A Phase II Trial of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan and Low Dose Total Body Irradiation
Phase: PHASE2
Conditions: Accelerated Phase Chronic Myelogenous Leukemia, 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 Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Aplastic Anemia, Burkitt Lymphoma, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Diffuse Large Cell Lymphoma, Childhood Grade III Lymphomatoid Granulomatosis, Childhood Immunoblastic Large Cell Lymphoma, Childhood Myelodysplastic Syndromes, Childhood Nasal Type Extranodal NK/T-cell Lymphoma, Chronic Myelomonocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, Congenital Amegakaryocytic Thrombocytopenia, Diamond-Blackfan Anemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Juvenile Myelomonocytic Leukemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Nodal Marginal Zone B-cell Lymphoma, Paroxysmal Nocturnal Hemoglobinuria, Peripheral T-cell Lymphoma, Polycythemia Vera, Post-transplant Lymphoproliferative Disorder, Previously Treated Myelodysplastic Syndromes, Primary Myelofibrosis, 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 Adult T-cell Leukemia/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 Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hairy Cell Leukemia, Refractory Multiple Myeloma, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Secondary Myelofibrosis, Severe Combined Immunodeficiency, Severe Congenital Neutropenia, Shwachman-Diamond Syndrome, Splenic Marginal Zone Lymphoma, T-cell Large Granular Lymphocyte Leukemia, Waldenstrom Macroglobulinemia, Wiskott-Aldrich Syndrome
Sponsor: Roswell Park Cancer Institute

Roswell Park Cancer Institute Study Number: 1177110
ROSWELL
CANCER fNSTJTUTE
STUDY PROTOCOL TITLE: A PHASE 11 TRIAL OF REDUCED INTENSITY
ALLOGENEIC STEM CELL TRANSPLANTATION WITH FLUDARABINE,
MELPHALAN AND LOW DOSE TOTAL BODY IRRADIATION
Roswell Park Cancer
Institute
Study Number: 1177110
Initial Submission Date: 2/15/11
Amendment 1: 1/4/12
Amendment 2: 10/7/14
Principal Investigator:
Approved By
RFC! IRB and UB-CYIRB
OCT 212014
G ch MD
Roff»^ii'park'CancerinstitutJnstitutional ReviewBoard
Elm and Carlton Street
Buffalo, New York 14263
716-845-8614
George.Chen@rosweHpark.org
Sponsor: RPCI
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall
remain the exclusive property of the parties mentioned above. The use of such confidential
information must be restricted to the recipient for the agreed purpose and must not be disclosed,
published or otherwise communicated to any unauthorized persons, for any reason, in any form
whatsoever without the prior written consent of the parties above.
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Roswell Park Cancer Institute Study Number: 1177110
Network Investigator Signature Page
STUDY PROTOCOL TITLE: A PHASE II TRIAL OF REDUCED INTENSITY
ALLOGENEIC STEM CELL TRANSPLANTATION WITH FLUDARABINE,
MELPHALAJV AND LOW DOSE TOTAL BODY IRRADIATION
Protocol Approval and Investigator Agreement
I have read and familiarized myself with this protocol and I agree to conduct the study as
described according to Good Clinical Practices (GCP) and International Conference on
Harmonisation (ICH) guidelines.
Principal Investigator
2/15/11 
Date
Print
Sign
George Chen
Address: Elm & Carlton Street, Buffalo, NY 14263
Phone: 716-845-8722 
Fax: 716-845-3272 
Email: George.Chen@roswellpark.org
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Roswell Park Cancer Institute Study Number: 1177110
STUDY PROTOCOL SYNOPSIS
Title / Phase
A PHASE II TRIAL OF REDUCED INTENSITY ALLOGENEIC
STEM CELL TRANSPLANTATION WITH FLUDARABINE,
MELPHALAN AND LOW DOSE TOTAL BODY
IRRADIATION
Roswell Park Cancer
Institute Study Number
1177110
Roswell Park Cancer
Institute Investigator
George Chen, MD
Sponsor
RPCI
Study Drug(S)
No investigational drug
Objectives
Primary
• To determine the transplant related mortality (TRM) of this novel
reduced intensity allogeneic stem cell transplantation (RIT)
conditioning regimen in a patient population usually not eligible or
unable to tolerate a full myeloablative allogeneic transplant.
Secondary
• To evaluate clinical response, progression free survival (PFS) at
one year, engraftment rate, and graft-vs.-host disease (GvHD)
incidence with this novel RIT regimen that utilizes a higher dose of
melphalan than the previous pilot study across a variety of
hematological conditions.
• Correlative studies will include chimerism analysis by molecular
analysis and evaluation of immune reconstitution by CMV
dextramer analysis using flow cytometry.
Study Design
This trial is designed as an open label, non-randomized, single
institution study. The primary objective of this study is estimation
of the true population TRM rate by day 100 for patients with co¬
morbidities undergoing RIT who would not be otherwise eligible
for or unable to tolerate a full myeloablative transplant. This study
will build on our previous experience on Clinical Trial 118807
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Roswell Park Cancer Institute Study Number: 1177110
which utilized a lower dose of melphalan.
Eligible patients will receive conditioning regimen and allogeneic
hematopoietic stem cell transplant as the following:
Fludarabine 40 mg/m2/day on days -5 to -2
Melphalan 75 mg/m2 on day -2
Total body irradiation (TBI) 400 cGy (two fractions of 200 cGy
each) on day -1
Hematopoietic stem cell infusion on day 0
Subjects will be followed for at least 12 months after
recruitment completion. A total of up to 81 evaluable patients
will be accrued. The study design will be a Kepner-Chang Type
II Phase II design that proceeds in two stages and stops early
only for futility. At the end of the first stage of accrual (41
evaluable patients), data will be reviewed to decide if the study
should be terminated due to unacceptable toxicity.
Evaluable patients are defined as patients who do not have
disease progression within day 100. Non-evaluable patients
will be excluded for the primary objective—day 100 TRM
evaluation. Non-evaluable patients will be included in the
secondary objective analysis including clinical response, PFS at
one year, engraftment rate, and GvHD incidence.
Accrual Target / Duration
Accrual target is 81 evaluable patients. The projected accrual is
approximately 2-3 patients per month, and therefore recruitment is
expected to be complete within 4 years following the study starting
point. Subjects will be followed for at least 12 months after
recruitment completion, so total study duration will be 5 years.
Evaluation Criteria
Safetv Assessments: The primary end point of this study is 1KM at
day 100. Safety will be evaluated on an ongoing basis with weekly
outcome assessment and grading for the first 100 days post
transplant. Descriptive statistics will be used to describe safety and
other outcomes. Toxicity will be scored according to the Bearman
Criteria in Appendix I, oral mucositis by the WHO criteria in
Appendix II, acute GvHD according to the criteria in Appendix III
and chronic GvHD by the criteria in Appendix IV.
Survival: PFS at one vear
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Roswell Park Cancer Institute Study Number: 1177110
Correlative Studies: 1. Myeloid and lymphoid chimerism
expressed as a percentage at the following time points (+/- 7 days):
day 30, day 100 after stem cell infusion. 2. Immune reconstitution
will be evaluated by CMV dextramer analysis using flow cytometry
at the following time points (+/- 7 days): baseline, day 30, day 100,
and one year after stem cell infusion.
Study Observations
Disease Evaluation: Baseline, day 100 post stem cell infusion and
every 3 months afterwards for lymphoma and multiple myeloma
patients up to a year. All other patients will have disease
evaluation at baseline, day 30, day 100, and one year post stem cell
infusion.
Serious Adverse Events: From first dose of study drug until 100
days after stem cell infusion. Severe adverse events defined as >
grade 3 toxicity by Bearman criteria, > grade 3 acute GvHD, death
or readmission due to any cause within day 100 post hematopoietic
stem cell infusion will be reported to Clinical Research Services.
Hematology: Baseline and daily during hospitalization for
transplant. Weekly after discharge until day 100 after hematopoietic
stem cell infusion. Important hematologic recovery endpoints:
The first of 3 consecutive days of absolute neutrophil count (ANC)
>0.5X109/L;
Platelets >20 xl09/L after 7 consecutive days with no platelet
transfusions;
Day of last platelet transfusion.
Serum chemistry: Baseline and daily during hospitalization for
transplant. Weekly after discharge until day 100 after stem cell
infusion.
Performance Status: Baseline and daily during hospitalization for
transplant. Weekly after discharge until day 100 after stem cell
infusion.
Physical examination includine neuroloeical examination, vital
sitms. and weieht: Baseline and daily during hospitalization for
transplant. Weekly after discharge until day 100 after stem cell
infusion.
Statistical Considerations
Samnle size determination: Since the melnhalan dose has been
increased to 75 milliprams/meter2 from nrevious dose of 50
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Roswell Park Cancer Institute Study Number: 1177110
mi 11 iprams/meter^. the nrimarv obiective is to evaluate dav 100
TRM to ensure this remmen remains safe without excessive
toxicity. The samnle size is determined based on the orimarv
obiective: assess the day 100 TRM rate of the study treatment as
compared to historical controls. The day 100 TRM for the historical
fludarabine/cyclophosphamide (FluCy) is 10% but it has a high day
100 rate of disease progression at 20%. The day 100 TRM for
fludarabine/melphalan 140 mg/m2 (FluMel) is 16% and the day 100
disease progression is 9%. The day 100 TRM from our pilot
FluMelTBI trial with 50 mg/m2 melphalan (protocol No. 1-118807)
is 11% with a day 100 disease progression rate of 11%. This
protocol increases the melphalan dose from 50 mg/m to 75 mg/m
with the goal of providing better disease control. We will study
whether or not this results a TRM rate betweenl 0% and 20%. The
sample size calculation is based on testing the hypotheses
concerning the proportion of the population who experience a TRM
at 100 days:
H0:p> 20%,
H0:p< 20%.
This two-stage design requires a potential total of 81 patients in
order to achieve approximately 80% power to detect differences of
10 percentage points (20% versus 10%).
Survival: The estimated distributions of overall and progression
free survival will be obtained using the product-limit based Kaplan-
Meier method. The Kaplan-Meier methodology will allow for
incorporation of the censored observations thereby resulting in a
more efficient estimate of the true distribution than if this
information was not used. Estimates of quantities such as median
duration will be obtained.
Duration of Treatment
Duration of Study
Duration of treatment: 5 days
Duration of study: 5 years
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Roswell Park Cancer Institute Study Number: 1177110
ROSWELL
PARK
CANCER INSTITUTE
Patient Name:    
Medical Record No.:        
Study Protocol Title: A PHASE II TRIAL OF REDUCED INTENSITY ALLOGENEIC
STEM CELL TRANSPLANTATION WITH FLUDARABINE, MELPHALAN AND LOW
DOSE TOTAL BODY IRRADIATION
INCLUSION CRITERIA
All answers must be "YES or "N/A" for patient enrollment
DATE
Y
N
N/A
1. The patient must have a diagnosis of one of the
following Cone must be yes"):
Bone marrow failure disorders:
Acquired bone marrow failure disorders include
aplastic anemia, PNH:
SAA must have failed at least one cycle of standard
immunosuppressive therapy with calcineurin inhibitor
plus anti-thymocyte globulin (ATG) if a fully-matched
donor is not available.
PNH should not be eligible for a myeloablative HSCT.
Hereditary bone marrow failure disorders include
Diamond-Blackfan Anemia, Shwachman-Diamond
Syndrome, Kostmann Syndrome, congenital
Amegakaryocytic Thrombocytopenia.
Other non-malignant hematologic or immunologic
disorders that require transplantation:
Quantitative or qualitative congenital platelet
disorders (including but not limited to congenital
amegakaryocytopenia, absent-radii syndrome,
Glanzmann's thrombasthenia)
Quantitative or qualitative congenital neutrophil
disorders (including but not limited to chronic
granulomatous disease, congenital neutropenia)
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Roswell Park Cancer Institute Study Number: 1177110
u
Congenital primary immunodeficiencies (including
but not limited to Severe Combined Immunodeficiency
Syndrome, Wiskott-Aldrich syndrome, CD40 ligand
deficiency, T-cell deficiencies)
n
Acute Leukemias:
AML - antecedent myelodysplastic syndrome, secondary
AML, high risk cytogenetic abnormalities or normal
cytogenetics with high-risk molecular mutations
(including but not limiting to Flt3-ITD mutation).
ALL
Chronic Myelocytic Leukemia:
Chronic phase (intolerant or unresponsive to imatinab
and/or tyrosine kinase inhibitors)
Second chronic phase or accelerated phase who are
ineligible for conventional myeloablative transplantation
Myeloproliferative and Myelodysplastic Syndromes:
Myelofibrosis (with/without splenectomy) with intermediate
to high risk features
n
Advanced Polycythemia Vera not responding to therapy
MDS with an EPSS score of INT-2 or higher
MDS with lower IPSS scores Int-1 or less with severe clinical
features; neutropenia, thrombocytopenia, high risk
chromosome abnormalities (monosomy 7)
Secondary MDS with any IPSS score
Chronic myelomonocytic leukemia
n
LvmohoDroliferative disease:
CLL, low-grade NHL (recurrent or persistent) cytotoxic
therapy refractory or with less than 6 months duration of
CR between courses of conventional therapy.
MM progressive disease after auto BMT, tandem alio after
prior auto
Waldenstrom's macroglobulinemia (failed one standard
regimen).
T or B Cell lymphoma with poor risk features
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Roswell Park Cancer Institute Study Number: 1177110
Hodgkin Disease:
Received and failed frontline therapy
Failed or not eligible for autologous transplantation
2. Histocompatible donor identified: (Syngeneic donors
are not eligible)
Related donor/recipient pairs: must be matched 6 of 6 or
5 of 6 HLA antigens (A, B, DRB1)
Unrelated donor/recipient pairs: a single antigen
mismatch at HLA A, B, or C, with or without additional
allele level mismatch. Must be at least antigen level
matched at DRB1.
PBSC minimum cell dose is 2 x 10A6 CD34+ cells/kg;
marrow 1 x 10A8 nucleated cells/kg
3. Age > 4 and <75 years for blood and bone marrow
transplants.
4. No serious uncontrolled psychiatric illness.
u
u
5. No concomitant active malignancy that would be
expected to require chemotherapy within 3 years of
transplant (other than non-melanoma skin cancer).
6. Non-pregnant and non-nursing woman. (Women or men
with reproductive potential should agree to use an
effective means of birth control).
u
7. Patients who have failed a prior autologous or allogeneic
transplant are eligible. However, at least 90 days must
have elapsed between the start of this reduced intensity
conditioning regimen and the last transplant if patient
had a prior autologous or myeloablative allogeneic BMT.
