Clinical trial NCT00397813
Conditions: Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Essential Thrombocythemia Myeloproliferative Neoplasm Paroxysmal Nocturnal Hemoglobinuria Polycythemia Vera Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase Primary Myelofibrosis Refractory Anemia Refractory Anemia With Excess Blasts Refractory Anemia With Ring Sideroblasts Refractory Cytopenia With Multilineage Dysplasia Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts
Sponsor: Fred Hutchinson Cancer Center
Start date: 2006-01-01; Completion date: 2018-03-01
Enrollment: 77 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects and best dose of total-body irradiation when given together with fludarabine phosphate followed by a donor peripheral stem cell transplant in treating patients with myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD). Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Detailed description:
PRIMARY OBJECTIVES:

I. Decrease the incidence of day-200 hematopoietic cell transplantation (HCT) failure to \< 20% in patients with MDS-Refractory anemia (RA)-(ringed sideroblasts \[RS\])/MPD and in patients with chronic myelomonocytic leukemia (CMML)/refractory anemia with excess blasts (RAEB).

SECONDARY OBJECTIVES:

I. The rate of relapse/progression in patients with MPD or MDS-RA and those with CMML or MDS-RAEB.

II. The probability of progression free survival (PFS) in patients with MPD or MDS-RA and those with CMML or MDS-RAEB.

III. The kinetics of donor engraftment.

IV. The incidence of infections.

OUTLINE: This is a dose-escalation study of total body irradiation (TBI).

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.

PERIPHERAL BLOOD STEM CELL (PBSC) TRANSPLANTATION: Patients undergo filgrastim (G-CSF)-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56, followed by a taper until day 180. Patients also receive mycophenolate mofetil (MMF) PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.

After completion of study treatment, patients are followed periodically.

Arms: arm 1: Arm A - patients with MPD or MDS-RA/RARS Dose Level 1 - 300 cGy TBI

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. arm 2: Arm A - patients with MPD or MDS-RA/RARS Dose Level 2 - 400 cGy TBI

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. arm 3: Arm A - patients with MPD or MDS-RA/RARS Dose Level 3 - 450 cGy TBI

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. arm 4: Arm B - patients with MDS-RAEB or CMML Dose Level 1 - 300 cGy TBI

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. arm 5: Arm B - patients with MDS-RAEB or CMML Dose Level 2 - 400 cGy TBI

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. arm 6: Arm B - patients with MDS-RAEB or CMML Dose Level 3 - 450 cGy TBI

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.

IMMUNOSUPPRESSION:

Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.

Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.
Interventions: intervention 1: Cyclosporine intervention 2: Fludarabine Phosphate intervention 3: Laboratory Biomarker Analysis intervention 4: Mycophenolate Mofetil intervention 5: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation intervention 6: Peripheral Blood Stem Cell Transplantation intervention 7: Total-Body Irradiation
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given PO intervention 5: Undergo transplantation intervention 6: Undergo PBSC transplant intervention 7: Undergo TBI

Protocol documents:
Prot_SAP_000.pdf: 
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1 
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
SEATTLE CHILDREN’S 
Current Version:   03/03/2016 
Previous Version:   02/09/2015 
 
1. LOW-DOSE TBI DOSE ESCALATION  
TO DECREASE RISKS OF PROGRESSION AND GRAFT REJECTION AFTER HEMATOPOIETIC 
CELL TRANSPLANTATION WITH NONMYELOABLATIVE CONDITIONING AS TREATMENT  
FOR UNTREATED MYELODYSPLASTIC SYNDROME OR MYELOPROLIFERATIVE DISORDERS 
– A MULTI-CENTER TRIAL 
 
Principal Investigators: Brenda M. Sandmaier, MD, Member, FHCRC; Professor of Medicine, UW, (206) 667-
4961; Bart Scott, MD, Associate Member, FHCRC; Associate Professor of Medicine, UW, (206) 667-1990; Joachim 
Deeg, MD, Member, FHCRC, Professor of Medicine, UW, (206) 667 5985; David Maloney, M.D., Ph.D., Member, 
FHCRC; Professor of Medicine, UW, (206) 667-5616 ; Mary E.D. Flowers, M.D, Member, FHCRC; Professor of 
Medicine, UW, (206) 667-5115; Rainer Storb, MD, Member, FHCRC; Professor of Medicine UW, (206) 667-4407. 
 
Statistician:  Barry Storer, Ph.D., Member, FHCRC; Affiliated Associate Professor of Biostatistics, UW, (206-667-
6151). 
 
Radiation Oncologist: Ralph Ermoian, MD., Assistant Professor, Radiation Oncology, UW, (206-598-4100) 
 
Research Nurse:   Michelle Bouvier, RN (206) 667-6993, pager (206) 995-7658 
 
Emergency Phone FHCRC: (206) 598-8902, fax (206) 598-4034 
 
Additional Performance Sites 
Contact 
Emergency Phone Number 
Veterans Affairs Puget-  
   Thomas Chauncey M.D., PhD 
(206) 762-1010 for  
Sound Health Care System  
    
the oncologist on-call 
LDS Hospital 
    Finn Petersen, MD 
(801) 408-3800  
  
                                                           pager: (801)248-0994 
 
 
 


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Table of Contents  
 
 
 
Page 
2.  Introduction ..................................................................................................................................................... 3   
3.  Background ..................................................................................................................................................... 3   
4.  Proposal ........................................................................................................................................................ 12 
5. Primary Objective ......................................................................................................................................... 12 
6. Secondary Objective ..................................................................................................................................... 12 
7.  Patient Selection............................................................................................................................................ 12 
8.  Donor Selection ............................................................................................................................................ 15 
9. Informed Consent.......................................................................................................................................... 16 
10. Protocol Registration ..................................................................................................................................... 16 
11. Plan of Treatment .......................................................................................................................................... 17 
12  Assessment of Disease Response .................................................................................................................. 26 
13. Patient Evaluations ........................................................................................................................................ 28 
14. Drugs and Toxicities ..................................................................................................................................... 35 
15. Records ......................................................................................................................................................... 37 
16. Statistical Considerations and Termination of the Study .............................................................................. 38 
17. Data and Safety Monitoring Plan .................................................................................................................. 40 
18. Targeted / Planned Enrollment ..................................................................................................................... 42 
19. References ..................................................................................................................................................... 43 
Appendices 
A Eligibility Guidelines For Donor PBMC Apheresis for Transfusion ............................................................ 47 
B. Karnofsky Performance Scale ....................................................................................................................... 48 
C. Lansky Performance-Play Scale ................................................................................................................... 49 
D. ABO Incompatibility .................................................................................................................................... 50 
E. Infectious Disease Guidelines ....................................................................................................................... 52 
F. Acute Graft-Versus-Host-Disease Grading  ................................................................................................. 53 
G. Chronic GVHD Grading  .............................................................................................................................. 54 
H. Evaluation of Disease Response ................................................................................................................... 57 
I. 
Study Coordinator’s Manual Including Procedure for Reporting Adverse Events ....................................... 59 
J. Adverse Event Report Form ......................................................................................................................... 63 
K. Notice of Death Form  .................................................................................................................................. 65 
L. Patient Demographics and Eligibility Form  ................................................................................................. 66 
M. Core Case Report Forms ............................................................................................................................... 73 
N. Intrathecal Therapy Administration .............................................................................................................. 74         
O. HLA Matching Requirements for URD ........................................................................................................ 75 
P. Adapted Common Toxicity Criteria ............................................................................................................. 79 
Q. Hematopoietic Cell Transplant-Comorbidity Index...................................................................................... 88         
R.   WHO classification and IPSS score……………………………………………………………………..…90 
S.   Weight / Adjusted Body Weight for Drug Dosing………………………………………………………....92 
T.   Radiotherapy Treatment Plan……………………………………………………………………………....93 
U.   Coordinating Center Functions………………………………………………………………………..…...94 
V.  Standard Donor Consent…………………………………………………………………………………....96 


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2. Introduction 
Hematopoietic cell transplantation (HCT) is the only curative option for patients with myelodysplastic syndromes 
(MDS) or myeloproliferative disorders (MPD)1. However, conventional HCT after intensive cytotoxic conditioning 
regimen has been restricted to relatively young patients, without comorbidities. We have developed a 
nonmyeloablative regimen that allows allogeneic HCT with HLA-matched related (MRD) or unrelated donors (URD) 
in older patients (up to 75 yrs old), and those with comorbidities. Results of phase I/II studies with this regimen have 
been very encouraging in most hematological malignancies2-5, but results in patients with chronic myelomonocytic 
leukemia (CMML) and in patients with previously untreated MDS or MPD have been disappointing.  
 
Sixty-one patients with CMML or previously untreated MDS/MPD were given grafts from MRD (n=32) or 
URD (n=29) after 200 cGy TBI with (n=59) or without (n=2) added fludarabine (90 mg/m²). Diagnosis were CMML 
(n=11), refractory anemia (RA, n=20), RA with ringed sideroblasts (RARS, n=2), RA with excess blasts (RAEB, 
n=11), RAEB in transformation (RAEB-T, n=4), and MPD (n=13). Forty-six patients had idiopathic diseases, while 
15 patients had secondary MDS.  Twenty patients achieved complete remissions 19 to 346 (median 32) days after 
HCT. Conversely, twenty-six of 61 patients (43%) had “HCT failure” due to graft rejection (n=11) and/or disease 
progression (n=24) before day 200 after HCT. Specifically, 15 of 26 (58%) patients with CMML or RAEB (T) and 11 
of 35 (31%) patients with RA (RS)/MPD had HCT failure before day 200. The 200-day, 1-yr and 2-yr probabilities of 
progression free survival (PFS) were 27%, 19% and 11%, respectively, in patients with CMML or RAEB (T), and 
46%, 40%, and 37% respectively, in patients with RA (RS)/MPD.  
 
We have recently shown that achievement of full donor T-cell chimerism was associated with a reduced risk 
of relapse (HR 0.5, P=0.002) in patients with hematological malignancies given nonmyeloablative conditioning6. 
Furthermore, a recent analysis comparing outcomes after nonmyeloablative versus myeloablative conditioning in 
previously untreated MDS patients has suggested that relapse/progression incidence might occur later (P=0.22) in 
patients given myeloablative conditioning7. Taken together, these data suggest that increasing the intensity of the 
conditioning regimen in order to prevent disease progression before establishment of full donor chimerism and 
occurrence of graft-versus-tumor (GVT) effects might improve outcomes of patients with CMML or untreated 
MDS/MPD given nonmyeloablative conditioning. 
 
The aim of the current protocol is to decrease the risks of HCT failure (defined as graft rejection and/or 
relapse) in patients with CMML or with previously untreated MDS/MPD given nonmyeloablative conditioning. To 
do so, the protocol will escalate the TBI dose (300 cGy TBI in level 1, 400 cGy in level 2, and 450 cGy in level 3) in 
order to define a low-dose conditioning regimen that is associated with a day-200 incidence of HCT failure < 20%. 
Dose escalation will be carried out independently in two groups of patients: 
Arm A – patients with MPD or MDS-RA/RARS 
Arm B – patients with MDS-RAEB or CMML. 
 
 
3.  Background 
 
A. Nonmyeloablative HCT with Fludarabine, Low-dose TBI and MMF/CSP  
The observations that GVT effects might be able to eradicate malignant cells more effectively than 
chemoradiotherapy, and that in an HLA-identical transplant setting, the host-versus-graft and the graft-versus-host 
reactions are mediated by T-cells led to the development of a nonmyeloablative HCT approach. In preclinical canine 
studies, it could be shown that a nonmyeloablative conditioning regimen consisting of 200 cGy TBI, followed by 
post-transplant immunosuppression with mycophenolate mofetil (MMF) for 28 days and cyclosporine (CSP) for 35 
days resulted in stable engraftment in DLA-identical littermates8. The initial transplant regimen was the same as that 
developed in dogs and consisted of 200 cGy TBI given on day 0, and postgrafting immunosuppression with MMF 
(given for 28 days) and CSP (discontinued on day 56) 2. The stem cell sources were peripheral blood stem cells 
(PBSC), and donors were HLA-identical siblings. The transplant regimen was remarkably well tolerated, with the 
majority of eligible patients receiving their transplants in the outpatient setting. Nine of the 44 first patients (20%) 
given this regimen had nonfatal graft rejections 2. In order to reduce the risk of graft rejection, fludarabine 30 
mg/m2/day × 3 days was added to the 200 cGy TBI, and the rejection rate decreased to 3% 9. In an attempt to reduce 
the incidence of acute GVHD, the duration of CSP administration was extended from 56 to 77 or 180 days, while the 


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duration of MMF (days 0 to 27) was kept constant. This strategy was associated with a significantly reduced 
incidence of grade III-IV acute GVHD10.  
 
The same regimen of fludarabine and 200 cGy TBI was used to condition patients with 10/10-HLA-antigen 
matched URD 3,4. The postgrafting immunosuppression with MMF was extended to 40 days with taper to day 96 and 
CSP was given for 100 days with taper through day 180. Durable engraftment was observed in 82% of PBSC (n=71) 
and 56% of marrow recipients (n=18). Based on this observation, all subsequent URD were given PBSC grafts. 
Among unrelated PBSC recipients, graft rejections were more frequently observed in patients given PBSC containing 
less than 6.8 x106 CD34+ cells/kg11. Further, sub-optimal postgrafting immunosuppression with MMF was suggested 
by pharmacokinetic studies showing that the t1/2 of mycophenolic acid, the active metabolite of MMF, was 3 hours, 
and its binding to IMPDH II rapidly reversible. Indeed, increasing administration of MMF from 15 mg/kg bid to 15 
mg/kg tid increased the rate of durable engraftment from 82% to 95% (98/103 patients) (P=0.004)12.   
 
More than 800 patients ineligible for conventional HCT have been treated with this approach so far in various 
centers in the United States and Europe. Preliminary data in the first 451 patients receiving HCT after 
nonmyeloablative conditioning for hematological malignancies have demonstrated that the nonmyeloablative regimen 
used was safe and was associated with minimal toxicity and relatively low nonrelapse mortality, even in patients 
otherwise excluded from allogeneic HCT (Table 1) 5. Given the age and status of disease of patients treated on the 
nonmyeloablative protocols, the rate of GHVD was not higher than in conventional HCT13, while transplant-related 
toxicities and 1-yr nonrelapse mortality were significantly lower14,15. 
 
Table 1.  Results of allogeneic HCT after a nonmyeloablative regimen consisting of 200 cGy TBI with or 
without fludarabine (30mg/m2/day x 3 days) in the first 451 patients transplanted for hematologic 
malignancies.5 
 
Patients 
Studied 
(#) 
 
% of Patients 
Acute GVHD 
 
% of 
Patients 
Chronic 
GVHD 
 
% of Mortality (2 yr Kaplan-Meier Estimates) 
% of Survival  
(2 yr Kaplan-
Meier Estimates) 
 
Relapse/ 
Progression 
NRM 
Overall 
Progr-
ession-
Free 
 
II 
 
III 
 
IV 
 
Overall 
GVHD + 
Infection 
 
Infection 
 
Other 
Total 
(n=451) 
34 
10 
4 
44 
26 
22 
11.2 
6.7 
4.1 
51 
37 
MRD 
(n=303) 
33 
10 
5 
43 
23 
22 
12.5 
6.5 
3.0 
54 
40 
URD 
(n=148) 
42 
9 
3 
45 
32 
22 
8.5 
7.1 
6.4 
45 
31 
 
MRD = HLA-matched related donor, URD = HLA-matched unrelated donor, NRM = nonrelapse mortality, GVHD 
= graft-versus-host disease. 
 
B. 
Results with reduced-intensity conditioning in patients with MDS/MPD 
 
Ho et al. reported results in 62 MDS patients (median age 56 yrs) given allografts from MRD (n=24) or URD (n=38) 
after reduced-intensity conditioning with fludarabine (150 mg/m²), oral busulfan (8 mg/kg), and alemtuzumab (100 
mg total dose)16. Postgrafting immunosuppression consisted of CSP alone. Sixteen patients had RA, 19 RAEB, 23 
RAEBT or tAML, and 4 CMML. The 1-yr probabilities of nonrelapse mortality, overall survival (OS) and PFS were 
5%, 73% and 61%, respectively for MRD recipients, and 21%, 71% and 59%, respectively, for URD recipients. 
Twenty-six patients required DLI, given 126-1323 days after HCT, for cytogenetic (n=4) or morphologic relapse 
(n=6), or for decreased donor marrow chimerism (n=16). Four of 4 patients given DLI for cytogenetic relapse but 
none of 6 patients given DLI for morphologic relapse responded, and 14 of 16 patients given DLI for decreasing 
marrow chimerism achieved full donor marrow chimerism after DLI. The 2-yr cumulative incidences (including 
patients given DLI) of grade III-IV acute GVHD were 17% and 23% for MRD and URD recipients, respectively. 
 
Bornhauser et al. reported data from 42 patients given allogeneic PBSC after conditioning with fludarabine 
(120 mg/m²) and busulfan (16 mg/kg, with dose adjustments to plasma levels of 900 +/- 100 ng/mL)17. Diagnosis 


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included chronic myeloid leukemia (n=4), MDS-RA (n=6), MDS-RAEB (n=11), MDS-RAEBT (n=4), untreated (n = 
2) or treated AML developing from MDS (n=10; 5 in CR; 5 resistant), and CMML (n=5). GVHD prophylaxis 
consisted of MTX and CSP. All patients had sustained engraftment. Grade II-IV acute GVHD occurred in 54% of 
patients, and extensive chronic GVHD was seen in 23% of patients. The 18-month incidences of nonrelapse mortality, 
relapse, OS and PFS were 24%, 41%, 42%, and 35%, respectively.   
 
Kroger et al. reported results from 37 MDS patients (median age 55 yrs) given grafts from MRD (n=19) or 
URD (n=18) after conditioning with fludarabine (120-180 mg/m²) and busulfan (8 mg/kg p.o. or 6.4 mg/kg i.v.) with 
(n=25) or without (n=12) added ATG18. GVHD prophylaxis combined CSP with MTX or MMF.  Diagnoses at 
transplantation were RA (n=8), RAEB (n=6), RAEBT (n=13), CMML (n=3), and secondary AML (n=7). Grade II-IV 
acute GVHD was seen in 37% of patients, and chronic GVHD in 48%. Nonrelapse mortality was 12% in patients 
given graft from MRD versus 45% in patients given grafts from URD. The 3-yr probabilities of OS and PFS were 
39% and 38%, respectively.  
 
De Lima et al. compared HCT outcomes of 94 patients given allogeneic HCT after nonmyeloablative 
(fludarabine (120 mg/m²), cytarabine (4 g/m²), and idarubicin (36 mg/m²)) or reduced-intensity (fludarabine (100-150 
mg/m²) and melphalan (140 or 180 mg/m²)) conditioning19.  The 3-yr probabilities of OS were 30% in the 
nonmyeloablative group and 35% (NS) in the fludarabine/melphalan group. Nonmyeloablative patients had less 
treatment related complications, a lower incidence of grade III-IV acute GVHD (11% vs. 19%, NS), a lower 
nonrelapse mortality (16% vs. 39%, p=0.036), and a higher risk of relapse (53% vs. 26%, p=0.029) than patients 
given fludarabine plus melphalan. However, these differences could not simply be explained by differences in the 
intensity of the conditioning, since nonmyeloablative recipients were mainly given bone marrow from MRD while 
fludarabine/melphalan patients mainly received PBSC from URD, and this could have impacted both the GVHD 
incidence and GVT effects. In addition, 19% of patients in the nonmyeloablative group experienced graft rejection, 
and most of the remainder had mixed chimerism, and this might explain the reduced GVT effects. 
 
C. Effects of TBI dose on outcome in patients given myeloablative conditioning 
Two randomized and one large nonrandomized trial have explored the importance of TBI dose on HCT outcomes20. 
In total, 71 patients with AML in first remission were treated with cyclophosphamide (120 mg/kg) and either 12 Gy 
(n=34) or 15.75 Gy (n=37) of TBI followed by HLA-matched sibling transplantation21. GVHD prophylaxis consisted 
of CSP and MTX. The relapse rate in the group receiving the lower TBI dose was 35% compared to 12% with the 
higher TBI dose (P=0.06).  
 
In a similar prospective randomized trial in patients with chronic myeloid leukemia in chronic phase, the 
relapse rate in the 57 patients treated with the lower TBI dose was 25% compared to 0% in the 59 recipients of the 
higher TBI dose (P=0.008)22. In both studies, nonrelapse mortality was higher with the higher TBI dose, thus 
balancing the reduction in relapse rates, with a result that in neither study OS was improved. Yet, these two 
prospective randomized studies argue that a relatively modest 30% increase in TBI dose could significantly reduce the 
risk of relapse, suggesting that increasing the TBI dose from 2 Gy to 3-4.5 Gy might by itself reduce the risk of 
relapse. 
 
D. Retrospective comparison on outcomes of MDS patients given allogeneic HCT after myeloablative or 
nonmyeloablative conditioning at FHCRC 
 
Scott et al. recently compared efficacy of HCT after myeloablative conditioning with busulfan [targeted (800-900 
ng/mL; starting dose 1 mg/kg every 6 hours for 16 doses)] and cyclophosphamide (120 mg/kg) (n=132), or 
nonmyeloablative conditioning with 200 cGy TBI and fludarabine (90 mg/m², n=40) conditioning in MDS patients 
over 40 yrs of age7. The WHO distribution (highest at any time before HCT) was RA/RARS in 38% of the 
myeloablative and 24% of the nonmyeloablative recipients, RAEB in 31% of the myeloablative and 24% of the 


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nonmyeloablative recipients, and transformed AML 31% of the myeloablative and 53% of the nonmyeloablative 
recipients. The 3-yr probabilities of PFS were 44% in myeloablative recipients, and 28% in nonmyeloablative 
recipients. In multivariate analyses, there were no significant differences in OS (HR 0.9, p=0.84), PFS (HR 1.0, 
p=0.93), and relapse risk (HR 0.8, p=0.43) between the myeloablative versus nonmyeloablative recipients, suggesting 
that GVT effects were more important than conditioning intensity in preventing relapse in patients with MDS. When 
considering only patients who had durable complete responses to pretransplant chemotherapy, progression-
free survival and progression rates did not differ between myeloablative and nonmyeloablative cohorts. This 
finding suggested that the intensity of transplant conditioning was not the decisive factor in preventing post-
transplant progression among patients with tAML and RAEB who had responded to treatment and had less 
than <5% marrow myeloblasts at the time of HCT. Presumably, the pretransplant induction chemotherapy 
substituted for a more intensive conditioning regimen by reducing the disease burden before HCT, and the 
use of myeloablative conditioning offered no additional gain in progression prevention but added regimen-
related toxicity.  
In contrast to patients with tAML and RAEB, looking at the 51 patients with RA (not given chemotherapy before 
HCT), 7 of 42 (17%) patients given myeloablative conditioning versus 3 of 9 (33%) patients given nonmyeloablative 
conditioning progressed/relapsed. As shown in figure 1, there was a suggestion that progressions occurred later in 
patients given myeloablative conditioning. This observation suggests that pretransplant chemotherapy may not 
only reduce the disease burden, as measured by pre-HCT marrow morphology in patients with advanced 
MDS, but may also have effects not measurable by morphology that facilitate donor T-cell engraftment 
(leading to faster achievement of full donor T-cell chimerism) in the nonmyeloablative cohort and decrease 
risk of disease progression. 
 
 
 
Figure 1. Cumulative incidence of progression in 
patients with RA/RARS given nonmyeloablative or 
myeloablative conditioning. 


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E. Results of nonmyeloablative HCT in patients with CMML or previously untreated MDS/MPD (FHCRC 
consortium) 
 
Patients 
Sixty-one patients with CMML or previously untreated MDS/MPD were given grafts from MRD (n=32) or URD 
(n=29) after 200 cGy TBI with (n=59) or without (n=2) added fludarabine. Median patient age was 59 (range, 5-73) 
yrs. Diagnoses were CMML (n=11), RA (n=20), RARS (n=2), RAEB (n=11), RAEB-T (n=4), and MPD (n=13). 
Forty-six patients had idiopathic diseases, while 15 patients had secondary MDS. 
 
