 APPENDIX H: FLOW S**HEET**
*If Clinically Indicated  
| Eligibility within  28 days Within 48 hrs  Pre-induction                                  | BiWk during  induction          | After each  induction   | Within 28 days  pre- condition/Tx  arm   | 48 hours pre - condition   | Day 0--DOT   | During Inpatient   | Post Therapy  Day 7   | Post Therapy  Day 14   | Post Therapy  Day 28   | Post Therapy  Day 42   | Post Therapy  Day 60   | Day 100   | Day 180   | 9 month   | Post Therapy 12   | Post Therapy 18   | Post Therapy 24   | Post Therapy 3,  4, 5 yrs   |
|-------------------------------------------------------------------------------------------|---------------------------------|-------------------------|------------------------------------------|----------------------------|--------------|--------------------|-----------------------|------------------------|------------------------|------------------------|------------------------|-----------|-----------|-----------|-------------------|-------------------|-------------------|-----------------------------|
| Observation Clinical Note                                                                 | X                               | X                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      | X                      |           |           |           |                   |                   |                   |                             |
| NIH Advanced                                                                              |                                 |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Directives Form (see  X section 7.3) 1 Nutrition & Social Work Consult X Dental Consult X | TMS                             | AC                      | X                                        |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| (biopsy)                                                                                  | X                               | X*                      | X*                                       | X*                         |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| (biopsy)                                                                                  | (biopsy)                        |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| CMV, adenovirus,                                                                          | Weekly Post transplant while on |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| EBV, Toxo                                                                                 | X                               | immunosuppression       |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Ab for Hep A,B, C,HIV, HTLV1, Syphilis X                                                  | X                               |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| PPD                                                                                       | X*                              |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| ABO typing                                                                                | X                               | X                       | X                                        | ABO Q4 days                |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Urinalysis & UPC                                                                          | X                               | X                       | X                                        | X                          | X            |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| 24 Urine for Cr clearance                                                                 | X                               | X *                     | X *                                      | X                          |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Bone Marrow                                                                               | X                               | FLAG & MM               | X*                                       | X*                         | X*           | X*                 | X*                    | X*                     | X*                     | X*                     | X*                     |           |           |           |                   |                   |                   |                             |
| EKG                                                                                       | X                               | X                       |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| pelvis & NECK*                                                                            | X                               |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| CT chest, abd,                                                                            | lymphoma & CLL                  | X                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      |                        |           |           |           |                   |                   |                   |                             |
| CT/MRI head                                                                               | X                               | X?                      |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| CSF cytology, cell counts, chemistries,                                                   | X*                              |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| flow*                                                                                     |                                 |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| PET scan for                                                                              | X if disease                    |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| patients with                                                                             | X                               | presentat               | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      |                        |           |           |           |                   |                   |                   |                             |
| Hodgkins and NHL*                                                                         | baseline                        |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| MM panel and workup X                                                                     | x                               | x                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      |                        |           |           |           |                   |                   |                   |                             |  
| Version Date: September 14, 2018 Eligibility within  28 days Within 48 hrs  Pre-induction BiWk during  induction   | After each  induction   | Within 28 days  pre- condition/Tx  arm   | 48 hours pre - condition   | Day 0--DOT   | During Inpatient   | Post Therapy  Day 7   | Post Therapy  Day 14   | Post Therapy  Day 28   | Post Therapy  Day 42   | Post Therapy  Day 60   | Day 100   | Day 180   | 9 month   | Post Therapy 12   | Post Therapy 18   | Post Therapy 24   | Post Therapy 3,  4, 5 yrs   |
|--------------------------------------------------------------------------------------------------------------------|-------------------------|------------------------------------------|----------------------------|--------------|--------------------|-----------------------|------------------------|------------------------|------------------------|------------------------|-----------|-----------|-----------|-------------------|-------------------|-------------------|-----------------------------|
| CBC with Diff, Acute Care Panel, Hepatitis Panel, Mineral Panel, PT, PTT Observation                               | BiWk post               |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| X                                                                                                                  | X                       | X                                        | X                          | X            | X                  | BID*                  | transplant             | X                      | X                      | X                      | X         | X         | X         | X                 | X                 | X                 | X                           |
| untilD+100                                                                                                         |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Urine/Serum Pregnancy X                                                                                            | X                       | X                                        | X                          |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| PCR of DNA for future chimerism                                                                                    | X                       |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| determination PFTs                                                                                                 | X                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      |                        |           |           |           |                   |                   |                   |                             |
| ECHO                                                                                                               | X                       | X                                        | X                          | X*           | X*                 | X*                    | X*                     | X*                     | X*                     |                        |           |           |           |                   |                   |                   |                             |
| GVHD prophylaxis                                                                                                   | 2X per                  |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| levels                                                                                                             | week                    | PRN if no                                |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Peripheral Blood Chimerism                                                                                         | X                       | X                                        | X                          | X            | x*                 | X*                    | X*                     | X*                     | PRN                    | PRN                    | 100%      |           |           |                   |                   |                   |                             |
| chimerism PRN if no                                                                                                |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Bone Marrow Chimerism                                                                                              | X                       | X                                        | X                          | PRN          | PRN                | 100%                  |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| chimerism                                                                                                          |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Acute GVHD Assessment                                                                                              | X                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      | X                      | X         |           |           |                   |                   |                   |                             |
| Chronic GVHD Assessment--NIH                                                                                       | X                       | X                                        | X                          | X            | X                  | X                     | X                      |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Staging DEXA Scan                                                                                                  | X                       | yearly if abnornal                       |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Dermatology                                                                                                        | TMS                     | AC                                       | X                          |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| (biopsy)                                                                                                           | X                       | X*                                       | X*                         | X*           |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Consult                                                                                                            | (biopsy)                | (biopsy)                                 |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Ophthamology Consult                                                                                               | X                       | X                                        | X*                         | X*           |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Gynecology                                                                                                         | X *                     | X                                        | X*                         | X*           |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Consult*                                                                                                           |                         |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| FSH, LH (females) Testosterone Level                                                                               | X                       | X                                        | X                          |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| (males only) TSH, Free T4, Ferritin, Vit D,  Quantitative Immunoglobulins                                          | X                       | X                                        | X                          | X            |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| TBNK                                                                                                               | X                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      | X                      | X         | X         | X         | X                 |                   |                   |                             |
| Research specimens                                                                                                 | X                       | X                                        | X                          | X            | X                  | X                     | X                      | X                      | X                      | X                      | X         | X         | X         | X                 | X                 | X                 |                             |  
| Version Date: September 14, 2018 Eligibility within  28 days Within 48 hrs  Pre-induction BiWk during  induction   | After each  induction                                                                                                                                                                                                                                                                                                                          | Within 28 days  pre- condition/Tx  arm   | 48 hours pre - condition   | Day 0--DOT   | During Inpatient   | Post Therapy  Day 7   | Post Therapy  Day 14   | Post Therapy  Day 28   | Post Therapy  Day 42   | Post Therapy  Day 60   | Day 100   | Day 180   | 9 month   | Post Therapy 12   | Post Therapy 18   | Post Therapy 24   | Post Therapy 3,  4, 5 yrs   |
|--------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|----------------------------|--------------|--------------------|-----------------------|------------------------|------------------------|------------------------|------------------------|-----------|-----------|-----------|-------------------|-------------------|-------------------|-----------------------------|
| Observation                                                                                                        | X (if catch                                                                                                                                                                                                                                                                                                                                    |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| Immunizations                                                                                                      | X*                                                                                                                                                                                                                                                                                                                                             | X*                                       | X*                         | X*           | up                 |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| needed)                                                                                                            |                                                                                                                                                                                                                                                                                                                                                |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |
| 1.                                                                                                                 | As indicated in section 7.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advance directives form. This should be done preferably at baseline but can be done at any time during the study  as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required. |                                          |                            |              |                    |                       |                        |                        |                        |                        |           |           |           |                   |                   |                   |                             |  
CC Protocol Number: 07-C-0195
untitled h1
11.9 appendix i risk of

