Clinical trial NCT00629798
Conditions: Acute Myeloid Leukemia Advanced Myelodysplastic Syndromes
Keywords: Busulfan Melphalan Fludarabine 08-008
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2008-02-12; Completion date: 2020-10-20
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will see if the researchers can lower that risk by giving the patient Palifermin. This drug helps protect the lining of the mouth, throat, and stomach. These areas typically get sores or ulcers while the blood cell counts are very low. The patient can get infections in or from these sores. Palifermin might also help the immune system recover faster. It is currently approved for patients who receive their own stem cells. That is called an autologous transplant. This study will test the use of Palifermin for T-cell depleted allogeneic stem cell transplants.

Detailed description:

Arms: arm 1: This is a single arm phase II trial to assess the efficacy (decrease the transplant related mortality) and safety of peri-transplant Palifermin in combination with a preparative regimen with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from a histocompatible related or unrelated donor in patients with advanced MDS and AML evolved from MDS. The addition of Palifermin is to decrease the toxicity and the infection rate associated with this regimen and transplant type and to foster earlier immune reconstitution.
Interventions: intervention 1: Busulfan, Melphalan, Fludarabine, Anti-Thymocyte Globulin, Palifermin, Stem cell transplant
Intervention descriptions: intervention 1: Patients will receive Palifermin 60 mcg/kg/day IV on three consecutive days with the last dose administered no less than 24 and no more than 48 hr prior to start of cytoreduction. The preparative regimen to be used for transplants will consist: of busulfan administered in 12 doses over three days of 0.8 mg/kg IV for patients \> or = to 4 years of age or 1.0 mg/kg IV for patients \< 4 years of age; melphalan 70 mg/m2 IV x 2 days; and, fludarabine 25 mg/m2 IV x 5 days

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
 
 
 
A Phase II Trial of Busulfan, Melphalan, and Fludarabine with Peri-transplant Palifermin, 
followe d by a T-Cell Depleted Hematopoietic Stem Cell Transplant from HLA Matched or 
Mismatched Related or Unrelated Donors in Patients with Advanced Myelodysplastic 
Syndromes (MDS) and Acute Myeloid Leukemia (AML) Evolved from MDS 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal 
Investigator/Department: 
Roni Tamari, MD 
Medicine, BMT 
 
 
Co-Principal 
Investigator(s)/Department: 
Farid Boulad, M.D. 
Pediatrics, BMT 
 
 
Investigator(s)/Departme nt: 
Hugo Castro-Malaspina, M.D. 
Juliet Barker, M.B.B.S 
Parastoo Dahi, M.D. 
Sergio A. Giralt, M.D. 
Katharine Hsu, M.D., Ph.D. 
Ann Jakubowksi, M.D., Ph.D. 
Esperanza Papadapoulos, M.D. 
Miguel Perales, M.D. 
Doris Ponce, M.D. 
Craig S. Sauter, M.D. 
Marcel R.M. van den Brink, M.D., Ph.D. 
James Young, M.D. 
Nancy A. Kernan, M.D. 
Richard J. O’Reilly, M.D. 
Susan Prockop, M.D. 
Andromachi Scaradavou, M.D. 
 
Genovefa Papanicolau, M.D. 
Lillian Reich, M.D. 
Virginia Klimek, M.D. 
 
Sean Devlin, Ph.D. 
Glenn Heller, Ph.D. 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
 
Medicine, Infectious Diseaase 
Medicine, Hematology 
Medicine, Hematology 
 
Epidemiology and Biostatistics 
Epidemiology and Biostatistics 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
 
 
 
Consenting 
Professional(s)/Department: 
Hugo Castro-Malaspina, M.D. 
Juliet Barker, M.B.B.S 
Parastoo Dahi, M.D. 
Sergio A. Giralt, M.D. 
Ann Jakubowksi, M.D., Ph.D. 
Katharine Hsu, M.D.,Ph.D. 
Esperanza Papadapoulos, M.D. 
Miguel Perales, M.D. 
Doris Ponce, M.D. 
Craig S. Sauter, M.D. 
Roni Tamari, M.D. 
Marcel R.M. van den Brink, M.D., Ph.D. 
James Young, M.D. 
Farid Boulad, M.D. 
Nancy A. Kernan, M.D. 
Richard J. O’Reilly, M.D. 
Susan Prockop, M.D. 
Andromachi Scaradavou, M.D. 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 2 
3.0 
BACKGROUND AND RATIONALE ............................................................................... 2 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION ..................................................... 9 
4.2 
DESIGN ........................................................................................................................... 9 
4.3 
INTERVENTION ................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ...................................................................... 10 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 13 
6.2 
SUBJECT INCLUSION CRITERIA ................................................................... 14 
7.0 
RECRUITMENT PLAN ................................................................................................... 14 
8.0 
PRETREATMENT EVALUATION ................................................................................ 14 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ......................................... 22 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 23 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ................ 27 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 29 
14.0 
BIOSTATISTICS ................................................................................................................... 29 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ................................................................................................................................... 32 
16.0 
DATA  MANAGEMENT ISSUES .................................................................................. 32 
17.1 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 33 
17.2 PRIVACY ...................................................................................................................... 34 
17.3 SERIOUS ADVERSE EVENT (SAE) REPORTING .............................................. 34 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................ 35 
19.0 
REFERENCE(S) .................................................................................................................... 37 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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1.0       PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single arm phase II trial to assess the efficacy (decrease the transplant-related 
morbidity) and safety of peri-transplant Palifermin in combination with a preparative regimen 
with busulfan, melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted 
stem cell transplant from a histocompatible related or unrelated donor in patients with advanced 
MDS and AML evolved from MDS. The addition of Palifermin is to decrease the toxicity and 
the infection rate associated with this regimen and transplant type and to foster earlier immune 
reconstitution. 
 
Candidates for this trial will include patients with MDS: refractory anemia with excess blasts 
type 1 and 2, and AML evolved from MDS who are in hematologic remission, in a second 
refractory cytopenia phase (no excess of blasts) or have a persistent blast count of 5-9% in the 
bone marrow after high or low dose chemotherapy. Pre-transplant chemotherapy prior to 
cytoreduction is required to participate in this trial. Patients with refractory disease and ≥10% 
blast in the peripheral blood or bone marrow are not eligible for this trial. 
 
Hematopoietic stem cell donors for this trial will include individuals who are 10/10 HLA 
matched or up two-antigen mismatched at the HLA A, B, C, DRB1, and DQB1 loci, as defined 
by high resolution methods. 
 
All patients will receive Palifermin (60 mcg/kg/day) for 3 days before the start of chemotherapy 
and for 3 days starting the day of transplantation. All patients will be conditioned for 
transplantation with busulfan (Busulfex®) (0.8-1.0 mg/Kg/dose Q6H x 12 doses), melphalan (70 
mg/m2/day x 2 doses) and fludarabine (25mg/m2/day x 5 doses). Doses of busulfan will be 
adjusted according to plasma levels. All patients will also receive ATG (Thymoglobulin®) prior 
to transplant to promote engraftment. 
 
The preferred source of stem cells will be peripheral blood stem cells (PBSC) induced and 
mobilized by treatment of the donor with G-CSF. PBSC will be isolated, and T-cells depleted by 
positive selection of CD34+ progenitor cells, using the CliniMACS Cell Selection System. The 
CD34+ T-cell depleted peripheral blood progenitors will then be administered to the patients 
after they have completed cytoreduction. If the use of CD34+ PBSC is not possible, the 
alternative graft will consist of bone marrow derived stem cells T-cell depleted by soybean 
agglutinin and E-rosetting (SBA-E-). No drug prophylaxis against GvHD will be administered 
post transplant. Patients will also receive G-CSF post-transplant to foster engraftment. 
 
Patients will be monitored post transplant for donor engraftment, chimerism, incidence and 
severity of acute and chronic GvHD, regimen-related toxicity, characteristics of hematopoietic 
and immune reconstitution, incidence of bacterial, fungal, viral and parasitic infections, 
transplant related and relapsed related mortality, and overall and disease- free survival. 
 
The data analysis and data monitoring will conducted separately in each HLA group. A 
maximum of 31 patients in the HLA matched donor group and 21 patients in the HLA 
mismatched donor group are planned for accrual onto the study. It is anticipated that acc rual will 
last three years and each patient will be followed for a minimum of two years if he/she has not 
relapsed. The primary endpoint of the study is one- year treatment related mortality (TRM). 
 
For patients in the HLA matched donor group, a study design that differentiates between 
treatment  related  mortality probabilities of 0.10  and 0.30  will  be  used  to  assess treatment 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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efficacy. At the conclusion of the study, if at least 25/31 patients do not experience treatment 
related mortality within the first year of transplant, the treatment will be declared a success in 
controlling treatment related mortality. The probability of declaring the treatment a success for 
TRM is 0.09 when the one- year TRM in the population is 0.30 and increases to 0.90 when the 
one-year TRM in the population is 0.10. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
This study is a prospective phase II trial of the safety and efficacy of the addition of peri- 
transplant Palifermin to a chemotherapy-based cytoreduction using busulfan, melphalan, 
fludarabine, and ATG with T cell depleted hematopoietic stem cell transplants (HSCT) from 
histocompatible related and unrelated donors, in patients with advanced myelodysplastic 
syndromes. This study follows our previous phase II trial with the same preparative regimen and 
the same type of transplant but without Palifermin in a specific disease group. 
 
Primary objective of this trial is: 
1. To reduce the early transplant-related mortality. 
 
Secondary objectives of this study are: 
1. To improve the quality of immune reconstitution following transplantation 
2. To reduce the incidence rate of fatal post transplant infectious complications. 
3. To improve the rates of overall (OS) and disease- free survival (DFS). 
4. To assess the incidence of and severity of GvHD. 
5. To assess the incidence and severity of mucositis 
 
3.0      BACKGROUND AND RATIONALE 
 
3.1. 
Adv anced Myelodysplastic Syndromes 
 
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders characterized by 
cytopenias with a high risk of transformation to acute leukemia. The median survival for MDS 
patients with refractory cytopenias without an excess of blasts is about 5 years and some of the 
variants such as the 5q- syndrome are very responsive to non-transplant options such as 
lenalidomide and can survive for many years 1. The more advanced forms of MDS, as defined by 
an increase in the blast count, have a shorter surviva l. The median survival for patients with 
refractory anemia with excess of blasts (RAEB-1) is 1.5 years and for patients with RAEB-2 is 
one year 2. The most common complication in patients with RAEB-1 and RAEB-2 is 
transformation to acute myelogenous  leukemia (AML). Although a variety of non-transplant 
options are currently being developed and survival has somehow improved, none of these 
treatments is curative in these patients with advanced MDS and AML evolved from MDS. 
Treatment of these patients with induction chemotherapy and then with high dose chemotherapy 
followed by autologous stem cell rescue has resulted in DFS at 5 years of less than 20% 3, 4. 
 
3.2. 
Allogeneic Hematopoietic Stem cell Transp lantation for MDS 
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative 
treatment available for patients with myelodysplastic syndromes5-15. However, the success rate in 
these patients has been hindered by two major problems: a high transplant-related mortality and a 
high post transplant disease relapse, particularly in patients with advanced MDS. The early 
allogeneic HSCT studies focused in transplantation of bone marrow from HLA- matched sibling 
donors following myeloablative conditioning regimens utilizing either total body irradiation and 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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cyclophosphamide or busulfan and cyclophosphamide. The best long term disease- free survival 
rates after HLA- matched unmodified marrow grafts were seen in younger patients (<40 years of 
age). However, one of the main obstacles limiting the success of allogeneic marrow 
transplantation was the high incidence of transplant-related mortality, due mostly to graft-versus- 
host disease (GvHD) and associated complications 5-7. 
 
In order to extend the potential benefits of allogeneic transplants to the full range of patients 
developing disorders for which a transplant is indicated, particularly older patients (> 40 years of 
age), who constitute the majority of patients with MDS, as well as patients lacking HLA- 
matched sibling donors, major emphasis has been focused on the development of approaches 
which could circumvent severe acute and chronic GvHD so as to reduce its morbidity and 
mortality  in both  HLA- matched  and  HLA-non- identical  transplant  recipients.  To  this  end, 
several groups have developed and evaluated combinations of immunosuppressive drugs for the 
prevention of GvHD 16-26. While no combination of immunosuppressive drugs administered to 
recipients of HLA- matched related or unrelated unmodified hematopoietic stem cells grafts has 
prevented the development of acute and chronic GvHD, this serious transplant related 
complication can be prevented by the depletion of T lymphocytes from the allograft prior to 
administration in HLA matched related and unrelated recipients as well as in HLA-disparate 
recipients 27-34. For example, in our own series, among 232 consecutive adult leukemic patients 
(median age 41) engrafted with marrow transplants from HLA- matched siblings depleted of T- 
cells by soy bean agglutinin and E rosette depletion, the incidence of grade II-III GvHD was 3% 
and the incidence of chronic graft vs. host disease was 5% 24. Similarly, in over 100 unrelated 
marrow grafts transplanted using this T-cell depletion technique, the incidence of grade II-IV 
GvHD and of chronic GvHD has been 8% 35. 
 
