Conditions: Leukemia, Myeloid, Chronic AML Leukemia, Lymphocytic, Acute MDS Leukemia, Lymphocytic, Chronic JMML Hodgkin's Disease Non-hodgkin's Lymphoma Multiple Myeloma
Keywords: stem cell transplant chronic leukemia acute leukemia irradiation chemotherapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 330
Healthy volunteers: no

Brief summary:
The purpose of this study is to develop a standard of care treatment using allogeneic stem cells for patients with cancers of the blood.

The protocol was revised to reflect that this study is considered "treatment guidelines", rather than a research study.

Detailed description:
Preparative regimen using total body irradiation (TBI) and cyclophosphamide:

1. on day -6 and -5: cyclophosphamide is given,
2. on day -4, -3, -2, and -1: TBI is given,
3. on day 0: stem cell or bone marrow is infused.

Alternate preparative therapy for patients not able to receive TBI

The chemotherapy (cyclophosphamide and busulfan) is given with the intent of destroying the bone marrow, eliminating any cancerous and preparing for the transplant of the donor's blood stem cells by suppressing the immune system.

l. Ten days before the transplant (Day 10), subjects will be admitted to the bone marrow transplant unit and placed in isolation to reduce exposure to infections. Isolation will be continued until adequate numbers of cells are present in the blood to fight infection.

2\. On day -9, -8, -7, -6 busulfan is given.

3\. On day -5, -4, -3, -2 cyclophosphamide is given.

4\. On day -1 no therapy is given (day of rest).

5\. On day 0 the donor stem cells are given intravenously. Additional cells may be given on day +1 or 2 as needed.

Transplant:

Subjects will be admitted to the bone marrow transplant unit and put in isolation to reduce exposure to infectious agents. During this time, they will receive the preparative treatment outlined above. Once they have received the preparative regimen, stem cells will be obtained from the donor and given intravenously.

The new stem cells will replace the bone marrow that was damaged by the treatment for the cancer.

Isolation will be continued until adequate numbers of cells are present in the blood to fight infection. Subjects will then be transferred from the bone marrow transplant unit and discharged from the hospital when medically ready. Subjects will be expected to return for follow-up to the bone marrow transplant clinic at specific dates as determined by their physician.

Arms:
arm 1: Patients who are not able to receive Total Body Irradiation (TBI) receives cyclophosphamide, Busulfan and Peripheral Blood Stem Cells (PBSC) as a source of transplant arm 2: Patients who are not able to receive Total Body Irradiation (TBI) receives cyclophosphamide, Busulfan and Bone Marrow as a source of stem cell transplant arm 3: Patients who are not able to receive Total Body Irradiation (TBI) receives cyclophosphamide, Busulfan and Umbilical Cord Blood (UCB) as a source of stem cell transplant arm 4: Patients who receives Umbilical Cord Blood (UCB) as a source of transplant and who have not had chemotherapy in the prior 3 months receives ATG in addition to cyclophosphamide, Busulfan preparative regimen arm 5: Patients receiving cyclophosphamide, Total Body Irradiation (TBI) and Peripheral blood stem cells as a source of transplant arm 6: Patients receiving cyclophosphamide, Total Body Irradiation (TBI) and Bone Marrow as a source of stem cell transplant arm 7: Patients receiving cyclophosphamide, Total Body Irradiation (TBI), and Umbilical Cord Blood (UCB) as a source of stem cell transplant arm 8: Patients receiving cyclophosphamide, Total Body Irradiation (TBI) , CD4+CD25+ and Peripheral Blood Stem Cells (PBSC) as a source of transplant. These patients are co-enrolled on the MT2004-03 trial (NCT00725062)

Interventions: intervention 1: Stem Cell Transplant intervention 2: Cyclophosphamide intervention 3: Total Body Irradiation intervention 4: Busulfan intervention 5: Equine ATG (ATGAM) intervention 6: CD4+/CD25+ cells
Intervention descriptions: intervention 1: Certain cancers can be treated by giving patients stem cells that come from someone else. This is called a stem-cell transplant. As part of the transplant process, patients receive high doses of chemotherapy and/or radiation to treat their underlying disease, such as cancer. As one of its effects, this treatment also kills the healthy stem cells that are already in the marrow. The transplant provides new stem cells for the patient from a healthy donor; that replace the bone marrow and allow the blood counts to recover. (Allowable sources of stem cells = related or unrelated bone marrow or peripheral blood, for Busulfan/cyclophosphamide/ATG preparative chemo only, umbilical cord blood is also permitted.) intervention 2: 60 mg/kg intravenously (IV) Days -6 and -5 or 50 mg/kg/day IV Days -5 through -2. intervention 3: On Day -4, -3, -2, -1 total body irradiation is given twice daily. intervention 4: When not receiving total body irradiation, administered Days -9 through -6, 0.8 mg/kg/dose by intravenous dosing every 6 hours. intervention 5: UCB recipients who have not had chemotherapy in the preceding 3 months will also receive Equine ATG (ATGAM) 15 mg/kg IV will be administered every 12 hours for 6 doses beginning on day -3 per institutional guidelines intervention 6: On days -2, patients will receive CD4+/CD25+ cells intravenously.