8. At least 2 weeks since prior chemotherapy, radiation
treatment and/or surgery.
n
9. Informed consent.
Investigator Signature:
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Roswell Park Cancer Institute Study Number: 1177110
ROSWELL
PARK
CANCER INSTITUTE
Patient Name:
Medical Record No.:       
Study Protocol Title: A PHASE II TRIAL OF REDUCED INTENSITY ALLOGENEIC
STEM CELL TRANSPLANTATION WITH FLUDARABINE, MELPHALAN AND LOW
DOSE TOTAL BODY IRRADIATION
EXCLUSION CRITERIA
N
N/A
All answers must be "NO" or "N/A" for patient enrollment
DATE
1. Uncontrolled CNS disease (for hematologic
malignancies).
2. Kamofsky (adult) or Lansky (for <16 years)
performance status < 50%.
3. Diffusing Capacity of the Lung for Carbon Monoxide
(DLCO) < 40% predicted, corrected for hemoglobin
and/or alveolar ventilation.   
4. Cardiac: left ventricular ejection fraction < 40%.
5. Bilirubin, liver alkaline phosphatase, SCOT or SGPT
> 3 x upper limit of normal.
6. Child's class B and C liver failure (see appendix no.
VII).
7. Calculated creatinine clearance < 40 cc/min by the
modified Cockroft-Gault formula for adults or the
Schwartz formula for pediatrics (see appendix no.
VII).
Patients who have received maximally allowed doses
(given in 2 Gy fractionations, or equivalent) of
previous radiation therapy to various organs as
follows:
Adult1
Pediatric (< 18 yrs)
Mediastinum
40
21
Heart*
36
26
Whole lung (s)
12
10
Small bowel
46
40
Kidneys
12
10
Whole liver
20
20
Spinal Cord1
36
36
Whole Brain
30
30
Abbreviations and Footnotes:' Dose in Grays (Gy); ''any volume
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Roswell Park Cancer Institute Study Number: 1177110
Patients who previously have received a higher
than allowed dose of radiation to a small lung, liver
and brain volume, will be evaluated by the
radiation oncologist to determine if the patient is
eligible for study.
9. Uncontrolled diabetes mellitus, cardiovascular disease,
active serious infection or other condition which, in
the opinion of treating physician, would make this
protocol unreasonably hazardous for the patient.
n
11
10. HIV positive.
u
11. Patients who in the opinion of the treating physician
are unlikely to comply with the restrictions of
allogeneic stem cell transplantation based on formal
psychosocial screening.
u
u
12. Females of childbearing potential with a positive
pregnancy test.
Study participant meets all entry criteria: ÿ Yes ÿ No
Investigator Signature:
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Roswell Park Cancer Institute Study Number: 1177110
Table of Contents
Page
A. GLOSSARY OF ABBREVIATIONS 13
B. SUMMARY 14
1. INTRODUCTION 16
2. INDICATIONS FOR RIT IN VARIOUS DISEASE STATES 24
3. OBJECTIVES 26
4. PATIENT ELIGIBILITY 26
5. DONOR ELIGIBILITY CRITERIA / STEM CELL SOURCE CRITERIA 30
6. TRIAL DESIGN, STATISTICAL CONSIDERATIONS 31
7. REGISTRATION AND DATA SUBMISSION 33
8. TREATMENT PLAN 35
9. POTENTIAL TOXICITIES & THEIR MANAGEMENT 39
10. DRUG FORMULATION, AVAILABILITY, AND PREPARATION 43
11. DATA & SAFETY MONITORING PLAN 50
12. REMOVAL OF PATIENTS FROM PROTOCOL & 52
ADVERSE EVENT REPORTING (AER)
13. CRITERIA FOR STUDY EVALUATION 53
14. GENDER AND MINORITY DECLARATION 54
15. CONFIDENTIALITY 54
16. REFERENCES 55
Appendices
I.
Bearman criteria for toxicity grading.
60
II.
WHO oral mucositis grading
62
III.
Criteria for acute graft-versus-host disease.
63
IV.
Clinical Grading of chronic graft-versus-host disease.
64
V.
Stem cell infusion.
65
VI.
Performance status: A. Kamofsky B. Lansky
66
VII.
Child-Pugh Classification of Liver Failure.
67
VIII.
Required tests and observations
68
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Roswell Park Cancer Institute Study Number: 1177110
GLOSSARY OF ABBREVIATIONS
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ATG
Anti-thymocyte globulin
BMT
Blood or Marrow Transplantation
BU
Busulfan
CLL
Chronic Lymphocytic Leukemia
CMV
Cytomegalovirus
CY
Cyclophosphamide
DLI
Donor Lymphocyte Infusion
DLT
Dose Limiting Toxicity
DVT
Deep Vein Thrombosis
EBV
Epstein Barr Virus
FK506
Tacrolimus
FLU
Fludarabine
G-CSF
Filgrastim
GM-CSF
Sargramostim
GvHD
Graft-versus- Host Disease
GvL
Graft-versus- Leukemia
GvM
Graft-versus- Malignancy
HSCT
Hematopoietic Stem Cell Transplantation
MDS
Myelodysplastic Syndrome
MM
Multiple Myeloma
MMF
Mycophenolate
MTD
Maximum Tolerated Dose
MUD
Matched Unrelated Donor
NHL
Non Hodgkin Lymphoma
NRM
Non Relapse Mortality
PBSC
Peripheral Blood Stem Cell
PMN
Polymorphonuclear Cell
PNH
Paroxysmal Nocturnal Hemoglobinuria
RIT
Reduced Intensity Transplantation
RRT
Regimen Related Toxicity
SOP
Standard Operating Procedure
SOS
Sinusoidal Obstructive Syndrome
TRM
Transplant Related Mortality
VOD
Veno-occlusive Disease
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Roswell Park Cancer Institute Study Number: 1177110
PROTOCOL SUMMARY
Title: A PHASE II TRIAL OF REDUCED INTENSITY ALLOGENEIC STEM
CELL TRANSPLANTATION WITH FLUDARABINE, MELPHALAN AND
LOW DOSE TOTAL BODY IRRADIATION
Precis:
Reduced intensity conditioning during allogeneic hematopietic stem cell transplant
(HSCT) reduces transplant related mortality (TRM) by relying more on the graft-versus-
malignancy effect rather than the conditioning regimen to eradicate disease. Reduced
intensity conditioning regimens can provide a curative option for patients with
hematologic malignancies who might otherwise not be candidates for myeloablative
(intensive) transplantation because of age or poor performance status. Since the ability to
perform transplant safely is the primary measure of efficacy for reduced intensity
conditioning, TRM is the appropriate measure of efficacy of the conditioning regimen.
Reduced intensity transplantation (RIT) is also the standard of care for certain bone
marrow failure states. However, at minimal levels of conditioning intensity such as with
the fludarabine/cyclophosphamide (FluCy) or the Fludarabine/200 cGy Total Body
Irradiation (Flu/200cGyTBI) regimens, high rates of relapse have been noted,
particularly in the myeloid malignancies (AML/MDS). Further improvement in reduced
intensity transplantation technique could therefore be achieved by greater cytoreduction
(by moderately increasing conditioning intensity) or to hasten the development of GvL
(by reducing the time to complete donor lymphoid chimerism). In our initial pilot trial of
reduced intensity allogeneic stem cell transplantation (RIT), we explored a lower dose
melphalan of 50 mg/m2 in combination with fludarabine (40 mg/m /day x 4 days) and a
lower dose TBI (400 cGy) (FluMelTBI) (Protocol No. 1-118807). While the regimen
was safe (Day 100 TRM^l 1%), the disease progression rate at day 100 was at 11%. In
this trial, we propose to increase the melphalan dose to 75 mg/m2 in combination
with fludarabine (40 mg/m2/day x 4 days) and low dose TBI with the intention to
improve cytoreduction and hence improve the disease control rate, while preserving
the low rate of TRM. Therefore, TRM will remain the primary objective and day 100
response rate, PFS at one year, engraftment rate, and GvHD incidence are the secondary
objectives.
Objectives:
Primary: To determine the TRM of this RIT combination in a patient population who
would be at risk for excessive TRM during a full myeloablative allogeneic transplant.
Secondary: To evaluate clinical response, PFS at one year, engraftment rate, and GvHD
incidence with our RIT regimen across a variety of hematological conditions. Correlative
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Roswell Park Cancer Institute Study Number: 1177110
studies will include chimerism analysis by molecular analysis and evaluation of immune
reconstitution by CMV dextramer analysis using flow cytometry.
Rationale For Regimen Dose Selection:
Fludarabine, a purine nucleoside analog is a potent immunosuppressant that will help
prevent donor cell rejection by the recipient. Doses range from 120-200 mg/m over 4 or
5 days and this protocol will utilize 40 mg/m2/ per day x 4 days.
Melphalan is an alkylating agent and doses above 140 mg/m2 are considered
myeloablative. In our initial pilot trial of reduced intensity allogeneic stem cell
transplantation, we evaluated a lower dose of 50 mg/m2 in combination with fludarabine
(40 mg/m2/day x 4 days) and lower dose TBI (400 cGy) (Protocol No. 1-118807). While
the regimen was safe (The day 100 TRM is 11%), the day 100 disease progression rate is
11%. In this trial, we propose to increase the melphalan dose to 75 mg/m x 1 dose in
combination with fludarabine (40 mg/m2/day x 4 days) and lower dose TBI (400 cGy) (2
doses over 1 day) with the intention to improve cytoreduction and improve disease
control while preserving the low rate of TRM.
Total Body Irradiation (TBI) is considered myeloablative above 500 to 600 centiGray
(cGy). There is extensive experience with lower dose TBI with fludarabine in
nonmyelobalative conditioning, usually at 200 cGy. The TBI dose in this study will be
400 cGy administered in 2 doses of 200 cGy. The conditioning intensity, even with 400
cGy TBI, is less than half that of a standard myeloablative Mel 140 mg/m2/1200 cGy
TBI regimen. We therefore consider the dosing range of our regimen to lie within the
parameters that define "reduced intensity" and to be a regimen that will not generate
excess TRM.
Trial Design:
A total of up to 81 evaluable patients will be accrued. The study design will be a
Kepner-Chang Type 11 Phase II design that proceeds in two stages and stops early only
for futility. At the end of the first stage of accrual (41 evaluable patients), data will be
reviewed to decide if the study should be terminated due to unacceptable toxicity.
Schedule:
Fludarabine 40 mg/m2/day on days -5 to -2 (4 total doses)
Melphalan 75 mg/m2 on day -2 (1 total dose)
TBI 400 cGy (two fractions of 200 cGy each) on day -1
Hematopoietic stem cell infusion on day 0
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OUTCOMES
1. TRM in the first 100 days.
2. Engraftment rate.
3. Evaluation of clinical response, one year PFS, GvHD incidence, chimerism analysis,
and immune reconstitution.
ELIGIBILITY, SAFETY, EFFICACY, STATISTICS
Please see the relevant sections in the body of the protocol.
1. INTRODUCTION
Early allogeneic Hematopoietic Stem Cell Transplant (HSCT), beginning in the late
1960s, utilized a high-dose pretransplant preparative (or conditioning) regimen to deliver
myeloablative anti-leukemic treatment. The fully myeloablative cyclophosphamide plus
total body irradiation (TBI) regimens pioneered by Thomas, et al resulted in donor cell
engraftment but still resulted in small level of relapse.1 Although increasing the dose of
conditioning intensity reduced relapse rates, overall survival was not improved because
of higher non relapse mortality or treatment related mortality (TRM).2 Regimen related
toxicities (RRT) limited the application of conventional allogeneic HSCT to patients less
than 50-60 years of age, thereby excluding the majority of patients with transplant
appropriate diseases. By the 1990s several lines of evidence suggested that allogeneic
HSCT had a potentially curative graft-versus-leukemia (GvL) effect in addition to the
anti-leukemic action of the myeloablative conditioning regimen. Leukemic relapse was
higher in patients who do not develop acute or chronic graft versus host disease, " who
undergo syngeneic (identical twin) transplant6"8 and who have T-cell depleted
allotransplants 3,9 due to lack of a GvL effect. Definitive evidence supporting the
existence of the GvL effect is the observation that certain patients who relapse after
allogeneic transplantation can be re-induced into complete remission by infusing
additional donor lymphocytes which generate a GvL effect and eradicate the relapsed
disease.10"15 By the late 1990s, growing confidence in the GvL effect led to the design of
several less intense or reduced intensity conditioning regimens designed not to
completely eradicate the malignancy but more to provide sufficient immunosuppression
to permit donor engraftment, particularly the lymphoid compartment. This strategy
reduces immediate RRT with preservation of the GvL effect.
RIT regimens are characterized by: 1) Reversible myelosuppression and autologous
hematopoietic recovery without allogeneic stem cell support (usually within 28 days). 2)
Mixed chimerism in a proportion of patients early after transplant. 3) Low rates of non-
hematologic toxicity. We now have over a decade of data pertaining to reduced
intensity conditioning regimens and over 10,000 reduced intensity transplants have been
reported worldwide.
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A spectrum of RIT regimens exist with varying immunoabiative and myeloablative
potential. The allogeneic conditioning regimen can be reduced in intensity yet still ^
achieve lymphoid and myeloid engraftment. Initially, up to 17% of patients conditioned
with 200 cGy low-dose TBI alone rejected the transplant,18 but the incidence was
decreased to < 3% with the addition of fludarabine (Flu).19 Rejection rates for Flu-based
conditioning regimens are <5% suggesting that Flu (120-200 mg/m ) can play a critical
role in the establishment of engraftment in RIC transplantation. Flu, as the
immunosuppressive component of the conditioning, has been successfully combined
with variety of other agents (TBI or alkylating agents) to create regimens of different
intensities. Of the alkylating agents, cyclophosphamide, busulfan and melphalan have
been frequently used. Cyclophosphamide is the most immunosuppressive; whereas
busulfan and melphalan provide greater degrees of cytoreduction. FluCy is extremely
immunoablative but not very stem cell toxic. Using the standard FluCy regimen, Childs
et al showed that donor T-cell engraftment precedes myeloid engraftment and that GvHD
and GvL effects only occurred after full donor T-cell chimerism.20 In contrast, the
Seattle group, using low-dose TBI regimens reported the early donor myeloid
engraftment, followed later by T-cell engraftment, demonstrating that the regimen was
more myelosuppressive than immunosuppressive. ' '
RIT is generally used when conventional myeloablative conditioning would not be
tolerated (due to age or comorbidities) or when conventional myeloablative conditioning
is not required (bone marrow failure states, indolent malignancies). The primary
measure of efficacy of RIT is the ability to allow safe transplantation.