Initially, the central limitation to the effectiveness of T-cell depleted marrow transplants was a 
high risk for graft rejections or late graft failures. Studies conducted at our institution 
demonstrated that such graft failures are principally caused by residual host T- lymphocytes 
which regenerate early after transplant and are able to reject donor hematopoietic cells through 
their cytotoxic interactions with major class I or class II HLA alloantigens in recipients of HLA- 
disparate transplants, or minor alloantigens presented by HLA class I determinants in recipients 
of HLA- matched grafts 36, 37.  Based on these findings, our group conducted a sequence of trials 
combining myeloablative doses of either total body irradiation, thiotepa and fludarabine or 
busulfan, melphalan and fludarabine with antithymocyte globulin (ATG) which reduced the 
incidence of graft failures following HLA- matched T depleted transplants to less than 2% and 
the incidence of graft failure following unrelated and 1-2 allele disparate marrow grafts to less 
than 8% 35, 38, 39. These rates of graft failure are comparable to those observed following 
unmodified transplants from such donors 
40. Additionally, Aversa et al 
41-43 (54-56) 
demonstrated that when G-CSF mobilized peripheral blood stem cells are utilized as the source 
of hematopoietic stem cells for a T-cell depleted graft, the doses of stem cells provided are 5-10 
fold higher than those that can be achieved in a marrow transplant and allow a durable 
engraftment and hematopoietic reconstitution even in HLA- haplotype disparate leukemic 
recipients 41. Based upon this observation,  G-CSF mobilized peripheral blood stem cells are 
currently the preferred source of hematopoietic cells for T cell depleted transplants. 
 
Another approach to overcome the problem of GvHD and the high incidence of transplant- 
related mortality in allogeneic SCT is the use of non-myeloablative or reduced intensity 
conditioning regimens. The administration of lower doses of the agents used in the conditioning 
regimen to decrease the direct organ toxicity, infections, and acute GvHD, particularly in older 
patients, has resulted in an improvement of regimen related toxicities and acute GvHD, but not in 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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significant improvement in the incidence of chronic GvHD 44-49. Moreover, the incidence of post 
transplant relapse, particularly in patients with advanced MDS, is higher in non- myeloablative 
transplant as compared to myeloablative transplants. A recent retrospective comparative analysis 
of the European experience of myeloablative versus non- myeloablative allogeneic SCT from 
HLA matched siblings in 836 patients with MDS revealed that the incidence of relapse after non 
myeloablative conditioning was higher whether the patient is in remission or has pers istent 
disease after induction chemotherapy 47. A major limitation of non-myeloablative transplants is 
that only patients with an HLA matched related or unrelated donor can benefit form this type of 
preparative regimen, as the risk of GvHD is too high  in HLA mismatched transplants 47. In 
contrast, T cell depleted transplants do not have the limitation of HLA matching. 
 
The other major problem limiting the success of allogeneic SCT in MDS, particularly in patients 
with advanced forms of MDS (≥5% blasts in the bone marrow or >1% blasts in the peripheral 
blood), and AML transformation is the high rate of post transplant relapse ranging from 30 to 
50% 4-15. This is in contrast to the lower relapse rate and better disease free survival in patients 
with refractory anemia, refractory cytopenias with multilineage dysplasia with or without ringed 
sideroblasts 50. Different approaches have been tried to reduce the incidence of post-transplant 
relapse in advanced MDS. The use of more intensive preparative regimens combining total body 
irradiation and busulfan reduced the incidence of relapse but resulted in an increased regimen 
related morbidity and mortality 51. The use of induction chemotherapy to achieve remission 
before the administration of cytoreductive therapies preceding the allogeneic transplant remains 
controversial. Several retrospective studies of myeloablative non T cell depleted transplants in 
patients with advanced MDS and AML evolved from MDS have shown discordant results. Data 
from the European and the French Registry showed a better DFS following allogeneic BMT in 
MDS patients who were transplanted in hematologic remission as compared to patients 
transplanted with  refractory disease (DFS at 3 years of 25% versus 15%) 4, 53.  However, 
induction chemotherapy was associated with a morbidity and mortality of 5 to 15%. More 
recently the Fred Hutchinson Cancer Center reported their experience in 125 patients with 
advanced MDS and AML evolved from MDS who received transplants from HLA identical 
siblings or unrelated donors after preparation with myeloablative conditioning regimes 52. 
Thirty–three of them received pre-cytoreduction induction chemotherapy. The relapse- free 
survival at 3 years was similar in patients receiving and not receiving induction chemotherapy, 
13% and 26% respectively. 
 
Since the focus of this institution’s transplant program has been T cell depletion, patients with 
MDS have been transplanted with this type of allograft. Our initial experience with T cell 
depleted transplants in patients with advanced MDS showed a high incidence of relapse and graft 
failure. Subsequent patients were treated with chemotherapy before undergoing a T cell depleted 
SCT. Our results summarized below showed that patients with advanced MDS have better 
transplant outcomes if they are transplanted in remission after chemotherapy. Also, in our earlier 
trials the preparative regimen was TBI based and throughout the years this regimen was modified 
to reduce some of the complications associated with T cell depleted transplants, such as graft 
rejection, as described above. Because MDS patients are mostly older patients (>age 40) and 
some of them are not eligible to receive total body irradiation, our institution also developed a 
chemotherapy only preparative regimen including busulfan, melphalan, fludarabine and anti- 
thymocyte globulin for these patients who could also benefit from T cell depleted SCT from 
HLA matched or HLA disparate related and unrelated donors. The results of our overall 
experience of T cell depleted SCT in patients with advanced MDS is described in the subsequent 
paragraphs and the results in patients treated with the chemotherapy only preparative regimen are 
summarized in the next section. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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From 1985 to 2004, 77 patients with advanced MDS  underwent TCD allogeneic SCT at this 
institution, 49  from HLA matched siblings and  28  from unrelated donors 54, 55. All patients 
received a myeloablative conditioning and the majority received a total body irradiation regimen 
combined with chemotherapy. Fewer patients received conditioning with a busulfan-containing 
regimen; 3 out 49  in the HLA  matched sibling transplants and 11 out 17  in the  unrelated 
transplants. The age range was 13 to 61 with a median of 48 in the HLA matched sibling group 
and an age range of 4 to 61 with a median of 61 in the unrelated group. Fifteen patients did not 
receive any chemotherapy prior to conditioning and the majority of the remaining 61 patients 
received induction dose of chemotherapy and a few received low dose chemotherapy. Of the 
patient  who  received  chemotherapy  before  cytoreduction  for  transplantation,  46  were  in 
remission (40) or in a second refractory anemia phase (6); and 16 had failed to respond to 
chemotherapy or their disease progressed before conditioning. The 5 year DFS for patients in 
remission or in a second refractory cytopenia phase was 50%, 23% for patients with residual 
disease, and 0%  for patients  with refractory disease.  The relapse rate after T cell depleted 
myeloablative transplants in our MDS patients in remission or second refractory cytopenia phase 
is lower or at least similar to that seen in recipients of T cell replete myeloablative transplants 
reported by other centers. The incidence of acute and chronic GvHD in this series of 77 patients 
was low, 11 patients developed acute GvHD (grade 1 to 3), and only 3 chronic GvHD (two 
patients after the infusion of donor lymphocytes). GvHD was the cause of death in two patients. 
The most common causes of non-relapse mortality in this series were graft failure and infections. 
Graft failure was a significant complication in the untreated group despite rejection prophylaxis 
with  ATG.  Most  of  these  patients  had  active  disease  and  had  a  high  blast  count  before 
transplantation. The most likely mechanism was persistent disease. Graft failure attributed to 
persistent disease has been also noted after T cell replete myeloablative and non- myeloablative 
transplants for advance MDS14. Bacterial,  fungal and  viral infections in  the post transplant 
period were the most common cause of non-relapse deaths. Infectious complications occurred in 
the early (<3 months) and particularly in the late post transplant period (>3 months). All patients 
who died of infections in the late post transplant period had poor immune function as determined 
by low CD4 counts and poor response to mitogens. Forty eight percent of patients were ≥50 
years old. Studies at our institution have shown that older patients have a poor immune recovery 
posttransplant56, suggesting that recipient factors such as thymic function are important 
contributors to the recovery of the immune function following allogeneic SCT. 
 
In summary, this study in a relatively large series with a long follow-up over 19 years showed 
that patients with advanced MDS can have a significant long-term disease- free survival after a T 
cell-depleted myeloablative allogeneic SCT if they receive chemotherapy and achieve sustained 
remission or a second refractory cytopenia phase before undergoing cytoreduction for 
transplantation. Patients with limited disease also had reasonable DFS, whereas patients with 
untreated or refractory disease had a poor outcome. The survival benefit in the patients 
transplanted in remission was largely due a significant decrease in GvHD and post-transplant 
relapse. Opportunistic infections were an important cause of non-relapse mortality in older 
patients. 
 
3.3. 
Summary of results of earlier phase II trial of chemotherapy only cytoreductiv e regimen 
comprised of busulfan, melphalan and fludarab ine followed by T -cell depleted transplants from 
matched related, mismatched related, matched unrelated or mismatched unrelated donors. 
 
This preparative regimen was designed as an alternative to TBI containing regimen that could be 
offered to patients who were not eligible to receive TBI because of previous exposure to high 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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dose radiation therapy or because of older age. The total dose of busulfan was decreased to 10 
doses of 0.8-1 mg/kg every 6 hours, versus the standard myeloablative dose of 16 doses of 0.8-1 
mg/kg every 6 hours, to reduce the toxicity of non-hematopoietic tissues, but maintaining its 
myeloablative and lymphoablative potency in combination with melphalan, fludarabine and 
ATG to allow the engraftment of a T cell depleted hematopoietic SCT. 
 
Overa ll Results 
 
The previous study (without Palifermin), in which this proposed trial is based, included 59 
patients; 6 children and 53 adults. The median age was 54.2 years with a range of 0.6 to 71.3; 
thirty-six were 50 or older. The diagnoses included: MDS and AML evolved from MDS (41 
patients), de novo AML in CR1 or 2 (10 patients), ALL (4 patients), CML (1 patient), NHL (2 
patients), and MPD (one patient). The donors were HLA matched (A, B, C, DR, DQ by high 
resolution) related (16), mismatched related (5), matched unrelated (20), and mismatched 
unrelated (18 patients). Except in two patients, the source of stem cells was peripheral blood. 
Fifty seven patients are evaluable for outcomes and have at least 6 months of post transplant 
followup. Results of this trial demonstrated that this preparative regimen was safe as determined 
by the low incidence of graft rejection, and GvHD. All but 3 patients achieved durable 
engraftment. Three recipients of unrelated HLA disparate transplants experienced primary (one 
patient) or late (2 patients) graft failure, of whom 2 achieved durable engraftment after a 
secondary transplant. Acute GVHD II or III developed in 3 patients and chronic GVHD in 2 
patients (1 extensive), despite the advanced age of this group. Moreover, oral mucositis was less 
severe as compared to the mucositis seen after myeloablative doses of TBI-containing regimens. 
Thus, the initial objectives of securing consistent engraftment with a GF <10% and grade II-IV 
acute GVHD in 1 HLA disparate locus recipient have been met. As far as efficacy, the DFS was 
disease and stage dependent. The most significant results which are described below were in the 
group of patients with MDS and AML evolved from MDS. This preparative regimen was not 
effective in preventing relapse in patients with advanced ALL and NHL, as their disease relapsed 
in all 4 patients. 
 
Results in M DS patie nts 
 
With the exception of one patient with RAEB-2 who had 10% blasts, MDS patients whose 
disease status following chemotherapy and prior to conditioning was RAEB-2 or AML were not 
enrolled in this trial based upon our earlier observations showing that the relapse rate was 
unacceptably high in these patients. MDS/AML patients enrolled on this protocol included 41 
patients with 19 males and 22 females, aged 0.6 – 71 years of age (median 56 years). This 
included 3 patients < 20 years, 9 patients aged 20-49 years, 20 patients aged 50-59 years and 9 
patients aged > 60 years, with 29 patients (70%) 50 years or older. Twenty three patients had 
primary MDS and 18 therapy-related. The MDS subtype at diagnosis included: refractory 
cytopenia (15 patients), RAEB-1 (9 patients), RAEB-2 (9 patients), 4 patients in AML, and 4 
patients with JMML/CMMoL (4 patients). Of these 41 patients, 14 patients had normal 
cytogenetics and 27 had abnormal cytogenetics with 14 patients with chromosome 7 
abnormalities, 7 patients with 11q abnormalities, 6 patients with chromosome 5 abnormalities 
and 2 patients with trisomy 8. Thirty-six patients (84%) received treatment with chemotherapy 
prior to proceeding to conditioning. Disease status pre-transplant included: 35 patients with 
minimal disease - CR (14 patients), RA (21 patients) – and 6 patients with persistent but limited 
disease – RAEB-1 (5 patients) and RAEB-2 (1 patient). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 7 - 
 
 
 
 
Donors for these patients included 11 HLA- matched related donors, 15 HLA- matched unrelated 
donors, 2 HLA- mismatched related donors, and 13 HLA- mismatched unrelated donors. Overall 
26 patients (63%) had HLA- matched donors and 15 patients (37%) had HLA-mismatched 
donors. HLA- mismatch included class I for 10 patients, class II for 3 patients, and class I and II 
for 2 patients. The matching level as per the 5 pairs of class I and II HLA antigens was; 9/10 
antigen matched in 8 patients and 8/10 antigen matching in 7 patients. 
 
