Clinical trial NCT00167219
Conditions: Juvenile Myelomonocytic Leukemia
Keywords: Stem cell transplant long term survival retinoic acid
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 1999-11-18; Completion date: 2023-08-09
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators hypothesize that long-term disease-free survival (DFS) in patients with JMML can be achieved with a treatment of busulfan (BU), cyclophosphamide (CY) and melphalan (L-PAM) followed by hematopoietic cell transplantation (HCT).

Detailed description:
Prior to transplantation, subjects will receive BUSULFAN via the central venous line, six times a day for four days, CYCLOPHOSPHAMIDE via the central venous line once a day for two days, and MELPHALAN via the central venous line for one day. Busulfan, cyclophosphamide, and melphalan are given to destroy the subject's leukemia. As well, these drugs will destroy the subject's own immune system to help ensure the new bone marrow takes and grows after transplantation.

On the day of transplantation, bone marrow or umbilical cord blood from the donor will arrive to the bone marrow transplant unit and be transfused via venous line. These new cells will replace the subject's bone marrow.

Arms: arm 1: Patients receiving study regimen.
Interventions: intervention 1: Stem Cell Transplant intervention 2: Preparative Regimen
Intervention descriptions: intervention 1: Transplantation on Day 0. intervention 2: * Busulfan
* Cyclophosphamide
* Mesna
* Melphalan
* Anti-thymocyte Globulin (ATG)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
  
  
  
  
  
  
  
  
UNIVERSITY OF MINNESOTA BONE MARROW TRANSPLANTATION PROTOCOL  
  
  
HEMATOPOIETIC CELL TRANSPLANTATION IN CHILDREN WITH JUVENILE  
MYELOMONOCYTIC LEUKEMIA  
  
MT1999-20  
  
  
  
  
  
  
  
Revised January 3, 2022  
  
  
Study Committee  
  
Margaret L MacMillan, MD  
John E Wagner, MD  
Todd E. DeFor, MS  
  
  
This document contains confidential information that is the property of the Blood and Marrow  
Transplant Program.  Do not copy, disclose, or circulate without written authorization from the 
University of Minnesota, Fairview Blood and Marrow Transplant Services Medical Director.  
  
  
DATE  
PROTOCOL CHANGE  
2/4/2005  
Section 5.1.2.5: values for creatinine clearance added to eligibility criteria.  
5/4/2006  
MMF replaces methylprednisone as GVHD prophylaxis in cord blood recipients  
07/15/2008  
Revised for study reapplication, increased enrollment goal to 20  


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Page 2 of 23  
02/16/2009  
Remove Scott Baker as co-investigator. Update registration, DSMP, time to keep 
study records, add adverse event reporting section per CPRC annual review.  
01/08/2015  
Protocol:  
MMF replaces methylprednisone (MP) as GVHD prophylaxis for all cell sources 
Add retinoic acid to begin on day 60 through 1 year post transplant (mentioned in 
the consent form, but not in the protocol)  
Add ATG to the preparative regimen in section 4.1, currently only in section 7.4  
Update seizure prophylaxis to levetiracetam (Keppra)  
Update adverse event reporting section to current IRB and MCC requirements 
Both treatment consent forms:  
Delete pregnancy language – JMML occurs only in very young children (< 4 
years of age) while retaining the risks of future fertility issues Correct Busulfan 
dosing schedule  
Add ATG treatment details  
Add risks of retinoic acid   
Update both treatment consents to match protocol and current template language 
Bone marrow as donor consent only (additional change):  
Replace MP with MMF as GVHD prophylaxis  
  
10/03/2017  
Protocol  
Revised ATG dosing to current standard of care  
Tacrolimus replaces  cyclosporineas GVHD prophylaxis  
Updated eligibility to current definition of JMML 
Updated toxicity information to current tables  
Consents  
Updated HRPP contact information  
Updated GVHD drug information  
10/19/2021  
Per IRB request, updated section 9.3 to match study accrual period in section 9.1  
1/3/2022  
Updated section 9.1 and 9.3 to match consent  
Section 4 - updated all chemotherapy dosing instructions to match current standard 
of care and   
Section 7 - removed redundancies  
Removed Appendix 1 – eligibility checklists are housed in Oncore  
Additional standard template language added to clinical follow up 
Corrected link to DSMP plan  
TABLE OF CONTENTS  
  
 
1.0  
TITLE   
  
  
  
  
  
  
  
  
  
4  
  
 
2.0  
OBJECTIVES   
  
  
  
  
  
  
  
  
4  
  2.1  
Primary objective  
  
  
  
  
  
  
  
4   
2.2 
 Secondary objective  
  
  
  
  
  
  
  
4  
  


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3.0  
BACKGROUND AND RATIONALE   
  
  
  
  
  
4  
  
 
4.0  
TREATMENT SCHEMA  
  
  
  
  
  
  
  
6  
 
  
4.1  
Preparative therapies  
  
  
  
  
  
  
  
7  
 
  
4.2  
Hematopoietic stem cell source   
  
  
  
  
  
8  
 
  
4.3  
Graft-versus-host disease prophylaxis    
  
  
  
  
8  
  4.4  
Retinoic acid    
  
  
  
  
  
  
  
9   
4.5 
 Supportive care   
  
  
  
  
  
  
  
9  
  
 
5.0  
ELIGIBILITY AND EXCLUSION CRITERIA   
  
  
  
  
9  
 
  
5.1  
Inclusion criteria  
  
  
  
  
  
  
  
9  
 
  
5.2  
Exclusion criteria  
  
  
  