Protocol document:
Prot_SAP_000.pdf: 
UNIVERSITY OF MINNESOTA BONE MARROW TRANSPLANTATION PROGRAM
ALLOGENEIC TRANSPLANT FOR HEMATOLOGICAL MALIGNANCY
MT2001-02
June 29, 2001
Revised October 6, 2001
Revised December 6, 2001
Revised October 4, 2002
Revised November 6, 2002
Revised January 8, 2004
Revised May 3, 2004
Revised June 14, 2005
Revised, April 28, 2008
Revised July 29, 2008
Revised January 26, 2010
Revised May 30, 2012
Admin Revision March 21, 2013
Study Committee
Daniel Weisdorf, M.D. -- Chair
Claudio Brunstein M.D.
Linda Burns, M.D.
Kathryn Dusenbery, M.D.
Margaret MacMillan, M.D.
Paul Orchard, M.D.
John Wagner, M.D.
Jeffrey Miller, M.D.


MT2001-02
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Page 2 of 25
DATE
PROTOCOL CHANGE
IRB approval
March 21, 2013
Added reference to use of MTX as standard GVHD prophylaxis
May 30, 2012
add UCB as a stem cell source option for CY/FLU prep;
add ATG to the preparative regimen for patients receiving cord
blood and who have not had chemotherapy in the prior 3 months;
delete oral option for busulfan as no longer given that way;
delete MT2004-03 treatment arm as study is closed to accrual;
change busulfan dose to 0.8 mg every 6 hours (currently 1.0 mg
every 6 hours)
Add statement to allow flexibility in treatment based on individual
patient needs
change to Keppra as seizure prophylaxis (currently Dilantin)
update the DSMP
add Claudio Brunstein to cover page (officially added as co-
Investigator 3/16/12)
5/31/12
January 26, 2010
Eligibility clarification
02/18/2010
July 29, 2008
Added an arm to co-enroll subjects from MT2004-03; added Dr.
Jeffrey Miller to the study committee, removed Dr. Juliet Barker
and Dr. Norma Ramsay from the study committee
09/25/2008
April 28, 2008
Increased enrollment goal to 350 subjects, updated study to
conform to current institutional standards
9/25/2008
June 14, 2005
Section 4.2: If the recipient is < 18 years of age with a related
donor, they will receive marrow.
May 3, 2004
Added myelproliferative diseases to the eligibility (section 3.4.5)
TBI dose rate changed to 10-19 cGy/min to conform to current
equipment in Therapeutic Radiation (section 4.3.1.1)
G-CSF dosing for donors changed to 10 mcg/kg/day – section
4.1.3, Appendix 1.
7/7/2004
January 8, 2004
Busulfan pharmacokinetics added (section 4.3.2)
January 8,
2004
November 6,
2002
Eliminated "rest day" from TBI pre-transplant regimen (section
4.3.1)
January 8,
2003
October 2002
1. Amendment Page added
2. Testicular boosts for males with ALL added to the TBI
guidelines. (section 4.3.1.1 and Appendix II)
December 5,
2002
December 6,
2001
Protocol revised to reflect that this study is considered "treatment
guidelines", rather than a research study, in the eyes of the CPRC.
References to this being a "phase II study" have been removed.
CPRC
approval, Jan
8, 2002
October 6, 2001
Added Data and Safety Monitoring plan, a schema, and a more
complete statistical section (stipulations of CPRC prior to opening
study).
October 31,
2001


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Page 3 of 25
TABLE OF CONTENTS
Section
Title
Page
1.0
Objectives
5
2.0
Background and Rationale
5
3.0
Eligibility and Exclusion Criteria
6
4.0
Treatment Schema
10
5.0
Required Observations - Donor
15
6.0
Required Observations - Recipient
16
7.0
Toxicities and Complications
16
8.0
Experimental Design and Statistical Consideration 19
Appendix I
Schedule for G-CSF Administration
21
Appendix II
TBI Guidelines
22
References
23


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Study Schema
Potential BMT candidate
to
Screen for eligibility after New Patient visit or during pre-BMT evaluation
Review eligibility for study with higher scientific priority
to
Present proposed plan to patient; secure written informed consent.
to
Screen donor for appropriate histocompatibility and medical suitability to donate
Present proposed plan to donor; secure written informed consent
to
Prepare patient for BMT using chemotherapy ± total body irradiation
Infuse donor stem cells
(allowable sources – related or unrelated BM or PB or, for BU/CY preparative chemo only, UCB is also
permitted)
to
Supportive care
to
Long-term follow-up for listed as well as unexpected complications and survival


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1.0
OBJECTIVES
The purpose of this protocol is to study the use of related or unrelated allogeneic stem cell
transplantation as therapy for individuals with acute myelocytic leukemia (AML), acute
lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic
leukemia, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma, myelodysplasia or
juvenile chronic myelogenous leukemia. Specifically, this study researches the following
question.
1.1With what frequency will allogeneic stem cell transplantation (BMT) along with
fractionated total body irradiation (TBI) and cyclophosphamide; or busulfan and
cyclophosphamide for patients who are ineligible for TBI, promote long-term disease-
free survival in patients with hematological malignancies?
2.0 BACKGROUND AND RATIONALE
Allogeneic bone marrow transplantation has been widely used for treatment of lethal
hematologic disorders. Extensive experience with bone marrow as the stem cell source
has documented the ability of engrafted marrow to restore hematopoiesis,
immunocompetence and protect against malignant recurrence leading to extended
disease-free survival for a sizable fraction of children and adults undergoing such
transplantation. Over the last 10 years, extensive clinical experience, confirmed in
several randomized trials, has suggested that for certain patient populations, G-CSF
mobilized peripheral blood from matched related or unrelated donors contains sufficient
stem cells for prompt engraftment and sustained hematopoiesis. While questions still
remain regarding the incidence, severity and duration of acute and chronic graft-versus-
host disease following allogeneic transplantation using blood-derived stem cells, it is well
established that these are a viable source of cells for use in allotransplantation. Peripheral
blood stem cell allografts have been associated with quicker neutrophil recovery and a
shorter time to platelet and red cell transfusion dependence then corresponding grafts
using marrow-derived stem cells. This has resulted in lesser early transplant-related
toxicity and mortality. Acute graft-versus-host disease has been either similar or slightly
less frequent than in marrow grafts, and chronic graft-versus-host disease has been
reported as either similar or slightly more frequent than grafts using marrow. Several
randomized trials have suggested a survival advantage for blood stem cell transplants,
particularly for high risk patients.
Experience at the University of Minnesota with over 100 such allografts confirms quicker
engraftment, but similar rates of graft-versus-host disease and disease-free survival,
compared to bone marrow transplants at our institution.
Recognizing this advantage for all, but the lowest risk group of patients, this study will
evaluate, in prospective fashion, the use of G-CSF mobilized donor blood stem cells in
patients undergoing allotransplantation. Those receiving unrelated donor grafts or those
whose donors are younger than age 12 will still undergo marrow harvests for stem cell


