Clinical trial NCT00536601
Conditions: Adult Acute Lymphoblastic Leukemia in Remission Adult Acute Myeloid Leukemia in Remission 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) Adult Nasal Type Extranodal NK/T-cell Lymphoma Childhood Acute Lymphoblastic Leukemia in Remission Childhood Acute Myeloid Leukemia in Remission Childhood Burkitt Lymphoma Childhood Diffuse Large Cell Lymphoma Childhood Immunoblastic Large Cell Lymphoma Childhood Nasal Type Extranodal NK/T-cell Lymphoma Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor (PNET) Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue Hepatosplenic T-cell Lymphoma Intraocular Lymphoma Nodal Marginal Zone B-cell Lymphoma Peripheral T-cell Lymphoma Plasma Cell Neoplasm Primary Systemic Amyloidosis Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Adult Burkitt Lymphoma Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Adult Diffuse Mixed Cell Lymphoma Recurrent Adult Diffuse Small Cleaved Cell Lymphoma Recurrent Adult Grade III Lymphomatoid Granulomatosis Recurrent Adult Hodgkin Lymphoma Recurrent Adult Immunoblastic Large Cell Lymphoma Recurrent Adult Lymphoblastic Lymphoma Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Recurrent Childhood Anaplastic Large Cell Lymphoma Recurrent Childhood Grade III Lymphomatoid Granulomatosis Recurrent Childhood Large Cell Lymphoma Recurrent Childhood Lymphoblastic Lymphoma Recurrent Childhood Small Noncleaved Cell Lymphoma Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Malignant Testicular Germ Cell Tumor Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Neuroblastoma Recurrent Small Lymphocytic Lymphoma Recurrent/Refractory Childhood Hodgkin Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Multiple Myeloma Regional Neuroblastoma Splenic Marginal Zone Lymphoma Testicular Lymphoma Unspecified Adult Solid Tumor, Protocol Specific Unspecified Childhood Solid Tumor, Protocol Specific Waldenström Macroglobulinemia
Sponsor: Roswell Park Cancer Institute
Start date: 2006-06-29; Completion date: 2018-07-09
Enrollment: 174 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot trial studies different high-dose chemotherapy regimens with or without total-body irradiation (TBI) to compare how well they work when given before autologous stem cell transplant (ASCT) in treating patients with hematologic cancer or solid tumors. Giving high-dose chemotherapy with or without TBI before ASCT stops the growth of cancer cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood or bone marrow and stored. More chemotherapy may be given to prepare for the stem cell transplant. The stem cells are then returned to the patient to replace the blood forming cells that were destroyed by the chemotherapy.

Detailed description:
PRIMARY OBJECTIVES:

I. Estimate the progression free survival (PFS) distribution for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) for each disease-specific high dose therapy regimen.

SECONDARY OBJECTIVES:

I. Estimate the PFS distribution for amyloidosis, acute leukemia and selected solid tumors for each disease-specific high dose therapy regimen.

II. Explore the role of risk factors in the outcome of all treated patients. III. Examine the high dose therapy regimen-related toxicity (RRT) and overall survival after bone marrow transplant (BMT).

OUTLINE:

Patients are assigned to conditioning regimens based on disease, age, and co-morbidities.

Arms: arm 1: Patients receive etoposide intravenously (IV) continuously over 34 hours on day -8, cyclophosphamide IV over 2 hours on days -7 to -4, and carmustine IV over 2 hours on day -3. Patients undergo ASCT on day 0. arm 2: Patients receive 200 or 120 mg/m\^2 of melphalan IV over 30 minutes on day -2. Patients undergo ASCT on day 0. arm 3: Patients receive busulfan IV over 2 hours then every 6 hours on days -7 to -4 for 16 total doses and cyclophosphamide IV over 2 hours on days -3 and -2. Patients undergo ASCT on day 0. arm 4: Patients receive cyclophosphamide IV over 2 hours on days -5 to -4. Patients then undergo TBI twice daily on days -3 to -1. Patients undergo ASCT on day 0. arm 5: Patients receive cyclophosphamide IV continuously, carboplatin IV continuously, and thiotepa IV continuously over 24 hours on days -7 to -4. Patients undergo ASCT on day 0. arm 6: Patients receive etoposide IV over 2-3 hours and carboplatin IV over 30 minutes on days -6 to -4. Patients undergo ASCT on day 0. At least 4 weeks after the first transplant, patients receive etoposide IV over 2-3 hours and carboplatin IV over 30 minutes on days -6 to -4. Patients then undergo a second ASCT on day 0. arm 7: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 2 hours on days -5 to -2. Patients undergo ASCT on day 0. At least 4 weeks after the first transplant, patients receive carboplatin IV continuously over 24 hours on days -7 to -4, etoposide IV continuously over 24 hours on days -7 to -4, and melphalan IV over 30 minutes on days -7 to -5. Patients undergo a second ASCT on day 0.
Interventions: intervention 1: etoposide intervention 2: cyclophosphamide intervention 3: carmustine intervention 4: melphalan intervention 5: busulfan intervention 6: carboplatin intervention 7: thiotepa intervention 8: total-body irradiation intervention 9: autologous hematopoietic stem cell transplantation intervention 10: autologous-autologous tandem hematopoietic stem cell transplantation
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV intervention 8: Undergo TBI intervention 9: Undergo ASCT intervention 10: Undergo tandem ASCT

Protocol documents:
Prot_SAP_000.pdf: 
Protocol No. I 72806
Page 1 of 73
Date: Feb 6, 2018
Roswell Park Cancer Institute
Protocol Number: I 72806                    NCT00536601
Protocol Title:
AUTOLOGOUS BLOOD AND MARROW TRANSPLANTATION 
FOR HEMATOLOGIC MALIGNANCIES AND SELECTED SOLID 
TUMORS
Principal Investigator:
Philip McCarthy, M.D.
.
Amendment #9
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Protocol No. I 72806
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Date: Feb 6, 2018
TABLE OF CONTENTS
Page
1.0
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
3
2.0
STUDY SCHEMA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
5
3.0
BACKGROUND INFORMATION FOR STUDY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
4.0
STUDY PURPOSES AND OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5.0
ELIGIBILITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
23
6.0
CONSENT FORM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
 26
7.0
STRATIFICATION AND RANDOMIZATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
8.0
TREATMENT PLAN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
27
9.0
CRITERIA FOR RESPONSE AND PROGRESSION . . . . . . . . . . . . . . . . . . . . . . . . . . . 
39
10.0
INFORMATION ON DRUG FORMULATION AND AVAILABILITY. . . . . . . . . 
39
11.0
REPORTING OF ADVERSE DRUG REACTIONS / DATA SAFETY 
MONITORING PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
12.0
STATISTICAL ANALYSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
45
13.0
GENDER AND MINORITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
47
14.0
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
48
15.0
APPENDICES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
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Date: Feb 6, 2018
1.0
ABSTRACT
Title:
AUTOLOGOUS BLOOD AND MARROW TRANSPLANTATION FOR 
HEMATOLOGIC MALIGNANCIES AND SELECTED SOLID TUMORS
P.I.
Philip McCarthy, M.D.
Investigator-initiated Study
Pilot Study
Objectives: Examine the Progression Free Survival (PFS) by high dose therapy regimen for 
Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).  For the diagnoses of HL, 
Multiple Myeloma (MM) and NHL, examine the PFS for those who are at high versus standard risk 
for disease progression or relapse after BMT.  For the diagnoses of Acute Lymphoblastic Leukemia 
(ALL) and Acute Myeloid Leukemia (AML) both acute leukemias (AL), determine if the known 
prognostic factors can be used to group patients into high and standard risk groups.  
Secondary Objectives: Examine the high dose therapy regimen-related toxicity (RRT) and overall 
survival after BMT for all groups.  For purposes of reporting to the Center for International Blood 
and Marrow Transplant Research  (http://www.cibmtr.org/) , all patients’ disease status at transplant 
will be determined prior to initiation of protocol therapy. For purposes of analysis, patients will be 
stratified into groups (low (standard) and high-risk for recurrence), since accrual of patients to some 
of the individual disease/status strata will be slow.
Treatment Overview
Eligible patients with HL, MM, NHL, ALL, AML and selected solid tumors (primarily testicular 
cancer and neuroblastoma) will undergo stem cell collection and autologous stem cell transplant 
according to the study schema in Section 2.  
Eligiblity Criteria
Disease Diagnoses:  Histologically confirmed diagnosis of malignant hematologic disorders, 
Amyloidosis or solid tumor malignancy including recurrent or refractory disease or disease at high 
risk for recurrence including HL, NHL, AML, ALL, MM, and other lymphoproliferative disorders 
such as CLL and Waldenstrom’s macroglobulinemia.  Solid tumor patients include testicular cancer 
patients who have relapsed disease or primary progressive disease which is responding to salvage 
therapy; relapsed or advanced-stage newly diagnosed neuroblastoma pediatric patients; other 
patients with solid tumors who have recurred following conventional treatment or are at high risk 
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Protocol No. I 72806
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Date: Feb 6, 2018
for relapse, and demonstrate chemosensitivity.
Subjects and Target Study Duration, Endpoints and Brief Statistical Section
This is a Pilot study of high dose therapy and autologous blood or marrow transplantation for 
patients with hematologic malignancies or disorders who have failed standard first-line 
chemotherapy or who are in their first remission, but are at high risk of relapse.  Patients will be 
stratified into 6 disease groups (acute leukemia (AL), HL, NHL, MM, Amyloidosis, and solid 
tumors) for analysis of high dose therapy regimens.  Response rates for each regimen will be 
determined separately for the individual disease strata.  This is a total of 224 and this population 
size will allow for estimation of interest.  The accrual rate of approximately 3 per month will allow 
for up to a total accrual of 252 over approximately 84 months.
The primary objective of this study is to determine the activity of the proposed blood or marrow 
transplant high dose therapy regimens.  Response rates and toxicities will be reported using 
descriptive statistics.  The Kaplan-Meier method will be used to construct progression-free and 
overall survival curves.  Patients will be stratified into 6 disease groups. The Overall Survival and 
Progression Free Survival will be estimated in addition to response and toxicity rates.
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2.0
STUDY SCHEMA
Figure 1a shows this study’s schema:
Disease
High Dose Treatment
Estimated Accrual
Acute Leukemia (ALL/AML)
BuCy2iv
11
Acute Leukemia (ALL/AML)
CT6
10
HL
BuCy2iv
10
HL
CBV
25
NHL
BuCy2iv
35
NHL
CBV
35
Amyloid
Mel120
5
Amyloid
Mel200
20
Myeloma
Mel120
9
Myeloma
Mel200
50
Solid Tumor
Solid Tumor Regimens*
14
* Testicular Cancer, VCp (Tandem); Neuroblastoma or Small Round Blue Cell Tumor, TtC1500 
followed by VCpM; Other Solid Tumors CTtCp. See Figure 1b for high Dose Treatment regimen 
abbreviations.
Figure 1b: High dose therapy regimens assigned by Disease, Age and co-morbidities:
Disease
Variables
Preferred 
Regimen (Old 
nomenclature)
Preferred Regimen (New 
nomenclature – Codes in the 
BMT database)
ALL
Any Risk, Radiation not 
contraindicated
CT
CT6 
ALL
Any Risk, Radiation 
Contraindicated
BuC
BuC2iv
AML
Any Risk
BuC
BuC2iv
HL/NHL
Any Risk under the age of 
60
CBV
CBV
HL/NHL
Any Risk over the age of 
60
BuC
BuC2iv
MM or 
Any Risk with adequate 
M200
M200
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Date: Feb 6, 2018
Disease
Variables
Preferred 
Regimen (Old 
nomenclature)
Preferred Regimen (New 
nomenclature – Codes in the 
BMT database)
Amyloidosis
organ function
MM or 
Amyloidosis
Any Risk with 
compromised organ 
function
M120
M120
Testicular Cancer
High Risk
VCp
VCp (tandem)
Neuroblastoma or 
small round blue 
cell tumor 
patients ≤ 30 
years of age)
relapsed or advanced-
stage newly diagnosed
Tt/C followed 
by VCpM
TtC1500 followed by VCpM
Other Solid 
Tumors (Not 
Testicular Cancer 
or 
Neuroblastoma)
High Risk
CTtCp
CTtCp
Abbreviations for new nomenclature: 
CT6: Cyclophosphamide 60 mg/kg IV daily x 2 days (120 mg/kg total dose) and 6 fractions of TBI -
1200 cGy.
BuC2iv: Busulfan 0.8 mg/kg IV every 6 hours x 16 doses (12.8 mg/kg intravenous total dose)   and 
Cyclophosphamide 60 mg/kg IV daily x 2 days (120 mg/kg total dose.)
CBV: Cyclophosphamide 1800 mg/m2 IV daily x 4 days (7200 mg/m2 total dose), BCNU 600 mg/m2 x 1 
dose and Etoposide 2400 mg/m2 total dose continuously over 34 hours.
M120/M200: Melphalan 120 mg/m2 x 1 dose; Melphalan 200 mg/m2 x 1 dose.
VCp: Etoposide 750 mg/m2 IV daily x 3 doses (2250 mg/m2 total dose) and Carboplatin 700 mg/m2 IV 
daily x 3 days (2100 mg/m2 total dose),.
TtC1500: Thiotepa 300 mg/m2 IV daily x 3 days (900 mg/m2 total dose)  and Cyclophosphamide (1500 
mg/m2 IV daily x 4 days (6000 mg/m2 total dose) V/Cp/M: Etoposide  200 or 300 mg/m2 IV daily x 4 
days (1200 mg/m2 total dose)   and Carboplatin 375 mg/m2 or AUC 4.1  IV daily x 4 days (1500 mg/m2 
total dose)  and Melphalan 60 mg/m2 IV daily x 3 days (180 mg/m2 total dose) See section 8.4 for details
CTtCp: Cyclophosphamide 1500 mg/m2 IV daily x 4 days (6000 mg/m2 total dose) Thiotepa 125 mg/m2 
IV daily x 4 days (500 mg/m2 total dose), and Carboplatin 200 mg/m2 IV daily x 4 days  (800 mg/m2 
total dose)
Etoposide Phosphate may be substituted for Etoposide in the event of anaphylaxis to Etoposide.  Dosing 
is the same, volume is different.
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3.0
BACKGROUND INFORMATION FOR STUDY
Autologous Blood and Marrow Transplantation (autoBMT) is the treatment of choice for 
selected patients with hematologic malignancies and solid tumors (Reviewed in Thomas’ 
Hematopoietic Cell Transplantation).  AutoBMT consists of collection of blood or bone 
marrow stem cells followed by intensive chemo/radiotherapy to treat and attempt to 
eradicate the patient’s cancer.  The appropriate intensive/chemotherapy regimen or high 
dose therapy regimens for selected diseases remain open questions as well as the appropriate 
patient population for autoBMT.  Variables associated with the appropriate high dose 
therapy include type of chemotherapy and/or radiation.  Patient variables include age, 
performance status, underlying organ function, disease, disease status at transplant and 
chemosensitivity.
The major problems associated with autoBMT include; regimen-related toxicity and relapse 
of the underlying malignancy.  We have attempted to limit autoBMT-associated mortality 
while preserving the anti-tumor effect of the intensive therapy by closely examining the high 
dose therapy regimens.  Patient characteristics are important in determining the response to 
and cure from autoBMT.  Patients with chemotherapy -sensitive are more likely to benefit 
from autoBMT than those with resistant disease.  However selected patients with 
chemotherapy-resistant disease such as Hodgkin Disease do benefit from autotransplant.  
The RPCI BMT program has accrued patients to the current autologous BMT protocol (DS 
91-15) since 1991.  The target accrual of 450 patients will be met this year and the proposed 
study will replace DS 91-15.  As of July 5, 2005, 419 patients had been enrolled to DS 91-
15.  Patients were stratified by risk for analysis as follows in Table 1:
Table 1
Acute Leukemia in 1st Complete Remission (CR)
Standard Risk
Lymphoma in 1st or 2nd CR
Leukemia and Lymphoma
>2nd CR
Resistant 1st Relapse
Primary Refractory Disease*
Multiple Myeloma
Amyloidosis
Recurrent or Primary refractory Testicular Cancer
High Risk
Other Solid Tumors
        * Refractory to standard chemotherapy
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Date: Feb 6, 2018
Results of DS 91-15 (Former Autologous BMT protocol):
The previous protocol was based on a disease and risk-adapted therapy for high dose therapy 
regimen selection.  This schema is demonstrated below in Figure 2.
Figure 2
High dose therapy 
Regimen:
BuC vs.          
Compare 
  
VCT vs.        
Toxicity (RRT) 
Standard Risk Group
CBV vs.          
& Response
MT
 (PFS)
Disease and 
         
Disease Status
         
At BMT
BuC vs.
Compare        
CTtCp vs.   
Toxicity (RRT) 
High Risk Group
CBV vs.         
& Response
MT vs.
(PFS)
M vs.
       
