Clinical trial NCT00119366
Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Childhood Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Myeloid Leukemia Refractory Anemia With Excess Blasts Refractory Anemia With Excess Blasts in Transformation Refractory Anemia With Ringed Sideroblasts Refractory Cytopenia With Multilineage Dysplasia Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndromes
Sponsor: Fred Hutchinson Cancer Center
Start date: 2003-05-01; Completion date: 2019-05-08
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase II trial studies the side effects and best dose of iodine I 131 monoclonal antibody BC8 when given together with fludarabine phosphate, total-body irradiation, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer or abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. Also, radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving fludarabine phosphate and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody together with donor stem cell transplant, cyclosporine, and mycophenolate mofetil may be an effective treatment for advanced acute myeloid leukemia or myelodysplastic syndromes.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the maximum tolerated dose (MTD) and the transplant-related mortality (TRM) and toxicity of delivering 131I-BC8 (iodine I 131 monoclonal antibody BC8) (anti-cluster of differentiation \[CD\]45 antibody) at a starting dose of 22 Gy to the normal organ receiving the highest dose in combination with the non-myeloablative regimen of fludarabine (fludarabine phosphate) (FLU), 2 Gy total body irradiation (TBI), cyclosporine (CSP), mycophenolate mofetil (MMF), and human leukocyte antigen (HLA)-matched related or unrelated allogeneic hematopoietic stem cell transplant (HSCT) in patients 16 to 50 years old who have advanced acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS).

II. To estimate rates of donor chimerism resulting from this combined preparative regimen and to correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic tissues via antibody.

III. To determine rates of disease relapse, graft vs. host disease, and 2-year disease-free survival in patients receiving 131I-BC8 antibody combined with FLU, 2 Gy TBI, CSP, MMF, and HLA-matched related or unrelated allogeneic HSCT.

OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.

RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 intravenously (IV) on day -12.

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

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO thrice daily (TID) on days 0 to 40 followed by a taper to day 96.

After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months and then annually thereafter.

Arms: arm 1: RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12.

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

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. arm 2: RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12.

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

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. arm 3: RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12.

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

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. arm 4: RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12.

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

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96. arm 5: RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12.

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

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96.
Interventions: intervention 1: iodine I 131 monoclonal antibody BC8 intervention 2: fludarabine phosphate intervention 3: total-body irradiation intervention 4: allogeneic hematopoietic stem cell transplantation intervention 5: peripheral blood stem cell transplantation intervention 6: cyclosporine intervention 7: mycophenolate mofetil intervention 8: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo TBI intervention 4: Undergo PBSC transplantation intervention 5: Undergo PBSC transplantation intervention 6: Given IV or PO intervention 7: Given PO intervention 8: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
FHCRC Protocol Cover Page 
 
 
FHCRC Protocol 1809: 
A Phase II Trial Combining Radiolabeled BC8 (Anti‐CD45) Antibody with Fludarabine and Low Dose TBI 
Followed by Related or Unrelated PBSC Infusion and Post‐Transplant Immunosuppression for Patients 
with Advanced AML or High Risk Myelodysplastic Syndrome 
 
Version: 9/17/2014 
 
NCT#:  NCT00119366 


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1 
 FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current Version: 9/17/2014 
Previous version: 5/28/2014 
 
1. A Phase II Trial Combining Radiolabeled BC8 (Anti-CD45) Antibody with Fludarabine and 
Low Dose TBI Followed by Related or Unrelated PBSC Infusion and Post-Transplant 
Immunosuppression for Patients with Advanced AML or High Risk Myelodysplastic 
Syndrome 
 
Principal Investigator:   
J.J. Orozco, M.D., Ph.D., Research Associate Member, FHCRC, 667-4102 
Co-Investigators:  
O. Press, M.D., Ph.D., Member, FHCRC, Professor of Medicine, UW 
F.R. Appelbaum, M.D., Member, FHCRC, Professor of Medicine, UW 
J. Rajendran, M.D., Professor, UW 
M. Matesan, M.D., Ph.D., UW Nuclear Medicine Dose Reviewer 
R. Storb, M.D., Member, FHCRC, Professor of Medicine, UW 
A. Gopal, M.D., Associate Professor, UW, Associate Member, FHCRC 
A.T. Shields, M.D., Clinical Assistant Professor, Radiology, UW 
P. Martin, M.D., Member, FHCRC, Professor of Medicine, UW 
B. Sandmaier, M.D., Member, FHCRC, Professor of Medicine, UW 
D. Maloney, M.D., Ph.D., Member, FHCRC, Professor of Medicine, UW 
 
 
Biostatistician: T. Gooley, Ph.D., Member, FHCRC (667-6533) 
 
Research Nurse: 
Sally Lundberg, R.N., 206-667-5184; Pager 206-540-1550 
Robyn Haaf, R.N., 206-667-5974; Pager 206-416-6445 
 
Emergency (24 hour) Phone: (206) 598-8902  
 
Fax: (206) 598-4034 
 
 
DADE MOELLER HEALTH GROUP: 
 
D.R. Fisher, Ph.D., Principal Dosimetrist, Dade Moeller Health Group, Affiliate Associate Professor, 
UW 


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2. Introduction 
 
A. Protocol Summary 
 
This trial combines targeted hematopoietic radiation delivered by 131I-BC8 antibody with the 
non-myeloablative transplantation approach in an effort to improve disease control, without substantially 
increasing the toxicity of the transplant regimen, for patients with advanced acute myeloid leukemia 
(AML) beyond first remission, with primary refractory disease, or evolved from myelodysplastic or 
myeloproliferative syndromes; and patients with high risk myelodysplastic syndrome (MDS).  
Specifically, this study will assess the feasibility and safety for patients with advanced AML or high risk 
MDS treated with 131I-BC8 antibody at a starting dose of 22 Gy delivered to the normal organ receiving 
the highest dose combined with fludarabine and 2 Gy total body irradiation (TBI), plus cyclosporine 
(CSP)/mycophenolate mofetil (MMF), followed by matched related or unrelated allogeneic 
hematopoietic stem cell transplantation (HSCT).  Determination of the maximum tolerated dose (MTD) 
will be the major study endpoint.  The study will also estimate the rates of transplant-related mortality 
(TRM), disease response and disease-free survival, and determine rates of donor chimerism and graft 
versus host disease (GVHD). 
 
B. Overview 
 
Allogeneic HSCT using standard myeloablative preparative regimens for patients with high-risk 
AML has been associated with an approximate 50% 5-year mortality from non-relapse causes and more 
than 75% of these events occur within the first 200 days after transplantation.  Moreover, the cumulative 
incidence of leukemic relapse remains high with standard unrelated HSCT and the probability of 
leukemia free survival (LFS) has been found to be <30% in patients transplanted in second remission or 
beyond1.  We have used 131I-labeled-anti-CD45 antibody to deliver targeted hematopoietic irradiation to 
marrow, spleen and lymph nodes in an effort to improve leukemia cell kill and decrease relapse for 
advanced AML patients with encouraging results.  Despite being able to deliver an additional average of 
25 Gy to bone marrow and 50 Gy to spleen using targeted radiation therapy, high rates of TRM (~50%) 
and associated poor outcome has limited our success of conventional HSCT in combination with 131I-
labeled-BC8 antibody (murine anti-human-CD45).   
 
In an effort to reduce the TRM associated with allogeneic HSCT and generate a graft vs. 
leukemia (GVL) effect for advanced AML/MDS patients, reduced intensity non-myeloablative 
allogeneic conditioning regimens have been developed that have been designed to be 
immunosuppressive to permit donor engraftment and to limit systemic toxicity.  These non-
myeloablative approaches, however, have been most successful in patients with chronic leukemias or 
with acute leukemias in remission.  The majority of patients with AML/MDS undergoing non-
myeloablative HSCT while in active relapse have subsequently relapsed with their disease relatively 
rapidly after transplantation.  The overall objective of this protocol is to reduce leukemic disease burden 
without adding excessive toxicity using targeted hematopoietic irradiation delivered by 131I-anti-CD45 
antibody combined with the non-myeloablative transplantation regimen.  It is unknown, however, if 
targeted hematopoietic irradiation delivered by 131I-anti-CD45 mAb can be added safely to the reduced 
intensity conditioning transplant regimen without a marked increase in TRM.  Therefore, we will 
estimate the MTD and the rate of TRM among patients receiving a conditioning approach using 
fludarabine and 2 Gy TBI coupled with 22 Gy (starting dose) of radiation delivered by 131I-anti-CD45 
mAb to the normal organ receiving the highest dose.  We believe that the day 200 TRM rate using a 
non-myeloablative regimen will be less than the 50% seen with conventional HSCT.  This reduction in 


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3 
TRM should translate into an increased overall survival rate for patients receiving a “mini”-transplant, 
even if no improvement in the rate of relapse is detected.  For example, for every 100 patients treated 
with standard allogeneic HSCT, a ~50% rate of relapse and a ~40% rate of day 200 TRM results in 30 
patients surviving leukemia free.  Conversely, a 20% improvement in the day 200 TRM rate for this 
same population of 100 patients transplanted using 131I-anti-CD45 antibody combined with the non-
myeloablative transplantation regimen would translate into 40 patients remaining alive without disease.   
 
3. Background 
 
 
Despite many improvements in bone marrow transplantation over more than two decades, the 
disease-free survival for patients transplanted for advanced AML remains relatively poor.  Relapse 
continues to be the major cause of failure for AML patients transplanted at advanced disease stage; 
relapse rates of up to 60% have been seen for patients transplanted while in relapse2-4.  Rates of relapse 
for a given stage of myeloid malignancy are often lower for recipients of unrelated marrow as compared 
to related marrow, presumably because of a greater degree of graft-versus-leukemia (GVL) effect.  
Relapse rates in excess of 40% were still seen, however, in patients transplanted with refractory or 
relapsed acute leukemia in a recent series of 161 patients receiving allogeneic HSCT1.  Moreover, 81% 
of the events seen in this study occurred within the first 100 days and 19% thereafter.  Disease status at 
time of transplant was the most important prognostic factor with the worst leukemia-free survival (LFS) 
seen in the patients with the most advanced leukemia.  The outcome was most encouraging in patients 
grafted during first complete remission (CR); the cumulative incidence of relapse in the first CR patients 
of this study was 19% at 4 years.  Patients receiving allografts in relapse had a very poor outcome with 
only 7% LFS at 5 years due to both high relapse rates and high mortality from non-relapse causes.  
Efforts to decrease the incidence of disease relapse have primarily included intensifying the transplant 
preparative regimen.  Several studies support a dose-response effect for myeloid leukemias to radiation 
and previous work by Clift et al. determined that increasing the TBI dose from 12 to 15.75 Gy in 
transplant preparative regimens could significantly decrease post-transplant relapse of acute and chronic 
myeloid malignancies [12% versus 35% for AML, 0% versus 25% for chronic myeloid leukemia, 
(CML)]5,6.  In each study, however, the higher TBI dose was associated with a higher rate of TRM, such 
that there were no significant differences in disease-free survival in either study.  These and other 
studies confirm that conventional transplant preparative regimens are at the limit of normal organ 
tolerance.  Therefore, more effective and yet more tolerable conditioning regimens are needed for 
patients with advanced AML considered for allogeneic transplantation. 
 
The anti-leukemic effects of radioimmunoconjugates that selectively deliver irradiation to 
targeted leukemic blasts, with less toxicity inflicted on normal tissues, have been investigated as therapy 
for myeloid malignancies in the hope that cure rates could be significantly improved.  The CD45 (T200) 
antigen is an attractive target for immunotherapy since the vast majority of hematologic malignancies 
express CD45, including 85-90% of acute myeloid leukemias, and this antigen is not found on tissues of 
non-hematopoietic origin7-9.  An antibody reactive with the CD45 antigen targets the primary sites of 
leukemic cell involvement in AML (the marrow and spleen), as well as lymphoid tissue.  By selecting 
an antibody reactive with normal myeloid precursors and all mature leukocytes, most malignant blasts, 
including blasts scattered in normal myeloid and lymphoid tissue, should receive relatively high doses of 
radiation given that the surrounding normal hematopoietic cells will be targeted as well.  For this reason, 
131I-anti-CD45 mAb (BC8) may offer clinical benefit both to patients with active disease and to those in 
remission.  Encouraging phase I results have been demonstrated using 131I-BC8 antibody combined with 


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4 
a transplant regimen employing 120 mg/kg cyclophosphamide (CY) and 12 Gy TBI for therapy of acute 
leukemias10.  Biodistribution of trace-labeled antibody was initially determined in 41 patients with 
advanced AML or acute lymphocytic leukemia (ALL), and 3 patients with advanced myelodysplastic 
syndrome (MDS).  The dose of 131I delivered to each patient was determined from dosimetry studies, 
and was escalated in cohorts of 3-7 patients to deliver estimated radiation doses of 3.5 Gy to 12.25 Gy to 
the normal organ receiving the highest dose.  Most (84%) patients had favorable biodistribution of 
monoclonal antibody (mAb), with improved therapeutic ratios of radiation delivered to marrow and 
spleen as compared to liver (2.3 and 4.8 times higher than liver, respectively).  Thirty-four patients were 
treated with the amount of 131I estimated to deliver from Dose level 1 (3.5 Gy) to level 6 (12.25 Gy) to 
the normal organ receiving the highest dose.  The average estimated radiation absorbed doses delivered 
to marrow and spleen, average 131I doses, and Grade III/IV toxicities (defined using Bearman criteria) at 
each dose level are summarized in Table 1.   
 
Table 1:  FHCRC #557 (Phase I Study) -- 131I Activity Administered, Total Radiation Absorbed Doses, 
and Grade III/IV Regimen-Related Toxicities 
Gy to Liver 
(Dose Level) 
(number) 
mCi 131I 
Mean ± SD 
(range)  
Gy to Marrow 
Mean ± SD 
(range) 
Gy to Spleen 
Mean ± SD 
(range) 
 
 
Grade III/IV Toxicities 
3.5  
(Level 1) 
 
(n=7) 
148±42 
(76-206) 
7.3±1.7 
(4-9) 
14.4±5.0 
(7.5-22.1) 
III GI – 1 pt. 
(1 N.E.) 
5.25  
(Level 2) 
 
(n=7) 
215±55 
(142-309) 
12.6±2.5 
(10.5-17.7) 
16.6±4.0 
(9.1-21.7) 
No 
(1 N.E.) 
7.0  
(Level 3) 
 
(n=6) 
250±83 
(149-389) 
24.8±6.1 
(13.2-30.6) 
36.5±13.8 
(22.9-59.2) 
IV Marrow – 1 pt. 
8.75  
(Level 4)a 
 
(n=3)  
304±92 
(226-405) 
20.4±7.3 
(14.7-28.6) 
52.4±10.0 
(41.7-61.5) 
No 
10.5 
(Level 5)a 
 
(n=6) 
255±73 
(148-350) 
18.3±5.5 
(11.6-24.0) 
61.7±21.1 
(34.0-92.8) 
Grade III Hepatic – 1 pt. 
12.25 (Level 6) 
 
(n=2) 
549 
(486-613) 
26.0 
(24.1-28.0) 
55.2 
(46.7-63.7) 
Grade III Mucosal – 1 pt. 
Grade III+ Mucosal – 1 pt. 
aThree patients scheduled to be treated at these dose levels (two at Level 4, one at Level 5) had their radiation absorbed dose 
to liver limited so that dose to marrow would not exceed 28 Gy.  These patients received 283, 275, and 459 mCi 131I 
delivering estimated radiation doses to liver of 4.8, 6.1, and 9.2 Gy respectively.  These patients had no Grade III/IV 
toxicities and were not counted as evaluable patients for purposes of dose escalation. 
 