MT2001-02
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Page 6 of 25
collection. All patients will receive uniform conditioning with cyclophosphamide and
fractionated total body irradiation for busulfan plus cyclophosphamide, if irradiation is
not possible. They will receive the multi-modal supportive care provided for all patients
undergoing transplantation at our institution. Standard post-transplant outcomes relating
to engraftment, graft-versus-host disease complications, malignant relapse and survival
will be evaluated.
3.0
ELIGIBILITY AND EXCLUSION CRITERIA
3.1
Donors will be < 75 years of age and in good health.
3.2
Recipients will be <55 years, will have normal organ function (excluding bone
marrow) and will have a Karnofsky activity assessment > 90%.
3.2.1
Creatinine <2.0 mg/dl for adults; or clearance > 50 ml/min for children
3.2.2
Bilirubin, AST, ALK <2 x normal.
3.2.3
Pulmonary function test > 50% of normal.
3.2.4
MUGA > 45% ejection fraction.
3.3
Recipients with related or unrelated donor matched at the HLA A, B, DRB1 loci,
or mismatched related or unrelated (if < 35 years old) at a single HLA A, B,
DRB1 locus. For the busulfan/cyclophosphamide (BU/CY) prep, UCB is also a
permitted stem cell source. If UCB is used, unit(s) will be selected according to
current University of Minnesota umbilical cord blood graft selection algorithm.
One or 2 UCB units may be used to achieve the required cell dose. The UCB
graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. This may
include 0-2 antigen mismatches at the A or B or DRB1 loci. If 2 UCB units are
required to reach the target cell dose, each unit must be a 4-6 HLA-A, B, DRB1
antigen match to each other, as well as a 4-6 antigen match to the recipient
3.4
Recipients will be eligible in one of the following disease categories
3.4.1
Chronic myelogenous leukemia in accelerated phase or in post blast crisis;
second or greater chronic phase; or in chronic phase but intolerant of or
resistant to tyrosine kinase inhibitors.
3.4.1.2
Accelerated Phase: Patients with hematologic peripheral blood or
bone marrow findings meeting standard criteria for CML, but who present
with or progress to express any of the following findings are considered as
having accelerated phase disease:
Leukocytosis (WBC greater than 50x109/L) uncontrolled by single
agent chemotherapy.


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May 30, 2012
Page 7 of 25
Thrombocytosis (Platelet count greater than 1x1010/L) uncontrolled
by single agent chemotherapy.
Anemia (hemoglobin less than 8 grams/dl) uncontrolled by single
agent therapy.
Peripheral blood blast percentage between 5 and 30%, uncontrolled
by single agent chemotherapy.
Cytogenetic abnormalities in addition to the Philadelphia
chromosome at presentation, or the development of new cytogenetic
abnormalities in addition to the Philadelphia chromosome during
observation.
Splenomegaly uncontrolled by single agent chemotherapy.
Extramedullary disease.
Severe, progressive myelofibrosis or osteosclerosis.
Achievement of a "second chronic phase" after blast crisis.
3.4.2
Acute myelocytic leukemia in first or greater remission, or first, second or third
relapse.
3.4.3
Acute lymphocytic leukemia in the 2nd or greater bone marrow remission.
3.4.3.1 High risk children will be transplanted in first remission if they meet one of
the following criteria:
Infants < 6 months at diagnosis;
Infants < 12 months at diagnosis with one or more of the following:
CD10 negative blasts
WBC > 100,000/l at diagnosis
M2 or M3 on day 14 bone marrow (M2 = 5-15% blasts; M3 > 15%
blasts)
Children > 12 months <10 years with one of the following:
High risk cytogenetics: t(9;22), t(4;11) or hypodiploidy (< 45
chromosomes)
Children and young adults > 10 years < 21 years of age with one or more of
the following:
High risk cytogenetics: t(9;22), t(4;11) or hypodiploidy (< 45
chromosomes)