VCp vs.
TtC + VCpM (tandem)
Abbreviations: 
C: Cyclophosphamide, B: BCNU (carmustine), V: Etoposide (VP-16), Tt: Thiotepa, Cp: Carboplatin, T: Total body 
irradiation, Bu: Busulfan, M: Melphalan, RRT: Regimen-related toxicity grade 3 -4, PFS: Progression Free Survival, 
OS = Overall Survival
Regimens were assigned by disease as follows:
Table 2
DISEASE
VARIABLES
PREFERRED REGIMEN
AML, ALL
any risk
MT
radiation contraindicated*
BuC
Hodgkin’s' Disease
any risk
CBV if <60 years old; BU/CY if >60 
years old
Non-Hodgkin’s' 
Lymphoma
standard risk under the age of 60
VCT
prior exposure to VP/CY and under the 
age of 60
MT
radiation contraindicated
BuC
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Protocol No. I 72806
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Date: Feb 6, 2018
DISEASE
VARIABLES
PREFERRED REGIMEN
Multiple Myeloma or 
Amyloidosis
any risk
M (100 per M2 for those with organ 
toxicity, 200 per M2 if adequate organ 
function
Testicular Cancer
recurrent or primary progressive disease
VCp
Neuroblastoma or 
small round blue cell 
tumor patients  ≤ 30 
years of age
relapsed or advanced-stage newly 
diagnosed
TtC followed by VCpM
Solid tumors, 
testicular
any stage
CTtCp
AML: Acute Myeloid Leukemia;   ALL: Acute Lymphoblastic Leukemia.
* For children under 16, BU/CY may be utilized.
Patient Accrual (through 7/5/2005).
Table 3
                                                  Number
Percent
Acute Leukemias
29
6.9
Amyloidosis
9
2.1
CML
5
1.2
HL
64
15.3
MM
119
28.4
NHL
140
33.4
Solid Tumors
53
12.6
Total
419
100
Accrual was initiated in 1991.  The protocol was modified in 1997 changing the delivery of 
radiation, dose of radiation and chemotherapy, as well as the regimen combinations.  
Diseases treated included: Acute Leukemias, Amyloidosis, HL, NHL, MM and selected 
solid tumors.  Acute Leukemia patients consisted of patients with AML (n=28) and ALL 
(n=1) and have remained consistent.  The frequency of transplant for amyloidosis has 
increased to approximately 2 per year.  HL and NHL accruals have remained consistent.  
MM transplants have decreased this past year to approximately half of the previous annual 
accrual.  The Solid Tumor numbers consist of 43 breast cancer patients who no longer 
would be offered transplant.  The remaining 10 patients are those with neuroblastoma, 
testicular cancer and primitive neuroectodermal tumors.
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Toxicity
We have demonstrated that the regimens in this study can be safely administered with 
acceptable toxicity:  The day 100 toxic death rate is 5.5% (23/419).  The day 100 toxic death 
rates for standard and high risk patients were 1.4% (1/71) and 6.3% (22/348) respectively.  
These toxic death rates are acceptable when compared to data from the Center for 
International Blood and Marrow Transplant Research (CIBMTR).  The early stopping rules 
(based on a high day 100 toxic mortality rate) were not violated for this study.  Secondary 
endpoints were incidence of severe to fatal regimen-related toxicity (RRT), graft 
failure/failure to engraft and secondary malignancy.  Some patients developed more than 
one toxicity. 
Table 4
RRT: Regimen-related toxicity (defined by the Bearman criteria: J Clin Oncol  6 (10): 1562-8, 1988)
Graft failure: defined as patient’s absolute neutrophil count falling to <500/mm3 not due to disease progression 
after previous documented engraftment;  Failure to engraft: defined as patient survival to day 60 with absolute 
neutrophil count <500/mm3;  Day 100 Toxic Death Rate: percent of patients who died before day +100 post-
transplant due to transplant-related causes including: RRT, GVHL, Infection, Hemorrhage, graft failure/failure to 
engraft.  Excludes the deaths before day +100 due to disease progression.
Toxicity
Standard Risk 
Transplants
High Risk
Transplants
All
Transplants
Total number (percent)
71 (100%)
348 (100%)
419 (100%)
RRT grade 3 or 4
6 (8.5%)
33 (9.5%)
39 (9%)
Graft failure or failure to engraft
1 (1.4%)
2 (<1%)
3 (<1%)
Secondary Malignancy
2 (2.8%)
5 (1.4%)
7 (1.7%)
Day 100 Toxic Death Rate
1 (1.4%)
22 (6.3%)
23 (5.5%)
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Outcomes
Response data for eligible patients who were evaluable for response as of July 5, 2005 are 
listed below:  
Table 5
                                                             Std Risk
High Risk
Total Pts
Total Number Entered
71
348
419
Total number evaluable
70
313
383
Number of Complete Responses
62
206
268
Number of Partial Responses
1
21
22
Number of Stable Responses
1
70
71
Number of Progression of Disease
6
16
22
Number of No Response
0
0
0
Number Too Early to evaluate
1
4
5
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Figure 3
Progression Free Survival by Risk Group, Protocol DS 91-15
Figure 3: Legend for Progression Free Survival by Risk Group DS 91-15: Standard and High Risk 
patients are defined in Table 1.  
Explanation: Solid line indicates patients who were at standard risk for relapse (n=70 evaluable 
patients).  Dashed line indicates patients who were at high risk for relapse (n=335 evaluable 
patients). Nine patients (all high risk) with 2 transplants had one BMT excluded so that each patient 
is included only once.  Five BMTs (1 standard risk, 4 high risk) were also excluded for PFS because 
they are too early to evaluate for best response to BMT.  
Conclusion: There was no difference in Progression Free Survival by high risk and low risk 
stratification. P>0.8.  Thus the risk stratification as defined in DS 91-15 has not proven to be 
predictive for PFS.  
Probability of Survival
High Risk Patients
Standard Risk Patients
Time in days post-transplant
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Figure 4
Progression – Free Survival by High dose therapy Regimen, Protocol DS 91-15
NON-TBI containing high dose therapy regimens:
Figure 4: Legend for Progression Free Survival by Risk Group DS 91-15: B: BCNU (Carmustine); 
Bu: Busulfan; C: Cyclophosphamide; Cp: Carboplatin; M: Melphalan; Tt: Thiotepa; V: VP-16 
(Etoposide).  
Explanation: CBV has been used primarily for HL patients.  M for myeloma patients, BuC for NHL 
patients over 60 years of age or if TBI contraindicated.  TtCp, VCp, CTtCp were used for solid 
tumor patients.  VCp is used for testicular cancer patients only.  CTtCp is used for solid tumor 
patients excluding neuroblastoma and testicular cancer patients.  TtCp is no longer used.
CBV
TtCp
BuC
CTtCp
VCp
M
P<0.0001
Time in days post-transplant
Probability of Survival
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Figure 5
Progression – Free Survival by Diagnosis, Protocol DS 91-15
Figure 5: Legend for Progression Free Survival by Diagnosis DS 91-15:  Amyloidosis (n=9) and 
HL (n=64) have the highest rates of PFS.  Acute Leukemias (n=29), NHL (n=140) Solid tumors 
(n=53) and MM (n=119) have similar PFS.  CML patients (n=5) have not been transplanted on this 
protocol since 1996
Hodgkin Lymphoma (HL)
Examining patient outcomes by disease, we found a PFS and OS of approximately 60% for HL 
patients receiving CBV.  This is equivalent or superior to results reported to other series that have 
examined CBV as the high dose therapy regimen during autotransplant (Salar et al).  Figure 6 
P=0.016
Acute Leukemia
Hodgkin Disease
Amyloidosis
Non-Hodgkin 
Lymphoma
Chronic Myeloid Leukemia
Solid 
Tumors
Multiple 
Myeloma
Time in days post-transplant
Probability of Survival
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demonstrates that CBV is a superior regimen to thiotepa-based regimens (Thiotep and Total Body 
Irradiation and Thiotepa and Carboplatinum).  The Thiotepa regimens have been discontinued as 
high dose therapy regimens.  We will continue to use CBV for HL patients who are less than 60 
years of age.  CBV is a moderately toxic regimen especially for older patients and BuC was used 
for patients 60 years and older.  There were not enough HL patients receiving BuC to analyze 
therefore it will be used for those older than 60 years.    An objective of this protocol is to compare 
the efficacy (PFS) of CBV vs. BuCy2iv in HL patients.
We developed and published the use of a prognostic model for outcome based on HL patient 
characteristics immediately prior to BMT (Hahn et al, 2005).  The 3 factors associated with shorter 
event –free survival (EFS) prognosis were chemotherapy-resistant disease, Karnofsky Performance 
Status (KPS) < 90% and > 3 chemotherapy regimens pre-BMT.  Patients with 0 or 1 prognostic 
factors are considered low risk and those with 2 or 3 prognostic factors are considered high risk.  
We will use these prognostic factors when available to determine patients at high risk for poor BMT 
outcomes.  If  the model continues to remain valid, this will corroborate the need for alternative 
approaches to the high risk population such as a more intensive high dose therapy regimen or an 
alternative approach such as allogeneic BMT.  
Figure 6
Progression – Free Survival For HL Patients by Regimen, Protocol DS 91-15
Figure 6 Legend: Progression-free survival for HL patients treated on DS 91-15 comparing TtT or 
TtCp (dashed line, n=16) vs. CBV (solid line n=46), p=0.0295.  Thiotepa-based regimens are 
significantly inferior to CBV and are discontinued for use in HL.
Time in days post-transplant
Probability of Survival
CBV
Tt-Based
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Non-Hodgkin Lymphoma (NHL)
Several regimens have been used for autotransplant (Hahn et al 2001).  RPCI regimens include 
VCT, TtCp, MT, TtT and BuC.  BuC was recently added for patients 60 years of age and older and 
for those who could not receive a TBI containing regimen.  VCT has been the primary TBI-
containing regimen for NHL patients since 1997.  When we examined the PFS and OS for BuC and 
VCT, there was a trend toward an improved PFS in the BuC group however this was not 
statistically significant (see Figure 7).  There is no difference in OS for VCT versus BuC.  There 
has been no conclusive evidence that one regimen is superior.  Chemotherapy-containing regimens 
may generate superior outcomes than TBI-containing regimens however this is not conclusive.  
(Salar et al, Peniket et al ).  In addition, TBI containing regimens appear to generate more toxicity.  
These toxicities are manifested by increased mucositis, lung toxicity and as well as secondary 
hematologic disorders including myelodysplastic syndrome and secondary Acute Myeloid 
Leukemia (AML).  Thus, based on data from 91-15, that multi-drug non-TBI containing regimens 
may have superior efficacy to TBI containing regimens, CBV will be used for NHL patients under 
the age of 60 and those 60 years and older will receive BuC.  CBV has a PFS of about 70% in HL 
patients, however CBV was used in only 3 DS 91-15 NHL patients, therefore a comparison of CBV 
in NHL patients cannot be made at this time.  We will compare the CBV and BuC patient groups 
with historical populations receiving TBI containing and non-TBI-containing regimens.  An 
objective of this protocol is to compare the efficacy (PFS) of CBV vs. BuCy2iv in NHL patients.
 Vandenberghe et al published registry data demonstrating that autotransplant for mantle cell 
lymphoma patients in 1st CR resulted in a Progression Free Survival of greater than 50% at 5 years.  
This is superior to results with standard chemotherapy.  There have been no randomized trials 
comparing autotransplant versus standard chemotherapy.  Thus, MCL patients will be offered auto 
BMT in first CR. 
Peniket et al have demonstrated that autologous BMT is associated with a lower morbidity and 
regimen related mortality than allogeneic BMT.  However allogeneic BMT is associated with a 
lower relapse rate.  Until the mortality associated with allo BMT is decreased, autologous BMT will 
be the preferred treatment unless the patient has high risk features more suitable for allo BMT.  
These include patients who do not attain a CR with salvage therapy and all NHL patients who 
relapse after autotransplant.  
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Figure 7
Progression – Free Survival For NHL Patients by Regimen, Protocol DS 91-15
Figure 7 Legend: Progression-free survival for NHL patients treated on DS 91-15 comparing 
BuCy2iv (solid line, hatched tick mark, n=27) vs. other high dose therapy regimens (dashed line, 
n=62) vs. VCT (solid line, closed triangle tick mark, n=45), p>0.05.  Other high dose therapy 
regimens included TtCp, TtT, and MT.  VCT-based and other high dose therapy regimens will no 
longer be used in NHL patients.  
Multiple Myeloma and Amyloidosis
BMT remains the standard of care for myeloma patients responding to initial therapy or in those 
who progress after response to initial therapy (Attal et al, Child et al Hahn et al 2003).  We had 
previously used Melphalan (M) only at a dose of 140 mg/m2 for patients above the age of 60 due to 
concerns regarding toxicity at a dose of 200 mg/m2.  This cutoff was changed to age 65 in January, 
2005 without deleterious effect.  Patients who are above the age of 65 can be treated with higher 
doses of melphalan up to 200 mg/m2 (Reece et al).  In addition, M was used in combination with 
total body irradiation (T) until February, 2002.  The use of MT was stopped when a randomized 
study demonstrated there was no difference in outcome when compared to M alone (Moreau et al).  
Our results confirm this finding as shown in Figure 8.  For this protocol, M will be used at a dose of 
200 mg/m2 for patients who have no evidence of organ dysfunction regardless of age.  This regimen 
is also safe for patients with amyloidosis without serious underlying organ dysfunction (Working 
Group of UK Myeloma Forum).  For patients with underlying organ dysfunction, we have 
Probability of Survival
Time in days post-transplant
Probability of Survival
BuC
All other
VCT
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historically utilized M at a dose of 100 mg/m2.  This has included patients who are in renal failure 
and those with cardiac dysfunction and it has been well-tolerated in patients who would otherwise 
not receive a BMT.  In an effort to increase the efficacy of the M, the regimen will be increased to 
120 mg/m2 for all patients who are otherwise not eligible for M at a dose of 200 mg/m2.  
In an effort to determine risk and assess outcome following BMT, we will utilize a new scoring 
system (when available) that is based on diagnostic criteria.  This simple outcome scoring system 
uses serum Beta-2 Microglobulin (β2M) and serum albumin at diagnosis for determining prognosis 
and is described as follows (Greipp et al):
Stage I, Serum β2M < 3.5 mg/L and serum albumin > 3.5 g/dL (med. survival, 62 
months); 
Stage II, neither stage I nor III (median survival, 44 months) 
Stage III, Serum β2M > 5.5 mg/L (median survival, 29 months).
This staging system will be used for assigning risk before BMT (by measuring this at time of 
BMT).  In addition, we will score patients with available data at the time of BMT to determine if 
this will be a useful prognostic score at time of BMT in addition to at time of diagnosis.  
Objectives of the section of the protocol will be to compare the utility of this staging system and to 
determine the toxicity of the M regimen in an older age population as well as the increase M dose 
for patients who would otherwise not have received a BMT in the past.
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Figure 8
Progression – Free Survival For MM Patients by Regimen, Protocol DS 91-15
Figure 8 Legend: Progression-free survival for MM patients treated on DS 91-15 comparing M 
(solid line, closed triangle tick mark, n=71) vs. MT (solid line, hatched tick mark, n=21) vs. 
TtT/TtCp (dashed line, n=22), p>0.05.  TtCp, TtT and MT high dose therapy regimens are no 
longer used in MM patients.  M was used at varying doses of 100, 140 or 200 mg/m2 in DS 91-15 
MM patients. 
Amyloidosis is an incurable plasma cell disorder that results in deposition of amyloid protein in the 
form of light chains.  There is no standard conventional therapy for Amyloidosis patients.  
Approximately 40% of Amyloidosis patients respond to autologous BMT (Comenzo et al).  
Amyloidosis patients will be treated on this protocol with doses of M at 120 and 200 mg/m2 
depending on underlying organ function.
Acute Leukemias
Autologous Blood or Marrow Transplant have been utilized for the treatment of acute leukemia 
since the 1958 (McGovern et al).  It was in the 1970s and 1980s when this form of therapy became 
more established as a therapy for patients who did not have suitable donor for allogeneic 
transplantation (Reviewed in Thomas’ Hematopoietic Cell Transplantation).   VCT, MT, TtT and 
BuC have all been used as high dose therapy regimens for acute leukemias, in first or second CR.  
BuC has been used for older patients and those who cannot receive total body irradiation (TBI).  In 
an attempt to standardize the regimens, all acute leukemia patients who are younger than 65 years 
of age will receive CT.  Those Acute Leukemia patients who are 65 years of age and older will 
receive BuC for high dose therapy.
Probability of Survival
Time in days post-transplant
MT
M
TtT/TtCp
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Figure 9
Progression – Free Survival For Acute Leukemia Patients by Regimen, Protocol DS 91-15
Progression-free survival for Acute Leukemia patients treated on DS 91-15 comparing Total Body 
Irradiation (TBI)-based high dose therapy regimens (dashed line, n=21) vs. non-TBI-based high 
dose therapy regimens (solid line, n=7), p>0.05.  A variety of TBI and non-TBI regimens were 
used, with small patient numbers in each group, making comparisons of superior high dose therapy 
regimens impossible.  An objective of this protocol is to compare the efficacy (PFS) of using 
consistent standardized high dose therapy regimens of CT (TBI-based) vs. BuCy2iv (non-TBI 
based) in Acute Leukemia patients.
Solid Tumors
Solid tumor patients have been treated with different regimens including TtCp as well as CTtCp.  
On protocol DS 91-15, there were 43 breast cancer, 5 testicular cancer, 1 PNET and 1 
neuroblastoma patients who received autologous transplants.  Breast cancer patients are no longer 
treated with autologous BMT.  The other diseases have too few historical patients to provide 
comparative PFS curves.  With the exception of neuroblastoma patients and testicular cancer 
patients, all eligible solid tumor patients will receive CTtCp for high dose therapy for BMT.  
Neuroblastoma patients will receive a tandem transplant with TtC followed by CpVM.  Testicular 
cancer patients will also receive a tandem transplant consisting of VCp given twice.  
TBI-Based Regimens
Non-TBI-Based Regimens
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4.0
STUDY PURPOSES AND OBJECTIVES
Primary Objective:
1) Estimate the Progression Free Survival (PFS) distribution for HL, NHL and MM for each 
disease-specific high dose therapy regimen.
Secondary Objectives
1) Estimate the PFS distribution for Amyloidosis, Acute Leukemia and Selected Solid 
Tumors for each disease-specific high dose therapy regimen.
2) Explore the role of risk factors in the outcome of all treated patients
3) Examine the high dose therapy regimen-related toxicity (RRT) and overall survival after 
BMT.
For purposes of reporting to the Autologous Blood and Marrow Registry (ABMTR), all 
patients’ disease status at transplant will be determined prior to initiation of protocol 
therapy.
For purposes of analysis, patients will be stratified into groups (low (standard) and high-risk 
for recurrence), since accrual of patients to some of the individual disease/status strata will 
be slow.  The assignment of risk is as follows:
Hodgkin Lymphoma (HL) patients
Hahn, et al., proposed a prognostic score for HL patients undergoing autologous 
or allogeneic BMT (Hahn et al, 2005).  An objective of this protocol is to 
validate this prognostic model.  The following factors will be collected when 
available:
Standard risk: 0-1 Risk Factors (chemotherapy-resistant disease, 
KPS <90 and > 3 chemotherapy regimens) 
High risk: 
2-3 Risk Factors (chemotherapy-resistant disease, 
KPS <90 and > 3 chemotherapy regimens)
Non-Hodgkin Lymphoma (NHL) patients
There are no pre-transplant prognostic or risk models for NHL.  The 
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International Prognostic Index (IPI) is a validated prognostic model but uses 
factors measured at diagnosis.  Since patients are referred from multiple non-
RPCI physicians, there is inconsistency in the completeness of collecting and 
reporting these diagnostic factors.  For this protocol, the IPI factors will be 
measured at time of BMT to determine in an exploratory manner if the IPI at 
BMT is predictive of post-transplant PFS.  In addition, we will examine other 
pre-transplant variables to determine if a prognostic model can be developed.  
The IPI definitions are located in Appendix I (The International Non-Hodgkin's 
Lymphoma Prognostic Factors Project).  These factors will be collected when 
available:
International Prognostic Index (All Patients)
Low Risk
0-1 risk factors
Low Intermediate
2 risk factors
High Intermediate
3 risk factors
High
4 or 5 risk factors
International Prognostic Index (< 60 years of age)
Low
0 risk factors
Low intermediate
1 risk factor
High intermediate
2 risk factors
High
3 risk factors
Multiple Myeloma patients 
There are three risk groups defined by the International Staging System (Greipp 
et al) as follows.  The following factors will be collected when available:
Standard risk:
Stage I, Serum β2M < 3.5 mg/L and serum albumin > 
3.5 g/dL (med. survival, 62 months); 
Intermediate risk: 
Stage II, neither stage I nor III (median survival, 44 
months) 
High risk:
Stage III, Serum β2M > 5.5 mg/L (median survival, 29 
months).
Acute Leukemia patients 
A study objective for acute leukemia is to identify which one or more of the 
below-mentioned individual prognostic factors are the most predictive of PFS.  
In addition, delineation between a standard and high risk group will be attempted 
based on a prognostic score using the below-mentioned factors.  The following 
factors will be collected when available:
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Prognostic Factors for adult (>18 years) ALL:
WBC >30,000/ml
Non-T-cell phenotype
t (9;22), t(4;11), t(1;19), t(8;14), trisomy 8, monosomy 7, hypodiploid 
karyotype
>1 course (4 weeks) to achieve first CR
Age >35 years
Prognostic Factors for pediatric (<18 years) ALL:
Age >10 years
T(9;22), t(4;11), t(8;14)
>12 weeks to achieve 1st CR
Prognostic Factors for pediatric and adult AML:
Antecedenct MDS
Therapy-related AML
FAB M0, 1, 5, 6, 7
WBC>100,000/L at diagnosis
>one course (4 weeks) to achieve first CR
Age>60 years
Complex karyotype abnormalities (monosomy 5, monosomy 7, 3q-, 
t(10;11)
Flt-3 positive mutation
Amyloidosis, primary or previously treated 
All amyloidosis patients will be grouped in the standard risk patient group and 
analyzed with the MM patients.  
Solid Tumor patients
All solid tumor patients will be considered high risk and analyzed for toxicity 
and overall survival.
5.0
ELIGIBILITY 
5.1
Disease Diagnoses:  Histologically confirmed diagnosis of malignant hematologic 
disorders, Amyloidosis or solid tumor malignancy.
 