  
  
  
  
10  
  
 
6.0  
REQUIRED OBSERVATIONS   
  
  
  
  
  
  
10  
 
  
6.1  
Patient pre-study assessment  
  
  
  
  
  
  
10  
 
  
6.2  
Patient evaluation during therapy until engraftment  
  
  
  
10  
 
  
6.3  
Patient evaluation on day 60, 100 and 180 and then annually for 2 years   
10  
  
 
7.0  
TOXICITIES AND COMPLICATIONS   
  
  
  
  
  
11  
 
  
7.1  
Busulfan  
  
  
  
  
  
  
  
  
11  
 
  
7.2  
Cyclophosphamide  
  
  
  
  
  
  
  
11  
 
  
7.3  
Melphalan  
  
  
  
  
  
  
  
  
12  
 
  
7.4  
Antithymoctye globulin   
  
  
  
  
  
  
13  
 
  
7.5  
Hematopoietic stem cell infusion  
  
  
  
  
  
14  
 
  
7.6  
Retinoic Acid   
  
  
  
  
  
  
  
14 
 
  
7.7  
Toxicities Associated with GVHD Prophylaxis   
  
  
  
14  
  
  
8.0  
ADVERSE EVENT REPORTING  
  
  
  
  
  
  
15  
  
 
9.0  
EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS  
  
16  
  
 
10.0  
INFORMED CONSENT  
  
  
  
  
  
  
  
18  
  
 
11.0  
DATA AND SAFETY MONITORING PLAN   
  
  
  
  
18  
  
 
12.0  
REGISTRATION PROCEDURES  
  
  
  
  
  
  
19  
  
 
REFERENCES   
  
  
  
  
  
  
  
  
  
19  
  
  
  
1.0  
TITLE  
  
Hematopoietic cell transplantation in children with juvenile myelomonocytic leukemia.  
  


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2.0  
OBJECTIVES  
  
2.1  
Primary Objective  
  
To determine the probability of long-term disease-free survival in patients with JMML treated with 
busulfan (BU), cyclophosphamide (CY) and melphalan (L-PAM) followed by hematopoietic cell 
transplantation.  
  
2.2  
Secondary Objectives  
  
To determine:  
  
1. 
probability of engraftment  
2. 
incidence and severity of acute and chronic graft-versus-host disease (GVHD)  
3. 
incidence of regimen-related toxicity  
4. 
incidence of relapse  
  
  
3.0  
BACKGROUND AND RATIONALE  
  
JMML is a rare myeloproliferative disease of very young children (age <4 years), accounting for less 
than 2% of childhood leukemias.  Approximately 40 cases occur annually in the US, corresponding to 
an incidence of 0.61 cases per year per million children.1  Few treatment approaches other than HCT 
have been shown to be beneficial for children with JMML with median survival of 1-2 years 
commonly reported.1-3  Intensive chemotherapy may prolong survival but has not been shown to be 
curative.4,5  Recent studies suggest that isotretinoin may benefit a proportion of children with JMML; 
however, its potential to affect long term survival is unclear.6,7  To date, long-term DFS has only been 
achieved using HCT.8-21  
  
Aricò et al (1997) reviewed the outcome of 91 patients with JMML treated with HCT in 16 different 
reports.3  Thirty-eight patients (41%) were still alive at time of reporting, including 30 of the 60 
(50%) patients who received grafts from HLA-matched or one-antigen mismatched familial donors, 2 
of 12 (17%) with mismatched donors, and 6 of 19 (32%) with matched unrelated donors.  Transplant 
results reported from the Fred Hutchinson Cancer Center (Sanders et al, 1988) and recently updated 
(Smith et al, 1994) include 27 children with JMML treated with preparative regimens that included 
dimethylbusulfan, busulfan, cyclophosphamide, and/or TBI followed by allogeneic HCT.8-10  
Unmodified marrow was obtained from HLA-identical siblings (n=10), family members differing by 
1, 2, or 3 antigens (n=14), or HLA minor-mismatched unrelated donors (n=3).  Graft-versus-host 
disease (GVHD) prophylactic regimens included the use of methotrexate (MTX), cyclosporine  
(CSA), anti-thymocyte globulin (ATG), steroids, and anti-T cell antibodies.  Acute GVHD (grades 
IIIV) occurred in 50% of recipients of matched sibling donor HCT and in 76% of recipients of 
mismatched or unrelated grafts.  Six patients died within the first three months from graft rejection 
(n=1), fungal infection (n=1), or interstitial pneumonia (n=4).  Two patients developed secondary 
malignancies, one with myelodysplasia at one year, and one with a fatal chondrosarcoma at 17 years.  


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Recurrent leukemia occurred in ten patients from 1.6 to 56 (median 2.8) months and nine have died.  
Seven patients underwent a second transplant for relapse of disease or graft rejection.  None of these 
patients survived.  While the numbers of patients are small, there was no apparent association 
between the type of preparative regimen, degree of HLA disparity, pre-transplant chemotherapy or 
pre-transplant splenectomy and survival.  Five patients survive disease-free (DFS) from 2.7-10 
(median 7.3) years.  Cumulative incidence estimates of non-relapse mortality and relapse at five years 
are 44% and 49%, respectively, with a Kaplan-Meier estimate of DFS at five years of 25%.  
  