Engraftment and graft rejection 
Median donor T-cell chimerism levels on days 28, 56 and 84 were 65%, 62% and 68%, respectively (Figure 2). The 
figures were 98%, 99% and 98% among granulocytes, and 92%, 90% and 92% among bone marrow cells. Twenty-
eight patients (46%) achieved full donor T-cell chimerism 26 to 789 days (median 144 days) after HCT. Eleven 
patients [6 patients given grafts from MRD (including 1 of 2 patients given 200 cGy TBI only as conditioning), and 
five additional patients given grafts from HLA-matched URD (including 1 of 2 marrow recipients)] had graft rejection 
14 to 184 (median 64 days) after HCT. 
 
0
28
56
84
0
20
40
60
80
100
Peripheral Blood T-cell
Peripheral Blood Granulocyte
Marrow nucleated cell
Figure 2. Engraftment kinetics.
Days after HCT
% of donor cells
 
 
GVHD and nonrelapse mortality 
Acute GVHD of grades I, II, III and IV were seen in 2 (4%), 19 (31%), 7 (11%) and 1 (2%) patients, respectively, 
while extensive chronic GVHD occurred in 24 patients (40%). Nonrelapse mortality was observed in 14 patients 
(23%) < day 200, and in 19 patients (31%) overall (Figure 3). 


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HCT outcomes in patients with RA (RS)/MPD (n=35) 
 
Sixteen of 35 patients (46%) achieved complete remissions 19 to 346 (median 56) days after HCT. Ten patients 
(29%) relapsed or progressed 117 (28-184) days after HCT, while 6 (17%) rejected their grafts 51 (23-184) days after 
HCT. All but one patient with graft rejection progressed. Eleven patients (31%) had “HCT failure” before day 200 
(Figure 4). The 200-day, 1-yr and 2-yr probabilities of PFS were 46%, 40%, and 37% respectively (Figure 5). 
 
 
 
HCT outcomes in patients with CMML/RAEB (t) (n=26) 
 
Four of 26 patients (15%) achieved complete remissions 25 to 33 (median 28) days after HCT. Seventeen patients 
(65%) relapsed or progressed 108 (28-1585) days after HCT, while 5 (19%) rejected their grafts 80 (14-127) days 
after HCT. All patients with graft rejection eventually progressed, although one CMML patient remained in complete 
remission for 4 yrs after graft rejection, before eventually progressing. Fifteen patients (58%) had “HCT failure” 
before day 200 (Figure 4). The 200-day, 1-yr and 2-yr probabilities of PFS were 27%, 19%, and 11% respectively 
(Figure 5). 
 
 


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0
365
730
1095
1460
1825
0
20
40
60
80
100
CMML (n=11)
MPD (n=13)
RA/RARS (n=22)
RAEB/RAEBT (n=15)
Figure 5. PFS according to diagnosis
Days after HCT
% of PFS
 
 
 
F. 
Impact of achievement of full donor T-cell chimerism on relapse after nonmyeloablative conditioning 
We have analyzed GVT effects in 322 patients given nonmyeloablative conditioning for hematologic malignancies6. 
Multivariate time-dependent cox regressions models were used to assess the impact of achievement of full donor T-
cell chimerism on HCT outcomes. Achievement of full donor T-cell chimerism was associated with a reduced risk of 
relapse/progression (HR 0.5, P=0.002), and a trend for a better PFS (P=0.11).   
 
 
G. Dose-response relationship of TBI with engraftment rates in a pre-clinical dog model. 
A close relationship between TBI dose and rate of sustained engraftment of dog leukocyte antigen (DLA) identical 
marrow has been demonstrated in a preclinical canine model (Table 2). A TBI dose of 920 cGy was sufficiently 
immunosuppressive to permit engraftment of DLA-identical littermate marrow in 95% of dogs, even without 
postgrafting immunosuppression23. When the TBI dose was decreased to 450 cGy, 48% of dogs achieved sustained 
engraftment24. Since both host-versus-graft (rejection) and graft-versus-host reactions are mediated by T-cells after 
DLA-identical HCT, it was hypothesized that optimizing post-transplant immunosuppression might not only prevent 
GVHD, but also increase the engraftment rate. Indeed, 7 of 7 dogs given 450 cGy TBI and postgrafting with CSP 
achieved sustained engraftment24. When the TBI dose was further decreased to 200 cGy, postgrafting 
immunosuppression either with CSP alone or with a combination of CSP and MTX resulted in graft rejection with 
autologous recovery in 4 of 4 dog and 3 of 5 dogs studied, respectively25. Conversely, stable mixed chimerism was 
achieved in 11 of 12 dogs given postgrafting immunosuppression with MMF and CSP25. When the TBI dose was 
further decreased to 100 cGy, all dogs experienced graft rejection, demonstrating a delicate balance between host-
versus-graft and graft-versus-host reactions25,26. These observations strongly support the hypothesis that increasing the 
dose of TBI will promote engraftment in MDS/MPD/CMML patients. 
 
 
  
 
 


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Table 2.  Effect of TBI Dose and Postgrafting Immunosuppression on Engraftment of DLA-identical Marrow Grafts 
 
Reference # 
Conditioning 
[TBI dose 
(cGy)] / other 
Stem cell 
source 
Postgrafting 
immunosuppression / 
Reference 
# of dogs with stable 
engraftment (%)*/# of 
dogs transplanted 
DLA-identical grafts 
23 
920 
Marrow 
None  
20/21 (95%) 
9 
800 
Marrow 
None  
4/5 (80%) 
9 
700 
Marrow 
None  
3/5 (60%) 
9 
600 
Marrow 
None  
12/23 (52) 
9 
450 
Marrow 
None  
10/21 (48%) 
24 
450 
Marrow 
CSP†  
7/7 (100%) 
25 
200 
Marrow 
CSP†  
0/4 (0%) 
25 
200 
Marrow 
MTX‡ + CSP†  
2/5 (40%) 
25 
200 
Marrow 
MMF§ + CSP†  
11/12 (92%) 
25 
100 
Marrow 
MMF§ + CSP†  
0/6(0%) 
*Mixed or full chimerism. 
† Cyclosporine, 15 mg/kg BID PO, days -1 to 35. 
‡ Methotrexate, 0.4 mg/kg IV on days 1, 3, 6 and 11. 
§ Mycophenolate mofetil, 10 mg/kg BID SC, days 0 to 27. 
TBI, total body irradiation. 
 
 
H. What is the upper limit for nonmyeloablative TBI? 
At the dose of 450 cGy, of 21 dogs studied, 14 (67%) receiving DLA-identical marrow but no growth factors 
survived, 10 with successful allografts (including 5 mixed chimeras) and 4 with autologous recovery; whereas 7 
animals died, 5 (24%) from infections during marrow aplasia, and 2 from acute GVHD27. In contrast, 30 of 34 dogs 
(88%) given hematopoietic growth factors (G-CSF, SCF, or the combination of G-CSF and SCF) in addition to the 
DLA-identical marrow graft survived, 17 with successful allografts (including 10 mixed chimeras), and 13 with 
autologous recovery; whereas 4 (12%) died, all with infection related to marrow aplasia after rejection of the 
allograft27. Thus, 13 of 17 (76%) dogs without evidence of donor engraftment had autologous recovery. Survival was 
similar for recipients of G-CSF, SCF, or the combination of G-CSF and SCF. Logistic regression analyses showed a 
trend for improved survival in dogs given growth factors (P=0.09), no change in allogeneic engraftment (P=0.74), and 
an increase in autologous recovery (P=0.22). The experiments suggested that, while a TBI dose of 450 cGy was 
myeloablative and supralethal in dogs not given hematopoietic growth factors, autologous reconstitution occurred in 
76% of dogs without donor engraftment in the presence of hematopoietic growth factors. Therefore, the upper limit 
dose of TBI will be 450 cGy in this protocol. 
 
 
I. Current experience with 300 cGy TBI as 2nd HCT regimen in patients with graft rejection. 
Three hundred cGy TBI in combination with 90mg/m2 of fludarabine have been used as a 2nd transplant regimen in 
12 patients with graft rejection both after nonmyeloablative and conventional conditioning regimens at FHCRC, 
Stanford University and University of Leipzig. Eleven patients had successful 2nd grafts, and one patient failed to 
engraft. Eight patients were alive 133 days to 4 yrs after 2nd HCT, while 4 patients died. There were no undue acute 
toxicities, and none of the four died as a direct consequence of the conditioning regimen. Two of the 4 patients died 
of pulmonary problems: one at day +456 from ARDS/pneumonitis and the other at day +36 from pre-existing 
advanced fungal pneumonitis. One of the other two patients died from GVHD/infections and the other from disease 
progression. 
 
 
 


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J.     Experience with unrelated HCT after 550 cGy TBI and Cyclophosphamide. 
Girgis et al. reported data from 110 patients with hematologic malignancies given unrelated marrow after 550 cGy 
TBI (given at 30 cGy/min) and cyclophosphamide (120 mg/kg)28. Postgrafting immunosuppression consisted of 
CSP, MTX and prednisone. Median patient age was 44 (range, 19 to 62) yrs. Twenty-six patients had good risk 
diagnosis (AML in CR1 or CML-CP), while 84 patients had poor risk diagnosis. Primary and secondary graft failure 
occurred in 6 patients (3 had CML, 2 had MDS, 1 had NHL) and 1 patient (with CML), respectively. Most patients 
with graft failure had autologous reconstitution (Adkins et al., personal communication), although 2 of them died 
because of graft failure. Fatal organ toxicity occurred in 2 patients (1 cardiac toxicity and 1 renal failure with TTP), 
whereas life-threatening grade IV organ toxicity occurred in 5 patients (1 mucositis, 3 SOS, 1 hemorrhagic cystitis). 
Incidences of grade II-IV and III-IV acute GVHD were 33% and 18%, respectively. Limited and extensive chronic 
GVHD were seen in 11% and 59% of patients, respectively. Cumulative rates of nonrelapse mortality in patients 
with good and poor risk diseases were 19% and 42%, respectively. The 3-yr probability of OS and PFS were 47% 
and 40% for good risk patients, and 25% and 21% for poor risk patients, respectively. We, therefore, believe it is safe 
to increase the dose of TBI from 200 to 300-450 cGy for patients with MDS/MPD/CMML. 
 
K.    Impact of TBI dose on testicular function. 
 
Most of our understanding of the effects of radiation on human testis came from 2 studies 29,30 of single exposure 
delivered directly to the testis of normal men. Men given < 10 rad did not have testicular damage. A transient 
reduction in sperm concentration was observed in patients whose gonadal dose was only 15 rad, while azoospermia 
occurred in all patients exposed to 100 to 600 rad29,30. Regarding recovery of testicular function following radiation 
exposure, Rowley et al. reported a return of sperm counts to pre-irradiation levels after 30 months when irradiation 
levels were between 200 and 300 rads, and after 5 yrs or more when irradiation doses were between 400 to 600 rad29. 
Paulsen et al. reported similar findings although earlier recovery at approximately 30 months was observed in 2 
patients given 400 rad who had sufficient long-term information30. 
 
 
L. 
Assessment of Pretransplant Comorbidities 
Charlson Comorbidity Index (CCI) is a well-known simple index to score comorbidities which was developed to 
provide prediction of risks of survival after treatment of chronic medical illnesses31. The Seattle team used this index 
in 2004 to score pretransplant comorbidities among patients diagnosed with hematological malignancies and offered 
HCT. The CCI was helpful in predicting risks of non-relapse mortality and survival32,33. However, the CCI showed a 
limited ability in capturing comorbidities among the transplanted population. Therefore, the same authors investigated 
the possibility of modifying the original CCI to better capture comorbidities among transplanted patients34. They tried 
to a) better define previously identified comorbidities utilizing pretransplant laboratory data, b) investigate additional 
HCT-related comorbidities, and c) establish comorbidity scores that were suited for HCT. This resulted in developing 
a new HCT-specific comorbidity index (HCT-CI), which captured comorbidities among 62% of patients with scores 
>0 compared to 12% captured by the original CCI34. Additionally, the new index was superior to the old CCI in 
prediction of survival (likelihood ratio of 23.7 versus 7.1 and c statistics of 0.661 versus 0.561, P=<0.0001, 
respectively).  
 
M.  Impact of PBSC composition on outcomes after nonmyeloablative conditioning 
 
Three recent studies have analyzed the impact of cell dose on outcome after nonmyeloablative conditioning. We 
reported data from 125 patients given PBSC from HLA-identical siblings after 2 Gy TBI with or without fludarabine. 
Higher number of CD34+ cells transplanted was associated with better OS (P = 0.03)39. No correlations between the 
doses of CD3, CD4 and CD8+ T cell transplanted and outcomes (and particularly acute GVHD) were identified. Cao 
et al., using the same preparative regimen combining 2 Gy TBI with or without fludarabine, found that a higher 
number of transplanted CD8+ T cells in the graft correlated with increased T-cell chimerism levels and better OS (P  = 
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(n = 25) donors40. We observed that higher numbers of grafted CD34+ cells (the median CD34 cell dose was 6.5 x 
10(6)/kg) were associated with higher levels of day 28 donor T-cell chimerism (P = 0.01), rapid achievement of 
complete donor T-cell chimerism (P = 0.02), and a trend for lower risk for graft rejection (P = 0.14) in 116 patients 
given unrelated PBSC after 2 Gy TBI and fludarabine. No correlations between doses of CD3, CD4 or CD8+ T-cell 
transplanted and GVHD/survival were identified.  Taken together, those data suggest that relatively high doses of 
CD34+ cells should be transplanted in patients given nonmyeloablative conditioning, particularly in patients with 
CML, MDS or MPD41. 
 
4. Proposal 
 
The current protocol’s primary objective is to decrease the incidence of day-200 HCT failure (graft rejection and /or 
progression) < 20% in patients with CMML or untreated MDS/MPD given related or unrelated HLA-matched HCT 
following nonmyeloablative conditioning.  The plan is to achieve these goals by increasing the intensity of the pre-
transplant TBI. The proposed conditioning regimen will continue to use fludarabine, 30 mg/m2/day x 3 days, while the 
initial TBI dose will be increased from 200 cGy to 300 cGy.  If this regimen fails to decrease the HCT failure rate 
sufficiently, the TBI dose will be increased to 400 cGy (level 2) and then to 450 cGy (level 3). Enrollment in each 
cohort will stop if the true rate of HCT failure on day +200 is greater than 20% (dose escalation rules; enrolment in 
each levels will occur in groups of 6 patients), and following patients will be included in the next cohort, or when 24 
patients will be included. Dose escalation will be carried out independently in two groups of patients: Arm A – 
patients with MPD or MDS-RA/RARS and, Arm B – patients with MDS-RAEB or CMML. Stopping rules for the 
protocol will be 25% nonrelapse mortality within 200 days. Secondary objectives will be relapse/progression, PFS, 
kinetics of donor engraftment (chimerism), and infections.  
 
 
5. Primary Objectives  
By escalating the intensity of the TBI prior to HCT, the primary objective is to: 
1. Decrease the incidence of day-200 HCT failure to < 20% in patients with MDS-RA (RS)/MPD and in patients 
with CMML/RAEB. 
 
6. Secondary Objectives: to determine: 
1. The rate of relapse/progression in patients with MPD or MDS-RA and those with CMML or MDS-RAEB. 
2. The probability of PFS in patients with MPD or MDS-RA and those with CMML or MDS-RAEB. 
3. The kinetics of donor engraftment. 
4. The incidence of infections. 
 
7. Patient Selection 
 
7.1 Inclusion Criteria 
(A) Patients aged 50 and < 75 yrs with CMML, or previously untreated MDS or MPD as described in Sections 7.1.1, 
7.1.2 and 7.1.3, 7.1.4, and 7.1.5. 
 
(B) Patients aged < 50 yrs at high risk for regimen related toxicity using standard high dose 
regimens. Factors considered high risk include pre-existing conditions such as a chronic 
disease affecting kidneys, liver, lungs, or heart or previous failed HCT. 
 
(C) An HLA-identical related or an HLA-matched unrelated donor (FHCRC matching allowed will be Grade 1.0 to 
2.1 (Appendix O)) is available (Refer to section 8.1 and 8.3). 
 
(D) Recovery from the effects of previous chemotherapy, with a minimum of 21 days from 
initiation of last therapy. Hydroxyurea or anagrelide may be used to manage elevated cell 


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counts in patients up to the time they begin therapy under this protocol. 
 
(E) Patients < 12 yrs of age must be discussed on a case by case basis with the PI of the protocol 
(Brenda Sandmaier M.D. (206-667-4961)) prior to protocol registration. 
 
(F) A signed informed consent form or minor assent form. 
 
7.1.1 MDS 
 
(A) MDS classifiable by the WHO system (see appendix R) as RA, RARS, refractory cytopenia with multilineage 
dysplasia (RCMD), RCMD and ringed sideroblasts (RCMD-RS) or RAEB. 
 
(B) No previous myelosuppressive therapy. For the purpose of this protocol myelosuppressive chemotherapy will be 
defined as chemotherapy given with the intent of inducing a complete remission (e.g. standard 7+3, HIDAC, or 
mylotarg). 
 
(C) Patients must have < 10% marrow blasts. Fewer than 10% marrow blasts must be documented by marrow 
examination within 3 weeks of initiation of conditioning.  
 
7.1.2 CMML 
 
(A) Patients with CMML1 who have not received myelosuppressive therapy must have < 10% marrow blasts. Fewer 
than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning. 
OR 
Patients with CMML who have progressed beyond CMML1 and have received myelosuppressive chemotherapy must 
have <5% marrow blasts. Fewer than 5% marrow blasts must be documented by marrow examination within 3 weeks 
of initiation of conditioning. 
 
7.1.3 MPD 
 
(A) Patients with polycythemia vera with persistent thrombotic or hemorrhagic 
complications despite conventional therapy, or who have progressed to postpolycythemic 
marrow fibrosis. 
 
(B) Patients with essential thrombocythemia with persistent thrombotic or hemorrhagic 
complications despite conventional therapy, or who have progressed to myelofibrosis. 
 
(C) Chronic idiopathic myelofibrosis with peripheral blood cytopenias. 
 
(D) Patients must have < 10% marrow blasts. Fewer than 10% marrow blasts must be documented by marrow 
examination within 3 weeks of initiation of conditioning. 
 
(E) No previous myelosuppressive therapy. For the purpose of this protocol myelosuppressive chemotherapy will be 
defined as chemotherapy given with the intent of inducing a complete remission (e.g. standard 7+3, HIDAC, or 
mylotarg). 
 
 
7.1.4 Atypical CML 
 
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(B) Patients must have < 10% marrow blasts. Fewer than 10% marrow blasts must be documented by marrow 
examination within 3 weeks of initiation of conditioning. 
 
(C) No previous myelosuppressive therapy. For the purpose of this protocol myelosuppressive chemotherapy will be 
defined as chemotherapy given with the intent of inducing a complete remission (e.g. standard 7+3, HIDAC, or 
mylotarg). 
 
7.1.5 Paroxysmal Nocturnal Hemoglobinuria (PNH) 
 
Patients with the non-aplastic form of PNH (cellular bone marrow) who have had a history of life-
threatening complications of their disease including thrombotic events, severe hemolysis or Budd Chiari 
syndrome are eligible.  Other patients may be considered following approval at PCC and approval by the 
protocol Principal investigator. 
 
 
7.2 Exclusion Criteria 
(A) Organ dysfunction as defined by the following: 
1. 
Symptomatic coronary artery disease or cardiac ejection fraction < 35% (or, if unable to obtain 
ejection fraction, shortening fraction of <26%).  If shortening fraction is <26% a cardiology consult is 
required with the PI having final approval of eligibility. Ejection fraction is required if age > 50 years 
or there is a history of anthracycline exposure or history of cardiac disease. 
2. 
DLCO <35%, TLC <35%, FEV1 <35% and/or receiving supplementary continuous oxygen. The 
FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules. 
3. 
Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease will be 
evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging 
fibrosis, and the degree of portal hypertension.  The patient will be excluded if he/she is found to have 
fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, 
esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable 
hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to 
portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with 
total serum bilirubin >3mg/dL, or symptomatic biliary disease. 
 
(B) Bone marrow documenting blast count >10% or >5% in CMML patients who have progressed beyond CMML1 
and received myelosuppressive chemotherapy 
 
(C) Patients with active non-hematologic malignancies (except non- melanoma skin cancers). 
 
This exclusion does not apply to patients with non-hematologic malignancies that do not 
require therapy 
 
(D) Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a 
complete remission, who are less than 5 years from the time of complete remission, and have a >20% risk of disease 
recurrence.   
 
 
(E) Presence of >5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology. 
 
(F) Active CNS involvement of disease (if LP requirement, see Appendix N).  
 
(G) Karnofsky performance score < 70% or Lansky-Play Performance score < 70 for pediatric 
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(H) Life expectancy severely limited by diseases other than malignancy 
 
(I) Fungal infections with radiological progression after receipt of amphotericin product or active 
triazole for > 1 month 
 
(J) Active bacterial infection 
 
(K) Patients of fertile age who refuse contraception for a twelve month period post-transplant 
 
(L) Females who are pregnant or breastfeeding 
 
(M) HIV seropositivity 
 
(N) Severe psychological illness such as major psychosis (e.g. schizophrenia), major bipolar depression, or suicidal 
situational depression. 
 
8.0 Donor Eligibility 
 
8.1 Inclusion Criteria – MRD 
 
(A) Related to the patient and is genotypically or phenotypically HLA-identical. 
 
(B) Donor age < 75 yrs unless cleared by institutional P.I 
 
(C) Capable of giving written, informed consent. 
 
(D) Donor must consent to PBSC mobilization with G-CSF and apheresis 
 
8.2 Exclusion Criteria – MRD 
 
(A) Identical twin 
 
(B) Any contra-indication to the administration of subcutaneous G-CSF at a dose of 16mg/kg/d for 
five consecutive days 
 
(C) Serious medical or psychological illness 
 
(D) Pregnant or lactating females 
 
(E) Prior malignancy within the preceding five yrs, with the exception of non-melanoma skin 
cancers. 
 
(F) HIV seropositivity 
 
8.3 Inclusion Criteria – URD 
 
(A) FHCRC matching allowed will be Grades 1.0 to 2.1 (Appendix O): Unrelated donors who are prospectively: 
i) 
Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing;  
ii) 
Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high 
resolution typing (see Appendix O for other donor selection details). 
 


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(B) Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-
allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed.  
 
(C) Only G-CSF mobilized PBMC only will be permitted as a HSC source on this protocol. 
 
(D)  Donor must consent to PBSC mobilization with G-CSF and apheresis. Bone marrow unrelated donors are not 
eligible for this protocol 
 
 
8.4 Exclusion Criteria-URD 
 
(A) A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion. Donors are excluded when 
preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. This 
determination is based on the standard practice of the individual institution. The recommended procedure for patients 
with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and 
class II antigens for all patients before HCT. If the PRA shows >10% activity, then flow cytometric or B and T cell 
cytotoxic cross matches should be obtained. The donor should be excluded if any of the cytotoxic cross match assays 
are positive.  For those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross 
matches should be obtained regardless of the PRA results. 
(B)  Marrow donors  
(C) Donors who are HIV-positive and/or medical conditions that would result in increased risk to the donor G-CSF 
mobilization and G-PBMC collections. 
(D) Serious medical or psychological illness 
(E) Pregnant or lactating females 
(F) Prior malignancy within the preceding five yrs, with the exception of non-melanoma skin cancers. 
(G) HIV seropositivity 
 
 9.   Informed Consent 
A conference will be held with the patient and family to discuss this study and alternative treatments available for the 
underlying disease.  A separate conference will be held for the donor. The conference will be conducted by the 
outpatient-attending physician.  All potential risks associated with the use of fludarabine, low dose TBI, 
immunosuppressive drugs, HCT, GVHD, infections, rejection, disease progression/recurrence, risk of infertility and 
DLI should be discussed as objectively as possible. Specifically, the advantages and risks of this approach in 
comparison to non transplant strategies and myeloablative HCT should be discussed.  Informed consent from the 
patient will be obtained using a form approved by the Institutional Review Board (IRB) of the Fred Hutchinson 
Cancer Research Center and the local IRB if the patient is treated in a collaborating institution. 
 