MT2001-02
May 30, 2012
Page 8 of 25
WBC at diagnosis > 200,000/OI
Any patient with M2 or M3 bone marrow on day 28 of initial induction (i.e. No CR
in 4 weeks).
3.4.3.2 Patients 21-30 years old are considered high risk and eligible in 1st CR if
they have either:
B-cell ALL (Surface immunoglobulin +) or with t(8;14); t(2;8); or t(8;22).
High risk Cytogenetic features: t(9;22; t(4;11); or hypodiploidy (< 45
chromosomes).
WBC at diagnosis > 20,000/l;
No CR by day 28 of initial induction therapy;
Extramedullary leukemia.
All patients > 30 years old.
3.4.4Myelodysplastic syndrome.
3.4.4.1 RAEB: "refractory anemia with excess of blasts" (RAEB)
3.4.4.2 Cytopenia affecting 2 or more myeloid lines.
3.4.4.3 Less than 5% circulating blasts.
3.4.4.4 Bone marrow evidence of dysgranulopoiesis, dyserythropoiesis, and/or
dysmegakaryocytopoiesis.
3.4.4.5 5-20% blasts in the bone marrow.
3.4.4.6 A history consistent with the above syndrome for greater than three months
prior to bone marrow transplantation.
3.4.4.7 RAEB in Transformation:RAEB as defined above with any of the following
modifications:
5% or more blasts in the peripheral blood.
20-30% blasts in bone marrow.
Presence of Auer rods in granulocytic precursors.
3.4.4.8 Severe Cytopenia and Severe Dysmyelopoiesis: Severe cytopenias of 2 or
more peripheral blood myeloid cell lines (Hb < 10.0 gm with < 1% retics;
absolute granulocyte count < 500/mm3 platelet count < 20,000/mm3)
associated with dysmyelopoietic changes in the bone marrow.


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Page 9 of 25
3.4.4.9 Severe Cytopenia and Clonal Chromosomal Abnormalities: Severe
cytopenias of 2 or more myeloid cell lines associated with clonal,
chromosomal abnormalities of the bone marrow.
3.4.5
Myeloproliferative Diseases – (i.e. myelofibrosis, CMML)
3.4.6
Juvenile myelomonocytic leukemia
3.4.7
Chronic lymphocytic leukemia -- must have all three:
Rai Stage III/IV
Progression after previous CR or PR
Recent chemotherapy responsiveness
3.4.8
Advanced non-Hodgkin's (NHL).
3.4.8.1 Low-grade NHL (working formulation A, B, C) following progression
after initial therapy if asymptomatic at diagnosis (> CR2, > PR2) or if no
CR was achieved (> PR1).
3.4.8.2 Mantle zone after initial therapy (> CR1, > PR1).
3.4.8.3 Intermediate grade lymphoma (> PR2).
3.4.8.4 High-grade NHL (IWF H, I, J) after initial therapy if > stage III at
diagnosis; after any progression even if localized (stage I, II) at diagnosis.
3.4.8.5 Recent chemotherapy responsiveness
3.4.9
Advanced Hodgkin's disease beyond PR2 (> CR3, > PR3).
3.4.9.1 Recent chemotherapy responsiveness
3.4.10 Multiple Myeloma after initial therapy.
3.4.10.1
Advanced (III) stage
3.4.10.2
Beta 2 microglobulin > 6
3.5 Donors and recipients will sign informed consent approved by the Committee on the Use
of Human Subjects at the University of Minnesota.


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4.0
TREATMENT SCHEMA
4.1 Stem Cell Acquisition by Source
4.1.1 Normal related donor priming and apheresis.

If donor is > 12 years of age, > 100 lb.

If recipient is not in Chronic Phase CML

G-CSF administration schedule (donor).
Day -4 through Day 0
Therapy
Transplant day -4
G-CSF, 10 mcg/kg subcutaneously
Transplant day -3
G-CSF, 10 mcg/kg subcutaneously
Transplant day -2
G-CSF, 10 mcg/kg subcutaneously
Transplant day -1
G-CSF, 10 mcg/kg subcutaneously
Transplant day 0
G-CSF, 10 mcg/kg subcutaneously
Apheresis schedule
Transplant day 0
Apheresis
Transplant day +1
G-CSF pre Apheresis if needed.
A target of 5 x 106/kg and a minimum of 4 x 106 CD34+ cell/kg recipient weight
will be collected by apheresis and used for transplant. In most cases this dose will
be recovered in a single apheresis; however, a second or rarely third apheresis
performed on the following days may be required to achieve the minimum dose.
The apheresis product will be administered to the recipient without
cryopreservation on each day of collection.
Donors will receive pre-medications for G-CSF consisting of acetaminophen 650
mg. p.o. every 8 h. beginning the day prior to G-CSF administration and ending
on the first day of apheresis.
Donors may experience any of the following side effects.
Bone pain
Nausea/vomiting
Rash
Headaches
Insomnia
Edema
Body ache
Dyspnea
Fatigue
Other complaints


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Donors experiencing intolerable symptoms (grade 3 toxicity, use CALGB
criteria) attributed to G-CSF therapy will receive dose reduction to 5.0
mcg/kg/d.
Apheresis procedure.
Peripheral blood progenitor cells will be collected with a blood cell separator
(Fenwal CS-3000 plus, Baxter Healthcare Corporation, Deerfield, IL) using a
granulocyte separation chamber, a small volume collection chamber and an
interface offset of 140. The flow rates will range from 50 to 70 mL/minute and a
total of 15 liters of whole blood will be processed over 4-6 hours. The volume of
the apheresis product collected should be 50 mL, but following the collection an
additional 250 mL of autologous plasma will be collected and added to the
apheresis product.
Analysis of CD34+ and CD3 content of blood and aphereses products.
Flow cytometry. Progenitor cell and T-cell (CD3) total content of PBSC
grafts will be determined by FACS.
4.1.2
The patient will receive marrow:

If the recipient is < 18 years of age with a related donor.

If donor is < 12 years of age.

If recipient is in Chronic Phase CML

Donor is unrelated.

Bone marrow will be harvested in accordance with
standard procedure.

Bone marrow dose: 2.0 x 108 nc/kg will be
collected.