Consequently, a TRM <20% is conventionally considered an appropriate measure
of efficacy of reduced intensity conditioning regimens.
RIT is dramatically safer in patients who are ineligible for standard myeloablative
conditioning regimen because of advanced age or co-morbid illness. The Charlson
Comorbidity Index (CCI) has been used to evaluate outcomes in myeloablative and RIT
and has proven useful in predicting TRM and overall survival in related and unrelated^
transplants in a group of patients who are increasingly older and heavily pretreated.
However the CCI lacks sensitivity; only 35% of RIT patients had co-morbidities
identifiable by the CCI and 12% for myeloablative transplants. A recent refinement has
been the validated HCT-specific comorbidity index (HCT-CI) which is more
discriminant than the CCI at low scores.25 Stratifying by HCT-CI allows improved
prognostication of TRM. Age and disease stage are independent of the HCT-CI. Twenty
eight percent of patients were found to have a pre-transplant HCT-CI of 3 or 4 and were
found to have a 2-year TRM of 40-43%; in contrast the remaining 72% of patients had a
pretransplant HCT-CI of 0 to 2 and were found to have a 2-year TRM between 9-27%.
First generation RIT regimens (FluCy, Flu/ 200cGyTBI and Flu/Bu) have proven to be
reliable in donor engraftment, and in reducing TRM. Slow growing malignancies and
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nonmalignant conditions generally respond favorably to the first generation RIC
regimens. However, we and others have experienced high rates of progression and
relapse in the myeloid malignancies (AML/CML/MDS).26 29 These increased rates in
progression and relapse can be attributed either to inadequate cytoreduction (such as with
FluCy) or slow achievement of complete donor lymphoid chimerism, a prerequisite for
GvL (such as FIu/200cGyTBI, the Seattle regimen). Consequently, further improvement
in RIT requires greater cytoreduction (without increasing toxicity) to control the
underlying disease until GvL is exerted and/or to hasten the onset of GvL by encouraging
the development of rapid donor lymphoid chimerism.30 Newer generation RIT regimens
are being developed by adding myelosuppressive agents such as busulfan or melphalan
to Flu/200cGyTBI for greater cytoreduction. The Flu/Bu/TBI conditioning regimen is
reported to be safe with 25% day 180 TRM and 50% 1 year overall survival rate. The
incidence of relapse at 3 years is still high at 25% with a low 25% 3 year progression free
survival (PFS).31,32 In addition, post-transplant lung toxicity is a concern when
combining busulfan and TBI due to the overlapping lung toxicity profile. Melphalan is
the alternative myeloablative chemotherapy that can be combined with Flu/TBI to
improve cytoreduction. The overlapping toxicities that fludarabine, melphalan, and TBI
have are immunosuppression and myelosuppression which are both desired in HSCT.
To date, there is no published data using FluMelTBI RIT conditioning regimen.
We are currently completing a pilot RIT trial (1 118807) using the novel combination of
fludarabine, low dose melphalan (50 mg/m2), and low dose TBI (400 cGy). In this novel
regimen, we intensified the Flu/200cGyTBI regimen because of high relapse rate and
added melphalan and a higher dose of TBI for improved disease control.
Fludarabine, a purine nucleoside analog is an important component of reduced intensity
regimens because of its potent immunosuppressive effects at doses ranging from 120-200
mg/m2 over 4 or 5 days. Melphalan is an alkylating agent. Doses above 140 mg/m are
considered myeloablative. In our initial pilot trial of reduced intensity allopneic
stem cell transplantation, we examined a low dose melphalan of 50 mg/m in
combination with fludarabine (40 mg/m2/day x 4 days) and low dose TBI
(FluMelTBI) (Protocol No. 1-118807).
Forty six patients have been accrued on 1-118807. The study did not meet the early
stopping rules for the 3 planned interim analyses of safety. We compared the day
100 TRM, 1 year TRM, day 100 PFS and 1 year PFS of FluMelTBI to our historical
data with other RIT regimens: FluCy and FluMel (Table 1). The day 100 TRM
with FluMelTBI is low at 11% compared to our historical data with other RIT
regimens (see Table 1 and Figure 1A). The FluCy regimen has a day 100 TRM rate
of 10% which is lower than the 16% day 100 TRM rate seen with FluMel
(fludarabine, total dose 125 mg/m2 and melphalan total dose 140 mg/m2). The
FluMelTBI regimen has a lower one year TRM (22%) compared to the FluMel (one
year TRM=33%) and FluCy (one year TRM=33%) regimens (Figure IB). The
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median age of patients in 1-118807 FIu/Mel/TBI is 10 years older than patients
receiving FluMel on RP 98-15 (58 vs. 48 years old), indicating that FluMelTBI is
likely better tolerated than FluMel especially in older patients. Although the FluCy
day 100 TRM is low, the Day 100 PFS is lower at 66% compared to FluMel (74%)
and FluMelTBI (81%), indicating poor disease control with FluCy. The 1-year PFS
is similar for the FluMel and FluMelTBI regimens (52 and 49%, respectively), both
of which are higher than FluCy (27%) (see Table 1 and Figure 2).
Regimen
Day 100 TRM
% (95% CD
1 year TRM
% (95% CI)
Day 100 PFS
% (95% CI)
1 year PFS
% (95% CI)
FluCy
10(1-19)
33 (17-49)
66 (51-81)
27(13-41)
FluMel
16(11-21)
33 (26-40)
74 (68-80)
52 (45-59)
FluMelTBI
11 (1-21)
22 (8-36)
81 (69-93)
49 (32-66)
Table 1. Comparison of day 100 TRM, 1 year TRM, day 100 PFS and 1 year PFS for
patients treated with 3 different reduced intensity regimens: FluCy (RP01-05); FluMel
(RP98-15); FluMelTBI (1-118807).
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Transplant-Related Mortality
BMTRegimen
—nnuCy
- •"•FfuMd
-nFMstelT®
H- FMCy-censored
-4- HuMetcensored
-H FftAtelTBI-censored
Days post BMT
Figure 1A: Cumulative incidence of TRM until day 100 for patients treated with 3
different reduced intensity regimens: FluCy (RP01-05); FluMel (RP98-15); FIuMelTBI
(1 118807).
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Transplant-Related Mortality
BMTRegimen
-npfciCy
- .'-nuMd
-H FluCy-certsofed
-+- Flufetel-censored
FtuMelTH-censored
180
Days postBMT
Figure IB: Cumulative incidence of TRM until 1 year for patients treated with 3 different
reduced intensity regimens: FluCy (RP01-05); FluMel (RP98-15); FIuMelTBI (X
118807).
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Progression-Free Survival
BMTRegimen
—n RuCy
- '"•FluMel
•JTlFluMelTBi
• FluCy-censored
FluMel-censored
Hh- FluMelTBI-censored
Days post BMT
Figure 2: Progression free survival (PFS) at one year for patients treated with 3 different
reduced intensity regimens: FluCy (RP01-05); FluMel (RP98-15); FluMelTBI (I
118807).
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Based on these results, FIuMel/TBI has an acceptable TRM rate, but to improve
disease control, this new phase II trial increases the melphalan dose from 50 mg/m
to 75 mg/m2 with the intention to improve the cytoreductive effect and decrease the
risk of disease relapse. The role of fludarabine is immunoablative, melphalan is
cytoreductive while the TBI is expected to be both immunoablative as well as
cytoreductive. Melphalan is dosed in a manner to obtain synergy with fludarabine.
This study will build on our previous experience on Clinical Trial 118807 which utilized
a lower dose of melphalan.
In the pilot FluMelTBI protocol (1 118807), the percentage of patients who achieved
complete donor lymphoid chimerism on day 30 and day 100 was 83% and 90%,
respectively (Table 2). We expect to improve the time to development of complete
donor lymphoid chimerism with the increased melphalan dose.
Patients
Day 30 Complete
Lymphoid Chimerism
(percent)
Day 30 Complete
Myeloid (percent)
Day 100 Complete
Lymphoid Chimerism
(percent)
Myeloid Day
100 (percent)
37*
31 of 37 (84)
36 of 37 (97)
28 of 31 (90)
29 of 31 (94)
Table 2. Peripheral Blood Lymphoid and Myeloid Chimerism Testing as of May 12
2011. Lymphoid and myeloid chimerism testing was performed on peripheral blood.
Peripheral white blood cells were separated by CD3 (T cell, lymphoid) and CD33
(myeloid) isolation. There are 46 patients on study to date. Seven patients were alive at
day 30 and did not have chimerism done. One patient died before day 30, thus 37
patients have day 30 chimerism testing results. The level of sensitivity is 5%. Ninety-
five percent and higher is considered complete chimerism. Most patients who did not
have chimerism performed had serious medical problems and the chimerism testing was
delayed. For Day 100 chimerism testing, 8 patients had died, 5 have not reached day 100
and 2 have not yet been tested but are beyond day 100. A total of 31 patients had day
100 chimerism testing results. We consider this engraftment rate to be excellent for a
reduced intensity regimen.
Low dose TBI- TBI will be administered at 400 cGy (two fractions of 200 cGy). TBI
doses ranging between 200 and 500 cGy are well tolerated and nonmyeloablative.
Fractionation enables tissue recovery and reduces toxicity.
In combination, the dose intensity of the study regimen (measured in terms of the
cumulative cytotoxic potential of the Mel and TBI components) is still less than half that
of the standard, fully ablative Mel 140/TBI 1200 cGy regimen.35'36 We consider our
study regimen to be safe and consider it a reduced intensity conditioning regimen.
Fludarabine, melphalan and TBI are well-characterized agents with a known safety
profile and we have experience using this combination at a lower dose of melphalan (50
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mg/m2). Potential overlapping "toxicities" are immunosuppression and
myelosuppression, both of which are desirable in an allogeneic transplant. There is a
known risk of mild mucositis from the combination of melphalan and TBI, both of which
continue to be dosed at half of the standard myeloablative dose. The mucositis in I-
118807 has been very low.
2. INDICATIONS FOR RIT IN VARIOUS DISEASE STATES
RIT now has an established role in therapeutic strategies for acute and chronic
leukemias, bone marrow failure states (aplastic anemia, paroxysmal nocturnal
hemoglobinuria, myelodysplastic syndromes), lymphomas, myeloma, second transplant
and immunodeficiencies.
2.1. Bone Marrow Failure States and other non-malignant hematologic or immunologic
disorders requiring transplantation
These are preferentially treated with RIT rather than conventional myeloablative HSCT.
Primary allogeneic HSCT is appropriate for selected patients with severe aplastic
anemia, PNH, and related marrow failure disorders, certain congenital platelet or
neutrophil disorders, congenital immunodeficiencies.37"43,83 Patients with chromosomal
breakage syndromes (such as Fanconi Anemia) or Dyskeratosis Congenita can tolerate
only very low doses of radiation or chemotherapy due to poor DNA repair capacity.
These patients will be excluded from this study.
2.2. AML
Less than 20% of adults > 60 years with AML in first complete remission (CR1) will
achieve a 3-year DFS with conventional chemotherapy-based consolidation.44 While
conventional risk factors like cytogenetics and antecedent hematological disorder plays a
role, age does appear to be an independent variable.45^7 Patients over the age of 60 to 65
and those with poor functional status have unacceptable TRM with myeloablative
transplant. Reduced intensity conditioning offers an opportunity to achieve a cure in a
subset of these patients with outcomes comparable to standard myeloablative allogeneic
HSCT.48'49
2.3. MDS
MDS is incurable except by alloHSCT. The risk-benefit ratio favors alloHSCT for
patients as soon as they progress to more advanced disease (Int-2 or higher IPSS score).
It is estimated that only about 5% of MDS patients are eligible to receive myeloablative
alloHSCT because of age and other exclusions. RIT may be able to reduce the TRM in
this group of patients and allow for wider application.
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2.4. MPDs
The only cure for a myeloproliferative disorder is an allogeneic HSCT, which needs to be
balanced against the TRM associated with conventional myeloablative HSCT. RIT may
be able to reduce the TRM in this group of patients.51"53
2.5. NHL
Reduced intensity allogeneic transplantation has a definite role in the treatment of
defined subgroups of patients with high-risk NHL with or without a prior autologous
transplant.5 Although aggressive relapse of NHL is not seen frequently as with myeloid
malignancies, nevertheless, there is a substantial incidence of relapse in NHL with
reduced intensity transplantation.55,56 This supports efforts to improve on the current
Flu/Cy protocol by an increase in cyto-reductive capability.
2.6. Hodgkin disease
Approximately 50% of patients with relapsed and progressive disease after autologous
HSCT can be rescued by a RIT.57
2.7. Multiple Myeloma
Durable remissions for multiple myeloma can occur after allogeneic HSCT. Previous
experience with standard myeloablative allogeneic HSCT was disappointing due to a
high early TRM despite achieving durable remissions for survivors. 8,59 Reduced
intensity transplantation from suitable related and unrelated donors may permit the
development of a curative graft-versus-myeloma effect without high TRM.60"62 The
usual approach is to utilize RIT for selected younger patients with well-matched donors
either right after auto transplant ("auto-allo") or after relapse from an auto-transplant. A
phase III trial has demonstrated improved overall and disease-free survivals in newly
diagnosed myeloma for recipients of a hematopoietic stem-cell autograft followed by a
stem-cell allograft from an HLA-identical sibling versus a standard tandem autologous
A3
transplant.
2.8. Non-hematologic Malignancy
Patients with solid tumors will be excluded from the current protocol.
2.9. Second Allogeneic Transplants
Second allogeneic transplantation is often offered for relapse after a first allogeneic or
autologous transplant and for graft failure. Higher conditioning intensities when used in
a second transplant are associated with high rate of RRT and TRM. Therefore, a RIT
regimen is an appropriate treatment option for these patients.
2.10. Matched Unrelated Donor (MUD) Transplants
TRM in well matched unrelated donor transplants now approximates that of related
transplants because of recent advances in supportive care including the use of
fludarabine-based conditioning regimens, tacrolimus-based GvHD prophylaxis, use of
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peripheral blood stem cells and high-resoiution HLA typing. In one retrospective study
of reduced intensity conditioning, overall survival for MUD transplants approximated
that of sibling donor transplants.64
3. OBJECTIVES:
3.1. Primary objectives:
To determine the TRM of this RIT combination^ fludarabine, melphalan and total body
irradiation in a patient population usually not eligible for a full myeloablative allogeneic
HSCT.