5.1.1   Recurrent or Refractory Disease or Disease at High Risk for Recurrence
5.1.1.1    Hodgkin Disease:  Relapsed or refractory disease after 
chemotherapy with a minimum of one standard regimen
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5.1.1.2    Non-Hodgkin Lymphoma: (Low, Intermediate or High Grade) 
Relapsed or refractory disease after chemotherapy with at least one 
standard regimen or first CR lymphoblastic or small, non-cleaved 
cell lymphoma at high risk of relapse by high International 
Prognostic Index (IPI) Score
5.1.1.3    Acute Myeloid Leukemia: Low or High Risk disease in first or 
second CR or greater in patients in whom the risks of an allogeneic 
transplant outweigh the benefits.
5.1.1.4   Acute Lymphoblastic Leukemia: Low or High Risk disease in first 
or second CR in whom the risks of an allogeneic transplant 
outweigh the benefits.
5.1.1.5   Multiple Myeloma: Low or High Risk in first or greater response 
(Stable disease or better) or for responding patients at first 
progression. 
5.1.1.6   Other Malignant Lymphoproliferative Disorders: (CLL, 
Waldenstrom's macroglobulinemia, relapsed or refractory disease 
after first-line chemotherapy
5.1.1.7   Amyloidosis:  primary or previously treated
5.1.1.8   Solid Tumors:  Testicular cancer patients who have relapsed disease 
or primary progressive disease which is responding to salvage 
therapy; relapsed or advanced-stage newly diagnosed neuroblastoma 
or small round blue cell tumors in patients ≤ 30 years of age;  other 
patients with solid tumors who have recurred following conventional 
treatment or are at high risk for relapse, and demonstrate 
chemosensitivity.
5.1.1.9 Patients with malignancies who would be treated with an autologous 
stem cell transplant but have a syngeneic donor.  A snyngeneic 
donor would be considered to have the same risk as an autologous 
stem cell transplant patient.
5.2.
Other Criteria
5.2.1.  Performance status  0-2  (Karnofsky ≥70%).
Patients with amyloidosis or MM with decreased KPS due to disease 
are eligible.
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5.2.2. Age  ≥4
5.2.3. Life expectancy  >2 months
5.2.4. Required initial laboratory data  
1.
Pulmonary function tests; DLCO or DLVA ≥50% predicted; 
DLCO to be corrected for hemoglobin and/or alveolar 
ventilation.  
2.
Cardiac ventricular ejection fraction ≥50% by radionuclide 
ventriculogram or echocardiogram.  
3.
Bilirubin, Alkaline phosphatase, SGOT < 3 x normal.
4.
Calculated creatinine clearance < 40 cc/min by the modified 
Cockroft-Gault formula for adults or the Schwartz formula for 
pediatrics. (Reference Appendix XII.) 
5.
Glomerular filtration rate by renal scan for NBL patients, to 
determine dosing parameters. 
6.
Positive CMV IgM and/or positive hepatitis serologies 
demonstrating infection will require an Infectious Disease 
consult and subsequent clearance.
7.
Any active infection will require an Infectious Disease consult 
and subsequent clearance
8.
Peripheral Blood Counts of PMN >1500/µL, and Plt 
>75,000/µL.
9.
Prior to stem cell storage:

No radiation within three weeks before stem cell harvest

Bone marrow may be used in conjunction with blood 
progenitor cells 
10.
Hematologic Malignancy patients with HIV positivity but on 
appropriate anti-retroviral therapy may go autotransplant with 
the following laboratory tests. (CD4+ cell count > 75 cells per 
microliter and HIV copy number < 100,000 per microliter and 
with Infectious Disease clearance.
11.
Acute Leukemia, HL, NHL, MM and Solid Tumor patients 
must have received 2 cycles of chemotherapy followed by 
disease-specific restaging prior to mobilization and collection 
of stem cells.  Small round blue cell tumor patients must have 
received either standard therapy or surgical intervention.  The 
disease status and response to therapy must be known prior to 
transplant to establish the disease status at transplant.  
Amyloidosis patients may proceed to BMT without receiving 
chemotherapy.  Please see Appendices in Section 15 for 
disease-specific restaging criteria and for definitions of 
disease status at transplant.
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5.2.5. No serious organ dysfunction unless it is caused by the underlying 
disease, exclusion criteria include the following:
1.
Uncontrolled or severe cardiovascular disease, including 
recent (<6 months) myocardial infarction, congestive heart 
failure, symptomatic angina, life-threatening arrhythmia or 
hypertension
2.
Active bacterial, viral, or fungal infection
3.
Active peptic ulcer disease
4.
Uncontrolled diabetes mellitus
5.2.6.  No serious medical or psychiatric illness; not pregnant
1.
No psychiatric conditions which would prevent delivery of care.  
Psychology clearance is necessary.
5.2.7.  Allogeneic BMT not possible, or not desirable
1. 
Age >65 years
2. 
No compatible donor identified
3.
Estimated risk of graft vs. host disease complications greater 
than risk of recurrence after autologous BMT
5.2.8. Adequate bone marrow or blood stem cell dose obtained 
For blood stem cells:  total CD 34+ = > 2x106/kg or if unable to 
collect this dose, a total nucleated cell bone marrow dose of > 
1x108/kg.
5.3
Registration:
To register a patient, contact the research nurse/transplant coordinator.  Transplant regimens 
will be assigned as per protocol guidelines by the BMT team.  For purposes of reporting to 
the Autologous Blood and Marrow Registry (ABMTR), all patients’ disease status at 
transplant will be determined prior to initiation of protocol therapy.
5.4
Data:
Data pertaining to this protocol will be collected by the research nurse, and/or any other 
persons assigned by the BMT department head.
 
6.0
CONSENT FORM
Patients must be aware of the nature of their disease and willingly consent after being 
informed of the procedure to be followed, the nature of the therapy, alternatives, potential 
benefits, side-effects, risks and discomforts.  There must be no other serious medical or 
psychiatric illness that would prevent informed consent. 
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7.0
STRATIFICATION AND RANDOMIZATION
There is no randomization or stratification schema for this protocol.  Patients will be 
assigned treatment (high dose therapy regimen) based on diagnosis, age and co-morbidities
There is no a priori stratification of patients at time of registration to determine treatment 
(high dose therapy regimen), except for the patient’s disease (as outlined in section 3.0 
Study schema).  Patients will be retrospectively stratified based on available data into 
standard and high risk groups (as defined in section 5.0 Study purposes and objectives) to 
analyze their impact on long-term PFS. 
8.0
TREATMENT PLAN
    