 
Of 25 patients with advanced AML or MDS treated on study, three died of infection in the 
early post-transplant period, one died of infection 4 months post transplant, and one patient with poor 
engraftment after receiving a 4-HC-purged autologous marrow died 54 months post transplant with 
infection.  Thirteen patients relapsed 2 to 77 months post transplant (Fig. 1).  Seven patients survive 
disease free 15 to 89 months (median 65 months) post-transplant.  Of the 9 patients with advanced acute 
lymphocytic leukemia (ALL), 2 died of infection, and 4 relapsed 0.5 to 11 months post-transplant.  
Three survive disease-free 23, 58, and 70 months post transplant.  At the maximum tolerated dose 
(MTD) of 10.5 Gy, it was determined that 131I-anti-CD45 antibody in combination with CY and TBI 
could deliver up to an additional dose of 24 Gy to marrow and 50 Gy to spleen.  This study 


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5 
0
12
24
36
48
60
72
84
0
20
40
60
80
100
AML/MDS
ALL
Months after transplant
% Survival
Fig. 1: Disease-free survival for patients receiving 131I-BC8 
Antibody/Cy/12 Gy TBI on FHCRC Protocol #557. 
demonstrated that ratios of at least 2 to 1 of 
radiation delivered to the target organs of 
marrow and spleen, as compared to the normal 
organ receiving the highest dose, can be 
reliably achieved in patients who are either in 
remission or acute leukemic relapse.  An 
incremental dose of at least 10.5 Gy to the liver 
(with less to lung, kidney, and total body) 
delivered by 131I-labeled BC8 has been well-
tolerated when administered in addition to 
cyclophosphamide 120 mg/kg and 1200 cGy 
TBI in patients under age 55.   
 
 
More recently we have conducted a 
Phase II study of I-131-anti-CD45 antibody 
combined with CY/TBI for patients with 
advanced AML and MDS (FHCRC Protocol #1297). Twenty-six patients, 10 to 55 (median 39) years 
old, with AML (5 CR2, 18 relapse or refractory) or MDS (1 RAEB, 2 RAEBT) have received a test 
infusion of BC8 antibody trace-labeled with I-131. Favorable biodistribution, with estimated radiation 
absorbed dose to bone marrow and spleen > to liver (normal organ receiving the highest dose), was 
observed in 24 (92%) patients.  Twenty patients received a therapy infusion of 0.5 mg/kg of antibody 
labeled with 127-389 (median 252) mCi of 131I, followed by 120 mg/kg CY over 2 days, 12 Gy TBI 
over 3 days and a matched related (n=9) or unrelated (n=11) HSCT.  Since the toxicity with 
conventional transplant regimens is higher for patients with MURD, the initial target radiation absorbed 
dose to the liver from radiolabeled antibody was set lower (8 Gy) than that for patients with MRD (10 
Gy). Three patients required a reduction from the planned liver dose to limit their marrow dose to the 
pre-established maximum of 33 Gy, with one patient receiving 8.4 instead of 10 Gy to liver, one 
receiving 6.9 instead of 8 Gy, and the third receiving 4 instead of 8 Gy. Mean estimated radiation 
absorbed doses from radiolabeled antibody were 21 + 8 Gy to marrow and 45 + 18 Gy to spleen, with a 
median of 2 (1-9.1) times greater radiation delivered to marrow than to liver. All patients engrafted 
(ANC > 500 cells/mm3) at a median of 18 (15-30) days post-HSCT. All patients experienced at least 
grade II (moderate) mucositis.  Although 4 related and 3 URD recipients are alive and disease-free at 2.2 
years (0.4 – 4.8 years) post-transplant, 6 patients have experienced TRM and 5 patients have 
experienced severe-to-fatal RRT. These results suggest that new therapeutic strategies are needed to 
reduce these rates of morbidity and TRM.   
A follow-up phase II study is underway investigating the use of 131I-anti-CD45 mAb in a 
preparative regimen for patients with AML in first remission11,12.  Fifty-six first remission patients have 
been studied with 131I-BC8 antibody.  Fifty have had favorable biodistribution of a trace-labeled dose of 
antibody (89%). Forty-three patients (median age 44, range 16-55 years) have been treated with 131I-
BC8 antibody combined with BU/CY, with the most recent 40 patients receiving estimated radiation 
doses of 5.25 Gy to the liver, the normal organ receiving the highest dose.  The most recent 13 patients 
were treated on our current active protocol, Protocol #1470.  The average estimated radiation absorbed 
dose delivered by I-131-BC8 antibody was 11 Gy to bone marrow and 29 Gy to spleen.  Of the 43 
patients treated to date, two are considered inevaluable, because they received PBSC off protocol.  
Neither of these patients experienced any Grade III/IV toxicities.  One patient is alive and disease-free 


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6 
Disease-Free Survival in
832/1470 pts
0
25
50
75
100
0
10
20
30
40
50
60
70
80
90
100
All pts (n=41)
Intermed pts (n=21)
Unfav pts (n=13)
Months post-transplant (median 47)
Percent Survival
 
Fig. 2:  Disease-free survival for patients with AML in first 
remission receiving a therapy dose of I-131-anti-CD45 
antibody combined with BU/CY on FHCRC Protocols #832 
and 1470.  Thick solid line = intermediate risk subgroup 
defined using SWOG cytogenetic criteria and lack of 
antecedent MDS or treatment with alkylating agents; thick 
dashed line = all patients, and thin solid line = poor risk 
subgroup defined by SWOG criteria and presence of 
antecedent MDS or treatment with alkylating agents. 
24 months post-transplant, and the other inevaluable patient relapsed four months post-transplant.  Five 
of the 41 evaluable patients (12%) have developed complications that were graded as Grade III/IV RRT, 
and three of these died, as did five additional patients from infection.  Seven patients (17%) have 
relapsed 3 to 13 months post-transplant.  Thus, 26 of 41 patients (63%) are surviving disease-free a 
median of 47 months post-transplant (Fig. 2).  Thirty-six patients had cytogenetics at diagnosis and were 
categorized using current Southwest Oncology Group (SWOG) criteria for cytogenetic risk group as 
follows: favorable – 1; intermediate – 23; unfavorable – 11, unknown – 1.  Two of the patients with 
intermediate-risk cytogenetics at diagnosis were considered in the unfavorable group because they 
developed AML following MDS or following treatment with alklyating agents.  Fifteen of the 21 
patients (71%) in the intermediate risk group are surviving disease-free, with two relapses (10%) and 4 
non-relapse deaths (19%).  Of the 13 patients in the unfavorable risk group, four have relapsed (31%) 
and three have died with RRT and/or infection (23%).  These data appear promising since approximately 
30% of patients with AML in first remission would be expected to develop leukemic relapse after being 
treated with standard BU/CY conditioning and stem cell transplantation13. 
 
 
As an alternative to conventional marrow transplant preparative regimens, several investigators 
have recently explored lower dose, non-myeloablative conditioning regimens.  This approach is 
designed to achieve mixed donor chimerism with the goal of optimizing a GVL effect.  The non-
myeloablative transplant regimen employs pre-transplant immunosuppression with low dose TBI and 
fludarabine, followed by intensive post-transplant immunosuppression with cyclosporine and 
mycophenolate.  The rate of day 200 TRM for patients treated with standard HLA-matched unrelated 
non-myeloablative transplantation has been found to be in the range of 10-15%, substantially less than 
that seen using conventional unrelated HSCT.  Since 1997, more than 200 patients with a variety of 
hematologic malignancies, including 12 patients with AML, have been treated with a non-myeloablative 
regimen consisting of 2 Gy TBI + CSP/MMF, 
followed by PBSC infusions from HLA-
phenotypically matched unrelated donors on a 
series of collaborative protocols at the 
FHCRC, Stanford, and the University of 
Leipzig14-18.  Given early concerns of graft 
rejection seen in some patients using the mini-
transplant approach, fludarabine has been 
included in the non-myeloablative regimen for 
patients 
regardless 
of 
their 
underlying 
diseases.  Since the time of inclusion of 
fludarabine in protocols used at FHCRC and 
Stanford, there has been an approximate 20% 
graft rejection rate for patients receiving 
unrelated donor non-myeloablative allografts.  
Engraftment has been affected by the patient’s 
diagnosis, degree of prior chemotherapy 
received, and source of stem cells, with the 
most impressive rates of engraftment seen in 
patients receiving stem cells from peripheral 


1809.00 
 
 
7 
blood as opposed to stem cells harvested from bone marrow.   
 
While this non-myeloablative transplantation approach has demonstrated impressive rates of 
engraftment with relatively low rates of non-hematologic toxicity, the GVL effect has been limited by 
the disease-stage at the time of transplantation and has been most effective in states of minimal residual 
disease.  Three of 5 patients who received a non-myeloablative unrelated donor allograft while in first 
complete remission (CR) remain alive and disease-free 15 to 29 months after transplantation.  
Conversely, only 2 of 7 patients with more advanced AML remain disease-free at 15 months.  The 
remaining advanced AML patients died following the unrelated donor non-myeloablative regimen, 
primarily due to progression or relapse of disease (1 of 3 in CR2, 3 of 3 beyond CR2, and 1 patient with 
primary refractory disease).  For patients with advanced disease and large leukemic burden, the anti-
leukemic efficacy of this mixed-chimerism approach may be improved by the addition of targeted 
hematopoietic irradiation delivered by 131I-anti-CD45 antibody to the relatively low-intensity therapy 
given in the non-myeloablative approach where the only anti-leukemic therapy is 2 Gy TBI.   
 
In an on-going study (FHCRC protocol #1432), we have examined the combination of 131I-BC8 
antibody with the non-myeloablative approach in patients over the age of 50 with advanced AML using 
HLA-matched related and unrelated donors.  To date, 25 patients have been treated on protocol #1432 
with adequate follow-up to assess toxicity and engraftment.  All patients have achieved a complete 
remission and all patients have engrafted at a median of 15 days post-transplant.  This experience 
suggests that this approach is feasible for patients with advanced AML who would be at high risk for 
TRM when using radiolabeled antibody combined with a conventional allogeneic transplant regimen.  In 
this group, the slightly greater toxicity anticipated from the addition of 131I-BC8 antibody to 2 Gy 
TBI/FLU + CSP/MMF would be warranted if the targeted radiation delivered to marrow and spleen 
decreases the leukemic burden to the extent that the GVL effect resulting from engraftment of donor T 
cells may eradicate remaining cells.   
 
The estimated MTD of radiation delivered to the normal organ receiving the highest dose by I-
131-BC8 antibody on our Phase I study (Protocol #557) was 10.5 Gy, a dose level at which only 1 of 6 
patients experienced Grade III (Bearman) regimen-related toxicity.  However, Protocol #557 combined 
I-131-BC8 antibody with a full-dose, conventional transplant regimen of 120 mg/kg cyclophosphamide 
and 12 Gy TBI, whereas this protocol combines I-131-BC8 antibody with the much lower dose, less 
toxic “non-myeloablative” (or “mini”) transplant regimen of fludarabine 90 mg/m2 and 2 Gy TBI, 
followed by the immunosuppressive regimen of cyclosporine and mycophenolate mofetil.  Patients 
receiving this non-myeloablative regimen alone have essentially no regimen-related toxicity other than 
cytopenias.  In addition, the MTD has not been reached on our Phase I study (Protocol #1432) 
combining the reduced-intensity regimen with 131-BC8 antibody.  This protocol will also combine I-
131-BC8 antibody in a similar dose escalation format with 2 Gy TBI and FLU. We anticipate that the 
combined toxicity of 22 Gy (starting dose) delivered by I-131-BC8 antibody combined with fludarabine 
and 2 Gy TBI to patients under the age of 50 on this protocol will be even less that which is anticipated 
in the older patients treated with the same dose of I-131-BC8 antibody..  The primary goals of this study 
will be to determine the MTD, rates of TRM, feasibility, and safety for patients receiving 131I-BC8 
antibody when combined with 2 Gy TBI + CSP/MMF. 
 
4. Objectives 
 
1. To evaluate the MTD and the TRM and toxicity of delivering 131I-BC8 (anti-CD45 antibody) at a 
starting dose of 22 Gy to the normal organ receiving the highest dose in combination with the 


1809.00 
 
 
8 
non-myeloablative regimen of fludarabine (FLU), 2 Gy TBI, cyclosporine (CSP), mycophenolate 
mofetil (MMF), and HLA-matched related or unrelated allogeneic hematopoietic stem cell 
transplant (HSCT) in patients 16 to 50 years old who have advanced AML or high risk MDS.   
2. To estimate rates of donor chimerism resulting from this combined preparative regimen and to 
correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic 
tissues via antibody. 
3. To determine rates of disease relapse, graft vs. host disease, and 2-year disease-free survival in 
patients receiving 131I-BC8 antibody combined with FLU, 2 Gy TBI, CSP, MMF, and HLA-
matched related or unrelated allogeneic HSCT. 
 
5. Patient Selection  
 
A.  Inclusions 
1. Patients with advanced AML defined as beyond first remission, primary refractory disease, or 
evolved from myelodysplastic or myeloproliferative syndromes; or patients with MDS expressed 
as refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in 
transformation (RAEBT [Note: classification removed under current WHO classification 
system]), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed 
sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML).   
2. Patients not in remission must have CD45-expressing leukemic blasts or myelodysplastic cells.  
Patients in remission do not require phenotyping and may have leukemia previously documented 
to be CD45 negative (because in remission patients, virtually all antibody binding is to non-
malignant cells which make up > 95% of nucleated cells in the marrow).  
3. Patients must be > 16 and < 50 years of age. 
4. Patients should have a circulating blast count of less than 10,000/mm3 (control with hydroxyurea 
or similar agent is allowed). 
5. Patients must have an estimated creatinine clearance greater than 50/ml per minute by the 
following formula (serum creatinine value must be within 28 days prior to registration):    
CrCl = (140-age) (Wt in Kg) x 0.85 (female) OR 1.0 (male) 
72 x serum Cr 
6. Patients must have normal hepatic function (bilirubin, AST and ALT < 2 times the upper limit of 
normal).   
7. Karnofsky score > 70 or ECOG < 2. 
8. Patients must have an expected survival of >60 days and must be free of active infection. 
9. Patients must have an HLA-identical sibling donor or an HLA-matched unrelated donor who 
meets standard Seattle Cancer Care Alliance (SCCA) and/or NMDP or other donor center 
criteria for PBSC donation.  Related donors should be matched by molecular methods at the 
intermediate resolution level at HLA-A, B, C, and DRB1 according to FHCRC Standard Practice 
Guidelines and to the allele level at DQB1.  Unrelated donors should be identified using 
matching criteria that follows the FHCRC Standard Practice Guidelines limiting the study to 
eligible donors that are allele matched for HLA-A, B, C, DRB1, and DQB1 (Grade 1; Appendix 
C), and accepting up to one allele mismatch as per Standard Practice Grade 2.1 for HLA-A, B, or 
C. 
 


1809.00 
 
 
9 
B.  Exclusions   
1. Circulating antibody against mouse immunoglobulin (HAMA). 
2. Prior radiation to maximally tolerated levels to any normal organ. 
3. Patients may not have symptomatic coronary artery disease and may not be on cardiac 
medications for anti-arrhythmic or inotropic effects. 
4. Inability to understand or give an informed consent. 
5. Patients who are seropositive for HIV. 
6. Perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in 
radiation isolation. 
7. Patients who have previously undergone autologous or allogeneic HSCT. 
 
6. Donor Selection 
 
Donors must meet HLA matching criteria as outlined under section 5.A.9 as well as standard SCCA 
and/or NMDP or other donor center criteria for PBSC donation. 
 
