A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing Mobilized Peripheral Blood Stem Cells
Phase: PHASE2
Conditions: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Leukemia in Remission, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia With FLT3/ITD Mutation, Acute Myeloid Leukemia With Gene Mutations, Aplastic Anemia, B-Cell Non-Hodgkin Lymphoma, CD40 Ligand Deficiency, Chronic Granulomatous Disease, Chronic Leukemia in Remission, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Myelomonocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Congenital Amegakaryocytic Thrombocytopenia, Congenital Neutropenia, Congenital Pure Red Cell Aplasia, Glanzmann Thrombasthenia, Immunodeficiency Syndrome, Myelodysplastic Syndrome, Myelofibrosis, Myeloproliferative Neoplasm, Paroxysmal Nocturnal Hemoglobinuria, Plasma Cell Myeloma, Polycythemia Vera, Recurrent Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome, Severe Aplastic Anemia, Shwachman-Diamond Syndrome, Sickle Cell Disease, T-Cell Non-Hodgkin Lymphoma, Thalassemia, Waldenstrom Macroglobulinemia, Wiskott-Aldrich Syndrome
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 
 Study Title:     A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing 
Mobilized Peripheral Blood Stem Cells 
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
04/19/2023 
NCT Number: 
NCT03333486 
IRB Number 
I 40916 
 

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PROTOCOL TITLE:
A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing 
Mobilized Peripheral Blood Stem Cells
PROTOCOL NUMBER: 
I 40916
PRINCIPAL INVESTIGATOR:
Philip McCarthy, MD
Roswell Park Cancer Institute
Elm and Carlton Street
Buffalo, New York 14263
716-845-1300, ext. 1444
Philip.McCarthy@roswellpark.org
VERSION NUMBER:
12
DATE:
 
19APR2023
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party(ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Center). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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Table of Contents
1
Objectives .............................................................................................................................7
2
Background...........................................................................................................................7
3
Inclusion and Exclusion Criteria ........................................................................................13
4
Local and Study-Wide Number of Subjects .......................................................................16
5
Local and Study-Wide Recruitment Methods ....................................................................16
6
Multi-Site Research ............................................................................................................16
7
Study Timelines..................................................................................................................17
8
Study Endpoints..................................................................................................................17
9
Design.................................................................................................................................17
10
Treatment............................................................................................................................18
11
Procedures Involved ...........................................................................................................26
12
Withdrawal of Subjects.......................................................................................................30
13
Risks to Subjects.................................................................................................................30
14
Potential Benefits to Subjects .............................................................................................34
15
Data and Specimen Banking...............................................................................................34
16
Measurement of Effect .......................................................................................................34
17
Safety Evaluation............................................................................................................3518
Data Management and Confidentiality...............................................................................39
19
Statistical Plan ....................................................................................................................40
20
Provisions to Monitor the Data to Ensure the Safety of Subjects.......................................42
21
Vulnerable Populations.......................................................................................................43
22
Community-Based Participatory Research.........................................................................43
23
Sharing of Results with Subjects ........................................................................................43
24
Setting.................................................................................................................................44
25
Provisions to Protect the Privacy Interests of Subjects ......................................................44
26
Resources Available ...........................................................................................................44
27
Prior Approvals...................................................................................................................44
28
Compensation for Research-Related Injury........................................................................44
29
Economic Burden to Subjects.............................................................................................44
30
Consent Process..................................................................................................................44
31
Process to Document Consent in Writing...........................................................................45
32
Drugs or Devices ............................................................................................................4533
References...........................................................................................................................49
34
Appendices/ Supplements...................................................................................................58
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List of Abbreviations
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
BM
Bone Marrow Stem Cell Transplant
BMT
Blood or Marrow Transplantation
BU
Busulfan
CLL
Chronic Lymphocytic Leukemia
CMV
Cytomegalovirus
CY
Cyclophosphamide
DLI
Donor Lymphocyte Infusion
DLT 
Dose Limiting Toxicity
DVT
Deep Vein Thrombosis
EBV
Epstein Barr Virus
FK506
Tacrolimus
FLU 
Fludarabine
G-CSF
Filgrastim (filgrastim-sndz or other approved 
biosimilar)
GM-CSF
Sargramostim
GVHD
Graft-versus- Host Disease
GvL
Graft-versus- Leukemia
GvM
Graft-versus- Malignancy
HSCT
Hematopoietic Stem Cell Transplantation
MDS
Myelodysplastic Syndrome
MM
Multiple Myeloma
MMF
Mycophenolate
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MTD
Maximum Tolerated Dose
MUD 
Matched Unrelated Donor
NHL
Non Hodgkin Lymphoma
NRM
Non Relapse Mortality
OS 
Overall Survival
PBSC
Peripheral Blood Stem Cell
PBSCT
Peripheral Blood Stem Cell Transplant
PMN
Polymorphonuclear Cell
PNH
Paroxysmal Nocturnal Hemoglobinuria
RIT
Reduced Intensity Transplantation
RRT
Regimen Related Toxicity
SOP
Standard Operating Procedure
SOS
Sinusoidal Obstructive Syndrome
TRM
Transplant Related Mortality
VOD
Veno-occlusive Disease
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1
OBJECTIVES
1.1
Primary Objective

To evaluate the rate of relapse, defined as recurrence of underlying disease or progression 
of underlying disease, at 1 year in patients who receive haploidentical PBSCs after 
reduced intensity conditioning and post-transplant cyclophosphamide and tocilizumab (or 
tocilizumab alternative).
1.2
Secondary Objective

To evaluate safety including development of acute GVHD and death at 100 days post-
transplant, as well as other treatment related toxicities including chronic GVHD, 
engraftment rate, non-relapse mortality, PFS at one year, and OS at one year, as compared 
with historical controls. 
1.3
Tertiary Objective

Correlative studies will include chimerism analysis by molecular analysis and evaluation 
of immune reconstitution by CMV dextramer analysis using flow cytometry.
2
BACKGROUND
In 2002, a Phase I study out of Johns Hopkins Hospital described the outcomes of patients with 
hematologic malignancies who underwent related haploidentical HLA matched HSCT. Bone 
marrow was used as the source of the graft and the conditioning was a nonmyeloablative regimen 
that consisted of fludarabine 30 mg/m2 given for 4 consecutive days and 2 Gy TBI. Post-transplant 
cyclophosphamide at 50 mg/m2 was administered on Day +3. Most patients in the study also 
received cyclophosphamide, 14 mg/Kg on Days -6 and -5, in order to improve engraftment. In 
addition to post-transplant cyclophosphamide, mycophenolate, and tacrolimus were given for 
GVHD prophylaxis. 80% of patients achieved engraftment. The rates of grades II-IV acute GVHD 
and III-IV GVHD were 46% and 23%, respectively. 6 of 10 patients were alive at 6.5 months post-
transplant and 5 remained in a complete remission.(1)
Subsequently, results from a Phase I/II trial were published by researchers from Fred Hutchinson 
Cancer Center (FHCC) and Johns Hopkins Hospital (JHH) in which patients with high-risk 
hematologic malignancies underwent haploidentical HSCT with bone marrow as the graft source. 
They received the following regimen for conditioning: fludarabine 30 mg/m2 on Days -6 through 
-2, cyclophosphamide 14.5 mg/Kg on Days -6 and -5, and 2 Gy TBI on Day -1. They received 
either one or two doses of post-transplant cyclophosphamide on Day +3 or Days +3 and +4. GVHD 
prophylaxis also included mycophenolate and tacrolimus. The rate of failure to engraft was 13%. 
Incidence of grades II-IV and III-IV acute GVHD were 34 and 6%. There was a trend toward less 
chronic GVHD in the patients who received 2 doses of post-transplant cyclophosphamide (5% vs 
25%). Day 100 and 1-year NRM was 4% and 15%, respectively. The rates of relapse, PFS, and 
OS at 3 years were 46%, 40%, and 50% respectively.(2)
The Blood and Marrow Transplant Clinical Trials Network performed multicenter Phase 2 trials 
using haploidentical HSCT for patients with leukemias or lymphomas who were candidates for 
HSCT but did not have appropriately HLA matched donors available. Patients received donor bone 
marrow after being conditioned with cyclophosphamide, fludarabine and 2 Gy TBI. Post-
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transplant, they received 50 mg/Kg of cyclophosphamide on Days +4 and +5 as well as 
mycophenolate and tacrolimus for additional GVHD prophylaxis. Similar to the previously 
discussed Phase I/II study from FHCC and JHH, the incidence of grades II-IV acute GVHD at 100 
days was 32%. 1-year NRM and relapse were 7% and 45%. OS and PFS at 1 year were 62% and 
48%, respectively.(3)
Based on the results of these studies and others, our current practice within the bone marrow 
transplant program at the Roswell Park Cancer Institute is to consider related haploidentical HSCT 
using bone marrow as a graft source in patients with advanced or high-risk hematologic 
malignancies who do not have a 10/12 or better matched HLA donor. We also consider 
haploidentical HSCT for patients in whom comorbid conditions increase the risk of treatment 
related toxicities and NRM with our standard reduced intensity conditioning regimen (fludarabine 
and melphalan and total body irradiation) and matched related or unrelated peripheral blood 
HSCT. The decision to perform haploidentical HSCT must additionally factor in the relatively 
high rate of disease relapse; for this reason, we strongly prefer that morphologic CR (at least) be 
attained prior to haploidentical HSCT. The conditioning regimen we utilize currently is based on 
the protocol developed at JHH, namely: fludarabine 30 mg/m2/day on days -6 through -2, 
cyclophosphamide 14.5 mg/Kg/day on Days -6 and -5, and total body irradiation of 200 cGy on 
day -1, followed by HSC infusion on Day 0. GVHD prophylaxis is with cyclophosphamide 50 
mg/Kg/day on Days +3 and +4, as well as mycophenolate from Day +5 through +35, and 
tacrolimus beginning Day +5. G-CSF is started on Day +5.
The outcomes seen with haploidentical HSCT utilizing post-transplant cyclophosphamide are 
leading to a shift in the clinical practice within the field of bone marrow transplantation, such that 
this is a treatment modality that is increasingly being considered as a therapeutic option. Although 
Phase III randomized studies comparing haploidentical and matched unrelated donor HSCT have 
yet to be performed, retrospective studies based on data collected from the Center for International 
Blood and Marrow Transplant Research suggest that rates of acute and chronic GVHD are less 
with haploidentical HSCT as compared with MUD HSCT and that OS is similar for adult patients 
with both AML and lymphomas.(4, 5)
Utilization of bone marrow as the graft source is challenging due to several issues. The first is 
logistical, in that the bone marrow harvest occurs in the operating room and therefore is time 
consuming to coordinate as compared with peripheral blood stem cell collection. Secondly, 
undergoing a bone marrow harvest is relatively more difficult for the donor as compared with 
peripheral blood stem cell collection. Thirdly, the targeted nucleated cell dose is sometimes unable 
to be obtained during bone marrow harvests, due in some cases to disparities between the donor 
and recipient weights.
Recently, encouraging data have emerged on the use of peripheral blood stem and progenitor cells 
(PBSCs) as a graft source for haploidentical HSCTs. In a prospective study including 55 patients 
who received related haploidentical PB HSCT utilizing fludarabine, cyclophosphamide and TBI 
conditioning, as well as post-transplant cyclophosphamide, as previously described(2, 3), the 
incidences of severe acute (grades III to IV) and chronic GVHD in recipients of haploidentical 
PBSCs were 8% and 18%, respectively.(6) Two-year incidences of NRM, relapse and OS were 
23%, 28% and 48%, respectively.
In 
a 
separate 
study 
of 
18 
patients 
receiving 
PB 
HSCT, 
with 
the 
fludarabine/cyclophosphamide/total body irradiation conditioning regimen(2) the incidence of 
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grades I-IV acute GVHD was 53%; the incidence of grades III-IV acute GVHD was 17%. The 2-
year incidence of chronic GVHD was 8%. 1-year incidences of NRM, relapse-free survival, and 
OS were 17%, 53%, and 62%, respectively.(7)
In another, retrospective study including recipients of haploidentical PBSCs, mostly with 
lymphoid malignancies, the incidences of grade II-IV acute GVHD, severe acute (grades III-IV) 
and chronic GVHD were 33%, 14% and 13%, respectively.(8) The 2 year incidences of NRM was 
12%. No differences in OS (68% at 2 years) or PFS (62% at 2 years) was seen between the 
recipients of haploidentical PB HSCs and the comparator cohort that received haploidentical BM 
as a source of HSCs.
Given the promising results of these studies and others(9), we have designed a Phase II trial in 
which patients with high risk hematologic malignancies will receive related peripheral blood 
haploidentical HSCT. We plan to utilize the JHH regimen as the chemotherapeutic backbone. For 
GVHD prophylaxis, we plan to use cyclophosphamide, as well as mycophenolate and sirolimus. 
Our choice of sirolimus is on the basis of recent data from JHH that suggests sirolimus may be less 
nephrotoxic than tacrolimus in this setting.(10) In the unexpected situation in which a patient is 
unable to tolerate oral medications, IV tacrolimus will be administered instead of sirolimus (which 
cannot be administered intravenously). If tacrolimus is utilized in lieu of sirolimus, it will be dosed 
and levels will be monitored as per Roswell Park guidelines.
The goal of this study is to determine whether the use of PBSCs for haploidentical HSCTs can 
reduce the rates of relapse without increasing rates of GVHD. We will compare relapse rates to 
those we have seen in our own transplant program with the use of BM haploidentical HSCTs; 
namely about 10% at one year for those in CR at the time of transplant and about 50% for those 
who are not in CR at the time of transplant.
Cytokine release syndrome (CRS), characterized by fevers, vascular leak, hypotension, and 
respiratory and renal compromise, in the context of elevated levels of inflammatory cytokines, is 
a complication that is commonly seen in recipients of peripheral blood haploidentical HSCT due 
to a higher dose of donor T cells as compared with BM haploidentical HSCT. Tocilizumab, a 
monoclonal antibody that targets interleukin 6 (IL-6), a key mediator of CRS, has been shown in 
a retrospective cohort study and a case study to be safe and well tolerated in the treatment of CRS 
in recipients of peripheral blood haploidentical HSCT.(11, 12) Data were encouraging in regard to 
efficacy for treatment of CRS, with a resolution of symptoms in 7 of 7 patients who were treated 
with tocilizumab; a Phase II clinical trial of prophylactic tocilizumab to mitigate the risk of CRS 
in patients undergoing haploidentical peripheral blood HSCT is ongoing. In an attempt to prevent 
CRS in this study, we will incorporate a prophylactic dose of tocilizumab on the first day after 
transplant. (Our BMT program is currently utilizing tocilizumab as standard (non-protocol) 
prophylaxis against CRS for patients who are at high risk for this syndrome). Siltuximab, a 
monoclonal antibody that targets IL-6, can be used a second line therapy for CRS or for Immune 
effector cell-associated neurotoxicity syndrome (ICANS) and CRS presenting together(13, 14). 
Siltuximab can be used as an alternative when tocilizumab is unavailable.
Inclusion criteria and exclusion criteria are delineated below but importantly both patients in CR 
and not in CR, (as defined by morphological studies, cytogenetic, molecular and imaging studies 
as pertinent to the particular disease), are eligible. However, patients in CR with hematologic 
malignancies and those with bone marrow failure disorders or non-malignant hematologic or 
immune disorders  should not have a 6/6 HLA matched sibling donor available or a 12/12 HLA 
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matched (including permissively mismatched at DP (10/12 or 11/12 HLA matched with permissive 
mismatches at DP are considered as similar to 12/12 HLA matches)) unrelated donor available 
(while availability of a lesser HLA matched donor is acceptable) whereas patients who are not in 
CR with hematologic malignancies should not have a 6/6 HLA matched sibling donor available or 
a 10/12 HLA matched (or better HLA matched) unrelated donor (while availability of a lesser 
HLA matched donor is acceptable. The rationale for these requirements is that there is a higher 
incidence of relapse with haploidentical HSCT as compared with myeloablative as well as reduced 
intensity sibling and (matched/mismatched) unrelated peripheral blood HSCT, and the risk of 
relapse is further increased when patients undergo HSCT without having attained a complete 
remission. Therefore, for patients who are not in CR at the time of transplant, we are willing to 
accept a higher risk of GVHD given a relatively high risk of relapse. For patients with hematologic 
malignancies who are in CR at the time of transplant, we are less willing to accept the increase in 
risk of GVHD development that occurs with a less than fully HLA matched donor; this holds true 
for patients with bone marrow failure and with non-malignant hematologic or immune disorders. 
In some clinical situations, as aforementioned, clinicians prefer haploidentical HSCT for patients 
in whom comorbid conditions increase the risk of treatment related toxicities and NRM from acute 
and chronic GVHD with a matched related HSCT or a MUD. For this reason, patients in CR may 
be enrolled on this study despite having an HLA matched related or unrelated donor, if the treating 
clinician has concerns about an above average risk of NRM for the patient with a sibling 6/6 HLA 
matched or unrelated 12/12 HLA matched PB allogeneic HSCT. In addition, patients who are not 
in CR may be enrolled on this study despite having a sibling 6/6 HLA matched or unrelated 10/12, 
11/12 or 12/12 HLA matched donor, if the treating clinician has concerns about an above average 
risk of NRM for the patient with a 10/12 or better HLA matched PB allogeneic HSCT.   Given that 
most studies to date have not included unrelated haploidentical donors; we will limit the current 
study to include only related haploidentical donors.
Depending upon the outcome of this study, our strategy for haploidentical hematopoietic stem cell 
transplant could change. If we find that haploidentical PBSCT is reasonably efficacious and well 
tolerated, it may replace haploidentical BMSCT; this change would diminish logistical and timing 
concerns that are sometimes impediments to moving forward efficiently with HSCT.
2.1
Indications for Allogeneic HSCT in Various Disease States 
Allogeneic HSCT has an established role in therapeutic strategies for acute and chronic leukemias, 
bone marrow failure states (aplastic anemia, paroxysmal nocturnal hemoglobinuria, and 
myelodysplastic syndromes), lymphomas, myeloma, second transplant and immunodeficiencies.
2.1.1 Bone Marrow Failure States
Bone Marrow Failure States and other non-malignant hematologic or immunologic disorders 
requiring transplantation are preferentially treated with RIT rather than conventional 
myeloablative HSCT. Primary allogeneic HSCT is appropriate for selected patients with severe 
aplastic anemia, PNH, and related marrow failure disorders, certain congenital platelet or 
neutrophil disorders, and congenital immunodeficiencies(15-22) and hemoglobinopathies 
including sickle cell disease and thalassemia.(23, 24) Haploidentical HSCT has shown 
encouraging results for patients with non-malignant hematologic disorders.(25, 26) Patients with 
chromosomal breakage syndromes (such as Fanconi Anemia) or Dyskeratosis Congenita can 
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tolerate only very low doses of radiation or chemotherapy due to poor DNA repair capacity. These 
patients will be excluded from this study.
2.1.2 AML
Less than 20% of adults that are ≥ 60 years with AML in first complete remission (CR1) will 
achieve a 3-year DFS with conventional chemotherapy-based consolidation.(27) While 
conventional risk factors like cytogenetics and antecedent hematological disorder play a role, age 
does appear to be an independent variable.(28-30) Patients over the age of 60 to 65 and those with 
poor functional status have unacceptable TRM with myeloablative transplant. Reduced intensity 
conditioning (RIT) offers an opportunity to achieve a cure in a subset of these patients with 
outcomes comparable to standard myeloablative allogeneic HSCT.(31, 32) Non myeloablative 
conditioning and haploidentical HSCT with post-transplant cyclophosphamide has been associated 
with similar success in AML patients.(4)
2.1.3 MDS
MDS is incurable except by allo-HSCT. The risk-benefit ratio favors allo-HSCT for patients as 
soon as they progress to more advanced disease (Int-2 or higher IPSS score).(33) It is estimated 
that only about 5% of MDS patients are eligible to receive myeloablative allo-HSCT because of 
age and other exclusions. RIT has allowed for a reduction in TRM in this group of patients and 
allowed for wider application of allo HSCT as a therapy for MDS. There is data to suggest that 
the outcomes for patients who undergo haploidentical HSCT for MDS are similar to those who 
undergo RIT MUD HSCT.(34)
2.1.4 MPDs
The only cure for a myeloproliferative disorder is an allogeneic HSCT, which needs to be 
balanced against the TRM associated with conventional myeloablative HSCT. RIT has been used 
in an effort to reduce the TRM in this group of patients.(35-37) Haploidentical HSCT experience 
for MPD is limited but has been associated with encouraging outcomes.(38, 39)
2.1.5 NHL
Reduced intensity allogeneic transplantation has a definite role in the treatment of defined 
subgroups of patients with high-risk NHL with or without a prior autologous transplant.(40) 
Recent retrospective data suggests lower rates of acute and chronic GVHD and similar OS with 
haploidentical HSCT as compared with RIT MUD PBSCT for adult patients with lymphomas.(5)
2.1.6 Hodgkin disease
HSCT can be rescued by a RIT.(41) Several studies have shown comparable outcomes between 
RIC MUD PBSCT and haploidentical HSCT.(42-44)
2.1.7 Multiple Myeloma
Durable remissions for multiple myeloma can occur after allogeneic HSCT. Previous experience 
with standard myeloablative allogeneic HSCT was disappointing due to a high early TRM 
despite achieving durable remissions for survivors.(45, 46) Reduced intensity transplantation 
from suitable related and unrelated donors may permit the development of a curative graft-
versus-myeloma effect without high TRM.(47-49) The usual approach is to utilize RIT for 
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selected younger patients with well-matched donors either right after auto transplant (“auto-
allo”) or after relapse from an auto-transplant. A Phase III trial has demonstrated improved 
overall and disease-free survivals in newly diagnosed myeloma for recipients of a hematopoietic 
stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling versus a 
standard tandem autologous transplant.(50) At this time, there is a paucity of data regarding the 
efficacy of haploidentical HSCT in patients with multiple myeloma or plasma cell leukemia. 
However, there is some data that suggests it can be an effective treatment for some patients.(51) 
Patients with amyloidosis will be excluded from the current protocol.
2.1.8 Non-hematologic Malignancy
Patients with solid tumors will be excluded from the current protocol.
2.1.9 Second Allogeneic Transplants
Second allogeneic transplantation is often offered for relapse after a first allogeneic or autologous 
transplant and for graft failure. Given that most studies of haploidentical HSCT for hematologic 
malignancies have demonstrated a higher risk of disease relapse and that some studies have shown 
higher rates of graft failure as compared with matched related or unrelated donor PBSCT, patients 
will be eligible to enroll on the current protocol for a first allogeneic transplant only but not for a 
second allogeneic transplant.
2.2
Rationale
During the past five years within our transplant program at the Roswell Park Cancer Institute, we 
have been utilizing bone marrow as a source of haploidentical donor HSCTs and have observed 
relapse rates at one year post transplant of ~10% in patients in CR at the time of transplant and of 
~50% in patients who are not in CR at the time of transplant. In this Phase II study, we aim to 
determine whether utilizing PBSCs as a source of haploidentical donor HSCTs can decrease the 
rate of relapse without increasing the rates of severe acute (grades 3 and 4) GVHD. For all patients, 
we do not expect that rates of severe acute GVHD should exceed 20%.
2.2.1 Rationale For Regimen Dose Selection
Fludarabine, a purine nucleoside analog is a potent immunosuppressant that will help prevent 
donor cell rejection by the recipient. Doses range from 120-200 mg/m2 over 4 or 5 days and this 
protocol will utilize 30 mg/m2/ per day x 5 days.
Cyclophosphamide is an alkylating agent that is, on its own, even in doses as high as 50 mg/Kg 
for four consecutive days, as has been used to treat autoimmune disease, is non-myeloablative.(52) 
Whereas HSCs are minimally affected by cyclophosphamide owing to high expression of aldehyde 
dehydrogenase, B and T lymphocytes and NK cells express low levels of this enzyme and are 
therefore extremely susceptible to the cytotoxic effects of this drug, making it an 
immunosuppressive agent. Cyclophosphamide will be given over 2 days at a dose 14.5 mg/Kg 
over 2 days prior to stem cell infusion in combination with fludarabine to help prevent donor cell 
rejection by the recipient. It will be given again at 50 mg/Kg over 2 days post stem cell infusion 
in an effort to prevent donor T-cell activation and subsequent GVHD.
Total Body Irradiation (TBI) is considered myeloablative above 500 to 600 centiGray (cGy). There 
is extensive experience with lower dose TBI with fludarabine in non-myeloablative conditioning, 
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usually at 200 cGy. This dose of radiation, in combination with the aforementioned doses of 
fludarabine and cyclophosphamide, is considered to be non-myeloablative(53, 54) and therefore, 
is a regimen that is considered unlikely to generate excess TRM. TBI will be used prior to stem 
cell infusion in this regimen in order to clear the marrow space to enable engraftment of donor 
cells.
3
INCLUSION AND EXCLUSION CRITERIA
3.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1.  Any disease that is considered transplant eligible per TCT standards. 
2. Disease response noted (i.e. CR, non-CR, or not applicable): Assessed as per disease 
specific criteria (see Section 3.5).
3. Suitable related haploidentical donor identified per transplant service.
Recipient should not have HLA antibodies to potential donor. If the recipient does have HLA 
antibodies to the potential donor, an alternative donor is preferred. However, if there are no 
suitable alternative donors, the anti-HLA antibodies should be depleted per transplant service 
guidelines.