8.1.
Chemotherapy:   Testicular Cancer, HL, NHL patients must have received 2 cycles 
of salvage chemotherapy followed by disease-specific restaging prior to mobilization 
and collection of stem cells.  Acute Leukemia and Neuroblastoma patients must have 
received at least induction therapy and mobilization chemotherapy as consolidation 
prior to stem cell collection.  Small round blue cell tumor patients must have 
received either surgical treatment or standard chemotherapy.  MM patients must 
have received at least 1 cycle of standard induction therapy.  Solid tumor patients 
must have received at least 2 cycles of chemotherapy before mobilization and stem 
cell collection.  Amyloidosis patients may proceed to BMT without induction 
chemotherapy.  The disease status and response to therapy if applicable must be 
known prior to transplant to establish the disease status at transplant.  Please see 
Appendices in Section 15 for disease-specific restaging criteria and for definitions of 
disease status at transplant.  Etoposide Phosphate may be substituted for Etoposide in 
the event of anaphylaxis to Etoposide.
8.2.
Involved-field radiation therapy:  For all patients for whom post-BMT radiation 
therapy is planned, in the absence of disease progression, radiation should begin no 
sooner than 4 weeks after transplant.  It is recommended that patients with adequate 
count recovery (PMN >1500/µL, and Plt >75,000/µL.)
8.3 
HIV positive patients:  For all patients with controlled HIV infections, CMV 
screening should be performed weekly  up count recovery until day 100 following 
transplant.  Anti-retroviral therapy should be stopped during chemotherapy and 
restarted after high dose therapy is completed.  Zidovudine should not be used due to 
myelosuppressive effects.  Ritonavir should not be used simultaneously with 
etoposide which is metabolized by the CYP3A4 pathway.  An infectious disease 
consult should be obtained as part of the transplant workup.
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8.4
Stem Cell Infusion:  Day 0 is the day on which the stem cells are infused.  As 
required by scheduling, the stem cells may be infused on the same day after the last 
fraction of TBI is given.  
The procedure of infusing stem cell products may be performed by a trained nurse 
under the direct supervision of a BMT physician or Nurse Practitioner/Physician 
Assistant.  The stem cells are to remain sterile throughout the infusion process.  All 
patients require continuous pulse oximetry monitoring during the procedure, with 
oxygen equipment available in the patient's room.  All patients will have vital signs 
recorded before the procedure and at timed intervals during and after stem cell 
infusion.  Emergency drugs, such as diphenhydramine, epinephrine, and 
corticosteroids will be available for use in appropriate doses.  No other blood 
products should be given electively on the day of transplant, especially within 8 
hours of planned infusion time.  Patients will be pre-medicated with the following 
medications:
1)  Diphenhydramine 25-50 mg IV, 30 minutes prior to infusion of stem 
cells.(Pediatric patients will receive Diphenhydramine 1-1.25 mg/kg IV 30 minutes 
prior to infusion of stem cells with a maximum dose of 50 mg)
2)  Hydrocortisone 50 mg IV, 30 minutes prior to infusion of stem cells. (Pediatric 
patients will receive Hydrocortisone 1 mg/kg IV 30 minutes prior to infusion of stem 
cells with a maximum dose of 50 mg)
8.5
Transplant Regimens
Ideal body weight calculations for all regimens where applicable should be 
obtained from Appendix II; 
Cyclophosphamide (C), BCNU (B), VP-16 (V) (CBV) Summary:
Day
-8
-7
-6 
-5 
-4 
-3
-2
-1
0
Etoposide 2400 mg/ m
2
(34 hr infusion)
X
Cyclophosphamide1800 
mg/ m
2 IV over 2 hrs daily 
x 4 days 
(total 7200 mg/ m
2)
X
X
X
X
BCNU 600 mg/ m
2
X
Stem Cell Infusion
X
VP-16 (Etoposide) (V) 2400 mg/ m
2 (actual body weight) is given by a 34 hr continuous IV 
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infusion (70 mg/ m
2/hr) beginning on day -8 at 0900 hour hrs and ending on day -7 on at 
1900 hours.  The undiluted VP-16 will be prepared per pharmacy to infuse with normal 
saline.  The  infusion time will be over 34 hrs).  During VP-16 infusion, other IV fluids 
should be kept to a minimum and blood products should not be given except in an 
emergency.  Etoposide Phosphate may be substituted for Etoposide in the event of 
anaphylaxis to Etoposide.
Cyclophosphamide (C)1800 mg/ m
2 (ideal body weight or actual body weight, whichever 
is less) in 500ml Dextrose 5% Water or Normal Saline, is given by 2 hr IV infusion (1930 -
2130 hrs) days -7, -6, -5, and -4 (total dose 7200 mg/ m
2).  Diphenhydramine  25-50 mg IV 
should be given 30 minutes prior to the administration of all Cyclophosphamide doses.  
When VP-16 infusion is completed, begin IV hydration with D5 1/2 Normal Saline, 1/2 
Normal Saline or Normal Saline alone or with 10 mEq Potassium Chloride/L at 150 ml/ 
m
2/hr.  Furosemide, 10-20 mg IV, will be given 2 hrs after each cyclophosphamide dose and 
then every 4 hrs. as needed to maintain urine output such that Fluids out (O) are at least 
equal to Fluids in (I).  Thus, O should be equal or greater than I once Cyclophosphamide is 
started.
BCNU (Carmustine) (B).  600 mg/ m
2  (actual body weight) in 500 ml Dextrose 5% Water  
is given by 2 hr IV infusion (1930-2130 hrs), day -3.  Hydrocortisone, 50 mg IV should be 
given 30 minutes prior to the administration of the BCNU dose.  Hyperhydration is 
continued until 24 hrs. after the BCNU dose (day -2).
Melphalan 200 (M200) Summary:
Day
-2 
-1
0
Melphalan 200 mg/ m
2 for 
myeloma 
and 
amyloidosis 
patients
X
Stem Cell Infusion
X
Melphalan (M200). 200 mg/ m
2 (actual body weight) in diluent provided by manufacturer 
to a final concentration of 5 mg/ml to infuse over 30 minutes, starting between 1800 and 
2100 hrs on day -2.  A minimum of 4 hours prior to first dose, begin IV hydration.  
Hyperhydration is continued until 24 hrs. after the melphalan dose.  A minimum of 4 weeks 
must pass before a second melphalan 200 mg/ m
2 dose is given for those patients who 
receive a second transplant.
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Protocol No. I 72806
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Melphalan 120 (M120) Summary to be used for patients not 
eligible for Melphalan 200 due to inadequate renal, cardiac, or 
other organ function or decreased KPS due to disease:
Day
-2 
-1
0
Melphalan 
120mg/ 
m2 
for 
amyloidosis, 
or 
multiple 
myeloma if indicated
X
Stem Cell Infusion
X
Melphalan (M120). 120 mg/ m
2 (actual body weight) in diluent provided by manufacturer 
to a final concentration of 5 mg/ml to infuse over 30 minutes, starting between 1800 and 
2100 hrs on day -2.  A minimum of 4 hours prior to first dose, begin IV hydration.  
Hyperhydration is continued until 24 hrs. after the melphalan dose.  A minimum of 4 weeks 
must pass before a second melphalan 120 mg/ m
2 dose is given for those patients who 
receive a second transplant.
Busulfan(B), Cyclophosphamide(C) (Bu/C2iv) summary:
Day
-8
-7
-6 
-5 
-4 
-3
-2
-1
0
Adult patients: 
levetiracetam  500 mg  
PO or IV twice daily 
Pediatric patients: 
levetiracetam 10 mg/kg 
PO or IV (max 500 
mg/dose) twice daily.
X
Adult patients: 
Levetiracetam 500 mg 
PO or IV twice daily 
Pediatric patients: 
levetiracetam 10 mg/kg 
PO or IV (max 500 
mg/dose) twice daily.
X
X
X
X
X
Busulfan (IV) 0.8mg/kg 
q6h for 4 days (total 
12.8 mg/kg
X
X
X
X
Cyclophosphamide  60 
mg/kg IV over 2 hours 
daily x 2 days 
(total 120 mg/kg)
X
X
Stem Cell Infusion
X
Patients receiving this regimen cannot start busulfan on a Friday or have levels drawn the 
day before a holiday unless the ideal body weight dose is used.  Busulfan levels are used to 
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Protocol No. I 72806
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Date: Feb 6, 2018
adjust dose in those receiving busulfan based on an adjusted body weight.  
All patients receiving busulfan must receive seizure prophylaxis:
Adults: Levetiracetam:  500 mg IV or PO twice daily to start on Day -8 and to continue until 
24 hours after busulfan is finished.  
Pediatrics: levetiracetam 10 mg/kg IV or PO (max 500mg/dose) IV or PO twice daily to 
start on Day -8 and to continue until 24 hours after busulfan is finished.  
Busulfan (Bu).  0.8mg/kg adjusted body weight for obese patients should be used and 
busulfan levels must be obtained unless not available.  If ideal body weight is greater than 
actual body weight, use actual body weight.  At 0900 hrs on day -7 begin busulfan over 2 
hours IV, then every 6h for 16 total doses ( total dose 12.8 mg/kg).  Hyperhydration is not 
required.  At the initiation of the first dose of busulfan begin IV hydration with D5 1/2 
Normal Saline, 1/2 Normal Saline or Normal Saline alone or with 10 mEq Potassium 
Chloride/L at 50 ml/ m
2/hr.
Pharmacy will calculate volume of Normal Saline or Dextrose 5%Water for the 2 hour 
infusion.  
Busulfan levels are to be drawn at least 4 time points:  1) One hundred and fifteen (115) 
minutes after start of infusion, 2) Two and one half (2.5) hours after start of infusion, 3) 
Four (4) hours after the start of infusion and 4) Six (6) hours after the start of the infusion 
(before the start of the 2nd dose).
If levels cannot be obtained, the busulfan will be dosed as follows:
Busulfan (Bu).  0.8mg/kg ideal body weight (IBW) or actual body weight whichever is less 
will be used.  At 0900 hrs on day -7 begin busulfan over 2 hours IV then every 6h for 16 
total doses ( total dose 12.8 mg/kg).  
Pharmacy will calculate volume of Normal Saline or Dextrose 5%Water for the 2 hour 
infusion.  
Cyclophosphamide (C). Cyclophosphamide, 60 mg/kg (ideal body weight or actual body 
weight whichever is less), in 500ml Normal Saline is given by 2 hr IV infusion (1100 -1300 
hrs) days -3, and -2 (total dose 120 mg/kg).  Diphenhydramine  25-50 mg IV should be 
given 30 minutes prior to the administration of all Cyclophosphamide doses.  Four hours 
prior to the first dose of Cyclophosphamide, begin IV hydration at 150 ml/ m
2/hr.  
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Protocol No. I 72806
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Date: Feb 6, 2018
Furosemide, 10-20 mg IV, will be given 2 hrs after each cyclophosphamide dose and then 
every 4 hrs. as needed to maintain urine output such that Fluids out (O) are at least equal to 
Fluids in (I).  
Thus, O should be equal or greater than I once Cyclophosphamide is started.
         Cyclophosphamide (C), TBI (CT6)  Summary:
Day
-5
-4 
-3
-2
-1*
0*
C 60 mg/kg
X
X
T 200 cGy
  (total 1200 cGy)
X/X
X/X
X/X
Stem Cell Infusion*
X
Cyclophosphamide (C). Cyclophosphamide, 60 mg/kg (ideal body weight or actual body 
weight whichever is less), in 500ml Normal Saline is given by 2 hr IV infusion (1100 -1300 
hrs) days  -4 and – 5 (total dose 120 mg/kg).  Diphenhydramine 25-50 mg IV should be 
given 30 minutes prior to the administration of all Cyclophosphamide doses.  Four hours 
prior to the first dose of Cyclophosphamide, begin IV hydration at 150 ml/ m
2/hr.  
Furosemide, 10-20 mg IV, will be given 2 hrs after each cyclophosphamide dose and then 
every 4 hrs. as needed to maintain urine output such that Fluids out (O) are at least equal to 
Fluids in (I).  Thus, O should be equal or greater than I once Cyclophosphamide is started.
Total Body Irradiation (T).   200 cGy twice daily will be given over 3 days (minimum 6 
hrs between fractions) at a dose rate of 5-25 cGy/min. Total dose 1200 cGy in 6 fractions 
over 3 days, with lung shielding. See Appendix III
*As required by scheduling, the stem cells may be infused on the same day after the last   
fraction of TBI is given.
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Protocol No. I 72806
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Date: Feb 6, 2018
Cyclophosphamide(C), Carboplatin Cp), Thiotepa(Tt) (CTtCp) 
summary:  
Day:
-7
-6 
-5 
-4 
-3
-2
-1
0
Cyclophosphamide 
1500 
mg/ m
2*/day
(total 6000 mg/m2)
X
X
X
X
Carboplatin 
200 
mg/ 
m
2*/day
(total 800 mg/m2)
X
X
X
X
Thiotepa 125mg/ m
2*/day
(total 500 mg/m2)
X
X
X
X
Mesna 1500 mg/ m
2*/day
(total 7500 mg/m2)
X
X
X
X
X
Stem Cell Infusion
X
* Please note:  To determine weight for m2 calculation for all four drugs in this 
regimen, use the average of the patient's actual and ideal body weights unless actual 
weight is less than ideal body weight, then use actual body weight
Cyclophosphamide (C)  1500 mg/ m
2/day (average of the actual and ideal body weights) - 
on days -7, -6, -5, -4 for a total dose of 6000 mg/ m
2  total dose..  Diphenhydramine 25-50 
mg IV should be given 30 minutes prior to the administration of all Cyclophosphamide 
doses.  Dilute cyclophosphamide in Normal Saline to a final volume of 1,000 ml and infuse 
over 24 hours.
Carboplatin (Cp)  200 mg/ m
2 /day (average of the actual and ideal body weights) on days 
-7, -6, -5, -4 for a total dose of 800 mg/ m
2total dose   Dilute carboplatin in Dextrose 5% 
Water to final volume of 500 ml and infuse over 24 hours.  Begin infusion to coincide with 
cyclophosphamide infusion, and infuse through a separate lumen.  Carboplatin solutions 
should not be prepared or administered with needles or IV administration sets containing 
aluminum parts that might come in contact with the drug.
Thiotepa (Tt)  125mg/ m
2 /day (average of the actual and ideal body weights) days -7, -6, -
5, -4 for a total dose of 500 mg/ m
2 / total dose. Reconstitute each thiotepa 15 mg vial with 
1.5 ml sterile water for injection to provide solution containing 10 mg of thiotepa per ml of 
sterile water.  Further dilute solution to 1 mg/ml with 0.9% Sodium Chloride and infuse over 
24 hours.  
Mesna.  
Mesna and cyclophosphamide should be mixed together and infused over days -7, -6, -5, and 
-4.  Mesna alone should then be continued over day -3 until 24 hours after the last 
cyclophosphamide dose.
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Protocol No. I 72806
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Date: Feb 6, 2018
VP-16 (V), Carboplatin(Cp) (VCp) summary:
Day
-6
-5 
-4 
-3
-2
-1
0
Etoposide 750 mg/m2 IV over 
2-3 hrs daily x 3 days/
   (total 2250 mg/ m2)
X
X
X
Carboplatin 700 mg/m2/day
(total 2100 mg/ m2 )
X
X
X
Stem cell Infusion
X
VP-16 (Etoposide) (V). 750 mg/ m2 (actual body weight) undiluted drug is to run with 
Normal Saline solution over 2-3 hours, beginning at between 9 and 11 AM, days -6, -5, -4 
for a total dose of 2250 mg/ m2. VP-16 should be given prior to the Carboplatin as the 
volume of saline with the VP-16 acts as a fluid load for the Carboplatin.  Etoposide 
Phosphate may be substituted for Etoposide in the event of anaphylaxis to Etoposide.  It 
may be run over 2-4 hours.
  
Carboplatin (Cp)  700 mg/m2 (actual body weight) to a final concentration of 0.5 – 2 
mg/mL Dextrose 5% Water IV infusion over 30 minutes, within 2 hours of  the completion 
of VP-16, days -6, -5, -4 for a total dose of 2100 mg/ m2.  Carboplatin solutions should not 
be prepared or administered with needles or IV administration sets containing aluminum 
parts that might come in contact with the drug.
Thiotepa(Tt), Cyclophosphamide(C), Mesna (TtC1500) Summary: 
(Please note change in dose for patients less than 12 kg)
 (Transplant #1:)
Day
-7
-6
-5 
-4 
-3
-2
-1
0
Tt 300mg/m2/day
(total 900 mg/m2)
X
X
X*
C 1500 mg/m2/day
(total 6000 mg/m2)**
X
X
X
X
Mesna 300 mg/m2/dose**
 x 4 doses/day
x/x/x/x
x/x/x/x
x/x/x/x
x/x/x/x
Stem Cell Infusion
X
*   Start early enough on Day -5 to give dose prior to  cyclophosphamide
 **  Initial dose of mesna added to cyclophosphamide bag, then doses at 3, 6 and 9 hours 
should be added to 50 ml D5W and infused over 15 minutes. 
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Protocol No. I 72806
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Date: Feb 6, 2018
If patient’s weight is less than 12 kg:
Thiotepa:
10 mg/kg/day
Cyclophosphamide : 50 mg/kg/day
Mesna:
10 mg/kg/dose x 4 doses as above
Thiotepa (T)  300mg/m2 (actual body weight) at a concentration of 1 mg per ml in NS to 
infuse over 2 hrs, starting between 0900 and1100 on days -7, day-6, and day-5 at a total 
dose 900 mg/m2.  A minimum of 12 hours prior to first dose, begin IV hydration per 
standard of care.  
Cyclophosphamide (C) 1500 mg/m2 (ideal body weight or actual body weight whichever 
is less) 500ml Normal Saline is given by 2 hr IV infusion for adults or for pediatric patients; 
100 ml per m2 NS is given by 1 hour IV infusion days -5, -4, -3 and -2 for a total dose of 6000 
mg /m2.  Diphenhydramine 1 mg/kg (maximum dose 25 mg) IV should be given 30 
minutes prior to the administration of all Cyclophosphamide doses.  .
Mesna:  The initial dose of Mesna, 300 mg/m2 (actual body weight) is mixed in the same 
bag  with the Cyclophosphamide and infused over 2 hours.  The three subsequent doses of 
Mesna 300 mg/m2 are mixed in 50 cc of D5W and infused at 200 ml/hr (over 15 minutes).
Note:  Urine output should be maintained at 2 cc/kg/hr averaged over 2 hours for 24 hours 
following Cyclophosphamide administration for pediatric patients.  If urine output falls 
below this parameter, give Furosemide 0.5 mg/kg IV (maximum dose 20 mg).  For adult 
patients, maintain urine output such that Fluids out (O) are at least equal to Fluids in (I).  
Thus, O should be equal or greater than I once Cyclophosphamide is started.  When the 
urine output falls below the above parameters, , call the clinical team.
Carboplatin(Cp), Etoposide (E), Melphalan (M) (ECpM) 
Summary:
(Please note change in dose for patient less than 12 kg and for adults 18-30 years old)
(Transplant #2)