Six bone marrow transplant recipients have been reported by Bunin et al (1992).12  These children 
received T-cell depleted bone marrow grafts (using T10B9 monoclonal antibody plus complement) 
from HLA-mismatched related donors or HLA-matched unrelated marrow donors after a preparative 
regimen of busulfan, cytosine arabinoside, cyclophosphamide, methylprednisolone and 
hyperfractionated TBI.  GVHD prophylaxis was with CSA.  All patients engrafted with acute GVHD 
< grade II in all patients.  Two patients died of infection with one patient relapsing on day +939.  
Three of six patients were disease-free survivors at days 180+, 1610+, and 2400+ at the time of the 
report.  
  
Twelve children with JMML, 5 of whom also had Monosomy 7, underwent transplantation in Paris.16  
Seven patients were recipients of matched sibling marrow, 4 from mismatched related donors and one 
from a matched unrelated donor.  Conditioning regimens were different for all patients, consisting of 
chemotherapy +/- TBI.  In the matched sibling recipients, five engrafted after chemotherapy 
conditioning.  Two patients failed to engraft, one having received chemotherapy alone, the other 
having had chemotherapy and TBI as conditioning.  Long-term remission was achieved in three 
patients and two others are in remission 6 and 11 months post HCT.  In contrast, HCT with marrow 
from mismatched related donors failed in five patients because of graft failure in 3 patients and 
relapse in two.  One patient engrafted well after receiving a chemotherapy regimen and a matched 
unrelated donor transplant and remains in remission.  
  
The European Working Group on Myelodysplastic Syndrome in Childhood (EWOG-MDS) report on 
43 children with JMML who underwent HCT.20  Eight of these patients also had Monosomy 7.  
Twenty-two patients were given TBI and chemotherapy, which included cyclophosphamide.  Twenty 
one patients were conditioned with busulfan in combination with cytoxan alone, or with etoposide, or 
melphalan.  Six of the total 43 patients (14%), 5 of whom received HCT from an alternative donor, 
failed to engraft.  GVHD prophylaxis consisted of CSA alone, MTX alone, both of these agents, or 
both agents with anti-thymocyte globulin or monoclonal antibodies.  One child received T-cell 
depleted marrow.  Grade II to IV acute GVHD occurred in eight of 24 patients (33%) transplanted 
from HLA-identical siblings or one-antigen-mismatched relatives and in eight of 13 patients (62%) 
given HCT from other HLA-partially matched family donors or unrelated donors.  Transplant related 
mortality was 20% for the entire group, 9% for children given HCT from HLA-identical/one-
antigendisparate relatives, and 46% for patients transplanted using other HLA-partially matched 
family donors or mismatched unrelated donors.  Twenty-two (58%) children relapsed, at a median of 
3.5 months after HCT.  The 5 year Kaplan-Meier DFS for the entire cohort of patients was 31  7%.  
The actuarial probability of DFS for children transplanted from HLA-partially matched family donors 
or unrelated volunteers was 22 +/- 10% whereas the DFS for children given HCT from an 


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Page 6 of 23  
HLAidentical sibling or one-antigen disparate relative was 38 +/- 10%.  A shorter interval between 
diagnosis and HCT was associated with improved DFS probability.  Patients who received 
chemotherapy alone preparative regimen had a better EFS compared to those treated with a TBI 
containing regimen (48 ± 11% vs 15 ± 8%, p <.05).  
  
At the University of Minnesota, seven children, 11 months to 5.9 years of age, with JMML underwent 
allogeneic HCT over the past 14 years.21  All patients had active disease at time of transplant despite 
chemotherapy in 4 patients and chemotherapy and splenectomy in one patient prior to conditioning.  
Patients received related or unrelated bone marrow or umbilical cord blood (UCB) after a preparative 
regimen of cyclophosphamide and TBI, with the addition of busulfan in two cases.  Six patients 
engrafted without difficulty; primary graft failure occurred in one patient who required two further 
HCT to achieve engraftment.  Six patients relapsed post HCT, at a median of 67 days, four of whom 
subsequently died.  One relapsed patient achieved a second sustained remission after CSA was 
abruptly withdrawn to induce graft-versus-leukemia (GVL).  Two patients are in remission more than 
2 years and 2.5 years after HCT.  
  
As JMML affects only very young children, preparative regimens which avoided radiation-induced 
long term sequelae, such as growth retardation and neuropsychological impairment were developed.  
A conditioning regimen consisting of three alkylating agents, busulfan, cyclophosphamide and 
melphalan has been shown to be effective in patients with JMML.  Results from the European Group 
(EWOG-MDS) showed that in the group of children given BMT from an HLA-identical sibling or 
one-antigen-disparate related donor, patients given busulfan had a lower risk of relapse (38 +/- 13% 
vs 78 +/- 17%), which resulted in a significantly better EFS in comparison to those treated with TBI  
  
(62% vs 11%).20 
  
The levels of oral busulfan have been shown to be quite variable, presumably due to  marked 
differences in absorption and/or clearance.22  In addition, there is some suggestion that increased 
plasma levels may relate to enhanced toxicity, while inadequate levels may be associated with graft 
failure.23  The recent availability of an intravenous form of the drug may result in decreased variation 
of the pharmacokinetics of the drug.24  The drug has been tested in children using a dose of 0.8 
mg/kg; however, it was determined that in children less than 4 years of age the clearance was more 
rapid and in this population a dose of 1.0 mg/kg will be used.25    
  
In summary, HCT offers the only possibility of a cure for patients with JMML.  To prevent relapse, 
abrupt withdrawal of CSA, inducing GVL has resulted in sustained second remissions in a few 
patients with relapsed JMML after HCT.21,26-28  Scheduled early tapering of CSA after HCT may 
promote GVL and prevent early relapse.  
  