Haploidentical donors that are ABO compatible with the recipient are preferred. 
Minor ABO incompatibility is preferred to major ABO incompatibility. Major ABO 
incompatibility between recipient and donor is the least preferred but still acceptable 
for this study.

It is preferred that the haploidentical donor must be available to donate on day -1 and 
day 0 at RPCI, so that fresh product can be processed by the RPCI Stem Cell Lab and 
administered to the patient on day 0. While less preferable, cryopreserved product 
may be utilized on this protocol.
4. Age ≥ 4 (age ≥ 1 once the Oishei Children’s Hospital BMT unit is open) and ≤ 80 years.
5. Have the following clinical laboratory values:

Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) > 40% predicted, 
corrected for hemoglobin and/or alveolar ventilation.

Cardiac: left ventricular ejection fraction > 40%.

Bilirubin, liver alkaline phosphatase, SGOT or SGPT ≤ 3 x upper limit of normal.

Calculated creatinine clearance> 40 cc/min by the modified Cockroft-Gault formula 
for adults or the Schwartz formula for pediatrics (refer to Appendix I).
6. Have a Karnofsky (adult) or Lansky (for ≤16 years) performance status ≥ 60% (refer to 
Appendix A).
7. Patient must be able to pass Radiation evaluation (i.e.: able to receive 200 cGy).
8. Patients who have failed a prior autologous transplant are eligible; however, at least 90 
days must have elapsed between the start of this reduced intensity conditioning regimen 
and the last transplant if patient had a prior autologous BMT.
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9. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
10. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure.
11. If patient is planned to use a fully matched donor, patient is excluded from trial; patient 
must be planned to undergo a haploidentical matched transplant to participate on study.  
Patient is still eligible for trial regardless of donor options if PI feels that haplo transplant 
is in the patient’s best interest per clinical decision.  
Refer to Appendix B for the ELIGIBILITY VERIFICATION FORM: INCLUSION CRITERIA 
checklist.
3.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. Participants who have had chemotherapy (not including molecularly targeted agents; 
examples include, but are not limited to, tyrosine kinase inhibitors such as FLT3 inhibitors 
and IDH2 inhibitors), radiation treatment and/or surgery 7 days prior to starting 
conditioning regimen. Those who have not recovered sufficiently from adverse events due 
to agents administered more than 2 weeks earlier are also ineligible.  Exceptions may be 
made on a case-by-case basis after discussion with the PI.
2. Uncontrolled CNS disease (for hematologic malignancies) per PI discretion.
3. Child-Pugh class B and C liver failure (refer to Appendix J).
4. Concomitant active malignancy that would be expected to require chemotherapy within 3 
years of transplant (other than non-melanoma skin cancer).  Exception would include any 
concurrently existing malignancy that could be treated with a transplant per PI discretion. 
(Example:  Patient has AML but a history of mastocytosis.)
5. Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other 
condition which, in the opinion of treating physician, would make this protocol 
unreasonably hazardous for the patient.
6. Known HIV positive.
7. Pregnant or nursing female participants.
8. Patients who in the opinion of the treating physician are unlikely to comply with the 
restrictions of allogeneic stem cell transplantation based on formal psychosocial screening.
9. Patients with donor specific HLA antibodies with a titer greater than 3000 MFI (whether 
or not they have undergone a desensitization protocol).
10. Patients who have undergone a prior allogeneic hematopoietic or (other organ) transplant.
11. Treating physician considers the potential HLA haploidentical donor to be ineligible to 
receive G-CSF, and/or concern on the part of the treating physician for risk of harm to the 
potential donor with administration of G-CSF, and/or refusal by the potential donor (or 
donor’s guardian) to receive G-CSF.
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12. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
13. Received an investigational agent within 14 days prior to enrollment.  Exceptions made be 
made on a case-by-case basis after discussion with PI.
Refer to Appendix C for the ELIGIBILITY VERIFICATION FORM: EXCLUSION 
CRITERIA checklist.
3.3
Special Populations
The following special populations may be included in this study:

Children ≥ 4 years of age at this time (≥ 1 year of age once the BMT unit of Oishei 
Children’s Hospital of Buffalo is open). 
The following special populations are excluded from this study:

Cognitively impaired adults/adults with impaired decision-making capacity

Prisoners

Pregnant women
3.4
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
3.5
 Arm Distribution
If a patient has multiple disease indications for transplant, arm distribution will be determined by 
the PI on a case-by-case basis.  If a patient is transplanted for a disease not mentioned below, the 
arm distribution will be determined by the PI.
14. Bone marrow failure disorders: All patients will be allocated to the non-CR arm.
15. Non-malignant hematologic and immunologic disorders: All patients will be allocated to 
the non-CR arm.
16. Acute Leukemias: Those with AML or ALL who meet disease response criteria for a CR 
or a CRi (complete remission with incomplete neutrophil and/or platelet recovery), 
regardless of minimal residual disease (MRD) status (see Appendix L), will be enrolled on 
the CR arm of this study. Patients who do not meet disease response criteria for a CR or 
CRi will be enrolled on the non-CR arm of this study. The Disease Risk Index (DRI) will 
be recorded (55),(56). 
17. Chronic Myelocytic Leukemia: The disease response criteria utilized for arm distribution 
will be as per the current NCCN guidelines(57). Regardless of molecular response, patients 
with a major cytogenetic response will be allocated to the CR arm. Patients with less than 
a major cytogenetic response will be allocated to the non-CR arm.(58) The DRI will be 
recorded.
18. Myeloproliferative and Myelodysplastic Syndromes: For myelofibrosis, patients will be 
allocated to either the CR arm or non-CR arm as per current definitions of disease 
response.(59) For polycythemia vera, disease response for arm distribution will be assessed 
as per recommendations from the European Leukemia Network and the International 
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Working Group on Myeloproliferative Neoplasms Research and Treatment.(60) For 
CMML, disease response for arm distribution will be determined on the basis of current 
uniform response criteria.(61) Those with CMML who meet the disease response criteria 
for a CR or a complete cytogenetic remission will be enrolled on the CR arm of this 
study.(61) MDS disease response for arm distribution will be assessed on the basis of the 
IWG response criteria in myelodysplasia.(62) The DRI will be recorded for all 
myeloproliferative and myelodysplastic syndromes.
19. CLL: Patients will be allocated to either the CR arm or non-CR arm as per Appendix L. 
Those with CLL who meet disease response criteria for a CR or a CRi will be enrolled on 
the CR arm of this study. The DRI will be recorded.
20. MM: Patients will be allocated to the CR arm or non-CR arm according to Appendix L 
(any response less than a CR, including VGPR, will be allocated to the non-CR arm).(63) 
The DRI will be recorded.
21. Waldenström’s Macroglobulinemia: The International Working Group on Waldenström’s 
Macroglobulinemia uniform response criteria will be utilized to assess disease response for 
corresponding study arm allocation (any response less than a CR, including VGPR, will be 
allocated to the non-CR arm).(64) The DRI will be recorded.
22. T or B cell Lymphoma (NHL): Disease response and corresponding study arm allocation 
will be determined as per Appendix L. Those with NHL who meet the disease response 
criteria for a CR or a CRu will be enrolled on the CR arm of this study. The DRI will be 
recorded.
23. Hodgkin Disease: Disease response and corresponding study arm allocation will be 
determined as per Appendix L. Those with Hodgkin disease who meet the disease response 
criteria for a CR or a CRu will be enrolled on the CR arm of this study. The DRI will be 
recorded.
4
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS
A maximum of 58 evaluable participants at RPCI will be enrolled.