Except for one patient who died prior to engraftment, all 40 other patients engrafted. Acute graft- 
versus-host disease developed in a total of 9 of 41 patients at risk. This included 1 of the 11 
recipients of HLA- matched related transplants, and 4 of 16 recipients of HLA- matched unrelated 
transplants, and 4 of 13 recipients of HLA-mismatched unrelated or related transplants. Staging 
included grade 1 in 4 patients, grade 2 in 4 patients, grade 3 in 1 patient, and no grade 4. The 
overall cumulative incidence of grade 2-4 acute GvHD was 12%. There was no difference 
between the recipients of HLA- matched or mismatched donors. Chronic GvHD developed in 2 
patients of 34 at risk. The overall cumulative incidence of chronic GvHD at one year was 5%. 
Thus, the overall incidence of engraftment and GvHD was quite safe 
 
 
Of the 41 patients, 25 are alive, all in remission and no patients with relapsed disease. The 
overall survival (OS) and disease- free survival at 2 years post transplant for all patients were 
64% and 57% respectively. For patients transplanted with minimal residual disease, the OS and 
DFS were 63% and 58% respectively, and for patients with persistent but limited disease 67% 
and 50%. For patients with primary MDS, the OS and DFS were 76% and 63% respectively and 
for patients with therapy-related MDS, 46% and 47%. For recipients of HLA- matched related 
donor transplants, the OS and DFS were 48% and 30% respectively, and for recipients o f HLA- 
matched unrelated donor transplants 65% and 65%, and for recipients of HLA-mismatched 
transplants 69% and 58%. 
 
Relapse occurred in a total of 4 patients; with a cumulative incidence at 2 years of 12%. One of 
the relapses occurred in 1 patient in CR (7%), 2 in patients with RA (10%), and 1 in a patient 
with RAEB-1/RAEB-2 (17%). Relapses occurred in 2 out of 25 patients (8%) with primary MDS 
and 2 out of 16 patients (12.5%) with therapy related MDS. Relapses occurred in 2 recipients of 
28 HLA- matched transplants and 2 recipients of 13 HLA- mismatched transplants. 
 
Non-relapse or transplant-related deaths occurred in 13 patients. The overall cumulative 
incidence of transplant-related mortality at one year post transplant was 22%. The CI of TRM by 
age was 17% for the 12 patients aged <50 years and 24% for the 29 patients aged > 50 years. 
This difference was not statistically different. The CI of TRM by donor was 27% for recipients 
of matched related transplants and 20% for recipients of unrelated transplants. Also, non-relapse 
deaths occurred in 7 of 25 patients with primary MDS (28%) and 6 of 16 patients with secondary 
MDS (37%). Infections were the most common cause of death. Of the 13 deaths, 4 were due to 
an infection occurring within the first 3 months post transplant (3 patients) or thereafter (1 
patients). All these patients had poor immune recovery as determined by low CD4 count and 
poor response to PHA. 
 
In summary, this phase II trial demonstrated that the use of busulfan, melphalan and fludarabine 
followed by T-cell depleted transplants from matched related, mismatched related, matched 
unrelated or mismatched unrelated donors in patients with advanced MDS is safe and has a 
significant efficacy as demonstrated by the improved DFS. Transplant related deaths were the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 8 - 
 
 
 
 
main cause of transplant failure and the leading causes were infections, which resulted from the 
delayed recovery of immune function in these patients. 
 
3.4. 
Palifermin 
 
Keratinocyte growth factor (KGF) is an endogenous protein in the fibroblast growth factor (FGF) 
family that binds to KGF receptor. Binding to its receptor has been reported to result in 
proliferation, differentiation, and migration of epithelial cells in many tissues including the 
buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, 
bladder, mammary gland, skin, the lens of the eye, and the thymus. Hematopoietic cells are 
unresponsive to KGF as they lack its receptor. 
 
Palifermin is a human keratinocyte growth factor produced by recombinant DNA technology in 
Escherichia coli. It differs from endogenous human KGF in that the first 23 N-terminal amino 
acids have been deleted to improve protein stability. In mice and rats Palifermin enhanced 
proliferation of epithelial cells and demonstrated an increase in tissue thickness of the tongue, 
buccal mucosa and gastrointestinal tract. Palifermin has been studied in murine models of 
chemotherapy and radiation- induced gastrointestinal injury. In such models, administration of 
Palifermin prior to and/or after the cytotoxic insult improved survival and reduced weight loss 
compared to control animals. 
 
The toxicity and pharmacokinetics of Palifermin was studied in healthy subjects and patients 
with hematologic malignancies. After single IV doses of 20 to 250 mcg/kg (healthy subjects) 
and 60 mcg/kg (cancer patients) Palifermin concentrations declined rapidly (over 95% decrease) 
in the first 30 minutes per dose. The elimination half- life was similar between healthy subjects 
and cancer patients (average 45 hours with a range of 3.3 to 5.7 hours). A phase I trial indicated 
that Palifermin at doses up to 80 mcg/kg/d/3 consecutive days was not associated with major 
adverse events 57. No accumulation of Palifermin occurred after 3 consecutive daily doses of 20 
or 40 mcg/kg in healthy volunteers, or 60 mcg/kg in cancer patients. 
 
The safety and efficacy of Palifermin were established in a randomized double-blind, placebo- 
controlled clinical study of 212 patients, who received high-dose cytotoxic therapy consisting of 
fractionated total-body irradiation (TBI) 12 Gy total dose), high dose etoposide (60 mg/kg) and 
high-dose cyclophosphamide (100mgkg) followed by peripheral blood progenitor cell (PBPC) 
support for the treatment of hematological malignancies (NHL, Hodgkin’s disease, AML, ALL, 
CML, CLL, or multiple myeloma) 58.  Patients were randomized to receive either Palifermin (n = 
106) or placebo (n = 106).  Palifermin was administered as a daily IV injection of 60 mcg/kg for 
3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following 
infusion of PBPC. Compared with placebo-treated patients, Palifermin–treated patients reported 
less mouth and throat soreness. There was a reduction in median days of WHO Grade 3-4 oral 
mucositis (4 vs. 6 days), lower incidence of WHO Grade 3-4 oral mucositis (67% vs. 80%) and 
lower incidence of WHO Grade 4 oral mucositis (26% vs 50%). Palifermin was approved by the 
FDA for the prevention of chemotherapy and or radiation induced mucositis. 
 
Palifermin has been also tested in the allogeneic HSCT setting for potential benefits on acute 
GvHD and hematopoietic reconstitution. The results of a phase 1-2 randomized, double-blind, 
placebo controlled dose-escalation trial of Palifermin in patients with hematologic malignancies 
conditioned with cyclophosphamide and fractionated total body irradiation or busulfan and 
cyclophosphamide was recently reported 59. No significant differences in the incidence or 
severity of acute GvHD, or neutrophil and platelet engraftment was observed between patients 


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IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 9 - 
 
 
 
 
receiving or not receiving Palifermin.  Palifermin was associated with reduced incidence and 
mean severity of mucositis in patients conditioned with cyclophosphamide and TBI. 
 
KGF has been shown to play an important role in T cell homeostasis by its role in regulating the 
proliferation and differentiation of thymic epithelium. In murine models, KGF regulates thymic 
development, as it is required for postnatal thymic regeneration 60-61. Also, in murine allogenic 
transplant models, KGF given before transplant has a protective effect on the thymus and 
thymopoiesis after transplantation 62 63. A recent study in rhesus macaques also showed that 
Palifermin augments T cell immune reconstitution after autologous HCST (58b). 
 
 
3.5. 
Summary 
 
Based on: (i) our previous trial of busulfan, melphalan, fludarabine, ATG and T cell depleted 
allogeneic SCT which showed a significant improvement in DFS for patients with myeloid 
malignancies, particularly in patients with advanced MDS and AML evolved from MDS. 
However, the major limitation to the success of these transplants in older patients and recipients 
of unrelated and HLA 1-2 allele disparate grafts in remission is the risk of the non-relapse 
mortality due to opportunistic infections which in these patients extends beyond the 6-14 months 
post transplant. (ii) observations in murine and primate models showing the beneficial effect on 
thymus and T cell lymphopoiesis; and safety and efficacy on mucositis and associated 
complications in patients undergoing autologous and allogeneic SCT. We propose this trial 
aimed at fostering earlier recovery of thymopoiesis and thereby to decrease the non-transplant 
morbidity and mortality and therefore to improve the overall and disease-free survival in patients 
with advanced MDS and AML evolved from MDS undergoing allogeneic transplantation from 
HLA- matched or mismatched related and unrelated donors. Patients will be evaluated for the 
incidence of opportunistic infections in the post transplant period, immune reconstitution, non- 
relapse mortality and morbidity and overall survival and disease free survival. 
 
The success of allogeneic SCT in patients with advanced MDS depends on multiple variables, 
our approach involving induction of remission before cytoreduction for transplantation and then 
a T cell depleted myeloablative allogeneic transplant markedly reduces two major obstacles 
limiting the success of allogenic transplantation, disease relapse and graft versus host disease. 
This phase II trial incorporating KGF is designed to reduce the non-relapse mortality post 
transplant and to improve the DFS 
 
4.0       OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
This is a single arm phase II trial to assess the efficacy (decrease the transplant related mortality) 
and safety of peri-transplant Palifermin in combination with a preparative regimen with busulfan, 
melphalan, fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell 
transplant from a histocompatible related or unrelated donor in patients with advanced MDS and 
AML evolved from MDS. The addition of Palifermin is to decrease the toxic ity and the infection 
rate associated with this regimen and transplant type and to foster earlier immune reconstitution. 
 
4.2 
Interve ntio n 
Patients will receive Palifermin 60 mcg/kg/day IV on three consecutive days with the last dose 
administered no less than 24 and no more than 48 hr prior to start of cytoreduction. The 
preparative regimen to be used for transplants will consist: of busulfan administered in 12 doses 


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IRB Number: 08-008 A(12) 
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- 10 - 
 
 
 
 
over three days of 0.8 mg/kg IV for patients > 4 years of age or 1.0 mg/kg IV for patients < 4 
years of age; melphalan 70 mg/m2 IV x 2 days; and, fludarabine 25 mg/m2 IV x 5 days. Patients 
will receive ATG for two doses prior to transplant. G-CSF mobilized CD34+E- PBSCs (or BM if 
donors are unwilling or unable to donate PBSC) obtained from the HLA compatible donor will 
be infused on day 0. Patients will receive three additional daily doses of Palifermin, the first 
approximately 6 hours after the stem cell infusion on day 0, followed by two daily doses given 
on d+1 and d+2. Supportive care will be administered as per the BMT Service guidelines. 
5.0       THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1. 
Busulfan (busulfex®) 
 
a. Source and pharmacology: Supplier: Otsuka Pharmaceutical; Busulfan is a bifunctional 
alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. BUSULFEX® 
(busulfan). This is an agent in which two labile methanesulfonate groups are attached to 
opposite ends of a four carbon alkyl chain. In aqueous media, busulfan hydrolyzes to release 
the methanesulfonate groups. This produces reactive carbonium ions that can alkylate DNA. 
DNA damage is thought to be responsible for much of the cytotoxicity of busulfan. 
 
b. Formulation and stability: It is supplied as a clear, colorless, sterile, solution in 10 mL 
single use ampoules. Each ampoule of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, 
the active ingredient, a white crystalline powder with a molecular formula of 
CH3SO2O(CH2)4OSO2CH3 and a molecular weight of 246 g/mole. Busulfan is dissolved in 
N,N-dimethylacetamide (DMA) 33% wt/wt and polyethylene glycol 400, 67% wt/wt. 
Busulfan’s solubility in water is 0.1 g/L and the pH of a >0.5% solution in 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects 
the pH of the diluent used and ranges from 3.4 to 3.9. 
c. Solution preparation: BUSULFEX is supplied as a sterile solution in 10 mL single-use 
clear glass ampoules each containing 60 mg of busulfan at a concentration of 6 mg/mL for 
intravenous use. BUSULFEX must be diluted prior to use with either 0.9% Sodium Chloride 
Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity 
should be 10 times the volume of BUSULFEX, ensuring that the final concentration of 
busulfan is approximately 0.5 mg/mL. 
d. Storage and stability: Unopened ampules of BUSULFEX must be stored under refrigerated 
conditions between 2° -8° C (36° -46° F). 
 
e. Administration:  Intravenous, over 2 hours. 
 