4.0  
TREATMENT SCHEMA  
  
This is a phase II single arm trial to evaluate the efficacy of busulfan, cyclophosphamide and 
melphalan and allogeneic hematopoietic cell transplantation in the treatment of JMML. This study 
will not be able to determine if pre-transplant chemotherapy or splenectomy is efficacious, nor will it 


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identify a superior stem cell source.  The intent of this proposal is to provide a common protocol that 
will use unmanipulated allogeneic hematopoietic stem cells from related and unrelated donors after a 
common preparative regimen.  Results will be compared to prior reports using cyclophosphamide and 
total body irradiation after which the probability of engraftment, toxicity, and event free survival are  
50-97%, 9-28% and 38-50% after sibling donor BMT and 50-65%, 46-67%, and 17-22% after 2- to  
3-antigen disparate relative or unrelated donor BMT.10,16,19  
  
4.1  
Preparative Therapies  
  
The preparative cytoreductive therapy will be identical for all patients.  Toxicities related to each 
regimen are defined in Section 9.0.  
  
 
4.1.1  Design/Therapy Plan  
  
Busulfan (intravenous) dose, administration and pharmacokinetic monitoring to be 
administered per institutional standard of care (SOC).    
Cyclophosphamide 60 mg/kg/day IV x 2 days (administered with Mesna 60 mg/kg/day)  
Melphalan 140 mg/m2 IV x 1 day  
ATG 30 mg/kg/day IV over 4-6 hours every 24 hours (UCB recipients only)   
  
  
Days Prior to BMT  
-7  
-6  
-5  
-4  
-3  
-2  
-1  
0  
+1  
Busulfan IV daily*  
•  •  •  
•    
  
  
  
  
Cyclophosphamide 60 mg/kg/day** 
Mesna 60 mg/kg/day   
  
  
  
  
•  •  
  
  
  
2 
Melphalan 140 mg/m ***  
  
  
  
  
  
  
•    
  
ATG 30 mg/kg/day IV over 4-6 
hours every 24 hours (UCB 
recipients only)  
  
  
  
  
•  •  
•    
  
Stem Cell Infusion  
  
  
  
  
  
  
  
•    
*  
Model-based dosing utilizing Bayesian methodology and therapeutic drug monitoring per 
Institutional SOC  
**  
Infusion over 2 hours.  
***  
Infusion over 15 minutes.  
  
 
4.1.2  Busulfan  
  
Busulfan is to be given as a 3 hour intravenous infusion.  As seizures have occurred following 
high dose busulfan, all patients will be treated with levetiracetam (Keppra) per institutional 
guidelines.. Busulfan area under the curve (AUC) analyses will be calculated in-house per 


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University of Minnesota BMT SOC guidelines. Busulfan therapeutic drug monitoring (TDM) 
will be used to target a cumulative exposure for the entire course cAUC=68-76 mg*hr/L 
(target 72 mg*hr/L). Results of TDM performed with the first dose will inform subsequent 
dosing. Refer to busulfan SOC for sample collection process, busulfan results reporting and 
TDM procedures.    
    
 
4.1.3  Cyclophosphamide  
  
Cyclophosphamide is to be given as a 2 hour intravenous infusion. Mesna 60 mg/kg and IV 
hydration will be administered per institutional guidelines. Cyclophosphamide dosing is 
calculated based on actual weight (ABW) unless ABW is >150% above Ideal Body Weight 
(IBW) per institutional guidelines.    
  
 
4.1.4  Melphalan  
  
Melphalan is to be given as a 15 minute infusion on day -1. For children < 10 kg, melphalan 
dosing will be 4.67 mg/kg IV x 1 dose.    
  
4.1.5 Antithymocyte Globulin - equine (ATG)  
  
ATG 30 mg/kg/day IV over 4-6 hours every 24 hours on day -3, -2 and -1 to umbilical cord 
blood (UCB) recipients only.  
  
Pre-medications will be administered 30 minutes prior to each dose of ATG including:  
• acetaminophen (10 mg/kg orally; maximum dose 500 mg)  
• diphenhydramine (1 mg/kg IV or PO; maximum dose 50 mg)  
• methylprednisolone (1 mg/kg IV; maximum dose 125 mg)  
  
4.2 
Hematopoietic Stem Cell Source  
  
Acceptable stem cell sources include: HLA-matched related or unrelated donor bone marrow (6/6 or 
5/6 antigen match) and related or unrelated donor umbilical cord blood (6/6, 5/6 or 4/6 match).  
HLAmatch is determined by serology for class I antigens (HLA A, B) and high resolution DNA 
typing for class II (DRB1) unless parental typing is available (DR is satisfactory).  The stem cell 
source will not be manipulated (T-cell depletion, CD34+ cell selection, etc.).  Cord blood units 
selected for transplantation as per institutional guidelines.  
  
  
4.3 
Graft-Versus-Host Disease Prophylaxis  
  
GVHD prophylaxis will be as per University of Minnesota GVHD prophylaxis protocols.   
  
All patients (regardless of allograft source) will receive tacrolimus therapy beginning on day –3.    
  


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Tacrolimus 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 tacrolimus levels.   
  
Tacrolimus taper begins at day +100 or 1 month after control of GVHD.  Taper to zero by 10% 
weekly dose reduction over approximately 10 weeks.    
  
  
All patients will begin mycophenolate mofetil (MMF) on day -3.  Patients ≥ 40 kilograms will receive 
MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).  Pediatric patient 
(<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day.  
  