Accrual target is 30 patients in the CR arm and 28 patients in the non-CR arm.

The projected accrual per year is approximately 10-15 patients in the CR arm and 7-10 
patients in the non-CR arm, and therefore recruitment is expected to be complete within 5 
years following the study starting point.

Subjects will be followed for 12 months after recruitment completion, so total study 
duration will be 6 years.
5
LOCAL AND STUDY-WIDE RECRUITMENT METHODS
Participants will be identified/recruited/screened from patients at the BMT clinic at RPCI and from 
multi-disciplinary conference discussion.
6
MULTI-SITE RESEARCH
Not applicable.
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7
STUDY TIMELINES
A maximum of 58 participants at RPCI will be enrolled. Accrual is expected to take 5 years, with 
follow-up for 12 months from the start of investigational treatment and, annually thereafter as per 
BMT clinic standard of care.
8
STUDY ENDPOINTS
8.1
Primary Endpoint

Relapse rate at 1 year from time of transplant
8.2
Secondary Endpoints

GVHD incidence (acute and chronic): 
o
Acute GVHD at 100 days post-transplant
o
Chronic GVHD at 1-year post-transplant

Engraftment rate at 1-year post-transplant

Clinical response: overall survival (OS) at 1-year post-transplant

Transplant related mortality (TRM) at 1-year post-transplant

Progression free survival (PFS) at one year from time of transplant
8.3
Tertiary Endpoints

Chimerism Analysis
o
Myeloid and lymphoid chimerism expressed as a percentage of donor cells at the 
following time points: Day 30 (± 10 days), Day 100 (± 14 days), and   one year 
(± 14 days).

Immune Reconstitution
o
Immune reconstitution is evaluated at the following time points: baseline, Day 30 
(± 10 days), Day 100 (± 14 days) and   one year (± 14 days) by the peripheral blood 
BMT SOC immunophenotyping panel and by analysis of CMV-specific immunity 
(CMV dextramer).
9
DESIGN
The study design will be a Kepner-Chang(65) Type II Phase II design that proceeds in two stages 
and stops early for futility. Patients in complete response (CR) at the time of transplant will 
constitute one arm of the study and those that are not in a CR at the time of transplant will constitute 
a separate study arm. At the end of the first stage of accrual, data will be reviewed to decide if the 
study should be terminated due to unacceptable toxicity, including an unexpectedly high rate of 
severe acute GVHD by Day 100 post-transplant or an unacceptably high number of deaths at 
100 days or less post-transplant.
In the CR arm, a total of 30 patients will be accrued in two stages. In the non-CR arm, a total of 
28 patients will be accrued in two stages.
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Evaluable patients are defined as patients who do not have disease progression within Day 100 
(and who are alive at day 100). Non-evaluable patients will be excluded in regard to primary 
outcome analysis but not in regard to analysis of secondary outcomes.
Non-evaluable patients may be replaced if the reason that they become non-evaluable is unrelated 
to disease progression or to an incident unrelated to treatment on this study (for example, 
involvement in an automobile accident that leads to fatality). Replacement of non-evaluable 
patients on this study will be as per the discretion of the study PI.
Subjects will be followed for 12 months after recruitment completion.
10 TREATMENT
Duration of treatment: 11 days (from start to completion of chemotherapeutic administration).
10.1 Dosing and Administration
Eligible patients will receive a non-myeloablative conditioning regimen and allogeneic 
haploidentical (5 of 10 to 7 of 10 HLA matched) related donor hematopoietic stem cell transplant 
with post-transplant cyclophosphamide as follows:
Conditioning regimen:

Fludarabine: 30 mg/m2/day on Days -6 to -2

Cyclophosphamide: 14.5 mg/kg IV on Days -6 and -5

Total body irradiation (TBI): 200 cGy on Day -1
Stem cell infusion:

Hematopoietic stem cell infusion on Day 0
Supportive care:

Filgrastim (filgrastim-sndz or other approved biosimilar is acceptable): 5 mcg/kg/day 
beginning Day +5 until ANC >1500/mm3 for 3 consecutive measurements on at least two 
different days. 
o
For patients with hematologic malignancies characterized by monosomy 7 or 
deletion of a portion of chromosome 7, rather than G-CSF, GM-CSF (granulocyte-
macrophage colony stimulating factor) 500 mcg will be utilized  for adults and 250 
mcg/m2  for pediatric patients (maximum dose for pediatric patients is 500 mcg).   This 
is due to a theoretical risk of stimulation of underlying malignancy post-
transplant.(66)
GVHD prophylaxis:

Cyclophosphamide: 50 mg/kg IV on Days +3 and +4 (with Mesna; see “treatment plan”)
Sirolimus and Mycophenolate will be administered as follows:

Sirolimus: Oral 1 mg starting daily on Day +5. The dose will be adjusted to maintain a 
trough of 5-10 ng/mL. 
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
Mycophenolate mofetil (MMF) 1000 milligrams orally every 8 hours or 1500 milligrams 
intravenously every 6 hours beginning Day +5 until Day +35 (± 5 days).
CRS prophylaxis:

Tocilizumab will be administered intravenously at 4 mg/kg of ideal body weight 24 hours 
(± 6 hours) post completion of stem cell infusion on Day +1.  In the event of a shortage, 
siltuximab at 11 mg/kg of ideal body weight (rounded to the nearest vial size) would be 
substituted.  
10.2 Treatment Plan
10.2.1 Stem Cell Collection
Fresh (or cryopreserved) peripheral blood stem cells (PBSCs) will be utilized. Donors will receive 
10 micrograms/kilogram G-CSF daily subcutaneously, starting on transplant Day -5. The dose will 
be rounded to nearest vial size if possible (i.e., 300 micrograms or 480 micrograms).
Mobilized peripheral blood stem cells will be collected by apheresis on transplant Day “-1” and 
again on Day “0”, to achieve a minimum target dose of 5 x 106 CD34+ cells/kilogram of recipient 
weight; a maximum of 30 x 106 CD34+ cells/kg of recipient weight will be infused into the 
recipient and excess product, up to a maximum of 50 x 106 CD34+ cells/kg, will be stored. These 
excess cells may be used by the treating BMT physician for treatment of primary or secondary 
engraftment failure within the first year of their collection. After 1 year, these cells may be used 
for laboratory-based research projects, as per discretion of the study PI. Newer stem cell 
mobilizing agents (such as plerixafor) may be substituted or added to filgrastim if they are FDA-
approved. PBSCs will be un-manipulated with the exception of red cell depletion. CD3+ and 
CD34+ cell counts as fractions of the total nucleated cells (TNC) will be determined according to 
established institutional flow cytometry protocols.
Donor lymphocyte collection: Donor lymphocytes will not be routinely collected using this 
protocol. When donor lymphocytes are required for clinical reasons, they will be collected and 
administered on the RPCI donor lymphocyte protocol.
10.2.2 Preparative Regimen
Day 
-6
Day
 -5
Day
 -4
Day
 -3
Day
 -2
Day
 -1
Day 
0
Day 
+1
Day 
+2
Day 
+3
Day 
+4
Fludarabine (mg/m2/day)
30
30
30
30
30
Cyclophosphamide (mg/kg, IV)
14.5
14.5
50
50
TBI (200 cGy)
200
Stem Cell Infusion
X
Fludarabine

Fludarabine: 30 mg/m2 (actual body weight) is infused over 30 minutes on Days -6, -5, -
4,-3, and -2 (total dose 150 mg/m2).
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Cyclophosphamide

Cyclophosphamide: 14.5 mg/kg (ideal body weight, or actual body weight if less than ideal 
body weight, or adjusted ideal body weight if actual weight is > 125% of ideal body weight) 
is infused over 2 hours after completion of fludarabine on Days -6 and -5 and, 
Cyclophosphamide 50 mg/kg (ideal body weight or actual body weight, whichever is less, 
or adjusted ideal body weight if actual weight is > 125% of ideal body weight) is infused 
over 2 hours on Days +3 and +4. Mesna 10 mg/kg (ideal body weight or actual body 
weight, whichever is less, or adjusted ideal body weight if actual weight is > 125% of ideal 
body weight) will be infused over 15 minutes on Days +3 and +4 at 30 minutes prior to 
Cyclophosphamide and at 3, 6, and 8 hours post cyclophosphamide.
Total Body Irradiation

Schedule: On Day -1, a single fraction of 200 cGy will be given.
Total Body Irradiation will be delivered using a nominal photon beam energy of no less than 4 
MV. Dynamic or static fields may be used. However, the patient should be entirely included within 
the dynamic or static treatment field. Lung shields are to be applied in pairs (both AP & PA) with 
evenly weighted mid-plane dose from each field. When necessary, lung shields can be combined 
with open (non-shield) fields during the same fraction to achieve the required mid-plane and lung 
dose. Dose heterogeneity resulting from lung transmission will be assessed using the AAPM Task 
Group 29/AAPM-Report Number 17, The physical aspects of total and half-body photon 
irradiation.(67)
TBI, 200 cGy, will be delivered as prescribed to mid-plane at the level of the umbilicus or pelvis; 
whichever region is thicker. Tissue compensators or other devices will be used to optimize dose 
homogeneity within ± 5 % of the prescribed dose. Dose homogeneity will be assessed at a 
minimum of  mid plane points at: a) head, at largest diameter, b) neck, at the level of thyroid notch, 
c) chest, at the xiphoid process, d) umbilicus or pelvis, whichever is thicker, e) mid-thigh, and, f) 
mid-calf. Optional dose points will be located at: g) knee, h) ankle and, i) umbilicus or pelvis, 
whichever is thinner. In addition, a set of lung shields, or an equivalent device, will be used to 
ensure that the lungs will receive within 90 to 100 % of the prescribed dose per fraction. The dose 
rate at the prescription point shall be between 10 cGy and 15 cGy per minute.
Hydration regimens

Per clinicians’ discretion.
Supportive medications

Medications prior to stem cell infusion in cases of ABO incompatibility and/or 
cryopreserved donor product may include diphenhydramine and histamine-2 blocker as per 
the treating clinicians’ discretion.

Antiemetics, antimicrobials, etc. will be used according to BMT standard of care.

Glucocorticoid therapy prior to Day +5 should be avoided unless a situation arises such 
that glucocorticoid therapy is considered necessary by the treating physician, as it may 
cause interference with the efficacy of cyclophosphamide for GVHD prophylaxis.
10.2.3 Allogeneic Stem Cell Reinfusion
On Day 0 donor hematopoietic stem cells will be infused. The minimum PBSC dose is 5 x 106 
CD34+ cells/kg of recipient weight; the maximum PBSC dose is 30 x 106 CD34+ cells/kg of 
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recipient weight (all PBSCs collected from the donor up to the maximum dose will be infused into 
the recipient) (see Appendix E).
10.2.4 GVHD Prophylaxis and CRS prophylaxis
GVHD prophylaxis will be with post-transplant cyclophosphamide, sirolimus and mycophenolate 
mofetil (MMF). Tacrolimus (IV or oral) or cyclosporine (IV or oral) may be substituted for 
sirolimus in the case of inability to tolerate oral medications or other intolerance or adverse 
reaction and dosed per Roswell Park standards (BMT SOP 104). If this is a temporary issue, a 
transition back to sirolimus will be made once it has resolved; otherwise, the patient may be 
continued on either tacrolimus or cyclosporine as per physician discretion. Prophylaxis against 
CRS will be with tocilizumab(11) (or siltuximab if tocilizumab is unavailable).
DAY
0
+1
+2
+3
+4
+5
+6
+7
+8
Sirolimus*
X
X
X
X
MMF*
X
X
X
X
Cyclophosphamide
X
X
Tocilizumab/ 
Siltuximab
X
* Continues beyond Day +8 (see text below).
Sirolimus

Starting dose will start as 1 mg PO orally daily beginning on Day +5 and thereafter 

The sirolimus dose will be adjusted to target levels between 5-10 ng/mL.

In the absence of GVHD, sirolimus will continue until Day +100 and then taper with a goal 
to be discontinued at approximately 6 months post-transplant. In the case of disease 
recurrence, sirolimus may be tapered off more rapidly and/or starting before Day +100 
post-transplant, as per the treating clinician’s discretion.
Mycophenolate mofetil (MMF)/ (Cellcept ®)

The dose will be 1000 milligrams orally every 8 hours or 1500 milligrams intravenously 
every 6 hours. Determination of intravenous and oral doses was based on pharmacokinetic 
levels and calculations to achieve total mycophenolic acid area under the plasma 
concentration-versus-time curve (AUC) between 30 and 60 microgram/milliliter to prevent 
graft rejection and graft versus host disease(68, 69): we have measured pharmacokinetic 
levels on the active drug and the inactive metabolite with Dr. G. Fetterly (unpublished 
data). Thus, the intravenous dosing is higher based on measured levels. The drug is 
inactivated by the liver and further dose escalation does not result in higher active drug 
levels, only higher levels of the inactivated metabolite. The reason for the lower oral dose 
is gastrointestinal intolerance at doses higher than 1000 mg per mg/m2 every 8 hours.

The MMF starts on Day +5 and, in the absence of GVHD or recurrent disease, will continue 
until Day +35 (±5 days) and then stop without taper.
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
MMF may be withheld at the discretion of the attending physician for patients with 
cytopenias or other toxicities that are thought to be related to the MMF. The clinical team 
should attempt to restart this medication when it is thought to be clinically safe.
Cyclophosphamide

Cyclophosphamide will be given as 50 mg/kg IV on Days +3 and +4 for GVHD 
prophylaxis, as described above.
Tocilizumab

Tocilizumab will be given intravenously at 4 mg/kg of ideal body weight, on Day +1.

In the event of a shortage, siltuximab given intravenously at 11 mg/kg of ideal body weight 
(rounded to the nearest vial size) would be substituted and given on Day +1.  
10.3 Supportive Care Recommendations
Prior to initiating therapy, placement of a multi-lumen indwelling silastic catheter is required, 
preferably a non-tunneled 5 lumen catheter.
Patients will receive full supportive care, including transfusions of irradiated blood and blood 
products, growth factors, antibiotics, anti-emetics, oral care, etc., when appropriate. Drugs 
administered for treatment of GVHD as well as anti-infective medications used to treat active 
infections will be recorded in the CRF. Drugs used to prevent GVHD and to prevent infections 
will not be recorded in the CRF, as these are given as standard of care.

Mucosal evaluation and care: Mucositis is expected to be mild to moderate with a RIT 
regimen. Stomatitis and esophagitis due to herpes virus may be confused with drug-induced 
mucositis and viral cultures should be obtained if clinically indicated. Patients should 
receive acyclovir according to the RPCI BMT standard operating procedure (SOP) for an 
allogeneic transplant patient.

Antifungal prophylaxis: Antifungal prophylaxis will follow the BMT SOP for allogeneic 
transplant patients.

Pneumocystis Pneumonia (PCP) Prophylaxis: Anti-PCP prophylaxis should be given 
according to the RPCI BMT standard operating procedure (SOP) for an allogeneic 
transplant patient.

CMV Infections: Surveillance and treatment for CMV will follow RPCI BMT standard 
operating procedure (SOP) for allogeneic transplant patients. Surveillance for CMV by 
CMV antigenemia or PCR is required once weekly until day +100 and then PRN (as 
needed). Patients with positive CMV antigenemia should receive induction and 
maintenance treatment as per the RPCI BMT SOP. A CMV level of 1 or less may be 
repeated on the next available weekday before initiating therapy and if negative, the patient 
may be screened again in a week. Treatment dosing will be adjusted for hematological and 
renal toxicity. CMV surveillance will start no later than day +21 unless patient has not 
engrafted.

For patients who are pancytopenic prior to transplant, antimicrobial screening prophylaxis 
should continue through the transplant.
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
Anti-bacterial prophylaxis: Patients will receive anti-bacterial prophylaxis during the 
transplant period as per the RPCI BMT SOP.