4.1.3
Umbilical Cord Blood as the cell source (BU/CY preparative regimen only)
Umbilical cord blood is an alternative to marrow or peripheral blood. The unit(s)
will be selected according to current University of Minnesota umbilical cord
blood graft selection algorithm. One or 2 UCB units may be used to achieve the
required cell dose. Co-enrollment on the University of Minnesota UCB
registration protocol MT2011-13R for minimally processed cords is required.


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4.2
Transplant procedure
4.2.1
Preparatory Regimen Using Total Body Irradiation (TBI) and
cyclophosphamide
Day
-6
cyclophosphamide 60 mg/kg I.V.
-5
cyclophosphamide 60 mg/kg I.V.
-4
TBI AM, PM 165 cGy each dose
-3
TBI AM, PM 165 cGy each dose
-2
TBI AM, PM 165 cGy each dose
-1
TBI AM, PM 165 cGy each dose
0
Stem cell or Bone Marrow Infusion
Total Body Irradiation/cyclophosphamide Regimen
1320 cGy administered in 8 fractions of 165 cGy each with 2 fractions being
given each day. Total body irradiation is given at a dose rate of 10-19
cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
The total body irradiation will be delivered with right and left lateral fields, with
the patient supine on a specially designed couch. Based on measurements of
transverse thicknesses, aluminum compensators will be used to ensure that the
dose homogeneity across the field is within 10% of the prescribed dose. Usually
head/neck, leg and lung compensators are used (although based on calculated
mid-mediastinal doses, lung compensators are often not needed). Total body
irradiation will be delivered with a linear accelerator using 6, 18 or 24 MV xrays.
The energy used will be based on the calculated dose to the midline at points up
and down the patient's torso. The lowest energy that gives 90-100% of the
prescription point dose will be used. A beam "spoiler" will be used to ensure a
full skin dose. Half value layer lung and kidney blocks will not be utilized.
Testicular boosts should be used for all males with ALL (and according to
institutional practice for other diseases). The testicular boost is given in a single
400 cGy fraction with either electrons prescribed to Dmax or photons prescribed
to the midplane of the scrotum. If electrons are used, the energy for the testicular
boost depends on the thickness of the testicles and is chosen so that the D90
corresponds to the posterior surface of the scrotum.
Patients are eligible for any GVHD prophylaxis studies active at the University of
Minnesota.
Cyclophosphamide is to be given as a 2 hour infusion with strict attention given to
vigorous hydration, fluid balance, and maintenance of urine output.


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4.2.2 Alternate preparative therapy for patients not able to receive TBI
Dose and/or schedule modifications based on weight (i.e. for pediatric patients),
clinical issues or current institutional practice are permitted at the discretion of the
treating physician for any drug.
Cyclophosphamide
50 mg/kg iv once daily x 4 days (total 200 mg/kg)
Busulfan
0.8 mg/kg/dose IV in 4 daily doses x 4 days(total
12.8 mg/kg)
Day
Agent
Dose; Administration
- 10
Begin Keppra
- 9
Busulfan
0.8 mg/kg/dose IV every 6 hrs
- 8
Busulfan
0.8 mg/kg/dose IV every 6 hrs
- 7
Busulfan
0.8 mg/kg/dose IV every 6 hrs
- 6
Busulfan
0.8 mg/kg/dose IV every 6 hrs
- 5
Cyclophosphamide
50 mg/kg/day iv over 2 hours
- 4
Cyclophosphamide
50 mg/kg/day iv over 2 hours
- 3
Cyclophosphamide
ATG*
Start GVHD prophylaxis
50 mg/kg/day iv over 2 hours
15 mg/kg IV every 12 hours
- 2
Cyclophosphamide
ATG*
50 mg/kg/day iv over 2 hours
15 mg/kg IV every 12 hours
-1
Rest
ATG*
15 mg/kg IV every 12 hours
0
Stem Cell infusion per current institutional guidelines
+1
Begin G-CSF 5 mcg/kg/day IV until ANC > 2500 x 2 days
*only for UCB recipients who have not had chemotherapy in the preceding 3 months
Keppra will be administered per institutional guidelines through 1 day after the
last dose of busulfan (through day -5).
Busulfan pharmacokinetic monitoring will be done according to institutional
guidelines.
UCB recipients who have not had chemotherapy in the preceding 3 months will
also receive Equine ATG (ATGAM) 15 mg/kg IV will be administered every 12
hours for 6 doses beginning on day -3 per institutional guidelines. The study team
may decide to omit the ATG on an individual patient basis if it is not clinically
warranted. Methylprednisone 1 mg/kg IV will be administered prior to each dose
of ATG per institutional guidelines. Additional steroids and/or other medications
may be used as needed per the discretion of the treating physician.


MT2001-02
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Cyclophosphamide will be given in a two-hour infusion with attention to vigorous
hydration, fluid balance and maintenance of urine output.
Mesna will be administered according to support protocol MT(S) 9006 during
cyclophosphamide infusion.
Patients will be started on G-CSF support on day +1 at 5 mcg/kg (IV/SQ)(round
to vial size) daily until ANC > 2500/μL for 2 consecutive days. Once a patient has 
met these criteria, the ANC will be monitored and G-CSF restarted if ANC falls
to < 1000.
Patients are eligible for any GVHD prophylaxis studies active at the University of
Minnesota or one of the regimens listed below:

Methotrexate and Cyclosporine A as per BMT standard of care protocol
MT1990-07S

Cyclosporine A and Mycophenolate mofetil as below
Cyclosporine A
Cyclosporine A (CSA) will start day -3 and will be administered PO/IV
maintaining a trough level between 200 and 400 ng/mL. For adults the
initial dose will be 2.5 mg/kg IV over 1 hour every 12 hours. For children
< 40 kg the initial dose will be 2.5 mg/kg IV over 1 hour every 8 hours.
CSA dosing will be monitored and altered as clinically appropriate per
institutional pharmacy guidelines. Dose adjustments will be made on the
basis of toxicity and/or low CSA levels.
Patients will receive CSA until approximately day +100. If no GVHD, the
dose will then be tapered 10% per week and discontinued approximately
at 6 months.
Mycophenolate mofetil (MMF)
Mycophenolate mofetil (MMF) 3 gram/day IV/PO for patients who are ≥ 
40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will
receive MMF at the dose of 15 mg/kg/dose every 8 hours beginning day -
3. MMF dosing will be monitored and altered as clinically appropriate
based on institutional guidelines. Patients will be eligible for MMF dosing
and pharmacokinetics studies.
Stop MMF at day +30 or 7 days after engraftment, whichever day is later,
if no acute GVHD. (Definition of engraftment is 1st day of 3 consecutive
days of absolute neutrophil count [ANC) > 0.5 x 109 /L]).


M T 2 0 0 1- 0 2
Ma y 3 0, 2 0 1 2
Pa ge 1 5 of 2 5
If t he pati e nt has ac ute G V H D re q uiri n g s yste mic t hera p y,
M M F ma y be
st o p pe d 7 da ys aft er i niti ati o n of s yst e mi c t hera p y f or ac ut e G V H D (e. g.
res ol uti o n of s ki n ras h, v o miti n g, a n d diarr h ea).
4. 3 
S u p p o rti ve C are
D ose a n d/ or sc he d ule m o dificati o ns base d o n wei g ht (i.e. f or pe diatric patie nts), cli nical iss ues or
c urre nt i nstit uti o nal practice are per mitt e d at t he discreti o n of t he treati n g p h ysicia n f or a n y dr u g.
4. 3. 1
All patie nts will recei ve all o p uri n ol ( 3 0 0 m g/ d or 1 5 0 m g/ M 2/ d p. o.) be gi n ni n g
o ne da y pri or t o c h e m ot hera p y a d mi nistrati o n a n d e n di n g o ne da y f oll o wi n g t he
last c he m ot hera p y or T BI a d mi nistrati o n u nl ess h y p er uri ce mi a ( > 1 0 m g/ dl)
persists.
4. 3. 2 
Vi g or o us i ntra ve n o us h y drati o n ( 2 0 0 0 3 0 0 0 ml/ m 2/ da y) s h o ul d be gi ve n fr o m 1 2
h o urs pri or t o t he first c ycl o p h os p ha mi de d os e u ntil 2 4 h o urs past t he t er mi nati o n
of c ycl o p h os p ha mi de t hera p y.
A de q uate di ureti cs s h o ul d be gi ve n a n d pati e nts
ur ge d t o uri nate e ver y 1- 2 h o urs t o e ns ure uri nar y o ut p ut of at l east 2 0 0 ml/t w o
h o urs t o mai nt ai n a p pr o pri at e fl ui d bala nc e. Patie nts s h o ul d be wei g he d BI D
d uri n g c ycl o p h os p ha mi d e a d mi nistrati o n t o ai d i n ma n a gi n g fl ui d bala nce.
4. 3. 3
Mes n a s h o ul d be gi ve n i n t otal milli gra m d ose e q ui vale nt t o t he
c ycl o p h os p ha mi de d ose q d ( di vi de d i n 5 d oses: pre, 3 h o ur, 6, 9 a n d 1 2 h o urs
after) be gi n ni n g at t he ti me of c ycl o p h os p ha mi de a d mi nistrati o n a n d
c o nti n ui n g u ntil c ycl o p h os p ha mi de t hera p y is ter mi nate d.
4. 3. 4
All reci pie nts re cei vi n g P B S C will recei ve G- C S F 5 mc g/ k g/ d a d mi nistere d I. V.
o ver 1 5 mi n. starti n g o n da y + 1 a n d c o nti n ui n g u ntil A N C > 2 5 0 0/ ml. x 2 da ys.
4. 3. 5
If
W B C < 1 0 0 at da y + 2 1, t he n a d d G M- C S F 2 5 0 mc g/ m 2/ da y I V i n a d diti o n t o G-
C S F. F oll o w s u p p ort pr ot oc ol f or " A p pr oa c h t o graft fail ure."
4. 3. 6
Patie nts will be eli gi bl e f or a d diti o nal s u p p orti ve care st u d y pr ot o c ols i ncl u di n g,
b ut n ot li mite d t o, t h ose relate d t o pr o p h yla xis a n d treat me nt of i nfe cti o n,
m uc ositis a n d/ or n utriti o nal s u p p ort.
4. 3. 7
All bl o o d pr o d uct s u p p ort a d mi nist ere d wit hi n o ne wee k prece di n g, a n d f oll o wi n g
i niti ati o n of c he m ot hera p y will be irr a diate d t o pre ve nt i na d verte nt bl o o d d o n or
l y m p h oi d e n graft me nt.
4. 3. 8
Sta n dar d bl o o d pr o d uct s u p p ort tec h ni q ues will be use d, i ncl u di n g pa c ke d re d cell
tra nsf usi o ns t o mai nt ai n he m o gl o bi n > 8. 0 g/ dl, pl at el et tra nsf usi o n s u p p ort t o