For the very few occasions where we identify a donor HPC-A from a non-NMDP source, we have 
procedures in place through our unrelated donor office to collect the information necessary to 
comply with donor testing, screening, and declaration of donor eligibility according to 21 CFR 1271.  
We require that the donor testing be performed by a U.S. CLIA approved laboratory.  In the very 
rare case where the donor testing is not able to be performed in a CLIA approved laboratory, or there 
is confirmatory testing that needs to be performed, or for any donor identified from Europe and at 
risk for CJD, we note this on the donor screening form and require that the unrelated donor Medical 
Director or the attending physician approves the use of the donor HPC-A product under Urgent 
Medical Need. 
 
7. Evaluation and Counseling of Patient and Donor  
 
 
Patients will be referred here for consideration of a marrow transplant.  The initial conference 
will be conducted by the outpatient attending physician.  A second conference will be conducted by the 
Principal Investigator, or designated sub-investigator, to describe the details of radiolabeled antibody 
administration.  The protocol will be discussed thoroughly with patient and family, and significant 
known risks to the patient described.  The stem cell transplant procedure and alternative forms of 
therapy will be presented as objectively as possible and the risks and hazards of the procedure explained 
to the patient or, in the case of minors, to the patient’s responsible family members.  Informed consent 
will be obtained using forms approved by the Institutional Review Board of the Fred Hutchinson Cancer 
Research Center. 
 
Related donors will be counseled and consented in accordance with standard Seattle Cancer Care 
Alliance procedures and using the standard donor consent form.  Unrelated donors will be counseled and 
consented according to the guidelines of the NMDP or other donor centers.   
 


1809.00 
 
 
10 
8. Protocol Registration  
 
 
Patients will be assigned to a protocol by the Clinical Coordinator’s office, which will register 
the patient 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. 
9.  
9.    Plan of Treatment  
A. Outline of Treatment Plan 
1. Basic Treatment Schema for Patients Meeting Inclusion Criteria: 
  
 
 
 
 
 
 
 
 
 
 
      + 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Transplant Day             Treatment 
-10 to -14 
131I-antibody therapeutic dose  
-11  
Rest & radiation isolation 
-10 
 
-9 
 
-8 
 
-7 
 
-6 
 
-5 
 
-4 
Fludarabine 
-3 
Fludarabine; start cyclosporine 
-2 
Fludarabine 
-1 
 
0 
2 Gy TBI, HSCT, start MMF  
 
Signed informed consent 
HAMA test 
(human anti-mouse antibody) 
Off study 
131I-antibody test dose 
Positive HAMA 
Negative HAMA 


1809.00 
 
 
11 
2.  Treatment Schema and Post-transplant Immunosuppression for Patients with Matched, Related 
Donors 
 
Table 2. Treatment schema for PBSC transplants to establish mixed chimerism in patients with HLA-
identical sibling donors 
 
Day 
-14 to -10 
-4 
- 3 
-2 
-1 
0a 
 
+ 27 
+28 
+ 56 
+84 
+180 
131I-BC8 Antibody Rx 
X 
 
 
 
 
 
 
 
 
 
 
 
Donor Leukapheresis 
 
 
 
 
X 
X 
 
 
 
 
 
 
TBI 200 cGy 
 
 
 
 
 
X  
 
 
 
 
 
 
Fludarabine 30 mg/m2/d 
 
X 
X 
X 
 
 
 
 
 
 
 
 
PBSC Transplant 
 
 
 
 
 
X 
 
 
 
 
 
 
CSP 
 
 
Start 
 
 
 
 
 
 
Taper 
 
Stop 
MMF 
 
 
 
 
 
Startb 
 
Stope 
 
 
 
 
Chimerism Evaluations 
 
 
 
 
 
 
 
 
X 
Xc  
Xd 
 
 
a Day 0 should be on a Tuesday to Thursday 
 
b First dose should be given 4-6 hours after stem cell infusion 
 
c Chimerism evaluation at d +56 from blood only, and only if day + 28 chimerism is  <50% donor 
d Bone marrow aspirate on  d +84 for chimerism to also include samples for flow cytometry (and cytogenetic analysis if 
appropriate) to assess for minimal residual disease.  
e MMF may be discontinued earlier than day +27 at the discretion of the study doctor in patients who are at least day +14 post 
transplant who exhibit no GVHD. 
 
 
3.  Treatment Schema and Post-transplant Immunosuppression for Patients with Matched, Unrelated Donors 
 
Table 3. Treatment schema for PBSC transplants to establish mixed chimerism in patients with HLA-
phenotypically matched unrelated donors. 
Day 
-14 to -10 
-4 
- 3 
-2 
-1 
 
0a 
+1 
+ 40 
+96 
+100 
 +180 
131I-BC8 Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
Donor Leukapheresis 
 
 
 
X 
X 
 
X 
 
 
 
 
 
TBI 200 cGy 
 
 
 
 
 
 
X 
 
 
 
 
 
Fludarabine  
30 mg/m2/d 
 
X 
X 
X 
 
 
 
 
 
 
 
 
PBSC Transplant 
 
 
 
 
      
 
X 
 
 
 
 
 
CSP 
 
 
Start 
 
 
 
 
 
 
 
Taper 
Stop 
MMF 
 
 
 
 
 
 
Startb 
 
Tapere 
Stope 
 
 
 
 
Day 
+28 
+56 
+84 
 
 
Chimerism studiesc 
X 
Xc 
Xd 
 
 
Chimerism evaluations will be done on days: + 28, +56 (only if donor is <50% on day + 28) and + 84 post-stem cell infusion 
a Day 0 should be on a Tuesday to Thursday 
b First dose should be given 4-6 hours after stem cell infusion 
c Chimerism evaluation at d +56 from blood only,  and only if day +28  <50% donor  
d Bone marrow aspirate for chimerism to include samples for flow cytometry (and cytogenetics if appropriate) to assess for 
minimal residual disease. 
e MMF may be discontinued earlier, at the discretion of the study doctor, in patients who are at least day +14 post transplant  who exhibit 
no GVHD. 
  


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12 
 
B. Radiolabeled Antibody Evaluation (Biodistribution Dose) and Treatment 
1. Biodistribution Study 
 
The radiation absorbed doses for each organ delivered by 131I-labeled antibody will be 
estimated for each patient prior to administration of therapeutic amounts of 131I-labeled antibody.  
For this purpose 1 to 10 mg of antibody will be labeled with 4-10 mCi 131I.  The 131I-labeled 
antibody will be mixed with unlabeled antibody to achieve a total dose of 0.5 mg/kg ideal body 
weight for patients at or above ideal body weight, or actual body weight for patients below ideal 
body weight.  Estimates of radiation absorbed doses for each organ will be calculated after each 
infusion.  These estimates will be used to determine the amount of 131I with which the therapeutic 
dose of isotope-antibody conjugate will be labeled.  
 
a.  Iodination and Characterization of Labeled Antibody 
 
Antibodies will be labeled in the radiochemical facilities of the Division of Nuclear 
Medicine at the University of Washington, using established techniques (Chloramine-T) for the 
radioiodination of antibodies for human use.  Following the labeling procedure, the antibody will 
be sterilized by filtration through a 0.1 μm filter and tested for endotoxin content.  Since 
antibody labeled with therapeutic amounts of 131I must be infused within a few hours of labeling 
to avoid radiolysis, the results of sterility testing will not be available at the time of antibody 
infusion.  131I-labeled antibody immunoreactivity will be determined following each labeling 
procedure. 
 
b.  Non-radioactive Iodine Solution 
 
The thyroid will be blocked with Lugol’s Strong Iodine Solution, 5 drops three times 
daily PO (depending on patient weight), or saturated solution of potassium iodide (SSKI) 4 drops 
three times daily PO, starting two days prior to the morning of the biodistribution dose of labeled 
antibody and continuing for three weeks following the last infusion (unless limited by other 
medical conditions). 
 
c.  Vital Signs 
 
Vital signs will be obtained prior to infusion and monitored every 30 minutes for the first 
2 hours and then hourly until the infusion is complete or more often if clinically indicated. 
 
d.  Antibody Administration 
Radiolabeled antibody will be administered through a central venous catheter. 
Premedications will include: 
acetaminophen 650 mg PO, 
diphenhydramine 25-50 mg IV, 
ondansetron 8 mg IV, 
hydrocortisone 100 mg IV, 
D51/2NS to start with the antibody infusion and to continue until the antibody infusion is 
complete. 
Hydrocortisone 100 mg IV will be repeated every 2 hours until the completion of the 
infusion.   
 


1809.00 
 
 
13 
The mixture of 131I-labeled BC8 antibody (4-10 mCi) will be diluted to approximately 25 ml 
and infused intravenously at 7.5 mg/hour.   
 
If grade II allergic-type toxicity is encountered (see section 13.A.1), the infusion should be 
paused, the patient treated as indicated below, and the infusion not restarted until symptoms have 
subsided.  If Grade III allergic toxicity is encountered, the infusion must be terminated and not 
restarted, and the patient will be off protocol.  If other Grade II or III toxicities are encountered 
(see section 11.A), the infusion may be slowed or paused.  If toxicity persists or progresses, the 
infusion will be terminated.  If grade IV toxicity occurs the patient will be off study.   
 
Potential acute side effects and their planned management are as follows: 
 
Fever: acetaminophen 650 mg (or 15 mg/kg) PO every 4 hours PRN. 
Rigors: meperidine 25-50 mg IV (or 0.5 – 1 mg/kg) every 2-4 hours PRN. 
Pruritis: diphenhydramine 25-50 mg (or 1 mg/kg) PO or IV every 2-4 hours PRN. 
Nausea: lorazepam 0.5-2 mg (0.05 mg/kg) IV every 4 hours PRN 
 
diphenhydramine 25-50 mg (1 mg/kg) IV every 4 hours PRN 
ondansetron 8mg IV every 8 hours for first 24 hours from start of infusion, then 
every 8 hours PRN for nausea. 
Cough, chest or throat tightness, wheezing:  
 
diphenhydramine and hydrocortisone may be repeated. 
 
albuterol nebulizer 2.5 – 5 mg up to every 1-2 hours PRN. 
Anaphylaxis:  Cessation of antibody infusion and treat per institution standards. 
 
e.  Antibody and Blood Samples 
 
Aliquots of the infusion mix will be taken prior to infusion, to be used as quantitative 
standards for assessment of counts in blood and marrow. A blood sample (5-7 ml) will be 
obtained at the time of marrow biopsy.  This sample will be obtained at the SCCA.  These 
samples will be used for analysis of antibody clearance. 
 
f.  Gamma Scanning 
Serial gamma camera images will be obtained in conjunction with dedicated computers at 
0 hours (i.e. end of infusion) on day 0, and on at least two of the following days: day 1, 2, and 3 
post infusion of antibody, to be stored on removable soft disks and magnetic tape.  Images will 
include anterior and posterior head/neck, anterior and posterior chest with upper humeri, 
abdomen, and pelvis with upper femurs.  At each imaging time a source of 131I will be counted 
and imaged on the gamma camera in a fixed geometry to account for radioactive decay and 
changes in camera sensitivity during the study so that body tissue activity curves and areas of 
interest, etc. can be temporally compared more accurately. 
Images will be inspected for general body distribution of activity, especially liver, 
kidney, bone marrow and spleen, and relative counts at various times over the organs for any 
organ with activity above background will be recorded and compared to the fixed 131I source.  
The methods used to calculate estimated radiation absorbed doses to each tissue or organ per 
mCi I-131 administered are described in Appendix D.  Reporting of dosimetry will include the 
MIRD/OLINDA-EXM calculations for all 25 organs included in the program.  These 


1809.00 
 
 
14 
calculations will include the use of quantitative data from serial gamma camera images 
performed after the biodistribution dose of trace I-131-BC8 antibody for all organs with activity 
above background.  Specifically, we will include estimated dosimetry for thyroid and bladder, 
although neither will be considered a dose-limiting organ. 
 
g.  Marrow Biopsies 
 
A unilateral bone marrow biopsy (no aspirate) will be performed at least one time on the 
day after antibody infusion (i.e. ~ 24 hours).  If that sample is judged to be inadequate, a second 
sample may be obtained within 48 hours of the infusion.  This will be performed in the SCCA 
Procedure Suite.  Small sections will be weighed and counted via gamma counter for 131I 
content, with comparison to a quantitative standard of the infusion mix, allowing calculation of 
% injected dose/gram marrow of labeled BC8 antibody.  The biopsy section will be collected 
using NO FIXATIVE agents.  A research technician from the Laboratory (D3-377) will prepare 
the research portion for the Lab and send the remaining portion to SCCA Pathology for 
morphology.  A portion of the biopsy may be analyzed using flow cytometry (for detection of 
bound antibody). 
 
h.  Laboratory Samples 
 
A blood sample for HAMA will be obtained the day prior to planned therapy infusion.  
Blood samples (CMP and CBC/CBD) will be obtained pre-infusion, at the end of infusion and on 
day 1 for CBC, BUN, creatinine, AST, ALT, and bilirubin.   
 
2. Requirements for Therapy 
All patients with a negative HAMA test will be eligible for 131I-labeled antibody infusion 
regardless of the estimates of radiation absorbed doses from the dosimetric analysis.   
 
C. Selection and Timing of 131I-Labeled Antibody Dose for Therapy 
 
131I-labeled antibody for therapy will be administered to each patient in a protein dose and 
infusion schedule identical to that used for dosimetry studies in the patient (see section 9.B.1).  The 
therapeutic dose will be generally infused 6 to 14 days after the trace-labeled biodistribution dose, but 
can be delayed further if necessary because of clinical circumstances (as long as the patient has not 
developed HAMA).  In previous patients, serum antibody concentrations after the dosimetry infusion 
have declined to much less than 10% of their initial level by this time.  At least 6 days is required to 
allow calculation of radiation absorbed dose and ordering of the therapeutic dose of isotope. The day of 
administration of the therapy dose will generally be day –12 (see 9.C.2 below) 
 
1. Selection of Isotope Dose 
 
The total amount of 131I administered will be individualized based on the biodistribution of 
the trace-labeled dose in each patient.  The dose of 131I will be calculated to deliver 22 Gy (at the 
starting dose) to the normal critical organ (almost always liver) predicted to receive the highest 
estimated dose of radiation, unless that would result in an unacceptable marrow dose (initially >43 
Gy; see sections 13.C and 19.B for further discussion).  For each patient, the dose level at which the 
patient will be treated will be discussed by the P.I. (or his designee) and Drs. Rajendran, Eary, or 
Shields (or designee).   
 


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15 
2. Timing of Peripheral Blood Stem Cell (PBSC) Infusion 
 
For patients with estimated marrow biologic half-times of less than 96 hours as estimated by 
the biodistribution dose, donor PBSC will normally be infused 12 days after the therapy dose of 131I-
BC8 antibody.  In the Phase I dose-escalation trial, the longest measured marrow biologic half-time 
was 86 hours.  In the unlikely event that a patient has an estimated marrow biologic half-time longer 
than 96 hours, PBSC infusion will be delayed until the estimated radiation dose rate in marrow is < 2 
mR/hour, and the actual number of days prior to PBSC infusion that the therapy dose of antibody is 
administered will be adjusted accordingly. 
 
D. Fludarabine 
 
Fludarabine will be administered at a dose of 30 mg/m2/day on days –4, -3, and -2.  Fludarabine 
will typically be given in the SCCA outpatient department. 
 
E. Total Body Irradiation 
 
TBI will be administered at a dose of 2 Gy (6-7 cGy/min delivered from a linear accelerator) on 
Day 0, followed by PBSC infusion.  TBI will be administered between 11:00 a.m. and 2:00 p.m. to 
avoid proximity to CSP/MMF administration. 
 