TRANSPLANTATION
Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning Christoph Kahl, 1 Barry E. Storer, 1.2 Brenda M. Sandmaier, 1.2 Marco Mielcarek, 1.2 Michael B. Maris, 3 Karl G. Blume, 4 Dietger Niederwieser, 5 Thomas R. Chauncey, 126 Stephen J. Forman, 7 Edward Agura, 8 Jose F. Leis, 8 Benedetto Bruno, 10 Amelia Langston, 12 Elliot Epner, 12 Peter A. McSweeney, 2 James C. Wade, 13 Elliot Epner, 2 Finn Bo Petersen, 14 Wolfgang A. Bethge, 15 David G. Maioney, 12 and Rainer Storb 1.4
'Fred Hutchinson Canoer Research Center, Seatlin, WA; "University of Washington, Seatlin, WA; "Focky Mountain Blood and Matrow Transplant Program, Dermar, CO; "Stanford University, CA; "University of Leipolig, Leipolig, Cermany; "Volvrans Affairs Puget Sound Hallh System, Seatle, WA; "City of Hope Nalional Modical Center, Duarte, CA: ' Baytor University, Dallas, TX: ' Otogon Health and Science University, Portiand: 31 University of Totino, Totino, Italy;
"Emory University, Allanta, GA. "University of Utah Hoalth Sciences Center, Sall Lake City; "Modical Cologe of Wesconsin, Miwoukoe, "Latter Day Saints
(LDS) Hospital, Salt Lake City, UT; and "University Hospital Tubingan, Tubingan, Centrany  
| Allogeneic hematopoietic cell transplanta-   | competing nonrelapse mortality, were cal-    | lymphoma and high-grade NHL) and my-      |
|----------------------------------------------|----------------------------------------------|-------------------------------------------|
| tion (HCT) after nonmyeloablative condi-     | culated for 29 different diseases and        | eloid malignancies in CR had rates of     |
| tioning for hematologic malignancies de-     | stages. The overall relapse rate per PY      | 0.26-0.37 (standard risk). In conclusion, |
| pends on graft-versus-tumor effects for      | was 0.36. Patients with chronic lympho-      | patients with low-grade lymphoprolifera-  |
| eradication of cancer. Here, we estimated    | cytic leukemia (CLL) and multiple my-        | tive disorders experienced the lowest     |
| relapse risks according to disease charac-   | eloma (MM) in remission (CR), low-grade      | relapse rates, whereas patients with ad¬  |
| teristics. Between 1997 and 2006, 834 con-   | or mantle cell non-Hodgkin lymphoma          | vanced myeloid and lymphoid malignan-     |
| (NHL) (CR + partial remission [PR]), and     |                                              |                                           |
| secutive patients (median age, 55 years;)    | cies had high relapse rates after nonmy-     |                                           |
| high-grade NHL-CR had the lowest rates       | eloablative HCT. The latter might benefit    |                                           |
| range, 5-74, years) received related         |                                              |                                           |
| (n = 493) or unrelated (n = 336) HCT after   | (0.00-0.24; low risk). In contrast, patients | from cytoreductive treatment before       |
| 2 Gy total body irradiation alone (n = 171)  | with advanced myeloid and lymphoid ma-       | HCT. (Blood. 2007;110:2744-2748)          |
| or combined with fludarabine (90 mg/m²;      | lignancies had rates of more than 0.52       |                                           |
| (high risk). Patients with lymphoprolifera-  |                                              |                                           |
| n = 663). Relapse rates per patient year     | tive diseases not in CR (except Hodgkin      |                                           |
| (PY) at risk, corrected for follow-up and    | © 2007 by The American Society of Hematology |                                           |  
Introduction We have developed a nonmyeloablative regimen for allogeneic hematopoietic cell transplantation (HCT) for the treatment of patients with hematologic malignancies. 1-3 The regimen has been translated from a preclinical canine model and uses conditioning with 2 Gy total body irradiation (TBI) with or without fludarabine, and postgrafting immunosuppression with an antimetabolite, mycophenolate mofetil (MMF), and a calcineurin inhibitor, cyclosporine
(CSP). 4 The latter 2 drugs are given for the dual purposes of enhancing engraftment and controlling graft-versus-host disease
(GVHD). The regimen relies virtually entirely on graft-versustumor effects for eradicating cancer and can largely be administered in the ambulatory care setting because of the lack of serious regimen-related toxicities. The latter characteristic has enabled us to loosen the age and comorbidity limitations currently existing for ment of the fact that ment ages at diagnosis for patients with most candidate diseases range from 65 to 70 years, the number of patients treatable by allogeneic HCT has been greatly increased. It is noteworthy that the regimen allows for the purest determination of graft-versus-tumor effects apart from conditioning and, therefore, provides an excellent foundation on which to add disease and disease stage–specific modalities (eg, targeted radiotherapy or cytoreductive autografts). Submitted March 16, 2007; accepted June 4, 2007. Prepublished online as Blood First Edition Paper, June 28, 2007; DOI 10.1182/blood-2007-03-078502.  
The publication cests of this article were datayed in part by page charge The aim of the current retrospective analysis was to estimate relapse risks after HCT according to pretransplant disease characteristics and define groups of patients with low, standard, or high risks for relapse after HCT.  
Patients, materials, and methods Eligibility criteria Betwees December 17, 1997, and June 30, 2006, 834 patients with various bematologic malignancies were treated under different nonmveloablative transplantation protocols within a consertium, consisting of the Fred Hutchinson Cancer Research Center (FHCRC), the University of Washington, Seattle Veteraas Affairs Modical Center, Childrens Hospital and Regional Modical Center, all in Seattle, WA; Rocky Moustain Blood and Marrow Transplatt Program, Denver, CO, Stanfeed University, Stanfeed, CA; the University of Leipzig, Leipzig, Germany, City of Hope National Medical Center, Duarte, CA, Baylor University, Dallas, TX, Oregon Health ard Science University, Portland, OR; the University of Torino, Torino, Italy; Emocy University, Atlanta, GA; University of Utah Health Sciences Center and LDS Hospital, Salt Lake City, UT, Medical College of Wisconsis, Milwankee, WI; and the Universaty Hospital Tabingen, Tubingen, Germany. FHCRC served as the cocolinating center for all payment. Therefore, and solely to indicate this fact, this article is hoteby marked "advertisemont" in accordance with 18 USC section 1734.  
10 2007 by The American Society of Homalology 2744 2746  
| Table 2. Relapse rates in 29 diagnosis and disease stage groups                      |                  |      |        |       |
|--------------------------------------------------------------------------------------|------------------|------|--------|-------|
| PY of                                                                                | Belance          |      |        |       |
| Pations                                                                              | follow           | rate |        |       |
| DS0000                                                                               | Disease stage    | SO   | per PY |       |
| Loorlick                                                                             | 000              |      |        |       |
| S                                                                                    | C                | 8.2  |        |       |
| NHL, for grade                                                                       | Not in CR        | 34   | 0.15   |       |
| .40.9                                                                                | 0.18             |      |        |       |
| NHL, low grade                                                                       | g                | 1.1  |        |       |
| Waldenstrom                                                                          | Avance           | 9    | 10.9   | 0.191 |
| MM                                                                                   | CR               | 29   | .12.9  | 0.19  |
| N-L, mantie cell                                                                     | CR               | .16  | 15.7   | 0.19  |
| NH., mantle cell                                                                     | Not in CR        | 25   | 30.4   | 0.20  |
| MPD                                                                                  | Advance          | 12   | 186    | 0.21  |
| NHL, high grade                                                                      | CS               | 28   | 31.0   | 0.23  |
| AL                                                                                   | 181 CR           | 19   | 21.0   | 0.24  |
| Stendard risk                                                                        | Not in CR        | 75   | 89.0   | 0.28  |
| cl                                                                                   |                  |      |        |       |
| MM                                                                                   | NX In CR         | 138  | 1749   | 0.27  |
| MES                                                                                  | rarran           | 20   | 182    | 0.33  |
| AML                                                                                  | 151 CR           | 783  | 0.33   |       |
| CML                                                                                  | 181 CP           | 26   | 328    | 0.34  |
| AML                                                                                  | ==ndCR           | 59   | 626    | 0.37  |
| High risk                                                                            |                  |      |        |       |
| MDS                                                                                  | RAEB/RAEB-1      | 23   | 19.2   | 0.52  |
| AML                                                                                  | Evolved from MDS | 42   | 2.1    | 0.55  |
| NHL, high grade                                                                      | Not in C8        | 36   | 283    | 0.57  |
| H                                                                                    | 13               | 9.6  | 0.62   |       |
| MES                                                                                  | Secondary        | 0.70 |        |       |
| 18                                                                                   | 14.4             |      |        |       |
| HD                                                                                   | Not in CR        | 38   | 30.6   | 0.72  |
| AML                                                                                  | Not in CR        | 13   | 92     | 0,07  |
| CML                                                                                  | AP/80            | 14   | 10.1   | 0.92  |
| CML                                                                                  | and CP           | 38   | 1.05   |       |
| Penal ce                                                                             | MARKER           | .18  | 10.6   | 1.23  |
| ALL                                                                                  | =2nd CR          | B    | 48     | 1.29  |
| AL                                                                                   | Not in CR        | 22   | 1.37   |       |
| CMM                                                                                  | Avanoed          | 1,42 |        |       |
| 12                                                                                   | 18.3             |      |        |       |
| CLL indicates chronic ismphogitic leckemia: 1 MML multiple myetoma: NHL              |                  |      |        |       |
| non-Hodgidn lymphoma; CR, complete remission; MPD, myeloprollerative disease;        |                  |      |        |       |
| ALL, accelymphoblastic leukemia; MDS, myelodysplastic syndrome; RA, refractory       |                  |      |        |       |
| anemia; RARS, retractory anemia with ringed siderchlasts; AML, acute myeloid         |                  |      |        |       |
| leukemia; CML, chronic myeloid leukemia; CP, chronic phase; RAEB, refractory         |                  |      |        |       |
| anemia with excess tilasts; RAEB4, refractory anemia with excess blasts in           |                  |      |        |       |
| transformation; HD, Hodglin disease; AP, aocelerated phase; BC, blast orisis; CMML   |                  |      |        |       |
| chronic myelomonogtic leukemia.                                                      |                  |      |        |       |
| * PY of follow-up is the total person-years of coservation time from transplant      |                  |      |        |       |
| until death, relapse/progression, last contact, or 2 years.                          |                  |      |        |       |
| T The criteria for complete remission from MM were absence of monoclonal             |                  |      |        |       |
| immunoglobulin and of discernible light chains in unine by standard electrophoresis, |                  |      |        |       |
| The absence of visible monocicnal bands on immunofication, < 1% plasma cells in      |                  |      |        |       |
| man ow aspirates, the absence of evidence of clonal disease according to flow        |                  |      |        |       |  
ortometry of marrow cells, and the absence of an increase in the size or number of ostechtic lesions CR (relapse rate per PY, 0.23); and acute lymphoblastic leukemia
(ALL) in CR1 (relapse rate per PY 0.24).  
The standard-risk group included patients with CLL or MM
with measurable disease at HCT (relapse rates per PY, 0.26 and 0.27, respectively; 94 of the 136 patients with MM had preceding autologous HCT after high-dose melphalan ?); myelodysplastic syndromes (MDS)-refractory anemia (RA)/refractory anemia ringed sideroblasts (RARS), AML in first CR, CML in first chronic phase
(CP), and AML in second or later CR (relapse rates per PY ranging from 0.33 to 0.37).  
The high-risk group included patients with myelodysplastic syndrome (MDS)-refractory anemia with excess of blasts (RAEB)/ RAEB in transformation (RAEB-t), AML after MDS or AML not in CR, high-grade NHL not in CR, Hodgkin lymphoma, MDS after chemotherapy, CML in second CP or accelerated phase/blast crisis, BLOOD, 1 OCTOBER 2007 - VOLUME 110, NUMEER 7 ALL in second or later CR, chronic myelomonocytic leukemia
(CMML), and renal cell carcinoma, with relapse rates per PY ranging from 0.52 to 1.42.  
Figure 1 illustrates the impact of relapse risk on overall survival. Three-year survival for low-risk patients was 60%
compared with 55% for those with standard risk and 26% for those in the high-risk group (Figure 1A). The survival differences were largely due to differences in relapse mortality (Figure 1B). The cumulative relapse incidences at 3 years were 25% for low-risk, 40% for standard-risk, and 57% for high-risk patients. In contrast, no significant differences in nonrelapse mortalities within the 3 risk groups were seen (Figure 1C). The cumulative nonrelapse mortality incidences at 3 years were 29% for low-risk, 21% for standard-risk, and 26% for high-risk patients.
untitled h1
discussion