 
10. Protocol Registration 
FHCRC patients:  Eligible patients will be identified by the Clinical Coordinators Office.  Patients will be registered 
with the Registration Office (206-667-4728) between 8:30 am and 4:00 PM, Monday through Friday. After hours, the 
Registration office can be reached by paging (206) 995-7437. 
 
 
Collaborating institutions:  Eligible patients will be identified by the principal investigator of the collaborating 
institution who will register the patient with the FHCRC.  Registration will include completion of the eligibility 
checklist/demographic form (Appendix L).  This form will be faxed to the trial coordinator (206-667-5378).  
Questions regarding eligibility or protocol information should be directed to Brenda Sandmaier, M.D. (206-667-
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11. Plan of Treatment  
 
A. Outline of Treatment Plan (refer to Figure 6 and Table 3) 
 
 
 
B. Cytoreduction:  Cytoreduction, radiation therapy or both may be given by the referring physician or the 
attending physician as determined on clinical grounds or to meet eligibility requirements of the protocol for 
patients with CMML.  However, no intensive chemotherapy can be given within 3 weeks prior to initiating 
conditioning (see exclusion criteria).  The need for this therapy should be discussed with the principal 
investigator. The referring oncologist may be asked to administer this therapy.  
 
C. Discontinuation of Hydroxyurea and other medications:  For patients who are under hydroxyurea prior to 
HCT, this medication should be discontinued on day -2. Thalidomide, lenalidomide, arsenic trioxide, imatinib 
mesylate and farnesyl transferase inhibitors should be discontinued at least 3 weeks prior to HCT. 
 
D. Conditioning Regimen: (refer to Figure 6 and Tables 3 A/B) 
 
 
Days -4, -3 and –2:  Fludarabine 30mg/m2/day IV. 
 
Day 0:  TBI 300 cGy (level 1), 400 cGy (level 2) or 450 cGy (level 3) at 6-7 cGy/min from linear 
accelerator followed by HCT.  Regardless of the actual time of TBI administration on DAY 0, 
immunosuppression should be given per schedule and prior to the infusion of PBSCs.  
 
 
 
 
 
 
Figure 6.  Protocol treatment Schema 
MRD
TBI*
HCT
Days
-4   -3   -2
0
28       40       56                  84             100   
180
Flu
30mg/m2/d
MMF
URD    
Chimerism Analyses
MMF
CSP
CSP
FLU: 30 mg/m² x 3 days (days -4, -3, -2).
TBI: Single fraction at 7 cGy/min. 300 cGy (level 1), 400 cGy (level 2), 450 cGy (level 3).
CSP:    MRD: 5.0 mg/kg po q12hrs days-3 to + 56 then taper to day +180.
URD: 5.0 mg/kg po q12hrs days-3 to + 100 then taper to day +180. 
MMF:    MRD: 15 mg/kg po q12hrs days 0 to + 27.
URD: 15 mg/kg po q8hrs days 0 to + 40, then taper to day + 96.


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Table 3A.  Patients with MRD - Conditioning Schema and Immunosuppression Schedule 
 
Day Number 
-4 
-3 
-2 
-1 
0 
+1 
+ 28 
+56 
+180 
Fludarabine 
X 
X 
X 
 
 
 
 
 
 
TBI 
 
 
 
 
300 cGy (level 1) 
400 cGy (level 2) 
450 cGy (level 3) 
 
 
 
 
PBSC 
 
 
 
 
Infusion 
 
 
 
 
CSP 
 
START 
 
 
 
 
 
TAPER 
STOP 
MMF 
 
 
 
 
STARTa 
BID 
STOP 
 
 
A The first dose of MMF is to be given 4-6 hours after the stem cell infusion. 
 
Table 3B.  Patients with URD - Conditioning Schema and Immunosuppression Schedule 
Day Number 
-4 
-3 
-2 
-1 
0 
+1 
+40 
+96 
+100 
+180 
Fludarabine 
X 
X 
X 
 
 
 
 
 
 
 
TBI 
 
 
 
 
300 cGy (level 1) 
400 cGy (level 2) 
450 cGy (level 3) 
 
 
 
 
 
PBSC 
 
 
 
 
Infusion 
 
 
 
 
 
CSP 
 
START 
 
 
 
 
 
 
TAPER 
STOP 
MMF 
 
 
 
 
STARTa 
TID 
TAPERb 
STOP 
 
 
A The first dose of MMF is to be given 4-6 hours after the stem cell infusion. 
B Taper of MMF will be a ~10% dose reduction per week x 8 weeks. 
 
 
E.  PBSC infusion 
G-CSF mobilized PBSC from MRD or URD will be the only source of hematopoietic stem cells. Two 12-liter 
leukaphereses on consecutive days, day –1 and day 0, will be obtained, and cells will be infused together on 
day 0 following TBI. Refer to institutional practice guidelines for methods of infusion. If the CD34 cell dose 
is <5.0 x 106/kg after the second collection, a third day collection should be added, and extra dose of G-CSF 
should be given to the donor before the final collection (see also section G). 
 
F.  Immunosuppression 
 
 
MRD 
 
Day –3:  CSP at 5.0mg/kg PO q12hrs, continue to day +56 and taper to day +180. CSP should be 
routinely taken at 9:00 a.m. and 9:00 p.m. 
 
Day 0:  After HCT on day 0, MMF will be given at 15mg/kg PO at 4-6 hours after PBSC infusion is 
complete, then to be given at 15mg/kg PO q12hrs until day +27 and then discontinued. 
  
 
URD 
 
Day –3:  CSP at 5.0mg/kg PO q12hrs, continue to day +100 and taper to day +180. CSP should be 
routinely taken at 9:00 a.m. and 9:00 p.m. 


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 
Day 0:  After HCT on day 0, MMF will be given at 15mg/kg PO at 4-6 hours after PBSC infusion is 
complete, then to be given at 15mg/kg PO q8hrs until day +40, and then taper to day +96. 
 
a. CSP 
1. Starting Dose:   
 
A. Adult dose. CSP (Neoral is preferred) is given orally at 5.0mg/kg q12hrs PO (based on adjusted body 
weight) from day –3 until day +56 (MRD) or +100 (URD).  Dose should be adjusted to maintain a high 
therapeutic CSP level as discussed below.  If there is nausea and vomiting at any time during CSP 
treatment the drug should be given intravenously at the dose that was used to obtain a therapeutic level.  
The conversion from oral CSP (Neoral) to intravenous cyclosporine = oral cyclosporine dose divided by 
2.5 equals IV dose.  Use CSP levels to further adjust the dose.  The formulation of CSP can be changed to 
Sandimmune if nausea and vomiting are persistent. 
 
B. Pediatric Dose:  Due to the variable and increased metabolism in children, CSP will be started 
intravenously at the following doses at day –3 to be adjusted to maintain a therapeutic level as 
specified below.  CSP trough level should be obtained on day 0 and CSP dose adjusted to ensure 
therapeutic levels.  The patient may be changed to oral CSP after HCT when he or she is able to 
take oral medications.  Dose should be adjusted to maintain high therapeutic levels as discussed 
below.  If nausea or vomiting occur at any time during CSP treatment, CSP should be administered 
intravenously at the dose that was used to obtain a therapeutic level.  The conversion from oral 
CSP (Neoral) to intravenous cyclosporine = oral cyclosporine dose divided by 2.5 equals the IV 
dose.  Use CSP levels to further adjust the dose.  
 Age 6 years old:  1.6mg/kg IV q8hrs 
 Age >6 years old:  2.0mg/kg IV q12hrs. 
 
Continuous infusion of cyclosporine may be appropriate due to toxicity or variable levels.  Infuse total 
daily dose over 22-24 hours by continuous IV infusion. 
 
2. In the absence of GVHD, for MRD recipients: CSP is to be tapered from day +56 and discontinued 
on day + 180; for URD recipients: CSP is to be tapered from day +100 and discontinued on day + 
180.  The referring physician, who will receive explicit instructions and guidelines for detecting and 
managing GVHD, will manage this. Modifications of the taper schedule may be indicated if 
significant disease progression occurs early post-transplant (see section K below). 
 
3. Blood pressure, renal function (serum creatinine, BUN), electrolytes and magnesium need to be 
followed at least three times per week during the first month, twice weekly until day +100, then once 
per week until CSP is stopped, unless clinical circumstances suggest the need for more frequent 
evaluations.   
 
4. CSP Dose Adjustments: Initial high Cyclosporine (CSP) doses are required based  
on the pre clinical nonmyeloablative canine studies, which used an equivalent dose to establish an 
allograft.  After day +28, CSP levels typical for unrelated HCT will be targeted.  Dose reduction should 
only be made if CSP toxicity is present, and/or levels exceed values provided in Table 4.  There are two 
methods for calculating CSP levels.  Table 4 provides desired levels for specific methods.  To avoid 
inadequate immune suppression, dose reductions should be conservative.  Therapeutic levels of CSP 
should be maintained. 
 
 
 
 


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Table 4:  CSP Dose Adjustment by Levels 
 
 
CSP Level to Target Using 
LC-MS/MS Method 
CSP Level to Target Using 
Immunoassay Method 
Day “0” – Day +28 
Whole blood “trough” (11-12 hrs from 
prior dose) 
 
400 ng/ml 
 
500 ng/ml 
(upper end therapeutic 
range for this method) 
 
 
 
After Day +28  
120 – 360 ng/ml 
 
150 – 450 ng/ml 
 
Levels >480 ng/ml by LC-MS/MS 
Method 
 
with or without CSP toxicity 
 
decrease GFR >50% 
 
increase creatinine 2x baseline 
due to CSP 
 
 
 
25% dose reduction 
 
 
 
N/A 
Levels >600 ng/ml by Immunoassay 
Method 
 
with or without CSP toxicity 
 
Decrease GFR >50% 
 
increase creatinine 2x baseline 
due to CSP 
 
N/A 
 
 
25% dose reduction 
Patients on Hemodialysis 
320 ng/ml 
400 ng/ml 
 
 
 
5. CSP Monitoring:  Further CSP determinations should be performed on a twice weekly basis for the 
first month and then weekly until day +100 unless high levels are detected (i.e., >600 ng/ml), or 
toxicity is suspected in which case more frequent monitoring will be performed as clinically 
indicated.  Routine monitoring of CSP will not be required for patients on a CSP taper unless 
clinically indicated. 
 
6. Drugs Interactions: Drugs that may affect CSP levels are shown in Table 5. 
 
 
 
 


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Table 5:  Drugs Affecting CSP Level 
 
*Discontinuation of fluconazole or itraconazole may lower CSP levels, and if used as antifungal 
 prophylaxis changes in these drugs should be avoided during the first month post-transplant. 
 
b. MMF 
 
1. Initiating MMF Therapy:  Oral administration of MMF will be given based on adjusted body weight 
at 15mg/kg q12hrs (30mg/kg/day) for MRD recipients, and at 15mg/kg q8hrs (45mg/kg/day) for 
URD recipients, from the evening of day 0 (i.e. first dose to follow 4-6 hours after HCT).  Doses will 
be rounded to the nearest 250mg (capsules are 250mg).  If there is nausea and vomiting at any time 
preventing the oral administration of MMF, MMF should be administered intravenously based on 
adjusted body weight at 15mg/kg q12hrs for MRD recipients, or 15mg/kg q8hrs for URD recipients. 
 
2. Tapering of MMF:  MRD recipients: MMF will be given daily at 15mg/kg q12hrs through day +27, 
and then in the absence of GVHD, discontinued on day 28.URD recipients: MMF will be given daily 
at 15mg/kg q8hrs through day +40 post transplant, and then in the absence of GVHD, MMF should 
be tapered at day +40 by 10%/week x 8 weeks and discontinued on day +96. 
 
3. Maintaining MMF:  Markedly low (<40%) donor T-cell chimerism after HCT may indicate 
impending graft rejection35. MMF should be continued at full dose or, if MMF taper has been 
initiated, reinstitution of full dose MMF should occur.  Consideration of graft salvage with use of 
pentostatin + DLI (as per protocol 1825) or other institutional protocol should be considered.  
 
4. Guidelines for MMF dose adjustment due to drug toxicity:  
 
If in the clinical judgment of the investigator the observed toxicity is related to MMF 
administration, a dose adjustment may occur.  The discontinuation of MMF at any point should 
be discussed with the Study PI and should be documented in the permanent medical record and 
all Case Report Forms (CRF). 
 
Gastrointestinal Toxicity.  Severe gastrointestinal toxicities such as gastrointestinal hemorrhage 
have been very rare after nonmyeloablative HCT. In the event of gastrointestinal toxicity that 
requires medical intervention including medication for control of persistent vomiting or diarrhea 
that is considered to be due to MMF after day +28, a 20% dose reduction will be made or the 
Decrease CSP Levels 
Increase CSP Levels    
Enhance Potential for Nephrotoxicity 
carbamazepine 
nafcillin 
octreotide 
phenobarbital 
phenytoin 
primidone 
rifampicin 
sulfonamides 
trimethoprim 
metoclopramide 
 azithromycin 
diltiazem 
alcohol 
acetazolamide 
caspofungin 
clarithromycin 
colchicine/diltiazem 
doxycycline 
erythromycin 
fluconazole*                                
fluoroquinolones 
imipenem 
itraconazole* 
ketoconazole 
nicardipine 
nifedipine 
verapamil 
voriconazole 
Aminoglycosides 
Loop diuretics (furosemide) 
Amphotericin formulations 


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drug may be given IV. If severe refractory diarrhea or overt gastrointestinal bleeding occurs, 
MMF may be temporarily stopped. The MMF should be restarted at 20% reduced dose when the 
underlying toxicity subsides. 
 
Neutropenia.  Based on previous experience in patients after nonmyeloablative HCT, dose 
adjustments are not likely to occur because of hematopoietic adverse effects, in particular 
neutropenia.  A thorough evaluation of neutropenia should occur including peripheral blood 
chimerism studies, marrow aspiration and review of marrow suppressive medications (e.g. 
bactrim, ganciclovir).  If all other potential causes of marrow toxicity are ruled out, dose 
adjustments will only be made for grade IV neutropenia that persists after day +28 post-
transplant. Dose reductions should be conservative (20%).  After day +21, the use of G-CSF will 
be permitted for neutropenia. For severe toxicity related to MMF (grade IV neutropenia > 5 days 
refractory to G-CSF), MMF may be decreased and if neutropenia persists, MMF can be stopped.  
The MMF should be restarted at 20% reduced dose when the underlying toxicity subsides.  
 
 
 
G. Collection and infusions of Donor PBSC (see also section 11.L) 
 
MRD  
G-CSF administration to Donors 
From day -4 to day 0, all PBSC donors will receive G-CSF at a dose of 16 µg/kg/day for 5 
consecutive days. G-CSF will be administered by a subcutaneous daily injection. These doses 
will be administered before 10:00 a.m. each day in the Outpatient Department. The schedule of 
G-CSF administration and PBSC collections can only be ascertained once day 0 is identified. 
Once a treatment regimen schedule has been fixed and the schedule of G-CSF administration 
and PBSC collections made, this has to be confirmed with the personnel in the apheresis room. 
Day 0 should be fixed on a Tuesday-Thursday. 
 
PBSC collection 
Donors will preferably undergo vein-to-vein collections or may receive an appropriate catheter 
inserted on or before day of apheresis. PBSCs will be collected in the afternoon of day -1, 
stored in the refrigerator at 4ºC overnight. A second collection will be performed the following 
afternoon and both collections will be transfused on day 0. If < 5 x 106 CD34+ cells/kg are 
collected an additional day of collection will be performed. If PBSCs cannot be collected by a 
vein-to-vein technique, a percutaneous Mahurkar catheter will be inserted. General procedures 
will include the use of a standard apheresis machine (COBE Spectra, Lakewood Colo.), and 
processing up to 16 liters of whole blood during the collection. The plan for PBSC collection is 
shown in Table 6. 
 
Immunophenotyping of the G-PBMC product will be performed by the cryobiology laboratory and 
will include T-cells and their subsets, monocytes, and NK cells.   
 
 
Table 6. Treatment Schema for Related Donors  
Day 
-4 
-3 
-2 
-1 
0 
G-CSF 16 µg/kg/SQ 
X 
X 
X 
X 
X 
PBSC collection 
 
 
 
X 
X 
 
 
 
 


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URD 
 
G-CSF Administration to Donors 
Timing of PBSC collection is prearranged through the NMDP. Day 0 should be fixed on a Monday-
Thursday when possible.  G-CSF will be administered by subcutaneous injection to the unrelated donor 
starting 5 days prior to the day of HCT (see Table 7) as per NMDP protocol.  Donors will receive 
approximately 10g/kg of G-CSF each day of mobilization.  A 12-liter apheresis will be obtained on day 
–1 and possibly on day 0 for a total of 12 to 24 liters of apheresis collection that will be infused on day 0. 
 
Table 7.  Treatment Schema for Unrelated Donor 
 
Day 
-5 
-4 
-3 
-2 
-1 
0 
G-CSF (~10g/kg) 
X 
X 
X 
X 
X 
 
PBSC collection 
 
 
 
 
X 
X 
 
 
PBSC Collection   
HCT scheduling and collection is arranged through the NMDP.  The schedule of G-CSF administration 
and collection of PBSC is determined as per NMDP protocol.  The physician responsible for 
hematopoietic cell collection will obtain informed consent from the donor.  
 
 Immunophenotyping of the G-PBMC product will be performed by the cryobiology laboratory and will 
include T-cells and their subsets, monocytes, and NK cells.   
  
 Collection of DLI.   Donor lymphocytes will be collected from unrelated donor G-PBMC products prior 
to transplant for potential future use of DLI on other protocol or treatment plans. A portion of the PBSC 
product (10%) from unrelated donors will be frozen according to standard cryopreservation for DLI. 
Unrelated donor PBSC products will be frozen in an aliquot of 1.0 x 107 CD3+ cells/kg. 
 
MRD/URD  
 
      PBSC infusion 
All patients will receive unmodified PBSC infusion on day 0 of the treatment regimen (Refer to 
institutional practice guidelines for methods of infusion). 
 
 
 
H. ABO Incompatibility 
 All patients with ABO incompatibility should be evaluated and treated as according to the standard practice of 
the individual institution. Recommendations are provided in Appendix D.  It should be noted that two cases 
of recipient host red blood cell hemolysis have been documented in patients with minor ABO mismatch with 
their donor36.  The suspected cause is donor anti-host hemagglutinin production from “passenger 
lymphocytes” in the donor PBSC that may expand post-transplant.  Therefore, these patients should be 
monitored and treated aggressively when there is any evidence of hemolysis. 
 
I. Post-transplant Growth Factors 
 
Patients should in general not receive post-transplant growth factors during the first 21 days after HCT. 
Growth factors should not be given unless grade IV neutropenia develops or persists past day +21 post-
transplant (ANC <500/L). 
 
 


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J. Infection Prophylaxis 
 
Recommended prophylaxis for PCP, VZV, and HSV are listed in Appendix E with the modification that 
PCP, VZV, and antifungal prophylaxis should be continued if the patient is receiving treatment for chronic 
GVHD.  Since antifungal prophylaxis strategies are evolving, patients may receive antifungal prophylaxis as 
per the standard practice of the treatment institution.  Standard CMV monitoring and prophylaxis should 
commence at the time of transplant and should continue until discontinuation of immunosuppression.  
Patients who reject their graft can discontinue this infection prophylaxis. 
 
K. Modifications of Immunosuppression for Low Donor T-cell Chimerism (impending graft rejection) and 
Disease Progression 
 
This section provides guidelines for management of patients with low donor chimerism and disease 
progression.  Those patients with significant progression of disease as defined in Table 8 will undergo more 
rapid reduction of immunosuppression.  DLI will not be given for progressive or relapsed disease on this 
protocol, and patients with relapse or progression would be eligible for other ongoing DLI protocols or 
treatment plans.  Note that persistence of disease in itself does not mandate accelerated taper of 
immunosuppression.  
 
1. Definition of mixed donor/host chimerism, engraftment, graft failure and rejection. For the purposes 
of this protocol, mixed chimerism will be defined as the detection of donor T-cells (CD3+) and 
granulocytes (CD 33+), as a proportion of the total T-cell and granulocyte population, respectively, of 
greater than 5% and less than 95% in the peripheral blood.  Full donor chimerism is defined as > 95% 
donor CD3+ T-cells. Mixed or full donor chimerism will be evidence of donor engraftment.  Increasing 
donor chimerism is defined as an absolute increase of 20% of CD3+ donor T-cells over the previous 
chimerism evaluation. Low donor chimerism is defined as < 40% CD3+ donor T-cells any time after 
HCT.  Low donor chimerism should always be confirmed with repeat peripheral blood T-cell and NK cell 
chimerism analysis.  A DNA-based assay that compares the profile of amplified fragment length 
polymorphisms (ampFLP) (or FISH studies or VNTR) of the patient and donor will be used to quantitate 
chimerism of sorted peripheral blood T-cells (CD3+) and granulocytes (CD 33+). The same assay should 
be used in a given patient for repeated studies of chimerism.  This DNA-based analysis will also be 
performed on the whole nucleated cell fraction from marrow aspirates. Therapeutic decisions (e.g. 
pentostatin + DLI as per protocol 1825) will be made based on the results of sorted T-cell studies of 
peripheral blood. For the purposes of this protocol, rejection is defined as the inability to detect or loss of 
detection of greater than 5% donor T-cells (CD3+) as a proportion of the total T-cell population, 
respectively, after nonmyeloablative HCT.  Also for the purposes of this protocol, graft failure is defined 
as grade IV thrombocytopenia and neutropenia after day +21 that lasts > 2 weeks and is refractory to 
growth factor support.  
 
2. Evaluation of chimerism.  Patients will have peripheral blood and whole bone marrow evaluations for 
chimerism at various time points through one year post transplant. If the patient has not obtained > 95% 
donor chimerism in CD+3 by one year continue to evaluate through 5 years post transplant as clinically 
necessary. Peripheral blood will be sorted to evaluate T-cell (CD+3), and NK cell (CD56) compartments. 
(See Patient Post Transplant Evaluation section for instructions and exceptions).  
 
3. Continuation of immunosuppression.  In the setting of low (<40%) donor chimerism, 
immunosuppression should be continued or reinitiated at full dose so that DLI can be administered after 
pentostatin administration according to protocol 1825.  If there is disease progression in the setting of low 
donor chimerism, the algorithm for disease progression (below) should be followed.  Patients who reject 
their graft will not be offered DLI and may be eligible for a second allogeneic transplant on other 
protocols. 
 


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4. Disease progression.  Evidence of disease progression (as defined in Table 8) will be an indication for 
therapeutic intervention.  In part, this will be dependent on where a patient is relative to the standard 
tapering schedule.  If the attending physician believes that the patient requires very aggressive therapy, 
the case will be presented to the institutions’ patient review committee (such as patient conference care at 
the FHCRC). Otherwise, priority should be given to rapid reduction of immunosuppression, option (a) 
below.  Therapeutic options include:  
 
 
Table 8.  Definition of Disease Progression. 
 