3.2. Secondary objectives:
To evaluate clinical response, PFS at one year, engraftment rate, and GvHD incidence
with the proposed RIT regimen across a variety of hematological conditions. Correlative
studies will include chimerism analysis by molecular analysis and evaluation of immune
reconstitution by CMV dextramer analysis using flow cytometry.
4. PATIENT ELIGIBILITY CRITERIA:
4.1. INCLUSION CRITERIA
1. Diagnosis of a histology documented hematologic malignancy or marrow disorder.
2. Diseases covered:
a. Bone marrow failure disorders:
i. Acquired bone marrow failure disorders include aplastic anemia, PNH:
1. Primary allogeneic HSCT is appropriate for selected patients with
severe aplastic anemia.37,38 However, patients with aplastic
anemia must have failed at least one cycle of standard
immunosuppressive therapy with calcineurin inhibitor plus anti-
thymocyte globulin (ATG) if a fully-matched donor is not
available.
2. Patients with PNH should not be eligible for a myeloablative
HSCT.
ii. Hereditary bone marrow failure disorders include Diamond-Blackfan
Anemia, Shwachman-Diamond Syndrome, Kostmann Syndrome,
congenital Amegakaryocytic Thrombocytopenia. Fanconi Anemia or
related chromosomal breakage syndrome. Dyskeratosis Congenita are
excluded from this study due to their poor DNA repair capacity.
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1. Fanconi anemia or related chromosomal breakage syndrome:
Positive chromosome breakage analysis using diepoxybutane
(DEB) or mitomycin C if applicable.
2. Dyskeratosis Congenita: Diagnosis is supported by using either
TERC gene mutation in autosomal dominant Dyskeratosis
Congenita or X-Hnked DKC1 gene mutation.
Hi. Other non-malignant hematologic or immunologic disorders that require
transplantation
1. quantitative or qualitative congenital platelet disorders (including
but not limited to congenital amegakaryocytopenia, absent-radii
syndrome, Glanzmann's thrombasthenia)
2. quantitative or qualitative congenital neutrophil disorders
(including but not limited to chronic granulomatous disease,
congenital neutropenia)
3. congenital primary immunodeficiencies (including but not limited
to Severe Combined Immunodeficiency Syndrome, Wiskott-
Aldrich syndrome, CD40 ligand deficiency, T-cell deficiencies)
b. Acute Leukemias:
i. Resistant or recurrent disease after at least one standard combination
chemotherapy regime.65"70
OR
First remission patients at high risk of relapse.
i. AML - antecedent myelodysplastic syndrome, secondary AML, high
risk cytogenetic abnormalities or normal cytogenetics with high-risk
molecular mutations (e.g. Flt3-ITD mutation).71
ii. ALL72'73
c. Chronic Myeloid Leukemia (CMP:
i. Chronic phase (intolerant or unresponsive to imatinib and/or other
tyrosine kinase inhibitors), second chronic phase or accelerated phase
who are ineligible for conventional myeloablative transplantation.
d. Myeloproliferative and Mvelodvsplastic Syndromes:
i. Myelofibrosis (with/without splenectomy) with intermediate to high
risk features.
ii. Advanced Polycythemia Vera not responding to standard therapy.
iii. MDS with an IPSS score of Int-2 or higher
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iv. MDS with lower IPSS scores Int-1 or less with severe clinical features
such as severe neutropenia or thrombocytopenia or high risk
chromosome abnormalities such as monosomy 7.
v. Secondary MDS with any IPSS scores
vi. Chronic myelomonocytic leukemia.
e. Lvmphoproliferative disease:
i. CLL, low-grade NHL (recurrent or persistent) cytotoxic therapy
refractory or with less than 6 months duration of CR between courses
of conventional therapy.
ii. Multiple myeloma (progressive disease after autologous stem cell
transplant, tandem allogeneic transplant after prior autologous stem
cell transplant).
iii. Waldenstrom's macroglobulinemia (failed one standard regimen).
iv. T or B Cell lymphoma with poor risk features
54,55,74-76
f. Hodekin lymphoma:
i. Received and failed front-line therapy
ii. Failed or were not eligible for autologous transplantation
3. Donor eligibility criteria are outlined in section 5. Permissible HLA matching:
Related donors- single antigen mismatch at HLA A, B or DRB1; Unrelated donors- a
single antigen mismatch at HLA A, B, or C, +/- additional single allele level
mismatch at A, B, C or DRB1.
4. Stem cell source criteria are outlined in section 8.1. Minimum goal for PBSC dose is
2 x 106 CD34+ cells/kg of recipient weight; minimum goal for the marrow dose is 1 x
108 nucleated cells/kg of recipient weight.
5. Age > 4 and <75 years for blood and bone marrow transplants.
6. No serious uncontrolled psychiatric illness.
7. No concomitant active malignancy that would be expected to require chemotherapy
within 3 years of transplant (other than non-melanoma skin cancer).
8. Non-pregnant and non-nursing woman. (Women or men with reproductive potential
should agree to use an effective means of birth control).
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9. Patients who have failed a prior autologous or allogeneic transplant are eligible.
However, at least 90 days must have elapsed between the start of this reduced
intensity conditioning regimen and the last transplant if patient had a prior autologous
or myeloablative allogeneic BMT.
10. At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery.
11. Informed consent.
4.2. EXCLUSION CRITERIA
1. Uncontrolled CNS disease (for hematologic malignancies).
2. Kamofsky (adult) or Lansky (for <16 years) performance status < 50%.
3. Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) < 40% predicted,
corrected for hemoglobin and/or alveolar ventilation.
4. Cardiac: left ventricular ejection fraction < 40%.
5. Bilirubin, liver alkaline phosphatase, SCOT or SGPT > 3 x upper limit of normal.
6. Child's class B and C liver failure (see appendix no. VII).
7. Calculated creatinine clearance < 40 cc/min by the modified Cockroft-Gault formula
for adults or the Schwartz formula for pediatrics (see appendix no. VII).
8. Patients who have received maximally allowed doses (given in 2 Gy fractionations,
or equivalent) of previous radiation therapy to various organs as follows:
Adult1
Pediatric (< 18 yrs)1
Mediastinum
40
21
Heart2
36
26
Whole lung (s)
12
10
Small bowel
46
40
Kidneys
12
10
Whole liver
20
20
Spinal Cord1
36
36
Whole Brain
30
30
Abbreviations and Footnotes:1 Dose in Grays (Gy); ^any volume
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Patients who previously have received a higher than allowed dose of radiation to a
small lung, liver and brain volume, will be evaluated by the radiation oncologist to
determine if the patient is eligible for study.
9. Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or
other condition which, in the opinion of treating physician, would make this protocol
unreasonably hazardous for the patient.
10. HIV positive.
11. Patients who in the opinion of the treating physician are unlikely to comply with the
restrictions of allogeneic stem cell transplantation based on formal psychosocial
screening.
12. Females of childbearing potential with a positive pregnancy test.
5. DONOR ELIGIBILITY CRITERIA/ STEM CELL SOURCE CRITERIA
5.1. Compatibility at the four most informative HLA loci: A, B, C and DRB1 are important
for reducing the risk of GVHD and successful transplant outcomes. The A, B, C and
DRB1 loci comprise 8 possible alleles (a haplotype being inherited from each parent).
One additional locus, HLA-DQ, is also typed to ascertain haplotypes and assist in the
search for a compatible donor; however mismatching at DQ has not been shown to be
associated with adverse outcomes. High resolution molecular typing (at the allele level)
is now the standard of care for unrelated donor searches and allows greater refinement of
the search strategy.
5.2. Matched Related Donor: A single antigen mismatch at A, B, or the DR transplant from a
family member is associated with a higher risk of GVHD but similar overall survival
when compared to full identity at these 3 regions. Related donor/recipient pairs must be
matched at 5 of 6 HLA antigens (A, B, DRB1).
5.3. Unrelated Donor: When evaluating patients for unrelated donor transplant, the higher
degree of matching, the lower risk of GvHD. The A, B, C, DRB1 and DQB1 loci,
comprising 10 possible antigen (with alleles), will be typed for all unrelated transplants.
Given the higher risk of TRM in mismatched transplants, RIT is often the best way to
mitigate the risk. Data from the National Marrow Donor Program makes it possible to
estimate the risk of donor-recipient HLA mismatch at the allele or antigen level. The
higher risk from HLA-mismatching must be balanced against the clinical urgency and
the patient's risk by the transplant team. At this time, antigen level mismatches at DQB1
do not affect outcomes and will not be used for matching purposes for donor seclection.
Thus, the matching required will be at the HLA A, B, C and DRB1 (8 loci). For this
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protocol, a single antigen mismatch at HLA A, B, or C, with or without additional single
allele level mismatch may participate in this protocol for voluntary unrelated donors
(blood or marrow).
5.4. Donor must be healthy and have nonreactive test results for all infectious disease assays
as required by state and federal regulations. Donors who screen seropositive for hepatitis
and/or syphilis must be cleared by infectious disease consultation.
5.5. The donor must have no uncontrolled cardiopulmonary, renal, endocrine, hepatic or
psychiatric disease to render donation unsafe.
5.6. The donor (or parent if minor) must give informed consent for peripheral blood stem cell
collection or bone marrow collection.
5.7. Syngeneic donors are not eligible.
5.8 Donors who have poor peripheral venous access, may require central venous line
placement for stem cell apheresis.
6. TRIAL DESIGN AND STATISTICAL CONSIDERATIONS:
This trial is designed as an open label, non-randomized, single institution study. The primary
objective of this study is estimation of the true population TRM rate by day 100 for patients
undergoing RIT with co-morbidities or who are otherwise not eligible or unable to receive a
myeloablative allogeneic HSCT. In addition to the sample estimate of this probability, an exact
95% confidence interval will also be provided.
6.1. Descriptive analyses
Descriptive statistics such as frequencies and relative frequencies will be computed for all
categorical variables. Numeric variables will be summarized using simple descriptive statistics
such as the mean, standard deviation and range. A variety of graphical techniques will also be
used to display data, ex. histograms, boxplots, scatterplots, etc.
6.2. Accrual
The projected accrual is approximately 2-3 patients per month, and therefore recruitment is
expected to be complete by 4 years following the study starting point. Subjects will be followed
for at least 12 months after recruitment completion. The total study duration will be 5 years.
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6.3. Efficacy analysis
The primary objective of this one-arm Phase II trial is to assess the day 100 TRM rate of the
study treatment as compared to historical control. The day 100 TRM for the historical
fludarabine/cyclophosphamide (FluCy) is 10% but it has a high day 100 rate of disease
progression at 20%. The day 100 TRM for fludarabine/melphalan 140 mg/m2 (FluMel) is 16%
with 9% disease progression rate at day 100. The day 100 TRM from our pilot FluMefTBI trial
with 50 mg/m2 melphalan (protocol No. 1-118807) is 11%, however, the day 100 rate of disease
progression rate is still somewhat high at 11%. This protocol increases the melphalan dose from
50 mg/m2 to 75 mg/m2 to provide better disease control which may result in a higher TRM than
10% but less than 20%. The sample size calculation is based on testing the hypotheses
concerning the proportion of the population who experience a TRM at 100 days. Let p
represent the proportion of the evaluable population of interest who experience a TRM by day
100 after the beginning of treatment. A true rate of more than 20% is considered unacceptable.
A rate of less than 10% is considered promising and evidence of such will deem the treatment
worthy of further study. The null and alternative hypotheses corresponding to the design are
tf0:/7>20%,
Ha'.p< 20%.
A total of up to 81 evaluable patients will be accrued. The evaluable population is defined as
patients who meet eligibility requirements and are observed for TRM at day 100 after the start of
treatment. Patients who have disease progression before day 100 are considered non-evaluable
and will be excluded for TRM analysis. Non-evaluable patients will be replaced. The study
design will be a Kepner-Chang Type II Phase II (2004) design that proceeds in two stages and
stops early only for futility. At the end of the first stage of accrual (41 evaluable patients), data
will be reviewed to decide if the study should be terminated due to unacceptable toxicity.
Stage 1: If 8 or more of the first 41 evaluable patients experience a TRM at day 100, it will be
concluded that the therapy is not promising and the study will end. Otherwise, the study will
progress to the second stage. Depending on the current TRM rate at the time the last patient in
Stage 1 is enrolled, study enrollment may be halted until TRM status at 100 days is evaluated in
all 41 patients.
Stage 2: We will accrue 40 additional evaluable patients. If 10 or less of the total of 81
evaluable patients experience a TRM at day 100, it will be concluded that p is less than 20%
and that the therapy is worthy of further study; otherwise, it will be concluded that there is no
evidence to suggest that the therapy is associated with acceptable transplant related toxicity.
With this design, the probability is bounded above by 4.9% of falsely concluding that the true
TRM rate is less than 20% and 80.9% is the probability of correctly concluding acceptable
toxicity when the true TRM rate is 10%.
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6.4. Secondary analyses
The toxicity and overall clinical benefit rates will be computed with corresponding exact 95%
confidence intervals based on the methodology of Clopper and Pearson (1934). The estimated
distributions of overall and progression free survival will be obtained using the product-limit
based Kaplan-Meier method. The Kaplan-Meier methodology will allow for incorporation of
the censored observations thereby resulting is a more efficient estimate of the true distribution
than if this information was not used. Estimates of quantities such as median duration will be
obtained.
6.5. Sample size
The sample size calculation is based on testing the hypotheses concerning the proportion of the
population who experience a TRM at 100 days:
: /> > 20%,
Ha:p< 20%.
This two-stage design requires a potential total of 81 patients in order to achieve approximately
80% power to detect differences of 10 percentage points (20% versus 10%).
This protocol will be subject to oversight by the Roswell Park Data Safety Monitoring Board.
7. REGISTRATION AND DATA SUBMISSION
Please contact the Transplant Program Coordinator or Clinical Research Coordinator to
enroll patients on the study.
Informed consent: Patient must be aware of the nature of his/her disease and willingly
consent after being informed of the procedure to be followed, the experimental nature of
the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Human
protection committee approval of this protocol and of its consent form is required and
will have been obtained before this study open.
Histological review: Submission of appropriate tissue samples or outside histo¬
pathologic slides to confirm the underlying diagnosis. Remission/relapse status should
be confirmed within 30 days and no later than 60 days before transplant conditioning
starts.
Radiological review: All patients with lymphoma/multiple myeloma must have
appropriate radiographic workup prior to registration and must be submitted for review.