If pediatric patient and  GFR is greater than 100 
ml/min/1.73m2
Day
-7
-6
-5 
-4 
-3
-2
-1
0
Carboplatin 375 mg/ m2/day, CIVI
(total 1500 mg/ m2)
X
X
X
X
Etoposide 300 mg/ m2/day, CIVI
(total 1200 mg/ m2)
X
X
X
X
Melphalan 60 mg/ m2/day
(total 180 mg/ m2)
X
X
X
Stem Cell Infusion
X
If patient’s weight is less than 12 kg and GFR>100 ml/min/1.73m2:
Cp:
12.5 mg/kg/day
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Protocol No. I 72806
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Date: Feb 6, 2018
E:
10 mg/kg/day
M:
  2 mg/kg/day
Carboplatin (Cp)  375 mg/ m2/day (actual body weight) CIVI on days -7, -6, -5, -4 at a 
total 1500 mg/ m2 if GFR is greater than 100 ml/min/1.73m2.  Carboplatin is given in 
Dextrose 5% IV infusion (0.5-2.0 mg/ml) over 24 hr CIVI on days -7, -6, -5, and -4.    
Carboplatin solutions should not be prepared or administered with needles or IV 
administration sets containing aluminum parts that might come in contact with the drug.
Etoposide  (E) 300 mg/ m2/day (actual body weight) CIVI on days -7, -6, -5, -4 for a total 
dose of 1200 mg/ m2.  The undiluted etoposide will be prepared per pharmacy to infuse with 
normal saline.  The  infusion will run over 24 hours CIVI.  This should be a separate 
infusion from the carboplatin in NS on these days.  Etoposide Phosphate may be substituted 
for Etoposide in the event of anaphylaxis to Etoposide.
Melphalan (M).  60 mg/m2 (actual body weight) in provided diluent at a final 
concentration of 5 mg/ml to infuse over 30 minutes per day on days -7, -6, 5 for a total dose 
of 180 mg/m2.  
Hyperhydration is continued until 24 hours after the melphalan dose.

If pediatric patient and GFR is less than 100 ml/min/1.73m2
Day
-7
-6
-5 
-4 
-3
-2
-1
0
Carboplatin 4.1   AUC* dose/day, 
CIVI*
X
X
X
X
Etoposide 200 mg/ m2/day, CIV1
(total 800 mg/ m2)
X
X
X
X
Melphalan 60 mg/ m2/day
(total 180 mg/ m2)
X
X
X
Stem Cell Infusion
X
*AUC dose is the Absolute Carboplatin dose (NOT per m2 or per kg).
  (See Appendix 2 for calculation)
If patient’s weight is less than 12 kg and GFR<100 ml/min/1.73m2:
Carbo:
AUC of 4.1
Etoposide:
6.7 mg/kg/day
Melphalan:
2 mg/kg/day
Carboplatin (Cp)  The dose is 4.1 AUC if the GFR is less than 100 ml/min/1.73m2. 
Carboplatin is given in Dextrose 5% IV infusion (0.5-2.0 mg/ml) over 24 hr CIVI on days -
7, -6, -5, and -4.    Carboplatin solutions should not be prepared or administered with 
needles or IV administration sets containing aluminum parts that might come in contact 
with the drug.
Etoposide  (E) 200 mg/ m2/day (actual body weight) CIVI on days -7, -6, -5, -4 for a total 
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dose of 800 mg/ m2.  The undiluted etoposide will be prepared per pharmacy to infuse with 
normal saline.  The  infusion time will be over run over 24 hours CIVI.  This should be a 
separate infusion from the carboplatin on these days.  Etoposide Phosphate may be 
substituted for Etoposide in the event of anaphylaxis to Etoposide.
Melphalan (M).  60 mg/m2 (actual body weight) in provided diluent at a final 
concentration of 5 mg/ml to infuse over 30 minutes per day on days -7, -6, 5 for a total dose 
of 180 mg/m2.  
Hyperhydration is continued until 24 hours after the melphalan dose.

If Patient is 18 to 30 years of age
Day
-7
-6
-5 
-4 
-3
-2
-1
0
Carboplatin 4.1   AUC* dose/day, 
CIVI*
X
X
X
X
Etoposide 300 mg/ m2/day, CIV1
(total 1200 mg/ m2)
X
X
X
X
Melphalan 60 mg/ m2/day
(total 180 mg/ m2)
X
X
X
Stem Cell Infusion
X
*AUC dose is the Absolute Carboplatin dose (NOT per m2 or per kg).  (See Appendix 2 for calculations)
Carboplatin (Cp)  The Carboplatin dose is based on an AUC of 4.1 using the Calvert 
Formula in Appendix 2.  The Creatinine Clearance will be based on a 24 hour creatinine 
clearance or Cockroft Gault formula (Appendix 2). Carboplatin is given in Dextrose 5% IV 
infusion (0.5-2.0 mg/ml) over 24 hr CIVI on days -7, -6, -5, and -4.    Carboplatin solutions 
should not be prepared or administered with needles or IV administration sets containing 
aluminum parts that might come in contact with the drug.
Etoposide  (E) 300 mg/ m2/day (actual body weight) CIVI on days -7, -6, -5, -4 for a total 
dose of 1200 mg/ m2.  The undiluted etoposide will be prepared per pharmacy to infuse with 
normal saline. The  infusion will run over 24 hours CIVI  This should be a separate infusion 
from the carboplatin on these days.  Etoposide Phosphate may be substituted for Etoposide 
in the event of anaphylaxis to Etoposide.
Melphalan (M).  60 mg/m2 (actual body weight) in provided diliuent at a final 
concentration of 5 mg/ml to infuse over 30 minutes per day on days -7, -6, 5 for a total dose 
of 180 mg/m2.  
Hyperhydration is continued until 24 hours after the melphalan dose.
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Protocol No. I 72806
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Date: Feb 6, 2018
REQUIRED DATA / Study Calendar
1. Important hematologic recovery endpoints
day PMN >500/µL, >1000/µL; Plt >25K, >100K; Hb >10gm%
day of last Plt transfusion, last RBC transfusion
2. Day(s) of occurrence of severe toxicity (gr3)
Tests/Observations
Pre-Rx
Post-Rx***
Post-Disch
Signed Consent Form
X
--
--
Ht / Wt /  BSA
X
--
--
Ideal Body Wt / Adjusted Body Wt 
(if applicable)
X
--
--
Serology (Infectious disease 
Screening)
X
--
--
Cr Clearance
X
--
--
PFTs / DLCO / DLVA
X
--
--
MUGA or ECHO
X
--
--
Ekg
X
--
--
Quantitative Ig’s
X
--
--
BM aspirate, biopsy*
X
d +100 for any not in marrow remission prior to 
transplant as clinically indicated.
Staging Profile**
X
Repeat positive studies d +100 and d+360; then as 
clinically indicated.
CBC 
X
q day to PMN > 500, Plt > 20K, then as clinically 
indicated
Urinalysis (biochemical)
X
As clinically indicated
--
PT-INR
X
As clinically indicated 
--
Full Chemistry Panel (Complete 
Metabolic Panel)
X
As clinically indicated
Chest X-ray
X
As clinically indicated --
Performance Status
X
qwk
As clinically indicated
Toxicity (Bearman and CTC)
--
Weekly
q l mo until nl
FLOW CYTOMETRY
Quantitative IGs day 100, 180, 360
§ d 0 is day of stem cell transplant; studies to be obtained as close to indicated time as possible.
*        If evidence of disease at any time prior to BMT. Obtain cytogenetics if previously abnormal.
**     For pts. with HL/NHL lymphoma: Non-invasive studies including:  (1) measurement (perpendicular diameters) of palpable 
        disease, (2) CT scan of chest, abdomen, pelvis, (3) Whole-body Gallium or PET scan.
   For pts. with testicular cancer:  AFP and/or beta HCG Pretransplant and at d +100
         For pts. with neuroblastoma:  HVA and VMA Pretransplant and 30 days after 2nd transplant;   Also, CT and bone scans and 
         skeletal survey 30 days after 2nd transplant.
***   Post therapy is defined as until engraftment and /or discharge from hospital.
Intervals shown are the minimum requirement
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Protocol No. I 72806
Page 39 of 73
Date: Feb 6, 2018
9.0
CRITERIA FOR RESPONSE AND PROGRESSION 
Response definitions for each disease are defined in the Appendices (Section 15.)
10.0
INFORMATION ON DRUG FORMULATION AND AVAILABILITY:
10.1
Etoposide (VP-16) is commercially available in vials containing 20 mg/ml of 
etoposide   
Drug is stable at room temperature.  The etoposide should be 
transferred to non-PVC (DHEP free) bags which is  chemically stable for 48 hours 
at room temperature.  Do not administer cloudy or precipitated drug.
10.2
Cyclophosphamide (Cytoxan) is commercially available in 500, 1000 mg, and 
2000 mg vials.  Dilute with 25, 50, or 100 ml, respectively, of 0.9% sodium 
chloride yielding a concentration of 20 mg/ml which is stable for 24 hours at room 
temperature.   Further dilute with 0.9% sodium chloride.
10.3
BCNU (carmustine) is commercially available in 100 mg vials of lyophylized drug 
which is stable for 2 years when stored refrigerated.  Immediately prior to 
intravenous administration, dissolve contents of vial in 1 ml of supplied diluent 
(absolute alcohol) and add 9 ml of Sterile Water for Injection, U.S.P. for a 
concentration of 10 mg/mL.  The dose of BCNU should be diluted further with 5% 
Dextrose Injection, U.S.P. to final concentration dose mg/mL in 500mL  in a glass 
container and protected from light. Product is only stable for 8 hours after 
reconstitution. 
10.4
Melphalan is commercially available in 50 mg vials.  It is to be admixed just prior 
to intravenous administration and is stable for 90 min. at 5 mg/mL.  The dose of 
melphalan will be diluted with diluent provided to a final concentration of 5 mg/ml 
and protected from light.
10.5
Busulfan is commercially available in 60 mg/10 ml (6 mg/ml) single-use ampules.  
IV busulfan should be diluted with 0.9% NaCl or 5% Dextrose Injection, U.S.P.  
The diluent quantity should be 10 times the volume of busulfan, ensuring that the 
final concentration of busulfan is approximately >0.5 mg/ml. Mixed solution is 
stable for 8 hours at room temperature (25° C), but the infusion must be completed 
within that time. Busulfan diluted in 0.9% NaCl is stable under refrigeration (2-8° 
C) for up to 12 hours, but the infusion must be completed within that time.
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Protocol No. I 72806
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Date: Feb 6, 2018
10.6
Thiotepa is commercially available as a lyophilized powder in 15 mg vials. After 
reconstitution with 1.5 ml Sterile Water for Injection, the resulting solution is 
stable for 8 hours.  It must be diluted further with D5W or NS for IV infusion. A 
0.22 micron filter recommended (see package insert). 
10.7
Carboplatin is commercially available in vials of 50 mg/5 ml, 150 mg/15 ml, 450 
mg/45 ml, and 600 mg/60 ml aqueous solutions.  A further dilution of up to 20-
fold with 0.9% Sodium Chloride Injection, U.S.P. or 5% dextrose in water can be 
made (final concentration >0.5 mg/ ml).  Do not use aluminum needles for 
preparation or administration of drug.  Unopened vials can be stored at room 
temperature in the dark. 
POTENTIAL TOXICITY - MANAGEMENT AND DOSE MODIFICATIONS
Toxicity Grading: The Bearman Toxicity Criteria will be used for the grading and reporting of all 
toxicities. (See Appendix IV).  Grade 4 hematosuppression does not have to be reported for agents 
known and expected to cause hematosuppression at the dose used.
Hematologic:  Three to four weeks of severe pancytopenia (PMN < 500/µL, Platelets < 20,000/µL) 
are expected, and rarely patients may fail to engraft.    Despite optimal antibiotics, 5% of patients 
treated with intensive chemotherapy may die as a result of infection.  Infection prophylaxis and 
treatment will be given according to standard accepted medical practice.  With prophylactic platelet 
transfusions, the risk of death from hemorrhage is <5%.  Use of purged marrow may delay recovery 
and increase the risk of graft failure to as much as 5%.
Hepatic:  Moderate toxicity is common.  More severe, possibly fatal, liver toxicity can occur, 
usually in the form of veno-occlusive disease. With the study regimens the incidence of fatal liver 
toxicity should be < 5%.  Management of liver toxicity is with standard supportive and 
symptomatic measures. Avoid exposure of patients to other hepatotoxic agents whenever possible.
Pulmonary:  Idiopathic interstitial pneumonitis (IP) is possible after high dose alkylating agent 
therapy or TBI.  With the study regimens the risk of fatal idiopathic IP is felt to be < 5%. Patients 
with diffuse pulmonary infiltrates often present a difficult diagnostic and management problem.  
Whenever possible, histologic confirmation of the diagnosis should be attempted by bronchoalveoar 
lavage, or transbronchial or open-lung biopsy to exclude infectious causes, including 
cytomegalovirus.
Cardiac:  High-dose cyclophosphamide can produce fatal hemorrhagic pancarditis.  The risk of 
fatal cardiac toxicity with the study regimens is <5%.  Patients who develop signs of congestive 
heart failure not attributable to fluid overload should be evaluated for signs of carditis before 
additional CPA is given.  Studies should include ECG (to compare voltage to pretreatment ECG), 
radionuclide ventriculogram, and/or echocardiography.  If evidence of pericarditis, pericardial 
effusion or impaired myocardial function (decreased ejection fraction) is found, no further 
chemotherapy will be administered. In this situation patients must be watched carefully for signs of 
pericardial tamponade; pericardiectomy may be required.
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CNS:
Busulfan, in high doses, can cause grand mal seizures.  Patients will be treated 
prophylactically with phenytoin to minimize the risk of busulfan-induced seizures.
Thiotepa can cause temporary confusion, loss of memory, and inappropriate behavior lasting 
several days.  In severe cases the damage may not be reversible.  One severe case has 
occurred in a patient at RPCI with the thiotepa dose used in the current study.  The patient 
had undergone surgical resection of a metastatic lesion and whole brain irradiation prior to 
thiotepa treatment.  
Some antibiotics, which may be needed to treat infections during the period of low white 
blood cell counts, can cause VIIIth nerve damage resulting in hearing loss (especially high-
frequency tones) and dizziness which may be permanent. To minimize this possibility, 
antibiotic levels will be monitored.
 