Disease 
Progression 
MDS/ CMML 
 
Any evidence by morphologic or flow cytometric evaluation of the bone 
marrow aspirate of an incremental increase in 5% blasts 
 
Agnogenic 
Myeloid 
Metaplasia / 
Atypical CML  
 
 
 
Any evidence of blastic transformation.  
Polycythemia 
Vera and 
Essential 
Thrombocythemia 
 
 
Progressive erythrocytosis, thrombocytosis, or evidence of leukemic 
transformation. 
 
  
a. Early discontinuation of immunosuppression (prior to day +100).  This should be considered the first 
therapeutic maneuver.  If there is no GVHD, MMF is to be stopped, and CSP tapered over 2 weeks.  
Bone marrow aspirate and blood chimerism studies will be performed when off immunosuppression 
after 2 weeks.  If there is no response to stopping immunosuppression and there is no GVHD, patients 
will be considered disease treatment failure.  DLI as treatment for disease progression or relapse will 
not be offered on this protocol, however patients may treated according to other research protocols 
such as FHCRC protocol 1803. If there is progressive disease that requires therapy before 4 weeks, or 
progressive disease occurs despite onset of GVHD, then patients can be treated off protocol with DLI 
or be considered for (c) or (d) below.    
 
b. Early discontinuation of immunosuppression (between day +100 and +180).  If there is no GVHD, 
CSP is to be stopped. Bone marrow aspirate and blood chimerism studies will be performed when off 
immunosuppression after 2 weeks.  If there is no response to stopping immunosuppression, and there 
is no GVHD, patients will be considered as treatment failure. DLI will not be offered for disease 
progression or relapse on this protocol but patients can be treated off protocol with DLI or be 
considered for (c) or (d) below.   
 
c. Treatment with chemotherapy.  Conventional chemotherapy should be considered in the setting of life 
threatening disease progression.  Patients in this situation would be considered treatment failures. 
After therapy is completed chimerism should be evaluated and the administration of DLI off protocol 
considered. 
 


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d. Conventional allogeneic HCT.  This option should be discussed with the institutions’ patient review 
committee and the principal investigator.  Patients who undergo conventional allogeneic HCT will be 
removed from this protocol at that time. 
 
L. Immunophenotyping of PBSC Administration Guidelines 
 
Immunophenotyping of the PBSC product will be performed by the cryobiology laboratory and will include 
T-cells and their subsets, monocytes, and NK cells.  Unrelated donor PBSC products will be frozen in an 
aliquot of 1.0 x 107 CD3+ cells/kg (for use as DLI if needed).  Infusions of cryopreserved PBSC should be 
performed as per standard practice for outpatient PBSC. 
 
12.  Assessment of Disease Responses (see also Appendix H) 
 
12.1 General guidelines 
 
(A) Any assessment of response must include a bone marrow aspirate. Patients with myelofibrosis will also 
require a biopsy. 
(B) All bone marrow aspirates must also have cytogenetics analysis. For some patients, there may be 
additional disease-specific FISH or PCR-assessed molecular markers that can be used to determine response. 
(C) Regimen-related toxicity, for example due to drug adverse effect, severe infection, or GVHD must be 
excluded as causes of peripheral blood cytopenias. 
 
12.2 Definition of Response 
 
12.2.1 Definition of Response: MDS/CMML 
 (A) Complete Response 
 
Bone marrow rating: Normal maturation of all cell lines, without morphologic significant dysplasia 
and with< 5% myeloblast. 
 
Peripheral blood rating: no peripheral blasts and no dysplasia. 
 
(B) Complete Response with normal blood counts37  
 
Bone marrow rating: Normal maturation of all cell lines, without morphologic significant dysplasia 
and < 5% myeloblasts.  
 
Peripheral blood rating: Hb >11 g/dL, neutrophils >1500/mm3, platelets >100 000/mm3, blast 0%, no 
dysplasia. 
 
(C) Progressive Disease 
 
Any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of an 
incremental increase in 5% blasts (e.g. if a patient is accrued with 9% blasts, HCT failure would be 
>14% blasts). 
 
12.2.2 Definition of Response: Agnogenic Myeloid Metaplasia38 
 
 (A) Complete Response 
In patients with marrow fibrosis: 
 Achievement of >95% donor chimerism in the bone marrow, and:  
 evidence of regression of fibrosis as determined by sequential bone marrow biopsies (however 
residual fibrosis may be present). 
In patients with myelodysplastic features or with leukemic transformation: 
 achievement of >95% donor chimerism in the marrow, and: 
 regression of marrow fibrosis, and: 


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 absence of leukemic blasts, and:  
 disappearance of dysplastic changes. 
 
(B) Progressive Disease  
 
Any evidence of blastic transformation. 
 
12.2.3 Definition of Response: Atypical CML 
 
(A) Complete Response 
 
normal peripheral blood counts and leukocyte differential OR achievement of >95% donor chimerism 
in the bone marrow, and:  
 
resolution of pretreatment cytogenetic abnormality, and: 
 
Normal maturation of all cell lines, without morphologic significant dysplasia, and: 
 
< 5% myeloblasts. 
  
(B) Progressive Disease 
 
Any evidence of blastic transformation. 
 
12.2.4 Definition of Response: Polycythemia Vera and Essential Thrombocythemia 
 
(A) Complete Response  
 
Hematocrit < 45% in the absence of phlebotomy, normal platelet count (< 400,000/ml) or 
achievement of >95% donor chimerism in the bone marrow. 
 
(B) Progressive Disease  
 
Erythrocytosis, thrombocytosis, or evidence of leukemic transformation. 
 
12.2.5 Definition of Response: PNH 
 
(A) Complete Response  
 
Greater than 95% of the red blood cells not expressing the anchor proteins (documented by flow 
cytometry) in the absence of transfusions or achievement of >95% donor chimerism in the bone 
marrow. 
 
No clinical evidence of hemolysis related to PNH 
 
 
 
 
 
 
 


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13.  
Patient and donor Evaluations 
 
A. 
Donor 
 
Related Donor 
Related donors will undergo standard evaluation for allogeneic stem cell donation, including: 
1. 
Complete history and physical examination. 
2. 
Lab tests: CBC with reticulocytes and platelet counts, serum sodium, potassium, chloride, 
CO2, BUN, creatinine, uric acid, LDH, calcium, magnesium, phosphate, alkaline phosphatase, AST, 
ALT, hepatitis screen, CMV, syphilis, HIV and HTLV I serologies and ABO Rh blood typing. If the 
donor has antibodies against red cell antigens of the recipient, the titers will be determined. 
Cytotoxic crossmatch between patient and donor (HLA Laboratory) will be performed. 
3. 
CBC prior and after leukapheresis collection, plus daily while on G-CSF and if clinically indicated. 
4. 
A re-evaluation in the OPD after apheresis is completed. 
5. 
Attainment of a heparinized blood sample for subsequent determination of the host or donor origin 
of relapse to the cytogenetics lab or the clinical immunogenetics lab as outlined in section 13.B.1.e. 
6. 
For females of child bearing age, serum pregnancy qualitative [PGSTAT] within 72 hours prior to 
initial dose of filgrastim (G-CSF).  Results must be available prior to filgrastim (G-CSF) dose. 
 
Unrelated Donor  
Unrelated donors will undergo evaluation for allogeneic hematopoietic cell donation at the collection 
center by NMDP standard.  The attending physician of the collection center will review the results of the 
donor evaluation.  Evaluations typically include: 
1. Complete history and physical examination.  
2. Lab tests: CBC with reticulocytes and platelet counts, chemistries and LFT’s, hepatitis screen, 
CMV, syphilis, HIV and HTLV I serologies and ABO Rh blood typing. If the donor has antibodies 
against red cell antigens of the recipient, the titers will be determined. Cytotoxic crossmatch 
between patient and donor (HLA Laboratory) will be performed.  
3. No placement of a central line is necessary for G-CSF stimulated PBSC collection unless it is 
determined that the donor has poor venous access.  If necessary, a temporary apheresis (e.g. 
Mahurkar) catheter will be placed at the time of leukapheresis.  
4. CBC will be checked prior to and after leukapheresis collection, and daily while on G-CSF. CBCs 
will be checked thereafter if clinically indicated. 
5. The donor will be reevaluated the day after the apheresis is completed. 
 


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B.    Patient Evaluation 
 
1. Patient Pre-transplant Evaluation for All Diseases 
1. History:  Complete history with full details of the patient’s prior treatment and response. 
2. Careful physical exam with determination of Karnofsky Performance Score (Appendix B) or 
Lansky Play-Performance Score (Appendix C) and HCT-comorbidity index score (Appendix Q). 
3. Chest x-ray, P and lateral views. 
4. ECHO or MUGA for patients > 50 years of age, or history of cardiac disease or 
anthracycline exposure. 
5. Pulmonary function test with corrected DLCO.  
6. CBC/differential, creatinine, BUN, uric acid, SMA-12, total bilirubin, alkaline phosphatase, AST, 
ABO/Rh typing, hepatitis screen, CMV and toxoplasma serology, and anti-HIV serology.  
7. For CNS Disease:  Please refer to Appendix N for recommendations for intrathecal diagnostic 
evaluation and prophylaxis for specific malignant diseases. If patients undergo intrathecal 
diagnostic evaluation, cerebral fluid should be sent for cell count and differential, cytospin, 
cytology, total protein, and glucose. 
 
Additionally, see Table 9 for disease specific pre-transplant evaluations. 
 
 
Table 9: Disease-Specific Pre-Transplant Evaluations 
 
Note: All bone marrow aspirates and biopsies are unilateral and must be collected within 21 days of 
treatment. See Tables 10 and 11 for post-transplant evaluations and additional lab instructions. 
 
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate *see biopsy 
 
Pathology 
Clinical 
 
Flow Cytometry 
Clinical 
 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
 
Bone marrow biopsy 
 
Pathology 
Clinical 
 
Peripheral Blood 
 
Storage for chimerism analysis 
Clinical 
 
LDH 
Clinical 
 
 
Flow Cytometry for PNH Panel 
Clinical  
*Only PNH 


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2. Patient Post-transplant Evaluation  
 
1. See Table 10 for disease specific post-transplant evaluation on Day +28, 56, 84, etc. This is 
a recommended evaluation schedule. 
 
Additionally, include the following for all diseases: 
2. CBC three times a week, or more often if clinically indicated, from day 0 until day +28, and twice 
weekly until 2 months post-transplant or later if clinically indicated 
3. Electrolytes (sodium, potassium, chloride, CO2, glucose, BUN, creatinine, calcium, magnesium, 
phosphorus, albumin) three times a week and liver function tests (ALT, AST, ALK, total bilirubin, 
direct bilirubin, total protein, albumin, LD) two times a week until day +28 and then every week. 
4. Evaluate at Day +84: 
A patient with an uncomplicated unrelated HCT would be discharged after the day +84 
workup and screening for chronic GVHD are completed and analyzed.  Since the patient may 
be discharged prior to starting CSP taper, instructions should be provided for preventing and 
detecting GVHD as per standard practice of collaborating institution. 
 
GVHD evaluation guidelines are as follows: 
 
History and physical exam. 
 
CBC/differential, serum IgG, total bilirubin, alkaline phosphatase, ALT and AST. 
 
Skin biopsy. 
 
Schirmer´s tear test. 
 
Pulmonary function test. 
 
Oral exam. 
 
Dietician assessment. 
 
Gynecological assessment (adult female). 
 
See Section 14.F for diagnosis and treatment guidelines of acute and chronic GVHD. 
 
 
5. Patients should be assessed for the need of IVIG monitoring and replacement therapy per 
Institutional Guidelines 


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Table 10: Post-Transplant Evaluation 
This is a recommended evaluation schedule. See Table 9 for pre-transplant evaluations. Additional lab instructions in Table 11. 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
CMML 
 
BM aspirate *see biopsy 
                       ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow Cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for t(5:12) and other 
clonal abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
*For pts. with evidence or 
history of myelofibrosis 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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FHCRC Current Version  03/03/2016 
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Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
MDS 
(RAEB) 
BM aspirate *see biopsy 
                        ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow Cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for del (5q), del (7q), 
trisomy 8, 11q23 (MLL), del 
(13q) 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
*For pts. with evidence or 
history of myelofibrosis 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
MPD 
BM aspirate *see biopsy 
                          ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow Cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for t(5:12) and other 
clonal abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
*For pts. with evidence or 
history of myelofibrosis 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
PNH 
BM aspirate *see biopsy 
                          ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment      
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
 
Cytogenetics 
 
Clinical 
 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
FISH for clonal abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
BM biopsy 
 
 
 
 
 
 
 
 
 
 
Pathology 
Clinical 
*For pts. with evidence or 
history of myelofibrosis 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
Peripheral blood 
 
 
 
 
 
 
 
 
 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if 
<50% on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside 
institutions 
x 
 
 
 
 
 
 
 
Flow Cytometry for PNH Panel 
Clinical 
*If abnormal pre-transplant 
x 
x 
x 
x 
x 
x 
x 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 


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Table 11: Additional Lab Instructions 
Note: All bone marrow tests are done on aspirate unless specifically identified as biopsy. All instructions 
apply to both pre- and post-transplant evaluations unless identified otherwise. 
 
Off-site providers may use local facilities for the tests.  
 
Volumes represent desired amounts. 
 
Specimen / 
Test 
Type 
Instructions 
Lab Name 
Contact Information 
Bone marrow 
 
Chimerism  
Clinical 
1-3mL bone marrow in green-
top tube 
Clinical Immunogenetics 
Lab 
Seattle Cancer Care Alliance 
 (206) 288-7700 
Pathology 
(aspirate) 
Clinical 
2mL bone marrow in EDTA/ 
formalin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
(206) 288-1355 
Pathology (biopsy) 
Clinical 
1cm bone marrow in formalin 
OR mounted in paraffin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-1355 
Flow Cytometry 
Clinical 
2mL bone marrow in green-
top tube 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-7060 
Cytogenetics 
Clinical 
3mL bone marrow in green-
top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 288-1390 
FISH 
Clinical 
2mL bone marrow in green-
top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 288-1390 
Peripheral blood 
 
Chimerism  
(CD3+), (CD33+) 
NK(CD56+) 
Clinical 
10mL blood in green-top tube 
for Flow sorting, then to CIL 
UW Hematopathology Lab, 
routed to Clinical 
Immunogenetics Lab 
Mailstop G7-800 825 Eastlake 
Ave, East Seattle, WA 98109 
(206) 288-7060 
LDH 
Clinical 
3mL blood in red-top tube 
SCCA Alliance Lab 
Seattle Cancer Care Alliance 
(206) 288-2057 
 
Outside institutions may use VNTR analysis (sex- matched transplants) or sex chromosome FISH-
analysis (sex-mismatched transplants) for chimerism analysis. 
 
14. Drugs and Toxicities 
  
A. Toxicity:  For the purposes of this protocol, toxicity will be graded using the modified NCI 
common toxicity scale (Appendix P). 
 
B. TBI:  TBI will be given in one 300 cGy (or 400 cGy in level 2 and 450 cGy in level 3) fraction 
from linear accelerator at a rate of 6-7 cGy/min.  Dosimetry calculations are performed by the 
radiation therapist. At the 300 cGy, side effects are not expected.  Nevertheless, there may be fever, 
alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including 
cataract formation, growth retardation, pulmonary damage, carcinogenesis, and sterilization. Those 
side effects might be more frequently seen in patients given 400 cGy or 450 cGy. 
 
C. CSP:  See section 11.F.a for information about administration and dosage adjustments. Side effects 
are generally reversible and may include renal insufficiency and failure, hypomagnesemia, 
paresthesias, tremor, seizures, visual disturbances, paresis, disorientation, depression, confusion, 
somnolence, coma, nausea, hypertension, hemolytic-uremic syndrome, hyperglycemia, 
gynecomastia, and hypertrichosis. 
 
D. MMF:  See section 11.F.b for information about administration and dosage adjustments. 
 
Precautions:  MMF has been studied extensively among patients after nonmyeloablative HCT. 
Previous clinical studies in patients after allografting suggest that the principal adverse reactions 


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associated with the administration of MMF include nausea, vomiting, neutropenia, diarrhea, and on 
one occasion bloody diarrhea. In the setting of marrow transplantation, several etiologic factors 
may contribute to alterations in gastrointestinal and hematologic parameters.  MMF has an 
increased incidence of digestive system adverse events, including GI tract ulceration, and 
hemorrhage (3% of patients receiving MMF). GI tract perforations have rarely been observed. 
Most patients in these studies were also on other drugs known to be associated with these 
complications. Up to 2% of patients receiving MMF for prevention of rejection developed severe 
neutropenia (ANC <500). The development of neutropenia may be related to MMF itself, 
concomitant medications, viral infections or some combination of these causes. MMF dose 
adjustments will be made if clinically indicated if in the opinion of the attending physician, no 
other cause is thought to be responsible for the abnormality.  These adjustments should be 
discussed with the principal investigator and documented in the medical records and the clinical 
reporting form (CRF).  
 
E. Fludarabine:  The doses of fludarabine used in this protocol are nonmyeloablative, but do cause 
significant immunosuppression.  Fludarabine can lower the white blood cell count, in particular the 
CD4+ T-cells.  The immunosuppression observed with the use of fludarabine increases the risk of 
infection, which can be life threatening. 
 
F. GVHD:  After nonmyeloablative conditioning, the incidences of grades II, III and IV acute GVHD 
were 33%, 10% and 5%, respectively, in MRD recipients, and 42%, 9% and 3%, respectively, in 
URD recipients (Table 1). Acute GVHD has been readily controlled in most patients with high 
dose corticosteroids, but PUVA (psoralen activated ultraviolet light) has been required on occasion.  
Chronic extensive GVHD has occurred in 43% and 45% of MRD and URD recipients, 
respectively. 
 
 
1. Diagnosis:  Skin involvement will be assessed by biopsy with percentage of body surface area 
involved recorded. GI symptoms suspicious for GVHD will be evaluated by biopsy as 
indicated.  Acute GVHD and chronic GVHD will be graded according to established criteria 
(Appendix F and G). 
 
2. Recommended Treatment: 
a. Patients developing acute GVHD > grade II off immunosuppression or while on a 
CSP taper: 
1). CSP 5mg/kg PO q12hrs.  If there is concern of GI absorption use IV route 
(1.5mg/kg q12hrs). 
2). Prednisone (2mg/kg/day) is to be added if there is no response by 72 hours or 
progression of GVHD during the 24 hours after the start of CSP 6.0mg/kg 
POq12hrs.  Patients who respond to steroids after 10 to 14 days of treatment, 
should begin a 6-week steroid taper. 
3). Patients may also be eligible for institutional trials of GVHD therapy. 
b. Patients who develop acute GVHD > grade II prior to day +100: 
1). Patients who develop acute GVHD > grade II while on full dose MMF should 
receive prednisone (2mg/kg/day) or intravenous equivalent.  When steroids are 
tapered to 0.5mg/kg PO QD then an MMF taper should be initiated.  In the 
absence of a GVHD flare, the MMF and prednisone tapers should continue until 
completion.  If nausea and/or vomiting prevent the oral administration of MMF, 
MMF should be administered intravenously at 15mg/kg q12hrs IV, or q8hrs if 
prior to Day + 28. Patients who respond to steroids after 10 to 14 days of 
treatment, should begin a 6-week steroid taper. 


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2). Patients who develop acute GVHD > grade II while not receiving full dose 
MMF should receive prednisone (2mg/kg/day) or intravenous equivalent. MMF 
need not be restarted at full dose. 
3). Patients may also be eligible for institutional trials of GVHD therapy. 
c. Patients with clinical extensive chronic GVHD: CSP 5.0mg/kg PO q12hrs and 
prednisone 1mg/kg QD or eligible protocols at the time.  The patient should receive 
antibiotic prophylaxis with daily double strength Bactrim.  
d. Patients off immunosuppression who develop concurrent manifestations of GVHD 
that satisfy criteria for acute GVHD > grade II (e.g. erythematous rash, diarrhea, 
hyperbilirubinemia) and have stigmates of clinical extensive chronic GVHD (e.g. 
lichenoid oral changes, ocular sicca, scleroderma, bronchiolitis obliterans, 
contractures), should receive prolonged immunosuppressive therapy similar to that 
for clinical extensive chronic GVHD. 
 
G. Myelosuppression 
Grade IV myelosuppression will be defined as a decrease in ANC to <500/µL and/or platelet count 
to  20,000/µL.  If myelosuppression occurs, a bone marrow aspirate and biopsy should be 
performed to exclude disease progression. Samples should be sent for chimerism analysis by a 
DNA-based assay that compares the profile of amplified fragment length polymorphisms 
(ampFLP) (or FISH studies or VNTR). Myelosuppression may occur in this patient population 
for a number of reasons such as direct toxic effect of drugs (MMF, ganciclovir etc.), rejection, 
relapse or after DLI.  
 
Patients with myelosuppression may be managed as follows:  
1. Suspected MMF toxicity:  refer to sections 11.F.b.4 Guidelines for MMF dose adjustment 
above for management recommendations.  
2. Suspected ganciclovir toxicity:  consider changing to foscarnet.  
3. Patients who are > 21 days after HCT with a hypoplastic marrow and an ANC of <750/µL may 
receive G-CSF. 
4. Thrombocytopenic patients will receive platelet transfusion as per standard care. 
 
15. Records 
Clinical records will be maintained as confidentially as possible by all collaborating institutions. 
Collection of Case Report Forms (CRF) at standard intervals is the primary method of collecting data 
from collaborating centers.  Clinical Statistics at FHCRC maintains a patient database to allow storage 
and retrieval of patient data collected from a wide variety of sources.  The principal investigator will 
ensure that data collected conform to all established guidelines for coding collection, key entry and 
verification.  These data are then entered into a secure dedicated database operated by a data manager.  
Any publication or presentation will refer to patients by a unique patient number and not by name to 
assure patient confidentiality.  The licensed medical records department, affiliated with the institution 
where the patient receives medical care, maintains all original inpatient and outpatient chart documents. 
 
At the FHCRC, patient research files are kept in a locked room.  They are maintained by the FHCRC 
data collection staff that is supervised by an A.R.T. Access is restricted to personnel authorized by the 
Division of Clinical Research. 
 
 
 
 
 
 
 


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16. Statistical Consideration and Termination of Study 
 
The primary objective of this protocol is to evaluate whether a more intense but still nonmyeloablative 
conditioning regimen can reduce the combined rate of graft rejection and disease progression (HCT failure) 
in this group of MDS and CMML patients, while maintaining an acceptable rate of nonrelapse mortality.  
Previous protocols with standard nonmyeloablative conditioning regimens have yielded HCT failure rates 
of 0.30-0.60.  For purposes of this protocol HCT failure will be defined as graft rejection (defined as < 5% 
donor T-cell chimerism) or disease progression (see table 8 page 25) within 200 days of transplant.  
 
Dose escalation will be carried out independently in two groups of patients: 
Arm A – patients with MPD, MDS-RA/RARS, or PNH 
Arm B – patients with MDS-RAEB or CMML 
 
In each arm, up to 24 patients will be accrued to each TBI dose level, in groups of 6 patients, with an 
escalation rule triggered for excessive HCT failure.  If 24 patients are successfully enrolled at a TBI dose 
level without triggering the escalation rule for HCT failure (or other stopping rule), then that dose level will 
be considered a success and accrual will be closed for that arm.  The proposed TBI dose levels are: 
 
Dose Level 1) 300 cGy TBI + fludarabine 30/m2/day IV x 3 days 
Dose Level 2) 400 cGy TBI + fludarabine 30/m2/day IV x 3 days 
Dose Level 3) 450 cGy TBI + fludarabine 30/m2/day IV x 3 days 
 
Dose escalation rules will be imposed for: 
 
HCT failure >20% at day 200 on Arm A or Arm B 
 
Stopping rules will be imposed for: 
 
NRM of > 25% at day 200 on Arm A 
 
NRM of > 35% at day 200 on Arm B 
 
Enrollment to a dose level will occur in groups of 6 patients.  Escalation to the next dose level will occur if 
there exists reasonable evidence that the true rate of HCT failure exceeds 0.20.  Reasonable evidence will 
be taken to mean that the lower bound of a one-sided 80% confidence interval for the true rate is greater 
than 0.20.  Operationally, this rule will be triggered if 3 or more of 6, 5 or more of 12, 6 or more of 18, or 7 
or more of 24 patients experience HCT failure.  Accrual may continue pending evaluability of enrolled 
patients; however, at any point the escalation rule is triggered the outcome of subsequently enrolled 
patients will not override it.  The operating characteristics of this escalation rule are provided in the table 
below. 
 