MT2001-02
May 30, 2012
Page 16 of 25
maintain platelet counts > 10,000/l. Leukocyte transfusions will be indicated
only under uncommon circumstances after discussion with the attending
physician.
5.0
REQUIRED OBSERVATIONS: DONORS
5.1
Anti-HIV, Hepatitis B, surface antigen, anti-HCV, CMV, HSV, EBV serologies,
pre-priming.
5.2
CBC, platelet count
5.2.1
CBC platelet count each day of aphereses, day 0 (or 1 or 2 as needed).
6.0
REQUIRED OBSERVATIONS: RECIPIENT
6.1
Anti-HIV, hepatitis B surface antigen, anti-HCV, CMV, HSV, or EBV serologics
pretransplant.
6.2
Suitable markers of donor recipient chimerism pretransplant to include
cytogenetics, RFLP.
6.3
Engraftment:
6.3.1
Time to first of 3 consecutive days with ANC > 500.
6.3.2
Time to platelet transfusion independence.
6.3.3
Time to RBC transfusion independence.
6.4
Incidence of late graft failure.
6.5
Incidence and severity of acute GVHD.
6.6
Incidence and severity of chronic GVHD.
6.7
Donor chimerism at +3 mos., +6 mos., +12 mos.
7.0
TOXICITIES AND COMPLICATIONS
7.1
Donor


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Page 17 of 25
7.1.1
G-CSF. Administration of G-CSF in normal donors can be associated
with bone pain, headaches, body aches, fatigue, nausea, vomiting,
insomnia, dyspnea and other symptoms. Such symptoms are usually
minor, and may be controlled with administration of acetaminophen.
However, symptoms can occasionally be dose-limiting or require
cessation of G-CSF administration.
G-CSF administered in normal donors has rarely been associated with
hypokalemia and hypoglycemia. G-CSF administration may also be
associated with elevation of bilirubin, ALT and alkaline phosphatase.
These are transient abnormalities.
7.1.2
Apheresis
If antecubital veins are not suitable for apheresis, large-bore, Quinton
catheters in neck veins are required for the venous access necessary to
perform apheresis and peripheral blood progenitor cell collections. The 4-
6 hour collection procedures are occasionally associated with reversible
hypotension. Thrombocytopenia may develop transiently following the
apheresis especially if several aphereses are performed. G-CSF
administration may suppress the marrow response to thrombocytopenia.
Hypocalcemia secondary to the citrate anticoagulation may produce
tingling or paresthesis. Calcium supplements will be given as needed.
7.2
Recipient
7.2.1
Cyclophosphamide or Busulfan
Hemorrhagic cystitis may occur following the use of cyclophosphamide
despite aggressive fluid replacement, frequent voiding and Mesna.
Cyclophosphamide can cause fatal cardiac necrosis with clinical
irreversible heart failure. EKG changes are not infrequent and reduction
in EKG voltage may be observed. Patients previously treated with
anthracyclines or with mediastinal irradiation may be at higher risk.
Cyclophosphamide (with or without irradiation) may also induce
pericarditis.
Nausea, vomiting and diarrhea are frequent following high doses of
cyclophosphamide or busulfan. Aggressive anti-emetic therapy, including
Ondansetron, may be helpful in minimizing this problem.
Alopecia is common. It is usually reversible, but changes in hair color or
texture after regrowth may occur.


MT2001-02
May 30, 2012
Page 18 of 25
Skin rash may occur, but is infrequent. Busulfan may produce skin
hyperpigmentation.
Sterility: Permanent sterility is likely at this dose of cyclophosphamide,
particularly when given with other drugs and/or irradiation.
Busulfan may produce lung inflammation (pneumonitis), liver injury
leading to veno-occlusive disease and rarely seizures.
7.2.2
Total body irradiation
1320 cGy is administered in 8 fractions over 4 days. Nausea, vomiting
and diarrhea are common.
Generalized mild cutaneous erythema is frequently seen.
Parotitis may occur.
Lung: Inflammatory pneumonitis or even respiratory failure may develop
in the first three months following TBI. Late respiratory failure has been
seen in a small fraction of patients.
Liver: veno-occlusive disease may cause fluid retention, ascites, or renal
failure.
Sterility: Sterility is common after this dose of total body irradiation.
Brain damage can develop in a small fraction of treated patients.
7.2.3
Myelosuppression
Both the chemotherapy + TBI, or the chemotherapy only conditioning
induce significant myelosuppression requiring reinfusion of viable
hematopoietic stem cells for prompt marrow recovery. During the period
of myelosuppression and pancytopenia, the patient is highly vulnerable to
infection and/or bleeding. Irradiated red cell transfusions will be given to
maintain adequate oxygen delivery and platelet transfusions will be given
in an attempt to prevent bleeding. Various isolation and prophylactic
measures to reduce risks of infection and to vigorously treat any infections
will also be required.
7.2.4
Graft Failure