5.2. 
Melphalan (Alk eran®) 
 
a. Source and pharmacology: Supplier: Glaxo Wellcome. A derivative of nitrogen mustard, 
an analog of mustard gas. It is a polyfunctional alkylating agent that causes miscoding, 
cross- linkage of DNA, and single-strand breakage of DNA. It inhibits cellular glycolysis, 
respiration, and protein synthesis.  It is cell cycle-phase non-specific. 
b. Formulation and stability: A lyophilized powder of 50 mg melphalan and 20 mg povidone 
per vial.  Also provided is 10 ml of sterile diluent for use in reconstituting the product and a 
0.45 micron filter. 
The special diluent has the following composition: Sodium citrate 0.2 g, 
Propylene glycol 6.0 ml, Ethanol (95%) 0.5 ml, and sterile water 10 ml. 
c. Solution preparation: Vial/50 mg: Reconstitute by rapidly injecting 10 ml of the supplied 
diluent into the vial to yield a final concentration of 5 mg/ml. Shake vigorously until the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 11 - 
 
 
 
 
solution is clear.  Immediately dilute the dose to be administered in 0.9% Sodium Chloride, 
USP, to a concentration no greater than 0.45 mg/ml 
d. Storage and stability: The intact packages should be stored at room temperature (15-30°C) 
protected from light. Shelf- life surveillance of the intact dosage form is ongoing. 
Constitution with the special diluent as directed results in a solution that retains at least 90% 
potency for about three hours at 30°C.  Storage at 5°C results in precipitation. 
e. Administration: Intravenous, over 30 minutes. Complete infusion within 60 minutes of 
preparation. 
 
5.3 
Fludarabine (FLUDA RA®) 
 
a. Source and pharmacology: Supplier: Berlex Laboratories, Inc. FLUDARA FOR 
INJECTION contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral 
agent vidarabine, 9-ß-D-arabinofuranosyladenine (ara-A) that is relatively resistant to 
deamination by adenosine deaminase. The chemical name for fludarabine phosphate is 9 H- 
Purin-6-amine, 2- fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl). Fludarabine phosphate is 
rapidly dephosphorylated to 2- fluoro-ara-A and then phosphorylated intracellularly by 
deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to 
act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus 
inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely 
characterized and may be multi- faceted. 
 
b. Formulation and stability: Each vial of sterile lyophilized solid cake contains 50 mg of the 
active ingredient fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust 
pH to 7.7. The pH range for the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile 
Water for Injection USP results in a solution containing 25 mg/mL of fludarabine phosphate 
intended for intravenous administration. FLUDARA FOR INJECTION is supplied in a clear 
glass single dose vial (6 mL capacity) and packaged in a single dose vial carton in a shelf 
pack of five 
 
c. Solution preparation: FLUDARA should be prepared for parenteral use by aseptically 
adding Sterile Water for Injection USP. When reconstituted with 2 mL of Sterile Water for 
Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the 
resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and 
sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. In 
clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection 
USP or 0.9% Sodium Chloride USP 
 
d. Storage and stability: FLUDARA is supplied as a white, lyophilized solid cake. Each vial 
contains 50 mg of fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to adjust 
pH to 7.7. The pH range for the final product is 7.2-8.2. Store under refrigeration, between 
2°-8° C (36°-46° F). 
 
e. Administration: Intravenous, over thirty minutes. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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5.4. 
Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®) 
 
a. Source 
and 
pharmacology: 
Supplier: 
Sangstat, 
The 
Transplant 
Company®. 
Thymoglobulin® [Anti- thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma 
immune  globulin,  obtained  by  immunization  of  rabbits  with  human  thymocytes.  This 
immunosuppressive 
product contains cytotoxic antibodies   directed   against antigens 
expressed on human T- lymphocytes. 
 
b. Formulation and stability: Thymoglobulin is a sterile, freeze-dried product for intravenous 
administration after reconstitution with sterile Water for Injection, USP (WFI). Each 
package contains two 7 mL vials: Vial 1: Freeze-Dried Thymoglobulin Formulation Active 
ingredient: Anti-thymocyte Globulin (Rabbit) 25 mg - Inactive ingredients: Glycine (50 mg), 
mannitol (50 mg), sodium chloride (10 mg); Vial 2: Diluent Sterile Water for Injection, USP 
5 mL. The reconstituted preparation contains approximately 5 mg/mL of Thymoglobulin, of 
which >90% is rabbit gamma immune globulin (IgG). The reconstituted solution has a pH of 
7.0± 0.4. Human red blood cells are used in the manufacturing process to deplete cross- 
reactive antibodies to non-T-cell antigens. The manufacturing process is validated to remove 
or inactivate potential exogenous viruses. All human red blood cells are from US registered 
or FDA licensed blood banks. A viral inactivation step (pasteurization, i.e., heat treatment of 
active ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is 
released following potency testing (lymphocytotoxicity and E-rosette inhibition assays), and 
cross-reactive antibody testing (hemagglutination, platelet agglutination, anti-human serum 
protein antibody, antiglomerular basement membrane antibody, and fibroblast toxicity assays 
on every 5th lot). 
 
c. Solution preparation: Each reconstituted vial contains 25 mg or 5 mg/mL of 
Thymoglobulin. Transfer the contents of the calculated number of Thymoglobulin vials into 
the bag of infusion solution (saline or dextrose). Recommended volume: per one vial of 
Thymoglobulin use 50 mL of infusion solution (total volume usually between 50 to 500 mL). 
Mix the solution by inverting the bag gently only once or twice. 
 
d. Storage and stability: Store in refrigerator between +2° C to +8° C (36° F to 46° F). Protect 
from light. Do not freeze. Do not use after the expiration date indicated on the label. 
Reconstituted vials of Thymoglobulin should be used within 4 hours. Infusion solutions of 
Thymoglobulin must be used immediately. Any unused drug remaining after infusion must 
be discarded. 
 
e. Administration: Infuse through a 0.22- micron filter. Set the flow rate to deliver the dose 
over 12 hours. 
 
5.5. 
 Palifermin : 
 
a. Source and pharmacology: Supplier: Amgen. Palifermin (Kepivance) is a human 
keratocyte growth factor produced by recombinant DNA technology in Escherichia coli. It 
differs from endogenous human KGF in that the first 23 N-terminal amino acids have been 
deleted to improve protein stability 
b. Formulation and stability: Palifermin is supplied in vials containing 6.25 mg. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 13 - 
 
 
 
 
c. Solution preparation: The dispensed Palifermin vial contains lyophilized powder.  It 
should be reconstituted with sterile water for injection, USP to yield a final concentration of 
5 mg/ml. 
 
d. Storage and stability: the lyophilized powder should be stored at 2 to 8 degrees centigrade 
and protected from light. The reconstituted solution should be also protected from light and 
administered immediately as it has no preservative. 
 
e. Administration: The reconstituted solution should be administered immediately by 
intravenous bolus injection. If heparin is used to maintain the IV line, saline should be used 
to rinse the line prior to and after Palifermin administration since Palifermin has been shown 
to bind to heparin in vitro. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Dia gnosis (this includes de novo or treatment- related cases): 
1. Myelodysplastic syndrome (MDS): RAEB-1 and RAEB-2. 
2. Chronic myelomonocytic leukemia: CMML-1 and CMML-2. 
3. Acute myelogenous leukemia (AML) evolved from MDS. 
 
Status a fter c he mo therap y a nd de termin ing e ligib ility o f the patie nt 
1. In hematologic remission. 
2. In second refractory cytopenia phase 
3. With persistent but limited disease after chemotherapy. 
 
DEFINITIONS OF DISEASE STATUS 
 
The MDS subtype and prognostic classification at diagnosis and before transplantation will be 
determined according to the WHO (World Health Organization) and IPSS (International 
Prognostic Scoring System) criteria 64, 65. 
 
Complete remission after chemotherapy is defined as a cellular marrow with <5% blasts with 
no overt dysplasia and blood count recovery 66, 67. 
 
Second refractory cytopenia after chemotherapy is defined as a marrow with <5% blasts with 
or without dysplasia, and with persistent pancytopenia with no circulating blasts 15. 
 
Persistent but limited disease after chemotherapy :  <5% blasts in peripheral blood and 5-9% 
blasts in the bone marrow (similar to RAEB-1). 
 
DONOR: Patients must have a healthy HLA matched or mismatched related or unrelated donor 
who is willing to receive G-CSF injections and undergo apheresis for PBSC collection, or 
undergo a marrow harvesting procedure. 
1. 
HLA-matched related and unrelated donors 
Patients who have an HLA- matched related or unrelated donor are eligible for entry on this 
protocol. This will include a healthy donor who is genotypically matched at all A, B, C, DRB1 
and DQB1 loci, as tested by DNA analysis. 
 
2. HLA- mismatched related and unrelated donors 


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IRB Number: 08-008 A(12) 
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Patients who do not have an HLA- matched donor but have a related or unrelated donor who is 
either matched at all A, B and DRB1 loci or who is at least 5/6 allele matched (HLA A, B and 
DR) and 8/10 allele matched (HLA A, B, C, DR, DQ) to the recipient will be eligible for entry 
on this protocol. 
 
 
6.1 
Subject inclusion criteria 
 
• 
Patients should be < 65 years. Patients > 65 years will be accrued on a case by case basis 
after discussion and approval by the BMT Service. 
• 
Patients may be of either gender or any ethnic background. 
• 
Patients must have a Karnofsky or Lansky Performance Status > 70% 
• 
Patients must have adequate organ function measured by: 
a) Cardiac: asymptomatic or if symptomatic then LVEF at rest must be > 50% and must 
improve with exercise. 
b) Hepatic: < 3x ULN ALT and < 1.5 total serum bilirubin, unless there is congenital 
benign hyperbilirubinemia. 
c) Renal: serum creatinine <1.2 mg/dl or if serum creatinine is outside the normal range, 
then CrCl > 60- ml/min/1.73 m2 
d) Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for 
hemoglobin) 
• Each patient must be willing to participate as a research subject and must sign an informed 
consent form. 
• Parent or legal guardians of patients who are minors will sign the informed consent form. 
 
6.2 
Subject exclusion criteria 
• Active CNS or skin leukemic involvement 
• Female patients who are pregnant or breast-feeding 
• Active viral, bacterial or fungal infection 
• Patient seropositive for HIV-I/II; HTLV -I/II 
• Patients who have undergone a prior allogeneic or autologous stem cell transplant within the 
previous six months. 
• Patients who have had a previous malignancy that is not in remission. 
 
7.0       RECRUITMENT PLAN 
 
Eligible patients will be identified through the weekly BMT review meeting. Once transplant 
dates and collection dates are set, they will be offered this trial and informed of the rationale for 
this trial, as well as the logistic implications and the risks and benefits. This protocol will take 
due notice of NIH/ADAMHA policies concerning inclusion of women and minorities in clinical 
research populations. 
 
8.0       PRETREATMENT EVALUATION 
8.1. 
Pre tre atme nt e valuatio n of the pa tie nt 
 
The patient will receive an extensive medical evaluation approximately 45 days prior to starting 
preparatory cytoreduction. This evaluation will include the below tests: 
 
- 
Physical exam and medical history 


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IRB Number: 08-008 A(12) 
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- 
Dental evaluation (may be completed outside of the 45 day window) 
- 
CBC 
- 
Coagulation profile 
- 
Blood Type and screen 
- 
Serum chemistries including BUN, creatinine, electrolytes, glucose, total protein, albumin, 
liver function tests (AST, ALT, bilirubin, alkaline phosphatase). 
- 
Serum will be tested for CMV, Herpes Zoster, Herpes Simplex, Hepatitis B, Hepatitis C, 
EBV, Syphilis (adolescents and adults), Measles (pediatric patients only) and Toxoplasmosis. 
- 
Blood will also be tested for HTLV-1 and 2 as well as HIV-1 and 2, and West Nile 
- 
Pregnancy test for women of childbearing age 
- 
Bone marrow aspirate and biopsy 
- 
Urinalysis 
- 
Electrocardiogram, echocardiogram or a gated pool scan if needed 
- 
Pulmonary function test if needed 
- 
Chest X-ray or other types of scans (i.e. CT scan or PET scan) as needed 
- 
Samples of bone marrow and/or peripheral blood cells will be obtained to define donor/host 
differences and to determine engraftment of donor cells. (may be completed outside of 45 
day window) 
- 
An additional 6 tablespoons of blood will be drawn for laboratory tests during routine blood 
tests if needed 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1. 
Preparative cytoreduction 
 
Patients will be treated as inpatient on the Memorial Hospital Allogeneic Transplant Services in 
Pediatrics or Medicine. The patient will have a central venous catheter present for the transplant. 
Once neutropenic, the patient will be maintained in reverse isolation until the day of discharge. 
 