The success of allogeneic HCT in curing patients with hematologic malignancies depends, in part, on cytotoxic antitumor effects of BLOOD, 1 OCTOBER 2007 - VOLUME 110, NUMBER 7 RELAPSE RISK AFTER REDUCED INTENSITY ALLOGRAFTING 2747 conditioning regimens and, in part, on immune-mediated destruction of cancer cells through grafted cells. Target antigens for T-cell-mediated graft-versus-tumor effects can be ubiquitous polymorphic minor histocompatibility antigens and/or antigens uniquely expressed on bematopoietic cells (hematopoietic antigens), 89 although a role for natural killer cells has also been postulated. 10 The current conditioning regimen of 2 Gy TBI with or without fludarabine was designed to reduce toxicities and allow extending HCT to older and sicker patients and, therefore, has few cytotoxic antitumor effects. As a result, tumor eradication relies virtually entirely on graft-versus-tumor activities. These, in turn, can vary in intensity, depending on the immunogenicity of the tumors and the respective proliferation rates both of the tumors and the donor immune cells poised to destroy them.  
The current study analyzed outcomes in 834 consecutive patients with various hematologic malignancies given either related or unrelated HCT and sought to determine which diseases and disease stages responded well and which less well to graft-versustumor effects as assessed by relapse trates per PY. Using this criterion, patients could be roughly divided into 3 groups that had either low, standard, or high risks of relapse, although nonrelapse mortalities among the 3 groups were comparable, the latter ranging from 21% to 29% at 3 years. Accordingly, differences in survival among the 3 groups were largely determined by differences in relapse rates. These ranged from as low as 0-0.24 relapses per PY in the low-risk group to 0.52-1.42 in the high-risk group, with the standard-risk patients placed in between (0.26-0.37). Three-year survival rates were 60% for the low-risk group, 55% for the standard-risk group, and 26% for the high-risk group.  
The low-risk group included patients with lymphoid malignancies who were in CR (eg, CLL, ALL in CR1, Waldenstrom's, MM,
and high-grade, mantle cell, and low-grade NHL [the latter 2 also included patients in PR]). The low tumor burden and slow-growing nature of these cancers combined with their presumed ability to present target antigens to the donor T cells were likely reasons for tlie low relapse rates and good posttransplantation survival. Similarly good outcomes in these diseases and disease stages have also been reported by others, with progression-free and overall survival rates ranging from 29.4% to 84% and 41% to 84%, respectively, although, as a rule, the conditioning regimens used were more intense. For example, Schetelig et al 11 used a combination of fludarabine, busulfan, and antithymocyte globulin for conditioning. Dreger et al 12 reported on various regimens, including fludarabine/cyclophosphamide and low-dose TBI; Khouri et al 13 combined fludarabine with cyclophosphamide; Lee et al 14 conditioned either with 100 mg melphalan/m 2 (related donors)
or melphalan/250 cGv TBI/fludarabine (unrelated donors); and Gerull et al 15 used fludarabine/low-dose TBI, similar to the current study. Patient ages in these studies were slightly, but not significantly, lower than current patients. Donors were more often related than unrelated. Current results suggested that a minimal conditioning regimen that enabled sustained allogeneic engraftment might be sufficient in patients with low-grade B-cell malignancies in CR or PR.  
The standard-risk group included patients with MM and CLL
not in CR, and various early-stage myeloid malignancies. Although the balance was still in favor of the grafted donor immune cells, with the result that a majority of patients either achieved CR or remained in CR, it was clear that larger tumor burden, relatively faster proliferation rates of tumor cells, and perhaps variable sensitivity of cancer cells to donor immune cells adversely affected outcomes in a strong minority of patients who experienced relapse/progression. To improve outcomes and avoid across-theboard increases in conditioning intensity (and toxicity), individual patients at risk of relapse need to be identified. For example, in the case of patients with CML in CP1, relapse/recurrence was a direct consequence of an initially observed high rate of nonfatal graft rejections, and this problem has since been addressed by adding fludarabine to 2 Gy TBI or increasing the TBI dose to 3 Gy. In patients with CLL who had bulky lymphadenopathy and thus were at high risk of relapse, a single dose of a radiolabeled monoclonal antibody to CD20 has been added to the conditioning regimen. 16 For other disease groups and stages, pinpointing risk factors might require larger numbers of patients, although the fact that almost half of the patients with AML in CR1 and CR2 were older than 60 years might have contributed to a higher relapse risk. Others have used a more intensive conditioning regimen of 8 Gy TBI plus fludarabine, and reported 60%-70% relapse-free survivals in a slightly younger cohort of patients with AML in first or second remission, supporting the notion that more intensive conditioning might be beneficial in some patients. 17 Nevertheless, their reported survival of patients with more advanced AML was not better than that observed among a similar group of patients reported here. Data comparable with ours were described by Gupta et al. 13 using fludarabine and 2 Gy TBI, and Sayer et al, 19 using fludarabine and reduced doses of busulfan both in patients with AML who were in morphologic CR at HCT and those with more advanced disease. Khouri et al 20 observed 83% 2-year survival in patients with CML in chronic phase conditioned with 50 cGy TBI (delivered at 35 cGy/min), a result that was comparable with the survival of those current patients who were conditioned with fludarabine and 2 Gy TBI.  
The high-risk group was comprised of patients with advanced stages of NHL (not in CR), Hodgkin lymphoma, MDS, CML, CMML, acute leukemias, and renal cell carcinoma. Here, the large numbers of cancer cells present at HCT might have shifted the
'balance in their favor, and they "outproliferated" the cytotoxic donor immune cells in a majority of patients. Cytotoxic donor immune cells tended to work slowly, and even under the best of circumstances, say, in patients with slow growing B-cell malignancies such as CLL, graft-versus-tumor effects might take many months before accomplishing molecular remissions. 21 It remains to be seen whether adding targeted therapy to the current regimen, including radiolabeled monoclonal antibodies to CD2016 or CD4522 expressed on tumor cells, will reduce the tumor burden sufficiently.  
to tilt the balance toward the donor immune cells. Alternatively, for patients with MDS, a dose escalation of TBI to 3 Gy is being explored, in part to decrease the relatively high rate of graft failure.  
A strong hint that increasing the intensity of the conditioning regimen might improve outcomes comes from a study in patients with Hodgkin lymphoma; in that study, patients were conditioned with fludarabine, melphalan, and alemtuzumab, and had 4-year overall and progression-free survivals of 55.7% and 39%,
respectively. 23 In conclusion, allogeneic graft-versus-tumor effects are powerful and can lead to cares of otherwise incarable hematologic malignancies. They work best in patients with relatively low tumor burdens and slow growing tumors (eg, NHL or CLL) and least well in patients who have bulky tumors with relatively fast proliferation rates (eg, acute leukemias in relapse). To improve ontcomes in such patients, either the option of allografting should be considered earlier in the disease course when the tumor burden is lower, or targeted therapies with limited systemic toxicities should be added,
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2748 kahl ot al

BLOOD, 1 OCTOBER 2007 - VOLUME 110, NUMBER 7 such as radiolabeled monoclonal antibodies directed against surface antigens that are specific for the tumor cells.
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authorship acknowledgments

We are grateful to the patients and their donors who participated in this study. In addition, we thank all physicians, nurses, and support personnel for their very dedicated care of patients on this study, the research nurses John Sedgwick, Mary Hinds, Michelle Bouvier, and data coordinator Heather Hildebrandt for their help in data acquisition, the long-term follow-up team, and Helen Crawford and Bonnie Larson for manuscript preparation.  
This work was supported by National Institutes of Health grants CA78902, CA18029, CA15704, CA49605, CA30206, DK064715, and HL3644. C.K. was supported by a fellowship from Deutsche Krebshilfe, Dr Mildred-Scheel-Stiftung für Krebsforschung. B.B.  
received support from the Fondazione Cassa di Risparmio di Torino and Comitato Regionale Piemontese Gigi Ghirotti, Progetto Vita Vitae.  
Contribution: C.K. performed retrospective data collection and drafted the manuscript. B.E.S. designed research, performed statistical analyses. B.M.S. and D.G.M. designed research protocol, entered patients on study, verified data, and participated in the writing of the manuscript. M.M. verified data and assisted in drafting the manuscript. M.B.M., K.G.B., D.N., T.R.C., S.J.F.,
E.A., J.F.L., B.B., A.L., P.A.M., J.C.W., E.E., F.B.P., and W.A.B.  
contributed patients to studies, verified patient data, and reviewed the manuscript. R.S. designed, directed, and provided funding for the study and edited the manuscript.  
Conflict-of-interest disclosure: The authors declare no competing financial interests.  
Correspondence: Rainer Storb, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D1-100, PO Box 19024, Seattle, WA 98109-1024; e-mail: rstorb@fhcrc.org.
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references

1. Mc:Sweeney PA, Niederweser D, Shizuru JA, et al. Hometopoietic cell transplantation in older pa tients with hemetologic melignancies: replacing high dose cylotoxic therapy with graft versus tumor effects. Blood, 2001;97:3090:3400.  
2. Nederwieser D, Marts M, Shizuru JA, et al. Low dose lotal body inadation (TBI) and fludarating followed by hematopoletic cell transplantation.  
(HCT) from HLA-malched or mismalched unrel lated donors and postgrafting immunosuppress sion with cyclosporine and myoophenolste moletile
(MMF) can induce durable complete chimerism and sustained remissions in patients with heme tological diseases. Blood. 2000;101:1620-1629.  
Maris MB, Niederwasar D, Sandmaier BM, et al.  
HLA metched unrelated donor hemetopolic cell transplantation after nonmystophative condition ing for patients with hematologic malignancies.  
Blood, 2003;102:2021:2030 Storb B, Yu C, Wagner JL, et al. Statle moved 4 hemotopolatic chimerism in EXA-klentical littler mate dogs given subjethal lotal body inactation before and pharmacological immunosuppression atter manow transplantation. Blood, 1997;89.  
3048-3054.  
Disconescu R, Florers CR, Storer B, et al. Morbldlty and morially with normyeloablative compared with myskablative conditioning before held malopoletic cell transplantation from HLA.
matched related donors. Blood, 2004;104:1550.  
1558 6. Sorror ML, Maris MB, Storer B, et al. Comparing morbidity and mortality of HLA matched unrel lated donor hematopoietic cell transplantation atter nonmrelative and myelceblative conditioning: influence of protransplant comorbidities Bbod. 2004;104:961-968.  
Maloney DG, Molina AJ, Sahebi F, et al. Allografts ing with nonmyeketslative conditioning tollow cytoreductive autografts for the treatment of pattients with multiple myeloma. Blood, 2000;102 347-3454.  
8. Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation  
| 1997;157:125-140.   |
|---------------------|
| 841-848             |
| 2001;98:3595-3599   |
| 80.                 |
| 15.                 |  
and adoptive immunotherapy. Immunol Rev 1997;157:125-140.  
Warron EH, Gavin M, Greenberg PD, Riddell SR,
Minor histocomparibility antigens as terrents for T coll therapy alter bone manow transplantation.  
Ruggeri L, Capanni M, Urbani E, et al. Effective ness of donor natural killer cell alkreactivity in mismalched hemetopoletic transplants. Science.  
Schetelig J, Thieds C, Bomhauser M, et al. Evidonce of a graft versus leukomia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stom cell transplantation.  
the Cooperative German Transplant Study.  
Droger P, Brand R, Hansz J, of al. Treatment related mortality and gratt-versus-leukemia activity ater allogeners stem cell transplantation for chronic lymphocytic leukemia using intensity reduced conditioning (Review). Leukemia, 2003;17:
Khouri IF, Salica RM, Girall SA, of al. Nonablative alogeneic hemetopoiatic transplantation as adoptive immunomerapy for indolent lymphorne low incidence of toxicity, acute graft versus host disease, and treatment related monality. Blood 2001;98:3595-3599 Lee C-K, Badros A, Barlogie B, et al. Progrostic tactors in allogeneic transplantation for petients with high-risk multiple myeloma after reduced in tensity conditioning. Exp Hematol. 2003;31:73.  
Gerull S, Geerner M, Benner A, et al. Long-term outcome of nonmyeloablative allogeneic trans plantation in patients with high-risk multiple my eloma. Bone Marrow Transplant. 2006;36:963.  
Gopell AK, Rejendran JG, Pagel JM, et al. A
phase II trial of 90Y-ibritumornab tiuxetan-based reduced intensity allogeneic peripheral blood stom coll (PBSC) transplantation for relapsed CD20+ B-cell non-Hodgkins lymphoma (NHL)
[abstract]. Bkxxl. 2006;108:888.  
17. Stelljas M, Bornhauser M, Kroger M, et al. Conditioning with 8-Gy total body irraciation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute mysloid leukamia. Blood, 2005;106:3314:3321.  
18.  
Gupta V, Daly A, Lipton JH, et al. Nonmyekaablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older. Biol Blood Marrow Transplant 2005;11:764:772.  
Sayer HG, Kroger M, Beyer J, et al. Reduced in19.  
tensity conditioning for allogeneic hematopoietic stom cell transplantation in patients with acute myekid loukomia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant. 2003;31:1089-1095.  
Khoury H, Adkins D, Brown R, et al. Lowingt dence of transplantation-related acute complexations in patients with chronic myeloid hukama undergoing allogeneic stem cell transcientation.  
with a lost dose (550 cGy) total body irradiation.  
conditioning regimen. Biol Blood Marrow Trans plant. 2001;7:352-358.  
Sorror ML, Maris MB, Sandmation BM, et al. Honotopoletic cell transplantation after nonmyeloablative conditioning for advanced chronic tymphocytic loukomia. J Clin Oncol. 2005;23:38192. Papel JM, Appelbaum FR, Sandmaior BM, et al.
131 -anti-CD45 antibody plus fludarabine, lowdose total body irradiation and peripheral blood stomcoll infusion for elderly patients with advenced acute myeloid leukemia (AML) or high ic myelodysplastic syndrome (MDS) [abstract].  
.8kcd.2006;106:119a.  
23. Peggs KS, Hunter A, Chopra R, et al. Clinical evidence of a grant-versus-Hodgkin's-lymphoma effoct after reduced intensity allogancic transplan talion. Lanost. 2006;365:1934-1941.  
Version Date: September 14, 2018
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11.10 appendix j comobidity index