Genitourinary:  Urinary metabolites of cyclophosphamide can produce hemorrhagic cystitis.  
Microscopic hematuria is common following high dose CPA regimens and up to 20% of patients 
may have gross hematuria or symptoms.  Vigorous hydration of patients (3,000 ml/m2/day) prior to 
beginning CPA and continuing until 24 hours after the final CPA dose produces a dilute urine and 
reduces the likelihood of severe cystitis.  The risk of life-threatening cystitis is estimated to be <1%.  
For patients with a history of previous cyclophosphamide induced hemorrhagic cystitis, MESNA 
may be used.
 Busulfan, thiotepa and TBI in the doses employed can cause permanent sterility in all patients.
Renal:  
Mild renal insufficiency is common in patients given nephrotoxic antibiotics 
(aminoglycosides and amphotericin B) which are avoided whenever possible.  
When 
aminoglycosides must be used, serum levels are closely monitored.  Carboplatin in high doses can 
produce renal toxicity which can be minimized by vigorous hydration and avoidance of 
concomitant exposure to other nephrotoxic agents. 
Gastrointestinal:
Nausea/Vomiting - Many patients will experience moderate to severe toxicity.  All patients 
should receive vigorous antiemetic treatment.
Stomatitis/Dysphagia - Many patients will experience moderate to severe toxicity.  
Adequate pain relief often requires parenteral narcotics.
Diarrhea - Most patients will experience moderate to severe diarrhea  which responds to 
standard symptomatic therapy.  Appropriate studies are needed to exclude infectious causes 
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of diarrhea, especially C. difficile.
Skin:  
Generalized erythroderma can occur with painful palms and soles and superficial 
desquamation at sites of mechanical trauma.  Topical steroid creams may provide symptomatic 
relief.  Severe cases may require a brief course (3-5 days) of systemic corticosteroids.  Long-lasting 
hyperpigmentation may follow resolution of the erythroderma.
Hair:  All patients will experience total (reversible) alopecia.
Allergy:  Mild allergic reactions including rash, hives, itching nasal stuffiness, sinus congestion, 
sneezing, watery eyes, and running nose occur occasionally; more severe reactions with low blood 
pressure and wheezing are rare.  
Risks of marrow donation:  The most frequent side effect of marrow donation is pain and stiffness 
over the hip bones lasting from several days to 1-2 weeks.  Blood loss from the procedure results in 
anemia which may require treatment with iron tablets or with red blood cell transfusions.  Infection 
of the skin, soft tissue, or bone is a rare possibility which could lead to the need for antibiotic 
treatment.  Rarely untoward reactions to anesthesia occur and can be fatal (risk estimated to be 1 in 
10,000).
Risks of stem cell collection:  The most frequent side effects are dysesthesias from citrate.  Other 
side effects include muscle cramps, infection, and bleeding.
Risks of blood or marrow infusion:  For transplantation, the blood or bone marrow is thawed and 
injected intravenously. Common side effects are transient cough, flushing, nausea and vomiting 
which may be caused by the chemical (DMSO, dimethylsulfoxide) used to protect the blood or 
marrow from damage during freezing, or possibly by temporary trapping cellular particles in the 
lungs. Rarely, severe allergic reaction to DMSO may occur and subsequent stem cell products may 
require volume reduction..  Hemoglobinuria may be present for several hours due to lysis of RBC's 
in the marrow damaged by freezing.  In rare circumstances, a seizure can occur during the stem cell 
reinfusion. 
In summary, overall transplant related mortality is expected to be approximately 5-10% due to graft 
failure, regimen-related organ toxicity, infection, and hemorrhage.  Risk factors associated with 
higher transplant related mortality include more prior therapy, poorer performance status, and more 
intensive transplant regimens. 
11.0   REPORTING OF ADVERSE DRUG REACTIONS/ DATA SAFETY MONITORING 
PLAN
In accordance with the NCI approved RPCI Data Safety Monitoring Plan, this study will conform 
to the stipulations of that Plan that are summarized below:
Investigator Requirements and Responsibilities
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The principal investigator (PI) of this study is ultimately responsible for every aspect of the 
design, conduct, and final analysis of his protocol.  The PI is responsible to insure continuous, 
close monitoring of subjects enrolled on his clinical trial.
SERIOUS ADVERSE EVENTS (SAE)
A serious adverse event (SAE) is any experience that suggests a significant hazard, 
contraindication, side effects or precaution.  This includes any experience that:

Results in death.

Is a life-threatening adverse drug experience.

Requires inpatient hospitalization or prolongation of existing hospitalization.
For the purpose of this study, hospitalizations for protocol-scheduled procedures, blood 
product transfusions, or for social reasons (i.e., awaiting transport home) will not be 
considered SAE’s.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Requires medical or surgical intervention to prevent one of the outcomes listed above.
Reporting Serious Adverse Events
All SAEs occurring during the course of the study or within 30 days of the last administration 
of study procedure must be reported to the Study Chair and Clinical Research Services (CRS) 
within 24 hours of the knowledge of occurrence (this refers to an AE that meets one or more 
of the aforementioned serious criteria), CRS will forward the SAE into the IRB.  This can be 
done by faxing a completed SAE Report form (716- 845-3562) or by e-mail description to 
Dawn Sullivan in CRS.  Where the initial report is made verbally or by telephone, a written 
confirmation within a further 24 hours must follow.
SAE Follow-up
For all SAE’s occurring during the study or within 30 days of the last administration of study 
procedure, the investigator must submit follow-up reports the Study Chair and Clinical 
Research Services, CRS will notify Institutional Review Board regarding the patient’s 
subsequent course until the SAE has subsided, or until the condition stabilizes, the patient 
dies, or receives alternative therapy.
Local reporting for data and safety monitoring for the protocol will require SAE’s to be 
reported to the IRB-01 and IRB-03, via the Clinical Research Service Office, using the 
Adverse Event Reporting form and the FDA MEDWATCH SAE reporting form.
On the anniversary date of the approved protocol at RPCI, the principal investigator will be 
required to report to the IRB the number of patients entered on the trial, the number of patients 
treated, a summary of all adverse events reported to date using CTC 3.0 grading and Bearman 
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(See Appendix X), a specific list of serious adverse events requiring immediate reporting, and 
significant literature reporting developments that may affect the safety of participants or the 
ethics of the study.
Reporting of SAEs includes:
1. failure to engraft (defined as a patient alive on day 45 with no ANC recovery)
2. graft failure (defined as a patient who had initial ANC recovery but subsequently had a 
deceline in ANC that required additional stem cell support).
The IRB will review annual data and safety monitoring reports and make recommendations on 
whether the study should continue unchanged, require modification/amendment, or be closed 
based on unacceptable risk to participants.
DATA AND SAFETY MONITORING PLAN
The Principal Investigator (PI) will be responsible for continuous monitoring of the safety of the 
study.  This monitoring is accomplished by the following:
Patient Outcomes Rounds are held weekly on the transplant unit, at which time all BMT patient 
care is reviewed, including:

medications (chemotherapy for high dose therapy regimens; graft-versus-host disease 
prophylactic and therapeutic medications; and possible drug interactions)

adverse events and/or adverse reactions to any medication, procedure, or other treatment; 
reports are filed according to RPCI policy and procedure

regimen-related toxicity, based on Bearman toxicity grading, and/or Common Toxicity Criteria 
(CTC) if the toxicity does not correlate with a Bearman grade

a properly signed and dated transplant consent

compliance issues that could compromise patient safety; pretransplant, a conference is held for 
all autologous patients for the purpose of describing the need for autologous patients to obtain 
lodging within a 30 mile radius of the hospital and to have a caregiver present at all times while 
the patient is an outpatient.  In addition, psychosocial evaluations are completed on all high-risk 
autologous transplant patients prior to transplant, to identify any compliance issues

other aspects of safety monitoring as prescribed by the BMT Standards of Care and common 
clinical practice.  These include daily physical examinations, clinical laboratory testing, routine 
surveillance cultures, therapeutic drug level monitoring (i.e., Busulfan, Vancomycin, FK506, 
Tobramycin, Cyclosporine).  Patients who have been discharged from the hospital are 
monitored in the BMT Clinic until all transplant-related issues are resolved and they are 
returned to the care of their referring physicians.
The BMT Quality Assurance plan requires quarterly reporting to the BMT Quality Assurance 
Committee, which in turn reports to the hospital Quality Assurance Committee.  Indicators for 
BMT patient safety monitoring include:

Patient complaints

Serious adverse events

Bearman toxicity grades 3 and 4
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
Variances in the delivery of standard care

Readmissions prior to day +60 post transplant

Deaths occurring prior to day +100 post transplant

Engraftment
Followup on all transplant patients is continued even after they have returned to the care of their 
referring physicians.  A Long Term Transplant Clinic has been established, which provides care for 
autologous patients with chronic complications, as well as assessments to identify dental, bone, and 
psychosocial complications.
All outcomes are reported to the Center for International Blood and Marrow Transplant Research 
(CIBMTR) which is a merger of the International Bone Marrow Transplant Registry (IBMTR) the 
Autologous Bone Marrow Transplant Registry (ABMTR), and the National Marrow Donor 
Program (NMDP).  Registry reports are reviewed internally prior to submission to the respective 
registry.  These data are also entered into the RPCI BMT Database, from which patient outcomes 
are assessed and reviewed on a regular basis.  Regimen-related toxicities reported in this fashion 
have resulted in a number of changes to transplant protocols since 1997, thus decreasing toxicity 
and improving outcomes in a number of patient groups.  
Registry reports also establish the efficacy of treatment as measured by overall best response to 
transplant at day +100 and on subsequent annual reports.  The patients’ medical records serve as 
original source documents for all reporting. Audits are conducted every two to three years by the 
CIBMTR and the Foundation for the Accreditation of Cellular Therapy (FACT).
12.0
 STATISTICAL ANALYSIS
12.1. Study Design:  
This is a pilot study of high dose therapy and autologous blood or marrow transplantation for 
patients with hematologic malignancies or disorders who have failed low-dose chemotherapy or 
who are in their first remission, but are at high risk of relapse.  Patients will be stratified by 6 
disease groups (acute leukemia, HL, NHL, MM/amyloidosis, and solid tumors).  All statistical 
analyses will be performed separately for each disease and regimen and no formal comparisons will 
be made between regimens.  
Design
The primary objective of this multi-arm Pilot is to assess the efficacy of the proposed blood or 
marrow transplant high dose therapy regimens for NHL, HL, and MM patients through estimation 
of the progression free survival distribution.  Progression free survival is defined as the time from 
date of transplantation to the date of first observed disease progression or death due to any cause.  
Patients who are alive and disease free at the last study assessment will be treated as censored.  The 
projected accrual is approximately 3 per month, and therefore recruitment is expected to be 
complete in 84 months follow the study starting point.  The target is 224 but up to 252 patients may 
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be accrued.  Please see the Table below for accrual by disease type.  Subjects will be followed for at 
least 60 months after recruitment completion, so total study duration will be 12 years.  The 
proposed samples sizes for each of the disease/regimen combinations appear in the table below.  
This is a total of 224 and this population size will allow for estimation of interest.  The accrual rate 
of approximately 3 per month will allow for up to a total accrual of 252 over approximately 84 
months.  Based on refinement of accrual rate, we were able to decrease the total from 530 to 224.  
This will still allow for estimation of parameters of interest.  These numbers are based on historical 
enrollment and the results of this exploratory pilot study will be used in the planning of future 
clinical trials.  An exact sample size is not necessary as we need an estimate of accrual. The 
precision associated with the survival estimates will be approximately the same for a range of pt 
sample sizes (e.g. 33 versus 37 will approximately be the same as35).  
Toxicity: The historical Treatment-Related (TRM) at 100 days has been less than 7% which was the 
original stopping parameter for this study.  As we have enrolled 91 patients receiving 95 transplant 
since 7/7/06 and have 1 death due to Regimen-Related Toxicity (1%).  This is considered 
acceptable when compared to National Standards (http://www.cibmtr.org/)
Disease (across)
NHL
HL
MM
Amyloid
Acute Leuk
ST
Regimens (below)
BuCy2iv
35
10
11
CBV
35
25
Mel120
20
5
Mel200
50
9
CT6
10
ST Regimens
14
Totals (224)
70
35
70
14
21
14
NHL, Non-Hodgkin Lymphoma; HL, Hodgkin Lymphoma; MM, Multiple Myeloma; Acute Leuk, Acute Leukemia; 
ST, Solid Tumor; BuCy2iv, Busulfan and Cyclophosphamide; CBV, Cyclophosphamide, BCNU (Carmustine), V, 
Etoposide (VP-16); Mel, Melphalan, 120 mg/m2; Mel 200 200 mg/m2; TBI, Total Body Irradiation.
Statistical methodology
The estimated progression free survival distribution will be obtained using the product-limit based 
Kaplan Meier method.  The Kaplan-Meier methodology will allow for incorporation of censored 
observations to be possibly expected in this study thereby resulting is a more efficient estimate of 
the true distribution of progression free survival than if this information was not used.  Estimates of 
quantities such as median survival will be obtained.  Using this distributional estimate, summary 
descriptive statistics, e.g. percentiles, will be obtained.  Additionally, a 95% confidence interval of 
the distribution will be computed based on Greenwood’s formula for the variance of the survival 
function.
Response rates and toxicities will be reported using descriptive statistics.  Overall survival for all 
groups and progression-free survival for amyloid, acute leukemia, and solid tumor patients will be 
assessed using similar methods as proposed in the primary analyses described above. Exploration of 
the role of risk factors in outcomes of all treated patients will be done using standard regression 
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techniques.
Sample size justification
Since no formal hypothesis testing is needed in this study, sample size calculations are based on 
precision of estimates.  Specially, we will consider the projected standard error of the estimated 
survival probabilities as estimated by Peto’s formula.  It has the advantage of being a simple 
estimate which is straightforward to manipulate for sample size calculations and it has been shown 
to be conservative as compared to Greenwood’s estimate of the standard error thereby giving 
conservative sample sizes.  Peto’s estimate is of the following form:
ˆ
ˆ
( ) 1
( )
S t
S t
N