The preparative cytoreduction will include the following: 
Days –9 to –7 Busulfan*  0.8 mg/Kg/dose Q6H X 12 doses/3 days IV 
If > 4 years of age over 2 hours 
(Busulfex®) 1.0 mg/Kg/dose Q6H X 12 doses/3 days IV 
If < 4 years of age over 2 hours 
Days -6 to -5 Melphalan** 70 mg/m2/day x 2 days IV over 30 minutes 
Days -6 to -2  Fludarabine** 25 mg/m2/day x 5 days IV over 30 minutes 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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SCHEMA OF CYTOREDUCTION AND PREPARATION FOR ALLOGENEIC PBSCT 
 
DONOR: 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
PATIENT: 
 
 
 
 
LEUKAPHERESIS 
T-ce ll De ple tio n 
 
Palifermin 
Palifermin 
Palifermin 
 
BU 
BU 
BU 
 
 
 
 
MEL MEL 
ATG  ATG ATG* 
 
 
 
 
FLU  FLU  FLU  FLU FLU  
PBSCT/BM T 
 
 
 
-13 -12 -11 
-10 -9  -8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
+2 
 
 
*Last dose of ATG is given to recipients of HLA- mismatched stem cell transplants ONLY. 
G-CSF 
Palifermin 
Palifermin 
Palifermin 


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IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
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AN EXAMPLE OF A ROAD MAP OF PREPARATION FOR TRANSPLANT 
 
SUNDAY 
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
-13 
Palifermin 
60 mcg/kg/dose 
IV X 1 
-12 
Palifermin 
60 mcg/kg/dose 
IV X 1 
-11 
Palifermin 
60 mcg/kg/dose 
IV X 1 
-10 
-9 
Busulfan IV 
0.8-1.0 
mg/Kg/dose 
IV Q 6H X4 
-8 
Busulfan IV 
0.8-1.0 
mg/Kg/dose 
IV Q 6H X4 
Busulfan dose 
will be adjusted 
per PK levels 
when available 
-7 
Busulfan IV 
dose per PK 
IV Q 6H X2 
Busulfan IV 
dose per PK 
IV Q 6H X2 
-6 
Fludarabine 
25 mg/m2/day 
IV X 1 
Melphalan 
70 mg/m2/day 
IV X 1 
-5 
Fludarabine 
25 mg/m2/day 
IV X 1 
Melphalan 
70 mg/m2/day 
IV X 1 
-4 
Fludarabine 
25 mg/m2/day 
IV X 1 
-3 
Fludarabine 
25 mg/m2/day 
IV X 1 
Rabbit ATG 
2.5 mg/Kg/d 
IV over 12 H 
-2 
Fludarabine 
25 mg/m2/day 
IV X 1 
Rabbit ATG 
2.5 mg/Kg/d 
IV over 12 H 
-1 
Rabbit ATG 
2.5 mg/Kg/d 
IV  over  12  H 
for 
HLA 
– 
mismatched 
SCTs only 
0 
T-cell 
depleted 
Stem cell 
transplant 
Palifermin 
60 mcg/kg/dose 
IV X 1 
+ 1 
Palifermin 
60 mcg/kg/dose 
IV X 
+2 
Palifermin 
60 mcg/kg/dose 
IV 
+3 
+4 
+5 
+6 
+7 
Start G-CSF 
Schedule may be adjusted for patient safety or donor scheduling issues, if unavoidable. 
 
* busulfan dosing and administration: 
Patients will have busulfan levels drawn whenever possible after the first dose on day 1, 
with adjustments in dosing based on the pharmacokinetics of the first dose according 
to “institutional” standard clinical practice as indicated.  Dose should be adjusted if patient is > 
125% ideal body weight and should be calculated on adjusted ideal body weight per MSKCC 
standard of care guidelines. 
 
** melphalan dosing and administration: 
Dose should be adjusted if patient is > 125% ideal body weight and should be calculated on 
adjusted ideal body weight per MSKCC standard of care guidelines. 
 
*** fludarabine dosing and administration: 
Dose administered is based on the patient’s actual weight per MSKCC standard of care 
guidelines. 
 
Anti-seizure prophylaxis with Keppra or Phenytoin will be administered to all patients starting 
day –10 or 24 hours prior to starting Busulfex for the prevention of busulfan-associated seizures. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 18 - 
 
 
 
 
9.2. 
Palifermin: will be administered intravenously to all patients on day -13, -12, -11 and 0, 
+1, +2. Dose will be calculated using actual body weight. 
 
9.3. 
Peri-transplant treatment to promote engraftment 
a. 
Rabbit anti-thymocyte globulin* (Thymoglobulin®) and methylprednisolone (MPD) 
Rabbit ATG will be given to all transplant recipients > 18 years old. Rabbit ATG will also be 
given to patients ≤ 18 years of age who receive transplants from donors other than HLA- matched 
related siblings. Patients will receive rabbit ATG (Thymoglobulin®) at 2.5 mg/Kg/day x 2 days 
on days -3 and -2. Recipients of HLA- mismatched stem cell transplants will receive an 
additional dose of rabbit ATG on day -1. If the patient has a history of allergy or intolerance to 
rabbit ATG, equine antithymocyte globulin at a dose of 15 mg/kg x 2 or 30 mg/kg x 1 may be 
used. An additional dose of equine ATG will be given to recipients of HLA-mismatched stem 
cell transplants. If severe reaction is encountered after the first dose of ATG, the second dose can 
be delayed until day +5. Methylprednisolone will be given at 1 mg/Kg/day with the ATG 
administration and will be discontinued thereafter. If patient is receiving a second transplant 
from the same donor, ATG administration will be at the discretion of the physician. ATG dosing 
should be adjusted if patient is > 125% of ideal body weight and should be calculated on 
adjusted ideal body weight per MSKCC standard of care guidelines. 
 
Patients may receive premedication consisting of acetaminophen, diphenhydramine, ranitidine, 
and an additional dose of methylprednisolone (1 mg/kg/dose) 
 
b. G-CSF will be given to all patients, regardless of transplant type, from approximately Day +7 
if absolute neutrophil count (ANC) is <500 and continue until ANC is >2000. G-CSF may be 
given earlier post transplant if clinically indicated at the discretion of the Attending Physician. 
G-CSF doses will be given and rounded according to Adult and Pediatric BMT guidelines. 
 
9.4. 
Prophylax is against acute graft-v ersus-host disease 
 
No further GvHD prophylaxis will be administered. 
 
9.5. 
Stem Cell Transplantation   
 
9.5.1.  PBSCT 
Do nor perip hera l b lood p ro ge nitor ce lls: stimu latio n, harve sting, iso latio n a nd T-ce ll dep letio n. 
 
For re la ted do nors, ideally 5-6 days before the day of transplant, the donor will receive GCSF per 
institutional guidelines. On approximately the fifth and sixth days of this course of G-CSF, the 
donor will undergo leukaphereses designed to provide a minimum of 109  mononuclear cells/kg of 
the transplant recipient's weight. For unre lated do nors, G-CSF will be administered and the 
leukaphereses obtained according to the National Marrow Donor Program pro tocol IND, and 
institutional guidelines. Mononuclear cell fractions collected on the fourth and fifth days will be 
pooled. 
The CliniMACS System for Positive Selection of CD34+ Progenitor Cells and Depletion of 
T-Cells. 
The CliniMACS System (Miltenyi Biotec, Auburn, CA) including the CliniMACSplus 
Instrument, a CliniMACS Tubing Set, the CliniMACS CD34 Reagent and the CliniMACS 
PBS/EDTA Buffer is intended for the selection and enrichment of human CD34 positive 
hematopoietic progenitor cells from a leukapheresis product. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 19 - 
 
 
 
 
The CD34 antigen is a cell membrane glycoprotein expressed by early hematopoietic stem and 
progenitor cells.  The CD34 positive cell separation process may be useful in several areas of 
clinical stem cell transplantation, including purging of tumor cells, T-cell depletion, ex vivo cell 
expansion and gene therapy.  When re- infused after myeloablative chemotherapy, CD34 positive 
peripheral blood progenitor cells have been shown to reconstitute all hematologic lineages and 
exhibit both short and long term repopulating capacities. 
The ClinMACS System uses selective CD34 monoclonal antibodies conjugated to super- 
paramagnetic particles.  The CD34 positive target cells are selected in an automated continuous 
flow separation system. 
The CD34 positive cells are specifically labeled for selection by incubation with the CliniMACS 
CD34 Reagent. After unbound reagent is washed from the suspension, the cells are ready for the 
automated separation process. The CliniMACS System passes the antibody- labeled suspension, 
the cells are ready for the automated separation process. The CliniMACS System passes the 
antibody- labeled suspension through a column in which strong magnetic gradients are generated. 
The Selection Column retains the magnetically labeled CD34 positive cells, while unwanted 
cells flow through the Selection Column and are collected in the Negative Fraction Bag. The 
system performs several washing steps, disposing most of the liquid into the Buffer Waste Bag. 
The Separated CD34 positive cells are released from the column by removing the column from 
the magnetic field and eluting the cells into the Cell Collection Bag. 
 
The components of the CliniMACS System include: 
 
The CliniMACS Instrument 
The CliniMACS Instrument is a bench-top instrument consisting of a supporting structure to 
hold the column/tubing assembly and various bags, a series of valves through which the 
tubing set is fitted, a magnet between the poles of which the separation column is placed, a 
peristaltic pump through which a section of tubing is placed, software to control the 
instrument and user interface and a computer touchpad with a display window. The 
instrument is operated at ambient temperature and it is intended to be multi- use item. 
 
The software for the CliniMACS Instrument controls the function of the electromechanical 
components of the instrument and the user interface.  Two separate computers, one a micro- 
controller located on a control board of the CliniMACS Instrument and the second a PC 
compatible computer which operates the user interface are incorporated with the instrument. 
Software Version 2.31, the current version of software is directly traceable to the version of 
software utilized in pre-clinical testing and European Safety trials, and has been inspected and 
approved by TÜV product services with the CE Mark. 
 
CliniMACS Tubing Set 
The CliniMACS Tubing Set consists of a tubing element combined with a pair of proprietary 
cell selection columns.  These form a closed, sterile system for processing the cells. The 
separation column is a proprietary component of the CliniMACS System consisting of a 
plastic column housing with polypropylene frits in each end.  The interior of the column 
housing is filled with a matrix of sub- millimeter iron beads coated with a heat-cured 
biocompatible resin.  The columns are placed at appropriate locations in the CliniMACS 
Tubing Set to facilitate the cell selection process. The first column serves as a device to 
remove components that bind non-specifically to the column.  The second column which is 
placed within a magnetic field performs the actual cell selection.  The columns are 
incorporated sterile as part of the tubing set and are intended for single use only. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 20 - 
 
 
 
 
 
 
The tubing element consists of a series of tubes, connectors, spikes, Luer locks, and collection 
bags.  The tubing of the tubing element is comprised of materials that have been qualified for 
use in this application by testing to ISO 10993. The principal constituents are polyvinyl 
chloride (PVC) and silicone.  The connectors are made of various polymers (e.g., ABS and 
PVC) suitable for use in a blood contact environment. They are solvent bonded to the PVC 
tubing.  The silicone pump tubing is softened with petroleum ether for manufacturing and 
mechanically fixed to connectors. The cell wash bags are composed of PVC. 
The CliniMACS Tubing Set is packaged in a thermoformed tray and heat sealed with a 
Tyvek® lid. The CliniMACS Tubing Set is sterilized by ethylene oxide gas in a validated 
sterilization cycle and supplied as a single- use component for the CliniMACS Instrument. 
 
CliniMACS CD34 Reagent 
The CliniMACS CD34 Reagent is a dark amber, nonviscous, colloidal solution containing the 
antibody conjugate in buffer.   The conjugate consists of a monoclonal antibody towards the 
human CD34 antigen.  The murine monoclonal IgG1 antibody is covalently linked to dextran 
beads having an iron oxide/hydroxide core. The concentration of the conjugate is equivalent 
to 20 micrograms (µg) per mL of antibody protein, 800 µg/mL of dextran and 800 µg/mL of 
iron.   The colloid is buffered in a phosphate-buffered saline (PBS) containing 
ethylenediaminetetraacetic acid (EDTA) and Poloxamer 188. The nominal concentrations of 
its components are 0.0095 M phosphate, 0.004 M potassium, 0.163 M sodium, 0.139 M 
chloride, 0.005 M EDTA and 0.03 % (w/v) Poloxamer 188.  The pH is 7.4 - 7.7. Poloxamer 
188 is added to the CliniMACS CD34 Reagent to stabilize it during shipping, handling and 
storage.   The CliniMACS CD34 Reagent is supplied sterile and pyrogen-free in glass vials 
containing 7.5 mL and is intended for single use and in vitro use only. 
 
The CliniMACS PBS/EDTA Buffer 
The CliniMACS PBS/EDTA Buffer is an isotonic and isohydric buffer solution with a pH- 
value of 7.2 and osmolarity of 290 mosmol/L.  Its formulation is shown in the following 
table. 
 
Table 1  Formulations of the CliniMACS PBS/EDTA Buffer 
Ingredient 
Compendial 
Amount 
NaCl 
Ph. Eur. 
8.0   g/L 
KCl 
Ph. Eur. 
0.19  g/L 
Na2HPO4 anhy. 
Ph. Eur. 
1.15  g/L 
KH2PO4 
Ph. Eur. 
0.19 g/L 
Na2EDTA 
Ph. Eur. 
0.37  g/L 
Water for Injection 
Ph. Eur. 
ad 1L 
 
The CliniMACS PBS/EDTA Buffer is used as external wash and transport fluid for the in vitro 
preparation of human heterogeneous cell populations intended to be separated with the 
CliniMACS Cell Selection System. Prior to and during incubation of the antiCD34 beads with 
the mobilized PBSC, intravenous gammaglobulin is added to the incubation fluid at a 
concentration of 1.5 mg IVIG/ml. 
 