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Registration procedures: Please confirm eligibility criteria for patients (see Section 4)
and donors (see Section 5). Please complete the transplant registration worksheets for
patient and donor. When the patient is registered, a patient identification number will be
generated. Data pertaining to this protocol will be collected by the BMT research nurses,
data coordinators and/ or any other persons assigned by the BMT department head.
7.1 Registration and Data submission
7.1.1 Protocol Date Definitions:
On-Study
Date
Start
Treatment
Date
Off-Treatment
Date
Off-Study
Date
Date of pre¬
admission
clinic visit
after consent
signed.
Date
conditioning
regimen
started
Date infusion of stem cells is
complete (relevant for
patients who have more than
one infusion over 2 or more
days)
Date of first disease
progression post-transplant or
date of death due to any cause
or date patient failed to
engraft
To be completed within 4 weeks before registration. (See appendix VIII)
Record on the flow sheets:
Patient name
Patient identification number
Date of birth
Patient's gender
Disease type and stage
Treatment start date
Date of signed consent
Patient's race/ethnicity
7.1.2. Important hematologic recovery endpoints;
First of 3 consecutive days ANC >0.5x109/L
Platelets >20 xl09/L after 7 days with no platelet transfusions
Date of occurrence of severe toxicity (>grade 3) by Bearman criteria.
7.1.3. Important immunologic recovery endpoints:
Myeloid and lymphoid chimerism expressed as a percentage of donor cells at the
following time points (+/- 7 days): day 30, day 100.
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Immune reconstitution is evaluated at the following time points (+/- 7 days):
baseline, day 30, day 100 and 1 year by the BMT SOC immunophenotyping
panel and by analysis of CMV-specific immunity (CMV dextramer).
8. TREATMENT PLAN:
8.1. STEM CELL COLLECTION
Fresh or frozen peripheral blood stem ceils (PBSCs) may be utilized. Donors will
receive 10 micrograms/kilogram G-CSF daily subcutaneously, starting on transplant day
-5. The dose will be rounded to nearest vial size if possible (i.e. 300 micrograms or 480
micrograms). Mobilized peripheral blood stem cells will be collected by apheresis on
transplant day "-1" and again on day "0", to achieve a minimum target dose of 2 x 10
CD34+ cells/kilogram of recipient weight. Newer stem cell mobilizing agents (such as
plerixafor) may be substituted or added to G-CSF if they are FDA-approved. PBSCs
will be unmanipulated with the exception of red cell depletion. CD3+ and CD34+ cell
counts as fractions of the total nucleated cells (TNC) will be determined according to
established institutional flow cytometry protocols.
PBSCs or Bone Marrow harvest for stem cells are acceptable. The target and minimum
doses for bone marrow harvest will be 3 x 108 and 1 x 108 nucleated cells per kilogram
of patient body weight respectively. Bone marrow stem cells will be unmanipulated with
the exception of red cell depletion..
Donor lymphocyte collection: donor lymphocytes will not be routinely collected using
this protocol. When donor lymphocytes are required for clinical reasons , they will be
collected and administered on the RPCI donor lymphocyte protocol.
8.2. PREPARATIVE REGIMEN
Day -5
Day -4
Day -3
Day -2
Day -1
Day 0
Fludarabine (total 160
mg/m2)
40
40
40
40
Melphalan (75 mg/m)
75
TBI (400 cGy)
200+200
Stem cell infusion
X
8.2.2. Fludarabine Fludarabine 40 mg/m2 (actual body weight) is infused over 30 minutes on
days -5, -4, -3, and -2 (total dose 160 mg/ m2).
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8.2.3. Melphalan Melphalan 75 mg/m2 (actual body weight) is infused over 30 minutes
following fludarabine on day -2.
8.2.4. Total Body Irradiation (TBI):
Total Body Irradiation shall be delivered using a nominal photon beam energy of no less
than 4 MV. Dynamic or static fields may be used. However, the patient should be
entirely included within the dynamic or static treatment field. Lung shields are to be
applied in pairs (both AP & PA) with evenly weighted mid-plane dose from each field.
When necessary, lung shields can be combined with open (non-shield) fields during the
same fraction to achieve the required mid-plane and lung dose. Dose heterogeneity
resulting from lung transmission will be assessed using AAPM report number 17
[TG#29], "The physical aspects of total and half-body photon irradiation".
We shall deliver, per fraction of TBI, 200 cGy prescribed to mid-plane at the level of the
umbilicus or pelvis, whichever region is thicker. Tissue compensators or other devices
shall be used to optimize dose homogeneity within +/- 5 % of the prescribed dose. Dose
homogeneity will be assessed at a minimum of six mid plane points at a) head, at largest
diameter b) neck, at the level of thyroid notch, c) chest, at the xyphoid process, d)
umbilicus or pelvis, whichever is thicker, e) mid thigh, and f) mid-calf. Optional dose
points will be located at g) knee, h) ankle, and i) umbilicus or pelvis, whichever is
thinner. In addition, a set of lung shields, or an equivalent device, shall be used to
ensure that the lungs will receive within 90 to 100 % of the prescribed dose per fraction.
The dose rate at the prescription point shall be between 10 cGy and 15 cGy per minute.
Schedule- on day -1. Two fractions of 200 cGy will be given at least six hours apart.
8.2.5. Hydration regimens per clinicians' discretion.
8.2. Supportive medications: Antiemetics, antimicrobials, etc. will be used according to
BMT standard of care.
8.3. GvHD PROPHYLAXIS
GvHD prophylaxis will be tacrolimus-based (FK506 orTacro)78'79with micro-dose
methotrexate (MTX) and mycophenolate mofetil (MMF) as per the BMT SOP.
Cyclosporine may be substituted for tacrolimus in case of intolerance and dosed per
BMT SOP.
DAY
-1
0
+1
+2
+3
+4
+5
+6
FK506X
X
X
X
X
X
X
X
X
MMF*
X
X
X
X
X
X
X
X
MTX3
X
X
X
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8.3.1. tacrolimus (FK506): Starting dose will be 0.015 mg/kg (ideal body weight or actual if
less than ideal) PO every 12 hours or IV equivalent, from day -1. The tacrolimus dose
will be adjusted to target levels between 5-15 ng/ml. In patients who are unable to take
oral tacrolimus, the intravenous dose is generally 1/3 of the oral dose every 12 hours. In
the absence of GvHD or recurrent disease, tacrolimus will continue until day 60 (for
patients at high relapse risk) or until day 100 (low relapse risk) and then taper over 4 to 6
months. Relapse risk is defined in the BMT Program's SOP on GvHD prophylaxis.
8.3.2. 2Mycophenolate mofeti! (MMF)/(Cellcept®)80: The dose will be 1000 milligrams orally
every 8 hours or 1500 milligrams intravenously every 6 hours for adults. For pediatric
patients the dose will be 600 mg/m2 orally or IV every 8 hours (maximum dose is 1000
mg/dose). Determination of intravenous and oral doses were based on pharmacokinetic
levels and calculations to achieve total mycophenolic acid area under the plasma
concentration-versus-time curve (AUG) between 30 and 60 microgram/milliliter to
prevent graft rejection and graft versus host disease.81,84 We have measured
pharmacokinetic levels on the active drug and the inactive metabolite with Dr. G.
Fetterly (unpublished data). Thus, the intravenous dosing is higher based on measured
levels. The drug is inactivated by the liver and further dose escalation does not result in
higher active drug levels, only higher levels of the inactivated metabolite. The reason for
the lower oral dose is gastrointestinal intolerance at doses higher than 1000 mg per
mg/m2 every 8 hours. The MMF starts on day -1 and, in the absence of GvHD or
recurrent disease, will continue until day 60 and then stop without taper. MMF may be
withheld at the discretion of the attending physician for patients with cytopenias or other
toxicities that are thought to be related to the MMF. The clinical team should attempt to
restart this medication when it is thought to be clinically safe.
8.3.3. Methotrexate (MTX): 2.5 milligrams/m2 (micro dose) IV on days 1, 3 and 6 will be
given for GVHD prophylaxis.
8.4. SUPPORTIVE CARE RECOMMENDATIONS
Prior to initiating therapy, placement of a multi-lumen indwelling silastic catheter is
required, preferably a non-tunnel!ed 5 lumen catheter.
Patients will receive full supportive care, including transfusions of irradiated blood and
blood products, growth factors, antibiotics, anti-emetics, oral care, etc., when
appropriate. The reason(s) for treatment, dosage, and the dates of treatment should be
recorded on the flow sheets.
8.4.1. Mucosal evaluation and care: Mucositis is expected to be mild to moderate with a RIT
regimen. Stomatitis and esophagitis due to herpes virus may be confused with drug-
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induced mucositis and viral cultures should be obtained if clinically indicated. Patients
should receive acyclovir according to the RPCIBMT standard operating procedure
(SOP) for an allogeneic transplant patient.
8.4.2. Antifungal prophylaxis: Antifungal prophylaxis will follow the BMT SOP for allogeneic
transplant patients.
8.4.3. Pneumocystis Pneumonia (PCP) Prophylaxis: Anti-PCP prophylaxis should be given
according to the RPCI BMT standard operating procedure (SOP) for an allogeneic
transplant patient.
8.4.4. CMV Infections: Surveillance and treatment for CMV will follow RPCI BMT standard
operating procedure (SOP) for allogeneic transplant patients. Surveillance for CMV by
CMV antigenemia or PCR is required once weekly until day +100 and then PRN (as
needed). Patients with positive CMV antigenemia should receive induction and
maintenance treatment as per the RPCI BMT SOP. A CMV level of 1 or less may be
repeated on the next available weekday before initiating therapy and if negative, the
patient may be screened again in a week. Treatment dosing will be adjusted for
hematological and renal toxicity. CMV surveillance will start no later than day +21
unless patient has not engrafted.
8.4.5. For patients who are pancytopenic prior to transplant, antimicrobial screening
prophylaxis should continue through the transplant.
8.4.6. Anti-bacterial propylaxis: Patients will receive anti-bacterial prophylaxis during the
transplant period as per the RPCI BMT SOP.
8.4.6. Deep Venous Thrombosis (DVT) prophylaxis will follow the RPCI BMT SOP.
8.4.7. Sinusoidal occlusive syndrome, also known as veno-occlusive disease (VOD)
prophylaxis will follow the BMT SOP.
8.5. Allogeneic Stem Cell Reinfusion (Appendix V)
On Day 0 blood or marrow hematopoietic stem cells will be infused. The minimum
PBSC dose is 2 x 106 CD34+ cells/kg of recipient weight and the minimum marrow dose
is 1 x 108 nucleated cells/ kilogram of recipient weight.
8.6. Chimerism Analysis
Chimerism analysis is clinically useful and important for this study. Samples for
chimerism analysis will be obtained on all donor and recipient pairs prior to transplant.
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After transplant, serial samples of blood and marrow will be analyzed for chimerism
analysis as per the Molecular Diagnostic Laboratory SOP. Lineage specific (separate
lymphoid and myeloid) chimerism will be analyzed in blood at the following time points
(+/- 7 days): day 30, day 100 and then at unscheduled intervals until full donor
chimerism is attained. Unseparated chimerism may also be analyzed in bone marrow
(for leukemia and patients with other malignancies if bone marrow was involved
previously) whenever a bone marrow is performed. Peripheral blood will be collected in
2 green top tubes for separated chimerism and 1 milliliter of bone marrow aspirate will
be collected in 1 purple top tube for non-separated chimerism. Chimerism studies will
be performed by the RPCI Moleular Diagnostic lab under Dr. Petr Starostik's direction
Patients not converting to 100% donor T-cell chimerism by day + 180 and/or showing
signs of progression of disease after FK506 and MMF withdrawal and/or with refractory
viral infection, will be evaluated for DLL Patients who have active GvHD will not
receive DLL
8.7. Immune Reconstitution
Peripheral blood will be collected at baseline (prior to transplant), day 30, day 100 and
one year after transplant for evaluation of immune reconstitution (+/- 7 days). Immune
reconstitution will be measured by flow cytometry using markers for T cells (CD3, CD4,
CDS, yS, CD45RA, CD45RO, CD27, HLADr,CD31, CD25, CD127), B cells (CD19,
CD20, CD27, CD38, IgD), and NK cells (CD56, CD16), as well as CMV dextramers.
Flow cytometry will be performed by the flow cytometry lab under Dr. Paul Wallace's
direction.
9. POTENTIAL TOXICITIES AND THEIR MANAGEMENT
Patients will be managed in the inpatient and outpatient setting. Safety will be monitored on an
ongoing basis and discussed, graded and recorded in weekly outcome rounds.
9.1. Management of Graft Versus Host Disease (GvHD):
Approximately 80% of patients will exhibit some manifestation of GvHD. Severe acute
GvHD (grade II-III) may occur in up to 20% of patients with an overall mortality of 40-
80% due to GvHD and its complications. The risk of severe or fatal GvHD is increased
for older patients and for patients receiving stem cells from partially-matched donors. A
chronic form of GvHD is expected to occur in up to 40% of patients who survive beyond
3 months. Ten percent of patients may experience significant disability due to chronic
GvHD that can persist for months to years post-transplant. Standard measures for
prevention and treatment of GvHD will be followed.
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Patients with symptomatic grade 1 acute GvHD of the skin will be treated with topical
steroids. Grade II or greater acute GvHD will be treated with high dose
methylprednisolone 1-2 milligrams/kilogram daily for 10-14 days. The goal will be at
Img per kg at 10 days followed by slow tapering in responders to a maintenance dose of
up to 0.25 mg/kg/day, continued for at least 2 weeks from the disappearance of all
symptoms of GvHD. FK506/MMF will be maintained or increased during active
aGvHD. Refractory GvHD will be treated as per attending physician's discretion and/or
BMT SOP.
9.2. Regimen Related Toxicity (Bearman Criteria; WHO mucositis scale; APPENDICES I
and II).
9.2.1. Cardiac:
Patients with pre-existing cardiac disease are at significant risk for developing congestive
heart failure and arrhythmias. Studies to be obtained when clinically indicated include
EKG (to compare voltage to pretreatment EKG), radionuclide ventriculogram, and/or
echocardiography.
9.2.2. Renal:
Many of the agents used in this study can cause renal toxicity, which can be minimized
by vigorous hydration, avoidance of exposure of multiple nephrotoxic drugs where
clinically possible, appropriate drug monitoring and dose adjustment. Kidney damage is
usually reversible, but severe cases may require dialysis.