Deep Venous Thrombosis (DVT) prophylaxis will follow the RPCI BMT SOP.

Sinusoidal occlusive syndrome, also known as veno-occlusive disease (VOD) prophylaxis 
will follow the BMT SOP.
10.4 Treatment Table Summary
Da
y -6
Da
y -5
Da
y -4
Da
y -3
Da
y -2
Da
y -1
Da
y 0
Da
y 
+1
Da
y 
+2
Da
y 
+3
Da
y 
+4
Da
y 
+5
Da
y 
+6
Da
y 
+7
Da
y 
+8
Fludarabine 
(mg/m2/day) 
30
30
30
30
30
Cyclophosphamid
e (mg/kg, IV)
14.
5
14.
5
50
50
TBI (200 cGy)
200
Stem cell infusion
X
Tocilizumab/ 
siltuximab
X
Sirolimus**
X
X
X
X
Mycophenolate**
X
X
X
X
Filgrastim *, **
X
X
X
X
* For patients with hematologic malignancies characterized by monosomy 7 or deletion of a 
portion of chromosome 7, rather than G-CSF, GM-CSF (granulocyte-macrophage colony 
stimulating factor) will be utilized.
** Continues beyond Day +8.
10.5 Potential Toxicities and their Management
Patients will be managed in the inpatient and outpatient setting per BMT standards of care. Safety 
will be monitored on an ongoing basis and discussed, graded and recorded in weekly outcome 
rounds.
10.5.1 Management of Graft Versus Host Disease (GVHD)
Standard measures for prevention and treatment of GVHD will be followed. 

Patients with symptomatic grade 1 acute GVHD of the skin will be treated with topical 
steroids. 

Grade II or greater acute GVHD will be treated with high dose methylprednisolone 1-2 
milligrams/kilogram daily for 10-14 days. The goal will be at 1 mg per kg at 10 days 
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followed by slow tapering in responders to a maintenance dose of up to 0.25 mg/kg/day, 
continued for at least 2 weeks from the disappearance of all symptoms of GVHD. 

Sirolimus /MMF will be maintained or increased during active aGVHD. Glucocorticoid 
refractory GVHD will be treated as per attending physician’s discretion and/or BMT SOP.
10.5.2 Regimen-Related Toxicity
Cardiac:
Patients with pre-existing cardiac disease are at significant risk for developing congestive heart 
failure and arrhythmias. Studies to be obtained when clinically indicated include EKG (to compare 
voltage to pretreatment EKG), radionuclide ventriculogram, and/or echocardiography.
Cytokine release syndrome, characterized by fevers, vascular leak, hypotension, and possibly by 
respiratory compromise, renal insufficiency, and neurologic dysfunction, will be treated with a 
second dose of tocilizumab at a dose of 4 mg/kg (in addition to the first, prophylactic dose given 
on Day +1, as long as it has been 24 hours since the previous dose), if determined to be severe 
enough to warrant treatment; in this case, a serum IL-6 level will be obtained and may be serially 
measured to assess response to treatment.(11)  In the event of a tocilizumab shortage, siltuximab 
at 11 mg/ kg of ideal body weight (rounded to the nearest vial size) would be substituted and given 
on Day +1.  
Renal:
Some of the agents used in this study can cause renal toxicity, which can be minimized by vigorous 
hydration, avoidance of exposure of multiple nephrotoxic drugs where clinically possible, 
appropriate drug monitoring and dose adjustment. Kidney damage is usually reversible, but severe 
cases may require dialysis. See Abboud et al. 2016 for renal dysfunction caused by cytokine release 
syndrome.
Pulmonary:
“Engraftment syndrome” consisting of hypoxia, pulmonary effusions and/or infiltrates may be 
seen at the time of donor cell engraftment and should be treated promptly with methylprednisolone 
2 milligrams/kilogram daily followed by rapid taper.
Patients with hypoxia or hypoxia with ambulation should be evaluated as soon as possible by CT 
scan. Whenever possible, histologic confirmation of the diagnosis should be attempted by 
bronchoalveolar lavage, transbronchial or open-lung biopsy. This would help to exclude infectious 
causes (cytomegalovirus/fungal) or confirm the diagnosis of hemorrhage. See Abboud et al(11) 
for respiratory dysfunction caused by cytokine release syndrome.
Hepatic:
Toxicity is expected to be minimal on this protocol. Management of liver toxicity is with continued 
ursodeoxycholic acid and standard supportive and symptomatic measures. The clinical team 
should avoid exposure of patients to hepatotoxic agents.
CNS:
Fludarabine can cause weakness, paraesthesias or peripheral neuropathies, visual or auditory 
impairment, and/or mental status changes such as confusion, agitation, depression, or coma. Some 
antibiotics, which may be needed to treat infections during the period of low white blood cell 
counts, can cause VIIIth cranial nerve damage resulting in hearing loss (especially high-frequency 
tones) and dizziness which may be permanent. To minimize this possibility, antibiotic levels will 
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be monitored. See Abboud et al. 2016 for neurologic dysfunction caused by cytokine release 
syndrome.
Mucositis:
Many patients will experience mild to moderate stomatitis and odynophagia. Adequate pain relief 
often requires parental narcotics. Prevention requires aggressive oral hygiene as per RPCI BMT 
SOPs.
Nausea/Vomiting:
Many patients will experience moderate to severe nausea and vomiting. All patients should receive 
vigorous antiemetic treatment as per RPCI BMT SOPs. At or after neutrophil engraftment, the 
development of nausea and vomiting must prompt evaluation for GVHD.
Diarrhea:
Most patients will experience moderate to severe diarrhea in the first three weeks, which responds 
to standard symptomatic therapy. Appropriate studies are needed to exclude infectious causes of 
diarrhea, especially C. difficile. At or after neutrophil engraftment, diarrhea must prompt 
evaluation for GVHD.
10.5.3 Other Toxicities
Infections:
Viral infections (CMV, EBV, respiratory viruses including RSV, influenza virus and parainfluenza 
virus, BK virus, adenovirus), fungal infections (candida and mold) and bacterial infections are 
commonly expected in the setting of an immunocompromised host, chemotherapy administration 
and delayed immune reconstitution. These will be managed according to the RPCI BMT SOPs.
Hematologic:
Major ABO incompatibility (recipient vs. donor RBCs) or minor ABO incompatibility (donor vs. 
recipient RBCs) or both may result in severe hemolysis. ABO incompatible transplants will be 
identified in advance and will be pre-medicated with a histamine-2 blocker and diphenhydramine, 
according to the direction of incompatibility as per the treating physician’s discretion.
All blood products will be irradiated (2500 cGy) to prevent GVHD. Infection prophylaxis and 
treatment will be given according to RPCI BMT SOPs and standard accepted medical practice. 
With prophylactic platelet transfusions, the risk of death from hemorrhage is <5%.
Skin:
Generalized erythroderma can occur with painful palms and soles and superficial desquamation at 
sites of mechanical trauma. Topical steroid creams may provide symptomatic relief. Severe cases 
may require a brief course (3-5 days) of systemic corticosteroids. Long lasting hyperpigmentation 
may follow resolution of the erythroderma.
Hair:
Some patients will experience total (reversible) alopecia.
Secondary malignancy:
The cumulative exposure to chemotherapeutic agents and radiation increases the risk of developing 
leukemia or a second cancer. The incidence of secondary malignancy is approximately 5%.
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Failure to engraft:
Autologous count recovery is the most likely outcome because this combination is sub-
myeloablative.
Toxicities of G-CSF (donor): 
These toxicities may include bone pain, headache and myalgias. These can be treated with non-
narcotic and narcotic analgesics. Splenic rupture in donors with an enlarged spleen and 
precipitation of an acute hemolytic episode in donors with sickle cell trait are rare and need to be 
evaluated.
Toxicities of Apheresis (donor):
With apheresis the following discomforts may occur: tingling around mouth or in fingers, feeling 
cold or feeling a pressure sensation in chest due to the blood thinner (sodium citrate), feeling light-
headed or fainting any time during or at the end of the procedure, pain, bruising or infection at the 
point of the needle entry into the skin. A reaction (such as a rash) to a drug is possible if the patient 
has an unknown allergy. Blood loss (less than a pint) may rarely occur because of equipment 
problems which make it impossible to return the blood to the donor. Air entering the blood stream 
causing air to go to body organs (very rare risk because of safety measures used).
11 PROCEDURES INVOLVED
Please contact the Transplant Program Coordinator or Clinical Research Coordinator to enroll 
patients on the study.
Informed consent:  Patient must be aware of the nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side-effects, risks, and discomforts. Human protection committee 
approval of this protocol and of its consent form is required and will have been obtained before 
this study open.
Histological review: Submission of appropriate tissue samples or outside histo-pathologic slides 
to confirm the underlying diagnosis. Remission/relapse status should be confirmed within 30 days, 
and no later than 60 days before transplant conditioning starts.
Radiological review: All patients with lymphoma/multiple myeloma must have appropriate 
radiographic workup (CT and/or PET/CT for lymphoma; PET for multiple myeloma (at a 
minimum)) prior to registration and must be submitted for review.
11.1 Registration
Registration procedures:

Confirm eligibility criteria for patients (Appendix B and Appendix D) and donors 
(Appendix D).

Complete the transplant registration worksheets for patient and donor.

Record on the flow sheets: patient name, patient identification number, date of birth, 
patient’s gender, disease type and stage, treatment start date, date of signed consent, 
patient’s race/ethnicity. When the patient is registered, a patient identification number will 
be generated.
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
Data pertaining to this protocol will be collected by the BMT research nurses, data 
coordinators and/ or any other persons assigned by the BMT department head.
Eligibility of each participant will be established prior to enrollment.
Informed consent MUST be completed prior to receiving any study related procedures.
11.2 Protocol Date Definitions
On-Study Date
Start Treatment Date
Off-Treatment Date
Off-Study Date
Date of pre-admission 
clinic visit
Date of conditioning 
regimen initiation
Date of completion of the last dose of 
cyclophosphamide
Date of death due 
to any cause or, 
until study 
completion
11.3 Study Observations 
(Baseline testing is to be obtained within 60 days of enrollment unless otherwise noted)

HCT-CI/Age composite score (70), (71) 
o
Baseline 

Karnofsky/ Lansky Performance Status: 
o
Baseline
o
Weekly after discharge until Day 100 after stem cell infusion

Temperature:
o
Baseline
o
Day +1 through + 10 ( including Day +1 and Day +10)

Hematology/ Chemistry:
o
Baseline
o
Important hematologic recovery endpoints:

The first of 3 consecutive days of absolute neutrophil count (ANC) 
≥0.5x109/L

Platelets ≥ 20 x109/L after 7 consecutive days with no platelet transfusions

Day (post stem cell infusion) of last platelet transfusion

Serology:
o
Baseline: HIV, hepatitis (Hep B virus surface, Ag; Hep B virus core antibody, total; 
Hep C virus, antibody; only if clinically indicated: HCV RNA, HBV DNA), CMV

Quantitative immunoglobulins:
o
Baseline
o
Post-transplant SPEP, IFE, Quantitative immunoglobulins, serum beta-2 
microglobulin, kappa/lambda free light chains and 24-hour urine for protein 
electrophoresis and free light chains will be done only for patients with multiple 
myeloma on Day 100-160 and then as clinically indicated

Urinalysis (biochemical):
o
Baseline and post-transplant as clinically indicated
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
HLA typing:
o
Baseline (this can be done at any time; does not have to be within 60 days of 
enrollment)

Creatinine clearance:
o
Baseline

Pulmonary function tests (including DLCO):
o
Baseline, Day 100 (±14 days), Day 365 (±14 days), and as clinically indicated.

MUGA or ECHO:
o
Baseline

EKG:
o
Baseline

Bone marrow aspirate/ biopsy (aspirate for molecular, flow, and cytogenetics analysis) will 
be performed for patients with leukemias and bone marrow failure states only; patients 
with other malignancies will have BM aspirate and biopsy only if bone marrow was 
involved previously:
o
Baseline, Day 30 (±10 days), Day 100 (±14 days), at 1 year (±14 days), and then as 
indicated

If the patient is medically unfit or has scheduling difficulty, delay is allowed 
at all follow-up time points.
o
Unseparated chimerism will be analyzed whenever a bone marrow aspirate is 
performed after transplant: refer to Section 11.8.1

Chest X-ray (PA and lateral):
o
Baseline

PET scan: for patients with myeloma (at baseline).

Disease Evaluation: CT Scan and/or PET and/or MRI
o
Patients with lymphoma: Baseline, Day 100 post stem cell infusion, and 1 year post 
stem cell infusion (± 14 days). Regions of imaging will be at the discretion of the 
clinician. Additional imaging studies including CT and/or PET may be performed 
as clinically indicated.
o
All other patients will have CT and/or PET scans and/or MRI performed as 
clinically indicated (which may or may not be as part of disease evaluation).

Peripheral blood for chimerism:
o
Day 30 (±10 days), Day 100 (±14 days), at 1 year (±14 days), and then as indicated: 
refer to Section 11.7.1.

Peripheral blood for immune reconstitution: CMV dextramer analysis and BMT SOC flow 
panel:
o
Baseline, Day 30 (±10 days), Day 100 (±14 days), at 1 year (±14 days) and then as 
indicated: refer to Section 11.7.2.
11.4 Follow-up Evaluations
The following BMT standard of care lab assessments will be performed at Day 30 (± 10 days), 
Day 100 (± 14 days) and at 1 year (± 14 days) following transplant:
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
Hematology: CBC with automated differentials

Chemistry: CMP

Bone marrow biopsy will be performed for chimerism and engraftment evaluation.
Patients with disease progression or who require a subsequent transplant will not be taken off 
protocol but will be followed for survival.
11.5 Important Immunologic Recovery Endpoints

Myeloid and lymphoid chimerism expressed as a percentage of donor cells at the following 
time points: Day 30 (±10 days), Day 100 (±14 days), and 1 year (±14 days) after stem cell 
infusion.

Immune reconstitution will be evaluated by CMV dextramer analysis and the BMT SOC 
panel (which measures lymphocyte subsets) using flow cytometry at the following time 
points: baseline, Day 30 (±10 days), Day 100 (±14 days), and 1 year (±14 days) after stem 
cell infusion.
11.6 Schedule of Procedures and Observations
The schedule of research-related procedures and observations for this study is summarized in 
Appendix F.
11.7 Correlative Studies
11.7.1 Chimerism Analysis
Chimerism analysis is clinically useful and important for this study. After transplant, serial samples 
of blood and marrow will be analyzed for chimerism analysis as per the Molecular Diagnostic 
Laboratory SOP. Lineage specific (separate lymphoid and myeloid) chimerism will be analyzed 
in blood (per BMT SOP) at the following time points: Day 30 (±10 days), Day 100 (±14 days), at 
1 year (±14 days), and then at unscheduled intervals until full donor chimerism is attained. 
Unseparated chimerism will also be analyzed in bone marrow whenever a bone marrow aspirate 
is performed.
Peripheral blood will be collected in 2 green top tubes for separated chimerism and 1 milliliter of 
bone marrow aspirate will be collected in 1 purple top tube for non-separated chimerism. 
Chimerism studies will be performed by the RPCI Molecular Diagnostic lab.
Patients not converting to 100% donor T-cell chimerism by Day + 180 and/or showing signs of 
progression of disease after sirolimus and MMF withdrawal, and/or with refractory viral infection, 
will be evaluated for DLI. Patients who have active GVHD will not receive DLI.
11.7.2 Immune Reconstitution
Peripheral blood will be collected (per BMT SOP) at baseline (prior to transplant), Day 30 (±10 
days), Day 100 (±14 days), and at 1 year (±14 days) for evaluation of immune reconstitution. 
Immune reconstitution will be measured by flow cytometry using markers for T cells (CD3, CD4, 
CD8, γδ, CD45RA, CD45RO, CD27, HLADr, CD31, CD25, CD127), B cells (CD19, CD20, 
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CD27, CD38, IgD), and NK cells (CD56, CD16), as well as CMV dextramers. Flow cytometry 
will be performed by the flow cytometry lab under Dr. Paul Wallace’s direction.
12 WITHDRAWAL OF SUBJECTS
12.1 Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted as per 
BMT standard of care. All participants who discontinue due to an AE must be followed until the 
event resolves or stabilizes. Appropriate medical care should be provided until signs and symptoms 
have abated, stabilized, or until abnormal laboratory findings have returned to acceptable or pre-
study limits. The final status of the AE will be reported in the participant’s medical records and 
the appropriate electronic case report form (eCRF).
Reasons for treatment discontinuation should be classified as follows*:

Death

Progressive disease

Toxicity; treatment related or unrelated

Investigator judgment
o
The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so.