Before infusion, the CD34+ cells will be washed in normal saline for intravenous infusion 
containing 1% human serum albumin, and suspended in a volume of 25-50 ml. for intravenous 
administration. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 21 - 
 
 
 
 
 
 
Throughout the process, critical control points and associated assays are identified and 
performed on each cellular therapy product. Aliquots of the same product sample are taken for 
in-process and final product testing. After each step (apheresis, platelet washing, CD34 labeling 
and washing, enrichment), QC testing includes; Sterility. Endotoxin, gram stain, Total nucleated 
cells (TNC), flow cytometry phenotype/analysis of CD45, CD34, and CD3, and viability 
assessed by 7-AAD is assessed. To ensure sterility, 14-day sterility tests are performed for in- 
process sterility testing and a gram stain is performed on the final product prior to release. 
 
9.5.2. BMT (if PBCST not possible) 
 
Approximately twenty- four to forty-eight hours after the patient has completed treatment with 
fludarabine, bone marrow will be harvested from the donor in the operating room according to 
standard procedure. The procedure for T cell depletion with soybean agglutinin (SBA) and sheep 
red blood cells (E) has been previously  described 38, 39 and the SOP from the MSKCC 
Cytotherapy Lab is appended. 
 
The amount of marrow harvested  will be such to provide a minimum of 1 x 107 SBA-E- 
mononuclear cells/kg of the transplant recipient's weight. In very rare instances, the amount of 
marrow cells harvested from the donor may be inadequate to provide a high enough cell yield 
after the complete T-cell depletion procedure outlined above, to ensure engraftment. This can be 
predicted at any of the initial steps before the final sRBC rosetting. In such a situation, the 
physician in charge of the study and/or the attending physician of the BMT service, in 
consultation with the laboratory investigators performing the T-cell depletion, may elect to 
administer either an unmodified or a partially T-cell depleted (SBA-) marrow transplant. The 
patient would then receive drug prophylaxis against GvHD. These patients will be statistically 
evaluated as recipients of T-cell depleted marrow, but will be analyzed separately in evaluation 
of the efficacy of the SBA- E- marrow grafts. 
Transplantation of the T-cell depleted stem cells. 
Ideally, the CD34+T-cell depleted peripheral blood progenitor cells or the SBA-E- fraction of the 
bone marrow, suspended in a volume of approximately 20-50 ml will be infused intravenously 
over approximately 15 minutes with monitoring of vital signs. The patient is premedicated as for 
blood product transfusions. 
9.6. 
Supportiv e Care 
 
a. Prophylaxis against infections 
Standard of care guidelines will be followed for prophylaxis against post transplant infections 
by opportunistic organisms, including Pneumocystis jiroveci, fungal organisms, DNA 
herpesviruses and more specifically CMV. 
 
b. Prophylaxis against menorrhagia 
Post-pubertal  females  may  receive  prophylaxis  against  menorrhagia  according  to  our 
standard of care guidelines. 
 
c. Transfusions 
Following initiation of the pre-transplant cytoreduction, all blood products for transfusion, 
with the exception of the marrow graft, will be irradiated to 3,000 cGy to inactivate 
lymphocytes capable of initiating lethal GvHD. Blood products are irradiated in the blood 
bank, using a cesium gamma emitter. Patients who are Cytomegalovirus (CMV)-seronegative 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 22 - 
 
 
 
 
pre-transplant will be permitted to receive only CMV-seronegative blood products, except in 
an emergency. 
 
Platelets may be administered for clinical evidence of active hemorrhage. To minimize 
bleeding, platelets will be transfused prophylactically in order to maintain a platelet count 
3 
greater than 20,000/mm . Post-transplantation, the marrow donor or selected family donors 
will be utilized, whenever possible, as platelet donors. Packed irradiated red blood cells will 
e administered as clinically indicated. 
 
d. Nutritional support 
Nutritional status will be carefully monitored by the physician, and high-calorie parenteral 
alimentation will be introduced as needed. Vitamin supplements will be as clinically 
indicated. 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.2 Post-tra nspla nt e valua tio n   
 
The chart below shows the approximate dates for tests and procedures performed after transplant. 
Certain tests may be held at the discretion of the treating physician and/or if deemed in the best 
clinical interest of the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after 
thereafter 
nths if 
ndicated 
ACTIVITY 
TRANSPLANT 
TO DISCHARGE 
DISCHARGE TO 
DAY 100 
DAY 100 - 6 
LONG TERM 
MONTHS 
FOLLOW-UP 
Blood counts and 
chemistry  (CBC, 
Comprehensive 
Metabolic Panel) 
CBC: daily 
Comp: 2 times per 
week 
CBC, Comp: weekly, 
or twice a week or 
every 2-3 weeks as 
needed 
9, 12 & 24 months 
Every 2-4 weeks 
after transplant; 
thereafter as 
clinically indicated 
Physical exam for 
GVHD evaluation 
Daily after 
engraftment until 
discharge from the 
hospital 
About weekly after 
discharge until day 100 
Every 2-4 weeks 
9, 12 & 24 months 
after transplant; 
thereafter as 
clinically indicated 
Disease evaluation, 
Bone marrow, & 
peripheral blood 
chimerism by 
cytogenetic tests 
28-30 days after 
transplant 
100 days after 
transplant 
6 months after 
9 months (if 
transplant 
clinically indicated) 
12 months, 18 
months (if clinically 
indicated) & 24 
months after 
transplant; thereafter 
as clinically 
indicated 
Peripheral blood 
lymphocyte (PBL) 
phenotyping 
NA 
90-120 days after transplant* 
9 months 
transplant;
every 3 mo
clinically i
In vitro response of PBL 
to standard panel of 
mitogens, antigens, and 
NA 
NA 
6 months after 
thereafter 
transplant 
months un
or plateau 
every 3-6 
til normal 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 23 - 
 
 
 
 
 
viral antigens 
Research Blood Tests 
15, 28 days after 
transplant 
60 and 100 days after 
transplant 
6 months after 
transplant 
12 months after 
transplant 
Tests may be done more frequently if there are complications such as GvHD or infections. 
* PBL phenotyping is part of standard of care; therefore it is billable to the patient or insurers. 
 
10.3 Research Samples (as listed in the chart above) 
Mononuclear cells (obtained from approximately 20-30cc of whole blood) may be obtained 
from the patient prior to transplant, as well as at approximately the same time points 
chimerism samples are obtained.  These cells will be studied for alloreactivity and antitumor 
reactivity in vitro. Research blood tests will be performed at the discretion of the physician. 
 
11.0     TOXICITIES/SIDE EFFECTS 
 
Patients recruited to this transplantation trial are individuals who are either referred by 
physicians or self-referred for marrow transplantation as a potentially curative treatment for their 
malignancy. Prior to consideration for transplant, all patients undergo a series of 1-3 hour 
consultations discussing the risks and potential benefits of an allogeneic stem cell tra nsplantation 
and the different procedures which will be a normal part of the transplant course. The risks and 
potential benefits of the transplant procedure, as well as the participation in any given research, 
experimental, or therapeutic protocol are also discussed. 
11.1. 
Risks to Related Peripheral Blood Stem Cell Donors 
 
The risks of short-term treatment with G-CSF are likely negligible. However, administration of 
GCSF is frequently associated with low grade fever and low back pain which usually resolves 
within one day following cessation of GCSF treatment. Furthermore, there has now been one 
recorded patient who developed acute splenomegaly and splenic rupture in response to high dose 
GCSF. The bone pain may require treatment with analgesics. The risks of a leukapheresis are 
negligible, involving an occasional vasovagal response to venipuncture and the minimal 
hemodynamic alterations associated with single unit phlebotomies. To protect against these risks, 
leukapheresis are conducted in the Blood Bank Donor Room with full medical and nursing 
supervision and support systems to address adverse events. 
 
For donors undergoing bone marrow harvest, the risks for the donor will mainly be those risks 
associated with general anesthesia. The side effects of the harvest itself will include pain at the 
site of harvest, i.e. posterior and/or anterior superior iliac crests, as well as minimal risks of 
bleeding at the site. There have been no problems with localized infections at the sites in the 
extensive experience of our service with marrow harvests over the last 20 years. 
 
11.2. 
General Description of Risks to Recipients 
 
Infections and hemorrhage constitute major and continuing risks throughout the period of 
marrow aplasia. These are, however, also the major risks associated with the primary disease. 
Certain opportunistic infections remain a risk in transplant patients beyond recovery of 
circulating leukocytes, for at least 9-12 months post-transplant, e.g. Pneumocystis carinii, 
cytomegalovirus and Epstein Barr virus. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 24 - 
 
 
 
 
Like ly: 
Busulfan: Myelosuppression tiredness, not sleeping well, anorexia, nausea, vomiting, diarrhea, 
mucositis weight gain and swelling, changes in blood sodium level, alopecia, needing 
transfusions of platelets and red blood cells, fever, needing antibiotics to treat infection. 
 
Melphalan: Myelosuppression tiredness, not sleeping well, anorexia, nausea, vomiting, diarrhea, 
mucositis weight gain and swelling, changes in blood sodium level, alopecia, needing 
transfusions of platelets and red blood cells, fever, needing antibiotics to treat infection, transient 
liver dysfunction. 
 
Fludarabine: Myelosuppression, tiredness, not sleeping well, anorexia, nausea, vomiting, 
diarrhea, mucositis weight gain and swelling, changes in blood sodium level, alopecia, needing 
transfusions of platelets and red blood cells, fever, needing antibiotics to treat infection, jaundice 
and elevations of liver enzymes. 
 
Reproductive risks: Sterility. Male patients may be offered sperm banking before admission for 
the transplant. Possibilities of preserving the ability to have children for female patients can be 
discussed with the doctor. Patients should not become pregnant or father a baby while on this 
study because the drugs in this study can affect an unborn baby. Women should not breast feed a 
baby while on this study. A pregnancy test is required of all females of childbearing age before 
starting the transplant. 
ATG: is a rabbit protein that may induce an immune response in humans. Fever, chills, changes 
in blood pressure, rash. Pre- medications (Benadryl, Tylenol and steroids before ATG) have been 
shown to be effective therapy. Side effects are usually only severe after the first dose. 
Palifermin: skin rash, itching, redness, swelling, skin sensitivity, muscle and joint aches, 
tingling in the mouth and lips, mouth/tongue thickness or discoloration, abnormal taste. Skin rash 
can be treated with anti- histamine medications and pain with Tylenol. The other symptoms 
resolve with no medications. 
 
Growth factor (G-CSF): bone pain, headache, body ache, feeling tired, swelling of hands/feet, 
nausea. These are generally mild and will go away when the growth factor is stopped. 
 
Le ss Like ly: 
 
Busulfan, melphalan, fludarabine: Late effects of these three chemotherapy agents include: 
cataracts and under-activity of the thyroid gland. Both of these side effects can be easily treated. 
 
Busulfan: Seizures that are generally preventable by phenytoin therapy started 24 hours prior to 
administration and continued for 24 hours post busulfan. Abnormal liver function, Pulmonary 
fibrosis. 
 
Melphalan: renal or bladder dysfunction (increased BUN, creatinine, necrosis) may be seen. 
 
Fludarabine: confusion, numbness, loss of vision, loss of balance, difficulty walking 
 
ATG: Prior exposure to rabbit proteins may predispose subjects to serious allergic reactions such 
as a drop in blood pressure, hives, bronchospasm, or serum sickness. Such reactions will be 
treated with epinephrine and anti- histamines. Serum sickness is an immune disease usually 
appearing 3-10 days after injection of a foreign serum or serum protein, with reactions such as 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 25 - 
 
 
 
 
hives, fever, swollen lymph nodes, edema, arthritis, protein in the urine, or severe inflammation 
of the kidney. In the event of a severe systemic allergic reaction, a trial of an alternative horse 
ATG will be administered. If a similar reaction occurs with the equine ATG, no further ATG will 
be administered. 
 
Tra nspla nt re late d risks: 
 
Blood transfusions: Transfusions may induce allergic reactions. Small, subclinical pulmonary 
emboli may occur, but these rarely if ever require any intervention. Standard pre-medications for 
blood products may be used before administration of the marrow graft. Fluid overload can be 
managed with diuretics. Allergic reactions of variable severity can be prevented or mitigated by 
premedication with antipyretics, antihistamines, and narcotics. These products may also serve as 
vectors of serious infection (e.g., CMV, hepatitis, AIDS). To circ umvent this, prospective blood 
and marrow donors will be screened per AABB and FAHCT guidelines. CMV antibody (-) blood 
products will be used in CMV (-) individuals, whenever possible, regardless of the antibody 
status of the marrow donor. ALL blood products are irradiated (3000r, 137Cs) to circumvent the 
risk of GvHD caused by contaminating lymphocytes in the transfused fractions. 
 
Receiving peripheral blood stem cells: The volume of the T-cell depleted peripheral blood 
stem cells infused is approximately 30-50 cc.  Possible side effects include: changes in blood 
pressure, fever, headache, shortness of breath, chills, sweats, nausea/vomiting, bad taste in the 
mouth. Pre- medications are given to reduce these side effects. 
 