From bloodjournal.hematologylibrary.org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For  
  
tersonal use only 2005 106: 2912-2919
Prepublished online June 30, 2005;
doi:10.1182/blood-2005-05-2004.  
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT
Mohamed L. Sorror, Michael B. Maris, Rainer Storb, Frederic Baron, Brenda M. Sandmaier, David G.
Maloney and Barry Storer Updated information and services can be found at:
http://bloodjournal.hematologylibrary.org/content/106/8/2912.full.html Articles on similar topics can be found in the following Blood collections
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Copyright 2011  
  
From bloodjournal hematologylibrary.org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For TRANSPLANTATION _
Hematopoietic cell transplantation (HCT)–specific comorbidity index: a new tool for risk assessment before allogeneic HCT
Mohamed L. Sorror, Michael B. Marts, Rainer Storb, Frederic Baron, Brenda M. Sandmaler, David G. Maloney, and Barry Storer  
| We previously reported that the Charlson     | tional HCT-related comorbidities, and (3)   | new index showed better survival predic¬     |
|----------------------------------------------|---------------------------------------------|----------------------------------------------|
| Comorbidity Index (CCI) was useful for       | establish comorbidity scores that were      | tion than the CCI (likelihood ratio of 23.7  |
| predicting outcomes in patients undergo¬     | suited for HCT. Data were collected from    | versus 7.1 and c statistics of 0.661 versus  |
| ing allogeneic hematopoietic cell trans-     | 1055 patients, and then randomly divided    | 0.561, respectively, P < .001). In conclu-   |
| plantation (HCT). However, the sample        | Into training and validation sets. Weights  | sion, the new simple index provided valid    |
| size of patients with scores of 1 or more.   | were assigned to individual comorbidi-      | and reliable scoring of pretransplant co-    |
| captured by the CCI, did not exceed 35%.     | ties according to their prognostic signifi¬ | morbidities that predicted nonrelapse        |
| Further, some comorbidities were rarely      | cance in Cox proportional hazard models.    | mortality and survival. This index will be   |
| found among patients who underwent           | The new index was then validated. The       | useful for clinical trials and patient coun- |
| HCT. Therefore, the current study was        | new index proved to be more sensitive       | seling before HCT. (Blood, 2005;106;         |
| designed to (1) better define previously     | than the CCI since it captured 62% of       | 2912-2919)                                   |
| identified comorbidities using pretrans-     | patients with scores more than 0 com-       |                                              |
| plant laboratory data, (2) investigate addi¬ | pared with 12%, respectively. Further, the  | C 2005 by The American Society of Hematology |
| Introduction                                 |                                             |                                              |  
Introduction Comorbidity, as defined by Feinstein, 1 is any distinct additional clinical entity that has existed or may occur daring the clinical course of a patient with a primary (index) disease. Comorbidities affect therapeutic plans and posttherapeutic outcomes of the index dsease. 1 In patients with cancer as the index disease, multiple studies have demonstrated the relevance of comorbidities in the prognosis (reviewed in Extermann 2 ). The number of comorbidities was suggested to increase with aging of cancer patients (reviewed in Extermann'). In Surveillance, Epidemiology, and End Results (SEER) registry data, 75% of patients 55 years and older with colon cancer had more than one comorbidity. 4 However, patients with comorbidities are often excluded from clinical trials, and there are little data on how to translate results from cooperative studies to patients with comorbid diseases. Therefore, the assessment of comorbidities should be integrated into clinical trials, in addition to functional status, particularly since comorbidities and functional status can be used independently to predict outcomes. 5-7 Efforts to analyze the impact of comorbidities on index diseases are still in their early stages. The interactions between the index diseases and different comorbidities are variable based on the type and degree of organ involvement. Therefore, several indices have introduced a From the Fred Hulchinson Cancer Research Center, Sealtho, WA, and the University of Washington, Sealtie, WA
Submilled May 19, 2005; accepted June 16, 2005. Prepublished ordina as Blood First Edition Paper, June 30, 2006; DOI 10,1182,blood 2005-05-2004; Supported  in  part  by  grants  CA78902,  CA92058,  CA18229,  CA49806,
HL36444, and CA15704 from the National Institutes of Health, Department of Health and Human Services (DHHS), Bethesda, MD, ML, S, mas supported by a grant from the Oncology Research Faculty Development Program of the Office of International Affairs of the National Cancer Institute ML.S. disigned the study, collected and extracted patients' data, performed the research, analyzed the statistical results, and wrote the paper. M.B.M.  
provided quidance for the state design, contributed to analysis of the statistical results, and edited the paper. R.S. provided guidance for the study design, has been senior investigator on underlying clinical studies, contributed to analysis way to rate the impact of different comorbidities on the index disease. One of these is the Charlson Comorbidity Index (CCI). The CCI was developed by assigning weights for 19 chronic conditions according to their association with 1-year mortality in a cohort of 559 patients admitted to a general medical center. Then, a summary score based on the sum of the weights was validated in a cohert of breast cancer patients by evaluating the ability of sceres to predict mortality. 3 Later, Charlson added age to her weighted comorbidity scores by assigning an extra point for every decade of age starting at 50 years. 9 The CCI has been widely used in predicting mortality risks in various medical conditions including solid malignancies. 3, 10-17 We have recently used the CCI in the settings of ablative and nonablative allogeneic hematopoietic cell transplantation (HCT) for patients with hematologic malignancies. In our studies, an adapted form of the CCI successfully predicted the risks of nonrelapse mortality (NRM) in patients receiving hematopotetic cell transplants from unrelated 18 or related 19 donors.  
Those initial observations have been confirmed in several subsequent reports analyzing outcomes after nonmyeloablative HCT. 2023 However, some of the comorbidities described by Charlson were rarely encountered in HCT patients due to existing exclusion of the statistical results, provided oversight, and obled the paper. F.B.  
contributed to collection of patient data and edited the paper. B.M.S. provided guidance for the study design and edited the paper. D.G.M. provided guidance for the study design and edited the paper. B.S. contributed to the statistical dissign of the staty, performed the statistical analyses, contributed to writing
"Patients, makrials, and mothods," and edited the paper An Inside Blood analysis of this article appears at the front of this issue.  
Reprints: Rainer Storb, Fred Hutchinson Cancer Research Center, 1100.  
Fainiew Ave N, D1-100, PO Bex 19024, Seattle, WA 96100-1024; e-mail:
rslorb & fictio.org. The publication costs of this article were detrayed in part by page charge payment. Therefore, and sololy to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.  
© 2005 by The American Society of Hemalology 2912 From bloodjournal.hematologylibrary.org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For BLOOD, 15 OCTOBER 2006 - VOLUME 106, NUMBER 8 personal use proteneic stem cell transplantation comorbidities 2913 criteria. This was particularly true for hepatic and pulmonary comorbidities. In addition, the CCI did not capture some frequent comorbidities, such as recent infections and psychiatric disturbances. Further, the CCI lacked sensitivity since comorbidities were found in only 35% of patients, and this percentage was even lower in patients undergoing ablative HCT (12% in unrelated 13 and 2% in related 19 ablative recipients). Some investigators have pointed out the somewhat limited ability of the CCI to capture comorbidities in patients with primary diagnoses other than hematologic diseases. 5.24 Others were successful in developing dsease-specific comorbidity indices by modifying the original CCI. 12 , 13 With the development of nonmyeloablative HCT regimens and improvements in the supportive care after myeloablative HCT regimens, more patients with comorbidities are being offered allogeneic HCT.  
Therefore, in the current study, we sought to identify those chronic medical conditions, which were important in predicting NRM in HCT patients, and then integrate these factors into a new scoring system to assess survival probabilities after allogeneic HCT.
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patients materials and methods.