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Page 19 of 25
Infusion of allogeneic peripheral blood or bone marrow may be associated
with failure to engraft, partial engraftment of one, two, or three cell
lineages or late graft failure. Risk of graft failure will be minimized by
providing a targeted CD34+ cell dose of 5 x 106/kg recipient weight.
Graft failure may be treated with growth factors, infusion of additional
PBPC or of marrow or PBPC obtained from the original donor after
recognition of graft failure.
7.2.5
Graft vs. Host Disease (GVHD)
Infusion of allogeneic PBPC may be associated with development of acute
and/or chronic GVHD. An attempt to reduce incidence and severity of
GVHD will be made by limiting infusion of peripheral cells to a target
dose of 5 x 106 34+/kg recipient weight or 2.0 x 108 nc/kg of marrow cells
and by using GVHD prophylaxis consisting of methotrexate (MTX) and
cyclosporine (CSA) or alternative GVHD prophylaxis study approaches.
If Greater than 45kg: Cyclosporine 2.5mg/kg over 2 hours every
12 hours, begin on Day -3.
If Less than 45Kg: Cyclosporine 2.5mg/kg over 2 hours every 8
hours, begin on Day -3.
Cyclosporine Levels every Monday, Wednesday, and Friday beginning
Day -1 to Day +7, then Cyclosporine Levels every Monday.
7.2.6
Second Malignancy
The potential carcinogenic effects of the pre-transplant chemotherapy
and/or radiation may compound any inherent risks of second malignancy
already induced by treatment the patient may have already received. Both
late second epithelial malignancies and early treatment-associated
neoplasms (particularly post-transplant lympho-proliferative disorders)
may develop after transplantation.
8.0
STATISTICAL CONSIDERATIONS
8.1
Patient Accrual


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May 30, 2012
Page 20 of 25
Based on the BMT patient referral pattern of the University of Minnesota, we
expect to accrue up to 50 cases to this study each year. The overall case accrual
will be 350.
8.2
Statistical Analysis
The major end points of this study are engraftment failure, time to engraftment,
incidence and severity of acute and chronic GVHD, persistence or relapse of
malignancy and survival of the recipient. Data will be collected by nurse
coordinators and the personnel of the Biostatistical Support Group of the
University of Minnesota Blood and Marrow Transplant Program using
prospective data plans already in place for all patients enrolled in institutional
BMT protocols. These standard clinical end points will be evaluated using
conventional survival analysis methods, including the Kaplan-Meier or
cumulative incidence method and Cox proportional hazard models. Results will
be compared to historical data of allogeneic bone marrow transplantation.
Complication rates of recipients (and donors, if any) will be monitored and
descriptive statistics will be employed to assess their incidence. These will
include pneumonitis, veno-occlusive disease of the liver, hemorrhagic cystitis and
serious infection.
Note: Patients enrolled on additional investigational studies including, but not
limited to Treg infusions, may have their outcomes analyzed separately
8.3
Study Data & Safety Monitoring
This institutional continuing case series will be monitored by the PI and the Study
Committee assisted by the personnel and facilities of the Biostatistical Support
Group of the University of Minnesota Blood and Marrow Transplant Program.
Major and unexpected serious adverse events will be examined and reviewed
periodically. All on study deaths will be reviewed by the PI and as indicated by
the study committee and are reported to the IRB. Examination of accrual and
survival outcomes will be performed as indicated by study events or as required
by regulatory committees including the Cancer Center Protocol Review
Committee and the IRB.
DATA AND SAFETY MONITORING PLAN
This study will be in compliance with the University of Minnesota Cancer Center's Data &
Safety
Monitoring
Plan,
which
can
be
accessed
at
http://www.cancer.umn.edu/page/resource/dataplan.html


May 30, 2012
Page 21 of 25
At the time of the IRB continuing review, the Principal Investigator will provide a copy of the
report to the DSMC.


May 30, 2012
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APPENDIX I
SCHEDULE FOR G-CSF (10 mcg/kg/day) ADMINISTRATION to DONOR
Number of G-CSF vials Given per Day
Donor Weight
(kg)
1.0 mL (300 µg)
Vials
1.1 mL (480 µg)
Vials
Daily G-CSF Dose
µg/kg/day
Daily G-CSF
Dose Response
(µg/kg/day)
40 to 48
0
1
480
10 to 12.0
49 to 60
2
0
600
10 to 12.2
61 to 78
1
1
780
10 to 12.8
79 to 90
3
0
900
10 to 11.4
91 to 96
0
2
960
10 to 10.5
97 to 108
2
1
1080
10 to 11.1
109 to 120
4
0
1200
10 to 11.0
121 to 126
1
2
1260
10 to 10.4
127 to 138
3
1
1380
10 to 10.9
139 to 144
0
3
1440
10 to 10.4
145 to 150
5
0
1500
10 to 10.3
151 to 168
4
1
1680
10 to 11.1
169 to 174
1
3
1740
10 to 10.3


May 30, 2012
Page 23 of 25
APPENDIX TWO: TBI GUIDELINES
Fractionated Total Body Irradiation (In Lateral Position)
1320 cGy administered in an 8 fractions of 165 cGy each with 2 fractions being given each day.
Total body irradiation is given at a dose rate of 10-19 cGy/minute prescribed to the midplane of the
patient at the level of the umbilicus.
The total body irradiation will be delivered with right and left lateral fields, with the patient supine on
a specially designed couch.
Based on measurements of transverse thickness, aluminum compensators will be used to ensure that
the dose homogeneity across the field is within 10% of the prescribed dose. Usually head/neck, leg
and lung compensators are used (although based on calculated mid-mediastinal doses, lung
compensators are often not needed).
Total body irradiation will be delivered with a linear accelerator using 6, 18, 24 MV X-rays. The
energy used will be based on the calculated dose to the midline at points up and down the patient’s
torso. The lowest energy that gives 90-100% of the prescription point dose will be used.
A beam “spoiler” will be used to ensure a full skin dose.
Half value layer lung and kidney blocks will not be utilized.
Testicular boosts should be used for all males with ALL (and according to institutional practice for
other diseases). The testicular boost is given in a single 400 cGy fraction with either electrons
prescribed to Dmax or photons prescribed to the midplane of the scrotum. If electrons are used, the
energy for the testicular boost depends on the thickness of the testicles and is chosen so that the D90
corresponds to the posterior surface of the scrotum.


May 30, 2012
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