Graft-versus-host-disease (known as GvHD): This condition happens when the transplanted 
donor cells recognizes the patient’s body as foreign and attacks it. At least 1-2 out of 10 patients 
receiving a T cell depleted transplant will get mild to moderate GVHD. GVHD can be treated 
with medications (either IV or tablets). A skin biopsy may be necessary to make the diagnosis of 
GVHD. 
 
Acute GVHD usually occurs in the first 3 months and may cause: skin rashes, nausea, vomiting, 
diarrhea, hepatitis, increased risk of infection, ulceration of the surfaces of the oral cavity, 
esophagus, and intestines, and suppressed or delayed recovery of the hematopoietic and immune 
system. In patients transplanted and engrafted with SBA- E- T-cell depleted marrow from HLA 1- 
3 allele disparate related donors, this complication has been observed in fewer than 20% of 
patients and has rarely been severe. It may be fatal in at least 20-50% of cases and may also 
predispose to lethal infections which contribute to an additional mortality of 10-25%. 
 
Chronic GVHD can occur any time after the first 3 months. Approximately 50% of patients 
with acute GvHD may also develop chronic GvHD, manifested to varying degrees by 
scleroderma- like changes of the skin, cirrhosis of the liver, sclerosis of lacrimal and salivary 
ducts, chronic inflammation and scarring of the gastrointestinal tract with consequent 
malabsorption and diarrhea, chronic bronchitis, and suppression of the immune system. This can 
be treated with standard or protocol-based experimental immunosuppression, but may be 
refractory. 
 
Steroids, as treatment for GvHD: inability to sleep, high blood sugar, puffiness of the face, 
changes in the skin, high blood pressure, increased risk of infection, weight gain, reduced growth 
in children, thinning of the bones 


Memorial Sloan Kettering Cancer Center 
IRB Number: 08-008 A(12) 
Approval date: 02-Jan-2019 
- 26 - 
 
 
 
 
Infections or bleeding: Full recovery of blood counts may take months. Full recovery of the 
immune system may take months to a few years. For this reason patients will be at increased risk 
of infections and bleeding. Medications are given to reduce the chance of those infectio ns. 
Patients will receive treatment if they do get an infection and most infections can be treated 
successfully with antibiotics. Patients will stay in the hospital longer or be readmitted if found to 
have an infection. Patients are watched closely for bleeding and given platelet transfusions to 
prevent serious bleeding, but minor bleeding may occur. 
 
Potential sensitization to murine proteins: Mouse protein (the anti CD34 antibody used in this 
device is of murine derivation) is used in the CliniMACS processing procedure. Marrow cells are 
also separated on bovine serum albumin gradients and exposed to sheep red cells to remove 
rosetting populations. It is possible that patients may have pre-existing immunity to these proteins 
and may be at risk for allergic reactions during infusion of the processed marrow and/or 
peripheral blood. No allergic reactions have been noted with infusions of cells processed by the 
CliniMACS system in clinical studies or from infusion of cells recovered by depletion of SRBC- 
rosette-positive cells. Precautions for an allergic event will be taken during the infusion of the 
processed cells. 
 
Pneumocystis jiroveci prophylaxis: The risk of trime thoprim a nd sulfa me tho xa zo le in the 
doses given are primarily hypersensitivity reactions and signs of folate deficiency. Any patient 
with known hypersensitivity to these compounds will not receive these drugs. The risks of 
parenteral pe nta mid ine are primarily hypotension and hypoglycemia both of which will be 
monitored during and following administration of the drug. Hypokalemia or hypomagnesemia 
associated with prolonged QT syndrome or torsade de pointe necessitates strict electrolyte 
monitoring. The risks of aerosolized pentamidine are mild bronchospasm primarily observed in 
(prior) tobacco abusers and easily managed with bronchodilator therapy. 
 
Rare but se rio us: 
 
Busulfan: high doses of Busulfan can cause Veno-Occlusive Disease (VOD). Symptoms include 
jaundice, liver enlargement with pain, fluid retention and increase risk of bleeding. This 
complication is managed by aggressive supportive care with monitoring of fluids and 
administration of diuretics and infusions of plasma and albumin. Veno-Occlusive Disease in its 
severe form can be life threatening. There is also a medication, Defibrotide, which has shown to 
be helpful in treating VOD. 
 
Melphalan: pulmonary fibrosis, respiratory distress has been rarely reported. Serious 
hypersensitivity reactions: Edema, rash, anaphylaxis 
 
ATG: renal toxicity, managed by Prednisone. Drop in white blood cells, drop in platelet count 
will be managed by transfusion therapy. 
 
Tra nspla nt re late d risks: 
 
Risk of a secondary cancer different from MDS/AML may happen after chemotherapy. The 
risk of developing a secondary cancer of the skin, cervix, etc., which has been seen in other 
studies of similar transplants, is less than 5%. There is a special concern in patients who receive 
a T cell depleted transplants because there is a risk of having a cancer of the lymph nodes 
(lymphoma) caused by the Epstein Barr virus (EBV). This virus causes mononucleosis in healthy 
people. Treatment of EBV includes Donor Leukocyte Infusion (DLI) and Rituximab. 


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Graft Failure: bone marrow graft may fail to grow. Past experience suggests that this may occur 
in about 10% of patients. If graft failure occurs, it is unlikely that bone marrow will recover and 
a second transplant with stem cells from the same donor or a different donor will be needed. 
 
Severe graft-versus-host disease. Rarely, GVHD can be severe or deadly. Severe acute GVHD 
could involve a severe skin rash like a burn, severe vomiting and/or diarrhea, liver failure and 
infections or bleeding. Severe acute GvHD will be treated with intense immunosuppressive 
therapy according to standard clinical practice or other experimental protocol. Severe chronic 
GVHD could involve similar symptoms but may produce other symptoms such as severe skin 
changes, severe dry eyes and weight loss. 
 
Serious infections or bleeding. Some infections are very difficult to treat, even with strong 
antibiotics. Rarely, serious infections can be passed on by the transfusion of blood products. 
Serious bleeding can happen in spite of platelet transfusions. Rarely infections or bleeding are 
lethal. 
 
Recurrence of MDS/AML is a risk even if the transplant is initially successful. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
De finition o f e ve nts in the post-tra nspla nt co urse impo rta nt fo r a na lysis and tre atme nt 
12.1. 
Regimen-related and transplant-related mortality 
 
Regimen related toxicity (RRT) refers to those toxicities that can be attributed directly to the 
preparative regimen (including chemotherapeutic agents, ATG, and Palifermin). 
 
Transplant-related mortality (TRM) includes the RRT and other fatal complications resulting 
from the allogenic transplant such as graft failure, GvHD, hemorrhages, and infections. 
 
The grading for monitoring the morbidity and mortality will be based on the NCI/CTEP common 
toxicity criteria. 
 
12.2. Infections. 
 
The occurrence of life-threatening opportunistic infections will be evaluated according to the 
criteria established by BMT CTN (see Appendix) and will correlate this with the level of 
immune recovery. The infection-related mortality will be also determined. 
 
12.3. 
Immunologic Reconstitution 
 
Our previously reported analyses have identified time points at which the various immunologic 
functions can be expected to return. Patients receiving T-cell depleted transplants from HLA- 
identical related donors can be monitored at fewer time points without compromising our ability 
to obtain critical information. However, patients receiving transplants from partially HLA- 
matched related donors may be evaluated more frequently, as graft rejection, late graft failures, 
more pronounced immune dysfunction, and more patient to patient variability have been 
observed. 


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Immunophenotyping and NK cell function will be performed on circulating lymphocytes of all 
recipients of T-cell depleted marrow transplants during the first post-transplant month to monitor 
engraftment. Lack of NK cells and NK function and predominance of CD8+ host cells have 
correlated with impending graft failure. Thereafter, immunophenotyping of T-cells, B-cells, and 
NK cells, will be performed at approximately 1, 3, and every 3-6 months post-transplant until 
normal values are reached. The approximate schedule tests are shown in the table on page 23. 
 
T-cell proliferations in response to PHA, Candida, viral antigens, and tetanus following 
immunization will be performed at approximately 6 months post-transplant and every 3-6 
months thereafter until normal values are reached 
 
Immunoglobulin levels will be tested at 6, 12, and 24 months post-transplant and thereafter as 
clinically indicated. Patients with normal total IgG levels and PHA response within the 10th 
percentile of normal may be re- immunized according to infection guidelines. 
 
12.4 Engraftment and chimerism 
 
Engraftment will be documented by analysis of T cells and bone marrow cells for chimerism by 
standard cytogenetic studies at about 1 month, 100 days, 6 months, 9 months (if clinically 
indicated), and 12 months, 18 months (if clinically indicated), and 24 months post transplant or 
as needed thereafter. 
 
12.5 Graft failure or rejection 
T cell depletion of donor cells is associated with an increased incidence of graft failure in 
allogeneic transplant recipients.  After allogeneic transplantation, the recipient's marrow function 
may be poor and leukopenia, anemia, or thrombocytopenia may result from many causes 
including graft rejection induced by surviving host immune T-cells, or ongoing suppression of 
engrafted donor blood- forming cells by GVHD, infection or marrow suppression or 
immunosuppressive drugs and other medications.  Graft failure may result in death if not 
reversed. In patients with immune rejection second transplants can be administered with 
immunosuppressive therapy, including non-myeloablative conditioning regimens. For patients 
who are engrafted with donor cells but have severe cytopenia affecting one or more blood cell 
lineages, secondary transplants of CliniMACS fractionated CD34+ T-cell depleted PBSCs may 
be administered to booster and replenish donor hematopoietic cells without conditioning or after 
treatment with anti- thymocyte globulin. 
 
 
12.6. Graft-versus-host disease 
Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al 68  (see 
appendix 2) will be used to establish and grade acute GvHD. 
 
To determine the severity of acute GvHD, data will be collected approximately weekly to 
characterize the severity of symptoms and signs caused by GvHD and to evaluate possible 
confounding factors. Data collection may include descriptive characteristics of rash and 
estimated body surface area involved, extent of dermal/epidermal separation, identification o f 
concomitant causes of increased bilirubin other than GvHD, presence or absence of nausea, 
vomiting or anorexia persistent after engraftment, peak diarrhea volume with annotations 
concerning the presence after engraftment, peak diarrhea volume with annotations concerning 
the presence or absence of urinary mixing and estimates of true diarrhea volume, presence or 


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absence of abdominal cramps, presence or absence of frank stool blood or melena, concomitant 
causes of GI symptoms other than GvHD, biopsy results, identification of any agents used for 
treatment and autopsy results. 
 
Patients will be observed for acute and/or chronic GvHD as long as they have not received donor 
derived leukocytes infusions (DLI) for the treatment of relapse or infections. If at any time, a 
patient receives DLI, that time will represent the end-time for evaluation of GvHD. Graft-versus- 
host disease occurring after DLI infusions will be analyzed separately. 
 
Patients with moderate to severe acute GvHD (grade II-IV) will be treated in standard fashion 
with high-dose I.V. methylprednisolone (2-20mg/kg/day) or in combination with other 
immunosuppressants as per ongoing trials on GvHD. Patients failing to respond to steroids will 
be considered for treatment with experimental treatments available at the time of diagnosis of 
GvHD. 
 
Late acute GvHD and Chronic GvHD will be defined according to the criteria of National 
Institutes 
of 
Health 
consensus 
criteria69 
treated 
with 
standard 
or 
experimental 
immunosuppressive therapy. Treatment may consist of corticosteroids, cyclosporin A, or 
azathioprine, or combinations of these agents. Other novel treatments could be used if available, 
i.e. thalidomide and psoralen/ultraviolet A phototherapy (PUVA). 
 
12.7. Disease relapse 
 
Relapse of MDS or AML will be analyzed as to type and genetic origin of the leukemic cells. 
These will be defined by an increasing number of blasts in the marrow over 5%, by the presence 
of circulating peripheral blasts, or by the presence of blasts in any extramedullary site. 
Cytogenetic analysis of the marrow and/or peripheral blood will also be obtained for the 
diagnosis of relapse. 
 
13.0    CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient is found to be ineligible for the protocol as designated in the section on 
Criteria for patient/subject eligibility (e.g. a change in diagnosis), the patient will be removed 
from the study. Also patients may be removed from the study if requested by the patient. 
Management will depend on where they are in their treatment course. Such patients will receive 
appropriate supportive care. Patients may also be removed from the study at any point deemed 
appropriate by the principle investigator. 
 
14.1 
BIOSTATISTICS 
 
This is a revision of a phase 2 trial designed to investigate the efficacy and safety of peri- 
transplant Palifermin in combination with a preparative regimen with busulfan, melphalan, 
fludarabine, and anti-thymocyte globulin (ATG), and a T cell depleted stem cell transplant from 
a histocompatible related or unrelated donor in patients with advanced MDS and AML evolved 
from MDS. This amendment is in response to excessive graft failure in patients with 
mismatched grafts. As a result, the study population will be divided into two groups: HLA 
matched and HLA mismatched donors. The data analysis and data monitoring will conducted 
separately in each HLA group. A maximum of 31 patients in the HLA matched donor group and 
21 patients in the HLA mismatched donor group are planned for accrual onto the study. It is 
anticipated that accrual will last three years and each patient will be followed for a minimum of 


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two years if he/she has not failed. The primary endpoint of the study is one-year treatment 
related mortality (TRM). 
 