where 
is the estimated survival distribution and 
 is the total number of subjects enter into the 
ˆ( )
S t
N
study.  The maximum of the above estimate is achieved at S(t) = 0.5.  Using this as a conservative 
basis for our calculations, it is seen that with the proposed sample sizes the resulting maximum 
standard error ranges from 0.16 to 0.07.
13.0
GENDER AND MINORITY
Women and members of minority groups and their subpopulations will be included in all study 
analyses.  There is no evidence to that gender or race/ethnicity differences will result in different 
clinical outcomes. 
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14.0     REFERENCES
Ambinder RF. The same but different: autologous hematopoietic stem cell transplantation
for patients with lymphoma and HIV infection. Bone Marrow Transplantation (2009) 44, 1–5
Attal, M., et al., A prospective, randomized trial of autologous bone marrow transplantation 
and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med, 
1996. 335(2): p. 91-7.
Bearman SI, Appelbaum FR, Back A, Petersen FB, Buckner CD, Sullivan KM, Schoch HG, 
Fisher LD, Thomas ED. Regimen-related toxicity and early posttransplant survival in 
patients undergoing marrow transplantation for lymphoma. J Clin Oncol. 1989 
Sep;7(9):1288-94.
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, 
Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients 
with multiple myeloma treated by high-dose therapy and haemopoietic stem cell 
transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and 
Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23.
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, 
Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, 
Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an International 
Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas  Journal of 
Clinical Oncology, Vol 17, Issue 4 (April), 1999: 1244
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, 
Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, 
Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD.  Revised 
Recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia.  Journal of Clinical Oncology, Vol 21, No 24 (December 15), 
2003: pp 4642-4649
Child, J.A., et al., High-dose chemotherapy with hematopoietic stem-cell rescue for multiple 
myeloma. N Engl J Med, 2003. 348(19): p. 1875-83.
Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic 
Amyloidosis Blood. 2002 Jun 15;99(12):4276-82
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Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, Boccadoro M, Child 
JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, 
Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J.  International staging system for 
multiple myeloma.  J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4
Hahn T, Wolff SN, Czuczman M, Fisher RI, Lazarus HM, Vose J, Warren L, Watt R, 
McCarthy, Jr. PL.  The Role of Cytotoxic Therapy With Hematopoietic Stem Cell 
Transplantation in the Therapy of Diffuse Large Cell B-Cell Non-Hodgkin’s Lymphoma: An 
Evidence-Based Review.  Biol Blood Marrow Transplantation 7:308-331, 2001
Hahn, T., et al., The role of cytotoxic therapy with hematopoietic stem cell transplantation in 
the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant, 
2003. 9(1): p. 4-37.
Hahn T, Benekli B, Wong C, Moysich KB, Hyland A, Michalek AM, Alam A, Baer MR, 
Bambach B, Czuczman MS, Wetzler M, Becker JL, McCarthy Jr PL. A Prognostic Model for 
Prolonged Event-Free Survival After Autologous or Allogeneic Blood or Marrow 
Transplantation for Relapsed and Refractory Hodgkin’s Disease. Bone Marrow 
Transplant;35(6):557-66., 2005 [Epub ahead of print], 2005. 
The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A Predictive Model 
for Aggressive Non-Hodgkin's Lymphoma. NEJM:329, 987-994, 1993
McGovern JJ Jr, Russell PS, Atkins L, Webster EW. Treatment of terminal leukemic relapse 
by total-body irradiation and intravenous infusion of stored autologous bone marrow 
obtained during remission. N Engl J Med. 1959 Apr 2;260(14):675-83
Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, 
Doyen C, Jaubert J, Fuzibet JG, Francois S, Benboubker L, Monconduit M, Voillat L, Macro 
M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, 
Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myelome. Comparison 
of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as 
conditioning regimens for peripheral blood stem cell transplantation in patients with newly 
diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 
9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5.
Peniket AJ, Ruiz de Elvira MC, Taghipour G, Cordonnier C, Gluckman E, de Witte T, 
Santini G, Blaise D, Greinix H, Ferrant A, Cornelissen J, Schmitz N and Goldstone AH on 
behalf of the European Bone Marrow Transplantation (EBMT) Lymphoma Registry  An 
EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic 
transplantation is associated with a lower relapse rate but a higher procedure-related 
mortality rate than autologous transplantation. Bone Marrow Transplantation (2003) 31, 667–
678
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Reece DE, Bredeson C, Perez WS, Jagannath S, Zhang MJ, Ballen KK, Elfenbein GJ, 
Freytes CO, Gale RP, Gertz MA, Gibson J, Giralt SA, Keating A, Kyle RA, Maharaj D, 
Marcellus D, McCarthy PL, Milone GA, Nimer SD, Pavlovsky S, To LB, Weisdorf DJ, 
Wiernik PH, Wingard JR, Vesole DH.  Autologous stem cell transplantation in multiple 
myeloma patients <60 vs >/=60 years of age.  Bone Marrow Transplant 32:1135-1143, 2003.
Salar A, Sierra J, Gandarillas M, Caballero MD, Marín J, Lahuerta JJ, Garcia-Conde J, 
Arranz R, Leon A, Zuazu J, Garcia-Larana J, Lopez-Guillermo A, Sanz MA, Granena A, 
Garcia JC, Conde E for the GEL/TAMO Spanish Cooperative Group Autologous stem cell 
transplantation for clinically aggressive non-Hodgkin’s lymphoma: the role of preparative 
regimens  Bone Marrow Transplantation (2001) 27, 405–412
TherasseP,Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van 
Glabbeke M, van Oosterom AT,  Christian MC, Gwythe SG. New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors Journal of the National Cancer Institute, Vol. 92, No. 
3, February 2, 2000.
Thomas’ Hematopoietic Cell Transplantation.  Eds Blume KG, Forman SJ, Appelbaum FR. 
Blackwell Publishing, Massachusetts, 2004.
Vandenberghe E, Ruiz de Elvira C, Loberiza FR, Conde E, López-Guillermo A, Gisselbrecht 
C, Guilhot F, Vose JM, van Beisen K, Rizzo JD, Weisenburger DD, Isaacson P, Horowitz 
MM, Goldstone AH, Lazarus HM, Schmitz N.  Outcome of autologous transplantation for 
mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and 
Autologous Blood and Marrow Transplant Registries  British Journal of Haematology, 2003, 
120, 793–800
Working Group of UK Myeloma Forum; British Commitee for Standards in Haematology, 
British Society for Haematology. Guidelines on the diagnosis and management of AL 
Amyloidosis    Guidelines Br J Haematol. 2004 Jun;125(6):681-700
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15.0
APPENDICES
APPENDIX I
INTERNATIONAL PROGNOSTIC INDEX NHL
Risk Group
Risk Factors,
Number
Complete 
Response (%)
2 Year Survival, 
%
International index, all patients
(n=2031)*
Low
0 or 1
87
84
Low intermediate
2
67
66
High intermediate
3
55
54
High
4 or 5
44
34
Age-adjusted index, patients 60 years
 (n = 1274)**
Low
0
92
90
Low intermediate
1
78
79
High intermediate
2
57
59
High
3
46
37
*  Risk factors in all patients:
Age ≥60 years
Serum LDH >1 times normal
Performance status 2
Stage III or IV disease
Extranodal involvement
** Risk factors in patients 60 years of age:
Stage III or IV disease
Serum LDH >1 times normal
Performance status 2.
Reference: The International Non-Hodgkin's Lymphoma 
Prognostic Factors Project. A Predictive Model for 
Aggressive Non-Hodgkin's Lymphoma. NEJM:329, 987-
994, 1993
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APPENDIX II
TABLE OF AVERAGE WEIGHT FOR HEIGHT AND CALVERT FORMULA FOR 
CARBOPLATIN DOSING FOR NEUROBLASTOMA PATIENTS
To calculate ideal body weight (IBW) for men:
50 + 0.91x(height in cm – 152) 
To calculate ideal body weight (IBW) for women:
45 + 0.91x(height in cm – 152) 
To calculate adjusted body weight (ABW) for men and women:
Ideal body weight + [0.25 x (actual body weight – ideal body weight)]
The calculation of ideal body weight is referenced in the package insert of Busulfex (busulfan) 
Injection, and also found in the article written by:  Gibbs, JP, Gooley, T, Comeau, B, et al, “The 
Impact of Obesity and Disease on Busulfan Oral Clearance in Adults”, Blood, Vol 93, No 12 (June 
15) 1999:  pp 4436-4440. 
Calvert Formula for Carboplatin dosing for neuroblastoma patients:
Dose =  [(GFR x BSA/1.73) + (15 x BSA)]  x 4.1
Dose obtained is ACTUAL dose in mg (NOT mg/kg). GFR is obtained by using a 99Tc-DTPA scan. 
BSA is body surface area = square root of the height (cm) x weight (kg)/3600
Calvert Formula for Carboplatin dosing for Adult patients (> 18 years of age) with small 
round blue cell tumors or neuroblastoma
Carboplatin Dose (mg) = (AUC) (Creatinine Clearance (ml/min) +25)) 
Creatinine Clearance is calculated using the Cockroft-Gault Formula or by 24 hour Urine collection 
and Creatinine Clearance
Cockroft-Gault Formula: CrCl = ((140-age) (Ideal Body Weight))/((72) (serum creatinine))
(For women, multiply the result by 0.85)
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APPENDIX  III
GUIDELINES FOR TOTAL BODY IRRADIATION (TBI)
1.
Equipment:
1.
Modality:  External photon irradiation
2.
Energy:  Use radiation of megavoltage quality:  i.e., cobalt-60 or accelerator beams with 
nominal energy of no less than 4 Mev.  High energy photons (6 Mev and above) must 
satisfy the same total dose requirements for skin surfaces.  It will be necessary for each 
institution to establish through experimental measurements whether the combination of 
entrance plus exit beams satisfy these conditions in the first few millimeters of tissue.
3.
Geometry:  Single or double head treatment units may be used.  Dynamic or static fields 
may be used.  The treatment configuration shall be such that the patient is entirely 
included within the treatment beam exclusive of the penumbra (i.e., the patient shall be 
situated well within the 90% decrement line at each depth; the 90% decrement line is 
defined as a line in each plane perpendicular to the central axis connecting points which 
are 90% of the central axis dose in that plane).  It is essential that agreement between the 
light and radiation fields be established and verified for the extended TBI treatment 
distance.
4.
Dose Rate:  The dose rate shall be between 5 and 25 cGy/min. defined at mid-plane.
5.
Treatment Volume:  The patient shall be entirely included within the static or sweeping 
treatment beam.  Care should be taken to guarantee that no part of the patient extends 
into the penumbra region of the beam.
2.
Treatment Dose:
1.
Prescription Point is defined as the point midplane at the level of the umbilicus.
2.
Dose Definition:  The dose shall be defined as centigray to muscle.  No inhomogeneity 
corrections shall be made in the calculation of the dose to the prescription point.
3.
Total Treatment Dose:  
1.
For protocol doses of 1200 cGy the total treatment dose shall be delivered in 
fractions of 200 cGy using a hyperfractionated regimen of 2 fractions per day on 3 
consecutive days, with a minimum interval of 6 hrs between fractions.
2.
The protocol total dose of 200 cGy shall be delivered in a single dose fraction for 6 
total doses.
4.
All patients will be treated in the sitting upright position using the TBI treatment stand.  
The patient treatment position should be recorded and submitted as part of the quality 
assurance documentation. 
5.
Tissue compensators may be used when necessary to improve dose homogeneity.  If 
used, a complete description of compensation technique and its effect on the prescription 
dose and dose distribution shall be reported and submitted as part of the quality 
assurance documentation.
6.
Skin bolus such as blankets or other body covers may be used to bring up the superficial 
dose to satisfy the homogeneity requirements.  The superficial dose shall be determined 
at a depth of 2-3 mm.
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7.
All fields should be treated each fraction.
8.  
Lung shielding will be utilized for all patients treated with total body irradiation to 
compensate for the lower density of the lung compared to soft tissues.  The total dose to 
the lung will not exceed 900cGy in the Melphalan/TBI regimen, or 900 cGy in the VCT 
regimen, but will be as close to it as possible and will never be less than 800cGy.  This 
will be accomplished by using partial lung cerebend blocks in an alternating fashion 
between anterior and posterior treatments.  The total number of fractions using lung 
shielding will vary depending on the total prescription dose.
A margin of approximately 1.5 cm from the chest wall and mediastinal tissues will be 
used to prevent underdosing of these regions.  After a chest x-ray is obtained in the 
treatment position, the physician will determine the lung volume to be shielded and will 
draw the shield dimensions.  Cerrobend blocks will then be made and verification films 
will be obtained at each fraction using shielding and checked by a physician to ensure 
proper coverage.  Any adjustments of the lung shields will be made prior to treatment.  
All patients will be treated in the sitting upright position using the TBI treatment stand.  
Verification of dose to the lungs will be accomplished by use of diodes at the entrance 
and exit side of the patient under the partial lung shield to determine the approximate 
dose to the midline of the patient by averaging the entrance and exit dose.
3.
Calculations and Treatment Planning:  It is recommended that the calculational method be 
based upon measurements that are made in a unit density phantom 35 x 35 x 35 cm3 in size.  
All measurements should be made at the appropriate TBI extended SSD.  The method of 
calculation should be specific to the institution's methods and clearly documented.
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APPENDIX IV
CRITERIA FOR GRADING TOXICITY
Regimen Related Toxicity in Patients Undergoing BMT
Bearman Sl et al, 1988
                   Grade I
Grade II
Grade III
Cardiac
Mild EKG abnormality, 
not requiring medical 
intervention; or noted 
heart enlargement on 
CXR with no clinical 
symptoms
Moderate EKG abnormalities 
requiring and responding to 
medical intervention; or requiring 
continuous monitoring without 
treatment; or congestive heart 
failure responsive to digitalis or 
diuretics
Severe EKG abnormalities with 
no or only partial response to 
medical intervention; or heart 
failure with no or only minor 
response to medical 
intervention; or decrease in 
voltage by more than 50%
Bladder
Macroscopic hematuria 
after 2 days from last 
chemotherapy dose with 
no subjective symptoms 
of cystitis and not caused 
by infection
Macroscopic hematuria after 7 days 
from last chemotherapy dose not 
caused by infection; or hematuria 
after 2 days with subjective 
symptoms of cystitis not caused by 
infection
Hemorrhagic cystitis with frank 
blood, necessitating invasive 
local intervention with 
installation of sclerosing 
agents, nephrostomy or other 
surgical procedure
Renal
Increase in creatinine up 
to twice the baseline 
value (usually the last 
recorded before start of 
high dose therapy)
Increase in creatinine above twice 
baseline but not requiring dialysis
Requirement of dialysis
Pulmonary
Dypsnea without CXR 
changes not caused by 
infection or congestive 
heart failure; or CXR 
showing isolated infiltrate 
or mild interstitial 
changes without 
symptoms not caused by 
infection or congestive 
heart failure
CXR with extensive localized 
infiltrate or moderate interstitial 
changes combined with dyspnea 
and not caused by infection or 
CHF; or decrease of PO2 (>10% 
from baseline) but not requiring 
mechanical ventilation or >50% O2 
on mask and not caused by 
infection or CHF
Interstitial changes requiring 
mechanical ventilatory support 
or >50% oxygen on mask and 
not caused by infection or CHF
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                   Grade I
Grade II
Grade III
Hepatic
Mild hepatic dysfunction 
with bili >2.0 mg% but  < 
6.0 mg %; or weight gain 
>2.5 % and 
< 5 % from baseline of 
noncardiac origin; or 
SGOT increase more than 
2-fold but less than 5-fold 
from lowest prehigh dose 
therapy
Moderate hepatic dysfunction with 
bili >6 mg% < 20 mg %; or SGOT 
increase with 
> 5-fold from prehigh dose 
therapy; or clinical ascites or image 
documented ascites >100ml; or 
weight gain >5% from baseline of 
noncardiac origin
Severe hepatic dysfunction 
with bili 
> 20 mg %; or hepatic 
encephalopathy; or ascites 
compromising respiratory 
function
CNS 
Somnolence but the 
patient easily arousable 
and oriented after arousal
Somnolence with confustion after 
arousal; or other new objective 
CNS symptoms with no loss of 
consciousness not more easily 
explained by other medication, 
bleeding, or CNS infection
Seizures or coma not explained 
by other medication, CNS 
infection, or bleeding
Stomatitis
Pain and/or ulceration not 
requiring a continuous IV 
narcotic drug
Pain and/or ulceration requiring a 
continuous IV narcotic drug
Severe ulceration and/or 
mucositis requiring preventive 
intubation; or resulting in 
documented aspiration 
pneumonia with or without 
intubation
GI
Watery stools >500 ml 
but <2,000 ml every day 
not related to infection
Watery stools >2,000 ml every day 
not related to infection; or 
macroscopic hemorrhagic stools 
with no effect on cardiovascular 
status not caused by infection; or 
subileus not related to infection
Ileus requiring nasogastric 
suction and/or surgery and not 
related to infection; or 
hemorrhagic enterocolitis 
affecting cardiovascular status 
and requiring transfusion
NOTE:  Grade IV regimen-related toxicity is defined as fatal toxicity.
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APPENDIX V
SOLID TUMOR AND  RESPONSE CRITERIA
Table 3 - Definition of best response according to WHO or
RECIST criteria*
Therasse et al, 2000
Best
WHO change in sum of
RECIST change in sums
Response
products
longest diameters
CR 
Disappearance; confirmed at 
Disappearance; confirmed at 
4 wks† 
4 wks† 
PR 
50% decrease; confirmed at 
30% decrease; confirmed at 
4 wks† 
4 wks† 
SD 
Neither PR nor PD criteria 
Neither PR nor PD criteria 
met 
met 
PD 
25% increase; no CR, PR, or 
20% increase; no CR, PR, or 
SD documented before 
SD documented before 
increased disease 
increased disease 
*WHO = World Health Organization; RECIST = Response Evaluation Criteria in Solid Tumors,
  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease. 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference:
Eligibility
Only patients with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint. 
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter  20 mm using conventional techniques or 10 mm with spiral CT scan.
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques; and.
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
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 

The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 

Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Methods of Measurement  

CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen and pelvis. 
Head and neck tumors and those of extremities usually require specific protocols.

Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 

When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. 
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination.

The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been 
fully and widely validated. Their uses in this specific context require sophisticated equipment 
and a high level of expertise that may only be available in some centers. Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in specialized centers. However, such techniques can be useful in confirming complete 
pathological response when biopsies are obtained.

Tumor markers alone cannot be used to assess response.  If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response 
when all lesions have disappeared.

Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in 
tumor types such as germ cell tumors).
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Baseline documentation of “Target” and “Non-Target” lesions

All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline. 

Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). 

A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to characterize the 
objective tumor.

All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
Response Criteria
Evaluation of target lesions
* Complete Response (CR):
Disappearance of all target lesions
* Partial Response (PR):
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD
* Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions
* Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started
Evaluation of non-target lesions
* Complete Response (CR):
Disappearance of all non-target lesions and normalization of 
tumor marker level
* Incomplete Response/          
Stable Disease (SD):
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits
* Progressive Disease (PD):
Appearance of one or more new lesions and/or unequivocal 
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Evaluation of target lesions
progression of existing non-target lesions (1) 
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed later on by the review panel (or study chair).
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria 
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
Incomplete 
response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD

Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 

In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status.
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Confirmation

The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed.

To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate. 