F. Immunosuppression 
1. Cyclosporine (CSP) 
a. For patients with matched sibling donors, CSP is given at 3.75 mg/kg PO Q12 hours from 
day –3 to day +56, then is tapered to be discontinued on day +180 unless GVHD develops.  
For patients with matched unrelated donors, CSP is given from day –3 to day +100.  The 
CSP starting dose is 3.75 mg/kg PO Q12 hours and continues to day +100.  CSP is then 
tapered to end at day +180.  If there is nausea and vomiting at any time during CSP 
treatment, the drug should be given IV at 1.5 mg/kg Q12 hours.  Both IV and oral doses of 
CSP are calculated using the adjusted weight.  Alternative formulations of CSP may be 
substituted if nausea and vomiting are persistent according to the Standard Practice Manual 
and at the discretion of the Attending Physician. 
 
b. Guidelines for CSP dose adjustments: CSP whole blood “trough” levels (i.e. just prior to the 
next dose) will be evaluated on day 0 and adjusted if necessary to maintain blood levels that 
target 240-320 ng/ml.  Dose reductions should only be made if CSP toxicity is present or at 
excessive levels in the discretion of the Attending Physician in the absence of toxicity.  
Further CSP determinations should be performed twice weekly until CSP is stopped unless 
excessive high levels are detected or toxicity is suspected, in which case more frequent 
monitoring will be performed as clinically indicated.  In this group of patients, close 
monitoring of renal function is essential.  Dose reductions for high levels without toxicity 
should be conservative (e.g. 25%), to avoid inadequate immunosuppression, particularly in 
the first month post-transplant. 
 
c. Blood pressure, renal function (creatinine, BUN), electrolytes and magnesium will be 
followed at least three times per week while receiving CSP. 
 


1809.00 
 
 
16 
d. Drugs that may affect CSP levels include: dilantin, phenobarbital (may lower CSP levels), 
steroids, fluconazole, ketoconazole, cimetidine (may increase CSP levels). 
 
2. Mycophenolate Mofetil (MMF) 
a. Oral MMF will be started 4-6 hours after PBSC infusion on day 0.  The drug should be given 
IV at the same dose level as oral MMF if there is nausea and vomiting at any time preventing 
oral administration.  Doses will be rounded to the nearest 250 mg.  Both IV and oral doses 
are calculated using the adjusted weight.  For patients with matched sibling donors, oral 
administration of MMF will be given daily at 15 mg/kg Q12 hours (30 mg/kg/day) until day 
+27 post-transplant, at which point it will be stopped without tapering.  For patients with 
matched, unrelated donors, MMF will be given daily at 15 mg/kg Q8 hrs (45 mg/kg/day) 
until day +40 post-transplant and then tapered off by day + 96.  In the case of impending 
graft rejection with markedly low (<40%) donor T cell chimerism after HSCT, MMF should 
be continued at full dose or, if MMF taper has been initiated, reinstitution of full dose MMF 
should occur.  Also in this case, if MMF has been discontinued, MMF should be reinitiated at 
full dose. Note that for patients exhibiting no signs of GVHD at day +14 post transplant, 
MMF may be discontinued sooner than described above at the discretion of the study doctor.   
 
b. Guidelines for MMF dose adjustment: The principal adverse reactions associated with the 
administration of MMF include diarrhea, leukopenia, sepsis, and vomiting.  If in the clinical 
judgment of the attending physician the observed toxicity is related to MMF administration, a 
dose adjustment may be made. Based on previous non-myeloablative transplant studies, dose 
adjustments are likely to occur because of hematopoietic adverse effects, in particular 
neutropenia.  The etiology of the neutropenia should be thoroughly investigated with the use 
of peripheral blood chimerism studies, marrow aspiration and review of marrow suppressive 
medications, such as Sulfa based drugs (e.g. Bactrim).  Conservative dose adjustments of 
~20% will only be made for grade IV neutropenia persisting after day +21 post-transplant 
once all other potential causes of marrow toxicity have been ruled out.  After day 28, the use 
of G-CSF will be permitted for neutropenia.  In the event of gastrointestinal toxicity that 
requires medication for control of persistent vomiting or diarrhea that is considered to be due 
to MMF, a 20% dose reduction will be made or the drug may be given IV.  For severe 
toxicity related to MMF (grade IV neutropenia > 5 days refractory to G-CSF, severe 
refractory diarrhea, or overt gastrointestinal bleeding), the MMF may be temporarily stopped. 
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).  MMF 
should be restarted at 20% reduced dose when the underlying toxicity subsides. 
 
G. Collection and Infusion of Donor PBSC 
1. G-CSF Administration to Related Donors and PBSC Collection 
 
Related donors will receive G-CSF 16 µg/kg/day for 5 consecutive days from day –4 to day 0. 
G-CSF will be administered by a subcutaneous daily injection beginning 4 days prior to day 0.  The 
schedule of G-CSF administration and PBSC collections can only be ascertained once day 0 is 
identified.  These doses will be administered before 10:00 a.m. each day in the Outpatient 
Department.  The treatment regimen schedule and the schedule of G-CSF administration and PBSC 
collections must be confirmed with the personnel in the apheresis room.  PBSC will be collected in 


1809.00 
 
 
17 
the afternoon of day –1, stored in the refrigerator at 4ºC overnight, and infused on day 0.  If the 
collection on day –1 contains less than 5.0 × 106 CD34+ cells per kg recipient weight, a second 
collection will be performed the following morning and transfused on day 0.  Donors will preferably 
undergo vein-to-vein collections.  If PBSC 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 l of whole 
blood during the collection. 
 
Treatment Schema for Donor 
 
Day 
-4 
-3 
-2 
-1 
0 
G-CSF 16 g/kg/SQ 
X 
X 
X 
X 
 X 
PBSC collection 
 
 
 
X 
X 
 
 
2. G-CSF Administration to Unrelated Donors and PBSC Collection  
 
Timing of PBSC collection for unrelated donors is prearranged through the NMDP or other 
donor center guidelines and the schedule of G-CSF administration and stem cell collections can only 
be ascertained once day 0 is identified.  PBSC will be collected according to NMDP or other donor 
center standards and the physician responsible for PBSC collection will obtain informed consent 
from the donor.  The target cell dose is 5.0 x 106 CD34+ cells/kg of patient weight for unrelated 
donor stem-cell collection.  If this collection goal is not met, the patient will be infused with all 
available cells at the discretion of the Attending Physician. 
 
3. PBSC Infusion 
 
All patients will receive unmodified HSCT (PBSC) infusion on day 0 of the treatment 
regimen.  Day 0 should be on a Tuesday when possible. 
 
H. Myelosuppression and Post-Transplant Growth Factors.   
 
Grade IV myelosuppression will be defined as a decrease in ANC to < 500/mm3 and/or platelet 
count to  20,000/mm3.  If myelosuppression occurs, a bone marrow aspirate and biopsy should be 
performed to exclude disease progression.  Samples should be sent for chimerism analysis by FISH or 
VNTR.  Patients with myelosuppression will be managed as follows:  
a. G-CSF (5g/kg/day S.C.) will be started in patients who are > 28 days after HSCT with a 
hypoplastic marrow and an ANC of < 500/mm3.  
b. Thrombocytopenic patients will receive platelet transfusion as per standard care. 
c. Prophylactic broad spectrum antibiotics e.g. ciprofloxacin, while ANC < 500/mm3. 
d. In cases of suspected MMF toxicity, refer to section 9.F.2 for management recommendations. 
e. In cases of suspected ganciclovir toxicity, consider changing to foscarnet.  
 
 
It is recommended that patients not receive growth factors during treatment with MMF because 
of the possible risk of potentiating MMF toxicity by forcing more progenitor cells into a dividing and 
proliferating state.  G-CSF may be administered to patients who have severe neutropenia (ANC 


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18 
<500/mm3).  If ANC drops to < 500/mm3 then prophylactic broad spectrum antibiotics should be given, 
e.g. PO ciprofloxacin. 
 
I. Intrathecal Therapy and Treatment of CNS Disease 
 
All patients will have a diagnostic lumbar puncture performed during the initial pre-transplant 
workup in the outpatient department.  Patients with past history of CNS disease may be considered for 
instillation of methotrexate as per the Standard Practice Manual.  Citrovorum factor will be administered 
to those patients who have high serum methotrexate according to the guidelines found in the Standard 
Practice Manual.  Patients with CNS disease will not be excluded.  Those patients with evidence of CNS 
leukemic involvement will have instillation of methotrexate (dose per Standard Practice Manual).  This 
regimen may be modified by the Attending Physician as clinically indicated.  Patients with evidence of 
CNS leukemic involvement will also be considered by the Attending Physician to receive up to 18 Gy 
(10 fractions of 1.8 Gy) cranial or cranial-spinal irradiation as consolidation if indicated, beginning 
approximately day 32 post transplant or as soon as engrafted, whichever comes later.   
 
J.  Infection Prophylaxis 
 
Patients will receive prophylaxis for PCP, HSV, and candida as per FHCRC Standard Practice 
Manual.  If amphotericin is required, patients should be considered to receive liposomal or other lipid-
based amphotericin rather than regular amphotericin in order to reduce risk of nephrotoxicity that may 
compromise the administration of CSP. 
 
K. Modifications of Immunosuppression for Low Donor T Cell Chimerism and Disease Progression 
Patients with progressive disease defined as any evidence of relapse (see Section 12 for definition) 
by morphologic or flow cytometric evaluation of a bone marrow aspirate will undergo rapid reduction of 
immunosuppression at the discretion of the Attending Physician, study P.I., and/or study sub-
investigator(s). Persistence of disease, in itself does not mandate accelerated taper 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.  This section provides guidelines for management of patients with low donor chimerism and 
disease progression.  
 
1.  Engraftment and Graft Rejection 
 
Mixed or full donor chimerism will be evidence of donor engraftment.  VNTR analysis or 
FISH studies will be used to quantitate chimerism.  The same assay should be used in a given patient 
for repeated studies of chimerism.  When possible, FISH analysis will be used for sex-mismatched 
donor-recipient combinations rather than VNTR studies.  Definitions of mixed and full chimerism, 
as well as increasing and low donor chimerism, are described in Section 12. 
 
Patients who obtain mixed or full donor chimerism after non-myeloablative HSCT, but 
subsequent chimerism studies cannot detect greater than 5% donor T cells (CD3+) as a proportion of 
the total T cell population, will be defined as having developed graft rejection. 
 
Graft rejection can occur because of immunologic rejection of donor cells, or because of 
inadequate stromal support of the growth of donor cells.  The risk of immunologic graft rejection is 
considered to be low for this protocol based on previous FHCRC mixed chimerism experience in 
which patients who had previously received intensive chemotherapy had <10% risk of graft 
rejection.  In this protocol, additional immunosuppression may be provided by lymphohematopoietic 


1809.00 
 
 
19 
irradiation from 131I-BC8 antibody.  However, in the event of marrow stromal damage from 
excessive radiation exposure, patients might have inadequate hematopoiesis yet not meet the 
previously defined criteria for graft rejection.  Every effort will be made to determine graft status for 
patients with slow recovery of neutrophils.  All patients will have marrow aspirates and/or biopsies 
performed at approximately day 28 and 84 for assessment of in vitro marrow stromal growth.  For 
patients who are critically ill and not expected to survive to day 28, an effort will be made to obtain a 
marrow sample prior to death in order to ascertain both graft and marrow stromal status.  Similarly, 
VNTR studies will be performed prior to day 28 if necessary.  
 
Patients with slow engraftment of neutrophils should be considered for treatment with 
hematopoietic growth factor as specified in section 9.H.  Those patients with grade IV 
thrombocytopenia and neutropenia after day +21 that lasts >2 weeks and is refractory to growth 
factor support, in the absence of contributing cause such as medication (e.g. MMF), sepsis, or CMV 
infection, will be considered to have never engrafted. 
 
2.  Evaluation of Chimerism  
 
At days +28, +56, and +84, patients will be evaluated for lymphoid and myeloid chimerism.  
In addition, bone marrow will be sent for histological examination, flow cytometry, and cytogenetic 
studies (if the patient had a known cytogenetic abnormality prior to transplant) at days +28 and +84 
to evaluate for relapse/persistence of AML.  Patients who have mixed or full donor chimerism at day 
56 or later, and who have evidence of persistent, progressive or relapsed AML will be considered on 
a separate protocol for DLI, with the goal of maximizing the potential GVL effect.  Patients who 
have stable mixed or full donor chimerism on day 56, whose disease is stable or responding, and 
who remain on full dose immunosuppression will continue to be observed, and will not be 
considered for DLI at that time.  Patients with evidence of Grade II or greater GVHD also will not be 
considered for DLI.   
 
3.   Modifications of Immunosuppression 
 
Immunosuppression should be discontinued as per protocol unless the patient develops 
GVHD or has falling donor chimerism without evidence of persistence, progression, or relapse of 
AML.  In the latter situation, MMF should be continued at full dose for a month and then tapered 
over a month.  CSP should be continued until MMF is discontinued and then tapered over 3 months.   
 
L. Recommended Treatment of GVHD: 
 
After non-myeloablative HSCT from 10/10 antigen matched unrelated donors, the incidence of 
grades II, III and IV acute GVHD in patients with sustained engraftment has been 46%, 4% and 0%, 
respectively.  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 34% of patients.  Acute GVHD and chronic GVHD will be graded according to 
established criteria (Appendix B). 
 
1.  Patients Developing  Grade 2 Acute GVHD: 
a. CSP 7.5 mg/kg/day PO in two divided doses.  If there is concern of GI absorption use IV 
route (1.5 mg/kg Q12 hours). 
b. Prednisone (2 mg/kg/day) to be added if severe GVHD and no GVHD response by 72 hours 
to one week after the addition of CSP. 


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20 
c. Patients with life-threatening grade III or IV acute GVHD and/or steroid refractory acute 
GVHD are eligible for institutional trials of GVHD therapy. 
 
2.  Patients with Clinical Extensive Chronic GVHD: 
a. LTFU consult should be obtained for patients with chronic GVHD and determination of the 
appropriate treatment for chronic GVHD will be based on the LTFU consult team 
recommendations. 
 
 
M. ABO Incompatibility 
 
All patients with ABO incompatibility should be evaluated and treated as according to the 
standard practice manual.  Acute hemolysis has been seen rarely in patients who had a minor ABO 
mismatch with their donor, and these patients should be monitored and treated aggressively if there is 
any evidence of hemolysis. 
 
10. Patient Evaluations 
 
A. Patient Pretransplant Baseline Evaluation 
 
See Standard Practice Policy Manual for standard “Evaluation Guidelines for Marrow Transplant 
Patients.”  In addition, obtain the following: 
 
1. CT scan of chest and abdomen for calculation of organ volumes.  Other imaging studies as 
clinically indicated.  
2. 10 cc blood in red top tube to D3-377 Thomas building for analysis of HAMA (Human Anti-
Mouse Antibody). 
3. Unilateral bone marrow biopsy and aspirate for pathology, flow cytometry, and cytogenetics 
within 30 days prior to consent signing/enrollment. 
4. To subsequently determine the host or donor origin of relapse, heparinized peripheral blood from 
the patient and donor will be drawn and sent to: 
a. Cytogenetics Lab if patient/donor are sex mismatched. 
b. Clinical Immunogenetics Lab (E-514) to do chimerism analysis by DNA.  Pretransplant 
samples to be sent to allow storage of DNA for evaluation of post-transplant chimerism.  
 
 
B. Post Transplant Patient Evaluation  
 
See Standard Practice Policy Manual for standard “Evaluation Guidelines for Marrow Transplant 
Patients.”  Data from these standard laboratory studies, other clinically indicated studies, and clinical 
assessments by the primary care team will be reviewed regularly to assess for regimen-related toxicity, 
occurrence of Serious Adverse Events, and other potential post-transplant complications such as GVHD 
and infections.   
 
The following additional studies and tests will be performed: 
 
1. Heparinized blood 10cc to clinical chimerism lab for quantifying of T cell and granulocyte 
chimerism on days +28, +56, and +84. 
2. Bone marrow aspirate to clinical chimerism lab for chimerism studies on days +28 and +84. 