After the first 16 patients were enrolled on this study, the transplant team altered the study design 
to make the treatment more effective and reduce the relapse rate and the rejection rate by 
changing the following: 
1. Increasing the number of Busulfan doses from 10 to 12 doses 
2. Increasing the number of ATG doses for recipients of HLA- mismatched transplants 
from 2 to 3 doses 
 
As a result of these changes to the study design, accrual for the study restarted from zero as of 
the Amendment 5 approval, 10/15/2009. 
 
For patients in the HLA matched donor group, a study design that differentiates between 
treatment related mortality probabilities of 0.10 and 0.30 will be used to assess treatment 
efficacy. At the conclusion of the study, if at least 25/31 patients do not experience treatment 
related mortality within the first year of transplant, the treatment will be declared a success in 
controlling treatment related mortality. The probability of declaring the treatment a success for 
TRM is 0.09 when the one- year TRM in the population is 0.30 and increases to 0.90 when the 
one-year TRM in the population is 0.10. 
 
For patients in the HLA mismatched donor group, a study design that differentiates between 
treatment related mortality probabilities of 0.10 and 0.35 will be used to assess treatment 
efficacy. At the conclusion of the study, if at least 17/21 patients do not experience treatment 
related mortality within the first year of transplant, the treatment will be declared a success in 
controlling treatment related mortality. The probability of declaring the treatment a success for 
TRM is 0.10 when the one- year TRM in the population is 0.33 and increases to 0.89 when the 
one-year TRM in the population is 0.10. 
 
In order to reduce patient risk, the study design includes early termination in the event of 
excessive graft failure, graft versus host disease, or early treatment related mortality during the 
accrual period. The stopping rules for excessive failure and the corresponding power 
calculations are derived separately for the matched and mismatched groups and are given in the 
tables below. In the event that the stopping boundary is crossed for one of the donor groups, the 
study will continue accrual in the other group. 
 
HLA matched donor transplants (n=31) 
 
 
 
Failure type 
# of failures needed 
Probability of 
Probability of study 
to stop the study 
failure type 
 completion 
One-year TRM 
2 within the first 3 patients 
3 within the first 8 patients 
4 within the first 13 patients 
5 within the first 19 patients 
6 within the first 26 patients 
7 in 31 patients 
0.30 
0.09 
0.10 
0.90 
2 within the first 7 patients 
0.21 
0.09 


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Graft failure 
3 within the first 17 patients 
4 within the first 29 patients 
5 in 31 patients 
0.05 
0.90 
Acute GvHD 
(grades 3-4) 
2 within the first 3 patients 
3 within the first 8 patients 
4 within the first 13 patients 
5 within the first 19 patients 
6 within the first 26 patients 
7 in 31 patients 
0.30 
0.09 
0.10 
0.90 
Chronic GvHD 
(extensive) 
2 within the first 3 patients 
3 within the first 8 patients 
4 within the first 13 patients 
5 within the first 19 patients 
6 within the first 26 patients 
7 in 31 patients 
0.30 
0.09 
0.10 
0.90 
 
 
HLA mismatched donor transplant (n=21) 
 
 
 
Failure type 
# of failures needed 
Probability of 
Probability of study 
to stop the study 
failure type 
 completion 
One-year TRM 
2 within the first  4 patients 
3 within the first  8 patients 
4 within the first 14 patients 
5 in 21 patients 
0.33 
0.10 
0.10 
0.89 
Graft failure 
2 within the first  4 patients 
3 within the first  8 patients 
4 within the first 14 patients 
5 in 21 patients 
0.33 
0.10 
0.10 
0.89 
Acute GvHD 
(grades 3-4) 
2 within the first  4 patients 
3 within the first  8 patients 
4 within the first 14 patients 
5 in 21 patients 
0.33 
0.10 
0.10 
0.89 
Chronic GvHD 
(extensive) 
2 within the first  4 patients 
3 within the first  8 patients 
4 within the first 14 patients 
5 in 21 patients 
0.33 
0.10 
0.10 
0.89 
 
 
Kaplan-Meier estimates of overall and disease- free survival will be computed for the entire 
cohort and for the following subgroups: minimal residual vs. extensive disease, matched donor 


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vs. mismatched donor, primary vs. secondary MDS, age <50 vs. age >50. The accuracy of the 
estimates within these subgroups will be a function of the patient distribution. Estimated 
probabilities for the time to treatment related mortality, the time to infectious complication, and 
the time to graft versus host disease will be computed using the cumulative incidence function. 
 
Immunologic reconstitution will be summarized by averaging the recorded results across patients 
at each time point. Graphic descriptions of the trajectories over time will be produced using 
kernel smoothing. To assess whether immune reconstitution is assoc iated with demographic or 
transplant related variables, marginal regression models, based on generalized estimating 
equations, will be developed. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.2 Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http ://pp r/).  The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 
 
16.1 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team. The data collected for this study will be entered into the Clinical Research Data Base 
(CRDB), a secure database. Source documentation will be available to support the computerized 
patient record. 
 
16.2 
Qua lity Assura nce 
 
Weeklyregistration will be generated to monitor patient accruals and completeness of registration 
data. Routine data quality reports will be generated to assess missing data and inconsistencies. 
Accrual rates and accuracy of evaluations and follow-up will be monitored periodically 
throughout the study period and potential problems will be brought to the attention of the study 
team for discussion and action. 


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Full sample data quality and protocol compliance audits will be conducted by the study tea m on 
an ongoing basis. 
 
16.3 
Data and Safe ty M onito ring 
 
The Data and Safety Monitoring Plans (DSM) at Memorial Sloan-Kettering cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Caner Institute for Data and 
Safety      Monitoring      of      Clinical      Trials”      which      can       be       found       at:  
Http ://ca nce rtria ls. nc i. nih. go v/re searc he rs/d sm/inde x. html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring      Plans       can       be       found       on       the       MSKCC       Intranet       at:  
http ://mskweb2. mskc c.org/irb /inde x. htm. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, 
and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the 
Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in- house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, and the 
monitoring procedures will be established at the time of protocol activation. 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Risks: From the studies that have been done so far there appears to be no increase in risk of 
addition of Palifermin. However, given this is a new treatment, it is possible that there are side 
effects that have not yet been seen. 
Benefits: The information from this study will help future cancer patients. 
 
Possible toxicities/side effects: Toxicities and side effects of the agents used are listed in section 
11 and reporting of serious adverse events is found in section 17.2. 
 
Consent Process: Participation in this study is voluntary. All patients will be required to sign a 
statement of informed consent which must conform to MSKCC IRB guidelines. 
 
Alternatives: Enrollment in this study is voluntary. Alternative treatment options will be 
presented to the patient prior to taking part in this study. Alternative treatment options may 
include getting a transplant from a volunteer unrelated donor, if one is available; getting 
treatment for the cancer with either chemotherapy or a transplant without being on a study; 
taking part in another study; or getting no treatment. 


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Costs: The patient’s health plan/insurance company will need to pay for all of the costs of 
treatment in this study. The patient will be responsible for the costs of standard medical care, all 
hospitalizations and any transplant complications. Pre-authorization for the transplant will be 
cleared with the health plan/insurance company prior to admission. Patients will not be paid for 
taking part in this study. Research tests will be done at no cost to the patient. 
 
Confidentiality: Every effort will be  made to  maintain patient confidentiality.  Research and 
hospital records are confidential. 
17.2 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
17.3 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@ mskcc.org containing the following information: 
 
Fie lds pop ulated fro m the CRDB: 
• Subject’s name (generate the report with only initia ls if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data need ing to be e ntered : 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE 
number written at the top of the report. If appropriate, the report will be forwarded to the 
FDA by the SAE staff through the IND Office. 


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17.2.1 Definition of SAE 
 
An SAE is an undesirable experience that meets one of the following criteria: 
 
• Is fatal or life-threatening 
• Is disabling 
• Results in hospitalization or prolongation of hospitalization 
• Results in congenital anomaly or occurrence of malignancy 
• Important medical event that jeopardizes the participant AND requires medical or 
surgical intervention to prevent one of the outcomes above. Note: Hospital admission 
for a planned procedure/disease treatment is not considered an SAE. 
 
Attribution: 
 
• Unrelated: The AE is clearly NOT related to the intervention 
• Unlikely: The AE is doubtfully related to the intervention. 
• Possible: The AE may be related to the intervention. 
• Probably: The AE is likely related to the intervention. 
• Definite: The AE is clearly related to the intervention. 
 
Expected and Unexpected Event: 
 
• Expected: Any experience previously reported (in nature, severity, or incidence) in 
the current Investigator’s Brochure or general investigational plan 
• Unexpected: Any experience not previously reported (in nature, severity, or 
incidence) in the current Investigator’s Brochure or general investigational plan 
 
UNEXP ECTED EV ENT : 
 
• Grades 1-2: Adverse Event Reporting NOT required. 
• Grades 3: Possible, Probable, or Definite attribution to the drug and/or device will be 
reported*. 
• Grades 4 and 5: Regardless of Attribution will be reported*. 
 
EXPECTED EVENT 
 
• Grades 1 – 3: Adverse Event Reporting NOT required. 
• Grades 4 and 5: Regardless of Attribution will be reported*. 
 
*Reportable events are those wich occur within 30 days of last dose of treatment on 
protocol. Events beyond 30 days will be reported at the discretion of the PI. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 


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meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 


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19.0 
REFERENCE(S) 
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chromosome 5 q deletion. N Eng J Med. 2006; 355 (14): 1456-1465. 
 
2. Malcovatti L, Della Porta MG, Pacutto C, et al. Prognostoc factors and life expectancy in 
myelodysplastic syndorms calassidies according to WHO criteria: a basis for clinical 
decision making. J Clin Oncol. 2005; 7594-7603. 
 
3. de Witte T, van Biezen A, Hermans J, et al. Autologous bone marrow transplantation for 
patients with myelodysplastic syndrome or acute leukemia following MDS. Blood. 1997; 
90: 38-53-3857. 
 
4. de Witte T, Hermans J, Vossen J, et al. Hematopoietic stem cell transplantation for 
patients with myelodysplastic syndromes and secondary acute myeloid leukemia: a report 
on behalf of the chronic leukemia working part of the EBMT. Br J Haematol. 2000; 110: 
62-230. 
 
5. Anderson JE, Appelbaum FR, Fisher LD, et al. Allogeneic Bone Marrow Transplantation for 
93 Patients with Myelodysplastic Syndrome. Blood. 1993;82:677-681. 
 
6. Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation for myelodysplastic 
syndrome: outcome analysis according to IPSS score. Leukemia. 1998; 12 (Suppl. 1) S25- 
S29. 
 
7. Ratanatharathorn V, Karanes C, Uberti J, et al. Busulfan-based regimens and allogeneic 
bone marrow transplantation in patients with myelodysplastic syndromes. Blood. 
1993;81:2194-2199. 
 
8. O'Donnell MR, Long GD, Parker PM, et al. Busulfan/cyclophosphamide as conditioning 
regimen for allogeneic bone marrow transplantation for myelodysplasia. J Clin Oncol. 
1995;13:2973-2979. 
 
9. Demuynck H, Verhoef GEG, Zachee P, at al. Treatment of patients with myelodysplastic 
syndromes with allogeneic bone marrow transplantation from genotypically HLA- 
identical siblings and alternative donors.  Bone Marrow Transplant. 1996;17:745-751. 
 
10. Ballen KK, Gilliland DG, Guinan EC, et al. Bone marrow transplantation for therapy-related 
myelodysplasia: comparison with primary myelodysplasia. Bone Marrow Transplant. 
1997;20:737-743. 
 
11. Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormalities in primary 
myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow 
transplantation. Blood. 1998;92:1910-1917. 
 
12. Sutton L, Chastang C, Ribaud P, et al. Factors influencing outcome in de novo 
myelodysplastic syndromes treated by allogeneic bone marrow transplantation: a long term 
study of 71 patients.  Blood. 1996;88: 358-365. 
 
13. Runde V, De Witte T, Gratwohl A, et al. Bone marrow transplantation from HLA- 
identical siblings as first line treatment in patients with myelodysplastic syndromes: early 


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transplantation   is   associated   with   improved   outcome. Bone Marrow Transplant. 
1998;21:255-261. 
 
14. Sierra,J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA- identical 
siblings as treatment for myelodysplasia. Blood. 2002; 100: 1997-2004. 
 
15. Castro-Malaspina H, Harris RH, Gajewski J. Unrelated donor marrow transplantation for 
myelodysplastic syndromes: outcome analysis of 510 transplants facilitated by the National 
Marrow Donor Program.  Blood. 2002;99:1943-1951. 
 
16. Deeg HJ, Storb R, Thomas ED, et al. Cyclosporine as prophylaxis for graft-versus- host 
disease: a randomized study in patients undergoing bone marrow transplantation for acute 
nonlymphoblastic leukemia. Blood. 1985: 65(6): 1325-1334. 
 
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