In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol 
Duration of overall response

The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started.
Duration of stable disease

SD is measured from the start of the treatment until the criteria for disease progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 

The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval required 
between two measurements for determination of SD. This time interval should take into account 
the expected clinical benefit that such a status may bring to the population under study. 
Response review

For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach. 
Reporting of results
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned 
one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient data).
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APPENDIX VI
RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA AND HL
Cheson et al 1999.
The following criteria are considered anatomic definitions (Table 1). In the future, as additional 
radiographic, laboratory, and functional studies become more widely available and clearly 
demonstrate predictive value, they may be recommended as well.
CR requires the following:
1. Complete disappearance of all detectable clinical and radiographic evidence of disease and 
disappearance of all disease-related symptoms if present before therapy, and normalization 
of those biochemical abnormalities (eg, lactate dehydrogenase [LDH]) definitely assignable 
to NHL.
2. All lymph nodes and nodal masses must have regressed to normal size (<1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have 
decreased to < 1 cm in their greatest transverse diameter after treatment, or by more than 
75% in the sum of the products of the greatest diameters (SPD).
3. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have 
regressed in size and must not be palpable on physical examination.  However, no normal 
size can be specified because of the difficulties in accurately evaluating splenic and hepatic 
size. For instance, spleens thought to be of normal size may contain lymphoma, whereas an 
enlarged spleen may not necessarily reflect the presence of lymphoma but variations in 
anatomy, blood volume, the use of hematopoietic growth factors, or other causes. The 
determination of splenic volume or splenic index by CT scan are cumbersome and not 
widely used.35,36 Any macroscopic nodules in any organs detectable on imaging 
techniques should no longer be present. Similarly, other organs considered to be enlarged 
before therapy due to involvement by lymphoma, such as liver and kidneys, must have 
decreased in size.
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must be 
cleared on repeat bone marrow aspirate and biopsy of the same site. The sample on which 
this determination is made must be adequate (> 20 mm biopsy core). Flow cytometric, 
molecular, or cytogenetic studies are not considered part of routine assessment to document 
persistent disease at the present time. These studies should only be incorporated into trials 
examining important research questions.
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CR/unconfirmed (CRu) includes those patients who fulfill criteria 1 and 3 above, but with one 
or more of the following features:
1. A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has 
regressed by more than 75% in the SPD. Individual nodes that were previously confluent 
must have regressed by more than 75% in their SPD compared with the size of the original 
mass.
2. Indeterminate bone marrow (increased number or size of aggregates without cytologic or 
architectural atypia).
PR requires the following:
1. > 50% decrease in SPD of the six largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to the following features: 
(a) they should be clearly measurable in at least two perpendicular dimensions, (b) they 
should be from as disparate regions of the body as possible, and (c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved.
2. No increase in the size of the other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by at least 50% in the SPD.
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease.
5. Bone marrow assessment is irrelevant for determination of a PR because it is assessable and 
not measurable disease; however, if positive, the cell type should be specified in the report, 
eg, large-cell lymphoma or low-grade lymphoma (ie, small, lymphocytic small cleaved, or 
mixed small and large cells).
6. No new sites of disease.
Stable disease is defined as less than a PR (see above) but is not progressive disease (see below).
Relapsed disease (CR, CRu) requires the following:
1. Appearance of any new lesion or increase by> 50% in the size of previously involved sites.
2. > 50% increase in greatest diameter of any previously identified node greater than 1 cm in 
its short axis or in the SPD of more than one node.
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Progressive disease (PR, nonresponders) requires the following:
1. > 50% increase from nadir in the SPD of any previously identified abnormal node for PRs 
or nonresponders.
2. Appearance of any new lesion during or at the end of therapy.
Response Assessment
Response is currently assessed on the basis of clinical, radiologic, and pathologic (ie, bone marrow) 
criteria.
1. CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, and 
pelvic CT scans are recommended even if those areas were not initially involved because of 
the unpredictable pattern of recurrence in NHL. Studies should be performed no later than 2 
months after treatment has been completed to assess response. This interval may vary with 
the type of treatment, eg, a longer period may be more appropriate for biologic agents where 
the anticipated time to response may be greater.
2. A bone marrow aspirate and biopsy should only be performed to confirm a CR if they were 
initially positive or if it is clinically indicated by new abnormalities in the peripheral blood 
counts or blood smear.
Table 1. Response Criteria for Non-Hodgkin’s Lymphoma 
Response Category 
Physical 
Examination 
Lymph Nodes 
Lymph Node 
Masses 
Bone Marrow 
CR 
Normal 
Normal 
Normal 
Normal 
CRu 
Normal 
Normal 
Normal 
Indeterminate 
Normal 
Normal 
> 75% 
decrease 
Normal or 
indeterminate 
PR 
Normal 
Normal 
Normal 
Positive 
Normal 
> 50% 
decrease 
> 50% 
decrease 
Irrelevant 
Decrease in 
liver/spleen 
> 50% 
decrease 
> 50% 
decrease 
Irrelevant 
Relapse/progression 
Enlarging 
liver/spleen; new 
sites 
New or 
increased 
New or 
increased 
Reappearance 
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APPENDIX VII
The following criteria will be used for ALL as well as AML for determining response.
Response Criteria in Acute Leukemia
Response Criterion 
Time of Assessment 
Neutrophils
(_L) 
Platelets 
(mcL) 
Bone Marrow Blasts (%) 
Morphologic CRi 
(absence of 
leukemia with 
incomplete count 
recovery) 
Day 100 +/- 20 days post 
BMT 
<1,500
<100,000 
< 5 
Morphologic CR 
Day 100 +/- 20 days post 
BMT
> 1,500 
> 100,000 
< 5 
Cytogenetic CR 
Day 100 +/- 20 days post 
BMT
> 1,500 
> 100,000 
< 5 
Molecular CR 
Day 100 +/- 20 days post 
BMT
> 1,500 
> 100,000 
< 5 
Partial remission 
Day 100 +/- 20 days post 
BMT
> 1,500 
> 100,000 
< 50% decrease in blast 
count or decrease in blast 
count to 5-25% 
Abbreviations: AML, acute myelogenous leukemia; EMD is defined as non-response or progressive disease; CR, complete 
remission. 
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APPENDIX VIII
Amyloidosis Response Criteria
Criteria for therapeutic response/outcome assessment (criteria used at Memorial Sloan Kettering 
Hospital) (Comenzo et al, 1998)
Amyloid-related organ response will be evaluated on the basis of the accepted criteria described 
below.  Based on the criteria below, amyloid-related organ involvement should be scored as
improved, stable or worsened at 6 months/1 year after initiation of therapy and annually thereafter.  
An improvement of one or more affected organ(s) is defined by:
Kidneys: A 50% reduction in 24-h urine protein excretion in the absence of progressive renal 
insufficiency.
Heart: A > 2 mm reduction in the mean left ventricular thickness (average of posterior wall and 
septal thickness) by echocardiogram, or a decrease by two points in NYHA classification (e.g. 
from 3 to 1).
Liver: A > 50% decrease of an initially elevated alkaline phosphatase level with reduction in 
the size of the liver by at least 2 cm [determined by ultrasound or computed tomography (CT) 
scan].
Neuropathy: Clinical improvement supported by clinical history, neurological examination, 
orthostatic vital signs, resolution of severe constipation or reduction of diarrhea to less than 50% 
of previous movements per day, and electromyography (EMG) studies if indicated.
Worsening of one or more affected organ(s) is defined by:
Kidneys: Doubling of urinary protein loss if <3 g/24 h at baseline, or 50% increase in urinary 
protein loss if > 3 g/24 h, or reduction of creatinine clearance by > 50%, or increase in serum 
creatinine of > 176.9 micromol/l.
Heart: Evidence of echocardiographic progression with an increase in cardiac wall thickness by 
> 2 mm or a decrease in ejection fraction by > 20%.
Liver: > 50% increase in the alkaline phosphatase level or doubling of serum bilirubin or liver 
enzymes (aspartate transaminase, alanine transaminase) due to amyloid, or increase in the size 
of the liver by at least 3 cm (determined by physical examination, ultrasound, or CT).
Neuropathy: Clinical worsening supported by history, worsening orthostatic vital signs and 
symptoms, and EMG studies if indicated.
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Stable disease: 
It is defined when none of the criteria for improvement or for worsening disease are met.
Response of the clonal plasma cell disease
Evaluation of the clonal plasma cell disease is based on standard electrophoretic and 
immunofixation tests of blood and urine for a monoclonal protein (M protein), and bone marrow 
biopsy stained for isotypic plasma cells. The difference between the serum and/or urine M protein 
pre- and posttreatment will be calculated. This may be in the form of an M spike or quantifiable 
immunoglobulin or light chain measurements. The percentage reduction in clonal plasma cell 
disease will usually be assessed by subtracting the postchemotherapy value from the baseline value, 
dividing by the baseline value, and multiplying by 100%. A reduction of > 50% in this 
measurement will be considered a ‘response’. A > 90% reduction of the M protein with its 
persistence by immuno-fixation will be considered a ‘very good response’. A ‘complete response’ 
to therapy requires the M protein to be undetectable by immunofixation of serum and/or urine and 
normalization of the bone marrow biopsy.  Monoclonal immunoglobulins are often difficult to 
detect or are unquantifiable in many patients with AL amyloidosis using traditional methods. The 
limitations and inaccuracies of using electrophoresis, etc., are therefore self-evident, and use of 
fully quantifiable serum FLC measurements are strongly encouraged
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APPENDIX IX
Myeloma Response Criteria
(Revised Blade et al 1998) 
1. 
CR = Complete Response and requires ALL of the following: 
a. 
Absence of the original monoclonal paraprotein in serum and urine by routine 
electrophoresis and by immunofixation. 
The presence of new monoclonal bands consistent with oligoclonal immune 
reconstitution does not exclude CR. 
b. 
<5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if 
biopsy is performed. If absence of monoclonal protein it 
is not necessary to repeat the bone marrow unless the patient had non-secretory 
myeloma. 
c. 
No increase in size or number of lytic bone lesions on radiological investigations, 
if performed (development of a compression fracture does not exclude response). 
d.
 Disappearance of soft tissue plasmacytomas. 
e. 
For plasma cell leukemia, absence of plasma cells in blood.
 
(Patients in whom some, but not all, the criteria for CR is fulfilled are classified as 
PR, 
providing the remaining criteria satisfy the requirements for PR. This includes 
patients in 
whom routine electrophoresis is negative but in whom immunofixation has not been 
performed). 
2. 
CCR = Continuing Complete Response requires ALL of the following: 
a. 
CR continuing from CR prior to high dose therapy.
 
3. 
PR = Partial Response requires the following: 
a. 
≤50% reduction in the level of the serum monoclonal paraprotein, maintained for 
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a minimum of 6 weeks. 
OR 
Reduction in 24 hour urinary light chain excretion either by ≥90% or to <200 
mg/24 hours in light chain disease. 
b. 
For patients with non-secretory myeloma or plasma cell leukemia only, ≥50% 
reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if 
biopsy is performed. 
c. 
≥50% reduction in the size of soft tissue plasmacytomas (by radiography or 
clinical examination). 
d. 
No increase in the size or number of lytic bone lesions on radiological 
investigations. If performed (development of a compression fracture does not 
exclude response). 
e. 
For plasma cell leukemia, absence of plasma cells in the blood. 
(Patients in whom some, but not all, the criteria for PR are fulfilled are classified as MR, 
providing the remaining criteria satisfy the requirements for MR.) 
4. 
MR = Minimal Response requires all of the following: 
a. 
25-49% reduction in the level of the serum monoclonal paraprotein maintained 
for a minimum of 6 weeks. 
OR 
50-89% reduction in 24 hour urinary light chain excretion, which still exceeds 
200 mg/24 hours, maintained. 
b. 
For patients with non-secretory myeloma only, 25-49% reduction in plasma cells 
in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, 
maintained. 
c. 
25-49% reduction in the size of soft tissue plasmacytomas (by radiography or 
clinical examination). 
d. 
No increase in the size of number of lytic bone lesions on radiological 
investigations, if performed (development of a compression fracture does not 
exclude response). 
(MR also includes patients in whom some, but not all, the criteria for PR are fulfilled, 
provided the remaining criteria satisfy the requirements for MR). 
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5. 
NR = No response 
a. 
Not meeting the criteria of either minimal response or progressive disease.
b. 
For plasma cell leukemia only, not meeting criteria for CR or PR. 
6. 
SD = Stable Disease 
a.
Stable values (within 25% above or below value at time response is assessed) 
maintained for at least 3 months. 
7. 
REL from CR = Relapse from CR requires one or more of the following: 
a. 
Reappearance of serum or urine paraprotein on immunofixation or routine 
electrophoresis, confirmed by at least one further investigation and excluding 
oligoclonal immune reconstitution. 
b.
 ≥5% plasma cells in a bone marrow aspirate or on trephine bone biopsy. 
c. 
Development of new lytic bone lesions or soft tissue plasmacytomas or definite 
increase in the size of residual bone lesions. Development of a compression 
fracture does not exclude continued response and may not indicate progression. 
d. 
Development of hypercalcaemia (corrected serum Ca >1.5 mg/dl or >2,8 
mmol/L) not attributable to any other cause. 
e. 
For plasma cell leukemia, reappearance of plasma cells in blood. 
8. 
PROG = Progressive Disease (for patients not in CR) requires one or more of the 
following: 
a. 
>25% increase in the level of the serum monoclonal paraprotein, which must also 
be an absolute increase of at least 5 g/L and confirmed by at least one repeated 
investigation. 
b. 
>25% increase in 24 hour urinary light chain excretion, which must also be an 
absolute increase of at least 200 mg/24 hours and confirmed by at least one 
repeated investigation. 
c. 
>25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, 
which must also be an absolute increase of at least 10%. 
d. 
Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
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e.
Development of new bone lesions or soft tissue plasmacytomas (development of a 
compression fracture does not exclude continued response and may not indicate 
progression). 
f. 
Development of hypercalcemia (corrected serum Ca >1.5 mg/dl or >2.8 
mmol/L) not attributable to any other cause. 
g.
For plasma cell leukemia, reappearance of plasma cells in blood. 
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APPENDIX XI
Definitions:  On/Off Study dates, On/Off Treatment dates
On-Study Date
Start Treatment Date
Stop Treatment Date
Off-Study Date
Date high dose therapy 
regimen started for first 
BMT
Date high dose therapy 
regimen started for first 
BMT
Date infusion of stem cells 
is complete (for second 
BMT unless second BMT 
is not able to be 
administered
Date of first disease 
progression post-
transplant or date of 
death due to any cause or 
at least 60 months of 
follow-up, whichever 
comes first”
**All >/=2nd BMTs and DLIs count toward accrual, except for planned tandem auto BMTs which count once 
toward accrual.
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APPENDIX XII
Child-Pugh Classification of Liver Failure
Measurement
Points Scored  1 Points Scored  2 Points Scored  3
Encephalopathy
None
1 and 2
3 and 4
Ascites
None
Slight
Moderate
Bilirubin (mg/100 ml)
1.0 – 2.0
2.0 – 3.0
> 3.0
Albumin (gm/ 100 ml)
3.5
2.8 - 3.5
< 2.8
Prothrombin time 
(sec. prolonged)
1 - 4
4 - 6
>6
For PBC, bilirubin 
(mg/100 ml)
1 - 4
4 - 10
>10
Child - Pugh Classification: 
A = 1 – 6,
B = 7 – 9,
C = 10-15
COCKROFT GAULT FORMULA (MODIFIED FOR BSA) FOR ESTIMATION OF 
CREATININE CLEARANCE ABOVE AGE 18
CLEARANCE (ml/min) 
Male = (140-age) x IBW (kg) / 72 x SrCr 
Female= male clearance x 0.85
IBW (male) = 50 + 0.91(Height(cm) - 152) 
IBW (female) = 45 + 0.91(Height (cm) - 152)
SrCr in mg/dL.
SCHWARTZ FORMULA FOR ESTIMATION OF CREATININE CLEARANCE UP TO 
AGE 18
CLEARANCE (ml/min/1.73 m2) =    K x L / SrCr 
K = age adjusted constant, L = length in centimeters, SrCr in mg/dL.
Age                                             K
2-12 y                                           0.55
13-21 y   female                            0.55
13-21 y   male                               0.70
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