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21 
3. Bone marrow aspirate (and biopsy if unable to obtain adequate aspirate sample) to pathology and 
cytogenetics (if previous cytogenetic abnormality was present) on days +28 and +84. 
4. Thyroid function (TSH) at approximately day 84 workup. 
5. Chronic GVHD screening between days 80 and 100 post-transplant. 
 
Following day +100 or discharge from the SCCA, patients will return to their primary care physicians 
under the guidance of the FHCRC/SCCA Long-Term Follow-Up After Hematopoietic Stem Cell 
Transplant General Guidelines for Referring Physicians, with additional recommendations for thyroid 
testing (and initiation of treatment if clinically indicated) at 6, 9, 12, 18 and 24 months after transplant, 
and then annually if still normal.  Patient follow-up will be performed primarily by the FHCRC Long-
Term Follow-Up Department under the FHCRC/SCCA Master Protocol for Collection of Clinical Data 
and Storage of Leftover Specimens from Patients Treated According to FHCRC Protocols (Protocol 
#0999.209).  The following data collected through this mechanism will be recorded for purposes of this 
study at 6, 9, 12, 18 and 24 months post transplant: 
 
1. Survival. 
2. Disease status. 
3. Hypothyroidism. 
4. Selected blood counts (WBC, hemoglobin, hematocrit, platelets). 
5. Renal (creatinine, BUN) and hepatic (Bilirubin, AST, ALT) laboratory values. 
6. Presence/treatment of chronic GVHD. 
7. Serious adverse events. 
8. Secondary malignancies. 
 
Any of these data that are unavailable through standard long-term follow-up will be requested directly 
from the patient or local physician.  After the two-year follow-up time point, we will continue to 
monitor any changes to survival and disease status reported under the standard long-term follow-up 
protocol, and will record this data for long-term analysis and reporting. 
 
11. Drugs and Toxicities 
 
A. 131I-BC8 antibody:   
 
131I-BC8 antibody will be given at a dose of 0.5 mg/kg ideal body weight, or actual body weight 
for patients below ideal body weight.  The antibody itself can cause side effects including fever, chills, 
nausea, vomiting, diarrhea, hypotension, dyspnea, joint pain, rash, and anaphylaxis.  See section 9.B.1.d 
for premedications and infusion guidelines, and 13.A.1 for details regarding grading of and response to 
antibody-related toxicities.  The biodistribution dose is labeled with 4-10 mCi 131I, which by itself does 
not cause symptoms.  This dose is usually administered as an outpatient in the UWMC General Clinical 
Research Center or current treating location.  Patients who are not stable at the end of infusion are 
admitted for overnight observation.  The therapy dose is labeled with larger amounts of 131I, as 
determined by the cGy/mCi 131I estimates calculated from the biodistribution antibody infusion for the 
normal organ receiving the highest dose and the current limit of radiation dose delivered to marrow 
(section 13.B).  The therapy dose of 131I can cause nausea and vomiting, in addition to myelosuppression 
and other organ toxicities seen with high dose radiation. 


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22 
 
Engraftment syndrome (ES) is an early complication of stem cell transplants that occurs around 
neutrophil engraftment. One patient experienced a life threatening side effect of ES about 2 weeks after 
stem cell transplant under this protocol. Usual symptoms of ES include fever around the time of 
engraftment, shortness of breath, weight gain, sudden rise in white blood count, and skin rash. 
 
B. Fludarabine:   
 
Fludarabine will be administered in the outpatient department.  The dose of fludarabine used in 
this protocol is non-myeloablative, but does 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.  Possible other side 
effects include nausea and vomiting.   
 
C. Total Body Irradiation:  
 
TBI will be given in one 2.0 Gy fraction from a linear accelerator at a rate of 6-7 cGy/min. 
Dosimetry calculations are performed by the radiation therapist.  At the dosage used, 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. 
 
D. CSP:  
 
See standard practice manual and section 9.F.1 for information about administration, toxicity and 
complications.  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. 
 
E. Mycophenolate Mofetil (MMF): 
 
See section 9.F.2 for information about MMF administration and dosage adjustments.  Previous 
clinical studies in patients after allografting suggest that the principal adverse reactions associated with 
the administration of MMF include neutropenia, nausea, vomiting, diarrhea, and on one occasion bloody 
diarrhea.  There may also be a higher incidence of certain viral infections (CMV, VZV, HSV).  MMF 
use during pregnancy carries a significant risk of miscarriage or birth defects.  In the setting of marrow 
transplantation, several etiologic factors may contribute to alterations in gastrointestinal and hematologic 
parameters.  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). 
 
12.  Definitions 
 
A. Complete Remission: complete resolution of all signs of leukemia for at least four weeks with all of 
the following: 
1. Normal bone marrow with blasts <5% with normal cellularity, normal megakarypoiesis, 
more than 15% erythropoiesis and more than 25% granulocytopoiesis. 
2. Normalization of blood counts (no blasts, platelets >100,000/mm3, granulocytes 
>1,500/mm3). 


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23 
3. No extramedullary disease. 
B. Partial Remission: 
1. Improvement of hematological parameters in the peripheral blood. 
2. 50% decline in marrow blasts from pre-transplant level with >10% erythropoiesis and 25% 
granulocytopoiesis. 
C. Non Responder: all patients not qualifying for complete or partial remission. 
D. Relapse: 
1. After CR: >5% blasts in the bone marrow and/or peripheral blood. Confirmation of relapse 
by bone marrow analysis with more than 10% blasts. 
2. After PR: increase of blasts cells in the marrow to >50% of those during PR. 
3. Extramedullary disease confirmed cytologically or histologically. 
E. Persistent Disease:  
1. >5% blasts in the bone marrow by histology 
2. presence of a clonal population of myeloid cells by flow 
3. persistence/recurrence of a previously documented cytogenetic abnormality, 
F. Full Chimerism: >95% donor CD3+ T cells.  
G. Mixed Chimerism: the detection of peripheral blood donor T cells (CD3+) and granulocytes 
(CD33+) as a proportion of the total peripheral blood T cell and granulocyte population, 
respectively.   
H. Increasing Donor Chimerism: an absolute increase of 20% of CD3+ T cells over the chimerism 
evaluation of the previous month.   
I. Decreasing Donor Chimerism: decreasing donor chimerism is defined as an absolute decrease of at 
least 20% of CD3+ T cell chimerism over the previous month.   
J. Low Donor Chimerism: low donor chimerism is defined as <40% CD3+ T cells after HSCT.  Low 
donor chimerism should always be confirmed with repeat peripheral blood T cell and granulocyte 
chimerism analysis.   
 
13.  Radiolabeled Antibody - Toxicities and Complications 
 
 
Two separate sorts of toxicities are anticipated, those due to antibody infusions (see 13.A below) 
and those due to the radiation delivery and combined preparative regimen.  In the prior Phase I dose-
escalation study of 131I-labeled BC8 antibody for patients with advanced AML, ALL, and MDS a dose 
of 10.5 Gy delivered to the liver by 131I-labeled BC8 has been well-tolerated when administered in 
addition to cyclophosphamide 120 mg/kg and 12 Gy TBI.  In this study, however, we will decrease the 
TBI to 2 Gy and use fludarabine, which may be less toxic than cyclophosphamide.  Therefore, by using 
22 Gy (starting dose) of 131I-BC8 antibody with the non-myeloablative allogeneic transplant regimen, 
we do not anticipate the same degree of regimen-related toxicities (RRT) seen in full transplants.  
Conversely, we do expect more RRT compared with other non-myeloablative regimens that do not 
employ radiolabeled antibody therapy. 
 
A. Toxicity Attributable to Monoclonal Antibody Infusions 
 
Allergic reactions to administration of foreign mouse protein may include fever, urticaria, 
bronchospasm, anaphylaxis, Arthus reaction, vasculitis and serum sickness.  In addition, rapid infusion 
of antibody may produce pulmonary, renal or hepatic toxicity as a result of lysis or agglutination of 
circulating cells.  Grading of acute toxicities due to antibody infusion is shown in Table 3. 


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24 
1. Modifications for Acute Toxicity 
 
Patients experiencing acute toxicity (i.e. allergic type reactions) during antibody 
infusion will have the infusion slowed or terminated as described in section 9.B.1.d. If Grade III 
allergic-type toxicity is encountered, the infusion must be terminated and not-restarted, and the 
patient will be off protocol. Other moderate (grade II - III) acute toxicity may be treated and the 
infusion restarted.  Patients with grade IV acute toxicity will have the infusion stopped and 
further participation in the study will be terminated.  Hepatic and/or renal toxicity will not be 
evident during the antibody infusion but instead will be determined by laboratory samples 
obtained at the end of infusion and the following day.  If a patient experiences Grade III hepatic 
or renal toxicity after the biodistribution dose, determination of whether or not the patient can 
proceed to the therapy dose will be made by the P.I. or his designee in consultation with the 
attending physician, and will depend in part upon the rate of recovery from the laboratory 
abnormalities.  A patient experiencing Grade IV hepatic or renal toxicity after the biodistribution 
dose will not receive the therapy dose and may be treated on an alternate protocol. 
 
Table 3: Grading of Acute Toxicities Due to Antibody Infusion (from NCI CTCAE version 3.0). 
 
Parameters 
 
I (Mild) 
 
II (Moderate) 
 
III (Severe) 
IV (Life- 
Threatening) 
 
 
 
 
 
Allergic reaction/ 
hypersensitivity 
(including drug 
fever) 
Transient flushing 
or rash; drug fever 
<38°C (<100.4°F) 
Rash; flushing; 
urticaria; dyspnea; 
drug fever ≥38°C 
(≥100.4°F) 
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
medication(s) 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Anaphylaxis 
 
 
 
 
 
Hepatic: 
1. Bilirubin 
2. AST 
 
>ULN – 1.5 × ULN 
>ULN – 2.5 × ULN 
 
>1.5 × ULN – 3.0 × 
ULN 
>2.5 × ULN – 5.0 × 
ULN 
 
>3.0 × ULN – 10.0 
× ULN 
>5.0 × ULN – 20.0 
× ULN e 
 
>10.0 × ULN  
>20.0 × ULN  
 
 
 
 
 
 
Renal: 
Creatinine 
 
>ULN – 1.5 × ULN 
 
>1.5 × ULN – 3.0 × 
ULN 
 
>3.0 × ULN – 6.0 × 
ULN 
 
>6.0 × ULN 
 
2. Long-Term Toxicities 
Hypothyroidism is the most common long-term effect of radiation exposure resulting from 
the 131I therapy dose and has been seen in approximately 70% of patients receiving this 
treatment.  Some incidence of avascular necrosis (AVN) has been seen in patients following 
treatment with 131I-BC8; however, it is not clear whether this represents any increase from AVN 
rates typically seen following transplant and use of prednisone for treatment of GVHD. 
 


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25 
B. Specifics of Radiolabeled Antibody Administration:  Therapeutic Dose  
 
The therapeutic dose of 131I-BC8 antibody will be administered according to the same schedule 
as the trace-labeled (biodistribution) dose.  The patient will continue taking non-radioactive iodine drops 
following the biodistribution dose until a minimum of three weeks after the therapeutic infusion (unless 
limited by other medical conditions).  The patient, when able, will be instructed in drawing his or her 
blood samples from a central venous catheter and in taking his or her own vital signs using an automated 
blood pressure machine.  The patient will be admitted to a special lead-lined isolation room at UWMC 
on the morning of the therapeutic infusion (generally day –12) and will remain there until total body 
activity is less than 30 mCi 131I, as estimated by a measurement of < 7 mR/hour one meter from the 
patient or as directed by the UWMC Radiation Safety Officer based on the public dose calculation from 
Nuclear Regulatory Commission Regulatory Guide 8.39.  The patient can then be discharged, and can 
remain an outpatient to complete treatment unless admission is medically indicated. 
 
C. Dose to Bone Marrow 
 
Initially, no patient in this study will receive a dose of 131I estimated to deliver more than 43 Gy 
to the marrow (+ 2 Gy TBI = 45 Gy total, i.e. 5 Gy more than the 28 Gy from 131I-BC8 antibody + 12 
Gy TBI previously shown to be tolerated).  Patients for whom the amount of 131I required to deliver the 
stipulated dose to liver would result in the delivery of more than the acceptable level of radiation to 
marrow will have the 131I dose limited to the amount which would deliver the maximum acceptable level 
(see section 19.B).   
 
D. Patients who become ineligible for therapeutic antibody infusion after biodistribution dose 
 
Patients who become ineligible for infusion of the therapeutic 131I-BC8 antibody will be 
considered for an alternate protocol.  The patient’s case will be presented to the Patient Care Conference 
to obtain a consensus opinion for the most appropriate protocol and treatment plan in this circumstance.  
Potential causes for ineligibility include development of a positive HAMA test or Grade IV toxicities 
after the biodistribution dose (section 13.A.1). 
 
14.  Special Considerations 
 
A. All patients will require placement of a large bore right atrial catheter. 
B. All patients receiving therapeutic amounts of 131I-labeled antibodies will be treated in single rooms 
at the University Hospital with appropriate shielding to minimize exposure of health care personnel 
and to prevent contamination of the room with radioisotope.  Patients will be instructed in self-care 
procedures, e.g. vital sign monitoring, blood drawing from central venous catheter as much as 
possible.   
C. All blood, urine, and tissue samples containing radioisotopes will be clearly identified as such.  
Samples containing high levels of activity (>50 uCi) will be transported in shielded containers.  All 
samples will be processed by personnel trained in the use of radioisotopes. 
 


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26 
15.  Targeted/Planned Enrollment Table 
Table 4: Targeted/Planned enrollment 
PROTOCOL #1809 
 
TARGETED/PLANNED ENROLLMENT:   
Number of Subjects (must provide actual numbers. I.e. no range) 
 
Ethnic Category 
 
 
 
Sex/Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
6 
12 
18 
Ethnic Category Total of All Subjects* 
7 
13 
20 
 
                  Racial Categories 
American Indian/Alaska Native 
 
1 
1 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
 
1 
1 
Black or African American 
 
1 
1 
White 
5 
8 
13 
Racial Categories: Total of All Subjects * 
7 
13 
20 
 
16.  Data Safety and Monitoring Plan 
 
A. Plans for assuring data accuracy and protocol compliance 
Clinical research personnel (monitors) who are contracted or assigned by the FHCRC Clinical 
Trials Support Office (CTSO) will conduct site visits to the investigational facilities.   The purposes of 
these site visits are to verify the accuracy of the study data, assess compliance with the protocol and with 
GCP regulations, and assure the timely and complete reporting of safety (adverse event) data.  Each visit 
will include review of relevant documents and data, including those at each institution at which a patient 
was treated while on study, and those kept in the UWMC Nuclear Medicine patient file, as stipulated in 
the Monitoring Plan and Monitor Orientation documents which are part of BB-IND 3771 files.  The 
frequency of the site visits will be at least twice per year, in accordance with FHCRC policies.  
Monitoring reports will be submitted to the Principal Investigator, the sponsor of BB-IND 3771, and the 
Protocol Data Monitoring Committee after each visit.  The Principal Investigator agrees to provide the 
monitors access to the clinical supplies, the dispensing and storage areas and records, the patients’ 
medical records and research files, the case report forms and data listings, and the IND and study files.   
 
B. Monitoring the progress of trial and safety of participants 
This is a single institution trial where all patients are followed closely by the investigators.  The 
trial design provides rules for dose de-escalation depending upon the rate of development of Grade 
III/IV RRT (Bearman Scale) in previous patients at a given Dose Level (Section 19).  This design 
mandates ongoing review of the outcome of previous patients treated on study so that the appropriate 
Dose Level for the current patient can be assigned.  The investigators meet at least monthly to review 
the course of each patient on study to identify the incidence of RRT or other adverse events requiring 
expedited reporting (see below).  Rules for dose de-escalation and termination of the study are detailed 
under Section 19. 
 