9.2.3. Pulmonary:
"Engraftment syndrome" consisting of hypoxia, pulmonary effusions and/or infiltrates
may be seen at the time of donor cell engraftment and should be treated promptly with
methylprednisolone 2 milligrams/kilogram daily followed by rapid taper.
Based on our previous protocol, the risk of fatal idiopathic interstitial pneumonitis is
estimated to be <10%. Patients with hypoxia or hypoxia with ambulation should be
evaluated as soon as possible by CT scan. Whenever possible, histologic confirmation
of the diagnosis should be attempted by bronchoalveolar lavage, transbronchial or open-
lung biopsy. This would help to exclude infectious causes (cytomegalovirus/fungal) or
confirm the diagnosis of hemorrhage.
9.2.4. Hepatic:
Moderate toxicity can occur. More severe, possibly fatal, liver toxicity rarely occur,
usually in the form of sinusoidal obstructive syndrome (SOS), also known as veno-
occlusive disease (VOD). With these study regimens the incidence of fatal liver toxicity
should be well less than 10%. Management of liver toxicity is with continued
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ursodeoxycholic acid and standard supportive and symptomatic measures. The clinical
team should avoid exposure of patients to other hepatotoxic agents.
9.2.5. CNS:
Fludarabine can cause weakness, paraesthesias or peripheral neuropathies, visual or
auditory impairment, and/or mental status changes such as confusion, agitation,
depression, or coma. Some antibiotics, which may be needed to treat infections during
the period of low white blood cell counts, can cause Vlllth cranial 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.
9.2.6. Mucositis:
Many patients will experience mild to moderate stomatitis and dysphagia. Adequate
pain relief often requires parental narcotics. Prevention requires aggressive oral hygiene
as per RPCIBMT SOPs.
9.2.7. Nausea/Vomiting:
Many patients will experience moderate to severe nausea and vomiting. All patients
should receive vigorous antiemetic treatment as per RPCI BMT SOP. At or after
neutrophil engraftment, the development of nausea and vomiting must prompt evaluation
for GvHD.
9.2.8. Diarrhea:
Most patients will experience moderate to severe diarrhea in the first three weeks, which
responds to standard symptomatic therapy. Appropriate studies are needed to exclude
infectious causes of diarrhea, especially C. difficile. At or after neutrophil engraftment,
diarrhea must prompt evaluation for GvHD.
9.3. Other Toxicities:
Infections:
Viral infections (CMV, EBV, respiratory viruses including RSV, influenza virus and
parainfluenza virus, BK virus, adenovirus), fungal infections (candida and mould) and
bacterial infections are commonly expected in the setting of an immunocompromised
host, chemotherapy administration and delayed immune reconstitution. These will be
managed according to the RPCI BMT SOP.
Hematologic:
Major ABO incompatibility (recipient vs. donor RBCs) or minor ABO incompatibility
(donor vs. recipient RBCs) or both may result in severe hemolysis. ABO incompatible
transplants will be identified in advance and will be treated according to the RPCI BMT
SOP.
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All blood products will be irradiated (2500 cGy) to prevent GvHD. Infection prophylaxis
and treatment will be given according to RPCIBMT SOPs and standard accepted
medical practice. With prophylactic platelet transfusions, the risk of death from
hemorrhage is <5%.
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:
Some patients, particularly those receiving melphalan and total body irradiation will
experience total (reversible) alopecia.
Secondary malignancy:
The cumulative exposure to chemotherapeutic agents and radiation increases the risk of
developing leukemia or a second cancer. The incidence of leukemia is probably
approximately 5%.
Failure to engraft:
Autologous count recovery is the most likely outcome because this combination is sub-
myeloablative.
Toxicities of G-CSF (donor):
These toxicities may include bone pain, headache and myalgias. These can be treated
with non-narcotic and narcotic analgesics. Splenic rupture in donors with an enlarged
spleen and precipitation of an acute hemolytic episode in donors with sickle cell trait are
rare and need to be evaluated.
Toxicities of Apheresis (donor)
With apheresis the following discomforts may occur: tingling around mouth or in
fingers, feeling cold or feeling a pressure sensation in chest due to the blood thinner
(sodium citrate), feeling light-headed or fainting any time during or at the end of the
procedure, pain, bruising or infection at the point of the needle entry into the skin. A
reaction (such as a rash) to a drug is possible if the patient has an unknown allergy.
Blood loss (less than a pint) may rarely occur because of equipment problems which
make it impossible to return the blood to the donor. Air entering the blood stream
causing air to go to body organs (very rare risk because of safety measures used).
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Toxicities of bone marrow harvest (donor)
In the event the patient cannot undergo apheresis or had a poor hematopoietic stem cell
collection, a bone marrow harvest will be performed. The risks of the bone marrow
harvest include anesthesia (general or spinal), pain, infection and bleeding at bone
marrow harvest sites (posterior iliac crests bilaterally).
10. DRUG FORMULATION, AVAILABILITY AND PREPARATION:
10.1. Fludarabine Monophosphate (Fludara®);
A purine nucleoside analog.
10.1.1 Availability:
Fludarabine monophosphate is commercially available as a clear, sterile solution. Each 2
milliliter vial contains 50 milligrams of fludarabine phosphate, 50 milligrams of
mannitol, water for injection, and sodium hydroxide to adjust pH to 6.8. Store at 2 to
80C (36 to 460F).
10.1.2. Storage & Stability:
Fludarbine phosphate contains no antimicrobial preservative and thus care must be taken
to assure the sterility of the prepared solutions and should be discarded eight hours after
initial entry.
10.1.3 Preparation:
Fludarbine phosphate vials containing 50 milligrams of fludarabine phosphate, 50
milligrams of mannitol, water for injection and sodium hydroxide to adjust the pH to 6.8.
The product may be further diluted for intravenous administration in 100 milliliters or
125 milliliters of 5% Dextrose for Injection USP or 0.9% Sodium Chloride, USP.
10.1.4. Administration:
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration. Fludarabine will be delivered as a piggy-bag via an
ongoing IV line, over a period of 30 minutes.
10.1.5. Toxicity:
Myelosuppression (dose limiting toxicity), fever, nausea, vomiting, stomatitis, diarrhea,
gastrointestinal bleeding, anorexia, edema, skin rashes, myalgia, headache, agitation,
hearing loss, transient episodes of somnolence and fatigue, autoimmune hemolytic
anemia, autoimmune thrombocytopenia, paresthesias, peripheral neuropathy, renal and
pulmonary toxicity (interstitial pneumonitis). Severe fatal CNS toxicity presenting with
loss of vision and progressive deterioration of mental status were encountered almost
exclusively after very high doses of fludarabine monophosphate. Such toxicity has only
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been rarely demonstrated at the 25-40 milligrams dosage of fludarabine monophosphate.
Very rarely described complications include transfusion-associated graft versus host
disease, thrombotic thrombocytopenic purpura, and liver failure. Tumor lysis syndrome,
complicating fludarabine monophosphate therapy has been observed, especially in
patients with advanced bulky disease. Opportunistic infections (protozoan, viral, fungal,
and bacterial) have been observed in both pre-treated patients receiving fludarabine and
in individuals receiving fludarabine combined with other agents (corticosteroids,
mitoxantrone, and cyclophosphamide).
10.2. Melphalan (Alkeran®):
An alkylating agent.
10.2.1 Availability:
Melphalan is commercially available as a powder for injection in 50 milligrams vials.
10.2.2. Storage & Stability:
Intact vials should be stored between 20 to 250C (68 to 770F) and protected from light.
Following reconstitution with sterile diluent, melphalan hydrochloride solution
containing 5 milligrams of melphalan per milliliters is stable for up to 60 minutes at
room temperature; this reconstituted solution should not be refrigerated since a
precipitate may form at 50C.
10.2.3. Preparation:
Reconstitute by adding 10 milliliters of diluent provided by the manufacturer to a vial
labeled as containing 50 milligrams of melphalan to provide a solution with a
concentration of 5 milligrams/milliliters. The diluent should be added rapidly and the
vial should be shaken vigorously until a clear solution is obtained. Reconstituted
solutions of melphalan should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
Administration should occur within one hour of drug dissolution.
10.2.4. Administration:
IV administration over 30 minutes. Administration should occur within 60 minutes of
dissolution.
10.2.5. Toxicity:
Leukopenia, thrombocytopenia, irreversible bone marrow failure, vasculitis, secondary
malignancies, vesiculation of the skin, alopecia, pruritis, rash, SIADH, sterility,
amenorrhea, nausea, vomiting, stomatitis, diarrhea, hemorrhagic cystitis, anemia,
hemolytic anemia, pulmonary fibrosis, interstitial pneumonitis.
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10.3. Tacrolimus (Prograf®);
Macrolide compound with potent immunosuppressant properties.
10.3.1. Storage & Stability:
Store tacrolimus capsules at controlled room temperature, 15-30oC (59-860F) (Prod Info
Prograf®, 1997). An extemporaneous suspension of tacrolimus with a final
concentration of 1 milligram/milliliter was stable for 56 days when it was stored at 24-
260C in glass or plastic amber prescription bottles.
10.3.2. Availability:
Tacrolimus is available for oral administration as capsules, containing the equivalent of
0.5, 1, or 5 milligrams of anhydrous tacrolimus and compounded oral suspension
containing the equivalent of 1 milligram/milliliter of anhydrous tacrolimus. For IV use,
tacrolimus is available as a sterile solution in 1 milliliter ampules containing the
equivalent of 5 milligrams of anhydrous tacrolimus per ml.
The oral absorption of tacrolimus is erratic and incomplete; absolute bio-availability is
approximately 25%. Peak serum levels are seen 1 to 3 hours after an oral dose.
Therapeutic trough blood concentrations have ranged from 5 to 15 nanograms/milliliter.
Tacrolimus is extensively metabolized in the liver, with only small amounts of
unchanged drug (2% or less) being recovered in the urine. The elimination half-life of
tacrolimus is approximately 10 hours.
Tacrolimus suppresses both humoral (antibody) and cell-mediated immune responses.
The compound is chemically distinct from cyclosporine but both agents elicit similar
immunosuppressant effects. The immunosuppressive activity of tacrolimus is, however,
more marked than that of cyclosporine.
10.3.3. Preparation: For IV use:
Tacrolimus concentrate for injection must be diluted prior to IV infusion. For IV
infusion, the concentrate is diluted with 0.9% sodium chloride or 5% dextrose injection
to a concentration of 4-20 micrograms/milliliter. Preparation of the solution in
polyethylene or glass containers allows storage for 24 hours beyond which unused
solution should be discarded. A plasticized polyvinyl chloride (PVC) container should
not be used because stability of the solution is decreased and polyoxyl 60 hydrogenated
castor oil contained in the formulation may leach phthalates from PVC containers.
Tacrolimus concentrate for injection and diluted solutions of the drug should be
inspected visually for particulate matter and discoloration prior to administration
whenever solution and container permit.
For Oral use:
Tacrolimus 1 milligram/miUiiiter suspension is compounded using twenty-four 5
milligram capsules, 60 milliliters of simple syrup, and 60 milliliters of Oraplus®
suspension. Capsules are emptied into an 8 ounce amber bottle and dissolved in 8
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milliliters of sterile water. Simple syrup and Oraplus® are added and shaken vigorously.
Storage is at room temperature for 56 days.
10.3.4. Administration:
Oral therapy should be started as soon as possible after transplantation at a dose of 0.015
miHigrams/kilogram (ideal body weight or actual if less than ideal) every 12 hours. In
patients unable to tolerate oral therapy, the recommended intravenous dose is one-third
of the oral dose administered every 12 hours.
10.3.5. Toxicity:
In patients receiving tacrolimus, 5% to 47% experienced anemia, 8% to 32% experienced
leukocytosis, and 14% to 24% experienced thrombocytopenia. Rare cases of
microangiopathic hemolytic anemia have been reported. Mild to moderate hypertension
was reported in 38% to 50% of patients receiving tacrolimus. Mild to moderate
hypertension is a common adverse effect associated with tacrolimus therapy. Chest pain
was reported in 19%. Antihypertensive therapy may be required. The most common
adverse effects of tacrolimus have involved the central nervous system, and include
headache (37% to 64%), tremors (48% to 56%), insomnia (32% to 64%), paresthesia
(17% to 40%); and dizziness (19%). Tremor and headache may respond to a dosage
reduction. Agitation, anxiety, confusion, seizures, depression, hallucinations, myoclonus,
neuropathy, psychosis, incoordination, and abnormal dreams have been reported in 3% to
15% of tacrolimus-treated patients. Hyperkalemia (13% to 45%), hypokalemia (13% to
29%), hypophosphatemia (49%), and hypomagnesemia (16% to 48%) have been
associated with tacrolimus therapy. In addition, hirsutism occurs only rarely with
tacrolimus. Hyperuricemia has been reported in greater than 3% of tacrolimus-treated
patients. Gastrointestinal adverse effects of tacrolimus have included nausea (32% to
46%), vomiting (14% to 29%), anorexia (7% to 34%), constipation (23% to 35%) and
diarrhea (37% to 72%). Gingival hyperplasia observed in patients treated with
cyclosporine has not been reported with tacrolimus therapy. Nephrotoxicity was
reported in 36% to 40% and 52% of liver and kidney transplant patients receiving
tacrolimus. Overt nephrotoxicity is usually seen early after transplantation and is
characterized by an increased serum creatinine and a decrease in urine output.
Hematuria has been reported in greater than 3% of tacrolimus-treated patients (Prod Info
Prograf®, 1997). Abnormal liver function tests have been reported in 6% to 36% of
patients receiving tacrolimus; ascites was reported in 7% to 27% of these patients.
Other miscellaneous effects that have occurred in clinical trials include pain (24% to
63%), fever (19% to 48%), asthenia (11% to 52%), back pain (17% to 30%), and
peripheral edema (12% to 36%). The incidence of hyperglycemia is 17% and may
require therapy with insulin. Other less frequently occurring effects (greater than 3%)
include abscess, chills, peritonitis, and photosensitivity reactions. Anaphylaxis has been
reported in a few patients receiving intravenous tacrolimus. Tacrolimus contains castor
oil which has been associated with anaphylaxis in other drugs containing castor oil
derivatives.
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10.4. Mycophenolate (CellCept®, MMF):
A 2-morphoHnoethyl ester of mycophenolic acid (MPA), inosine monophosphate
dehydrogenase (IMPDH) inhibitor.
10.4.1. Storage & Stability
The MMF powder for reconstitution and reconstituted solution should be stored at 25
degrees Celsius (C) (77 degrees Fahrenheit (F)); however, temperature excursions
between 15 to 30 degrees C (59 to 86 degrees F) are permitted (Prod Info CenCept(R),
2003e).