Stopping rules will also be applied in each arm for non-relapse mortality within 200 days of transplant.  
Accrual to a dose level will stop if there exist reasonable evidence that the true rate of nonrelapse mortality 
exceeds 0.25.  Reasonable evidence will be taken to mean that the lower bound of a one-sided 80% 
confidence interval for the true rate is greater than 0.25.  Operationally, this rule will be triggered if 3 or 
more of 6, 5 or more of 12, 7 or more of 18, or 9 or more of 24 patients experience NRM.  Accrual may 
continue pending evaluability of enrolled patients; however, at any point the stopping rule is triggered the 
outcome of subsequently enrolled patients will not override it.  If the stopping rule is triggered, then dose 
escalation is not permitted and consequently accrual to that arm of the protocol will be closed. The 
operating characteristics of this escalation rule are provided in the table below. 
 
 


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True rate of 
HCT failure 
Probability 
of escalation* 
True rate of 
nonrelapse 
mortality 
Probability of 
stopping* 
0.25 
47% 
0.30 
46% 
0.30 
67% 
0.35 
64% 
0.35 
82% 
0.40 
79% 
0.40 
92% 
0.45 
90% 
 
*based on 10,000 Monte Carlo simulations 
 
Additional accrual to Arm A 
If ARM A completes accrual of 24 patients at a dose level, up to 12 additional patients may be accrued at 
the same dose level while accrual to Arm B continues.  Stopping rules for non-relapse mortality will 
continue to be monitored.  Additional stopping points will be 10 NRM deaths in 30 or fewer patients and 
12 NRM deaths in 36 or fewer patients.  
 
 
Revised stopping rule for Arm B 
The initial cohort of 6 patients enrolled into Arm B experienced 3 non-relapse deaths before day 200, 
triggering the original stopping rule.  Of the 5 patients evaluable for disease response (one patient died day 
19 from Human metapneumovirus and, thus, was not evaluable), all 5 engrafted with day 28 CD3 
chimerism ranging from 64-89% and 4 of 5 patients achieved a complete remission.  After reviewing recent 
data with similar patient populations (26 patients with CMML/RAEB), it was determined that the original 
threshold rate of 0.25 for non-relapse mortality was too conservative.  Although a rate of 0.25 accurately 
reflects the observed NRM in these patients, it does not accommodate the increase in NRM that might 
occur if better engraftment and disease control is successfully achieved, thus placing more patients at risk 
for NRM.  Specifically, 17 patients (65%) relapsed or progressed 108 (28-1585) days after HCT, while 5 
(19%) rejected their grafts 80 (14-127) days after HCT. All patients with graft rejection eventually 
progressed. Consequently, accrual to Arm B will be restarted with a revised stopping rule based on a 
threshold rate of 0.35 for non-relapse mortality.  The outcome of the initial 6 patients enrolled at the first 
dose level in Arm B will carry forward and be included in the evaluation of the stopping rule after 
restarting.  Escalation and stopping rules for Arm A are unchanged. 
 
The revised stopping rule for Arm B will be triggered if 4 or more of 6, 7 or more of 12, 9 or more of 18, or 
11 or more of 24 patients experience NRM before day 200.  The operating characteristics of this stopping 
rule are provided in the table below. 
 
True rate of 
HCT failure 
Probability 
of escalation* 
True rate of 
nonrelapse 
mortality 
Probability of 
stopping* 
0.25 
47% 
0.40 
43% (50%)  
0.30 
67% 
0.45 
63% (66%) 
0.35 
82% 
0.50 
77% (80%) 
0.40 
92% 
0.55 
90% (90%) 
* based on 10,000 Monte Carlo simulations. The percent in parentheses is the conditional probability of 
stopping in the restarted Arm B, given that 3 of 6 patients already have experienced NRM by day 200.  The 
other percent applies if the stopping rule is applied to a higher dose level within Arm B. 
 
If a cohort of 24 patients is completed without excessive HCT failure, then no more than 6 HCT failures 
will have occurred.  Nominally this would mean that we could be 80% confident that the true rate of HCT 


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failure was less than 35%; however, because of the continuous monitoring and escalation rule for HCT 
failure, the final estimated failure rate will be an underestimate of the true failure rate. 
 
Secondary endpoints to be evaluated will include: 
 
the rate of relapse/progression in patients with MPD or MDS-RA and those with CMML or 
MDS-RAEB. 
 
the probability of PFS in patients with MPD or MDS-RA and those with CMML or MDS-
RAEB. 
 
the kinetics of donor engraftment. 
 
the incidence of infections. 
 
17. Data and Safety Monitoring Plan  
 
A. FHCRC Protocol 2056 Data and Safety Monitoring Plan 
1. Monitoring the progress of trials and the safety of participants 
Protocol 2056 is a multi-institutional clinical trial that is monitored by the principal 
investigator (PI), Dr. Sandmaier, a Data Safety and Monitoring Board (DSMB), the Data and 
Safety Monitoring Committee (DSMC) and the Institutional Review Board (IRB).  The PI 
reviews outcome data with the protocol mentor for each individual patient at a minimum of 3 
months after unrelated donor HCT and the updated data are presented at Mixed Chimerism 
Meetings (includes co-investigators).  
 
Please see Appendix I for definitions of adverse events, serious adverse events (SAE) and 
serious and unexpected events as well as mechanisms for reporting these events. SAEs are 
reported to the trial coordinator.  The trial coordinators at collaborating centers or the local PIs 
will report SAEs within 10 days to the coordinating center (FHCRC). The SAEs report is 
reviewed by Dr. Sandmaier.  If the SAE meets the FHCRC expedited criteria for reporting then 
an official signed report is submitted to the FHCRC Institutional Review Office (IRO).  All 
deaths, regardless of the cause, are reported to the IRB. Protocol 2056 has a dedicated 
independent DSMB responsible for monitoring patient safety on this clinical trial.  The DSMB 
will meet at six-month intervals for this protocol and all outcome data is reviewed including all 
adverse events and SAEs reported to the coordinating center (FHCRC) along with those 
officially reported to the FHCRC IRO.  The DSMB confirms whether the trial has met any 
stopping rules and reviews any patient safety problems necessitating discontinuation of the 
trial.  A report from the DSMB is submitted to the FHCRC IRB as well as the trial 
coordinators/local PIs of this protocol.  The DSMB will discontinue the review of outcomes 
when this protocol is closed to accrual. Furthermore, the FHCRC also has a DSMC that 
reviews the progress of the protocol with respect to the monitoring plan at the time of each 
annual renewal.  As with initial review, annual IRB review and approval is also required.  
  
Flow of information concerning clinical trial participants originates with the clinicians and 
nurses in the clinic or referring clinicians at other institutions and is transmitted to the trial 
coordinator and data manager.  At the FHCRC, health care providers and rotating attending 
physicians assess patients and record their observations regarding toxicity and response 
outcomes in the medical record.  This documentation is extracted by the study nurse at 100 
days after HCT via chart review and collection of copies of source documents and entered into 
a hard copy or electronic Case Report Form (CRF) by approximately day +140 post transplant.  
The PI reviews the official CRF and primary source documents.  When the CRFs are verified, 
they are signed by the PI.  Thus, multiple health care providers provide independent 
observations and participate in monitoring this trial. The PI may be a clinician for some 
patients entered on this trial.  However, assessments are the sum total of the primary health 
care provider (fellow or physician assistant), floor or outpatient nurse and the PI or other 


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attending clinician involved with the patient averting possible conflict of interest having the PI 
as the attending clinician for protocol patients.  If determination of adverse events is 
controversial, co-investigators will convene on an ad hoc basis as necessary to review the 
primary data and render a decision.  
 
Protocol 2056 will be a multi-institutional protocol. All collaborating centers sign an 
agreement with the FHCRC stating that data generated from patients from the protocol will be 
reported accurately in a timely manner to the FHCRC.  All centers have an IRB that reviews 
the protocol and that the local PIs contact when an adverse event on the protocol occurs.  Most 
of the centers have internal auditing mechanisms that assure accurate assessment of clinical 
outcomes.  Clinical outcome data are summarized and transmitted from collaborating centers 
as CRFs.  When possible, primary source documents regarding patient outcomes are collected 
with patients’ names removed and replaced by Unique Patient Numbers (UPNs).  The CRFs 
are generated from the collaborating centers at defined time points (100 days, 6 months, and 
yearly).  They are reviewed by local PI, signed, and sent for encoding in the database.  
 
 
2. Plans for assuring compliance with requirements regarding the reporting of Serious Adverse 
Events SAEs 
The adverse event reporting in this multi-institutional clinical trial will follow an adapted 
version of the FHCRC Guidelines for SAE reporting.  These guidelines (attached in Appendix 
I.) detail the expedited reporting requirements, definitions of particular events.  All SAEs that 
meet expedited criteria are reported to the IRO within 10 days by the investigator, trial 
coordinator, or research nurse upon learning of the event.  A completed SAE report form, 
signed by the PI, must be received by the IRO within 10 calendar days.  The PI’s protocol 
mentor reviews all SAEs and annual reports at the time of submission.  For patients being 
cared for at the FHCRC, health care providers communicate with the PI, trial coordinator or 
research nurses as events occur triggering subsequent reporting.  For patients not being cared 
for at FHCRC the outside facilities communicate with the PI, trial coordinator, or research 
nurse for these reporting purposes.  All other deaths and expected serious adverse events are 
reported to the IRB at the time of annual renewal and at the biannual mixed chimerism 
meeting.  The PI for a study is responsible for this reporting and the IRO assures adverse event 
reporting on an annual basis.  The PI in the annual application for grant continuation will 
summarize reports of toxicities.  Furthermore, an additional safeguard for adverse event 
analysis and reporting in this protocol is provided by stopping rules and interim analysis after 
every 10th patient is enrolled. All collaborating PIs have fulfilled all NIH requirements for 
training in human subjects protection. 
                               
3.  Plans for assuring that any action resulting in a temporary or permanent suspension of an NCI-
funded clinical trial is reported to the NCI grant program director responsible for the grant 
This clinical research trial uses commercial agents and there is no associated Investigational 
New Drug (IND) or Investigational Device Exemption (IDE).  Any temporary or permanent 
suspension, as determined by the PI, IRB, or DSMC, of this clinical research trial will be 
reported to the NCI grant program director by the PI.  
 
 


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4.  Plans for assuring data accuracy and protocol compliance 
Collaborating sites send signed consents, eligibility forms, and CRFs with source 
documents demonstrating eligibility, treatment, and serious adverse events (if applicable) 
to the study staff. These are reviewed for eligibility, adherence to the protocol, accuracy, 
and completeness by the study staff. Queries are sent to the collaborating investigators if 
CRFs are inaccurate or incomplete.  
 
The study is monitored under the FHCRC Monitoring Plan. The FHCRC Data and 
Safety Monitoring Plan details the full scope and extent of monitoring and provides for 
immediate action in the event of the discovery of major deviations.  
 
 
18. Targeted / Planned Enrollment 
 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects 
Ethnic Category 
Sex / Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
58 
82 
140 
Ethnic Category Total of All Subjects* 
60 
84 
144 
Racial Categories 
American Indian / Alaska Native 
2 
2 
4 
Asian 
2 
2 
4 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
2 
4 
6 
White 
54 
76 
130 
Racial Categories:  Total of All Subjects* 
60 
84 
144 
*The “Ethnic Category Total of All Subjects” must be equal to the “Racial Categories Total of All Subjects.” 


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Reference List 
 
 
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complete chimerism and sustained remissions in patients with hematological diseases. Blood. 
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(4)  Maris MB, Niederwieser D, Sandmaier BM et al. HLA-matched unrelated donor hematopoietic cell 
transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 
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(5)  Sandmaier BM, Maris M, Maloney DG et al. Low-dose total body irradiation (TBI) conditioning for 
hematopoietic cell transplants (HCT) from HLA-matched related (MRD) and unrelated (URD) donors for 
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#264. 
 
(6)  Baron F, Maris MB, Sandmaier BM et al. Graft-versus-tumor effects after allogeneic hematopoietic cell 
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(7)  Scott BL, Maris M, Sandmaier B et al. Myeloablative versus nonmyeloablative hemopoietic cell 
transplantation (HCT) for patients with myelodysplasia (MDS) or AML with multinlineage dysplasia 
following MDS (tAML) [abstract]. Blood. 2004;104 (Part 1):638a, #2320. 
 
(8)  Storb R, Yu C, Wagner JL et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs 
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transplantation. Blood. 1997;89:3048-3054. 
 
(9)  Sandmaier BM, Storb R. Nonmyeloablative therapy and hematopoietic cell transplantation for hematologic 
disorders. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas' Hematopoietic Cell Transplantation. 
Oxford, UK: Blackwell Publishing Ltd.; 2004:1164-1176. 
 (10)  Burroughs L, Leisenring W, Maloney DG et al. Extending postgrafting cyclosporine does not decrease the 
risk of graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation [abstract]. Blood. 
2003;102 (Part 1):242a-243a, #852. 
 (11)  Baron F, Maris MB, Storer BE et al. High doses of transplanted CD34+ cells are associated with rapid T-cell 
engraftment and lessened risk of graft rejection, but not more graft-versus-host disease after 
nonmyeloablative conditioning and unrelated hematopoietic cell transplantation. Leukemia. 2005;19:822-
828. 
 (12)  Maris MB, Sandmaier BM, Storer B et al. Unrelated donor peripheral blood stem cell (PBSC) transplantation 
using nonmyeloablative conditioning and mycophenolate mofetil (MMF) TID results in high engraftment 
rates [abstract]. Blood. 2004;104 (Part 1):503a, #1818. 
 (13)  Mielcarek M, Martin PJ, Leisenring W et al. Graft-versus-host disease after nonmyeloablative versus 
conventional hematopoietic stem cell transplantation. Blood. 2003;102:756-762. 


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 (14)  Sorror ML, Maris MB, Storer B et al. Comparing morbidity and mortality of HLA-matched unrelated donor 
hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of 
pretransplant comorbidities. Blood. 2004;104:961-968. 
 (15)  Diaconescu R, Flowers CR, Storer B et al. Morbidity and mortality with nonmyeloablative compared to 
myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. 
Blood. 2004;104:1550-1558. 
 (16)  Ho AYL, Pagliuca A, Kenyon M et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation 
for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, 
busulphan and alemtuzumab (FBC) conditioning. Blood. 2004;104:1616-1623. 
 (17)  Bornhauser M, Storer B, Slattery JT et al. Conditioning with fludarabine and targeted busulfan before 
transplantation of allogeneic hematopoietic stem cells [abstract]. Blood. 2002;100 (Part 1):213a, #799. 
 (18)  Kroger N, Bornhauser M, Ehninger G et al. Allogeneic stem cell transplantation after a fludarabine/busulfan-
based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid 
leukemia. Ann Hematol. 2003;82:336-342. 
 (19)  de Lima M, Anagnostopoulos A, Munsell M et al. Nonablative versus reduced-intensity conditioning 
regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is 
relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 
2004;104:865-872. 
 (20)  Appelbaum FR. Dose intensity and the toxicity and efficacy of allogeneic hematopoietic cell transplantation 
(Keynote Address). Leukemia. 2005;19:171-175. 
 (21)  Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with acute 
myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood. 1990;76:1867-
1871. 
 (22)  Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with chronic 
myeloid leukemia in the chronic phase:  A randomized trial of two irradiation regimens. Blood. 
1991;77:1660-1665. 
 (23)  Storb R, Raff RF, Appelbaum FR et al. What radiation dose for DLA-identical canine marrow grafts? Blood. 
1988;72:1300-1304. 
 (24)  Yu C, Storb R, Mathey B et al. DLA-identical bone marrow grafts after low-dose total body irradiation: 
Effects of high-dose corticosteroids and cyclosporine on engraftment. Blood. 1995;86:4376-4381. 
 (25)  Storb R, Yu C, Wagner JL et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs 
given sublethal total body irradiation before and pharmacological immunosuppression after marrow 
transplantation. Blood. 1997;89:3048-3054. 
 (26)  Hogan WJ, Little M-T, Zellmer E et al. Postgrafting immunosuppression with sirolimus and cyclosporine 
facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before 
marrow transplantation from DLA-identical littermates. Biol Blood Marrow Transplant. 2003;9:489-495. 
 (27)  Storb R, Raff RF, Appelbaum FR et al. DLA-identical bone marrow grafts after low-dose total body 
irradiation: the effect of canine recombinant hematopoietic growth factors. Blood. 1994;84:3558-3566. 
 (28)  Girgis M, Hallemeier C, Blum W et al. Chimerism and clinical outcomes of 110 unrelated donor bone 
marrow transplants who underwent conditioning with low-dose, single-exposure total body irradiation and 
cyclophosphamide. Blood. 2005;105:3035-3041. 


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 (29)  Rowley MJ, Leach DR, Warner GA, Heller CG. Effect of graded doses of ionizing radiation on the human 
testis. Radiat Res. 1974;59:665-678. 
 (30)  Sanders JE. Growth and development after hematopoietic cell transplantation. In: Blume KG, Forman SJ, 
Appelbaum FR, eds. Thomas' Hematopoietic Cell Transplantation. Oxford, UK: Blackwell Publishing Ltd.; 
2004:929-943. 
 
(31).  Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in 
longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383.  
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(32).  Diaconescu R, Flowers CR, Storer B, et al. Morbidity and mortality with nonmyeloablative compared to 
myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. 
Blood. 2004;104:1550-1558.  
Reference ID: 24498 
(33).  Sorror ML, Maris MB, Storer B, et al. Comparing morbidity and mortality of HLA-matched unrelated donor 
hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of 
pretransplant comorbidities. Blood. 2004;104:961-968.  
Reference ID: 24482 
(34)    Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation-specific comorbidity index: a new 
tool for risk assessment before allogeneic HCT. Blood. 9999;prepublished online June 30, 2005; DOI 
10.1182/blood-2005-05-2004-  
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 (35)  Baron F, Baker JE, Storb R et al. Kinetics of engraftment in patients with hematologic malignancies given 
allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood. 2004;104:2254-
2262. 
 (36)  Salmon JP, Michaux S, Hermanne JP et al. Delayed massive immune hemolysis mediated by minor ABO 
incompatibility after allogeneic peripheral blood progenitor cell transplantation. Transfusion. 1999;39:824-
827. 
 (37)  Cheson BD, Bennett JM, Kantarjian H et al. Report of an international working group to standardize 
response criteria for myelodysplastic syndromes. Blood. 2000;96:3671-3674. 
 (38)  Deeg HJ, Gooley TA, Flowers MED et al. Allogeneic hematopoietic stem cell transplantation for 
myelofibrosis. Blood. 2003;102:3912-3918. 
 
    (39)  Panse JP, Heimfeld S, Guthrie KA, et al. Allogeneic peripheral blood stem cell graft composition  affects 
early T-cell chimaerism and later clinical outcomes after nonmyeloablative conditioning.  
Br J Haematol. 
2005;128:659-667. 
 
   (40)  Cao TM, Shizuru JA, Wong RM, et al. Engraftment and survival following reduced-intensity  
allogeneic 
peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose.  Blood. 2005;105:2300-
2306. 
 
   (41)  Baron F, Maris MB, Storer BE, et al. High doses of transplanted CD34+ cells are associated with  rapid T-
cell engraftment and lessened risk of graft rejection, but not more graft-versus-host disease  
after 
nonmyeloablative conditioning and unrelated hematopoietic cell transplantation. Leukemia.  2005;19:822-828. 
 
 
 


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APPENDICES - Table of Contents 
 
Appendix A 
Eligibility Guidelines for Donor PBSC Apheresis for Transfusion 
Appendix B 
Karnofsky Performance Status Scale 
Appendix C 
Lansky Play-Performance Scale 
Appendix D 
ABO Incompatibility 
Appendix E 
Infectious Disease Guidelines 
Appendix F 
Acute Graft-Versus-Host Disease Grading 
Appendix G 
Chronic Graft-Versus-Host Disease Grading 
Appendix H 
Evaluation of Disease Response 
Appendix I 
Study Coordinator Manual (includes procedures for reporting adverse events) 
Appendix J 
Adverse Event Report 
Appendix K 
Notice of Death Form 
Appendix L 
Patient Demographics and Eligibility Form 
Appendix M 
Core Case Report Forms 
Appendix N 
Intrathecal Therapy Administration 
Appendix O 
HLA Matching Requirements For Unrelated Donors  
 
Appendix P 
Adapted Common Toxicity Criteria 
Appendix Q 
Hematopoietic Cell Transplant-Comorbidity Index 
Appendix R 
WHO classification and IPSS score 
Appendix S 
Weight / Adjusted Body Weight for Drug Dosing 
Appendix T 
Radiotherapy Treatment Plan 
Appendix U 
Coordinating Center Functions  
 
 
 
 


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Appendix A 
ELIGIBILITY GUIDELINES  
FOR DONOR PBSC APHERESIS FOR TRANSFUSION 
 
  
 
Immunization 
Donor Eligibility 
Cholera 
No wait 
Diphtheria 
No wait 
Flu 
24 hour wait 
Gamma globulin  
(Immune serum globulin) 
No wait unless for hepatitis 
Hepatitis B vaccine 
No wait unless given for hepatitis exposure 
Measles (Rubella) 
1 month wait 
Mumps 
2 week wait 
Polio – Sabin (inj) 
No wait 
Plague 
No wait 
Rabies 
1 year wait if given as treatment for bite.  2 week wait if 
given as prophylaxis (DMV’s or zoo workers) 
Smallpox 
2 week wait 
Tetanus toxoid 
No wait 
Typhoid 
No wait 
Typhus 
No wait 
Yellow Fever 
2 week wait 


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


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Appendix C 
LANSKY PLAY-PERFORMANCE SCALE 
(for use with persons ages 1-6 years) 
 
Score (%) 
Description 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both, greater restrictions of, and less time spend in play activities 
60 
Up and around, but minimal active play, keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play; able to participate in 
all quiet play activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
Unresponsive 
0 
Dead 
 


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Appendix D 
ABO INCOMPATIBILITY 
 
Red Blood Cell - Incompatibility (Major): 
Occasional patients may have antibodies directed against red blood cell antigens found on the donor's cells.  
These are generally ABO or Rh antigens, although incompatibility with other red cell antigens identified by 
donor-recipient crossmatch may occur.  Although the volume of red blood cells (RBC) in most PBMC 
products will only be 2-5% of the product volume before infusion, the small quantity may cause a 
hemolytic transfusion reaction.  According to the FHCRC policy it is generally acceptable to infuse a 
volume of about 10ml RBCs per product. If the recipient shows an anti-donor titer of  1:32 or the RBC 
volume is greater than 10ml (or >20ml in two products combined) the PBMC components should be RBC 
depleted by Starch Sedimentation (flowsheet below). Refer to the Clinical Coordinator's Patient 
Information Sheet for instructions regarding management of a specific patient. 
 
Post transplant blood component support will be according to Standard Practice Guidelines. 
 
Timing: Every attempt should be made to infuse red cell depleted PBMC products within 2 hours of 
depletion. 
 
Expected Results:  Red blood cell depleted PBMC products will contain < 10ml of red blood cells and  
90% nucleated cell recovery. 
 
Red Blood Cell - Incompatibility (Minor):  Occasional donors may have antibodies directed against red 
blood cell antigens (ABO, Rh, or other antigen system) found on the recipient's cells. The risk of hemolysis 
of recipient red cells immediately after transplant is not of very much clinical import. Due to the high 
number of lymphocytes in the PBMC inoculum, recipients may be at much greater risk for a delayed type 
of hemolysis that can be severe. PBMC products contain < 200ml of plasma according to FHCRC policy 
and no deleterious effects have been observed so far. However, if donors show an anti-recipient titer  
1:256, the PBMC component should be plasma depleted (see flowsheet below). Refer to the Clinical 
Coordinator's Patient Information Sheet for instructions regarding management of a specific patient. 
 
Post transplant blood component support will be according to Standard Practice Guidelines. 
 
Timing:  Every attempt should be made to infuse plasma-depleted PBMC within 2 hours of depletion. 
 
Expected Results:  The plasma depletion should not affect the nucleated cell recovery. 
 