Noncompliance

Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.
* If the constraints of this protocol are detrimental to the patient's health and/or the patient no 
longer wishes to continue protocol therapy, the patient will be removed from protocol treatment 
and placed on follow-up. In this event the reason for withdrawal will be documented, the PI will 
be notified and the patient will be followed for toxicity, survival, progression and relapse.
Any patient with disease progression or who requires a subsequent transplant will be placed on 
survival follow-up. Details including last staging, patient survival, and secondary malignancies 
should be documented in the eCRF.
13 RISKS TO SUBJECTS
13.1 Fludarabine Monophosphate

Myelosuppression (dose limiting toxicity), fever, nausea, vomiting, stomatitis, diarrhea, 
gastrointestinal bleeding, anorexia, edema, skin rashes, myalgia, headache, agitation, 
hearing loss, transient episodes of somnolence and fatigue, autoimmune hemolytic anemia, 
autoimmune thrombocytopenia, paresthesias, peripheral neuropathy, renal and pulmonary 
toxicity (interstitial pneumonitis).

Severe fatal CNS toxicity presenting with loss of vision and progressive deterioration of 
mental status were encountered almost exclusively after very high doses of fludarabine 
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monophosphate. Such toxicity has only been rarely demonstrated at the 25-40 milligrams 
dosage of fludarabine monophosphate.

Very rarely described complications include transfusion-associated graft versus host 
disease, thrombotic thrombocytopenic purpura, and liver failure.

Tumor lysis syndrome, complicating fludarabine monophosphate therapy has been 
observed, especially in patients with advanced bulky disease.

Opportunistic infections (protozoan, viral, fungal, and bacterial) have been observed in 
both pre-treated patients receiving fludarabine and in individuals receiving fludarabine 
combined with other agents (corticosteroids, mitoxantrone, and cyclophosphamide).
13.2 Cyclophosphamide
The most frequently reported adverse events include: nausea/vomiting, cardiomyopathy, rash, 
mucositis, stomatitis, sterility, diarrhea, hemorrhagic cystitis, edema, alopecia, anemia, hemolysis, 
leukopenia, alopecia, appetite loss, amenorrhea, thrombocytopenia, anemia, fatigue, pulmonary 
fibrosis, secondary malignancies including urological malignancies.
13.3 Sirolimus
In patients receiving sirolimus, 23% to 33% experienced anemia, and 14% to 30% experienced 
thrombocytopenia. Leukopenia has also been reported. Rare cases of microangiopathic hemolytic 
anemia have been reported. Cases of lymphoproliferative disorders have been reported. 
Lymphocele development has been reported.
Hypertension has been reported in 49% of patients receiving sirolimus. Antihypertensive therapy 
may be required. Edema has been reported in 18% to 20% of patients receiving sirolimus. Chest 
pain, venous thromboembolic disease, and tachycardia have also been reported.
Headaches have occurred in 20% to 34% of patients on sirolimus, pain has occurred in 29% to 
33% of patients, and dizziness has also been reported. Gastrointestinal adverse effects of sirolimus 
have included constipation (36% to 38%), and stomatitis (3% to >20%).
Hypertriglyceridemia has been reported in 45% to 57% of patients taking sirolimus. Amenorrhea, 
diabetes mellitus, hypermenorrhea, hypervolemia, hypokalemia, elevated lactate dehydrogenase, 
menstrual disease and ovarian cyst formation have also been reported.
In patients taking sirolimus, 33% have had urinary tract infections. Herpes simplex infection, 
herpes zoster, pyelonephritis and sepsis have also been reported.
Arthralgia has been reported in 25% to 31% of patients taking sirolimus. Osteonecrosis has also 
been reported. 
A decline in kidney function has been seen in 39% to 40% of patients taking sirolimus.
Epistaxis and pneumonia have been reported in patients who were taking sirolimus.
Other miscellaneous effects that have been noted to occur in patients taking sirolimus include but 
are not limited to wound healing impairment, skin cancers, interstitial pulmonary disease 
(including pneumonitis, pulmonary fibrosis, and bronchiolitis obliterans organizing pneumonia), 
pulmonary alveolitis, pulmonary hemorrhage, reversible posterior leukoencephalopathy 
syndrome, liver toxicity, and cardiac tamponade.
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13.4 Mycophenolate mofetil
The principal adverse reactions associated with the administration of mycophenolate include 
diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types 
of infections. Patients receiving immunosuppressive regimens involving combinations of drugs, 
including mycophenolate, as part of an immunosuppressive regimen are at increased risk of 
developing lymphomas and other malignancies, particularly of the skin. The risk appears to be 
related to the intensity and duration of immunosuppression rather than to the use of any specific 
agent. Over suppression of the immune system can also increase susceptibility to infection, 
including opportunistic infections, fatal infections, and sepsis.
As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should 
be limited by wearing protective clothing and using a sunscreen. Lymphoproliferative disease or 
lymphoma developed in 0.4% to 1% of patients receiving mycophenolate (2000 to 3000 
milligrams daily) with other immunosuppressive agents in controlled clinical trials of renal, 
cardiac, and hepatic transplant patients.
There are no adequate and well-controlled studies in pregnant women. However, as 
mycophenolate has been shown to have teratogenic effects in animals, it may cause fetal harm 
when administered to a pregnant woman. Therefore, mycophenolate should not be used in pregnant 
women unless the potential benefit justifies the potential risk to the fetus. It is recommended that 
mycophenolate therapy should not be initiated by the physician until a report of a negative 
pregnancy test has been obtained.
In patients receiving mycophenolate (2000 or 3000 milligrams) in controlled studies for prevention 
of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal 
and cardiac patients and in 5% of hepatic patients.
Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 103 / microliter] developed in up to 
2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving 
mycophenolate 3000 milligrams daily respectively. If neutropenia develops (ANC <1.3 × 103 / 
microliter), dosing with mycophenolate should be interrupted or the dose reduced, appropriate 
diagnostic tests performed, and the patient managed appropriately. Gastrointestinal bleeding 
(requiring hospitalization) has been observed in approximately 3% of renal transplant patients 
treated with mycophenolate 3000 milligrams daily. Gastrointestinal perforations have rarely been 
observed.
Allergic reactions to mycophenolate have been observed; therefore, mycophenolate is 
contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid 
or any component of the drug product. Mycophenolate intravenous is contraindicated in patients 
who are allergic to Polysorbate 80 (TWEEN).
13.5 Tocilizumab
Data on the safety of tocilizumab has mostly been in the context of treatment of rheumatoid 
arthritis, often in combination with other agents; infections have been seen in this setting.(72) 
However, data on safety of tocilizumab in the post hematopoietic stem cell transplant setting are 
few, but they suggest that it is well tolerated.(12, 73)
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13.6 Siltuximab
Commonly seen risks for siltuximab are: edema (≤26%), localized edema (≤26%), pruritus (28%), 
skin rash (28%), weight gain (19%), hyperuricemia (11%), and upper respiratory infection (26%).
13.7 Infusion Risks
Stem Cell reinfusion is associated with the following hazards:

Temporary shortness of breath due to the lodging of small particles in the blood vessels of 
the lungs may occur. This is a less likely side effect.

If the bone marrow or stem cells that are to be used have been cryopreserved (frozen), a 
chemical called DMSO (dimethylsulfoxide) is used during the freezing process. This 
chemical is used to protect the cells from damage during freezing. DMSO produces an odor 
on the breath that lasts 1 to 2 days. In rare instances, severe allergic reaction may occur.

There is also a chance of developing a blood transfusion reaction during the reinfusion of 
stem cells. The following less likely side effects may occur: chills, back pain, decreased 
blood pressure, chest pain, and increased rate of breathing. Wheezing, hives, rash, as well 
as difficulty breathing, and increased heart rate are considered unlikely. Rarely, temporary 
life support with artificial ventilation is required.

CRS (cytokine release syndrome) is a potentially life-threatening reaction that may occur 
hours to days post stem cell infusion. It is caused by high levels of T cell activation and is 
characterized by high levels of inflammatory cytokines, and clinically manifests with high 
fevers, and may also involve neurologic dysfunction, nephrotoxicity, cardiovascular and 
pulmonary compromise. Tocilizumab , an antibody against IL-6, has been successfully 
used to treat CRS.(11).  The alternative siltuximab, is also an antibody against IL-6 that 
can be used  as a second-line treatment for CRS.

Failure to engraft is a rare complication and it is possible that the recipient’s own bone 
marrow might grow back. A second transplant may be needed.
13.8  Total Body Irradiation
During treatment the most common side effects include:

Headache

Nausea and vomiting

Diarrhea

Fatigue

Skin reaction
Less common is swelling of the salivary glands, which can produce pain in front of the ear and in 
the jaw.
The following may occur after receiving TBI (and may be caused, in part, by any subsequent 
chemotherapy):

Hair loss.
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
Discomfort in the throat and mouth.

Change in taste.

Mouth sores.

Nausea and vomiting.

Diarrhea.

Bone marrow suppression (low blood counts).
TBI can cause long-term side effects. They can occur months or years after your transplant.

Sterility is an expected side effect. Sexual function and pleasure will not be affected. Please 
talk to your doctor or nurse about any concerns you have.

About half of the patients will need thyroid supplements.
Other long-term side effects are rare but can occur. They include:

Inflammation of the sac that surrounds the heart.

Inflammation of the lungs.

Cataracts.

Second malignancies or new cancers
14 POTENTIAL BENEFITS TO SUBJECTS
There is no direct benefit to the patient.
15 DATA AND SPECIMEN BANKING
Not Applicable
16 MEASUREMENT OF EFFECT
The following criteria will be used for study evaluation:
16.1 Disease Response Criteria

Please refer to Appendix M and Appendix N for post-transplant response criteria.
16.2 Study Endpoints

The primary endpoint is relapse rate at one year.
16.3 Engraftment
Neutrophil engraftment is defined as the first day in which ANC is > 0.5x109/ liter for three 
consecutive days. Platelet engraftment is the first day that platelets are > 20 x109/ liter for seven 
consecutive days without transfusion support.
Chimerism analysis will be performed at regular intervals. Lineage specific (separate lymphoid 
and myeloid) chimerism will be analyzed in blood at the following time points: Day 30 (±10 days), 
Day 100 (±14 days) and then at unscheduled intervals until full donor chimerism is attained.
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Primary engraftment failure is defined as lack of evidence of neutrophil or platelet engraftment at 
Day +35, confirmed by a bone marrow biopsy showing < 5% cellularity in the absence of 
persistent malignancy. Late graft failure will be defined as initial neutrophil engraftment by 
Day +35 documented to be of donor origin followed by a drop in ANC to < 500 for more than 
three days, independent of myelosuppressive drugs, severe GVHD or infection.
Graft rejection is defined as graft failure with documentation of return of recipient hematopoiesis 
as determined by cytogenetic/chimerism analysis.
17 SAFETY EVALUATION
17.1 Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
17.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
17.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
17.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
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If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
17.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
17.2  Grading and Reporting Adverse Events
17.2.1 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
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explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
17.3 Reporting Adverse Events:
The following AEs occurring between the start date of intervention until Day +30, or until the 
event has resolved, the study participant is lost to follow-up, the start of a new treatment, or until 
the study investigator assesses the event(s) as stable or irreversible, will be reported: New 
information will be reported after it is received.

≥ Grade 3 toxicity by CTCAE version 4 (see Section 17.2), excluding hematologic 
toxicities

> Grade 1 but < grade 4 cytokine release syndrome (CRS) by CTCAE version 4 (see section 
17.2)
o
> Grade 4 CRS will be reported as a SAE
Additionally, patients will undergo outcome assessment for and grading of acute and/or chronic 
GVHD weekly for the first 100 days post-transplant, every 3 weeks (± 7 days) from Day 100 
through Day 180, and monthly (±14 days) through Day 365 post-transplant. 

Acute GVHD will be graded according to the criteria in Appendix G.

Chronic GVHD according to the criteria in Appendix H.

Any histologic evidence of GVHD (from tissue biopsies) will be noted.
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
17.4 Serious Adverse Events
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).
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
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
For the purposes of this study, the following events will also be considered SAEs:

≥ Grade 3 acute GVHD

> Grade 4 CRS
17.4.1 Reporting Serious Adverse Events
All new SAEs occurring from the start date of intervention until Day +30 will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention, should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer to 
Section 17.6 for details on reporting Unanticipated Problems.
17.5 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
17.6 Unanticipated Problems
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
o
The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 17.4.
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17.6.1 Reporting Unanticipated Problems:
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
CRS QA will submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA with an updated Reportable New Information Form. The site Investigator 
or designated research personnel will report all unanticipated problems to the IRB in accordance 
with their local institutional guidelines.
17.7 FDA Reporting
Not applicable for this study.
18 DATA MANAGEMENT AND CONFIDENTIALITY
18.1 Data Collection
Full build studies are managed by RPCI CRS Data Management for analysis by RPCI 
Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs.
18.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the applicable 
local regulatory requirements or by an agreement with RPCI.
18.3 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
18.4 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or the Sponsor, may terminate 
this study, provided a written notice is submitted within the time period provided for in the Clinical 
Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice if 
it believes termination is necessary for the safety of participants enrolled in the study.
18.5 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
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confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
19 STATISTICAL PLAN
The primary objective of this study is to evaluate the rate of relapse, defined as recurrence of 
underlying disease or progression of underlying disease, at 1 year in patients who receive 
haploidentical PBSCs after reduced intensity conditioning and post-transplant cyclophosphamide 
and tocilizumab (or tocilizumab alternative). 
The design of this trial will consist of two concurrent two-stage trials with a common endpoint 
stratified by complete responders and non-responders. (Patients with non-malignant hematologic 
disorders will be considered as non-responders). 
The primary endpoint will be the relapse rate at 1 year. The dates of relapse will be recorded as 
the date upon which the data to make a diagnosis of relapse was attained (for example, the date 
upon which a diagnostic bone marrow biopsy was performed). (For patients with non-malignant 
hematologic disorders, the primary endpoint will be rate of disease persistence at 1 year). 
The goals within the complete responder arm will be slightly different than that of the non-
responder arm in that in the complete responder arm we do not wish to see an elevated relapse rate 
increased over the currently assumed rate of 10%, while in the non-responder arm we wish to see 
a substantial drop in the relapse rate at 1 year, which is currently 50%.
19.1 Sample Size Determination
A maximum of 58 participants will be enrolled in this study. Accrual is expected to take 5 years.  
Subjects will be followed for 12 months after recruitment completion, so total study duration will 
be 6 years. 
19.2 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min, and max) will be used to 
summarize demographic and baseline characteristics.
Additionally, descriptive statistics such as frequencies and relative frequencies will be computed 
for all categorical variables. Numeric variables will be summarized using simple descriptive 
statistics such as the mean, standard deviation and range. A variety of graphical techniques will 
also be used to display data, ex. histograms, boxplots, scatterplots, etc.
19.3 Primary Analysis: Efficacy
Complete Responders
In terms of the complete responders we will use two-stage design43 where a true response of 
greater than 
 is considered unacceptable in terms of 1 year relapse rates and evidence of such 
0p
will deem the treatment not worthy of further study in this arm. The null and alternative hypotheses 
to be tested are 
 versus
. The study design stops early for elevated relapse rates 
𝐻0:𝑝= 𝑝0
𝐻1:𝑝> 𝑝0
only and will proceed in two stages.
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For the complete responder strata we set the acceptable 1-year relapse rate at 
, which 
𝑝0 = 0.10
leads to the following decision rule:
Stage 1:  If 4 or more of the first 
 evaluable patients relapse, it will be concluded that the 
𝑛1 = 15
therapy is not promising in terms of elevated relapse rates and the study will end. Otherwise, the 
study will progress to the second stage.
Stage 2:  We will accrue 15 additional evaluable patients. If 6 or more of the total of
 