In this protocol for patients with advanced AML, the dose adjustment schema is designed to 
accept a 25% rate of Grade III/IV RRT given that these patients are at such high risk of relapse post-
transplant and could benefit from the delivery of maximum radiation doses to leukemic cells in bone 


1809.00 
 
 
27 
marrow and spleen.  Patients on this study represent a high risk population for whom HSCT offers the 
only chance of potential cure, and whose survival following conventional HSCT would be at most 20% 
for those patients young enough to tolerate a conventional, full-dose preparative regimen.  Because of 
this, as well as the use of the dose adjustment schema noted above, strict stopping rules for rates of 
death, severe GVHD, or lack of efficacy will not be used.  In addition to the regularly scheduled review 
of patient outcome by the investigators, results will be summarized in the Annual Renewal Report to the 
IRB, and the investigators will comment regarding the implications of these results for ongoing risk-
benefit ratios for patients.  In any year in which more than 15 patients are treated on study, an interim 
report will be submitted to the IRB addressing these issues after the first 15 patients for that year are 
treated and evaluable through day 90 post-transplant. 
 
C. Plans for assessing compliance with requirements regarding the reporting of adverse events 
Detailed guidelines are provided in Appendix E for the definition of Adverse Events and 
delineation of AE’s requiring expedited reporting to the IRB and FDA or reporting in Annual Reports. 
Dr. Orozco and the research nurse and/or the data coordinator will meet routinely to review the interval 
course for every patient enrolled on this protocol who is being treated on an SCCA HSCT team, whether 
pre or post-transplant.  The review of each patient’s course will be documented on a patient specific “AE 
review sheet”, which will be filed in the patient research record.  In Dr. Orozco’s absence (e.g. for travel 
or illness), review will be supervised by a designated physician sub-investigator.     
 
17.  Termination of Study Participation by Individual Patients 
 
 
A. Patient request. 
 
B. Unacceptable toxicity during dosimetry antibody infusions. 
 
C. Development of anti-mouse antibodies. 
 
18. 
Records 
 
 
Clinical Statistics maintains a patient database at FHCRC to allow storage and retrieval of patient 
data collected from a wide variety of sources.  The investigator will ensure that data collected conform 
to all established guidelines for coding, collection, key entry and verification.  Each patient is assigned a 
unique patient number (UPN) to assure patient confidentiality.  Any publication or presentation will 
refer to patients by this number and not by name.  The licensed medical records department, affiliated 
with the institution where the patient receives medical care, maintains all original inpatient and 
outpatient chart documents.  Patient research files are kept in a locked room and are maintained by the 
FHCRC data collection staff.  Access is restricted to personnel authorized by the Division of Clinical 
Research.  Information forwarded to the NCI and the FDA about patients on this protocol refers to 
patients by their UPN only. 
 
The study nurse and/or data coordinator maintains a Case Report Form (CRF) and associated 
research documentation for each patient treated under the auspices of BB-IND 3771, including all 
patients on this study.  This documentation includes both clinical data and IND-specific documents for 
each patient (including, but not limited to Absorbed Dose Estimate report from Dr. Fisher, the UW 
notice of Patient inclusion, the Dosimetry and Therapy Radiopharmaceutical Dose Sheets, Dosimetry 
and Therapy Radiolabeled Antibody Infusion Records, and HAMA reports). Additional IND-specific 
documents are kept in the UWMC Nuclear Medicine patient study files.  All data required for analysis 
of patients treated on this protocol will be maintained in a password-protected IND-specific Access 


1809.00 
 
 
28 
Database application. This single Access application will be used to retrieve the data for analysis on all 
patients treated under the auspices of IND 3771, and will include two sources of data. The first source of 
data is the Fred Hutchinson core database (Gateway).  The second type of data will be antibody-specific 
and other CRF data.  These data will be keyed directly into the database by the research nurse or other 
authorized research staff and will be extracted from the CRF forms or source documents maintained as 
part of each patient’s research documentation.  Dr. Orozco or a designee will review data entry on an 
ongoing basis, as it is completed for individual patients, by cross-checking the entered data against the 
source documents or the CRFs, and will initial and date the data printouts as documentation that the 
accuracy of entered data has been verified. 
 
19.  Dose Escalation/De-Escalation, Statistical Considerations, and Termination of Study 
 
A. Dose Escalation/De-Escalation 
Dose escalation/de-escalation will be conducted by the “two-stage” approach introduced by 
Storer19.  The starting dose level will be a total isotope dose estimated to deliver Dose Level 6, 20 Gy to 
the normal organ receiving the highest dose.  Single patients will be entered on the first stage, and 
escalation by 2 Gy increments (in the radiation dose delivered to the normal organ receiving the highest 
dose – Table 5) will occur until a patient experiences a Grade III/IV regimen-related toxicity (Bearman) 
or dose-limiting toxicity (DLT), at which point the second stage will begin at the next lower dose level.  
If the first patient (i.e., at the starting dose level) has DLT, de-escalation will occur by 2 Gy increments 
(Table 5) until the first patient does not have DLT, at which point the second stage will begin at that 
dose level.  In the second stage, patients will be entered in cohorts of 4 evaluable patients (i.e. patients 
not dying within the first 30 days of infection, unless they clearly have Grade III/IV RRT).  If the 
current cohort is treated at dose level k, the next cohort will be treated according to the following: level 
k-1 if 2 or more DLT’s are encountered in the cohort; level k if 1 DLT is observed within the current 
cohort; level k+1 if 0 DLT’s are seen in the current cohort.  These rules are followed until a total of 20 
evaluable patients have been treated at the second stage.  Following the completed observation of the 
20th patient, a two-parameter logistic model will be fit to the data, thereby generating a dose-response 
curve based on the observed toxicity rate at the various dose levels visited.  Based on this fitted model, 
the MTD is estimated to be the dose that is associated with a toxicity rate of 25%.  If the estimate of the 
slope parameter for the fitted curve is not positive and finite, the geometric mean of the dose level used 
for the last cohort and the dose level that would have been assigned to the next cohort is taken as the 
MTD.  It is possible that a patient will be entered on the protocol before a patient currently enrolled on 
Stage 1 or all 4 patients in a cohort in Stage 2 have been followed sufficiently long to evaluate toxicity.  
Such patients will be treated at the current dose level and will be used for purposes of fitting the dose-
response curve upon completion of the second stage.  These patients will not be used for purposes of 
dose modification, however, nor will they be counted towards the total of 20 patients for completion of 
the second stage. 
 


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29 
Table 5:  Dose Levels for Escalation/De-Escalation 
 
 
Dose Level 
Gray delivered by 131I-BC8 antibody to normal organ 
receiving the highest dose (liver) 
1 
10 Gy 
2 
12 Gy 
3 
14 Gy 
4 
16 Gy 
5 
18 Gy  
6 
20 Gy 
7 
22 Gy (starting dose level) 
8 
24 Gy 
9 
26 Gy 
10 
28 Gy 
 
B.  Dose to Bone Marrow and Graft Failure  
Initially no patient will receive a dose of 131I estimated to deliver more than 43 Gy to the marrow 
(+ 2 Gy TBI = 45 Gy total, i.e. 5 Gy more than the 28 Gy from 131I-BC8 antibody + 12 Gy TBI tolerated 
on Protocol #557).  Patients for whom the amount of 131I required to deliver the stipulated dose to liver 
would result in the delivery of more than 43 Gy to marrow will have the 131I dose limited to the amount 
which would deliver 43 Gy to marrow.  If 0 of 3, or no more than 1 of 6 patients treated at this estimated 
dose to marrow experiences graft failure (see below), we will then escalate in increments of 5 Gy to 
marrow in those patients as allowed by the marrow:liver radiation absorbed dose ratio (i.e. without 
exceeding intended estimated radiation absorbed dose to liver).  The MTD of radiation dose to marrow 
will be estimated to be the dose below any dose where > 2 patients of up to 6 treated experience graft 
failure. 
The risk of immunologic graft rejection is considered to be low for this protocol based on 
previous FHCRC mixed chimerism experience in which patients who had previously received intensive 
chemotherapy have not rejected the donor graft.  In this protocol, additional immunosuppression may be 
provided by lymphohematopoietic irradiation from 131I-BC8 antibody.  However, in the event of marrow 
stromal damage from excessive radiation exposure, patients might have inadequate hematopoiesis yet 
not meet the criteria for graft failure.  Every effort will be made to determine graft status for patients 
with slow recovery of neutrophils.  All patients will have marrow aspirates and/or biopsies performed at 
approximately day 28 and 84 for assessment of in vitro marrow stromal growth.  For patients who are 
critically ill and not expected to survive to day 28, an effort will be made to obtain a marrow sample 
prior to death in order to ascertain both graft and marrow stromal status.  Similarly, VNTR studies will 
be performed prior to day 28 if necessary.   
Patients with slow engraftment of neutrophils should be considered for treatment with 
hematopoietic growth factor.  Those patients who fail to achieve an ANC > 500/mm3 for two 
consecutive days by day 40, in the absence of contributing cause such as medication, sepsis, or CMV 
infection, will be considered to have graft failure. 
 
 


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30 
C. Statistical Considerations 
 
This is a Phase II dose-escalation study whose primary objective is the determination of the 
maximum tolerated dose of radiation delivered to normal organs by 131I-BC8 antibody when combined 
with the non-myeloablative regimen of 2 Gy TBI + CSP/MMF.  For this group of patients at extremely 
high risk of relapse after marrow transplantation, it is reasonable to accept a rate of grade III/IV 
regimen-related toxicity as high as 25% if anti-leukemic efficacy is improved by the therapy.  Thus in 
this study we will accept Grade III/IV RRT in an average of 1 of 4 patients, and the dose escalation/de-
escalation schema outlined above is based upon this. Monte Carlo analysis of a thousand simulated trials 
for each of 3 different scenarios of “True” Grade III/IV toxicity rates demonstrate the range of potential 
estimates of MTD which would arise from this dose-escalation design.  
 
We anticipate treating 25 to 30 patients, with the final number treated dependent upon the extent 
of dose escalation and the number of patients treated at each dose level to achieve 20 patients evaluable 
for RRT in the second phase of the trial. 
Because the anti-leukemic effect of 131I-BC8 antibody combined with this non-myeloablative 
regimen is unknown, but likely to increase at higher dose levels, we will follow disease response and 
duration of remission, but rates of relapse post-transplant, or failure to enter remission, will not halt the 
study. 
As discussed in section 19.B, we do not anticipate difficulties with graft rejection on this study.  
However, if graft rejection in excess of 20% was experienced, we would need to re-evaluate this 
approach.  If there ever exists sufficient evidence suggesting that the true rate of graft rejection exceeds 
20%, the protocol will be suspended and alternative approaches explored.  Sufficient evidence will be 
taken to be a lower limit of the appropriate 80% one-sided confidence interval associated with the 
estimated proportion of rejections in excess of .20.  These proportions and associated confidence 
intervals will be calculated after every 5th patient enrolled is evaluable.  Operationally, any of the 
following occurrences would meet the limits of this stopping rule: 3 or more of the first 5, 4 or more of 
the first 10, 5 or more of the first 15, 6 or more of the first 20, 8 or more of the first 25, 9 or more of the 
first 30, or 10 or more of the first 35 patients enrolled experience graft rejection. 
 
The following table summarizes the operating characteristics of this stopping rule. 
 
Number 
of 
Patients 
True Rate of 
Graft Rejection 
Probability of 
Stopping1 
10 
.10 
.02 
20 
.10 
.03 
10 
.30 
.37 
20 
.30 
.64 
10 
.40 
.64 
20 
.40 
.90 
1Represents estimate of the probability of stopping by associated number of 
patients due to excess graft rejection.  Estimated from 5,000 Monte Carlo 
simulations. 
 
We anticipate that the proposed regimen will result in better disease control.  We will also thus 
follow disease response and duration of remission and Kaplan-Meier estimates of disease-free survival 
and overall survival will be determined.  However, because the anti-leukemic effect of 131I-BC8 
antibody combined with this non-myeloablative regimen is unknown, the expected rate of relapse post-


1809.00 
 
 
31 
transplant or failure to enter remission after treatment is unpredictable.  If the rate of relapse or 
refractory disease exceeds 50% within the first 200 days post-transplant, similar to rates seen using 
standard myeloablative unrelated donor SCT, we would need to re-evaluate this approach. 
 
 
Lastly, we will calculate descriptive statistics on the number and percent of toxicities and 
compare the results obtained with historical patients treated with 131I-BC8 antibody + 12 Gy TBI.  The 
cumulative incidence of GVHD and the proportion of patients achieving donor chimerism, and the 
respective 95% confidence intervals, will be reported.   
 
20.  Other Criteria if Applicable: 
 
 
See appendix A for the Bearman criteria for grading regimen-related toxicity and Appendix B for 
grading of acute GVHD. 
 
21.  References 
 
1. Sierra J, Storer B, Hansen JA, Bjerke JW, Martin PJ, Petersdorf EW, Appelbaum FR, Bryant E, 
Chauncey TR, Sale G, Sanders JE, Storb R, Sullivan KM, Anasetti C: Transplantation of marrow 
cells from unrelated donors for treatment of high risk acute leukemia: the effect of leukemic 
burden, donor HLA-matching, and marrow cell dose. Blood 89:4226, 1997 
2. Doney K, Fisher LD, Appelbaum FR, Buckner CD, Storb R, Singer J, Fefer A, Anasetti C, 
Beatty P, Bensinger W, Clift R, Hansen J, Hill R, Loughran TP, Jr., Martin P, Petersen FB, 
Sanders J, Sullivan KM, Stewart P, Weiden P, Witherspoon R, Thomas ED: Treatment of adult 
acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis 
of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival. Bone 
Marrow Transplant 7:453, 1991 
3. Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, Champlin 
RE, Dicke KA, Goldman JM, Good RA, et al: T-cell depletion of HLA-identical transplants in 
leukemia. Blood 78:2120, 1991 
4. Miller CB, Zehnbauer BA, Piantadosi S, Rowley SD, Jones RJ: Correlation of occult clonogenic 
leukemia drug sensitivity with relapse after autologous bone marrow transplantation. Blood 
78:1125, 1991 
5. Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, Anasetti C, Beatty 
P, Bensinger WI, Doney K, Hill R, McDonald G, Martin P, Sanders J, Singer J, Stewart P, 
Sullivan KM, Witherspoon R, Storb R, Hansen J, Thomas ED: Allogeneic marrow 
transplantation in patients with acute myeloid leukemia in first remission. A randomized trial of 
two irradiation regimens. Blood 76:1867, 1990 
6. Clift RA, Buckner CD, Appelbaum FR, Bryant E, Bearman SI, Petersen FB, Fisher LD, Anasetti 
C, Beatty P, Bensinger WI, Doney K, Hill RS, McDonald GB, Martin P, Meyers J, Sanders J, 
Singer J, Stewart P, Sullivan KM, Witherspoon R, Storb R, Hansen JA, Thomas ED: Allogeneic 
marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a 
randomized trial of two irradiation regimens. Blood 77:1660, 1991 
7. Omary MD, Trowbridge IS, Battifora HA: Human homologue of murine T-200 glycoprotein. 
J.Exp.Med. 152:842, 1980 