10.4.2. Availability and administration:
Mycophenolate is available for oral administration as capsules containing 250 milligrams
of mycophenolate mofetil, tablets containing 500 milligrams of mycophenolate mofetil,
and as a powder for oral suspension, which when constituted contains 200
milligrams/milliliter mycophenolate mofetil. Each vial of mycophenolate intravenous
contains the equivalent of 500 milligrams mycophenolate mofetil as the hydrochloride
salt. Reconstitution and dilution with 5% Dextrose Injection USP yields a solution of
mycophenolate mofetil, 6 milligrams/milliliter.
10.4.3. Clinica! Pharmacology:
Mechanism of Action: Mycophenolate mofetil is rapidly absorbed following oral
administration and hydrolyzed to form MP A, which is the active metabolite. MPA is a
selective and uncompetitive, inhibitor of inosine monophosphate dehydrogenase
(IMPDH), and therefore inhibits the de-novo pathway of guanosine nucleotide synthesis
without incorporation into DNA. Because T- and B-lymphocytes are critically
dependent for their proliferation on de- novo synthesis of purines, whereas other cell
types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes.
MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and
allospecific stimulation.
10.4.4. Pharmacokinetics:
Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to
form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active.
10.4.5. Metabolism:
Following oral and intravenous dosing, mycophenolate mofetil undergoes complete
metabolism to MPA, the active metabolite. MPA is metabolized principally by
glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not
pharmacologically active. In vivo, MP AG is converted to MPA via enterohepatic
recirculation. Increased plasma concentrations of mycophenolate mofetil metabolites
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(MPA 50% increase and MP AG about a 3-fold to 6-fold increase) are observed in
patients with renal insufficiency.
10.4.6. Excretion:
Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of
the administered dose, with 93% of the administered dose recovered in the urine and 6%
recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as
MPAG.
10.4.7. Contraindications:
Allergic reactions to mycophenolate have been observed; therefore, mycophenolate is
contraindicated in patients with a hypersensitivity to mycophenolate mofetil,
mycophenolic acid or any component of the drug product. Mycophenolate intravenous is
contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).
10.4.8. Toxicities:
The principal adverse reactions associated with the administration of mycophenolate
include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher
frequency of certain types of infections. Patients receiving immunosuppressive regimens
involving combinations of drugs, including mycophenolate, as part of an
immunosuppressive regimen are at increased risk of developing lymphomas and other
malignancies, particularly of the skin. The risk appears to be related to the intensity and
duration of immunosuppression rather than to the use of any specific agent.
Oversuppression of the immune system can also increase susceptibility to infection,
including opportunistic infections, fatal infections, and sepsis.
As usual for patients with increased risk for skin cancer, exposure to sunlight and UV
light should be limited by wearing protective clothing and using a sunscreen.
Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving
mycophenolate (2000 to 3000 milligrams daily) with other immunosuppressive agents in
controlled clinical trials of renal, cardiac, and hepatic transplant patients.
There are no adequate and well-controlled studies in pregnant women. However, as
mycophenolate has been shown to have teratogenic effects in animals, it may cause fetal
harm when administered to a pregnant woman. Therefore, mycophenolate should not be
used in pregnant women unless the potential benefit justifies the potential risk to the
fetus. It is recommended that mycophenolate therapy should not be initiated by the
physician until a report of a negative pregnancy test has been obtained.
In patients receiving mycophenolate (2000 or 3000 milligrams) in controlled studies for
prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in
approximately 2% of renal and cardiac patients and in 5% of hepatic patients.
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Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 10 3 / microliter] developed
in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant
patients receiving mycophenolate 3000 milligrams daily respectively. If neutropenia
develops (ANC <1.3 x 10 3 / microliter), dosing with mycophenolate should be
interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient
managed appropriately. Gastrointestinal bleeding (requiring hospitalization) has been
observed in approximately 3% of renal transplant patients treated with mycophenolate
3000 milligrams daily. Gastrointestinal perforations have rarely been observed.
10.5. METHOTREXATE (MIX):
Antimetabolite that interferes with DNA synthesis, repair and cellular replication
10.5.1. Availability and Stability:
Methotrexate LPF® Sodium (methotrexate sodium injection), Isotonic Liquid,
Preservative Free, for single use only, is available in 25 milligrams/milliliter, 2, 4, 8, and
10 milliliter vials, containing 50, 100, 200, and 250 milligrams of methotrexate
respectively. If desired, the solution may be further diluted immediately prior to use with
an appropriate sterile, preservative-free medium.
Methotrexate Sodium for Injection, Freeze Dried, Preservative Free, Low Sodium, for
single use only, is available in 20, 50, and 1000 milligrams vials, containing
approximately 0.14, 0.33 and 7 meq of sodium respectively. Reconstitute immediately
prior to use with an appropriate sterile, preservative-free medium.
Methotrexate Sodium Injection, Isotonic Liquid, Preservative Protected, is available in
25 milligrams/milliliter, 50, and 250 milligrams vials. The preservative formulation
contains benzyl alcohol and must not be used for intrathecal or high dose therapy. If
desired, the solution may be further diluted with a compatible medium.
10.5.2. Dosage and Administration:
There is a wide range of dosing of methotrexate up to 10,000 mg per M2 over 15 to 30
minutes that would include leucovorin rescue. For this protocol, the dose of
methotrexate is very low and will not require a leucovorin rescue.
10.5.3. Toxicities:
Hematologic: myelosuppression [leukopenia (nadir 7 days), thrombocytopenia, anemia].
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Hepatic: acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatic
toxicity. Chronic toxicity has generally occurred after prolonged use (generally 2 years
or more) and after a total dose of at least 1.5 grams.
Urogenital: severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective
oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction and vagina!
discharge; infertility, abortion, fetal defects. Close attention to renal function including
adequate hydration, and urine alkalinization are essential for safe administration.
Gastrointestinal: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea,
hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis. Should be used
with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
Therapy may be discontinued if ulcerative stomatitis or other severe GI adverse reactions
occur.
Pulmonary: interstitial pneumonitis deaths have been reported, and chronic interstitial
obstructive pulmonary disease has occasionally occurred. Pulmonary symptoms or a
nonspecific pneumonitis may be indicative of a potentially dangerous lesion and require
interruption of treatment and careful investigation; infection needs to be excluded. This
lesion can occur at all dosages.
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes,
alopecia, ecchymosis, telangiectasia, acne, furunculosis.
Central Nervous System: headaches, drowsiness, blurred vision. There have been reports
of leukoencephalopathy following intravenous administration of methotrexate to patients
who have had craniospinal irradiation. Aphasia, hemiparesis, paresis, and convulsions
have also occurred following administration of methotrexate. Following low doses,
occasional patients have reported transient subtle cognitive dysfunction, mood alteration,
or unusual cranial sensations.
Other: opportunistic infection, arthralgia/myalgia, loss of libido/impotence, diabetes,
osteoporosis and sudden death. A few cases of anaphylactoid reactions have been
reported.
11. DATA AND SAFETY MONITORING PLAN
The Principal Investigator (PI) will be responsible for continuous monitoring of the
safety of the study.
Patient Outcomes Rounds are held weekly on the transplant unit, at which time all BMT
patient care is reviewed, including:
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Medications (chemotherapy for conditioning regimens; prophylactic, empiric and
therapeutic antimicrobials; 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.
Additional testing or therapies such as biopsies, scans or xrays that will direct
therapeutic interventions.
Consent, a properly signed and dated transplant consent.
Patient Psychosocial Status, compliance issues that could compromise patient safety.
A pretransplant, a conference is held by the BMT for all BMT patients for the purpose
of describing the need for allogeneic 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
up to 100 days following transplant. In addition, psychosocial evaluations are completed
on all transplant patients by one of the BMT social worker prior to transplant, to identify
any compliance issues.
Safety Monitoring, mandated 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., Vancomycin, Tacrolimus,
Tobramycin, Cyclosporine, Sirolimus, Mycophenolate). They are found in the BMT
SOP. 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.
Performance Status, assignment of KPS/Lansky Score (Appendix VI)
Quality Assurance, 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
¦ Reportable adverse events (serious)
¦ Bearman toxicity grade >3
¦ Variances in the delivery of standard care that do or do not result in a change in
practice
¦ Readmissions prior to day +100 post transplant
¦ Deaths occurring prior to day +100 post transplant
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¦ Engraftment of neutrophils and plateietes
Long Term Follow-up is conducted on all transplant patients even after they have
returned to the care of the referring physicians. An Annual Transplant Clinic has been
established, which provides care for allogeneic patients with chronic complications, as
well as assessments to identify clinical problems such as dental, bone, and psychosocial
complications.
BMT Patient Outcomes are reported to the Center for International Blood and Marrow
Transplant Research (CIBMTR), and/or 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 NMDP.
12. REMOVAL OF PATIENTS FROM PROTOCOL AND ADVERSE EVENT
REPORTING (AER):
12.1. Removal From Protocol:
If the constraints of this protocol are detrimental to the patient's health and/or the patient
no longer wishes to continue protocol therapy, the patient will be removed from
protocol treatment and placed on follow-up. In this event the reason for withdrawal will
be documented, the PI will be notified and the patient will be followed for toxicity,
survival, progression and relapse. Any patient with disease progression will be removed
from the protocol treatment and placed on follow-up. Document details, including last
staging on flow sheets and follow the patient for survival and secondary malignancies.
12.2. Expected Toxicity: (recorded in protocol consent form or manufacturer's literature).
Within 10 days of occurrence, written reports should be submitted to the IRB and the
protocol chairman in the following circumstances (Bearman toxicity):
Any fatal toxicity.
Any non-hematologic grade 3 or higher toxicity.
Grade 3-4 acute GVHD will be reported by written notification.
Failure to engraft (defined as a patient alive on day 30 with no
ANC recovery)
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Late graft failure (defined as a patient who had initial ANC
recovery but subsequently had a decline in ANC that required
additional stem cell support.
Readmission due to any reason up to 100 days post BMT
12.3. Unexpected Toxicity: All severe AEs not listed in expected toxicity will be reported
within 72 hours.
13. CRITERIA FOR STUDY EVALUATION
13.1. Disease Response Criteria:
Patients will be followed according to response criteria as referenced in BMT SOP
"Standards of Therapy" last updated 2008.
http://internal.roswenpark.org/flles/l 2 1 /Internal/patient care/bmt/BMT%20Standards/
8-2006%20BMT%20Standards.pdf
13.2. Study Endpoints:
The primary endpoint is Transplant Related Mortality in the first 100 days from day 0 of
the transplant. TRM is defined as death due to any cause except for disease progression.
13.3. Safety And Toxicity:
Safety will be evaluated on an ongoing basis with weekly outcome assessment and
grading for the first 100 days post transplant. Descriptive statistics will be used to
describe safety and other outcomes. Toxicity will be scored according to the Bearman
Criteria in Appendix I, oral mucositis by the WHO criteria in Appendix II, acute GvHD
according to the criteria in Appendix III and chronic GvHD by the criteria in Appendix
IV.
13.4. Engraftment:
Neutrophil engraftment is defined as the first day in which ANC is > 0.5xl09/ liter for
three consecutive days. Platelet engraftment is the first day that platelets are >20 xl 09/
liter for seven consecutive days without transfusion support.
Engraftment is a dynamic process in RIT, and chimerism analysis will be performed at
regular intervals. Lineage specific (separate lymphoid and myeloid) chimerism will be
analyzed in blood at the following time points (+/- 7 days): day 30, day 100 and then at
unscheduled intervals till full donor chimerism is attained.
Primary engraftment failure is defined as lack of evidence of neutrophil or platelet
engraftment at day +35, confirmed by a bone marrow biopsy showing <5% cellularity in
the absence of persistent malignancy. Late graft failure will be defined as initial
neutrophil engraftment by day +35 documented to be of donor origin followed by a drop
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in ANC to <500 for more than three days, independent of myelosuppressive drugs,
severe GvHD or infection.
Graft rejection is defined as graft failure with documentation of return of recipient
hematopoiesis as determined by cytogenetic/chimerism analysis.
14. GENDER AND MINORITY DECLARATION
This protocol does not restrict enrollment on the basis of gender or race.
15. CONFIDENTIALITY
All information provided to the Investigator by RPCI including preclinical data,
protocols, CRFs, and verbal and written information, will be kept strictly confidential and
confined to the clinical personnel involved in conducting this study, and no disclosure
shall be made except in accordance with any right of publication granted to the
Investigator. This information may be related in confidence to the IRB/ERC or other
committee functioning in a similar capacity. No report or information about the study will
be provided to anyone not involved in the study without consent of RPCI except if
required by law.
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REFERENCES
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myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:1867-1871.
3. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow
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4. Sullivan KM, Storb R, Buckner CD, et al. Graft-versus-host disease as adoptive immunotherapy in patients
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6. Fefer A, Cheever MA, Greenberg PD. Identical-twin (syngeneic) marrow transplantation for hematologic
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7. Gale RP, Champlin RE. How does bone-marrow transplantation cure leukaemia? Lancet. 1984;2:28-30.
8. Gale RP, Horowitz MM, Ash RC, et al. Identical-twin bone marrow transplants for leukemia. Ann Intern
Med. 1994;120:646-652.
9. Antin JH. Graft-versus-leukemia: no longer an epiphenomenon. Blood. 1993;82:2273-2277.
10. Cullis JO, Jiang YZ, Schwarer AP, Hughes TP, Barrett AJ, Goldman JM. Donor leukocyte infusions for
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23. Sorror ML, Maris MB, Storer B, et al. Comparing morbidity and mortality of HLA-matched unrelated
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immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell
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43. Takahashi Y, McCoy JP, Jr., Carvallo C, et al. In vitro and in vivo evidence of PNH cell sensitivity to
immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. Blood. 2004;103:1383-1390.
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myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331:896-903.
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older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom
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standard chemotherapy. A Southwest Oncology Group study. Blood. 1997;89:3323-3329.
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the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United
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1999;107:69-79.
48. Alyea EP, Kim HT, Ho V, et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic
hematopoietic cell transplantation for patients older than 50 years of age. Blood. 2005;105:1810-1814.
49. Scott BL, Sandmaier BM, Storer B, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for
patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a
retrospective analysis. Leukemia. 2006;20:128-135.
50. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for
the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved
outcome. Blood. 2004;104:579-585.