Red Blood Cell – Bidirectional Incompatibility:  Patients undergoing transplants for bidirectional RBC 
incompatibility should be managed according to both algorithms shown below. Most red cell depletion 
techniques also deplete plasma from the PBMC component with no additional cell loss. Refer to the 
Clinical Coordinator's Patient Information Sheet for instructions regarding management of a specific 
patient. 
 
Post transplant blood component support will be according to Standard Practice Guidelines. 


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Appendix D (cont’d) 
ABO INCOMPATIBILITY 
 
MAJOR ABO INCOMPATIBLE 
Recipient anti-
Donor titer 
 1:32 
<20ml RBC total 
 Infuse without modification 
>20ml RBC total 
 RBC depletion of component 
 1:16 
 
 
Infuse without modification 
MINOR ABO INCOMPATIBLE 
Donor anti-
Recipient titer 
 1:256 
Plasma depletion of component 
 1:128 
Infuse without modification 
 
 
 
 
 
 
 
 


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Appendix E 
INFECTIOUS DISEASE GUIDELINES 
Please note that the content of these PDFs is from the Fred Hutchinson Clinical Research Division 
Standard Practice Manual and does not contain research related procedures. 
 
Herpes Simplex and Varicella Zoster Virus Prevention and Treatment 
 
HSV-VZV.pdf
 
CMV Prevention: Surveillance and Preemptive Therapy 
cmvprevention.pdf
 
CMV Disease: Diagnosis and Treatment 
cmvdiseasetreatmen
t.pdf
 
Antifungal Therapy Guidelines 
antifungal_therapy.p
df
 
Pneumonia / Pneumocystis Carinii Prophylaxis 
pneumocystisjiroveci
.pdf
 
Antibiotic Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic GvHD 
Requiring Immunosuppressive Therapy 
Antibiotic.Prophylaxi
s-Encapsulated
 
Vaccinations 
 
Foscarnet 
 
foscarnet.pdf
 
 
 
 


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Appendix F 
 
  GRADING OF ACUTE GRAFT-VERSUS-HOST DISEASEa 
Severity of Individual Organ Involvement 
Skin 
+1 
a maculopapular eruption involving less than 25% of the body surface 
+2 
a maculopapular eruption involving 25-50% of the body surface 
+3 
generalized erythroderma 
+4 
generalized erythroderma with bullous formation and often with 
desquamation 
Liver 
+1 
bilirubin (2.0-3.0mg/100ml) 
+2 
bilirubin (3-5.9mg/100ml) 
+3 
bilirubin (6-14.9mg/100ml) 
+4 
bilirubin > 15mg/100ml 
Gut 
Diarrhea is graded +1 to +4 in severity. Nausea and vomiting and/or anorexia 
caused by GVHD is assigned as +1 in severity. 
The severity of gut involvement is assigned to the most severe involvement noted.  
Patients with visible bloody diarrhea are at least stage +2 gut and grade +3 overall 
Diarrhea 
+1 
 1000 ml of liquid stool/day* ( 15ml of stool/kg/day)† 
+2 
>1,000 ml of stool/day* (> 15ml of stool/kg/day)† 
+3 
>1,500 ml of stool/day* (> 20ml of stool/kg/day)† 
+4 
2,000 ml of stool/day* ( 25ml of stool/kg/day)† 
*In the absence of infectious/medical cause 
†For pediatric patients 
 
Severity of GVHD 
Grade I 
+1 to +2 skin rash 
No gut or liver involvement 
Grade II 
+1 to +3 skin rash 
+1 gastrointestinal involvement and/or +1 liver involvement 
Grade III 
+2 to +4 gastrointestinal involvement and/or 
+2 to +4 liver involvement with or without a rash 
Grade IV 
Pattern and severity of GVHD similar to grade 3 with extreme constitutional 
symptoms or death 
 


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a From “Graft-vs-host disease” Sullivan, Keith M. Hematopoietic Cell Transplantation Ed: D. Thomas, K. 
Blume, S. Forman, Blackwell Sciences; 1999, pages 518-519. 


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Appendix G 
CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) 
Chronic GVHD in allogeneic transplant recipients resembles autoimmune disorders such as scleroderma, 
Sjogren syndrome, primary biliary cirrhosis, lichen planus, wasting syndrome, bronchiolitis obliterans 
among others manifestations (see below).  Approximately 50% of patients will develop this complication 
within 6 months after the transplant despite continued treatment with immunosuppressive medications.  
Close monitoring is recommended during the first 2 years after allogeneic stem cell transplantation so that 
appropriate treatment can be instituted promptly in patients who develop chronic GVHD.  Debilitation, 
joint contractures and profound immunosuppression resulting in recurrent bacterial infections are 
prominent characteristics of untreated chronic GVHD. 
 
A. Classification of Chronic GVHD 
The purpose of this classification is to identify patients with cGVHD who need long-term systemic 
immunosuppression according to clinical and laboratory findings and risk factors at the time of initial 
diagnosis. In addition, a morbidity scale has been developed to help grade the severity of manifestation of 
chronic GVHD (Appendix D) at the time of diagnosis, when changes in treatment are made and when 
assessing treatment response. 
1. Chronic GVHD not requiring systemic treatment: mild abnormalities involving a single site, 
with platelet count >100,000 and no steroid treatment at the onset of chronic GVHD 
a) Oral abnormalities consistent with cGVHD, a positive skin or lip biopsy, and no other 
manifestations of cGVHD. 
b) Mild liver test abnormalities (alkaline phosphatase ≤2 x upper limit of normal, AST or ALT ≤3 
x upper limit of normal and total bilirubin ≤1.6) with positive skin or lip biopsy, and no other 
manifestations of cGVHD. 
c) Less than 6 papulosquamous plaques, macular-papular or lichenoid rash involving <20% of 
body surface area (BSA), dyspigmentation involving <20% BSA, or erythema involving <50% 
BSA, positive skin biopsy, and no other manifestations of cGVHD. 
d) Ocular sicca (Schirmer’s test ≤5mm with no more than minimal ocular symptoms), positive 
skin or lip biopsy, and no other manifestations of cGVHD. 
e) Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations of cGVHD. 
2. Chronic GVHD requiring systemic treatment: more severe abnormalities or involvement of 
multiple sites, or platelet count <100,000, or steroid treatment at the onset of chronic GVHD 
a) Involvement of two or more organs with symptoms or signs of cGVHD, with biopsy 
documentation of cGVHD in any organ. 
b) ≥15% base line body weight loss not due to other causes, with biopsy documentation of 
cGVHD in any organ. 
c) Skin involvement more extensive than defined for clinical limited cGVHD, confirmed by 
biopsy. 
d) Scleroderma or morphea. 
e) Onycholysis or onychodystrophy thought to represent cGVHD, with documentation of cGVHD 
in any organ. 
f) Decreased range of motion in wrist or ankle extension due to fasciitis caused by cGVHD. 
g) Contractures thought to represent cGVHD. 
h) Oral involvement with functional impairment, refractory to topical treatment. 
i) Vaginal involvement with functional impairment, refractory to topical treatment. 
j) Bronchiolitis obliterans not due to other causes. 
k)    
Positive liver biopsy; or abnormal liver function tests not due to other causes with alkaline 
phosphatase >2 x upper limit of normal, AST or ALT >3 x upper limit of normal, or total 
bilirubin >1.6, and documentation of cGVHD in any organ. 
l)  
Positive upper or lower GI biopsy. 
m)  Fasciitis or serositis thought to represent cGVHD and not due to other causes 
 


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B. Physical manifestations of Chronic GVHD 
Manifestations that are distinctive for chronic GVHD can begin before day +100 after the transplant, and 
manifestations that are typical of acute GVHD can persist long after day +100.  For this reason, the 
differential diagnosis between acute and chronic GVHD cannot be made solely according to the time 
interval from transplant. The diagnosis of chronic GVHD requires at least one manifestation that is 
distinctive for chronic GVHD (identified by italic print below) as opposed to acute GVHD. In all cases, 
infection and others causes must be 
ruled out in the differential diagnosis of chronic GVHD. 
 
Karnofsky or Lansky Clinical Performance scores <60%, ≥15% weight loss, and recurrent infections are 
usually signs of clinical extensive chronic GVHD.  Abnormalities that could indicate chronic GVHD are 
categorized by organ system are listed below (italic print identifies manifestation more distinct of chronic 
GVHD): 
Skin 
Erythema, dryness, pruritis, macular-papular or urticarial rash, pigmentary changes (i.e., 
hyperpigmentation, vitiligo), mottling, papulosquamous or lichenoid plaques, 
hyperkeratosis, exfoliation (ichthyosis), nodules, scleroderma, morphea (one or several 
circumscribed, indurated and shiny lesions). The extent of skin involvement and the skin 
thickness score for patients with scleroderma needs to be recorded at the time of 
diagnosis, when changes in treatment are made and when assessing treatment response. 
Medical photos are also useful for assessing the extent of skin involvement and response 
to treatment. 
Nails 
A. 
Ridging, onychodystrophy, onycholysis 
Hair 
Premature graying (scalp hair, eyelashes, eyebrows), thinning scalp hair, alopecia, 
decreased body hair 
Mouth 
Dryness, burning, gingivitis, mucositis, striae, dryness, atrophy, erythema, lichenoid 
changes, ulcers, labial atrophy or pigmentary changes, tightness around the mouth, 
sensitivity to acidic, strong flavors, heat or cold, tooth decay 
Eyes 
Dryness, burning, blurring, gritty eyes, photophobia, pain 
Vagina/vulva 
Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid changes not 
induced by ovarian failure or other causes 
Liver 
Jaundice and elevated liver function tests not due to other causes (see laboratory tests) 
Lung 
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on 
exertion, history of recurrent bronchitis or sinusitis 
GI 
Anorexia, nausea, vomiting, diarrhea, malabsorption, dysphagia, odynophagia 
Myofascial 
Stiffness and tightness with restriction of movement, occasionally with swelling, pain, 
cramping, erythema and induration, most commonly affecting the forearms, wrists and 
hands, ankles, legs and feet, inability to extend the wrists without flexing the fingers or 
the elbows, contractures 
Muscle 
B. 
Proximal muscle weakness, cramping 
Skeletal 
Arthralgia of large proximal girdle joints and sometimes smaller joints 
Serosal 
Unexplained effusions involving the pleural, pericardial, or peritoneal cavities not due to 
venocclusive disease of the liver, cardiac insufficiency, malignancy, infection, GM-CSF 
toxicity or other causes 
 
 
 
 
 
 
 
 


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C. 
Laboratory Testing and Diagnostic Indicators of Chronic GVHD 
 
Eye 
Schirmer’s test with a mean value ≤ 5 mm at 5 minutes, or values of 6-10 mm in patients 
who have sicca symptoms, or keratitis detected by slit lamp examination 
Liver 
Elevated liver function tests not due to other causes (alkaline phosphatase ≥2 x upper 
limit, of normal, AST or ALT >3 x upper limit of normal or total serum bilirubin ≥1.6) 
Lung 
New obstructive lung defect defined as an FEV1 <80% of predicted with either an FEF 
25-75 <65% of predicted or RV >120% of predicted, or a decrease of FEV1/FVC by 
>12% within a period of less than 1 year, though not to be caused by an infectious 
process, asthma or recurrent aspiration from the sinuses or from gastroesophageal 
reflux. In the absence of GVHD in any other organ, the diagnosis of bronchiolitis 
obliterans requires negative microbiological tests from bronchoalveolar lavage, 
evidence of air trapping by high resolution end-expiratory and end-inspiratory CAT scan 
of the lungs, or confirmation by thoracoscopic biopsy. 
Esophagus 
Esophageal web formation, stricture or dysmotility demonstrated by barium swallow, 
endoscopy or manometry 
Intestine 
Endoscopic findings of mucosal edema and erythema or focal erosions with histological 
changes of apoptotic epithelial cells and crypt cell drop out. Patients with unresolved 
acute GVHD may have more severe intestinal mucosal lesions including ulcers and 
mucosal sloughing. 
Muscle 
Elevated CPK or aldolase, EMG findings consistent with myositis with biopsy revealing 
no other etiological process 
Blood 
Thrombocytopenia (usually 20,000-100,000/l), eosinophilia (> 0.4 x 103/uL), 
hypogammaglobulinemia. Hypergammaglobulinemia and autoantibodies occur in some 
cases. 
 
D. Guidelines for Treatment of Chronic GVHD after allogeneic HSCT 
We strongly recommend that you consult the LTFU office before beginning treatment for chronic GVHD 
and before making changes in immunosuppressive treatment. Clinical trials should always be considered 
because current standard therapies are associated with high morbidity and decreased survival for patients 
with high risk chronic GVHD  
 
Standard treatment of chronic GVHD usually begins with administration of glucocorticoids (1mg/kg/day) 
followed by taper to eventually reach an alternate-day regimen, with or without daily cyclosporine or 
tacrolimus (FK506). Other medications used for treatment of corticosteroid-resistant chronic GVHD are 
summarized on the next page. Telephone consultation with the LTFU medical team is available to you, 
seven days a week, to discuss appropriate treatment and provide other follow up recommendations. In 
addition to immunosuppressive treatment, antibiotic prophylaxis for encapsulated 
bacterial infections and PCP must be given to all patients being treated for chronic GVHD 
(see Appendix E). 
 
The duration of systemic immunosuppressive treatment of chronic GVHD varies but requires at least one 
year of therapy. Approximately 80% of patients require systemic immunosuppressive for 2 years and 40% 
of them requires therapy for at least 4 years. 
 
Adapted From: Long-Term Follow-up After Hematopoietic Stem Cell Transplant General Guidelines For 
Referring Physicians, Fred Hutchinson Cancer Research Center Standard Practice Manual, Section X, 
Chronic Graft Versus Host Disease (GVHD), Nov/2003 Version 
 
 


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Appendix H 
EVALUATION OF DISEASE RESPONSE 
 
 
General guidelines 
 
(A) Any assessment of response must include a bone marrow aspirate. Patients with myelofibrosis 
will also require a biopsy. 
(B) All bone marrow aspirates must also have cytogenetics analysis. For some patients, there may 
be additional disease-specific FISH or PCR-assessed molecular markers that can be used to 
determine response. 
(C) Regimen-related toxicity, for example due to drug adverse effect, severe infection, or GVHD 
must be excluded as causes of peripheral blood cytopenias. 
 
Definition of Response 
 
1 Definition of Response : MDS/CMML 
 (A) Complete Response 
 
Bone marrow rating: Normal maturation of all cell lines, without morphologic dysplasia and 
with< 5% myeloblast. 
 
Peripheral blood rating: no peripheral blasts and no dysplasia. 
 
 
(B) Complete Response with normal blood counts33  
 
Bone marrow rating: Normal maturation of all cell lines, without morphologic dysplasia and 
< 5% myeloblasts.  
 
Peripheral blood rating: Hb >11 g/dL, neutrophils >1500/mm3, platelets >100 000/mm3, 
blast 0%, no dysplasia. 
 
(C) Progressive Disease 
 
Any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of 
new blasts (>5%). 
 
 
2 Definition of Response: Agnogenic Myeloid Metaplasia34 
 
 (A) Complete Response 
In patients with marrow fibrosis: 
 
Achievement of >95% donor chimerism in the bone marrow, and:  
 
evidence of regression of fibrosis as determined by sequential bone marrow biopsies 
(however residual fibrosis may be present). 
In patients with myelodysplastic features or with leukemic transformation: 
 
achievement of >95% donor chimerism in the marrow, and: 
 
regression of marrow fibrosis, and: 
 
absence of leukemic blasts, and:  
 
disappearance of dysplastic changes. 
 
(B) Progressive Disease  
 
Any evidence of blastic transformation. 
 
 


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3 Definition of Response: Atypical CML 
 
(A) Complete Response 
 
normal peripheral blood counts and leukocyte differential OR achievement of >95% donor 
chimerism in the bone marrow, and:  
 
resolution of pretreatment cytogenetic abnormality, and: 
 
Normal maturation of all cell lines, without morphologic dysplasia (if present pre-
treatment), and: 
 
< 5% myeloblasts. 
  
 
(B) Progressive Disease 
 
Any evidence of blastic transformation. 
 
4 Definition of Response: Polycythemia Vera and Essential Thrombocythemia 
 
(A) Complete Response  
 
Hematocrit < 45% in the absence of phlebotomy, normal platelet count (< 400,000/ml) or 
achievement of >95% donor chimerism in the bone marrow. 
 
(B) Progressive Disease  
 
Erythrocytosis, thrombocytosis, or evidence of leukemic transformation. 
 
5 Definition of Response: PNH 
 
(A) Complete Response  
 Greater than 95% of the red blood cells not expressing the anchor proteins (documented by 
flow cytometry) in the absence of transfusions or achievement of >95% donor chimerism 
in the bone marrow. 
 No clinical evidence of hemolysis related to PNH 
 


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Appendix I 
STUDY COORDINATOR’S MANUAL 
 
 
I.  
Introduction 
The mixed chimerism protocols have been opened to multiple sites to increase the referral base and accrual. 
Because of this expansion of collaborators, the data collection procedures are being revised. The procedure 
manual was created to assure consistency of data reporting across the centers and to assure compliance with 
regulations. General expectations of collaborators are that they will comply with appropriate regulatory 
requirements, specified protocol requirements, and provide outcome data. 
 
The manual translates working procedures for study coordination. Its goal is to describe the procedures 
with sufficient clarity to ensure that all study centers will use the same procedures and follow-up schedules 
for participant data management and reporting. Changes to the manual and relevant forms will be made as 
soon as practical and will become effective on receipt of the revised procedures at the study centers, unless 
otherwise noticed. 
 
II. 
Institutional Review Board Review of Protocols and Modifications 
All research protocols proposed for use that involves human subjects must be reviewed and approved by 
the Institutional Review Board (IRB) prior to implementation. New protocols will undergo review at the 
FHCRC IRB and then will be distributed to sites that wish to participate for their IRB’s review. For Centers 
that have a Federal Wide Assurance (FWA), formal collaboration includes submission of a form 310 and a 
copy of the IRB approved protocol and consent forms to the FHCRC.  For sites without a FWA, an FWA 
form needs to be filed. Once the paperwork is submitted to the Office for Human Research Protection, the 
approval process can take up to a couple of months, and must be completed before collaboration on a 
protocol can begin.  
 
In addition, all amendments and/or revisions to on-going, approved activities must be submitted for review 
and approved prior to implementation at an institution.  No revisions may be implemented at outside 
institutions without the prior approval of the FHCRC Principal Investigator.  The FHCRC and the local 
site’s IRB must review all protocol activities at least once annually. This must be done within 365 days of 
the last review regardless of the policies of the institution. A copy of annual renewal approvals must be 
received for collaboration to continue for the next year. 
 
III. 
Registrations 
Collaborating Institutions: The principal investigator of the collaborating institution who will register the 
patient with the FHCRC will identify eligible patients. Registration will include completion of the 
eligibility checklist/demographic form. This form will be faxed (206-667-5378) prior to treatment 
initiation. Patients should be registered prior to treatment initiation for valid registration 
 
IV. 
Reporting Adverse Events 
The following guidelines are the minimum serious adverse event (SAE) reporting guidelines for Category 1 
and 2 studies conducted at the Fred Hutchinson Cancer Research Center.   
Expedited Reporting Requirements  
All unexpected and serious adverse events which may be due to study treatment or intervention must 
be reported to the FHCRC Institutional Review Office as soon as possible but within at least 10 
calendar days of the investigator learning of the event. 
 
 
 
 


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Appendix I (cont’d) 
STUDY COORDINATOR’S MANUAL 
 
Definitions 
Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, medical treatment or procedure and which does not necessarily 
have to have a causal relationship with this treatment.  An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, medical treatment or procedure whether or not 
considered related to the medicinal product.  
 
Life-threatening Adverse Event  – Any adverse event that places the patient or subject, in view of the 
investigator, at immediate risk of death from the reaction.  Study toxicities are graded using the adapted 
NCI Common Toxicity Criteria (where appropriate use the criteria for transplant patients.)  All Grade 4 
(life-threatening) toxicities occurring between start of conditioning to day 200 that meet expedited 
reporting requirements must be reported as soon as possible but within at least 10 calendar days of the 
investigator learning of the event.  
 
Unexpected Adverse Event – An adverse event, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an unapproved investigational product or 
package insert/summary of product characteristics for an approved product).  If applicable product 
information is not available, such as for studies that do not involve pharmaceutical products or devices, an 
unexpected adverse event is an adverse event that was not described in the study protocol or informed 
consent. 
 
 
Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the following 
outcomes:   
 
Death – start of conditioning to day 200, regardless of cause. 
 
life-threatening adverse event (see above). 
 
persistent or significant disability/incapacity. 
 
congenital anomaly. 
 
requires intervention to prevent permanent impairment or damage.  
 
Hospitalization, in general, will not be considered a serious adverse event as approximately half of 
evaluable MRD patients AND the majority of evaluable URD patients receiving nonmyeloablative 
transplants were hospitalized.  Hospitalization will be considered a serious adverse event if it fulfills the 
criteria for a serious and unexpected adverse event as described above. 
 
To ensure no confusion or misunderstanding exist of the differences between the terms “serious” and 
“severe,” which are not synonymous the following note of clarification is provided: 
 
The term “severe” is often used to describe the intensity (severity) or a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache).  This is not the same as “serious,” which is based on patient/event outcome or 
action criteria usually associated with events that pose a threat to a patient’s life or functioning.  
Seriousness (not severity) serves as a guide for defining regulatory obligations. 
 


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Appendix I (cont’d) 
STUDY COORDINATOR’S MANUAL 
 
Attribution - The FHCRC designation for the determination of whether an adverse event is related to a 
medical product, treatment or procedure will be as follows: 
 
Related – includes adverse events that are definitely, probably, or possibly related to the medical 
treatment or procedure. 
 
Not Related – includes adverse events are doubtfully related or clearly not related to the medical 
treatment or procedure. 
 
The FHCRC Serious Adverse Event (SAE) Report Form should be completed for all adverse events that 
meet the expedited reporting requirements.   All available information should be submitted but it is 
acceptable to fax an incomplete report form at the initial report.  A completed report should be faxed as 
soon as possible but must be received within 10 calendar days. 
 
It is the responsibility of the FHCRC Principal Investigator to notify the sponsor, NIH, FDA or other 
agencies of serious adverse events as required in the protocol. 
 
Serious adverse events that do not meet the requirement for expedited reporting (not related to study 
treatment or expected) will be reported to the IRB as part of the annual renewal of the protocol. 
 
FHCRC is acting as the Coordinating Center for this multi-institutional study, and it is the responsibility of 
the FHCRC Principal Investigator (or designee) to complete the FHCRC Serious Adverse Event Report for 
all serious adverse events that meet the expedited reporting requirements that are received from the 
participating sites.   
 
Procedure for Reporting Serious and Unexpected Adverse Events from Participating Sites 
Regulations defining the responsibilities for reporting serious and unexpected adverse reactions are defined 
above.  Serious and unexpected adverse events must be reported to the FHCRC Investigator within 10 days 
of learning of the event. This includes patient deaths (serious, unexpected, and related/possibly related), 
regardless of cause, occurring start of conditioning to day 200 post-transplant procedure.  The immediate 
telephone report must be followed by faxed comments to the FHCRC Trial Coordinator at (206) 667-5378. 
This will be followed by detailed written report (See Appendix J) within 10 working days.  The report must 
include the date and time of onset, severity and duration of the event, the relationship to the study, the 
treatment given and eventual outcome.  Follow-up information to a SAE report must be submitted as soon 
as the relevant information is available. 
 
Obligation of Investigators 
All grade 3 or 4 adverse events (or highly unusual grade 2 adverse events), which occur between start of 
conditioning to day 100 during the study will be recorded on the Case Report Form (Appendix M).  These 
adverse events which are observed by the Investigator or reported by the patient, whether or not attributed to 
the study, will be reported on the Case Report Form using the modified (for HSCT) NCI Common Toxicity 
Criteria (Appendix P). Attributes will include a description, date of onset, maximum severity, and assessment 
of relationship to the study agent or other suspect agent(s). 
 
Adverse events will be graded accordingly: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life 
threatening or debilitating, and 5 = fatal.   All Grade 4 (life-threatening) or Grade 5 (fatal) events on the 
Adapted HSCT NCI scale meet expedited reporting requirements. 
 