Patients will be eligible for MMF dosing and pharmacokinetics studies.   
  
Use IV route between days –3 and +5, then, if tolerated, may change to PO between days +6 and +30.   
  
Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute GVHD.  
Engraftment is defined as the 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 
x 109 /L.   
  
  
4.4  
Retinoic Acid  
 Retinoic acid 100 mg/m2/day starts at the day 60 visit and continues daily until 1 year posttransplant.  
  
4.5  
Supportive Care  
  
Growth Factors: As the malignant cell population of JMML is known to be hypersensitive to 
GM-CSF, this cytokine will not be used in this protocol.  Patients with ANC <0.2 x  
8 
10 /L on day 21 may receive G-CSF at 5μg/kg/day.  
  
5.0  
ELIGIBILITY AND EXCLUSION CRITERIA  
  
5.1  
Inclusion Criteria  
  
A diagnosis of JMML requires the presence of all of the following Category 1 criteria:  
●Peripheral blood monocyte count of >1000/microL   
●Blast percentage in peripheral blood and bone marrow <20 percent ●Splenomegaly  
●Absence of t(9;22) BCR-ABL1 fusion gene  
  
In addition, the patient must have at least one of the following Category 2 criteria:  
●Somatic mutation of PTPN11, KRAS, or NRAS  
●Clinical diagnosis of neurofibromatosis-1 or NF1 mutation   


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●Germline CBL mutation or loss of heterozygosity of CBL  
●Monosomy 7  
  
If none of the Category 2 criteria are met, the child must have at least two of the following 
Category 3 criteria:  
●Clonal cytogenetic abnormality other than monosomy 7  
●White blood cell >10,000/microL   
●Increased fetal hemoglobin (HbF) for age  
●Circulating myeloid precursors ●GM-CSF 
hypersensitivity   
  
 
5.1.1  Adequate major organ function including:  
  
5.1.1.1 Cardiac: ejection fraction >45%  
5.1.1.2 Hepatic: no clinical evidence of hepatic failure   
5.1.1.3 Karnofsky performance status >70% or Lansky score >50%  
5.1.1.4 GFR>40  
  
5.1.3  Voluntary written consent signed before performance of any study-related procedure 
not part of normal medical care.  
  
5.2  
Exclusion Criteria  
  
 
5.2.1  Active uncontrolled infection within one week of HCT.  
  
6.0  
REQUIRED OBSERVATIONS  
  
6.1  
Patient Pre-study Assessment  
  
 
6.1.1  Past Medical History  
A complete medical history with full details of the patient at time of diagnosis.  
  
 
6.1.2  Physical Examination  
  
 
6.1.3  Investigations  
  
6.1.3.1  Complete blood count with differential, platelet count, serum electrolytes, 
liver and renal function tests  
  
 
6.1.3.2  Bone marrow aspiration and biopsy;   
  
  


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6.1.3.3  Chest radiograph and other radiographic studies (as clinically indicated)  
  
6.1.3.4  Electrocardiogram; echocardiography with measurement of the left 
ventricular ejection fraction (LVEF)  
  
 
6.1.3.5  Viral titers as per institutional guidelines  
  
6.2  
Patient Evaluation During Therapy Until Engraftment - follow-up evaluations may be altered 
as clinically appropriate without being considered a deviation  
  
6.2.1  Routine practices at the University of Minnesota will be maintained.  
  
6.2.2  Bone marrow aspirate, biopsy, and chimerism studies on day 21.  
  
6.3  
Patient Evaluation on Day 60, 100 and 180, and then annually for 2 years- follow-up 
evaluations may be altered as clinically appropriate without being considered a deviation  
  
 
6.3.1  History and physical examination  
  
 
6.3.2  GVHD evaluation  
  
6.3.3  Bone marrow aspirate, biopsy, and chimerism studies on days 60, 100, 180 and at 1 
year and 2 years  
  
 
6.3.4  Other studies clinically indicated.  
  
  
7.0  
TOXICITIES AND COMPLICATIONS  
  
 
7.1  
Busulfan  
  
   
  
 
7.1.1  Toxicities:  
  
  
Busulfan  
 
 
Common   
Less Common  
Rare  


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• low white blood cell count 
with increased risk of  
infection   
• low 
platelet 
count 
with 
increased risk of bleeding   
• low red blood cell count 
(anemia) which may cause 
tiredness, headache,  
dizziness   
• hair 
loss 
or 
thinning, 
including face and body hair 
(usually grows back after 
treatment)   
• long-term 
or 
short-term 
infertility (inability to have  
children) in men and women  
  
• tiredness (fatigue)   
• sores in mouth or on lips   
• fever   
• nausea   
• vomiting   
• rash   
• loss of appetite   
• diarrhea   
• serious infection due to low 
white blood cell count   
  
  
• abnormal blood tests results which 
suggest that the drug is affecting the 
liver   
• allergic reaction with hives, itching, 
headache, coughing, shortness of 
breath, or swelling of the face, 
tongue, or throat   
• scarring of lung tissue, with cough, 
difficulty breathing, and shortness 
of breath that may occur after 
prolonged use, or even months or 
years after stopping the drug   
• leukemia  
(several 
 
years  after treatment)   
• darkened skin   
• heart problems with high-dose 
treatment, most often in people 
with thalassemia (a type of genetic 
anemia that is present at birth)   
Busulfan  
 
 
Common   
Less Common  
Rare  
 
 
• problems with the hormone system 
that cause weakness, tiredness, poor 
appetite, weight loss, and darker 
skin   
• death due lung damage, bone 
marrow shutdown, or other causes   
  