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32 
8. Andres TL, Kadin ME: Immunologic markers in the differential diagnosis of small round cell 
tumors from lymphocytic lymphoma and leukemia.  Am.J.Clin.Pathol. 79:546, 1983 
9. Caldwell CW, Patterson WP, Hakami N: Alterations of HLe-1 (T200) fluorescence intensity on 
acute lymphoblastic leukemia cells may relate to therapeutic outcome.  Leuk.Res. 11:103, 1987 
10. Matthews DC, Appelbaum FR, Eary JF, et al: Phase I study of (131)I-anti-CD45 antibody plus 
cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic 
syndrome. Blood 94:1237-47, 1999. 
11. Matthews 
DC, 
Appelbaum 
FR, 
Eary 
JF, 
et 
al: 
131I-anti-CD45 
antibody 
plus 
busulfan/cyclophosphamide in matched related transplants for AML in first remission. Blood 
88:142a, 1996. 
12. Ruffner KL, Matthews DC: Current uses of monoclonal antibodies in the treatment of acute 
leukemia. Semin Oncol 27:531-9, 2000. 
13. Blaise D, Maraninchi D, Michallet M, et al: Long-term follow-up of a randomized trial 
comparing the combination of cyclophosphamide with total body irradiation or busulfan as 
conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic 
leukemia in first complete remission. Blood 97:3669-71, 2001.  
14. McSweeney PA, Wagner JL, Maloney DG, Radich J, Shizuru J, Bensinger WI, Bryant E, 
Chauncey TR, Flowers MED, Kauffman M, Minor CS, Nash RA, Blume K, Storb R: Outpatient 
PBSC allografts using immunosuppression with low-dose TBI before, and cyclosporine (CSP) 
and mycophenolate mofetil (MMF) after transplant.  Blood 2001. 
15. Storb R, Yu C, McSweeney P: Mixed chimerism after transplantation of allogeneic 
hematopoietic cells, in Thomas ED, Blume KG, Forman SJ (eds): Hematopoietic Cell 
Transplantation, Boston, Blackwell Science, p 287, 1999. 
16. Georges GE, Maris M, Sandmaier BM, et al. Related and unrelated nonmyeloablative 
hematopoietic stem cell transplantation for malignant diseases. Int J Hematol 76 Suppl 1:184-9, 
Aug 2002. 
17. Maris MB, Niederwieser D, Sandmaier BM, et al. Nonmyeloablative Hematopoeitic Stem Cell 
Transplants (NM-HSCT) Using 10 HLA Antigen Matched Unrelated Donors (URDs) for 
Patients with Advanced Hematologic Malignancies. J Am Soc Hem 100:11 Abst. 275, 2002. 
18. Niederwieser D, Maris M, Shizuru JA, et al. Low-dose total body irradiation (TBI) and 
fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or 
mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and 
mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions 
in patients with hematological diseases.  In Press.  2002. 
19. Storer B: Small-sample confidence sets for the MTD in a Phase I clinical trial.  Biometrics 
45:1117, 1993 


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33 
APPENDIX A 
 
CRITERIA FOR TOXICITY 
The criteria for toxicity were developed to convey the following considerations about the toxicity 
of the preparative regimen.  It is the responsibility of the principal investigator to try and distinguish 
toxicities due to the preparative regimen from these due to other features of transplantation. 
 
Grade 1 
Development of transient chemical abnormalities which are not of major clinical 
consequence and which reverse without requiring major medical interventions.  In 
general, the intent of this toxicity scale is to observe transient target organ toxicity 
which is reversible. 
 
Grade 2 
Development of chemical or laboratory abnormalities which are persistent and which 
may represent target organ damage which may not be readily reversed.  It is 
anticipated that at this dose of drug, the toxicity obtained would be manageable by 
clinical methods but may interfere with other therapies. 
 
Grade 3 
Development of major clinical, chemical or laboratory abnormalities which represent 
maximum toxicities without being fatal.  This grade of toxicity is designed to be the 
dose limiting toxicity.  Further, the development of this degree of toxicity cannot be 
considered to be a regular acceptable but rather an occasional toxicity (<20%), 
acceptable given the severity of the disease.  Included in this would be the need for 
life support techniques such as renal dialysis and ventilation therapy. 
 
Grade 4 
Fatal. 
 
A. Cardiac 
 
Grade 1 
EKG voltage decrease by 25% or less, resting tachycardia with weight gain but 
responsive to diuretic therapy. 
 
Grade 2 
EKG voltage decrease by 25-50%, congestive heart failure responsive to diuretic 
therapy, arrhythmias manageable with medical therapy. 
 
Grade 3 
Symptomatic CHF unresponsive to diuretic therapy, decrease in EKG voltage by 
more than 50%, life-threatening arrhythmia. 
 
Grade 4 
Fatal toxicity. 
 
B. Bladder 
 
Grade 1 
Microscopic hematuria for more than 7 days. 
 
Grade 2 
Macroscopic hematuria. 
 


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34 
Grade 3 
Hemorrhagic cystitis requiring transfusion and placement of an indwelling catheter to 
remove clots, or cystoscopy with or without installation of sclerosing agents. 
 
Grade 4 
Fatal toxicity. 
 
C. Renal 
 
Grade 1 
Increase in creatinine up to twice baseline value. 
 
Grade 2 
Increase in creatinine above twice baseline value but not requiring dialysis. 
 
Grade 3 
Requirement of dialysis. 
 
Grade 4 
Fatal toxicity. 
 
D. Pulmonary 
 
 
 
Grade 1 
Decrease in pO2 or dyspnea without an infiltrate or, at most, a transient patchy 
infiltrate. 
 
Grade 2 
Transient interstitial pneumonia (either idiopathic or unbiopsied) that does not require 
ventilatory support). 
 
Grade 3 
Interstitial pneumonia requiring ventilatory support. 
 
Grade 4 
Fatal toxicity. 
 
E. Hepatic 
 
Grade 1 
Transient elevations in liver function tests less than those listed as Grade 2 toxicity. 
 
Grade 2 
Hepatic dysfunction with bilirubin elevation greater than 5, SGOT increase greater 
than five-fold or ascites.  
 
Grade 3 
Hepatic failure including hepato-renal syndrome, hepatic encephalopathy, bilirubin 
elevation greater than 20, or Grade 3 VOD as defined by Shulman et al. 
 
Grade 4 
Fatal toxicity. 
F. Central Nervous System 
 
Grade 1 
Transient somnolence. 
 
Grade 2 
Somnolence more than 36 hours or other signs of CNS toxicity. 
 


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35 
Grade 3 
Seizures or coma. 
 
Grade 4 
Fatal. 
 
G. Stomatitis 
 
Grade 1 
Ulceration or pain but not prohibiting oral intake. 
 
Grade 2 
Painful ulceration prohibiting oral intake. 
 
Grade 3 
Severe ulceration requiring intubation. 
 
Grade 4 
Fatal. 
 
H. Gastrointestinal 
 
Grade 1 
Watery stools, but less than 6 stools/day. 
 
Grade 2 
Watery stools more than 6-12 stools/day, or hemorrhagic enterocolitis not requiring 
transfusion, or transient ileus. 
 
Grade 3 
Hemorrhagic enterocolitis requiring transfusion, or ileus requiring nasogastric 
suction. 
 
Grade 4 
Fatal. 
 


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36 
APPENDIX B 
GRADING OF GVHDa 
 
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 (2.0-3.0 mg/100 ml) 
 
 
 
+2 
bilirubin (3-5.9 mg/100 ml) 
 
 
 
+3 
bilirubin (6-14.9 mg/100 ml)  
 
 
 
+4 
bilirubin > 15 mg/100 ml  
 
Gut 
 
Diarrhea is graded +1 to +4 in severity.  Nausea and vomiting and/or anorexia 
caused by GVHD is assigned as + 1 severity. 
 
The severity of gut involvement is assigned to the most severe involvement 
noted. Patients with visibly bloody diarrhea are at least a stage +2 gut and 
grade +3 overall. 
 
Diarrhea   
+1 
< 1000 ml of liquid stool/day in the absence of infectious/medical 
cause. 
 
 
 
+2 
>1,000 ml of stool/day 
 
 
 
+3 
>1,500 ml of stool/day 
 
 
 
+4 
2,000 ml of stool/day 
 
Severity of GVHD 
Grade I 
 
+1 to +2 skin rash 
 
 
 
No gut or liver involvement 
 
 
 
 
 
Grade II 
 
+3 skin rash or  
 
 
 
+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 
 
_______________ 
a  From Graft-vs-Host Disease, Sullivan, Keith M in Hematopoietic Cell Transplantation.  Ed: E. 
Donnall Thomas, Karl G. Blume, Stephen J. Forman.  Pages 518-519.* 


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37 
APPENDIX C 
 
Class I HLA-A, -B, -C Antigens (or Equivalents) That Must Be Identified for Donor Matching 
 
HLA-A 
HLA-B 
HLA-B 
HLA-C 
A1 
B7 
B45(12) 
Cw1 
A2 
B703(7) 
B46(15) 
Cw2 
A3 
B8 
B47 
Cw3 
A11 
B13 
B48(40) 
Cw4 
A23(9) 
B14 
B49(21) 
Cw5 
A24(9) 
B62(15) 
B50(21) 
Cw6 
A25(10) 
B63(15) 
B51(5) 
Cw7 
A26(10) 
B70(15) 
B52(5) 
Cw8 
A29(19) 
B75(15) 
B53 
A30(19) 
B76(15) 
B54(22) 
A31(19) 
B77(15) 
B55(22) 
A32(19) 
B21 
B56(22) 
A33(19) 
B18 
B57(17) 
A34(10) 
B27 
B58(17) 
A36 
B35 
B59 
A43 
B37 
B67 
A66(10) 
B38(16) 
B73(7) 
A68(28) 
B39(16) 
B78(5) 
A69(28) 
B60(40) 
B81(7) 
A74(19) 
B61(40) 
A80 
B41 
 
B42 
 
B44(12) 


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38 
APPENDIX D 
 
METHODS USED TO ESTIMATE RADIATION ABSORBED DOSES TO PATIENTS 
Absorbed radiation doses are calculated for each patient’s normal organs and tissues, the whole 
body, and for tumor masses.  Doses are calculated using the formal methods that are recommended by 
the Medical Internal Radiation Dose (MIRD) Committee of The Society of Nuclear Medicine (a, b, c).  
These methods account for both the penetrating gamma and the non-penetrating beta radiation emitted 
by radioactivity distributed throughout the body.  Dosimetry calculations are based on a set of direct 
measurements in individual patients.  These include, based on gamma-camera measurements of iodine-
131 activity in the major source organs, tumor tissue (the red marrow) and the total body at various 
time-points post-infusion of the radiolabeled antibody.  Red marrow biopsies indicate the activity 
concentration in marrow at specific time points.  Organs for which measurement data are obtained are 
called “source organs.”  Organs, tissues, and the whole body for which radiation absorbed doses are 
estimated, are called “target organs.”   
 
Direct Measurements in Patients 
Conjugate-view quantitative planar imaging with anterior and posterior measurements is the most 
widely used method for assessing source-organ activity in patients (d, e).   The conjugate view method 
does not require knowing the depth of the source region and does not depend on assumptions inherent in 
single-view phantom simulations. 
After a tracer level of iodine-131 (usually about 5 to 8 mCi) on the monoclonal antibody is 
administered, the patient is imaged using collimated anterior and posterior planar gamma-camera 
imaging.  Images are acquired over the source organs using a large-field-of-view camera.  Anterior plus 
posterior conjugate view are obtained using a collimated system with the photon energy window set 
over the relevant energy peak at about  15-20% (full width at half-maximum).  Images will include 
head/neck, chest with upper humeri, abdomen, and pelvis with upper femurs. 
Regions of interest are selected for the major source organs, such as the liver, spleen, red marrow 
space, and occasionally for the lungs and kidneys (when suitable images can be obtained), and for any 
other tissue with activity above background, including thyroid and bladder.  Measurements are also 
made of representative background tissue (such as the thigh muscle), and a counting standard with and 
without the patient in the camera field-of-view.  The outlines for the regions of interest are drawn by a 
technician from the acquired image, and counts are obtained from the selected regions.  The counts are 
appropriately decay-corrected to a radionuclide standard.  Patient thickness and the distance from the 
gamma camera to the source organ are determined.  The geometric mean of the anterior and poster 
counts is obtained for each region of interest.  Counts are then corrected for attenuation, geometry, and 
background. 
 
Total body measurements will be obtained using an external, non-imaging gamma probe at a 
distance of 4 meters from the patient to quantify the absolute I-131 activity in the patient, over time, as a 
fraction of the total administered activity.  
 
Sampling Times 
Selecting an appropriate number of counting times requires a trade-off between the desire for 
sufficient data, while economizing the overall costs and minimizing patient inconvenience.   Our 
objective is to select the fewest time points that will provide a reasonable description of the time-activity 
curve.  The minimum number of data measurement points is typically four.  These include one 


1809.00 
 
 
39 
measurement at or near the zero time point (time of radionuclide infusion), plus additional 
measurements at about 18, 44, and 66 hours post-infusion.  These analyses provide an estimate of the 
fraction of the administered activity that resides in each source organ (and in the total body) at each 
measurement time post-infusion. 
 
Time-Activity Curves 
 
The sequential measurement data are plotted to determine the cumulated activity and residence time 
for each source organ.  Plotted are the fractions of the total administered activity that are present at each 
measurement time point.  Time-activity curves are constructed from the measurement data and are 
integrated out to infinite time to determine the residence times (, hours) for each source organ, the red 
marrow, and for the whole body.  The points are fitted to an exponential or sum of exponentials.   An 
estimate of the long-term tail of the time activity curve may be made by fitting an exponential function 
to the last two points. 
We plot the effective fractions present (as measured), rather than the values that were decay-
corrected from a radionuclide standard, because internal doses are approximately proportional to the 
integral areas under the effective time-activity curves.   
 
Residence Time Calculations: Integrating the Time-activity Curves 
The residence time for a source organ is the fraction of the administered activity in a source organ 
over time to complete decay, obtained by integrating the time-activity curve. Thus, the residence time is 
the area under the fractional time-activity curve.  The residence times are the basic input value to the 
software packages MIRDOSE2 and MIRDOSE3 (f) (Oak Ridge Associated Universities, Oak Ridge, 
Tennessee) and OLINDA-EXM (Vanderbilt University, Nashville, Tennessee) that implement the 
MIRD dosimetry schema.. 
The cumulated activity, Ã h, and residence time,  h, are determined by integrating the area under the 
time-activity curves for the clinical measurement data for each source organ and the remainder tissues.  
The integrations are carried to infinity for accuracy and simplicity.   
Residence times for red marrow are determined from a set of gamma camera measurements of 
iodine-131 activity in marrow spaces (usually the right and left acetabula), and from a bone marrow 
biopsy that is weighed and then counted in a standard well-type counter.  The time-activity curve is 
developed from the marrow counts, and then the curves are adjusted to exactly cross through the data 
point for the marrow activity concentration.  The long-term tail of the exponential may be estimated by 
curve-fitting.   
 
According to the MIRD schema, the cumulated activity, Ã h, is proportional to the sum of all nuclear 
transformations during the time of interest in a source organ, h.  The cumulated activity is also called the 
time integral of Ah(t), or  
 
Ã h  =   Ah(t) dt,  
(1) 
 
where the units of cumulated activity are given in Ci-hr or Bq-sec.  If a single exponential is fit to the 
data points representing simple clearance, then the activity in the source organ at any point in time, t, 
may be estimated by the equation: 
 


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40 
Ah(t)  =   Ah(0) exp(-t), 
(2) 
 
where Ah(0) is the y-axis intercept of the exponential equation, and where  is the long-term effective 
(not corrected for radioactive decay) constant.  The effective clearance constant  is:   
 
. =  (ln 2)/(T1/2eff),  
(3) 
 
and therefore the effective clearance halftime, T1/2eff, is: 
 
T1/2eff  =  (ln 2)/  =  1.443 / . 
(4) 
 
The integral of the single exponential for the cumulated activity, or area under the curve is:  
 
 Ah(t) dt    =   Ah(0) (1/ln 2) (T1/2eff), and 
(5) 
 
 Ah(t) dt    =   Ah(0) (1.443) (T1/2eff), 
(6) 
 
where Ah(0) is the y-axis intercept.  It follows that the residence time,  h , is: 
 
 h   =   [Ah(0)/Ao] (1.443) (T1/2eff). 
(7) 
 
If a multi-exponential function is needed to describe the pharmacologic uptake, retention, clearance, and 
physical decay processes, the time-activity curves are described using multiple exponential functions of 
the form: 
 
y  =  A exp(-1t)  + B  exp(-2t) . . . 
(8) 
 
where 1 and 2 are the effective retention constants.  If a multi-exponential function is fit to the 
measurement data, then the integral of the function (or area under the curve) is simply 
 
 y  dt   =   A/1 + B/2   . . . .  
(9) 
 
Patient-specific Dosimetry 
The residence times for each source organ are corrected for actual patient mass (if known from CT-
imaging volumetrics) using a method described by Fisher et al. (g, h).  Methods for this correction for 
patient-specific dosimetry are described in the following paragraphs.  
 