 
 


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Appendix I (cont’d) 
STUDY COORDINATOR’S MANUAL 
 
Association or relatedness to the study agent will be graded as follows: 1 = unrelated, 2 = unlikely, 3 = 
possibly, 4 = probably, and 5 = definitely related. 
 
V. 
Case Report Forms 
Case report forms must be completed for all patients registered onto the protocols and submitted to the 
FHCRC data coordinating center. The first case report form (day 28) is due on day 50.  For outside centers 
a Staging Form must accompany the form with the patient staging at registration, day 28, day 56, day 84 
and day 100. Staging forms should also be completed with each Follow Up Form completed on day 180, 1 
year, 1.5 years, 2 years, 3 years, and yearly thereafter. For Outside Centers, case report forms are expected 
to be submitted no later than 30 days following the scheduled follow up date.  
 
VI. 
Protocol Monitoring 
As the coordinating center, FHCRC will monitor accrual at the outside institutions. The guidelines below 
are intended to guide the reviewers in their assessment of items that significantly alter the clinical 
effectiveness of the treatment or the evaluation of its toxicity. 
 
A. Registration/Randomization 
1. Patient was registered prior to treatment and approval by FHCRC PI occurs prior to 
randomization.  
2. Information given at registration represents actual data in medical records (stage, diagnosis, cell 
type, etc.) 
 
B. Informed Consent/IRB Approval Dates 
1. The consent was signed prior to registration 
2. The consent is in language was approved by the institution’s IRB. IRB approval and reapproval 
are documented including appropriate use of full-board review and proper review of appropriate 
amendments or revisions 
3. Consent was dated and has written witness signature. IRB approval was obtained prior to the 
patient signing the consent form and start of treatment. 
 
C. Patient Eligibility 
1. Eligibility criteria and exclusion criteria were met 
2. Treatment/Intervention Administration 
3. Doses were modified according to protocol 
4. Accurate documentation of drug administration 
 
D. Study Tests/Evaluation 
1. Protocol specified laboratory tests or diagnostic studies are available 
2. Appropriate record of protocol intervention is documented. 
 
E. Study Events/Adverse Drug Experience 
1. Serious Adverse Evens reported according to protocol specifications 
 
F. 
Follow-Up 
1. Disease status assessed according to the required protocol guidelines documenting response to 
treatment. 
2. Accurate determination of cancer progression 


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Appendix J 
Fred Hutchinson Cancer Research Center/ Clinical Research Division / Institutional Review Office 
SERIOUS ADVERSE EVENT REPORT (SAE) Form IRO-08 
 
FHCRC IR File Number: _________________ 
 
FHCRC Protocol Number: ___________________ 
FHCRC Unique Patient #:  ________________ 
 FHCRC/SCCA   
  Other 
Gender:  
 Male  
 Female 
Age:  ________   
FHCRC Principal Investigator:  ____________________________________________________ 
  
Phone Number:  ___________________________ 
Mailstop:  __________________ 
 
Date of Report:  _____/______/______ 
 
 
 Initial Report ______________ 
 Follow-Up Report #:  ______________ 
 Other 
Date Study Staff Became Aware of Event: _________________ 
Date Serious Adverse Event Began:  _____/_____/_____ 
Date Ended: _____/_____/_____ 
Or  
 Ongoing (if ongoing – must submit follow up report) 
Adverse Event: 
 
 
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
(Or attach a MedWatch Form or other SAE reporting form if one has been completed.)  Use Page 2, if 
necessary:____________________________________________________________________________ 
 
Outcomes Attributed to adverse event:  (Check all that apply) 
 Death:  _____/_____/_____ 
 Life-Threatening 
 Hospitalization (initial or prolonged) 
 
 Disability 
 Congenital Anomaly 
 Required intervention to prevent permanent             
impairment/damage 
Specify Agent(s) and/or Procedure(s) involved in this protocol: 
 
#1:  ___________________________________ 
Pharmaceutical product/medical 
treatment/procedure 
 
#2:  ______________________________________ 
Pharmaceutical product/medical treatment/procedure 
 Not Related (Unrelated, Unlikely) 
 Not Related (Unrelated, Unlikely) 
 Related (Possible, Probable, Definite) 
 Related (Possible, Probable, Definite) 
 
 
 Follow-up Report Required 
 Final Report (PI must sign final report) 
Report Completed by: 
 
Date: 
 
The PI has determined that the consent form must be revised: 
 Yes      
 No 
Does this study involve the deliberate transfer of recombinant DNA or DNA or RNA derived from 
recombinant DNA, into human subjects (human gene transfer)? 
 Yes  
 No  If yes and the activity 
involves the SCCA outpatient clinic, a copy of this Protocol Modification Form and any supporting 
documents to be reviewed and approved, will be forwarded to the FHCRC’s Institutional Biosafety 
Committee (IBC) by the Protocol Office (Mailstop:  LM-230). 
 
Signature of Principal Investigator 
 
Date: 
 


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Appendix J (cont’d) 
Fred Hutchinson Cancer Research Center / Clinical Research Division / Institutional Review Office 
SERIOUS ADVERSE EVENT REPORT (SAE) Form IRO-08 
page 2 
 
 
FHCRC IR File Number: ______________ 
 
FHCRC Protocol Number: ____________ 
 
FHCRC Unique Patient #: __________  
Date of Report: _______________ 
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix K 
NOTICE OF DEATH 
 
 
Patient ID: ________________  Date of Death:  _________________ 
 
Place of Event: ____________________________________________  
 
 
Apparent cause of death (Please be specific.  Attach hospital summary or death summary when possible): 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
___________________________________________________________________________________ 
 
 
 
Form completed by: __________________________________________  Date: __________________ 
 
 
 


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Appendix L 
PROTOCOL 2056.00  
PATIENT DEMOGRAPHICS AND ELIGIBILITY FORM 
Please fax this completed form to (206) 667-5378 for patient registration. 
Questions regarding eligibility should be directed to the Brenda Sandmaier, MD (206-667-4961). 
 
UPN#: _____________ 
Patient Name: 
_______________________________ 
(Last) 
________________________ 
(First) 
_____  
(MI) 
Date of 
Birth: 
_____ / _____ / __________Age:________ 
 (Mo)    (Day)         (Year) 
Gender (choose one): 
 Male    
 Female   
 Unknown 
Patient Diagnosis:_______________________________  
Status at Transplant:_____________________________ 
Planned Day 0: _____/______/_____ 
 
(Mo) (Day)  (Year) 
Ethnicity (choose one):  Instruct the research subject to select one of the following. 
 Hispanic (A person of Cuban, Mexican, Puerto Rican, South or Central American, or other 
Spanish culture or origin, regardless of race.  Term “Spanish Origin” can also be used in 
addition to “Hispanic” or “Latino”. 
 Not Hispanic or Latino 
 
 Declined to report 
 
Race (check all that apply):  Instruct the research subject to select one or more of the following. 
 American Indian/Alaska Native (A person having origins in any of the original peoples of 
North, Central, or South America, and who maintains tribal affiliations or community 
attachment). 
 Asian (A person having origins in any of the original peoples of the Far East, Southeast, Asia, or 
the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam). 
 Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of 
Hawaii, Guam, Samoa or other Pacific Islands). 
 Black/African American (A person having origins in any of the black racial groups of Africa). 
 White (A person having origins in any of the original peoples of Europe, the Middle East or 
North Africa). 
 Research subject does not know race 
 Declined to report 
 
 


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PROTOCOL ELIGIBILITY 
 
Inclusion Criteria 
 
1. Yes 
  No 
  Patient has signed IRB approved consent form. 
Date:  ___________________________ 
IRB File Number:  __________________  
Date of IRB Approval: ______________ 
 
2.  Yes 
 No 
    Called FHCRC for Arm and Dose confirmation.  Date.  _________ 
            
 Arm A: MPD or MDS-RA/RARS, or PNH    
 
      TBI DOSE LEVEL:   
 
1st dose level: 300 cGy                    
 
                    
 
2nd dose level: 400 cGy                    
 
                    
 
3rd dose level:  450 cGy                    
 
                                 OR      
 
            
 Arm B: MDS-RAEB or CMML 
             
      TBI DOSE LEVEL:    
 
1st dose level: 300 cGy                    
 
                     
 
2nd dose level: 400 cGy                    
 
                     
 
3rd dose level:  450 cGy                    
                                                        
 
One of the following criteria questions (3-4) must be marked “Yes” for the patient to enroll in this 
study 
 
   3.   Yes 
  No 
 
Related donor who is genotypically or phenotypically HLA-identical. 
 
4. Yes 
  No 
 Unrelated donors who are prospectively: 
a. Matched for HLA-A,B,C, DRB1 and DQB1 alleles by high resolution 
typing  
AND 
b. Only a single allele disparity will be allowed for HLA-A, B, or C as 
defined by high resolution typing (See appendix O for other donor 
selection details) 
 
 
 
 
 


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Patient 
 
 
 
 
 
A: ________ 
A:_________ 
C:_________ 
C:_________ 
B:_________ 
B:_________ 
DRB1:_________ 
DRB1:_________ 
DQB1: _________ 
DQB1: _________ 
 
 
Donor 
 
 
 
 
 
A:_________ 
A:_________ 
C:_________ 
C:________ 
B:_________ 
B:_________ 
DRB1:_________ 
DRB1:_________ 
DQB1: _________ 
DQB1: _________ 
 
 
 
 
c.    Yes 
  No 
 
Have a negative anti-donor cytotoxic crossmatch.  
                    NA 
       Cytotoxic crossmatch not done as patient and donor 
are phenotypically identical by molecular 
methods.              
 
d. Yes 
  No 
 
Patient and donor pairs must not be homozygous at 
mismatched allele. 
 
   
One of the following criteria questions (5-6) must be marked “Yes” for the patient to enroll in this 
study. 
 
5. Yes 
  No 
 Age  50 years and <75 years with CMML, or previously untreated MDS or 
MPD.   
 
6.   Yes 
  No 
  Age < 50 years of age at high risk for regimen related toxicity using standard 
high dose regimens. Factors considered high risk include pre-existing 
conditions such as a chronic disease affecting kidneys, liver, lungs, or heart or 
previous failed HCT. All children < 12 years must be discussed with the 
FHCRC PI (Brenda Sandmaier, MD 206-667-4961) prior to registration.  
  
Pre-existing condition(s) precluding conventional tx:  ____________ 
*Patients  50 years of age who have received previous autologous 
transplantation do not require patient review committee approval. All 
children < 12 years must be discussed with the FHCRC PI (Brenda 
Sandmaier, MD 206-667-4961) prior to registration.  
 
 
One of the following criteria questions (7 - 14) must be marked “Yes” for the patient to enroll in 
this study.  
 
7.   Yes 
  No 
  MDS classifiable by the WHO system (see appendix R) as RA, RARS, 
refractory cytopenia with multilineage dysplasia (RCMD), RCMD and ringed 
sideroblasts (RCMD-RS) or RAEB.  No previous myelosuppressive therapy. 
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defined as chemotherapy given with the intent of inducing a complete 
remission (e.g. standard 7+3, HIDAC, or mylotarg). Patients must have < 
10% marrow blasts. Fewer than 10% marrow blasts must be documented by 
marrow examination within 3 weeks of initiation of conditioning.  
 
8. Yes 
  No 
   Philadelphia chromosome-negative patients with a diagnosis of atypical 
CML. No previous myelosuppressive therapy. For the purpose of this 
protocol myelosuppressive chemotherapy will be defined as chemotherapy 
given with the intent of inducing a complete remission (e.g. standard 7+3, 
HIDAC, or mylotarg).  Must have < 10% blasts at HCT.* 
  
9. Yes 
  No 
   Polycythemia vera with persistent thrombotic or hemorrhagic complications                         
despite conventional therapy, or who have progressed to postpolycythemic            
marrow fibrosis. No previous myelosuppressive therapy. For the purpose of 
 
this protocol myelosuppressive chemotherapy will be defined as 
chemotherapy given with the intent of inducing a complete remission (e.g. 
standard 7+3, HIDAC, or mylotarg).  Must have < 10% blasts at HCT.* 
                                   
10. Yes 
  No 
   Chronic idiopathic myelofibrosis with peripheral blood cytopenias. No previous 
myelosuppressive therapy. Must have < 10% blasts at HCT.* 
 
11. Yes 
  No 
  Essential thrombocythemia with persistent thrombotic or hemorrhagic 
                                 complications despite conventional therapy, or who have progressed to 
myelofibrosis. No previous myelosuppressive therapy. Must have < 10% 
blasts at HCT.* 
 
12. Yes 
  No 
  Agnogenic myeloid metaplasia with peripheral blood cytopenias. No previous 
myelosuppressive therapy. Must have < 10% blasts at HCT.* 
 
 
13. Yes 
 No 
   Chronic Myelomonocytic leukemia. Patients with CMML1 who have not 
received myelosuppressive therapy must have < 10% blasts at HCT.* 
Patients with CMML who have progressed beyond CMML1 and have received 
myelosuppressive chemotherapy must have <5% marrow blasts. *   
 
14. Yes 
 No 
   Paroxysmal nocturnal hemoglobinuria.  Patients with the non-aplastic form of 
PNH (cellular bone marrow) who have had a history of life-threatening 
complications of their disease including thrombotic events, severe hemolysis 
or Budd Chiari syndrome are eligible.  Other patients may be considered 
following approval at PCC and approval by the protocol Principal 
investigator.    
 
*Note: Date of most recent marrow examination (must be within 3 weeks of initiation of conditioning 
regimen). _____/__  /______ 
 
 
 


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Exclusion Criteria 
Each of the following questions must be marked “No” or “NA” for the patient to enroll in this study. 
 
15.  Yes 
  No 
   Bone marrow documenting blast count >10% or > 5% in CMML patients who 
 
 
 
have progressed beyond CMML1 and received myelosuppressive chemotherapy. 
 
16.  Yes 
  No 
     Active CNS involvement of disease (if LP requirement, see Appendix N) 
 
17.  Yes 
  No 
     Presence of >5% circulating leukemic blasts (in the peripheral blood) 
detected by standard pathology. 
 
18. Yes 
  No 
      Patients with active non-hematologic malignancies (except non- melanoma 
skin cancers). 
This exclusion does not apply to patients with non-hematologic malignancies that 
do not require therapy 
 
19. Yes 
  No 
     Patients with a history of non-hematologic malignancies (except non- 
melanoma skin cancers) currently in a complete remission, who are less 
than 5 years from the time of complete remission, and have a >20% risk of 
disease recurrence. 
 
 
 
 
20.  Yes 
  No 
  NA 
 Fertile men or women unwilling to use contraceptive techniques 
during and for 12 months following treatment. 
 
21.  Yes 
  No 
  NA 
 Females who are pregnant or breastfeeding. 
 
 
22.  Yes 
  No 
   
Fungal infections with radiological progression after receipt of 
amphotericin B or active triazole for > 1 month. 
 
23.    Organ Dysfunction 
Please check yes if patient meets any of the following. 
 
 
 
 
 
 
 
 
 
Yes 
   No 
 
Cardiac:  Symptomatic coronary artery 
disease or ejection fraction < 35% (or, if 
unable to obtain ejection fraction, shortening 
fraction of <26%).  Ejection fraction is 
required if age > 50 years or there is a history 
of anthracycline exposure or history of 
cardiac disease.   
NOTE: If shortening fraction is <26%, a cardiology consult 
is required.  The PI of the study must approve eligibility 
  
  
  
 
  
 
 
 
 
 
 
 
                         
 
       PI Signature:  
 
 
              Date:               
 
 
 
 


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Yes 
   No 
 
Pulmonary:  DLCO < 35%, TLC <35%, 
FEV1 <35% and/or receiving    
supplementary continuous oxygen.  
 
            Additionally, the FHCRC PI of the study 
must approve of enrollment of all patients 
with pulmonary nodules. 
 
             PI Signature: ____________________ Date: _________ 
 
 
Yes 
  No 
  Liver function abnormalities: Patient with clinical 
or laboratory evidence of liver disease will be 
evaluated for the cause of liver disease, its clinical 
severity in terms of liver function, bridging fibrosis, 
and the degree of portal hypertension.  The patient 
will be excluded if he/she is found to have 
fulminant liver failure, cirrhosis of the liver with 
evidence of portal hypertension, alcoholic hepatitis, 
esophageal varices, a history of bleeding 
esophageal varices, hepatic encephalopathy, 
uncorrectable hepatic synthetic dysfunction evinced 
by prolongation of the prothrombin time, ascites 
related to portal hypertension, bacterial or fungal 
liver abscess, biliary obstruction, chronic viral 
hepatitis with total serum bilirubin >3mg/dL, or 
symptomatic biliary disease. 
 
24. Yes 
   No 
     
Karnofsky Performance Score < 70 (adult patients) or Lansky-Play  
 
 
 
 
Performance score < 70 (pediatric patients). 
 
25. Yes 
   No 
    
Patient is HIV-positive. 
 
26. Yes 
   No 
    
Life expectancy severely limited by diseases other than malignancy. 
 
27. Yes 
   No 
    
Severe psychological illness such as major psychosis (e.g. 
schizophrenia), major bipolar depression, or suicidal situational 
depression. 
 
28. Yes 
   No 
    
Patient has an active bacterial infection. 
 
29. Yes 
   No 
     
Patient has received chemotherapy (with the exception of    
hydroxyurea and anagrelide) within 21 days of initiation of 
conditioning. 
 
*Note – the HCT-Comorbidity score is:  _______________ (fax HCT-CI worksheet with 
registration—see Appendix Q) 
 


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Signature of person completing form: ______________________________ Date: ____________ 
 
Signature of Principal Investigator: ________________________________ Date: ____________ 


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Appendix M 
CORE CASE REPORT FORMS 
 
 
 
Acrobat Document
 
 
 
 
 
 
 


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Appendix N 
INTRATHECAL THERAPY ADMINISTRATION 
Please note that the content of this PDF is from the Fred Hutchinson Clinical Research Division Standard 
Practice Manual and does not contain research related procedures. 
 
 
intrathecaltherapy-c
ombined.pdf
 
 
 
 
 
 
 


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Appendix O 
HLA MATCHING REQUIREMENTS FOR UNRELATED DONORS  
AT THE SCCA / FRED HUTCHINSON ALLIED SYSTEM 
 
Human Leukocyte Antigen (HLA) Terminology. The HLA region consists of genes that encode two 
classes of HLA molecules. HLA class I molecules, HLA-A, -B, and –C, are composed of a single 
glycoprotein chain that is expressed in association with 2-microglobulin on most tissue cells. HLA class 
II molecules, HLA-DR, -DQ, and –DP, are heterodimers consisting of 
and 
glycoprotein chains. 
HLA class I and HLA class II molecules are highly polymorphic. 
 
 
HLA Typing Methods. At the Seattle Cancer Care Alliance Clinical Immunogenetics Laboratory (CIL) 
DNA-based methods of HLA-A, B, C, DRB1, DQB1 typing are now performed routinely. High resolution 
typing is required to define individual alleles and the level of mismatching between donor and recipient. 
High resolution data are reported with four or more digits (e.g., A*0201, A*0205, B*1504, or 
DRB1*0401). A current listing of recognized HLA alleles and their sequences can be found at the 
Immunogenetics/HLA sequence database website at www.anthonynolan.org.uk/HIG/data.html. 
 
 
Initial typing reports obtained through the international marrow donor registries may consist of 
intermediate resolution typing. Intermediate resolution defines alleles in groups of related families 
historically defined as antigens by alloantisera. Intermediate resolution typing results are reported as two 
digits (e.g., A*02, B*15, or DRB1*04). In cases where the HLA-A, B and C loci are typed at intermediate 
resolution and high resolution data are not available, it should be understood that unidentified allele 
disparity might be present. 
 
 
Donor Selection. Final selection of an unrelated donor should be based upon results of high resolution 
typing of HLA-A, B, C, DRB1, DQB1 alleles. Cross match assay is not required when high resolution 
typing indicates matching for HLA-A, B, C, DRB1 and DQB1 AND the platelet reactive antibody (PRA) 
screen is not elevated (defined as ≤10%). A negative cross match test result is required for final donor 
selection in the following situations: 1) PRA screen is positive (>10%), or 2) high resolution typing 
indicates mismatching for one or more HLA-A, B, C, DRB1 and DQB1 alleles. A positive anti-donor 
cytotoxic crossmatch absolutely excludes the donor. 
 
 
Donor Selection Criteria. Protocols and treatment plans must specify donor inclusion and exclusion 
criteria, using terminology indicated below. 
 
Donor inclusion criteria must specify 1) the allowable genetic relationship between the patient and donor 
(related and/or unrelated), 2) the allowable limits of mismatch, and if applicable 3) any modification of 
mismatch criteria according to type of disease or patient characteristics. 
 
 
 
 
 
 
 
 


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Acceptable levels of recipient-donor mismatch for research related treatment protocols or standard 
treatment plans include the following: 
Allele-match for HLA-A, B, C, DRB1 and DQB1. 
Single allele disparity for HLA-A, B, C, or DRB1 or DQB1 
Two allele disparities for HLA-A, B, or C. 
Single allele disparity for HLA-DRB1 and/or a single DQB1 antigen or allele disparity. 
Single antigen plus single allele disparity for HLA-A, B, or C. 
 
The following levels of patient-donor mismatch should be restricted to research protocols: 
Two antigen disparity, either HLA-A plus C or HLA-B plus C. 
Single antigen disparity for HLA-DRB1 with or without DQB1 allele or antigen disparity 
Combined disparity of class I and class II loci, i.e. disparity for HLA-A, or B, or C, and any 
additional disparity for DRB1 or DQB1 
 
 
Donor Exclusion Criteria to be considered for protocols or standard treatment plans include: 
Double locus disparity. Two disparities are not allowed when they both involve the same locus, 
i.e., the patient is A*0101, A*0201 and the donor is A*0102 and A*0205. 
Recipient and donor homozygous at mismatched locus. Patient and donor pairs homozygous at 
the mismatched locus are considered a two-locus mismatch, i.e., the patient is A*0101 and the 
donor is A*0201, and this type of mismatch is not allowed. 
Recipient homozygous at mismatched locus. If the recipient is homozygous at HLA-A, B, or C 
and the donor is mismatched at that locus, i.e., patient is A*0101 and donor is A*0101 and 
A*0201, the risk of rejection is increased. Such a donor should be avoided if there is already an 
appreciable risk of rejection, i.e., in patients with CML/MDS/Severe Aplastic Anemia (SAA) or 
those receiving reduced conditioning. 
 
 
Relevance of HLA matching for transplantation of unrelated hematopoietic cells: 
Human Leukocyte Antigen (HLA) typing of patients and prospective hematopoietic stem cell (HSC) 
donors is carried out to identify and match for HLA determinants associated with successful HSC 
transplant outcome. While several preliminary studies (1, 2, 3) suggested the importance of allele level 
matching in hematopoietic cell transplantation (HCT), recent comprehensive studies confirmed that allele-
level typing and matching is necessary to optimize clinical outcome in hematopoietic cell transplantation 
(4, 5, 6, 7). 
 
 The pervasiveness of occult HLA mismatch was shown by Petersdorf, et al in an analysis of 300 CML/CP 
unrelated donor-recipient pairs matched for HLA-A and B by serologic typing, and matched for the DRB1 
alleles. (4) The percent of patient-donor pairs found to be matched at the allele level for all 5 loci (HLA-A, 
B, C, DRB1, DQB1) was only 47% (n=142). High resolution typing demonstrated previously undetected 
mismatches in 53% (158), indeed 26% (79) pairs were mismatched for multiple alleles. Mismatch of class I 
HLA was found at one locus in 55 pairs (18%) and at two or more loci in 35 pairs (12%). A single 
mismatch of class II HLA was detected in 24 pairs (8%), whereas 7 pairs (2%) had multiple class II 
mismatches, and 37 pairs (12%) had multiple mismatches involving both class I and class II. These data 
show the  
 
 


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HLA Matching Requirements For Unrelated Donors At The SCCA/Fred Hutchinson Allied 
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importance of high resolution typing for defining the degree of mismatching between potential unrelated 
patient-donor pairs. 
 