The analysis was approved by the institutional review board of the Fred Hutchinson Cancer Research Center (FHCRC, Seattle, WA). Informed consent was provided according to the Declaration of Helsinki.  
Patients: data source and patient selection This analysis included consecutive and concurrent patients given either nablative (n = 294) or ablative (n = 761) conditioning followed by hematopoietic cell grafts from related (1997-2003) or unrelated (20002003) donors. Nonablative patients were conditioned with 2 Gy total body irradiation (TBI) either alone (n = 68) or proceded by fludarabine (n = 226)
and were given postgrafting immanosuppression with cyclosporine (CSP)
and mycophenolate mofetil (MMF). 20-28 Ablative patients were conditioned with either busulphan/cyclophosphamide 20 or cyclophosphamide/TBI 3430 and, in almost all cases, were given postgrafting immunosuppression with CSP/methotsexate. 34 Diagnoses and clinical grading of acute and chronic graft-versus-host disease (GVHD) were performed using standard criteria. 33 -34 Primary treatment of GVHD consisted of systemic corticosteroids, oral beclomethasone with or without systemic corticosteroids, or reinstitution of CSP.  
Early detection of cytomegalovirus antigenemia and preemptive ganciclovir therapy were used for all patients 35 as were standard prophylaxis against Candida infections (fluconazole), 36 bacterial infections (ceftazidime or ciprofloxacin), Pneumocystis carinii infection (trimethoprimsulfamethoxazole or dapsone), 23 and herpes simplex virus 28 and varicella zoster virus 30 reactivation in serologically positive patients (acyclovir).  
Low disease risk included acute leukenna in first complete remission, chronic myeloid leakemia in first chronic phase, myelodysplasia-refractory anemia, and nonmalignant hematologic diseases; while high disease risk included all other diagnoses.  
Data collection and modified comorbidities Demographic data were obtained from the FHCRC database. Information on comorbidities was extracted from detailed review of the patients' medical charts and laboratory values at the time of HCT. All comorbidities, which were encountered in the 1055 reviewed patients, were included in the current study. Patients were given scores based on the original CCI. 8 A new HCT-specific comorbidity index (HCT-CI) was then developed as follows:
Finst, definitions of several comorbidities were modified as described in Table 1. Second, comorbidities that were not found in the original CCI were identified as newly investigated or additional comorbidities. Those included bleeding, headache, cateoarthntis, osteoporosis, asthma, obesity, infection, and psychiatric disturbances. The added comorbidities had to be active or requiring treatment at the time of HCT, as defined by Charlson et al. 8 Third, all other comorbidities were assigned new weights in the HCT-CI using the original definitions in the CCI, 5 including gastrointestinal disease, coagulopathy, endocrine disease, hypertension, arrhythmia, inflammatory bowell disease, diabetes, cerebrovascular disease, rheumatologic disease, pepticuucer, and heart valve disease.  
Assignment of new comorbidity weights In order to develop the new HCT CI, patients were randomly divided into 2 cohorts. Two thirds of the patients were assigned to a training set to develop the scoring weights (n = 708), and one third was assigned to a validation set (n = 347). Integer weights for the HCT-CI were derived from Cox proportional hazards modeling applied to the training set, with NRM over the first 2 years as the outcome. NRM was used instead of survival for development of the scores, since deaths from nonrelapse causes are more likely influenced by pretransplant comorbidities than deaths caused by disease progression or relapse, which were treated as competing risks.  
Adjusted hazard ratios (HRs) for NRM over the first 2 years after transplantation were calculated for each comorbid condition, controlling for the presence of all coexisting comorbidities as well as for age (younger versus older than 50 years), type of conditioning (nonablative versus ablative), and disease risk (high versus low). The adjusted HRs were converted to integer weights according to the following: comorbidities with adjusted HR of 1.2 or less were dropped from consideration, comorbidities with adjusted HR of 1.3 to 2.0 were assigned a weight of 1, comorbidities with adjusted. HR of 2.1 to 3.0 were assigned a weight of 2. and  
| Table 1. Refinement of definitions of comorbidities                                                                                                                 |                                                             |                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|----------------------------------------------------------------------------------------|
| Comorbidity                                                                                                                                                         | CCI definition                                              | New definition, from HCT-CI                                                            |
| MI pulmonary                                                                                                                                                        | Dysprea on moderate activity                                | Dyspnea on moderate activity or DLco and or FEV+ 81%-90%                               |
| Moderate pumonary                                                                                                                                                   | Dysprea on slight activity                                  | Dyspnea on slight activity or DLco and or FEV1 66%-80%                                 |
| Dyspnen at rest or requires caygen or DLoo and/or FEV1 ≤ 65%                                                                                                        |                                                             |                                                                                        |
| Severe pulmonary                                                                                                                                                    | Dyspnaa at rest or requires oxygen                          |                                                                                        |
| Cordiac                                                                                                                                                             | Congestive heart latium (symptomatic and requiring          | Includes coronary artery disease, "congestive heart leiture, myocardial interction, or |
| treatment) and myocardial interction were included                                                                                                                  | election traction = 50%; one or more acquiring a score of 1 |                                                                                        |
| as independent comorbicities, each acquiring a                                                                                                                      |                                                             |                                                                                        |
| soon of 1                                                                                                                                                           |                                                             |                                                                                        |
| Mkl hepatic                                                                                                                                                         | Chronic hepotitis or circhosis                              | Chronic hopetitis, bilitutin > ULN to 1.5 × ULN, or AST/ALT > ULN to 2.5 × ULN         |
| Moderate severe hepatic                                                                                                                                             | Cinhosis with portal hyportension ± bleading various        | Cinhosis, fibrosis, bilitubin > 1.5 × ULN, or AST/ALT > 2.5 × ULN                      |
| MIKI renal                                                                                                                                                          | Sorum creatining 2-3 mg/dL.                                 | Creating 1:2-2 mg/dL.                                                                  |
| Moderate severe renal                                                                                                                                               | Creatining > 3 mg/dl., renal dialysis, or renal transplant  | Creatining > 2 mgAlL, renal dialysis, or renal transplant                              |
| Prior solid turnor                                                                                                                                                  | Initially treated in the last 6 y                           | Treated at any time point in the petient's past history, excluding nonmelanomet skin   |
| cancer                                                                                                                                                              |                                                             |                                                                                        |
| To convert creating from miligrams per decilism to micromoles per liter, multiply miligrams per decilism by 88.4.                                                   |                                                             |                                                                                        |
| *One or more vessel coronary artery stenosis requiring medical treatment, stent, or bypass graft.                                                                   |                                                             |                                                                                        |
| DLoo indicates diffusion capacity of carbon monoools; FEV, forced explitatory volume in one second; UEN, upper limit of normal; AST, asperials aminotemslerase; and |                                                             |                                                                                        |
| ALT, alaning aminotransforase                                                                                                                                       |                                                             |                                                                                        |  
From bloodjournal.hematologylibrary.org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For personal use only.  
BLOOD, 15 OCTOBER 2005 - VOLUME 106, NUMBER 8  
SORROR et al 29146
comorbidities with adjusted HR of 3.1 or more were assigned a weight of 3.  
The HCT-CI score was the sum of these integer weights. The HCT-CI
scores were further collarsed into 3 risk groups: 0 (low risk), I to 2
(intermediate risk), and 3 or more (high risk). For comparative purposes, the original CCI was also reduced to 3 risk groups: 0, 1, and 2 or more. Model validation The scores of the new HCT-CI were applied to patients of the validation set to test their ability to predict for HR and cumulative incidence of NRM. The new HCT-CI was then compared with the original CCI for prediction of both NRM and survival. Survival was added as an end point for comparison between the 2 indices since the CCI scores were derived from Cox proportional hazards modeling for survival. 3 Cumulative incidence 40 curves for NRM and Kaplan-Meser curves for survival were computed for each risk group defined by the 2 indices. Likelihood ratio statistics from proportional hazards models were computed for both indices for events.  
over the first 2 years. Although a larger likelihood ratio statistic indicated a better fit to the data, the likelihood ratio by itself had no intuitive interpretation in terms of prediction. For this parpose, we also computed the c-statistic. 41 For a continuous predictor, the c-statistic could be interpreted as the probability that a random pair of observations whose event times could be ordered would have a concordant ordering of the predictor. A value of 1.0 indicated perfect predictive discrimination, whereas a value of 0.5 indicated no ability to discriminate. If the data were collapsed to indicate a binary outcome (survival larger or smaller than a fixed point in time), then the c -statistic was also interpretable as the area under a receiver operating characteristic curve. Pairs of observations whose ordering could not be assigned because of censoring were excluded from the calculation. The c-statistic was computed for NRM and survival, based on both time to event over the first 2 years and as a binary outcome indicating event times before/after 1 year or 2 years. For computing e-statistic for NRM, patients, were censored at the time of relapse/progression. Standard errors for the c statistic were estimated by applying a bootstrap procedure to the validation dataset, using 100 bootstrap samples. Similarly, the standard error for the difference in c-statistic between the CCI and HCT-CI was estimated from the bootstrap samples and used to calculate a z-score and P
value for the difference.  
| Table 2. Patient and disease characteristics                                    |                  |
|---------------------------------------------------------------------------------|------------------|
| Characteristics                                                                 | Data             |
| Conditioning regimens, %                                                        |                  |
| 2 Gy TBI                                                                        | o                |
| Fluderabine + 2 Gy TBI                                                          | 22               |
| CY + at least 12 Gy TBI                                                         | 29               |
| BU + CY                                                                         | 43               |
| Postgrafting immunosuppression, %                                               |                  |
| CSP + MMF                                                                       | 18               |
| CSP + MTX                                                                       | 02               |
| Donor type, %                                                                   |                  |
| Pelsted donor                                                                   | 58               |
| Unrelated donor                                                                 | 42               |
| Dagnoses, %                                                                     |                  |
| AL                                                                              | 27               |
| CML                                                                             | .201             |
| MDS                                                                             | 19               |
| AL                                                                              | 10               |
| NH                                                                              | g                |
| M                                                                               | A                |
| a                                                                               | 4                |
| HD                                                                              |                  |
| Nonmalignant hematological                                                      | 3                |
| Dsease risk group, % t                                                          |                  |
| High                                                                            | .41              |
| LOR                                                                             | .59              |
| Age at transplantation                                                          |                  |
| Modian (range), y                                                               | 144.8 (0.8-72.7) |
| Preceding myeloablative HCT, 36                                                 |                  |
| Alogeneic                                                                       | 2                |
| Failed autologis                                                                | B                |
| Planned autologous                                                              | 5                |
| Hematopoietic cell source, %                                                    |                  |
| G-PBMC                                                                          | 71               |
| Marrow                                                                          | 29               |
| Male/lemale, 91                                                                 |                  |
| Patients                                                                        | 58/44            |
| Donors                                                                          | 51.49.           |
| n = 1065.                                                                       |                  |
| TBI indicates total body inaciation; CY, cyclophosphemide; BU, busullan; CSP,   |                  |
| cyclospotine; MMF, mycophenolate moletil; MTX, metholrexate; AML, acute myeloid |                  |
| leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndromes; ALL    |                  |
| acule hmoboblastic leukemia: NHL, non-Hodgkin lymphoma; MA, multiple myeloma;   |                  |
untitled h1
results