It has been well documented by this and other studies that the actual patient weights and organ sizes 
may vary considerably from those used in the standard MIRD dosimetric models.  Since organ dose is 
approximately proportional to the inverse of target mass, a correction may be made for patient weight 
and organ mass when actual organ weights are known from CT-imaging.  The correction involves 
recalculating the S values for each of the source-target combinations where patient-specific organ 
volumes are known.  The recalculated S values will account for both the gamma component specific 
absorbed fraction of energy and the mass over which the beta component is averaged.  For most 
radionuclides, the beta self-irradiation dose in a source organ is the greater contributor to total organ 
dose (usually more than 90 percent of the total). 


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41 
 
A less-accurate, but more convenient “short-cut” method for correcting for known organ mass is 
given below.  This short-cut method corrects the beta component but does not correct for the lesser-
important gamma component.  For individual organs and for the whole-body, the correction may be 
made by multiplying the calculated source-organ residence time,  h, by the ratio of the defined reference 
man or reference woman organ mass to the known organ mass: 
 
 new     ( h ) (mMIRD/mactual). 
(10) 
 
This correction may be appropriate when most of the organ dose is due to non-penetrating radiation. The 
new residence time for each source organ and for the remainder tissues may then be entered into 
MIRDOSE or OLINDA-EXM to estimate normal organ and whole-body doses (in rad/mCi or 
mGy/MBq administered) for the patient.   
 
Dose Calculations 
In the MIRD schema, the absorbed dose, D, to target organs or tissues (rk), and the whole body, is 
calculated from the sum of the products of the cumulated activity Ã (Ci-hours) in each source organ 
(rh) and the S value (the absorbed dose per unit cumulated activity in rads per Ci-hour, or gray per 
becquerel-second) for each source-target organ pair, according to the MIRD equation 
 
D(rkrh)  =   Ã S(rkrh),  
(11) 
 
                                 h 
 
where the cumulated activity Ã in a source organ is also the product of the residence time and the 
administered activity A0.  Thus,  
 
ÃA0and = Ã/A0  
(12) 
 
The dose calculations are implemented by the MIRDOSE2 and MIRDOSE3 computer software for 
medical internal dose assessment (Oak Ridge Associated Universities, Oak Ridge, Tennessee) or 
OLINDA-EXM (Vanderbilt University, Nashville, Tennessee).   
Relevant to the use of MIRDOSE2 and MIRDOSE3 software, The S values used for the calculations 
MIRDOSE2 computer software are the same as those that were previously implemented in ICRP 
Publication 30 (i).  Revised S values for marrow and the skeleton are implemented in MIRDOSE3 (f).  S 
values for solid tumors are estimated by extrapolation using normal organs of similar size and location 
in the body.  In this leukemia trial, we assume that the cancer cells are in the red marrow, and therefore 
the dose to red marrow and the dose to leukemia cells are assumed to be the same.  MIRDOSE2 S 
values for red marrow are used when appropriate, since a new evaluation of the S values at the 
University of Florida has shown that MIRDOSE3 S values may underestimate the mean dose per unit 
cumulated activity to red marrow. 
 
Therapy Doses 
The radiation absorbed doses that are estimated for the tracer infusion of iodine-131-labeled 
monoclonal antibody are extrapolated linearly to higher levels of activity that are later administered for 
the therapeutic infusion. 
 


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42 
REFERENCES: APPENDIX D 
 
a. International Commission on Radiation Units and Measurements (ICRU).  Methods of assessment of 
absorbed dose in clinical use of radionuclides.  ICRU Report No. 32.  Washington, DC: International 
Commission on Radiation Units and Measurements, 1979. 
b. National Council on Radiation Protection and Measurements (NCRP).  The experimental basis for 
absorbed dose calculations in medical uses of radionuclides.  NCRP Report No. 83.  Bethesda, 
Maryland: National Council on Radiation Protection and Measurements, 1985. 
c. Loevinger, R., Budinger, T. F., and Watson, E. E.  MIRD primer for absorbed dose calculations.  
New York: The Society of Nuclear Medicine, Inc., 1988. 
d. Leichner PK, Koral KF, Jaszczak RJ, Green AJ, Chen GTY, Roeske JC: An overview of imaging 
techniques and physical aspects of treatment planning in radioimmunotherapy.  Med Phys 1993, 
20:569-577. 
e. Thomas SR, Maxon HR, Kereiakes JG:  In vivo quantitation of lesion radioactivity using external 
counting methods.  Med Phys 1976, 3:253-255. 
f. Stabin MG:  MIRDOSE: Personal computer software for internal dose assessment in nuclear 
medicine.  J Nucl Med 37:538-546, 1996. 
g. Fisher, D. R., Badger, C. C., Breitz, H, Eary, J. F., Durham, J. S., Hui, T. E., Hill, R. L., and Nelp, 
W. B.  Internal radiation dosimetry for clinical testing of radiolabeled monoclonal antibodies.   
Antibody Immunocon. Radiopharm 4:655-664, 1991.  See equation (7) on p. 658. 
h. Fisher, D. R. 2000.  “Internal Dosimetry for Systemic Radiation Therapy.”  Sem. in Rad. Oncol. 
10(2):123-132. 
i. International Commission on Radiological Protection.  Limits for intakes of radionuclides by 
workers.  ICRP Publication 30.  Oxford: Pergamon Press, 1979. 


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43 
APPENDIX E 
SERIOUS ADVERSE EVENT (SAE) DEFINITION AND REPORTING GUIDELINES 
 
HSCT involves the administration of high doses of chemotherapy and or radiation and is 
associated with a high rate of adverse events which are to be considered “Expected” in the setting of 
HSCT.  For patients on this protocol, there is also an expected incidence of side effects associated with 
the administration of the biodistribution and therapy dose of I-131-BC8 antibody.  While we will use the 
Bearman Scale of Regimen-Related Toxicity detailed in Appendix A of the protocol for decisions 
regarding 1) continuation on study depending on antibody infusion-related toxicities (Section 13.A.1. 
and 2.) dose adjustment or invocation of stopping rules, for the purposes of SAE reporting, and defining 
which adverse events require expedited SAE reporting or reporting in the Annual Report to the FDA for 
BB-IND 3771, we will use the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0, (http://ctep.cancer.gov/forms/CTCAEv3.pdf).  The criteria for “Expected” toxicities are 
outlined separately for: 1) antibody infusion-related toxicities, and 2) transplant-related toxicities and 
adverse events. 
 
A. Grading of Acute Toxicities due to I-131-BC8 Antibody Infusion: 
 
In our experience in over 130 patients receiving a biodistribution dose of I-131-BC8 antibody, 
approximately 31% developed Grade II allergic side effects, and 6% developed Grade III allergic side 
effects when graded using our protocol-delineated 5 point scale (Section 13.A.1), where the absence of 
side effect is considered “0”.  All patients had resolution of these side effects, and only two of these 
patients did not complete their antibody infusion. No patient had worse side effects upon resumption of 
antibody infusion (in those for whom the infusion was held temporarily because of their side effects), 
and very few patients had side effects during their therapy infusion of I-131-BC8 antibody that were 
more severe than the patient had experienced during his/her biodistribution infusion.   
 
Thus the following events are to be considered expected as a consequence of the infusion of I-
131-BC8 antibody, and will only be undergo expedited reporting as SAEs if they are of > Grade 4 
severity by the NCI CTCAE scale, or if they result in hospitalization: 
 
Chills 
Fever 
Hypotension 
Nausea 
Vomiting 
Diarrhea 
Allergic 
reaction/hypersensitivity 
Dyspnea 
Conjunctivitis 
Urticaria 
Myalgia 
Arthralgia 
Arthritis 
Headache 
Fatigue 
Hand/foot skin reaction 
Allergic rhinitis 
 
 


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44 
The following events may be expected, but will undergo expedited SAE reporting if they are of > Grade 
3 severity: 
 
SGOT (AST) elevation 
SGPT (ALT) elevation 
 
 
Many patients entered on this study will have limited marrow reserve because of either recent 
therapy or because of leukemic relapse.  It is expected that patient may have transient leukopenia and/or 
thrombocytopenia following the biodistribution dose of I-131-BC8 antibody, and that the patient may 
require a platelet transfusion because of the transient effect on circulating platelet count.  Leukopenia, 
lymphopenia, neutropenia and thrombocytopenia will not be reported as SAEs.  Life-threatening 
infection or bleeding will undergo expedited SAE reporting. 
 
Other adverse events that are unexpected will undergo expedited reporting if they are of Grade 3 
severity with possible, probable or definite attribution, and if they are of > Grade 4 severity regardless of 
attribution. 
 
B. Grading of Transplant-Related Toxicities and Adverse Events 
 
All patients undergoing HSCT are expected to have Grade 4 pancytopenia as an intended 
therapeutic effect, and thus this will not be reported as an SAE.  Graft rejection or Graft Failure will 
undergo expedited reporting as an SAE.  Certain Grade 4 toxicities under particular categories in the 
CTCAE are common in the HSCT setting and do not represent a life-threatening event as detailed.  
These toxicities are not likely to be particularly due to the administration of the investigational agent as 
part of the preparative regimen, and will not undergo expedited reporting as an SAE.  These include: 
 
Fatigue 
Fever 
Anorexia (as defined under “Gastrointestinal”) 
Vomiting 
Hypokalemia (e.g., potassium < 2.5 can result from wasting induced by amphotericin) 
Sterility/infertility 
 
 
Any other Grade 4 toxicity occurring within 100 days of transplant will undergo expedited SAE 
reporting, regardless of attribution. This will include SAEs due to infection or complications associated 
with GHVD.  The following events are to be considered expected in the setting of HSCT, and will not 
be reported in an expedited fashion unless they are of > Grade 4 severity: 
 
CTCAE Category 
Toxicity 
Cardiac (General) 
Edema 
Hypertension 
Hypotension 
Coagulation 
DIC 
Thrombotic microangiopathy 
 
Constitutional Symptoms 
Graft versus host disease 
Rigors, chills 
Stem cell infusion complications 
Veno-Occlusive Disease 
(VOD) 
Weight gain associated with 
VOD 


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45 
CTCAE Category 
Toxicity 
Dermatology/Skin 
Hand-foot skin reaction 
Pruritis/itching 
Rash/desquamation 
 
Gastrointestinal 
Anorexia 
Colitis 
Dehydration 
Diarrhea 
Dysphagia 
Esophagitis 
Gastritis 
Ileus 
Mucositis/Stomatitis 
Nausea 
Typhlitis 
Vomiting 
Hemorrhage/Bleeding 
Hemorrhage/bleeding with grade 3 or 
4 thrombocytopenia 
Hemorrhage, GI – Lower GI NOS 
Hemorrhage, GI – Rectum 
Hemorrhage, GI – Stomach 
Hemorrhage, GU – Bladder 
Hemorrhage, GU – Vagina 
Hemorrhage, pulmonary/ 
upper respiratory – nose 
Hemorrhage, pulmonary/ 
upper respiratory – 
Respiratory tract NOS 
Hepatobiliary/Pancreas 
Hepatic enlargement 
Pancreatitis 
 
Infection 
Catheter-related infection 
Febrile neutropenia 
Infection with grade 3 or 4 
neutropenia 
Infection with unknown 
ANC 
Infection without 
neutropenia 
Metabolic/Laboratory 
Acidosis 
Albumin, serum-low 
(hypoalbuminemia) 
Alkaline phosphatase elevation 
Alkalosis 
ALT, SGPT 
Amylase elevation 
AST, SGOT 
Bilirubin (hyperbilirubinemia) 
Creatinine 
GGT elevation 
Hypercalcemia 
Hypercholesterolemia 
Hyperglycemia 
Hyperkalemia 
Hypermagnesemia 
Hypernatremia 
Hypertriglyceridemia 
Hyperuricemia 
Hypocalcemia 
Hypoglycemia 
Hypokalemia 
Hypomagnesemia 
Hyponatremia 
Hypophosphatemia 
Lipase elevation 
Musculoskeletal/Soft Tissue 
Muscle weakness 
 
Pain 
Pain – abdomen NOS 
Pain – bladder 
 
Pulmonary/Upper Respiratory Cough 
Hypoxia 
Pleural effusion 
Pneumonitis/pulmonary 
infiltrates 
Voice changes/dysarthria 
Renal/Genitourinary 
Bladder spasms 
Renal failure 
Urinary electrolyte wasting 
Urinary frequency/urgency 
Urinary retention 


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46 
CTCAE Category 
Toxicity 
Sexual/Reproductive Function Persistent amenorrhea 
 
Syndromes 
Tumor lysis syndrome 
 
 
 
 
 
Engraftment syndrome is an early complication of stem cell transplants that occurs around 
neutrophil engraftment. One patient experienced a life threatening side effect of ES about 2 weeks after 
stem cell transplant under this protocol. Usual symptoms of ES include occurrence or re-occurrence of 
fever around the time of engraftment, shortness of breath, weight gain, sudden rise in white blood count, 
and skin rash. 
 
 
Grade 3 toxicities which are considered unexpected and possibly, probably or definitely related 
to the investigation drug will undergo expedited SAE reporting.   
 
The primary transplant hospitalization will not be reported itself as an SAE, although >Grade 4 
toxicities occurring during the hospitalization will be reported, as above.  All hospitalizations other than 
the hospitalization for administration of the therapy dose of I-131-BC8 antibody and the primary 
transplant hospitalization will undergo expedited reporting as an SAE.   
All deaths except for those from relapse of malignancy, but otherwise regardless of attribution, 
which occur within the first 100 days will be undergo expedited reporting as an SAE.  If the patient has 
returned to the care of the referring physician prior to day 100 post-transplant, we will report the death 
as an SAE with expedited reporting based on the time we learn of the death.  Deaths and events 
occurring after 100 days will not undergo expedited SAE reporting although they will be included in 
Annual Reports and publications of the study.  Grade 3 toxicities that are considered “expected” will be 
reported in the Annual Report.  Patients will be followed for long-term toxicities that may be related to 
the administration of I-131-BC8 antibody, such as hypothyroidism, and such toxicities will continue to 
be reported in the Annual Report. 
All adverse events meeting criteria for expedited reporting will be reported within 7 days to the 
IRB and the FDA.  Because IRB reports are routed through the Protocol Office, every effort will be 
made to notify the Protocol Office within 5 days in order to allow time for processing.  When that is not 
possible, the Protocol Office will be notified that immediate processing is required.  Notification will 
consist 
of 
a 
completed 
“Fred 
Hutchinson 
Cancer 
Research 
Center/Clinical 
Research 
Division/Institutional Review Office Serious Adverse Event Report” and a brief narrative letter to the 
FDA.  Notification will be made by the principal investigator, a sub-investigator, or the Study 
Coordinator/Research Nurse.