 𝑛1 +  𝑛2 = 30
evaluable patients do relapse, it will be concluded that 
 is greater than 
and that the therapy is 
p
0p
not promising; otherwise, it will be concluded that the therapy is worthy of further study.
The nominal significance level of this design is 
=0.10. The sample size calculation is based on 

testing the hypotheses concerning the proportion of the population with a response to the treatment. 
For the complete responder strata this two-stage design requires a potential total of 
=15+15 
1
2
n
n

patients in order to achieve approximately 
=0.80 power to detect differences of 
=0.15 
1 


percentage points (
 versus
).
0p
𝑝0 +  𝛥
Non-Responders
For the non-responder strata we are testing 
 versus 
 For this test we set  
𝐻0:𝑝= 𝑝0
𝐻1:𝑝< 𝑝0.
𝑝0
 and our goal is to reduce the rate of 1 year relapse, which leads to the following decision 
= 0.50
rule:
Stage 1:  If 7 or more of the first 
 evaluable patients relapse, it will be concluded that the 
𝑛1 = 15
therapy is not promising and the study will end. Otherwise, the study will progress to the second 
stage.
Stage 2:  We will accrue 13 additional evaluable patients. If 17 or more of the total of 𝑛1 +  𝑛2
 evaluable patients do not relapse, it will be concluded that 
 is less than 
and that the 
= 28
p
0p
therapy is efficacious; otherwise, it will be concluded that the therapy is not promising.
The nominal significance level of this design is 
=0.10. The sample size calculation is based on 

testing the hypotheses concerning the proportion of the population with a response to the treatment. 
For the non-responder strata this two-stage design requires a potential total of 
=14+14 
1
2
n
n

patients in order to achieve approximately 
=0.80 power to detect differences of 
=0.20 
1 


percentage points (
 versus
).
0p
𝑝0 ‒  𝛥
19.4 Secondary Analysis
The acute and chronic GVHD rates, TRM, toxicity and overall clinical benefit rates will be 
computed with corresponding exact 95% confidence intervals based on the methodology of 
Clopper and Pearson.(74) The estimated distributions of overall and progression free survival will 
be obtained using the product-limit based Kaplan-Meier method. The Kaplan-Meier methodology 
will allow for incorporation of the censored observations thereby resulting is a more efficient 
estimate of the true distribution than if this information was not used. Estimates of quantities such 
as median duration will be obtained.
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19.5 Interim Analysis and Criteria for Early Termination of the Study
Safety evaluation
For each strata if 3 or more out of the first 10 subjects have a SAE the trial will be suspended for 
the given strata enrollment and the treatment regimen will be re-evaluated.
19.6 Correlative Data Analysis

Myeloid and lymphoid chimerism expressed as a percentage at the following time points: 
Day 30 (±10 days), Day 100 (±14 days) after stem cell infusion.

Immune reconstitution will be evaluated by CMV dextramer analysis using flow cytometry 
at the following time points: baseline, Day 30 (±10 days), Day 100 (±14 days), and one 
year (±14 days) after stem cell infusion.
20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS
Data and Safety Monitoring Plan
The Principal Investigator (PI) will be responsible for continuous monitoring of the safety of the 
study.
Daily inpatient rounds are held on the transplant unit at which time a BMT physician reviews:

Medications: Chemotherapy for conditioning regimens; prophylactic, empiric and 
therapeutic antimicrobials; graft-versus-host disease prophylactic and therapeutic 
medications and, possible drug interactions.

Adverse events and/or adverse reactions to any medication, procedure, or other treatment; 
reports are filed according to RPCI policy and procedure.

Regimen-related toxicity

Additional testing or therapies such as biopsies, scans or x-rays that will direct therapeutic 
interventions.

Consent: properly signed and dated transplant consent.

Patient Psychosocial Status:
o
Compliance issues that could compromise patient safety.
o
At pretransplant, a conference is held by the BMT for all BMT patients for the 
purpose of describing the need for allogeneic patients to obtain lodging within a 
30 mile radius of the hospital and to have a caregiver present at all times while the 
patient is an outpatient up to 100 days following transplant.
o
In addition, psychosocial evaluations are completed on all transplant patients by 
one of the BMT social workers prior to transplant, to identify any compliance 
issues.

Safety Monitoring mandated by the BMT Standards of Care and common clinical 
practice. These include daily physical examinations, clinical laboratory testing, routine 
surveillance cultures, therapeutic drug level monitoring (i.e., Vancomycin, Tacrolimus, 
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Tobramycin, Cyclosporine, Sirolimus, Mycophenolate), as an inpatient. They are found in 
the BMT SOPs. 

Patients who have been discharged from the hospital are monitored in the BMT Clinic until 
all transplant-related issues are resolved and they are returned to the care of their referring 
physicians.

Performance Status: assignment of Karnofsky Performance Status (KPS)/ Lansky Score 
(Appendix A).
In addition to weekly monitoring, the BMT Quality Assurance plan requires quarterly reporting 
to the BMT Quality Assurance Committee, which in turn reports to the RPCI Quality Assurance 
Committee. Indicators for BMT patient safety monitoring include:

Patient complaints

Reportable serious adverse events

Variances in the delivery of standard care that do or do not result in a change in practice

Readmissions prior to day +100 post-transplant

Deaths occurring prior to day +100 post-transplant

Engraftment of neutrophils and platelets
Long Term Follow-up is conducted on all transplant patients even after they have returned to the 
care of the referring physicians. An Annual Transplant Clinic has been established, which provides 
care for allogeneic patients with chronic complications, as well as assessments to identify clinical 
problems such as dental, bone, and psychosocial complications.
BMT Patient Outcomes are reported to the Center for International Blood and Marrow Transplant 
Research (CIBMTR), and/or the National Marrow Donor Program (NMDP). Registry reports are 
reviewed internally prior to submission to the respective registry. These data are also entered into 
the RPCI BMT Database, from which patient outcomes are assessed and reviewed on an annual 
basis. The patients’ medical records serve as original source documents for all reporting. Audits 
are conducted every two to three years by the CIBMTR and the NMDP.
Additionally, the RPCI Data and Safety Monitoring and Accrual Board (which reviews clinical 
research studies for overall study conduct, study design, rate of accrual, participant response and 
toxicity profile) will assess the progress of the study, the safety data, and critical efficacy 
endpoints. The DSMB will review the study annually and will make recommendations that include 
but not limited to; (a) continuation of the study, (b) modifications to the design (c) or termination 
of the study.
21 VULNERABLE POPULATIONS
The RPCI “SOP: Legally Authorized Representatives, Children, and Guardians (HRP-013)” will 
be followed.
22 COMMUNITY-BASED PARTICIPATORY RESEARCH
Not Applicable
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23 SHARING OF RESULTS WITH SUBJECTS
Individual response data is shared with the participant as a part of their clinical care.
24 SETTING
Treatment will be conducted in the inpatient and outpatient setting per BMT standards of care at 
RPCI’s BMT Center within Roswell Park Cancer Institute. For patients younger than 18 years of 
age or those between 18-21 years of age who are followed by the pediatric BMT physicians who 
attend both at RPCI as well as at Oishei Children’s Hospital of Buffalo, their outpatient care will 
be performed mainly in the Pediatric Oncology clinic at RPCI and their inpatient BMT care will 
take place mainly within the BMT units at RPCI; they will have pediatric BMT attending 
physicians supervising their care. However, if pediatric patients require care in a pediatric intensive 
care unit or if they require certain procedures such as endoscopy or surgery, they will be transferred 
to Oishei as per BMT SOPs.
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
26 RESOURCES AVAILABLE
Not Applicable
27 PRIOR APPROVALS
Not Applicable
28 COMPENSATION FOR RESEARCH-RELATED INJURY
Roswell Park Cancer Institute and Oishei Children’s Hospital of Buffalo, its agents, or its 
employees do not compensate for or provide free care for human subjects/participants in the event 
that any injury results from participation in a research project. In the unlikely event that a 
participant/participant’s child become ill or injured as a direct result of participating in this study, 
the participant/participant’s child may receive medical care, but it is not the policy of Roswell Park 
Cancer Institute, Oishei Children’s Hospital of Buffalo, University at Buffalo Pediatrics or the 
University at Buffalo, State University of New York to provide this care free even if the injury is 
a direct result of participation.
29 ECONOMIC BURDEN TO SUBJECTS
The participants will not be subject to any economic burden.
30 CONSENT PROCESS
The RPCI SOP: Informed Consent Process for Research (HRP-090) will be followed.
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This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
The RPCI “SOP: Legally Authorized Representatives, Children, and Guardians (HRP-013)” will 
be followed when determining study and consent eligibility 
31 PROCESS TO DOCUMENT CONSENT IN WRITING
The RPCI “SOP: Written Documentation of Consent (HRP-091)” will be followed.
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant in accordance with GCP guidelines using the approved informed consent form, before 
any study specific procedures (including screening procedures) are performed. The informed 
consent form acknowledges all information that must be given to the participant according to 
applicable GCP guidelines, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The participant should also be made aware that by signing the 
consent form, processing of sensitive clinical trial data and transfer to other countries for further 
processing is allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
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32 DRUGS OR DEVICES
32.1 Fludarabine Monophosphate 
32.1.1 Availability
Fludarabine monophosphate (Fludara®), a purine nucleoside analog, is commercially available as 
a clear, sterile solution. Each 2 milliliter vial contains 50 milligrams of fludarabine phosphate, 50 
milligrams of mannitol, water for injection, and sodium hydroxide to adjust pH to 6.8. Store at 2 
to 8°C (36 to 46°F).
32.1.2 Storage and Stability
Fludarabine phosphate contains no antimicrobial preservative and thus care must be taken to assure 
the sterility of the prepared solutions and should be discarded eight hours after initial entry.
32.1.3 Preparation
Fludarabine phosphate vials containing 50 milligrams of fludarabine phosphate, 50 milligrams of 
mannitol, water for injection and sodium hydroxide to adjust the pH to 6.8. The product may be 
further diluted for intravenous administration in 100 milliliters or 125 milliliters of 5% Dextrose 
for Injection USP or 0.9% Sodium Chloride, USP.
32.1.4 Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration. Fludarabine will be delivered as a piggy-bag via an ongoing IV line, over a 
period of 30 minutes.
32.2 Cyclophosphamide
32.2.1 Availability
Cyclophosphamide (Cytoxan®), an alkylating agent for injection, is commercially available as a 
powder for injection in 500 milligram, 1 gram, and 2 gram vials.
32.2.2 Storage and Stability
Intact vials should be stored at or below 25°C (77°F). Following reconstitution with sterile diluent, 
cyclophosphamide is stable for up to 24 hours at room temperature and for up to 36 hours if 
refrigerated.
32.2.3 Preparation
Reconstitute Cyclophosphamide using 0.9% Sodium Chloride Injection, USP or Sterile Water for 
Injection, USP, with 25 mL for a 500 mg vial, 50 mL for a 1 g vial, and 100 mL for a 2 g vial, for 
a total concentration of 20 mg/mL.
32.2.4 Administration
Cyclophosphamide to be administered IV over 2 hours.
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32.3 Sirolimus
32.3.1 Availability
Sirolimus is an agent that inhibits the activation of the mammalian Target of Rapamycin (mTOR). 
It is available for administration as an oral solution containing 1 mg/mL of sirolimus or as a white, 
triangular-shaped tablet containing 1 mg of sirolimus, or as a yellow triangular-shaped tablet 
containing 2 mg of sirolimus. Sirolimus is rapidly absorbed. The systemic availability of sirolimus 
is 14% after administration of the solution and 27% after administration of tablets. Sirolimus is 
extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. The majority of 
sirolimus is ultimately excreted into the stool, with a small amount excreted in the urine. Due to 
the reduced intensity nature of the conditioning regimen, an oral regimen should be tolerated.
32.3.2  Storage and Stability
Sirolimus solution should be stored, protected from light, and refrigerated at 2°C to 8°C (36°F to 
46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the 
patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time 
(e.g., not more than 15 days for the bottles). A dose of sirolimus solution may be kept in an oral 
syringe at room temperature for up to 24 hours. Sirolimus tablets should be stored at 20°C to 25°C 
(USP Controlled Room Temperature) (68° to 77°F). Use cartons to protect blister cards and strips 
from light.
32.3.3 Preparation
For Oral Use
For sirolimus solution, a syringe and cap are provided for dosing and the product may be kept in 
the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 
2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the 
preparation should be used immediately.
Sirolimus solution provided in bottles may develop a slight haze when refrigerated. If such a haze 
occurs allow the product to stand at room temperature and shake gently until the haze disappears. 
The presence of this haze does not affect the quality of the product.
Sirolimus tablets should be dispensed in a tight, light-resistant container.
32.3.4 Administration
Oral therapy should be started on Day +5, at a dose of 1 mg daily, with dose adjustments to keep 
the trough between 5-10 ng/mL. Either sirolimus solution or tablets may be utilized, as per 
discretion of the treating physician. Co-administration with azole anti-fungal therapy will be 
avoided whenever possible in order to mitigate the risk of drug-drug interactions (for example, if 
posaconazole is given between 6 – 8 AM then sirolimus will be given between 1 - 3 PM).
32.4 Mycophenolate
32.4.1 Availability
Mycophenolate (CellCept®), a 2-morpholinoethyl ester of mycophenolic acid (MPA), inosine 
monophosphate dehydrogenase (IMPDH) inhibitor, is available for oral administration as capsules 
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containing 250 milligrams of mycophenolate mofetil, tablets containing 500 milligrams of 
mycophenolate mofetil, and as a powder for oral suspension, which when constituted contains 
200 milligrams/milliliter mycophenolate mofetil.
Each vial of mycophenolate intravenous contains the equivalent of 500 milligrams mycophenolate 
mofetil as the hydrochloride salt. Reconstitution and dilution with 5% Dextrose Injection USP 
yields a solution of mycophenolate mofetil, 6 milligrams/milliliter.
32.4.2 Storage and Stability
The mycophenolate mofetil powder for reconstitution and reconstituted solution should be stored 
at 25°C (77°F); however, temperature excursions between 15°C to 30°C (59°F to 86°F) are 
permitted.
32.4.3 Preparation and Administration
Mycophenolate mofetil hydrochloride for injection (CellCept Intravenous) must be reconstituted 
and diluted to a concentration of 6 mg/mL using 5% Dextrose Injection USP. CellCept Intravenous 
is incompatible with other intravenous infusion solutions. Following reconstitution, CellCept 
Intravenous must be administered by slow intravenous infusion over a period of NO LESS THAN 
2 HOURS by either peripheral or central vein. 
CAUTION: 
CELLCEPT 
INTRAVENOUS 
SOLUTION 
SHOULD 
NEVER 
BE 
ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION
Refer to package insert for detailed instructions.
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34 APPENDICES/ SUPPLEMENTS
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Appendix A
Karnofsky/ Lansky Scale
Karnofsky Scale 
(recipient age ≥ 16 years)
Lansky Scale 
(recipient age ≥ 1 year and <16 years)
Able to carry on normal activity; no 
special care is needed
Able to carry on normal activity; no special care is 
needed
100 
Normal, no complaints, no evidence 
of disease
100 
Fully active
90 
Able to carry on normal activity
90 
Minor restriction in physically strenuous play
80 
Normal activity with effort
80 
Restricted in strenuous play, tires more easily, 
otherwise active
Unable to work, able to live at home, 
cares for most personal needs, a varying 
amount of assistance is needed
Mild to moderate restriction
70 
Cares for self, unable to carry on 
normal activity or to do active work
70 
Both greater restrictions of, and less time spent in 
active play
60 
Requires occasional assistance but is 
able to care for most needs
60 
Ambulatory up to 50% of time, limited active play 
with assistance/supervision
50 
Requires considerable assistance and 
frequent medical care
50 
Considerable assistance required for any active 
play, fully able to engage in quiet play
Unable to care for self, requires 
equivalent of institutional or hospital 
care, disease may be progressing rapidly
Moderate to severe restriction
40 
Disabled, requires special care and 
assistance
40 
Able to initiate quite activities
30 
Severely 
disabled, 
hospitalization 
indicated, 
although 
death 
not 
imminent
30 
Needs considerable assistance for quiet activity
20 
Very sick, hospitalization necessary
20 
Limited to very passive activity initiated by others 
(e.g., TV)
10 
Moribund, fatal process progressing 
rapidly
10 
Completely disabled, not even passive play
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Appendix B
ELIGIBILITY VERIFICATION FORM: 
INCLUSION CRITERIA 
Participant Name:___________________________________________________
Medical Record No.: _________________________________________________
Title: A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing 
Mobilized Peripheral Blood Stem Cells.
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Any disease that is considered transplant eligible per TCT standards.
2.
Disease response noted (i.e. CR, non-CR, or not applicable): Assessed 
as per disease specific criteria (see Section 3.5).  
3.
Suitable related haploidentical donor identified per transplant service:
Recipient should not have HLA antibodies to potential donor. If the 
recipient does have HLA antibodies to the potential donor, an alternative 
donor is preferred. However, if there are no suitable alternative donors, the 
anti-HLA antibodies should be depleted per transplant service guidelines.