Patient characteristics Characteristics of the 1055 patients included in this study are shown in Table 2. A majority of patients received cyclophosphamide/ busulphan conditioning (43%), 29% received cyclophosphamide/
TBI (12-14.4 Gy), 22% received fludarabine/TBI (2 Gy), and 6%
received 2 Gy TBI. GVHD prophylaxis was MTX/CSP in 69% of patients and MMF/CSP in 31%. Myeloid malignancies constituted the majority of diagnoses (66%). Forty-one percent of the patients had high risk disease. Median age was 44.8 years. Related grafts were used in 58% of patients, while the remainder received urelated grafts. Thirteen percent of patients had preceding myeloablative HCT, of which 2% were allogeneic, 6% were failed autologous, and 5% were planned autologous. A majority of patients received peripheral blood stem cell grafts (71%).  
The HCT-CI
The prevalence of various comorbidities together with the cumulative incidence and multivariate HR for 2-year NRM, as predicted by each comorbidity, are shown in Table 3. The definitions of comorbidities included in the HCT-CI, along with the integerweights compared with those of the CCI, are shown in Table 4.  
Pulmonary and hepatic abnormalities, as defined by laboratory data, were the most frequent comorbidities in the new HCT-CI and, CLL, chronic lymphocytic leukemia; HD, Hodgkin disease; HCT, hemotopolatic cell transplantation; and G-PBMC, granulocyte colony stimulating factor-mobilized peripheral blood mononuclear cells
"Immunodeficiency syndrome, chronic granulometous disease, congenital dyser, ythropoletic anamia, paroxysmal nocturnal hemoglobinuria, polycythemia vera, thalassemic syndrome, and sicide cell anomia.  
↑Low indicates acute foukernia in first remission, CML in first chronic phase, MDS retractory anemia, or nonmalignant hometologic disease; while high indicates all other diagnose together with prior solid tumor and heart valve disease, had the highest assigned weights. By comparing conditions in the newly derived HCT-CI with those of the CCI, a number of comorbidities increased in relative importance, including arrhythmia, inflammatory bowel disease, rheumatologic disease, peptic ulcer, moderately and severe pulmonary comorbidity, prior solid tumor, and heart valve disease. Other conditions, including cardiac disease, diabetes mellitus, cerebrovascular disease, mild bepatic comorbidity, modesate/severe renal comorbidity, and moderate/severe hepatic comorbidity, had comparable weights both in the HCT-CI and the original CI. Of the 8 comorbidities tested that were not specified by Charlson, obesity, peritransplant infections, and psychiatric disturbances were assigned weights in the HCT-CI, whereas bleeding, headache, ostecarthritis, osteoporosis, and asthma were not because of low predictive HR for NRM (0.0, 0.3, 0.4, 0.7, and 1.1, From bloodjournal hematologylibrary org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For BLOOD, 15 OCTOBER 2006 - VOLUME 106, NUMBER 8 personal use proteneic stem cell transplantation comorbidities 2915  
| Table 3. Prevalence of comorbidities among 708 patients included                 |                                                 |     |       |
|----------------------------------------------------------------------------------|-------------------------------------------------|-----|-------|
| In the training set with cumulative incidences and multivariate HRs              |                                                 |     |       |
| of comorbidities for 2-year NRM                                                  |                                                 |     |       |
| Comorbidity                                                                      | Prevalence, %, 12-year NRM, %, Multivariate HR* |     |       |
| 0.0                                                                              |                                                 |     |       |
| Booking                                                                          | 1                                               | o   |       |
| Headacheter                                                                      | .                                               | 0.3 |       |
| Oxeconthritist                                                                   | 1                                               | 11  | 0.4   |
| Gastrointestinal disease                                                         | e                                               | 20  | 0.5   |
| Conguic patty                                                                    | 6                                               | 30  | 0.6   |
| OSTECOLOGIST                                                                     | 75                                              | 0.7 |       |
| Banal, mixture                                                                   | 10                                              | 24  | 0.8   |
| Endocrine disease                                                                | 5                                               | 31  | 1.0   |
| Astrmat                                                                          | 2                                               | 14  | 1.1   |
| Pulmonary, mikst                                                                 | 16.                                             | 18  | 1.1   |
| Hpertension                                                                      | 3                                               | 1.2 |       |
| 10                                                                               |                                                 |     |       |
| Artrythmia.                                                                      | 1.6                                             | 35  | 1.3   |
| Codact                                                                           | 37                                              |     |       |
| 5                                                                                | 1.3                                             |     |       |
| Inflammatory bowel disease                                                       | 31                                              | 1.3 |       |
| Diabetes                                                                         | 3                                               | 50  | 1.6   |
| Corobrovascular disoase                                                          | < 1                                             | 67  | 1.6   |
| Psychiatric disturbance f                                                        | 9                                               | 29  | 1.8   |
| Heparic, midi                                                                    | 16                                              | 3   | 1.9   |
| Obesity t                                                                        | 2                                               | 3   | 1.9   |
| Infoction t                                                                      | 4                                               | .40 | 1.9   |
| Rnumerologic                                                                     | 45                                              |     |       |
| A                                                                                | 2.3                                             |     |       |
| Peptic ulcer                                                                     | 2.5                                             |     |       |
| 38                                                                               |                                                 |     |       |
| Benal, modarate/severet                                                          | 2                                               | 42  | 2.6   |
| Pulmonary, moderate t                                                            | 24                                              | 3   | 3.3.0 |
| Prior solid tumor f                                                              | 2                                               | :38 | 3.1   |
| Heart valve diseas                                                               | 3                                               |     |       |
| Pulmonary, severe t                                                              | 9                                               | 3   | 37    |
| Hopelic, moderate/serverst                                                       | 43                                              | 3.9 |       |
| Peripheral vascular disease                                                      | o                                               |     |       |
| - indicates not applicable                                                       |                                                 |     |       |
| * Adjusted for all other comorbidities, age, high disease risk, and conditioning |                                                 |     |       |
| type                                                                             | ↑ Nowly investigated comorbidities,             |     |       |
| #Completes with modified definitions compered with the original CCI.             |                                                 |     |       |  
respectively). For peripheral vascular disease, no conclusions could be drawn since none of the current patients had this comorbidity at the time of HCT.  
The HCT-CI scores ranged from 0 to 11 in the training set, compared with 0 to 4 for the original CCI scores.
untitled h1
validation of the new hct-ci

The newly developed HCT-CI scores were then calculated for patients in the independent validation set (n = 347). The HR
and 2-year cumulative incidence of NRM are summarized by HCT-CI scores for the training and validation sets in Table 5. Due to small numbers, patients with scores of 4 or more were collapsed into one group. Probably due to the smaller number of patients, there was an apparent shrinkage of the discriminatory ability for NRM among various risk groups between the training and validation sets; nevertheless, the HCT-CI continued to be strongly associated with NRM.
untitled h1
comparing the new hct-ci with

For the purpose of comparison, the 2 comorbidity indices were each separated into 3 risk groups. For the HCT-CI these were low
(0), intermediate (1-2), and high (= 3) and for the CCI, low (0),
intermediate (1), and high ( : 2). Results for NRM and survival are summarized by risk group in Table 6 and Figure 1. It was clear that the risk groups based on the HCT-CI scores were more evenly distributed and provided better discrimination of NRM risks than the risk groups defined by the CCI. Although the risk groups for both indices provided some discrimination for survival, the CCI had a lower overall predictive value for survival because of the concentration of nearly 90% of scores in the 0 score category.  
Statistical comparisons between the HCT-CI and CCI are ummarized in Table 7. There was stronger association of higher HCT-CI scores with worse NRM and survival based on the likelihood ratio. In addition, the c-statistics were significantly, higher using the HCT-CI compared with the CCI, whether as an overall measure of association (the percent of pairs of patients where the patient with the higher comorbidity score failed first) or for association with a dichotomized end point at 1 year or 2 years. (the percent of pairs of patients where the patient failing before 1 year or 2 years had a higher comorbidity score than the patient failing after that time).
untitled h1
correlation between causes of death

Pulmonary comorbidities, as defined by impairments of forced expiratory volume in one second (FEV i ) and/or diffusion capacity of carbon monoxide (DLco), and hepatic comorbidities, as defined by elevations of bepatic function tests, were the most prevalent comorbidities captured by the new HCT-CL. There were 347 patients with moderate (score 2) or severe (score 3) pulmonary, comorbidities, and 122 died from nonrelapse causes. Causes of NRM among these 122 patients included pulmonary toxicities
(24%), GVHD (11%), and infections (45%) with (18%) or without
(27%) GVHD (infections involved the lungs in almost half of the cases), and 20% died from other causes.  
Mild (score 1) and moderate-severe (score 3) hepatic comorbidities were encountered in 215 patients, of whom 72 died of nonrelapse causes. Twenty-one percent of these 72 patients died from GVHD; 10%, from hepatic causes; 36%, from infections with or without GVHD; 15%, from pulmonary causes; and 18%, from other causes Overall, fewer nonablative than ablative patients had scores of 0
(29% versus 41%) and 1 to 2 (31% versus 35%), while more norrablative than ablative patients had scores of 3 or more (40% versus 24%).
untitled h1
discussion