  
  
  
  
7.2  
Cyclophosphamide (Cytoxan)  
  
  
  
 
7.2.2  Toxicities:  
  
Cyclophosphamide  
 
 
Common  
Less Common  
Rare  


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• low white blood cell count 
with increased risk of infection  
• hair loss or thinning, including 
face and body hair (usually 
grows back after treatment)   
• nausea   
• vomiting   
• loss of appetite   
• sores in mouth or on lips   
• bleeding from bladder, with 
blood in urine   
• diarrhea   
• long-term or short-term 
infertility (inability to have 
children) in women and men  
• 
low platelet count (mild) 
with increased risk of 
bleeding   
• 
darkening of nail beds   
• 
acne   
• 
tiredness   
• 
infection  
• 
fetal changes if you become 
pregnant while taking 
cyclophosphamide   
  
• heart problems with high 
doses, with chest pain, 
shortness of breath, or swollen 
feet  
• severe allergic reactions  
• skin rash   
• scarring of bladder  
• kidney damage (renal tubular 
necrosis) which can lead to 
kidney failure  
• heart damage, with trouble 
getting your breath, swelling 
of feet, rapid weight gain  
• scarring of lung tissue, with 
cough and shortness of breath  
• second cancer, which can 
happen years after taking this 
drug  
• death from infection, bleeding, 
heart failure, allergic reaction, 
or other causes  
  
  
7.3  
Melphalan  
  
  
  
 
7.3.1  Toxicities:  
  
  
Melphalan  
 
 
Common  
Less Common  
Rare  


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• 
nausea (at higher doses)   
• 
vomiting (at higher doses)   
• 
low white blood cell count 
with increased risk of 
infection   
• 
low platelet count with 
increased risk of bleeding   
• 
anemia (low red blood cell 
count) with symptoms like 
tiredness, paleness, or 
trouble catching breath  
  
• short-term or long-term 
infertility (inability to 
have children)   
• weakness  
  
• 
severe allergic reaction   
• 
loss of appetite   
• 
scarring (fibrosis) or 
inflammation of lungs   
• 
hair loss, including face 
and body hair   
• 
rash   
• 
itching   
• 
second type of cancer (may 
happen years after 
treatment)   
• 
death from lung damage or 
other causes   
  
7.4  
Antithymocyte Globulin  
  
  
 
7.4.1  Toxicities:  
  
Anti-Thymocyte globulin (ATG)  
Common  
Less Common  
Rare  
• fever  
• chills  
• leukopenia  
• pain  
• headache  
• abdominal pain  
• diarrhea  
• hypertension  
• nausea  
• thrombocytopenia  
• peripheral edema  
• dyspnea  
• asthenia  
• hyperkalemia  
• tachycardia  
• 
malaise  
• 
dizziness  
•  severe allergic reaction 
(anaphylaxis)  
  
7.5  
Hematopoietic Stem Cell Infusion  
  
7.5.1  Volume overload: This is of particular importance in small recipients who have 
previously received red cell or platelet transfusions.  Diuresis with infusion may be indicated.  


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Allergic reactions: Chills, fever and hives occasionally occur presumably due to antigenic 
plasma components.  These reactions are rarely severe and respond to parenteral ephedrine or 
antihistamines.  
  
7.6  
Retinoic Acid  
7.6.1  Daily by mouth beginning day 60 (at the time of the 2 month follow-up visit) and 
continuing until 1 year post transplant.  
  
7.6.2  Toxicity  
Typical retinoid toxicity: (symptoms that are similar to those found in patients taking high 
doses of vitamin A) Headache, fever, dry skin, dry mucous membranes (mouth, nose), bone 
pain, nausea and vomiting, rash, mouth sores, itching, sweating, eyesight changes.   
Flu-like symptoms: malaise, chills   
Bleeding problems   
Infections    
Swelling of feet or ankles   
Pain:  bone and joint pain, chest discomfort, abdominal pain  
  
7.7  
Toxicities Associated with GVHD Prophylaxis  
Mycophenolate mofetil (MMF)  
 
Common  
Less Common  
Rare, but may be serious  
• miscarriage  
• birth defects  
• diarrhea  
• damage to unborn baby  
• limited effectiveness of 
birth control  
• stomach pain  
• upset stomach  
• vomiting  
• headache  
• tremors  
• low white blood cell count 
with increased risk of 
infection  
• increased blood 
cholesterols  
• swelling of the hands, feet, 
ankles or lower legs  
• anemia  
• rash  
• difficulty falling asleep or 
staying asleep  
• dizziness  
• uncontrollable hand shakes  
• difficulty breathing  
• unusual bruising  
• fast heartbeat  
• excessive tiredness  
• weakness  
• blood in stool  
• bloody vomit  
• change in vision  
• secondary cancers, such as 
lymphoproliferative disease 
or lymphoma  
• Progressive Multifocal 
Leukoencephalopathy  
  
  


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Tacrolimus (FK506, Prograf®)  
Common   
occurs in more than 20% of patients  
Less Common  
Rare  
 
occurs in 5 to 20% of 
patients  
occurs in fewer than 5% of 
patients  
 Kidney problems  
 Loss of magnesium, calcium, 
potassium  
 Cardiovascular: hypertension  
 Tremors  
 hyperlipidemia   
 thrombocytopenia   
 Infections  
  
 Nausea  
 Vomiting  
 Liver problems  
 Changes in how 
clearly one can think  
 Insomnia  
 Unwanted hair growth  
 Confusion  
 Seizures  
 Changes in vision  
 Dizziness  
 microangiopathic 
hemolytic anemia  
 post-transplant 
lymphoproliferative 
disorders  
It is very important that grapefruit or drinks with grapefruit juice are not consumed while 
taking Tacrolimus.  Grapefruit has an ingredient called bergamottin, which can affect some of 
the treatment drugs used in this study.  Common soft drinks that have bergamottin are Fresca, 
Squirt, and Sunny Delight.  
  