51. Barosi G, Hoffrnan R. Idiopathic myelofibrosis. Semin Hematol. 2005;42:248-258.
52. Hoffman R, Prchal JT, Samuelson S, Ciurea SO, Rondelli D. Philadelphia chromosome-negative
myeloproliferative disorders: biology and treatment. Biol Blood Marrow Transplant. 2007;13 Suppl 1:64-72.
53. Rondelli D, Barosi G, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation with
reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia.
Blood. 2005;105:4115-4119.
54. Khouri IF. Reduced-intensity regimens in allogeneic stem-cell transplantation for non-hodgkin lymphoma
and chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2006:390-397.
55. Rodriguez R, Nademanee A, Ruel N, et al. Comparison of reduced-intensity and conventional
myeloablative regimens for allogeneic transplantation in non-Hodgkin lymphoma. Biol Blood Marrow Transplant.
2006;12:1326-1334.
56. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative
conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23:3819-3829.
57. Peggs KS, Hunter A, Chopra R, et al. Clinical evidence of a graft-versus-Hodgkin-lymphoma effect after
reduced-intensity allogeneic transplantation. Lancet. 2005;365:1934-1941.
58. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose
chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol.
2006;24:929-936.
59. Bensinger WI, Maloney D, Storb R. Allogeneic hematopoietic cell transplantation for multiple myeloma.
Semin Hematol. 2001;38:243-249.
60. Badros A, Barlogie B, Siegel E, et al. Improved outcome of allogeneic transplantation in high-risk multiple
myeloma patients after nonmyeloablative conditioning. J Clin Oncol. 2002;20:1295-1303.
61. Kroger N, SayerHG, Schwerdtfeger R, et al. Unrelated stem cell transplantation in multiple myeloma after
a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low
transplantation-related mortality. Blood. 2002;100:3919-3924.
62. Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following
cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 2003;102:3447-3454.
63. Bruno B, Rotta M, Patriarca F. A Comparison of Allografting with Autografting for Newly Diagnosed
Myeloma. NEJM. 2007;356:1110-1120.
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64. Uzunel M, Remberger M, Sairafi D, et al. Unrelated versus related allogeneic stem cell transplantation
after reduced intensity conditioning. Transplantation. 2006;82:913-919.
65. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation during untreated first
relapse of acute myeloid leukemia. J Clin Oncol. 1992;10:1723-1729.
66. Gupta V, Yi QL, Brandwein J, et al. The role of allogeneic bone marrow transplantation in adult patients
below the age of 55 years with acute lymphoblastic leukemia in first complete remission: a donor vs no donor
comparison. Bone Marrow Transplant. 2004;33:397-404.
67. Sebban C, Lepage E, Vemant JP, et al. Allogeneic bone marrow transplantation in adult acute
lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute
Lymphoblastic Leukemia. J Clin Oncol. 1994;12:2580-2587.
68. Sutton L, Kuentz M, Cordonnier C, et al. Allogeneic bone marrow transplantation for adult acute
lymphoblastic leukemia in first complete remission: factors predictive of transplant-related mortality and influence
of total body irradiation modalities. Bone Marrow Transplant. 1993;12:583-589.
69. Barrett AJ, Horowitz MM, Pollock BH, et al. Bone marrow transplants from HLA-identical siblings as
compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Engl J Med.
1994;331:1253-1258.
70. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic
leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950.
71. Schlenk RF, Corbacioglu A, Krauter J, et al. Gene Mutations as Predicitive Markers for Postremission
Therapy in Younger Adults with Normal Karyotype AML. ASH Annual Meeting Abstracts. 2006;108:4-.
72. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute
lymphoblastic leukemia (ALL): Analysis of cytogenetic data from patients treated on the Medical Research Council
(MRC) UKALLXII / Eastern Cooperative Oncology Group (ECOG) 2993 Trial. Blood. 2006.
73. Rowe JM, Buck G, Fielding A, et al. In Adults with Standard-Risk Acute Lymphoblastic Leukemia (ALL)
the Greatest Benefit Is Achieved from an Allogeneic Transplant in First Complete Remission (CR) and an
Autologous Transplant Is Less Effective Than Conventional Consolidation/Maintenance Chemotherapy: Final
Results of the International ALL Trial (MRC UKALL XII/ECOG E2993). ASH Annual Meeting Abstracts.
2006;108:2-.
74. Hertzberg M, Grigg A, Gottlieb D, et al. Reduced-intensity allogeneic haemopoietic stem cell
transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders. Bone Marrow
Transplant. 2006;37:923-928.
75. Kiss TL, Mollee P, Lazarus HM, Lipton JH. Stem cell transplantation for mantle cell lymphoma: if, when
and how? Bone Marrow Transplant. 2005;36:655-661.
76. van Besien KW, de Lima M, Giralt SA, et al. Management of lymphoma recurrence after allogeneic
transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant. 1997;19:977-982.
77. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class I and class 11 high-resolution
matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a
strong adverse effect on transplantation outcome. Blood. 2004;104:1923-1930.
78. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with
methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from
unrelated donors. Blood. 2000;96:2062-2068.
79. Ratanatharathom V, Nash RA, Przepiorka D, et al. Phase EI study comparing methotrexate and tacrolimus
(prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical
sibling bone marrow transplantation. Blood. 1998;92:2303-2314.
80. Maris MB, Sandmaier BM, Storer BE, et al. Unrelated donor granulocyte colony-stimulating factor-
mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of
postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant. 2006;12:454-465.
81. Luisa Giaccone, Jeannine S. McCune, Michael B. Maris . Pharmacodynamics of mycophenolate mofetil
after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation. Blood, 2005; 106,13,
4381-4388.
82. A Elefantel, J Muindi, K West, et. al, Long-term stability of a patient-convenient 1 mg/ml suspension of
tacrolimus for accurate maintenance of stable therapeutic levels. Bone Marrow Transplantation 2006: 37,781-784
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83. Baron F., Storb R. Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning
as treatment for hematologic malignancies and inherited blood disorders. Mol Ther. 2006;13:26-41.
84. Haentzschel I, Freiberg-Richter J, Platzbecker U, et al. Targeting mycophenolate mofetil for graft-versus-
host disease prophylaxis after allogeneic blood stem cell transplantation. 2008:42:113-20
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Appendix No. I
BEARMAN* CRITERIA FOR TOXICITY GRADING
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 conditioning)
Increase in creatinine above twice
baseline but not requiring dialysis
Requirement of dialysis
Pulmonary
Dyspnea 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
P02 (>10% from baseline) but not
requiring mechanical ventilation or >
50% 02 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
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
preconditioning
Moderate hepatic dysfunction with bili
>6 mg% < 20 mg %; or SGOT increase
with
> 5-fold from preconditioning; 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
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CNS
Somnolence but the patient easily
arousable and oriented after arousal
Somnolence with confusion 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
*Bearman SI et al. Regimen Related Toxicity in Patients Undergoing Bone Marrow Transplantation. JCO1988,
6(10); 1562-15
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Appendix No. II
WHO ORAL MUCOSITIS GRADING
Grade 0
No changes
Grade 1
Soreness/erythema
Grade 2
Soreness/erythema + ulceration + can eat solid foods
Grade 3
Soreness/erythema + ulceration + can use a liquid diet
only
Grade 4
Soreness/erythema + ulceration + oral alimentation is not
possible
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Appendix No. Ill
CRITERIA FOR ACUTE GRAFT-VS-HOST DISEASE
Clinical staging of acute graft-vs.-host disease according to organ involvement
STAGE
SKIN
LIVER
INTESTINAL TRACT
0
No rash
Bilirubin
Diarrhea
< 2.0 mg/dL
500 ml/day
< 34^mol/L
+
Maculopapular rash
Bilirubin
Diarrhea
<25% of body surface
2-2.9 mg/dL
500-1000 ml/day
34-50 (imol/L
Peds: >30 ml/kg, < 60ml/kg
++
Maculopapular rash
Bilirubin
Diarrhea
25-50% of body surface
3.0-6.0 mg/dL
1000-1500 ml/day
51-102 jxmol/L
Peds: > 60 ml/kg, < 90 ml/kg
-HH-
> 50% body surface
Bilirubin
Diarrhea
6.1-15 mg/dL
1500 ml/day
103-255 (imol/L
Peds: >90 ml/kg
+H-++
Generalized erythroderma
Bilirubin
Severe abdominal pain with or
with bullous formation
>15 mg/dL
without ileus
and desquamation
> 255 umol/L
Clinical grading of severity of acute graft-vs-host disease
GRADE DEGREE OF ORGAN INVOLVEMENT
I
+ to ++skin rash;
no gut involvement;
no liver involvement;
no decrease in clinical performance
II
+ to +++ skin rash;
+ gut involvement or
+ liver involvement (or both);
mild decrease in clinical performance
III
-H- to +++ skin rash;
++ to +++ gut involvement or
++ to ++++ liver involvement (or both)
marked decrease in clinical performance
IV
Similar to Grade n with
++ to ++++ organ involvement and
extreme decrease in clinical performance
Source: Thomas etal, N Engl. J Med. 1975; 292, 832
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Appendix No. IV
CLINICAL GRADING OF CHRONIC GVHD
Limited Chronic GVHD:
1. Localized skin involvement,
and/or
2. Hepatic dysfunction due to chronic GVHD.
Extensive Chronic GVHD:
1. Generalized skin involvement, or
2. Localized skin involvement and/or hepatic dysfunction due to chronic GVHD
Plus 
3a. Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis, or
3b. Involvement of eye (Schirmer's test with less than 5 mm wetting), or
3c. Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy, or
3d. Involvement of any other target organ.
Clinical impression of overall chronic GvHD severity will be described as: mild, moderate and
severe.
1. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in
man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204-
217
2. Lee SJ, Klein JP, Barrett AJ, et al. Severity of chronic graft-versus-host disease:
association with treatment-related mortality and relapse. Blood. 2002;100: 406-414
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Appendix No. V
Stem Cell Infusion:
Day 0 is the day on which the stem cells are infused. The procedure of infusing stem cell
products may be performed under the supervision of the attending physician. 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 benadryl,
epinephrine and corticosteroids will be available for use in appropriate doses. No other
blood products should be given on the day of transplant, especially within 8 hours of
planned infusion time. Stem cells must be infused without the use of a blood filter
through a wide lumen central catheter. No more than 480 ml of stem cells may be
infused at one time and the transplant may need to be split into a morning and afternoon
infusion at the discretion of the attending physician. Patients will be pre-medicated
according to RPCI Standard Operating Procedure for Stem Cell reinfusion.
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Appendix No. VI
VI A. Karnofsky Performance Status (KPS)
KPS
DEFINITION
100 Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most personal needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
Karnofsky DA, Burchenal JH The Clinical Evaluation of Chemotherapeutic Agents in Cancer.
In: MacLeod CM (Ed), 'Evaluation of Chemotherapeutic Agents." Columbia Univ Press,
1949:196.
VIB. Lansky Performance Status (16 years and younger)
¦ 100 - fully active, normal
¦ 90 - minor restrictions in strenuous physical activity
¦ 80 - active, but tired more quickly
¦ 70 - greater restriction of play and less time spent in play activity
60 - up and around, but active play minimal; keeps busy by being involved in quieter
activities
¦ 50 - lying around much of the day, but gets dressed; no active playing participates in all
quiet play and activities
¦ 40 - mainly in bed; participates in quiet activities
¦ 30 - bedbound; needing assistance even for quiet play
20 - sleeping often; play entirely limited to very passive activities
¦ 10 - doesn't play; does not get out of bed
0 - unresponsive
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in
childhood cancer patients. Cancer 1987;60:1651-6
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
Protocol Template Version Date: 29 December 2010, Amendment 2, 10/7/14 Page 66 of 68

Roswell Park Cancer Institute Study Number: 1177110
Appendix No. VII
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)
o
cs
1
o
1—^
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
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
Protocol Template Version Date: 29 December 2010, Amendment 2,10/7/14 Page 67 of 68

Roswell Park Cancer Institute Study Number: 1177110
Appendix No. VIII
Tests/Observations*
Pre-Rx
Post-Rx A
History and physical exam.
Comorbidity Index
X
—
Signed Informed Consent
X
"
Ht/Wt/BSA
X
"
Serology (HIV, Hepatitis, CMV)
X
"
HLA typing
X
"
Cr Clearance
X
"
PFT's including DLCO
X
At day 100, then as indicated [+/- 7 days] €
MUGA or ECHO
X
-
EKG
X
Quantitative Immunoglobulins
X
xt
BM aspirate, biopsy §
X
day 30, day 100 and then as indicated [+1-1 days] €
Peripheral blood for chimerism
X
day 30, day 100 and then as indicated [+/-7 days] €
Molecular, flow and cytogenetics
analysis
X
day 30, day 100,1 year and then as indicated [+1-1
days] €
CBC/diff
X
q day till PMN>500, Plt>20K, then as indicated
Urinalysis biochemical
X
as clinically indicated
PT
X
as clinically indicated
Comprehensive metabolic panel,
LDH
X
q wk x 4 and then as indicated
Chest X-ray (PA and lateral)
X
—
CT Scan and/or PET f f
X
At day 100 and then as indicated [+1-1 days] €
Kamofsky/Lansky Performance
Status
X
q wk x 4 and then as indicated
Toxicity (Bearman/WHO
mucositis)
—
wkly x 4 and then day 100 & then as indicated
Acute GVHD assessment
q wk till day +100
Chronic GVHD assessment
as indicated
* Day 0 is day of stem cell transplant; studies to be obtained as close to indicated time as
possible. Intervals shown are the minimum requirement,
t Post transplant SPEP, IFE, Quantitative immunoglobulins, serum beta-2 microglobulin,
kappa/lambda free light chains and 24 hour urine for protein electrophoresis and free
light chains will be done only for patients with multiple myeloma on day 100-160 and
then as clinically indicated.
§ BM aspirate and biopsy will be performed for patients with leukemias and bone marrow
failure states only. Patients with other malignancies will have BM aspirate and biopsy
only if bone marrow was involved previously. Chimerism study will be done on each
specimen. Cytogenetics will be done if it was abnormal previously,
tf For patients with lymphoma only. Also palpable tumor measurement should be recorded
for lymphoma patients.
A All testing will be performed post-Rx as clinically indicated. Only mandatory tests are
included in this table.
€ If the patient is medically unfit or has scheduling difficulty, delay is allowed.
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK CANCER INSTITUTE
Protocol Template Version Date: 29 December 2010, Amendment 2,10/7/14 Page 68 of 68