We previously reported on the importance of pretransplant comorbidities for outcomes after allogeneic HCT 18 , 19 using the CCI, given that it was a validated and simple scoring system for comorbidities.  
The studies were confined both by small sample sizes and the limited ability of the CCI to comprehensively capture comorbidities, particularly in patients given ablative conditioning. The current study refined comorbidity definitions, added newly identified comorbidities, and evaluated each comorbidity category by Cox regression hazard models. A new index of scores for each comorbidity was then developed and validated in another randomly selected group of HCT recipients. We found that the HCT-CI captured more pretransplant comorbidities and provided better assessment of NRM and survival risks compared with the original CCI.  
The adverse impact of comorbidities on cancer patients was likely due to the physiologic burden of chronic disease and its interactions with cancer and cancer treatment. 42 Therefore, increased severity of comorbidities increased the risk of toxicities in response to specific treatments and, hence, shortened life expectancy and canceled gains derived from specific therapies. 43 There has been ample evidence in the literature that comorbidities and 2916 From bloodjournal hematologylibrary org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For SORROR et al personal use only.  
BLOOD, 15 OCTOBER 2005 - VOLUME 106, NUMBER 8  
| Table 4. Definitions of comorbidities included in the HCT-CI and HCT-CI scores compared with original CCI scores                                                               |                                                                            |                        |                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|------------------------|---------------------|
| Comorbidity                                                                                                                                                                    | Definitions of comorbidities included in the new HCT-CI                    | HCT-CI weighted scores | Original CCI scores |
| Atrial fibrilation or flutter, sick sinus synchome, or ventricular arrhythmias.                                                                                                |                                                                            |                        |                     |
| Arrtrythmia                                                                                                                                                                    |                                                                            |                        |                     |
| Code                                                                                                                                                                           | Coronary artery disease, § congestive heart lature, myocardial infarction, |                        |                     |
| or EF ≤ 50%                                                                                                                                                                    |                                                                            |                        |                     |
| Inflammakry bowel disease                                                                                                                                                      | Crohn disease or ulcerative collis-                                        |                        |                     |
| Diabotes                                                                                                                                                                       | Requiring treatment with insulin or oral hypoglycemics but not dist alone  | 1                      |                     |
| Controlsscular dissass                                                                                                                                                         | Transient ischemic allack or cerebrovascular accident                      |                        |                     |
| Psychiatric disturbance f                                                                                                                                                      | Depression or anxiety requiring psychiatric consult or treatment           | 1                      | Not included        |
| Hepatic, midi                                                                                                                                                                  | Chronic hepatitis, bilinbin > ULN to 1.5 × ULN, or AST/ALT > ULN to        | 1                      |                     |
| 25 × ULN                                                                                                                                                                       |                                                                            |                        |                     |
| Patients with a body mass index > 36 kg/m²                                                                                                                                     | Not included                                                               |                        |                     |
| Obesity t                                                                                                                                                                      | l                                                                          |                        |                     |
| Intection 1                                                                                                                                                                    | Requiring continuation of antimicrobial treatment after day 0              | 1                      | Not includid        |
| Rhournatologic                                                                                                                                                                 | SLE, RA, polymyositis, mixed CTD, or polymyakia rhoumatical                | 2                      |                     |
| Peptic ulcer                                                                                                                                                                   | Requiring treatment                                                        | 2                      | 1                   |
| Moderate/servere renal t                                                                                                                                                       | Serum creatining > 2 mgdL, on dialysis, or prior renal transplantation     | 2                      | s                   |
| Moderate pumonary f                                                                                                                                                            | DLco and or FEV, 66%-80% or dyspnea on slight activity                     | 2                      | 1                   |
| Prior solid tumor t                                                                                                                                                            | Treated at any time point in the pationt's past history, cocluding         | 3                      | 2                   |
| nonmelanoma skin cancel                                                                                                                                                        |                                                                            |                        |                     |
| Heart valry disease                                                                                                                                                            | Except mitral valve prolopse                                               | 3                      | o                   |
| Severe pulmonary f                                                                                                                                                             | DLoo and for FEV 1 = 65% or dyspnea at rest or requiring oxygen            | 3                      |                     |
| Moderate/servere hepatic to                                                                                                                                                    | Liver circhosis, bilitubin > 1.5 × ULN, or AST/ALT > 2.5 × ULN             | 3                      |                     |
| To convert creating from miligrams per decisior to micromoles per liter, multiply miligrams per decisior by 80.4.                                                              |                                                                            |                        |                     |
| EF indicates ejoction issues of complexity of complexity or even according to the effects or even according to the effects or even as the effects or even as the effects or ea |                                                                            |                        |                     |
| capecity of cartion monoxide                                                                                                                                                   |                                                                            |                        |                     |
| 'Definitions of comprodities included in the original CCI are defined in the appendix of a prior publication. 2                                                                |                                                                            |                        |                     |
| t Now Investigated comprodities.                                                                                                                                               |                                                                            |                        |                     |
| t Comorbidities with modified definitions compared with the original CCI.                                                                                                      |                                                                            |                        |                     |
| §One or more vessel-coronary artery stenosis requiring medical treatmant, stent, or bypass gratt,                                                                              |                                                                            |                        |                     |  
performance scales both independently predicted for outcome. 5 However, contrary to functional status, comorbidities presented the unique challenge of being a multidimensional variable, since diseases influencing mortality might not be the same as diseases influencing function or tolerance to treatment. 2 Translating comorbidities into weighted scores appeared to be the best way to use comorbidities for prediction of ontcome. 2844 In the current study, we sought to modify the CCI in a way to improve sensitivity and specificity for predicting risks of NRM
after HCT. The primary modification was refinement of several comorbidity definitions, which was done by introducing objective laboratory and functional testing data, thereby incorporating subclinical organ impairments that could result in partial compromise in patients subjected to the intensive physiologic challenge of HCT.  
Pulmonary function tests were used to define different grades of pulmonary comorbidities. Similarly, liver function tests and cardiac ejection fraction were added to definitions of hepatic and cardiac comorbidities. This introduction of laboratory data constituted the main change for increasing the sensitivity of the new HCT-C1, in particular since pulmonary and bepatic comorbidities achieved the highest prevalence among our transplant populations. The new HCT-CI captured 62% of patients with scores more than 0 compared with 12% captured by the original CCI. In particular, 59% of ablative patients had scores more than 0 using the HCT-CI
compared with 10% by the original CCL
The improvement in the new HCT-CI over the criginal CCI was demonstrated by likelihood ratio and c statistics. The improvement was likely related to the assignment of comorbidity weights specific to patients who underwent transplantation. Several common comorbidities were assigned higher weights than in the original CCI, likely reflecting their importance for tolerating HCT. In addition, new comorbidities, such as infections, obesity, and psychiatric disturbances, were found to be clinically relevant. The use of laboratory data in the new HCT-CI accounted for larger nmbers of patients with scored comorbidities, which added to the utility of the new HCT-CI over the original CCI.  
In all cases, the c -statistic calculated for the HCT-CI was 7 to 15 percentage points higher than that for the CCI, with the value for the CCI being only slightly better than a coin flip (0.50). Although the difference between HCT-CI and CCI was highly statistically significant, it should be noted that the magnitude of the c-statistic for the HCT-CI reflected a fairly modest level of prediction. This was not  
| Table 5. The new HCT-CI scores and prediction for NRM and survival the training versus the validation set   |                 |                 |           |                |               |           |
|-------------------------------------------------------------------------------------------------------------|-----------------|-----------------|-----------|----------------|---------------|-----------|
| Training self                                                                                               | Validation set  | NRM             |           |                |               |           |
| NRM                                                                                                         |                 |                 |           |                |               |           |
| Soore                                                                                                       | Patients, 99    | HR' (95% CI)    | 2-year, % | Patients, %    | HR' (86% CI)  | 2-year, % |
| 14                                                                                                          |                 |                 |           |                |               |           |
| 17                                                                                                          | 1.06 (0.9-3.1)  | 14              | 18        | 1.57 (0.7-3.3) | 2             |           |
| 17                                                                                                          | 3.48 (2.0-6.0)  | 27              | 17        | 1.26 (0.6-2.8) | 19            |           |
| 17                                                                                                          | 6.09 (3.7-10.1) | 41              | 15        | 3.85 (2.1-7.5) | 41            |           |
| 4 or more                                                                                                   | 11              | 6.93 (4.0-12.0) | e         | 13             | 3.05 (15:6.2) | 40        |
| For the training set, n = 708; for the validation set, n = 346.                                             |                 |                 |           |                |               |           |
| * Adjusted for ago, disease risk, and conditioning                                                          |                 |                 |           |                |               |           |  
From bloodjournal.hematologylibrary.org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For personal use LED VENEIC STEM CELL TRANSPLANTATION COMORBIDITIES
BLOOD, 15 OCTOBER 2005 - VOLUME 106, NUMBER 8 2917.  
| Table 6. HCT-CI versus CCI for prediction of 2-year NRM and survival in the validation set   |        |                |              |                |     |              |                |                |                |     |
|----------------------------------------------------------------------------------------------|--------|----------------|--------------|----------------|-----|--------------|----------------|----------------|----------------|-----|
| HCT-CI                                                                                       |        |                |              |                |     |              |                |                |                |     |
| NRM                                                                                          | NRM    |                |              |                |     |              |                |                |                |     |
| 2 year                                                                                       | 2 year | 2 year         | 2 year       |                |     |              |                |                |                |     |
| Score                                                                                        | No.    | H" (95% CI)    | HR" (95% CI) | Score          | No. | HR" (95% CI) | H" (95% CI)    |                |                |     |
| 38                                                                                           | 1.0    | 14             | 1.0          | .71            | 87  | 1.0          | 23             | 1.0            | 59             |     |
| 102                                                                                          | 34     | 1.42 (0.8-2.7) | 21           | 1.31 (0.8-2.0) | B   | 10           | 1.26 (0.6-2.6) | 29             | 1.32 (0.8-2.2) | .49 |
| 3 or more                                                                                    | 28     | 3.54 (2.0-6.3) | 41           | 2.69 (1.8-4.1) | 34  | ≥ 2          | 1.46 (0.5-4.7) | 2.78 (1.4:5.6) | 17             |     |
| * Adjusted for age, disease risk, and conditioning.                                          |        |                |              |                |     |              |                |                |                |     |  
surprising given the multiple factors that also contributed to both NRM
and survival and the smaller patient sample in the validation set.  
Even though the HCT-CI scores were highly effective in predicting outcome of patients after HCT, other major pretransplant factors played significant roles. Age and disease stage of a specific hematologic malignancy were additional factors that should be considered when determining HCT risks. Age has been used independently to determine if patients should be referred for HCT
and to stratify patients for the different intensity conditioning regimens. 46 -49 For that reason and also since age is a demographic variable, we decided not to include age as a scored comorbidity in the HCT-CI. Instead, in the current study, age was used to adjust the Cox regression hazards' modeling for developing the new HCT-CL
We and other investigators had shown the importance of single organ comorbidities and abnormal laboratory data, as markers of organ dysfunction, on outcome of patients who underwent transplantation. 50 -52 However, none have attempted to evaluate multiple comorbidities into a scoring system with predictive power to determine survival risks after HCT. On the other hand, some disease-specific prognostic scoring systems 53 , 54 have been developed for assessing patient risk prior to specific therapies including HCT. However, none of those scores took into account the impact of different comorbidities on outcome.  
There were several limitations to our study. The first was the retrospective nature of the data collection. Since we relied on data recorded in medical charts, some potentially important data might not have been recorded and hence not been included in this analysis. However, the introduction of laboratory and functional data, most of which were stored in the database, has likely reduced the possibility of missing comorbidities. To better address this problem, new protocols include prospective scoring of enrolled patients. The second limitation was that patients from the same institution were used to validate the new HCT-CI. Efforts are under way to further validate the HCT-CI on patients who underwent transplantation in other institutions. The third limitation was the lack of interrater and test-retest reliabilities in this study. However, reports on the original CCI had previously shown both good interrater reliability between 0.74 and 0.945 by interclass correlation coefficient in older cancer patients 5,55 and good test-retest reliability of 0.92. 56 Since we used many of the definitions of the CI with additional refinements based on laboratory and functional testing, which were not subject to investigator variations, it was likely that the HCT-CI had at least the same interrater reliability as the original CCI. We plan to test the HCT-CI reliability among different investigators located in different institutions.  
The current HCT-CI could be applied to a number of settings.  
Our study identified prevalent and prognostically important coexisting illnesses that should be measured and considered in clinical trials and HCT registries. This would help to extrapolate the results of transplant recipients with significant comorbidities to the entire spectrum of HCT patients. A second application of this HCT-CI involves the consideration of medical evidence for individual patients at the bedside. The index can be widely used by referring physicians, oncologists, and hematologists when assessing the risks of patients with hematologic diseases for specific therapies and particularly referral for HCT. Currently, we investigate the importance of the new HCT-CI on outcomes in disease-specific patients given HCT. The third application includes a wide area of research concerning the correlation between comorbidities captured by the HCT-CI and different complications.  
after HCT, such as infections, GVHD, and respiratory or hepatic  
  
| Table 7. Comparisons between the HCT-CI and the CCI in the   |               |               |        |
|--------------------------------------------------------------|---------------|---------------|--------|
| validation set (n = 347) for events within first 2 years     |               |               |        |
| HCT-CI for                                                   | Cl for        |               |        |
| 3 risk groups                                                | p:            |               |        |
| 3 risk groups                                                |               |               |        |
| Nonrelapse mortality                                         |               |               |        |
| ostatistic (SE*), overall                                    | 0.849 (0.029) | 0.520 (0.019) | < .001 |
| ostatistic (SE*), yes/no 2 y                                 | 0.685 (0.037) | 0.532 (0.023) | < :001 |
| ostatistic (SE*), yes/no 1 y                                 | 0.692 (0.038) | 0.548 (0.025) | < .001 |
| Likelihood ratio                                             | 26.6          |               |        |
| Adjusted likelihood ratiot                                   | 21:4          | 0.7           |        |
| Overall survival                                             |               |               |        |
| ostatistic (SE*), overall                                    | 0.624 (0.021) | 0.538 (0.015) | < .001 |
| ostatistic (SE*), yes/no 2 y                                 | 0.657 (0.031) | 0.548 (0.019) | < .001 |
| ostatistic (SE*), yes/no t y                                 | 0.681 (0.030) | 0.581 (0.021) | < .001 |
| Likelihood ratio                                             | 31.8          |               |        |
| Adjusted likelihood ratio t                                  | 23.7          | 7.1           |        |
| *Estimated from 100 bootstrap samples                        |               |               |        |
| tAdjusted for age, disease risk, and conditioning            |               |               |        |  
From bloodjournal.hematologylibrary.org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For SORROR et al personal use only.  
BLOOD, 15 OCTOBER 2005 - VOLUME 106, NUMBER 8 2918 failure. The final application will be stratifying patients for eligibility of nonablative versus ablative HCT.  
In summary, we have developed a new tool for capturing pretransplant comorbidities that could be used in predicting outcomes and stratifying patients for HCT. In the future, we will further validate this index on patients from different institutions.  
and compare its performance to comorbidity indices other than the CI, such as The Curnulative Illness Rating Scale and the Adult Comorbidity Evaluation (ACE-27). Further, it would be of interest to develop a scaling system for increments of age and different stages of diseases to be used in concert with the HCT-CI in assessing pretransplant patient risk for failure of disease-free survival.
untitled h1
references