  
8.0  
ADVERSE EVENT REPORTING   
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE can be downloaded from 
the CTEP home page  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 ).  
  
 
7.7.1  Definitions  
An adverse event (AE) is any symptom, sign, illness or experience, regardless of 
causality, that develops or worsens in severity during the course of the study.  
Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal 
results of diagnostic procedures are considered to be adverse events if the abnormality:  
• 
results in study withdrawal  
• 
is associated with a serious adverse event  
• 
is associated with clinical signs or symptoms  
• 
leads to additional treatment or to further diagnostic tests  
• 
is considered by the investigator to be of clinical significance  
  
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
 Results in death. (death due to disease specifically addressed below)  Is life-
threatening.    
 Requires inpatient hospitalization or prolongation of existing hospitalization.    


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 Results in persistent or significant disability/incapacity.    
 Is a congenital anomaly/birth defect.  
 Is an important medical event.      
  
An unexpected adverse experience is defined as any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information provided 
for IRB review (typically the protocol, investigator’s brochure and prescribing 
information) nor mentioned in the consent form. Unexpected adverse experience and 
unanticipated adverse experience are synonymous terms.  
  
Problems/events that are unanticipated and serious should be reported only if in the 
opinion of the treating investigator they are possibly, probably or definitely related 
to the research treatment.  
  
 
7.7.2  Adverse Event Documentation  
Adverse events occurring after the initiation of any study procedure must be fully 
recorded in the subject’s case record form.  Each event should be described in detail 
along with start and stop dates, severity, relationship to investigational product, action 
taken and outcome.   
  
All subjects will be monitored through engraftment or the start of a new treatment, 
which ever occurs earlier, as it is expected that most treatment related adverse events 
will occur during this period.    
  
After engraftment, follow-up is planned for 2 years (per section 6.3).  The investigator 
is obligated, upon knowledge of, to report any adverse event that requires expedited 
reporting per section 7.6.3.  
  
 
7.6.3  Required Reporting (U of MN IRB and Masonic Cancer Center’s DSMC)  
  
Agency  
Criteria for reporting  
Timeframe  
Form to 
Use  
Submission 
address/ fax 
numbers  
Copy AE to:  
U of  
MN  
IRB  
Events requiring prompt reporting including, but not limited to 
unanticipated death of a locally enrolled subject(s); new or 
increased risk; any adverse event  that require a change to the 
protocol or consent form or any protocol deviation that resulting 
in harm.   Refer to 
http://www.research.umn.edu/irb/guidance/ae.html#.VC7xraI0sh  
Within 5 
business 
days of 
event  
discovery  
  
Report Form  irb@umn.edu  
  
SAE Coordinator 
mcc-saes@umn.edu  
Cancer  
Center  
DSMC  
any stopping rule event  
upon 
reporting to 
database  
stopping rule 
form  
SAE  
Coordinator 
mccsaes@umn.edu Not applicable  
  
  
  


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9.0  
EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS  
  
9.1  
Objective and Primary Outcome Variable  
  
Evaluate long-term DFS in JMML using a common preparative regimen. P1 is the product limit 
estimate of the cumulative proportion of children surviving disease free at 1 year after transplant.   
Secondary outcome measures are the incidence of neutrophil engraftment, GVHD, regimen-related 
toxicity, and relapse.  The study is planned for 25 years with a total enrollment of 20 patients (about 2 
patients per year).  Since it will be impossible to reach any definitive conclusions about efficacy or 
toxicity of the proposed regimen for this rare disease, analysis will be descriptive.  The study will be 
monitored for excessive combined incidence of grade III-IV toxicity or primary graft failure, using 
standard definitions.  
  
9.2  
Statistical Analysis  
  
The principal analysis is to compute the 1-year DFS (P1), the standard error (SE), and 95% 
confidence interval using the product limit (Kaplan Meier survival) estimate at 12 months.   
Experience shows that about 35% of transplanted patients have long-term DFS, but among those that 
relapse the median DFS is a very short 2.8 months, the survival curve is therefore expected to have 
reached a stable plateau by one year post transplant.  
  
The incidence of GVHD, time to engraftment, and relapse will be similarly evaluated.  Because death 
is a competing risk for these outcomes, the cumulative incidence may also be used.  The time course 
of all events may be described using event charts.  The analyses can only be descriptive because of 
the sample size constraints of this rare disease.  For example, if the true incidence rate (for a primary 
or secondary outcome) is about .75, then the observed rate is 90% likely to be in the interval (0.53 
0.98).  It will therefore not be possible to make definitive comparisons with historical rates observed 
here and elsewhere for other preparatory regimens.  
  
  
9.3  
Rationale for Sample Size  
  
Based on our past experience we expect to enroll 2 patients per year for a total of 20 patients in 25 
years.  
  
9.4  
Toxicity and Graft Failure Monitoring   
  
The combined incidence of grade III or IV toxicity and primary graft failure associated with the 
preparative regimen (Section 7) will be monitored using a stopping rule of R = {2 events in 12 
patients, 3/15 or 4 anytime}.  This stopping rule has a type I error rate of 0.05 if the true rate is 5%, 
and a power of 80% if the rate is 25%.29,30  
  
9.5  
Data Collection   
  


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The standard data will be collected, as specified for JMML (CML) patients who receive stem cell 
transplantation.  All patients will be followed until death or loss-to-follow up.  
  