 
The degree of HLA mismatch, as well as the locus of mismatch, influence the development of alloimmune 
reactions and have significant implications for the outcome of HSC transplants. Studies of patient-donor 
pairs have shown an increased risk for graft failure with multiple mismatches that involve at least one class 
I allele. The incidence of graft failure was 29% in pairs where the mismatch involved more than one class I 
allele mismatch and 12% for mismatches involving both class I and class II alleles, compared with 2% or 
less for pairs with either no mismatch or mismatch confined to a single HLA-A, B, C, DRB1 and DQB1 
allele. The risk of developing grades III-IV acute GVHD also has been shown to be influenced by the 
number and class of mismatched alleles. In studies involving primarily Caucasian patient-donor pairs, the 
highest risk for severe acute GVHD was observed for multiple mismatches involving both class I and class 
II alleles (2.0 hazard ratio and p=0.02). Pairs with a single class I mismatch did not have a significant 
increase in acute GVHD compared with matched recipients, but a single class II mismatch or multiple class 
I mismatches both appeared to confer a higher (though not significant) hazard of severe GVHD. As results 
of future studies further define risks of mismatches, particularly in nonCaucasian populations, we may be 
able to delineate more precisely “low risk” from “high risk” mismatches. Until then, the donor selection 
process should endeavor to identify the best matched donor within the time allowed by the clinical 
situation. 
 
 
References: 
1. Petersdorf EW, Longton GM, Anasetti C, Martin PJ, Mickelson EM, Smith AG, Hansen JA. The 
significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor 
marrow transplantation. Blood 1995: 86:1606-1613. 
2. Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, Smith AG, Martin PJ, Hansen JA. Definition 
of HLA-DQ as a transplantation antigen. Proc. Natl. Acad. Sci. USA 1996; 93: 15358. 
3. Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, McKinney SK, Smith AG, Martin PJ, Hansen 
JA. Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. 
Blood 1997: 89: 1818. 
4. Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson EM, Woolfrey AE, Hansen JA. 
Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I 
and II alleles in the donor and recipient. Blood 1998: 92: 3515. 
5. Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H, Yoshida T, Kimura A, Akaza 
T, Kamikawaji N, Kodera Y, Takaku F. Importance of HLA-class I allele matching for clinical outcome 
after unrelated donor hematopoietic stem cell transplantation. New Engl J Med 1998: 339: 1177. 
6. Hansen JA, Yamamoto K, Petersdorf E, Sasazuki T. The role of HLA matching in hematopoietic cell 
transplantation. Reviews in Immunogenetics 1999: 1: 359. 
7. Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, Storer B, Mickelson E, Smith 
A, Anasetti C. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell 
transplantation. New Engl J Med 2001: 345: 1794. 
8. Bodmer JG, Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Hansen JA, Mach 
B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GMTh, Strominger JL, Svejgaard A, 
Terasaki PI. Nomenclature for factors of the HLA system, 1998. Tissue Antigens 1999: 53: 407. 
9. List of known HLA allele sequences: www.anthonynolan.org.uk/HIG/data.html. 
10. Information on HLA complex: http://www.ebi.ac.uk/imgt/hla/intro.html. 
 


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References continued:  
 
11. Little AM and Parham P. Polymorphism and evolution of HLA class I and II genes and molecules. Reviews in 
Immunogenetics 1999: 1: 105. 
12. Schreuder GMTh, Hurley CK, Marsh SGE, Lau M, Maiers M, Kollman C, Noreen H. The HLA Dictionary 2001: 
A summary of HLA-A, B, C, DRB1/3/4/5, DQB1 alleles and their association with serologically defined HLA-A, B, 
C, DR, and DQ antigens. Tissue Antigens 2001: 58: 109-140. 
13. Smith A, McKinney S, Menninger O, Warnock S, Hansen JA. Detection of a novel “nonexpression” HLA-B*15 
allele adds to data on the frequency of class I expression variants in a hematopoietic transplant population. Human 
Immunology 29th Annual ASHI Meeting Abstracts 2003: 64: S159. 
14. Hurley CK, Baxter Lowe LA, Logan B, Karanes C, Anasetti C, Weisdorf D, Confer DL. National marrow donor 
program HLA-matching guidelines for unrelated marrow transplants. Biology of Blood and Marrow Transplantation 
2003: 9. 
15. Petersdorf, E.W., Anasetti, C., Martin, P.J., Gooley, T., Radich, J., Malkki, M., Woolfrey, A., Smith, A., 
Mickelson, E., Hansen, J.A. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood, (in 
press). 
 
 
Approved by the Standard Practice Committee January 16, 2002 (Donor Selection Matching Requirements.doc) 
HLA_matching_for_URD_selection.doc 
Approved by the Medical Advisory Committee (Medical Exec. Comm.) April 9, 2002 
Approved by the Clinical Sectional Meeting April 16, 2002 
Revised by the Standard Practice Committee June 15, 2005 
Minor wording change approved by SPC chairperson March 13, 2006 
 
 
 
 
 
 


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Appendix P 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
ALLERGY/IMMUNOLOGY 
Adverse Event 
Grade 3 
Grade 4 
Allergic reaction/ hyper-
sensitivity (including drug 
fever) 
Symptomatic bronchospasm, 
requiring parenteral medication(s), 
with or without urticaria; allergy-
related edema/angioedema  
 
Anaphylaxis  
Vasculitis  
Requiring steroids  
Ischemic changes or requiring 
amputation 
 
Allergy/Immunology – Other 
(specify):________________ 
 
Severe 
Life-threatening or disabling  
BLOOD/BONE MARROW 
Adverse Event 
Grade 3 
Grade 4 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis, other) 
Requiring transfusion and/or 
medical intervention (e.g., 
steroids) 
Catastrophic consequences of hemolysis 
(e.g., renal failure, hypotension, 
bronchospasm, emergency 
splenectomy)  
 
For BMT studies, if specified 
in the protocol.   
 
 
 
For pediatric BMT studies, if 
specified in the protocol.   
>4 u pRBC in 24 hours  
 
 
 
 
>30mL/kg in 24 hours 
Hemorrhage or hemolysis associated 
with life-threatening anemia; medical 
intervention required to improve 
hemoglobin  
 
Hemorrhage or hemolysis associated 
with life-threatening anemia; medical 
intervention required to improve 
hemoglobin 
 
CARDIOVASCULAR - ARRHYTHMIA 
Adverse Event 
Grade 3 
Grade 4 
Cardiovascular/Arrhythmia -
Other (specify): __________ 
_______________________ 
Symptomatic, and requiring 
treatment of underlying cause 
Life-threatening (e.g., arrhythmia 
associated with CHF, hypotension, 
syncope, shock) 
 
CARDIOVASCULAR - GENERAL 
Adverse Event 
Grade 3 
Grade 4 
Acute vascular leak syndrome Respiratory compromise or 
requiring fluids 
Life-threatening;  requiring pressor 
support and/or ventilatory/support 
 
Cardiac-ischemia/infarction 
Angina without evidence of 
infarction 
 
Acute myocardial infarction 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
CARDIOVASCULAR - GENERAL (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
Cardiac left ventricular 
function 
CHF responsive to treatment 
Severe or refractory CHF or requiring 
intubation 
 
Cardiac troponin I (cTnI) 
Levels consistent with unstable 
angina as defined by the 
manufacturer 
Levels consistent with myocardial 
infarction as defined by the 
manufacturer 
 
Cardiac troponin T (cTnT) 
 0.1 - <0.2ng/mL 
 0.2ng/mL 
 
Hypotension 
 
  
Requiring therapy and sustained 
medical attention, but resolves 
without persisting physiologic 
consequences 
 
Shock (associated with acidemia and 
impairing vital organ function due to 
tissue hypoperfusion) 
Myocarditis  
CHF responsive to treatment 
 
Severe or refractory CHF 
Pericardial effusion/ 
pericarditis 
With physiologic consequences 
Tamponade (drainage or pericardial 
window required) 
 
Syncope (fainting) is graded 
in the Neurology category.   
 
- 
- 
Thrombosis/embolism 
Deep vein thrombosis, requiring 
anticoagulant therapy 
Embolic event including pulmonary 
embolism 
 
Vein/artery operative injury is 
graded as Operative injury of 
vein/artery in the 
Cardiovascular (general) 
category. 
 
 
 
Cardiovascular/General – 
Other (specify):___________ 
 
Severe 
Life-threatening or disabling 
 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
COAGULATION 
Adverse Event 
Grade 3 
Grade 4 
DIC (disseminated intravascular 
coagulation) 
 
Also consider 
Platelets. 
 
Note:  Must have increased fibrin 
split products or D-dimer in order 
to grade as DIC. 
 
Laboratory findings present with 
no bleeding 
Laboratory findings and bleeding  
Thrombotic microangiopathy 
(e.g., thrombotic 
thrombocytopenic purpura/TTA or 
hemolytic uremic syndrome/HUS) 
 
 
 
Also consider  
Hemoglobin, platelets, creatinine.  
 
Note:  Must have micro-
angiopathic changes on blood 
smear (e.g., schistocytes, helmet 
cells, red cell fragments).  
 
Laboratory findings present 
without clinical consequences  
 
 
 
 
 
Evidence of RBC destruction with 
creatinine (>3 x ULN) not 
requiring dialysis  
Laboratory findings and clinical 
consequences, (e.g., CNS 
hemorrhage/bleeding or 
thrombosis/embolism or renal 
failure) requiring therapeutic 
intervention  
 
Evidence of RBC destruction with 
renal failure requiring dialysis 
and/or encephalopathy. 
 
Coagulation - Other (specify): 
_________________________ 
 
Severe 
Life-threatening or disabling  
CONSTITUTIONAL SYMPTOMS 
Adverse Event 
Grade 3 
Grade 4 
Weight gain associated with 
Veno-Occlusive Disease (VOD) 
for BMT studies, if specified in 
the protocol.  
 
Also consider  
Ascites Edema, Pleural effusion 
(non-malignant). 
>10% or as ascites 
>10% or fluid retention resulting in 
pulmonary failure 
DERMATOLOGY/SKIN 
Adverse Event 
Grade 3 
Grade 4 
Erythema multiforme (e.g., 
Stevens-Johnson syndrome, toxic 
epidermal necrolysis) 
Severe or requiring IV fluids (e.g., 
generalized rash or painful 
stomatitis) 
Life-threatening (e.g., exfoliative or 
ulcerating dermatitis or requiring 
enteral or parenteral nutritional 
support) 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
DERMATOLOGY/SKIN (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
Rash/desquamation associated 
with graft versus host disease 
(GVHD) for BMT studies, if 
specified in the protocol. 
Symptomatic generalized 
erythroderma or symptomatic 
macular, papular or vesicular 
eruption, with bullous formation, 
or desquamation covering 50% of 
body surface area. 
 
Generalized exfoliative dermatitis 
or ulcerative dermatitis or bullous 
formation 
 
GASTROINTESTINAL 
Ascites (none-malignant) 
Symptomatic, requiring 
therapeutic paracentesis  
 
Life-threatening physiologic 
consequences 
Colitis  
 
 
Also consider  
Hemorrhage/ bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
melena/GI bleeding, rectal 
bleeding/hematochezia, 
hypotension.   
 
Abdominal pain, fever, change in 
bowel habits with ileus or 
peritoneal signs, and radiographic 
or biopsy documentation 
Perforation or requiring surgery or 
toxic megacolon 
Diarrhea associated with graft 
versus host disease (GVHD) for 
BMT studies, if specified in the 
protocol. 
 
For pediatric BMT studies, if 
specified in the protocol. 
 
Also consider  
Hemorrhage/ bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
pain, dehydration, hypotension. 
 
>1500mL of diarrhea/day 
 
 
 
 
>15mL/kg of diarrhea/day 
Severe abdominal pain with or 
without ileus 
 
 
 
 
 
 
 
Duodenal ulcer (requires 
radiographic or endoscopic 
documentation) 
Uncontrolled by outpatient 
medical management; requiring 
hospitalization 
 
Perforation or bleeding, requiring 
emergency surgery 
 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
GASTROINTESTINAL (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
Gastric ulcer (requires 
radiographic or endoscopic 
documentation) 
 
Also consider  
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
 
Bleeding without perforation, 
uncontrolled by outpatient medical 
management; requiring 
hospitalization or surgery 
Perforation or bleeding, requiring 
emergency surgery 
Gastritis 
 
Also consider  
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
 
Uncontrolled by out-patient 
medical management; requiring 
hospitalization or surgery 
Life-threatening bleeding, requiring 
emergency surgery 
Pancreatitis 
 
Also consider  
Hypotension. 
 
Note:  Amylase is graded in the 
METABOLIC/LABORATORY 
category. 
 
Abdominal pain with pancreatic 
enzyme elevation 
Complicated by shock (acute 
circulatory failure) 
Mucositis 
 
Note:  Radiation-related mucositis 
is graded as Mucositis due to 
radiation. 
 
Painless erythema, edema, or 
ulcers preventing swallowing or 
requiring hydration or parenteral 
(or enteral) nutritional support 
Severe ulceration requiring 
prophylactic intubation or resulting 
in documented aspiration 
pneumonia 
Typhlitis 
(inflammation of the cecum) 
 
Also consider  
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
hypotension, febrile neutropenia.  
 
Abdominal pain, diarrhea, fever, 
and radiographic or biopsy 
documentation 
Perforation, bleeding or necrosis or 
other life-threatening complication 
requiring surgical intervention (e.g., 
colostomy) 
 
 
 
 
 
 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
HEMORRHAGE 
Notes:   
Transfusion in this section refers to pRBC infusion. 
For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to 
grading severity by grading the site or type of bleeding.   
 
If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: 
NS Hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, 
Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/ 
hematochezia, Vaginal bleeding. 
 
Adverse Event 
Grade 3 
Grade 4 
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia   
 
Also consider  
Platelets, hemoglobin, transfusion: 
platelets, transfusion: pRBCs, site 
or type of bleeding.  
 
If the site is not listed, grade as 
Hemorrhage – Other (specify 
site):___________ 
 
Note:  This adverse event must be 
graded for any bleeding with 
grade 3 or 4 thrombocytopenia. 
 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
 
 
 
 
 
 
 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
HEMORRHAGE (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
CNS hemorrhage/bleeding 
Bleeding noted on CT or other 
scan with no clinical consequences 
Hemorrhagic stroke or hemorrhagic 
vascular event (CVA) with 
neurologic signs and symptoms 
 
Hemoptysis  
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
 
Melena/GI bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Rectal bleeding/hematochezia 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Vaginal bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Hemorrhage – Other (specify 
site): _____________________ 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
HEPATIC 
Adverse Event 
Grade 3 
Grade 4 
Bilirubin  
 
Bilirubin associated with graft 
versus host disease (GVHD) for 
BMT studies, if specified in the 
protocol. 
 
>3.0 – 10.0 x ULN 
 
>6 - <15mg/100mL 
>10.0 x ULN 
 
>15mg/100mL 
INFECTION/FEBRILE NEUTROPENIA 
Adverse Event 
Grade 3 
Grade 4 
Febrile neutropenia (fever of 
unknown origin without clinically 
or microbiologically documented 
infection). 
 
Present 
Life-threatening sepsis (e.g., septic 
shock) 
Infection/Febrile Neutropenia – 
Other (specify): ______________ 
 
Severe 
Life-threatening or disabling 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
NEUROLOGY 
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Adverse Event 
Grade 3 
Grade 4 
CNS cerebrovascular ischemia 
Transient ischemic event or attack 
(TIA) 
Permanent event (e.g., 
cerebral vascular accident) 
 
Leukoencephalopathy associated 
radiological findings 
Severe increase in SAS; severe 
ventriculomegaly; near total white 
matter T2 hyperintensities or 
diffuse low attenuation (CT); focal 
white matter necrosis (cystic) 
Severe increase in SAS; 
severe ventriculomegaly; 
diffuse low attenuation with 
calcification (CT); diffuse 
white matter necrosis (MRI) 
 
Seizure(s) 
Seizure(s) in which consciousness 
is altered  
Seizures of any type which 
are prolonged, repetitive, or 
difficult to control (e.g., 
status epilepticus, intractable 
epilepsy) 
 
PULMONARY 
Adverse Event 
Grade 3 
Grade 4 
Adult Respiratory Distress Syndrome 
(ARDS) 
 
- 
Present 
Apnea 
 
Present 
Requiring intubation 
Carbon monoxide diffusion capacity 
(DLCO) 
 
>25 - <50% of pretreatment or 
normal value 
<25% of pretreatment or 
normal value 
FEV1 
>25 - <50% of pretreatment or 
normal value 
 
<25% of pretreatment or 
normal value 
Hypoxia 
Decreased O2 saturation at rest, 
requiring supplemental oxygen 
Decreased O2 saturation, 
requiring pressure support 
(CPAP) or assisted 
ventilation 
 


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Appendix P (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
RENAL/GENITOURINARY  
Adverse Event 
Grade 3 
Grade 4 
Creatinine 
 
Note:  Adjust to age-appropriate 
levels for pediatric patients. 
 
>3.0- 6.0 x ULN 
>6.0 x ULN 
Renal failure 
 
Requiring dialysis, but reversible 
Requiring dialysis and irreversible 
SECONDARY MALIGNANCY 
Adverse Event 
Grade 3 
Grade 4 
Secondary Malignancy – Other 
(specify type): _______________  
 
Excludes metastasis from initial 
primary. 
 
- 
Present 
 
 
 
 


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Appendix Q 
The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 9/7/10 
 
Assign scores appropriately if the patient has any of these comorbidities 
 
Patient ___________________________________ (name), UPN______________ Date_____________ 
Instructions: Circle applicable scores and provide actual value or cause of co-morbidity. Fax to FHCRC 
w/registration. 
Comorbidities 
Definitions 
HCT-CI scores 
Actual Lab 
Values/Comments 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, 
and ventricular arrhythmias requiring treatment 
in the patient’s past history 
1 
 
Cardiac 
Coronary artery disease†, congestive heart failure, 
myocardial infarction in patient’s past history or 
EF of 50% at time of HCT 
1 
 
Inflammatory bowel 
disease 
Crohn’s disease or ulcerative colitis requiring 
treatment in the patient’s past history 
1 
 
Diabetes 
Requiring treatment with insulin or oral 
hypoglycemic, but not diet alone, at time of HCT 
1 
 
Cerebro-vascular 
disease 
Transient ischemic attack or cerebro-vascular 
accident in patient’s past history 
1 
 
Psychiatric disturbance 
Depression/anxiety requiring psychiatric consult 
or treatment at time of HCT 
1 
 
Hepatic – mild 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN at time of HCT 
1 
 
Obesity 
Patients with a BMI of 
>35 for adults or with BMI-for-age percentile of 
≥ 95th percentile for children at time of HCT 
1 
 
Infection 
Documented infection or fever of unknown 
etiology requiring anti-microbial treatment before, 
during and after the start of conditioning regimen 
1 
 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica in patient’s past history  
2 
 
Peptic ulcer 
Requiring treatment in patient’s past history 
2 
 
Renal 
Serum creatinine >2 mg/dl, on dialysis, or prior 
renal transplantation at time of HCT 
2 
 
Moderate pulmonary 
DLco and/or FEV1 >65%-80% or 
Dyspnea on slight activity at time of HCT 
2 
 
Prior solid tumor 
Treated at any time point in the patient’s past 
history, excluding non-melanoma skin cancer 
3 
 
Heart valve disease 
At time of HCT excluding mitral valve prolapse 
3 
 
Severe pulmonary 
DLco and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen at time of 
HCT 
3 
 
Moderate/severe 
hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or 
AST/ALT >2.5XULN at time of HCT 
3 
 
Please provide (KPS): 
 
Karnofsky Performance Score = _______% 
Total Score 
=________ 
Signature of Provider: 
________________ 


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†One or more vessel-coronary artery stenosis, requiring medical treatment, stent, or bypass graft. 
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythmatosis; RA, rheumatoid arthritis; CTD, connective 
tissue disease; DLco, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; AST, aspartate aminotransferase; 
ALT, alanine aminotransferase. 
 


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Appendix R 
WHO classification and IPSS score 
 
 
WHO Classification and criteria for the myelodysplastic syndromes 
 
 
  
 
 
 
 


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Appendix R (cont’d) 
WHO classification and IPSS score 
 
IPSS score 
 
 


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Appendix S 
 
Weight / Adjusted Body Weight for Drug Dosing 
 
weight_for_drug_do
sing.pdf
 
 
 
 
 
 


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Appendix T 
 
Radiotherapy Treatment Guidelines per Standard Practice 
 
 
TBI_Adult_Non_Myel
oablative.pdf
                                      
TBI_Pediatric_NON_
Myeloablative.pdf  
 
 
 
 


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Appendix U 
 
 
COORDINATING CENTER FUNCTIONS 
Outside Center – PI Communication in Hematologic Malignancies 
 
I. 
Study Management, data analysis, and Data and Safety Monitoring 
 
a. Study Management: 
i. 
Each local PI is responsible for selection, training and oversight of local study 
coordinators 
ii. 
The Coordinating Center registers subjects on the study and assigns study IDs 
iii. 
One copy of the research data is retained by the site. Another data set (identified only 
by study IDs) is transmitted to the Coordinating Center to create the master data file. 
All data are kept in locked areas and password protected databases accessible only to 
study staff 
iv. 
The quality of data is monitored in an ongoing fashion with the study team and 
corrective action plans instituted as necessary  
b. Data Analysis: 
i. 
Study staff review data for completeness as it is submitted by the sites 
ii. 
The study statistician is responsible for data cleaning and the conduct of analyses as 
outlined in the protocol and grant 
c. Data Safety and Monitoring: 
i. 
The trial coordinators at collaborating centers or the local PIs will report SAEs (as 
defined by the protocol) to the Coordinating Center and an official report of an SAE is 
faxed to the Coordinating Center within ten days 
ii. 
The SAE report is reviewed by the Overall PI. If the SAE meets the FHCRC criteria 
for expedited reporting then an official signed report is submitted to the IRB 
iii. 
An independent DSMB will meet at six-month intervals and all outcome data is 
reviewed including all adverse events and SAEs reported to the Coordinating Center 
along with those officially reported to the IRB 
iv. 
A report from the DSMB is submitted to the IRB as well as the trial coordinators/local 
PIs participating in the protocol 
 
II.  
Protocol and informed consent document management 
a. A master protocol is maintained by the Coordinating Center and distributed to the sites for 
customization and local IRB review 
b. All protocol and consent modifications initiated by the Coordinating Center are sent to the 
Collaborating Sites following approval by the Coordinating Center IRB, for review and 
approval by the local IRB 
c. Changes required by local IRBs are reviewed by the Coordinating Center and approved prior 
to implementation at local sites 
 
III. 
Assurance of local IRB OHRP-approved assurance 
a. Each site provides their OHRP assurance number and evidence of IRB certification 
b. Study staff monitor maintenance of institutional assurance and IRB certification 
 
 
 
 
 
 


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IV. 
Assurance of local IRB approvals 
a. The Coordinating Center maintains copies of the most current collaborating site Consent 
Forms and IRB approval documentation 
b. No site may enroll subjects until the Coordinating Center has received confirmation of local 
IRB approval 
c. Each site is responsible for preparation and submission of their continuing reviews. Any 
changes to the protocol or consent form will be communicated to the Coordinating Center 
d. Sites are required to have active IRB approvals to participate in any study related activities 
 
V. 
Any substantive modification by the Collaborating Institution related to risks or alternative 
procedures is appropriately justified 
a.   The Coordinating Center reviews any modifications to consent forms to ensure that site 
consents do not delete or change the basic or additional elements or alternatives required in 
the sample consent form 
 
VI. 
Informed consent is obtained from each subject in compliance with HHS regulations 
a. Subjects must provide written informed consent prior to study participation 
b. The Coordinating Center verifies eligibility and signed consent prior to assigning a study ID 
number 
 
 
 
 
 


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APPENDIX V 
Standard Donor Consent 
standard donor 
consent.pdf