1. Feinstein AR. The pro-therapoutic classification of co-morbidity in chronic disease. J Chron Dis.  
197023455468.  
2. Exterment M, Measurement and import of comorbidity in older cancer perients. Crit Pey Oncol Hematol. 2000;35:181-200.  
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acknowledgments

The authors wish to thank Dr Karen Syrjala, associate professor for Psychiatry and Behavioral Sciences at University of Washington and FHCRC, for her valuable advice. We also thank the data coordinators, Chris Davis, Heather Hildebrant, and Deborah Bassuk, and the study nurses, Steve Mince, Mary Hinds, and John Sedgwick, for their invaluable help in making the study possible Bonnie Larson, Helen Crawford, and Sue Carbonneau provided invaluable help with article preparation. We also wish to thank all the Transplant Teams versus-tumor effects. Blood, 2001;97:3390-  
| 3400.   |
|---------|  
29. Deeg HJ, Storer B, Stattery JT, et al. Conditioning with targeted busultan and cyclophospharnide for hemocolatic stam cell transclantation from rel lated and unrelated donors in patients with my ekdysplastic syndroma. Blood. 2002;100:120130.  
CART RA, Backner CD, Thomas ED, et al. Marrow transplantation for chronic myoloid leukemia; an randomized study comparing cyclophosphamide and tolal body irrackstion with busulfan and cyclos phosphanide. Blood. 1994;84:2006-2043.  
Domiror T, Poterson FB, Appolbeum FR, of all Alogeneic marrow transplantation following cycle clophospharnido and escalating doses of hypot fractionated total body inactiation in patients with advanced lymphold malignancies: a phase I/II
trial. Int J Radiat Oncol Biol Phys. 1995;32:1103-
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3 Sultiven KM, Agura E, Anasem C, et al. Chronic graft-versus-bost disease and other late complications of bone menon transplantation. Semin Hamenol, 1991;23:250:259.  
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Corey L. Successful modification of a pp65 am gonomia-based early treatment strategy for provention of cytomegalovirus disease in allogene marrow transplant recipients [Jetter]. Biocol. 1999.  
93:1781-1782 Marr KA, Soldel K, Slavin M, et al. Prolonged fluconazole prophytods is associated with persis tent protection against candidiasis-related death in allogeneic manow transplant recipiants; longterm follow-up of a randomized, placeto-
Boeckh M, Marr KA. Infection in hematopoletic 37.  
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LS, eds. Clinical Approach to Infection in the Compromised Host, New York: NY: Klussor Acad demic Plenum Publishers, 2002 527-571 Boockh M, Gooley TA, Myerson D, Canningham 38.  
T, Schoch G, Bowden RA. Cytomegalovirus pp66 clovir versus panciclovir at engramment after allow gancic marrow transplantation; a randomize double-band study. Blood. 1996;88:4063-4071.  
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kw-dose acyclovir against vericella-zoster virus reactivation after allogeneic hematopoietic stems cell transplantation. Bone Marrow Transplant 2001 28:689-092 From bloodjournal hematologylibrary org at NATIONAL INSTITUTES OF HEALTH LIB on April 23, 2012. For BLOOD, 15 OCTOBER 2006 - VOLUME 106, NUMBER 8 personal use proteneic stem cell transplantation comorbidities 2919 40. Kalbilsisch JD, Prentice RL. The Statistical Analysis of Failure Time Deta, New York, NY: John Wloy & Sons, 1980.  
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after nonmysicablative conditioning folioued by alogeneic hematopoistic cell transplantation; a study of 193 patients. Biood. 2004; 103 78-84.  
51. Fujimaki K, Maruta A, Yoshida M, et al. Severe cardiac toxicity in hemalological stem cell trans-  
| plantation: prodictive value of reduced left ventric   |                                                 |
|--------------------------------------------------------|-------------------------------------------------|
| ular ejection traction. Bone Marrow Transplant         |                                                 |
| 2001 27:307-310.                                       |                                                 |
| 52                                                     | Loberiza FRJ, Rizzo JD, Bredeson CN, et al. As- |
| socialion of depressive syndrome and early
deaths among perients after stem cell transplan                                                        |                                                 |
| tation for matignant diseases. J Clin Oncol. 2002      |                                                 |
| 202118 2128                                            |                                                 |
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| plantation, Lancat, 1998;352:1087-1002.                |                                                 |  
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11.11 appendix k case report

Please enter this Data in Protocol Visit Transplant Note ACUTE GVHD
Date of Visit:_____________  
$\square$12 Mos $\square$18 Mos $\square$24 Mos $\square$36 Mos $\square$48 Mos $\square$Other  
Time point: Day 100 6 Mos 9Mos 12 Mos 18 Mos 24 Mos 36 Mos 48 Mos Other
___________
Does the patient have aGVHD ___________Y/N Type of aGVHD (Classic or Late Acute)___________ Late aGVHD type (Recurrent, Persistent, Late Onset)____________ Glucksberg Scoring System:  
| aGVHD Organ       | Date of Diagnosis   | Biopsy  Proven?     | Date of Biopsy   | Gluckbergs Organ  Stage   | Overall Grade   |
|-------------------|---------------------|---------------------|------------------|---------------------------|-----------------|
| involved          | (Y/N)               | (0,1,2,3,4,unknown) |                  |                           |                 |
| (GI, Liver, Skin) |                     |                     |                  |                           |                 |  
BSA = body surface area; use "rule of nines" or burn chart to determine extent of rash  
| Stage   | Skin                    | Liver                       | Gut                    |
|---------|-------------------------|-----------------------------|------------------------|
| +       | Rash < 25% BSA          | . Total bilirubin 2-3 mg/dl | Diarrhea 500-1000ml/d  |
| ++      | Rash 25-50% BSA         | Total bilirubin 3-6 mg/dl   | Diarrhea 1000-1500ml/d |
| +++     | Generalized erythoderma | Total bilirubin 6-15 mg/dl  | Diarrhea >1500ml/d     |
| ++++    | Desquamation and bullae | Total bilirubin > 15 mg/dl  | Pain +/- ileus         |  
| Grade    | Skin     | Liver   | Gut   | PS   |
|----------|----------|---------|-------|------|
| 0 (none) | 0        | 0       | 0     | 0    |
| I        | + to ++  | 0       | 0     | 0    |
| II       | + to +++ | +       | +     | +    |  
| III                    | ++ to +++        | ++ to +++    | ++ to +++   | ++                      |
|------------------------|------------------|--------------|-------------|-------------------------|
| IV                     | + +to ++++       | + +to ++++   | + +to ++++  | +++                     |
| Current Therapy        | Current Dose     | Date started | Date Ended  | Response from Treatment |
| (topical and systemic) | (CR, PR, NR, PD) |              |             |                         |  
PI Signature: _______________________________ RN Signature: _______________________________
Date of Visit: __________
Time point: Day :100 6 Mos 9Mos 12 Mos 18 Mos 24 Mos 36 Mos 48 Mos Other _______
Does the patient have cGVHD ___________Y/N?  
Type of cGVHD (Classic or Overlap)___________
Type of Onset (De Novo, Progressive, Quiescent)  
| ___________    |                                                                                                                                                                                                  |                      |                 |         |                          |                                |
|----------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|-----------------|---------|--------------------------|--------------------------------|
| cGVHD          | Grade                                                                                                                                                                                            | Date of  Diagnosis : | Biopsy  Proven? | Date of | Current Therapy (Topical | Intensity of Immunosuppression |
| Biopsy:        | and systemic)                                                                                                                                                                                    |                      |                 |         |                          |                                |
| Anatomic Site: | □ None                                                                                                                                                                                           |                      |                 |         |                          |                                |
| (Y/N)          | □ Mild (single agent prednisone < 0.5  mg/kg/day) □ Moderate (prednisone ≥ 0.5  mg/kg/day and/or any single  agent/modality) □ High (2 or more agents/ modalities  ± prednisone ≥ 0.5 mg/kg/day) |                      |                 |         |                          |                                |
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global stage (mild moderate severe)

If 1-2 Grade 1=Mild If at least 1 Grade 3=severe Anything between=Moderate EXCEPT if Lung Grade 1=moderate Lung Grade 2=severe Therapeutic intent at time of visit: Circle one Does not require systemic therapy Continue current systemic therapy Alter systemic therapy due to toxicity Decrease systemic therapy b/c cGVHD is better Increase systemic therapy b/c cGVHD is stable or worse Substitute systemic therapy due to lack of response Withdraw systemic therapy due to lack of response Clinician's Impression of Activity: Circle one Active, irrespective of the level of current therapy Highly active, irrespective of the level of current therapy Inactive, off systemic therapy or immunosuppression Inactive, on systemic therapy or immunosuppression BOS Y/N__________________  
PI Signature: _______________________________ RN Signature: _______________________________  
  
  
Date of Assessment: ____ ________ Date of transplant: ________________
Select Time point Day 28 Day 100 3 Mos 6 Mos 9Mos 12 Mos 18 Mos 24 Mos 36 Mos 48 Mos Other ______________
A. Current Response Assessment: N/A N/E CR CRu PR SD PD Date___________
B. Minimal residual disease (circle one): Positive Negative Date___________
C. Central nervous system involvement (circle one): Yes No Unknown Describe positive results below________________________________________
D. Radiology response assessment: Pet Scan Response Assessment: Y/N?________If yes: CR/PR/SD/PD/NA/NE--------------- CT Scan Response Assessment: Y/N?___________If yes: CR/PR/SD/PD/NA/NE-------------- Other diagnostic studies_______________________________________________ E. Pathology response assessment (complete for all performed evaluations):
➢ Bone Marrow Response Assessment: Positive Negative NE
Morphology: Positive Negative Unknown a. Flow Cytometry: Positive Negative Unknown  
b. Molecular: Positive Negative Unknown c. Cytogenetics: Positive Negative Unknown
➢ LP Response Assessment: Positive Negative NE
Morphology: Positive Negative Unknown  
a. Flow Cytometry: Positive Negative Unknown b. Molecular: Positive Negative Unknown c. Cytogenetics: Positive Negative Unknown ➢ Blood Response Assessment: Positive Negative NE
Morphology: Positive Negative Unknown a. Flow Cytometry: Positive Negative Unknown b. Molecular: Positive Negative Unknown c. Cytogenetics: Positive Negative Unknown
➢ Tissue Response Assessment: Positive Negative NE
Morphology: Positive Negative Unknown a. Flow Cytometry: Positive Negative Unknown b. Molecular: Positive Negative Unknown c. Cytogenetics: Positive Negative Unknown
➢ Other pathology studies response assessment (name study): ____________________________
Positive Negative NE  
  
Abbreviated Title: RIST using Unrelated Donors CC Protocol Number: 07-C-0195 132.