  
  
  
10.0  
INFORMED CONSENT  
Both the patient and donor are completely evaluated and presented at a conference with family 
members where the transplant physician outlines the course of therapy.  These recommendations are 
then discussed thoroughly with the patient and family, including the donor (if of appropriate age).  
The risks of the procedure to the donor are outlined.  The marrow graft procedure and rationale as 
well as alternative forms of therapy are presented as objectively as possible.  All the risks and hazards 
of the procedure are explained to the patient, or in the case of minors, to the patient's responsible 
family members.  Informed consent is obtained using forms approved at the University of Minnesota 
Committee on the Use of Human Subjects in Research.  
  
  
  
11.0 DATA AND SAFETY MONITORING PLAN  
  
This study’s Data and Safety Monitoring Plan will be in compliance with the University of Minnesota 
Cancer Center's Data & Safety Monitoring Plan, which can be accessed at https://z.umn.edu/dsmp   
  
For the purposes of data and safety monitoring, this study is classified as moderate risk (phase II).   
Therefore the following requirements will be fulfilled:  
• 
The PI will complete and submit a twice yearly Trial Progress Report to the Masonic Cancer 
Center Data and Safety Monitoring Council (DSMC) with the understanding more frequent 
reporting may be required by the DSMC.  
• 
The PI will comply with at least twice yearly monitoring of the project by the Masonic Cancer 
Center monitoring services.  
• 
The PI will oversee the reporting of all adverse events meeting the definition of reportable in 
section 7.6.3 to the DSMC and the University Of Minnesota IRB.    
  
In addition, at the time of the continuing review with the University Of Minnesota IRB, a copy of the 
report will be submitted to the Cancer Protocol Review Committee (CPRC).  
  
  
12.0 REGISTRATION PROCEDURES  
  
Registration will occur after eligibility is confirmed and the patient has signed the informed consent, 
but before any treatment has been administered.  Eligible patients will be invited to participate in the 
study by their physician, who will explain the details of the trial and obtain informed consent.    
  


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Registration with the Clinical Trials Office (CTO)  
Upon completion of the screening evaluation, eligibility confirmation and obtaining informed 
consent, a designated study site staff person will enroll the patient into ONCORE.  
  
Record Retention   
The investigator will retain study records, including source data, copies of CRF’s and all study 
correspondence for at least 6 years beyond closure of the IRB file in a secure facility.  In addition, the 
Clinical Trials Office will keep a master log of all patients participating in the study with sufficient 
information to allow retrieval of the medical records.  
  
  
  
REFERENCES  
  
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Haas OA, Gadner H. Pathogenesis, biology and management of myelodysplastic syndromes 
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Aricò M, Biondi A, Piu C-H. Juvenile myelomonocytic leukemia. Blood 90: 479, 1997  
  
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Lilleymann JS, Harrison JF, Black JA: Treatment of juvenile chronic myeloid leukemia with 
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Sanders JE, Buckner CD, Stewart P, Thomas ED. Successful treatment of juvenile chronic 
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Sanders JE, Bucker CD, Thomas ED, Fleischer R, Sullivan KM, Appelbaum FA, Storb R.  
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10. 
Smith FO, Sanders JE, Robertson KA, Gooley T, Sievers EL. Allogeneic marrow 
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Pamphilon DH, Cornish JM, Goodman S, Ball L, Lawler M, McCann S, Humphries P, 
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Donadieu J, Stephan JL, Blanche S, Cavazzana-Calvo, Baruchel A, Herbelin C, Benkerrou M, 
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Chown SR, Potter MN, Cornish J, Goulden N, Pamphilon D, Steward CG, Oakhill A. 
Matched and mismatched unrelated donor bone marrow transplantation for juvenile chronic 
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Locatelli F, Pession A, Comoli P, Bonetti F, Giorgiani G, Zecca M, Taibi RM, Mongini ME, 
Ambroselli F, De Stefano P, Severi F, Paolucci G. Role of allogeneic bone marrow 
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20. 
Locatelli F, Niemeyer C, Angelucci E, Bender-Götze C, Burdach S, Ebell W, Friedrich W,  
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Stary J, Suttorp M, Uderzo C, van’t Veer-Korthof E, Vossen J, Zecca M, Zimmermann M, for the 
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Myelodysplastic Syndrome in Childhood. J Clin Oncol 15:566, 1997  
  
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MacMillan,ML, Davies SM, Orchard PJ, Ramsay NKC, Wagner, JE. Haematopoetic cell 
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Schuler US, Ehrsam M, Schneider A, Schmidt H, Deeg J, Ehninger G: Pharmacokinetics of 
intravenous busulfan and evaluation of the bioavailability of the oral formulation in 
conditioning for haematopoietic stem cell transplantation. Bone Marrow Transplant 22:241, 
1998  
  
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Andersson B, McWilliams K, Tran H, Fernandez H, Cagnoni P, Jones R, Gian V, Tarantolo 
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cyclophosphamide in pediatric patients: preliminary pharmacokinetics. Proceedings of 
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Philippe, N. Otten, J. (1996) Juvenile myelomonocytic leukemia: analyses of treatment results 
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Rassam, S.M.B., Katz, F., Chessells, J.M. & Morgan, G. (1993) Successful allogeneic bone 
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