Haploidentical donors that are ABO compatible with the 
recipient are preferred. Minor ABO incompatibility is 
preferred to major ABO incompatibility. Major ABO 
incompatibility between recipient and donor is the least 
preferred but still acceptable for this study.

It is preferred that the haploidentical donor must be available 
to donate on day -1 and day 0 at RPCI, so that fresh product 
can be processed by the RPCI Stem Cell Lab and administered 
to the patient on day 0. While less preferable, cryopreserved 
product may be utilized on this protocol.
4.
Age ≥ 4 (age ≥ 1 once Oishei Children’s Hospital BMT unit is 
open) and ≤ 80 years.
5.
Have the following clinical laboratory values: 

Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) 
> 40% predicted, corrected for hemoglobin and/or alveolar 
ventilation.

Cardiac: left ventricular ejection fraction > 40%.

Bilirubin, liver alkaline phosphatase, SGOT or SGPT ≤ 3 x upper 
limit of normal.

Calculated creatinine clearance> 40 cc/min by the modified 
Cockroft-Gault formula for adults or the Schwartz formula for 
pediatrics (refer to Appendix I). 
6.
Have a Karnofsky (adult) or Lansky (for ≤16 years) performance status 
≥ 60% (refer to Appendix A).
7.
Patient must be able to pass Radiation evaluation (i.e.: able to receive 
200 cGy).
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
8.
Patients who have failed a prior autologous transplant are eligible; 
however, at least 90 days must have elapsed between the start of this 
reduced intensity conditioning regimen and the last transplant if patient 
had a prior autologous BMT.
9.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.
10. Participant must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board 
approved written informed consent form prior to receiving any study 
related procedure.
11. If patient is planned to use a fully matched donor, patient is excluded 
from trial; patient must be planned to undergo a haploidentical matched 
transplant to participate on study.  Patient is still eligible for trial 
regardless of donor options if PI feels that haplo transplant is in the 
patient’s best interest per clinical decision.  
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
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Appendix C
ELIGIBILITY VERIFICATION FORM:
EXCLUSION CRITERIA
Participant Name: ___________________________________________________
Medical Record No.: _________________________________________________
Title: A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing 
Mobilized Peripheral Blood Stem Cells.
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Participants who have had chemotherapy (not including molecularly 
targeted agents; examples include, but are not limited to, tyrosine 
kinase inhibitors such as FLT3 inhibitors and IDH2 inhibitors), 
radiation treatment and/or surgery 7 days prior starting conditioning 
regimen. Those who have not recovered sufficiently from adverse 
events due to agents administered more than 2 weeks earlier are also 
ineligible. Exceptions may be made on a case-by-case basis after 
discussion with the PI.
2.
Uncontrolled CNS disease (for hematologic malignancies) per PI 
discretion.
3.
Child-Pugh class B and C liver failure (refer to Appendix J).
4.
Concomitant active malignancy that would be expected to require 
chemotherapy within 3 years of transplant (other than non-melanoma 
skin cancer).  Exception would include any concurrently existing 
malignancy that could be treated with a transplant per PI discretion. 
(Example:  Patient has AML but a history of mastocytosis.)
5.
Uncontrolled diabetes mellitus, cardiovascular disease, active serious 
infection or other condition which, in the opinion of treating physician, 
would make this protocol unreasonably hazardous for the patient.
6.
Known HIV positive.
7.
Pregnant or nursing female participants.
8.
Patients who in the opinion of the treating physician are unlikely to 
comply with the restrictions of allogeneic stem cell transplantation 
based on formal psychosocial screening.
9.
Patients with donor specific HLA antibodies with a titer greater than 
3000 MFI (whether or not they have undergone a desensitization 
protocol).
10. Patients who have undergone a prior allogeneic hematopoietic or (other 
organ) transplant.
11. Treating physician considers the potential HLA haploidentical donor to 
be ineligible to receive G-CSF, and/or concern on the part of the 
treating physician for risk of harm to the potential donor with 
administration of G-CSF, and/or refusal by the potential donor (or 
donor’s guardian) to receive G-CSF.
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
12. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
13. Received an investigational agent within 14 days prior to enrollment. 
Exceptions made be made on a case-by-case basis after discussion with 
PI.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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Appendix D
Donor Eligibility Criteria

Haploidentical Related Donor: Matched at a minimum of 6 to a maximum of 8 of 12 HLA 
loci: A, B, C, DRB1, DQ and DP. 

Donor must be healthy and have nonreactive test results for all infectious disease assays as 
required by state and federal regulations. Donors who screen seropositive for hepatitis 
and/or syphilis must be cleared by infectious disease consultation.

The donor must have no uncontrolled cardiopulmonary, renal, endocrine, hepatic or 
psychiatric disease to render donation unsafe.

The donor (or parent if minor) must give informed consent for peripheral blood stem cell 
collection.

Donors who have poor peripheral venous access, may require central venous line 
placement for stem cell apheresis.

Pediatric relatives of the patient (< 18 years of age) who are at least 2.5 years of age, and 
who have been medically cleared for peripheral blood stem cell mobilization and collection 
by a pediatric hematologist/oncologist who is not primarily responsible for the oncologic 
care of the intended related recipient, are eligible to donate PBSCs on this trial.

In the case of a potential pediatric donor (< 18 years of age), as recommended by the 
Worldwide Network for Blood and Marrow Transplantation(75), donor evaluation and 
medical clearance for PBSC mobilization and collection must be performed by a pediatric 
hematologist (or pediatric oncologist) who is not the primary hematologist/oncologist for 
the patient (the potential recipient). If the physician who is evaluating the potential 
pediatric donor does not feel that it is safe for the potential donor to undergo PBSC 
mobilization and collection, or that it is otherwise not in the best interest of the potential 
donor to do so (an ethics consultation may be utilized as per the evaluating physician’s 
discretion), then the potential donor will not undergo PBSC mobilization and collection. If 
another suitable haploidentical donor cannot be found for the patient, then the patient will 
be ineligible for this study.  PBSC collection on pediatric donors will be performed as per 
BMT SOPs. Given that the use of G-CSF has not been studied in donors younger than 2.5 
years of age but data demonstrating safety of G-CSF in donors 2.5 years of age and older 
is available(76), donors must be at least 2.5 years of age at the time of PBSC mobilization 
for this study. 

PBSC donation is not allowed from individuals who are less than 30 months of age on this 
trial.

Pregnant women are not eligible to be donors on this study. 
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Allogeneic Hematopoietic Cell Verification Form: 
Donor Acceptance Criteria
Donor Name: ___________________________________________________
Medical Record No.: _________________________________________________
Title: A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing 
Mobilized Peripheral Blood Stem Cells.
ACCEPTANCE CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for an acceptable donation.
Date
1.
Haploidentical related donor identified.
2.
Documented verification of healthy donor with nonreactive test 
results for all infectious disease assays as required by state and 
federal regulations (Donors who screen seropositive for hepatitis 
and/or syphilis must be cleared by infectious disease consultation).
3.
Donor has no documented uncontrolled cardiopulmonary, renal, 
endocrine, hepatic or psychiatric disease to render donation unsafe.
4.
Donor (or parent if minor) has given informed consent for 
peripheral blood stem cell collection.
5.
Criteria for donation as per BMT SOPs are fulfilled.
Donor/donation meets all acceptance criteria:
  Yes
  No
If “NO”, donation cannot be used for this study.
Investigator (or designee) Signature: ____________________________Date: __________
Printed Name of Investigator (or designee): ______________________________________
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Appendix E
Stem Cell Infusion
Day 0 is the day on which the stem cells are infused. The procedure of infusing stem cell products 
may be performed under the supervision of the attending physician.

See BMT form 519-F-626 for standard ordering process, and Stem Cell Lab Policies as per 
SOPs)

Stem cells are to remain sterile throughout the infusion process. 

All patients require continuous pulse oximetry monitoring during the procedure, with 
oxygen equipment available in the patient's room. 

All patients will have vital signs recorded before the procedure and at timed intervals 
during and after stem cell infusion. 

Emergency drugs, such as Benadryl, epinephrine and corticosteroids will be available for 
use in appropriate doses. As noted below, corticosteroids should be avoided if possible.

No other blood products should be given on the day of transplant, especially within 8 hours 
of planned infusion time. 

Stem cells must be infused without the use of a blood filter through a wide lumen central 
catheter. 

The minimum PBSC dose is 5 x 106 CD34+ cells/kg of recipient weight; the maximum 
PBSC dose is 30 x 106 CD34+ cells/kg of recipient weight.

No more than 480 ml of stem cells may be infused at one time and the transplant may need 
to be split into a morning and afternoon infusion at the discretion of the attending physician. 

Patients will be pre-medicated according to RPCI SOP Stem Cell reinfusion (see 511 F-
422 Physician Order Form) however hydrocortisone and all glucocorticoids will be avoided 
if considered safe to do so by the treating clinician.
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Appendix F
Schedule of Research-Related Procedures and Observations
Tests/Observations
Pre-Rx 
(Screening/ 
Baseline) 1
Day 02
Post-Rx3
HCT-CI/Age composite score
X
Karnofsky/Lansky Performance 
X
X4
Temperature
X
X Starting on Day +1 through + 10 ( including Day +1 
and Day +10)
Hematology (CBC/ Diff)
X
Chemistry (CMP) with LDH
X
Serology (HIV, Hepatitis5, 
CMV)
X
Quantitative Immunoglobulins
X
X6
Urinalysis biochemical
X
As clinically indicated
HLA typing
X
Creatinine Clearance 
X
PFT's including DLCO
X
Day 100, Day 365 [±14 days], then as clinically indicated 
PET scan (for patients with 
myeloma)
X
MUGA or ECHO
X
EKG
X
BM aspirate, biopsy7
X
Day 30 (±10 days) , Day 100 (±14 days), and 1 year (±14 
days)8 (refer to Section 11.7.1)
Chest X-ray (PA and lateral)
X
Disease Evaluation: Assessment 
of Response, to include CT 
Scan and/or PET as clinically 
appropriate9
X
X 
Peripheral blood for chimerism
Day 30 (±10 days) , Day 100 (±14 days), at 1 year (±14 
days), then as indicated (refer to Section 11.7.1)
Peripheral blood for flow
X
Day 30 (±10 days) , Day 100 (±14 days) at 1 year (±14 
days), then as indicated  (refer to Section 11.7.2)
Stem Cell Infusion
X
Adverse events10
X
X
X11
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1
Pre-Rx testing is to be obtained within 60 days of enrollment unless otherwise noted.
2
Day 0: Date/Day of stem cell infusion.
3
All testing will be performed post-Rx as clinically indicated. Only mandatory tests are included in this table.
4
Weekly after discharge until Day 100 after stem cell infusion.
5
Hep B virus surface, Ag; Hep B virus core antibody, total; Hep C virus, antibody; only if clinically indicated: 
HCV RNA, HBV DNA
6
Post-transplant SPEP, IFE, Quantitative immunoglobulins, serum beta-2 microglobulin, kappa/lambda free 
light chains and 24 hour urine for protein electrophoresis and free light chains will be done only for patients 
with multiple myeloma on Day 100-160 and then as clinically indicated.
7
BM aspirate and biopsy will be performed for patients with leukemias and bone marrow failure states only. 
Patients with other malignancies will have BM aspirate and biopsy only if bone marrow was involved 
previously.
8
If the patient is medically unfit or has scheduling difficulty, delay is allowed at all follow-up time points.
9
Patients with non-Hodgkin’s and Hodgkin’s lymphoma only: Baseline, Day 100 (± 14 days) post stem cell 
infusion and one year (± 14 days) post stem cell infusion. All other patients: as clinically indicated. Restaging 
workup for assessment of disease response per Appendix M and Appendix N.
10
Serious Adverse Events from Day -6 until Day +30 will be reported to Clinical Research Services.
11
Post-infusion assessments:

Acute GVHD: weekly for the first 100 days post-transplant, every 3 weeks (±7 days) 
from Day 100 through Day 180, and monthly (±14 days) through Day 365 post-
transplant.

Chronic GVHD: weekly for the first 100 days post-transplant, every 3 weeks (± 7 days) 
from Day 100 through Day 180, and monthly (± 14 days) through Day 365 post-
transplant. 
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Appendix G
Criteria for Acute Graft-vs-Host Disease
Clinical staging of acute graft-vs.-host disease according to organ involvement
STAGE
SKIN
LIVER
LOWER 
INTESTINAL TRACT
UPPER INTESTINAL 
TRACT
0
No rash
Bilirubin
< 2.0 mg/dL
< 34 
µmol/L
Diarrhea
< 500 ml/day
Peds: < 10 ml/kg/day
No persistent anorexia, 
nausea, or vomiting
+
Maculopapular rash
< 25% of body 
surface
Bilirubin
2.0-3.0 
mg/dL
34-52 
µmol/L
Diarrhea
500-1000 ml/day
Peds: 10-19.9 ml/kg/day
Persistent anorexia, nausea, 
or vomiting 
++
Maculopapular rash
25-50% of body 
surface
Bilirubin
3.1-6.0 
mg/dL
53-103 
µmol/L
Diarrhea
> 1000-1500 ml/day
Peds: 20-30 ml/kg/day
+++
> 50% body surface
Bilirubin
6.1-15.0 
mg/dL
104-256 
µmol/L
Diarrhea
> 1500 ml/day
Peds: > 30 ml/kg/day
++++
Generalized 
erythroderma
with bullous 
formation
and/or 
desquamation
Bilirubin
> 15.0 
mg/dL
> 256 
µmol/L
Severe abdominal pain with 
or without ileus
(https://www.cibmtr.org/DataManagement/DataCollectionForms/Documents/2450/Rev4.0/
2450R4.0.pdf)
Clinical (Glucksberg) grading of severity of acute graft-vs-host disease
GRADE
DEGREE OF ORGAN INVOLVEMENT
I
+ to ++skin rash; 
no gut involvement; 
no liver involvement; 
no decrease in clinical performance
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II
+ to +++ skin rash;
+ gut involvement or
+ liver involvement (or both);
mild decrease in clinical performance
III
++ to +++ skin rash;
++ to +++ gut involvement or
++ to ++++ liver involvement (or both)
marked decrease in clinical performance
IV
Similar to Grade II with 
++ to ++++ organ involvement and 
extreme decrease in clinical performance
Source: Thomas et al, N Engl. J Med. 1975; 292, 832
IBMTR Severity Index
A – Stage 1 skin involvement, no liver or gut involvement
B – Stage 2 skin involvement; Stage 1 to 2 gut or liver involvement
C – Stage 3 skin, liver, or gut involvement
D – Stage 4 skin, liver or gut involvement
Source: Rowlings et al., Br J Haematol 1997; 97:855
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Appendix H
Clinical Grading of Chronic GVHD
Involvement
Description
Limited
Localized skin involvement and/or hepatic 
dysfunction due to chronic GVHD.
Extensive
One or more of the following:
1)
Generalized skin involvement; or
2)
Liver histology showing chronic aggressive 
hepatitis, bridging necrosis or cirrhosis, or
3)
Involvement of the eye, or
4)
Involvement of minor salivary glands or oral 
mucosa, or
5)
Involvement of any other target organ (lung, 
GI, GU, musculoskeletal, serositis, etc…).
Severity
Description
Mild
Signs and symptoms of chronic GVHD do not 
interfere substantially with function and do not 
progress once appropriately treated with local 
therapy or standard systemic therapy (i.e., 
corticosteroids and/or CSA/Tacro).
Moderate
Signs and symptoms of chronic GVHD interfere 
somewhat with function despite appropriate 
therapy or are progressive through first line 
systemic therapy (i.e., corticosteroids and/or 
CSA/Tacro).
Severe
Signs and symptoms of chronic GVHD limit 
function substantially despite appropriate therapy 
or are progressive through second line therapy.
*Modified from CIBMTR Form 2100, revision 4 (.Center for International Blood & Marrow Transplant Research: 
Post-HCT Follow-Up Data. (77)
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Appendix I
Creatinine Clearance
COCKROFT GAULT FORMULA (MODIFIED FOR BSA) FOR ESTIMATION OF 
CREATININE CLEARANCE ABOVE AGE 18*
CLEARANCE (ml/min) 
Male = (140-age) x IBW (kg) / 72 x SrCr
Female= male clearance x 0.85
IBW (male) = 50 + 0.91(Height (cm) - 152)
IBW (female) = 45 + 0.91(Height (cm) - 152)
SrCr in mg/dL
SCHWARTZ FORMULA FOR ESTIMATION OF CREATININE CLEARANCE
UP TO AGE 18*
CLEARANCE (ml/min/1.73 m2) = K x L / SrCr 
K = age adjusted constant, L = length in centimeters, SrCr in mg/dL.
Age
K
Children 1-13 years old
0.55
Adolescent females 13-18 years old
0.55
Adolescent males 13-18 years old
0.70
Based on: Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A: A simple estimate of glomerular 
filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259-263, 
1976.
*Can  use either serum or plasm a creatinine levels 
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Appendix J
Child-Pugh Classification of Liver Failure
Points Scored
Measurement
1
2
3
Encephalopathy
None
1 and 2
3 and 4
Ascites
None
Slight
Moderate
Bilirubin (mg/100 mL)
1.0 – 2.0
2.0 – 3.0
> 3.0
Albumin (gm/100 mL)
3.5
2.8 - 3.5
< 2.8
Prothrombin time 
(sec. prolonged)
1 - 4
4 - 6
>6
For PBC, bilirubin 
(mg/100 mL)
1 - 4
4 - 10
>10
Child - Pugh Classification:
A = 1 – 6
B = 7 – 9
C = 10-15
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Appendix K
AML – Prognostic Groups(78)
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Appendix L
Arm Distribution Criteria (79) 
Acute Myeloid Leukemia
Complete Remission (CR)
Hematologic complete remission is defined as meeting all of the following response criteria:

< 5% blasts in the bone marrow

Evidence of trilineage hematopoiesis in the bone marrow  

No extramedullary disease (e.g., CNS, soft tissue disease)

Neutrophils ≥ 1,000/μL

Platelets ≥ 100,000/μL

Transfusion independent
Complete Remission with Incomplete Hematologic Recovery (CRi)
Hematologic complete remission with incomplete hematologic recovery is defined as meeting all 
of the following response criteria:

< 5% blasts in the bone marrow

Evidence of trilineage hematopoiesis in the bone marrow  

Normal maturation of all cellular components in the bone marrow

No extramedullary disease (e.g., CNS, soft tissue disease)
Acute Lymphoblastic Leukemia
Complete Remission (CR)
Hematologic complete remission is defined as meeting all of the following response criteria:

< 5% blasts in the bone marrow

Evidence of trilineage hematopoiesis in the bone marrow

No extramedullary disease (e.g., CNS, soft tissue disease)

ANC (absolute neutrophil count) ≥ 1,000/μL

Platelets ≥ 100,000/μL
Complete Remission with Incomplete Hematologic Recovery (CRi)
Hematologic complete remission with incomplete hematologic recovery is defined as meeting all 
of the following response criteria:

< 5% blasts in the bone marrow

Evidence of trilineage hematopoiesis in the bone marrow  

No extramedullary disease (e.g., CNS, soft tissue disease)
Multiple Myeloma* / Plasma Cell Disorder
Stringent Complete Remission (sCR)
Follows criteria for CR as defined below, plus all of the following:
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
Normal free light chain ratio

Absence 
of 
clonal 
cells 
in 
the 
bone 
marrow 
by 
immunohistochemistry, 
immunofluorescence, flow cytometry (MRD testing)
Complete Remission (CR)
A treatment response where all of the following criteria are met:

Negative immunoelectrophoresis (immunofixation) on serum and urine samples

Disappearance of any soft tissue plasmacytomas

< 5% plasma cells in the bone marrow (confirmation with repeat bone marrow biopsy not 
needed)

No known evidence of new or progressive bone lesions on radiographic studies.
For recipients with non-secretory myeloma, all of the following criteria must be met:

Disappearance of all soft tissue plasmacytomas

< 5% plasma cells in the bone marrow (confirmation with repeat bone marrow biopsy not 
needed)

No known evidence of new or progressive bone lesions on radiographic studies.
Very Good Partial Response (VGPR)

Absence of soft tissue plasmacytoma
One or more of the following must be present:

≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours
OR

Serum and urine M-protein detectable by immunofixation but not on electrophoresis
At diagnosis, if:

M protein is < 1 g/dL, you must use serum free light chain or urine measurement

IgA monoclonal protein, you must use an estimate by total IgA or HevyLite®

Urine M-protein is < 200 mg/24 hours, use serum free light chains or if serum free light 
chains are not elevated, then use nonsecretory myeloma criteria
*Modified based on the International Myeloma Working Group (IMWG) Uniform Response 
Criteria for Multiple Myeloma(80) 
Hodgkin and Non-Hodgkin Lymphoma
Complete Remission (CR)

Complete disappearance of all known disease. For typically PET-avid lymphoma, a post-
treatment residual mass of any size is permitted as long as it is PET negative. For variably, 
PET-avid lymphoma, all lymph nodes and nodal masses must have regressed as measured 
by CT to < 1.5 cm (for nodes > 1.5 cm before therapy) or < 1 cm (for nodes 1.1 cm to 1.5 
cm before therapy)
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CRu

All CR criteria are met except, there may be CT scan abnormalities of uncertain 
significance. PET scan must be negative.
Chronic Lymphocytic Leukemia
Complete Response (CR)
All of the following:

Any lymphadenopathy must be ≤ 1.5 cm in the widest dimension

If present, splenomegaly must be < 20 cm in the widest dimension on radiographic imaging 

Neutrophils ≥ 1.5 × 109/L

Platelets > 100 × 109/L

Hemoglobin > 11 g/dL

Lymphocytes < 4 × 109/L

Bone marrow < 30% lymphocytes 

Absence of constitutional symptoms (including weight loss, fever, and night sweats)
CRi
All of the following:

No evidence of lymphadenopathy

No organomegaly
Absence of constitutional symptoms (including weight loss, fever, and night sweats)
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Appendix M Post-Transplant Response Criteria (79)
Acute Myeloid Leukemia
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Complete Remission (CR)
Hematologic complete remission is defined as meeting all of the following response criteria for at 
least four weeks.

< 5% blasts in the bone marrow

No extramedullary disease (e.g., CNS, soft tissue disease)
Relapse (REL)
Relapse is defined as the recurrence of disease after CR, meeting one or more of the following 
criteria:

≥ 5% blasts in the marrow or peripheral blood

New or recurrence of extramedullary disease
Acute Lymphoblastic Leukemia
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Complete Remission (CR)
Hematologic complete remission is defined as meeting all of the following response criteria for at 
least four weeks.

< 5% blasts in the bone marrow

No extramedullary disease (e.g., CNS, soft tissue disease)
Relapse (REL)
Relapse is defined as the recurrence of disease after CR, meeting one or more of the following 
criteria:

≥ 5% blasts in the marrow or peripheral blood

New or recurrence of extramedullary disease
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Myelodysplastic Syndrome (MDS)
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Complete Remission (CR)
Bone marrow evaluation:

< 5% myeloblasts with normal maturation of all cell lines
Peripheral blood evaluation:

Hemoglobin ≥ 11 g/dL un-transfused within 7 days without erythropoietic support

ANC ≥ 1000/mm3 without myeloid growth factor support

Platelets ≥ 100,000/mm3 without thrombopoietic support

0% blasts in blood
Hematologic Improvement (HI)

<5% blasts in the bone marrow
Hematologic improvement – erythropoietic (HI-E)

Hemoglobin increase of ≥ 1.5 g/dL un-transfused for 7 days
Hematologic improvement – platelets (HI-P)

For pre-treatment platelet count of > 20 ×109, platelet absolute increase of ≥ 30 ×109

For pre-treatment platelet count of < 20 ×109, platelet absolute increase of ≥ 20 ×109 and 
≥ 100% increase from pre-treatment level
Hematologic improvement – neutrophils (HI-N)

Neutrophil count increase of ≥ 100% from pre-transplant level and an absolute increase of 
≥ 500/mm3
No Response (NR)/Stable Disease (SD)

Does not meet the criteria for at least HI; but no evidence of disease progression to AML.
Relapse/Progression from Complete Remission (Rel from CR or HI)
Requires at least one of the following:

Bone marrow blasts >5% and clonal

At least a 50% decrease in platelets or granulocytes that is related to the malignant clonal 
population of cells (not due to ABO incompatibility, medication, angiopathy, or other 
nonmalignant causes)

The hemoglobin level must decrease by at least 1.5 g/dL from pre-transplant level.
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Progression to AML

≥ 20% blasts in the blood or bone marrow
Multiple Myeloma / Plasma Cell Disorder (Including WM)
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Stringent Complete Remission (sCR)
Follows criteria for CR as defined below, plus all of the following:

Normal free light chain ratio

Absence 
of 
clonal 
cells 
in 
the 
bone 
marrow 
by 
immunohistochemistry, 
immunofluorescence, flow cytometry (MRD testing)
Complete Remission (CR)

A treatment response where all of the following criteria are met:

Negative immunoelectrophoresis (immunofixation) on serum and urine samples

Disappearance of any soft tissue plasmacytomas

< 5% plasma cells in the bone marrow (confirmation with repeat bone marrow biopsy not 
needed)

No known evidence of new or progressive bone lesions on radiographic studies.
For recipients with non-secretory myeloma, all of the following criteria must be met:

Disappearance of all soft tissue plasmacytomas

< 5% plasma cells in the bone marrow (confirmation with repeat bone marrow biopsy not 
needed)

No known evidence of new or progressive bone lesions on radiographic studies.
Very Good Partial Response (VGPR)

Absence of soft tissue plasmacytoma
One or more of the following must be present:

≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours
OR

Serum and urine M-protein detectable by immunofixation but not on electrophoresis
At diagnosis, if:

M protein is < 1 g/dL, you must use serum free light chain or urine measurement)

IgA monoclonal protein, you must use an estimate by total IgA or HevyLite®

Urine M-protein is < 200 mg/24 hours, use serum free light chains or if serum free light 
chains are not elevated, then use nonsecretory myeloma criteria
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Partial Response (PR)
Both of the following must be present:

≥ 50% reduction in serum M-protein

Reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg/24 hours.
At diagnosis, if:

M protein is < 1 g/dL, you must use serum free light chain or urine measurement)

IgA monoclonal protein, you must use an estimate by total IgA or HevyLite®

Urine M-protein is < 200 mg/24 hours, use serum free light chains or if serum free light 
chains are not elevated, then use nonsecretory myeloma criteria
In addition to the above-listed criteria, if soft tissue plasmacytomas were present at baseline, a ≥ 
50% reduction in their size is also required.
Stable Disease (SD)

Does not meet the criteria for CR, VGPR, PR, or PD.
Progressive Disease (PD)
Requires one or more of the following:

Increase of ≥ 25% from the lowest post-transplant response value achieved in:

Serum M-component with an absolute increase ≥ 0.5 g/dL 

Urine M-component with an absolute increase ≥ 200 mg/24 hours; 

For recipients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved free light chain levels with an absolute increase > 10 
mg/dL; 

Bone marrow plasma cell percentage with absolute percentage increase of ≥ 10%; 

Definite development of new bone lesions or soft tissue plasmacytomas, or definite 
increase in the size of any existing bone lesions or soft tissue plasmacytomas
Chronic Myeloid Leukemia
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Complete Hematologic Remission (CR)
A treatment response where all of the following criteria are met:

White blood count is < 10 × 109/L, without immature granulocytes and with < 5% basophils

Platelet count < 450 × 109/L

Non-palpable spleen
Complete Molecular Remission (81)

0% BCR/ABL transcripts detected in peripheral blood or bone marrow 
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Major Molecular Remission

>0-0.1% BCR/ABL transcripts detected in peripheral blood or bone marrow
Complete Cytogenetic Response

0% Ph+ cells detected in bone marrow
Partial Cytogenetic Response

>0-35% Ph+ cells in bone marrow
Minor Cytogenetic Response

>35-65% Ph+ cells in bone marrow
Minimal Cytogenetic Response

>65-95% Ph+ cells in bone marrow
No Cytogenetic Response

>95% Ph+ cells in bone marrow
Chronic Phase

Characterized by relatively few blasts (<10%) present in the blood and bone marrow. 
Symptoms are often not present. The chronic phase may last several months to years, 
depending on the recipient and the treatment they receive.
Accelerated Phase
One or more of the following must be present:

10%-19% blasts in blood or marrow

≥ 20% basophils in peripheral blood

Clonal marrow cytogenetic abnormalities in addition to the single Philadelphia 
chromosome (clonal evolution)

Increasing spleen size, unresponsive to therapy

Increasing WBC, unresponsive to therapy

Thrombocytopenia (platelets < 100,000), unrelated to therapy

Thrombocytosis (platelets > 1,000,000), unresponsive to therapy
Blast Phase
Characterized by having ≥ 20% blasts (formerly ≥ 30%) in the peripheral blood or bone marrow. 
Having extramedullary blastic infiltrates (i.e., myeloid sarcoma, granulocytic sarcoma, or 
chloroma) also qualifies as blast phase. The red cell, platelet, and neutrophil counts may decrease 
and episodes of infection and bleeding may result. Symptoms such as fatigue, shortness of breath, 
abdominal pain, bone pain, and spleen enlargement may occur.
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Relapse
For reporting purposes, relapse is defined as recurrence of disease after complete hematologic 
remission. In general, relapse should be confirmed by a clinical / hematologic assessment (e.g., 
pathology, CBC, or clinical exam).
Progression
For reporting purposes, progression is defined as any of the following changes in disease status:

Advancement from chronic phase to accelerated phase.

Advancement from chronic phase to blast phase.

Advancement from accelerated phase to blast phase.
Hodgkin and Non-Hodgkin Lymphoma
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Complete Remission (CR)
Complete disappearance of all known disease. For typically PET-avid lymphoma, a post-treatment 
residual mass of any size is permitted as long as it is PET negative. For variably PET-avid 
lymphoma, all lymph nodes and nodal masses must have regressed as measured by CT to ≤ 1.5 
cm (for nodes > 1.5 cm before therapy) in the longest diameter or ≤ 1 cm (for nodes 1.1 cm to 1.5 
cm before therapy).
Bone Marrow (optional as part of work-up unless it was positive for disease immediately prior to 
transplant): If bone marrow was positive any time prior to transplant, it must be repeated and 
negative to confirm CR.
Partial Remission (PR)

≥ 50% reductions in the greatest diameter of up to six of the largest dominant nodes or 
nodal masses, extranodal sites and no new sites of lymphoma
Stable Disease

Does not meet criteria for CR, PR, or PD
Progressive Disease

Any new lesion and/or > 50% increase in the least diameter of previously involved sites

New or recurrent involvement of bone marrow

New or recurrent extranodal disease
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Chronic Lymphocytic Leukemia
Continued Complete Remission (CCR)

For patients transplanted in CR, the best response post BMT is CCR as long as there is no 
documented disease progression
Complete Response (CR)
All of the following:

Any lymphadenopathy must be ≤ 1.5 cm in the widest dimension

If present, splenomegaly must be < 20 cm in the widest dimension on radiographic imaging 

Neutrophils ≥ 1.5 × 109/L

Platelets > 100 × 109/L

Hemoglobin > 11 g/dL

Lymphocytes < 4 × 109/L

Bone marrow < 30% lymphocytes 

Absence of constitutional symptoms (including weight loss, fever, and night sweats)
Partial Response (PR)

≥ 50% decrease in peripheral blood lymphocyte count from pretreatment value

≥ 50% reduction in lymphadenopathy if present pretreatment

≥ 50% reduction in liver and/or spleen size if enlarged pretreatment
One or more of the following:

Neutrophils ≥ 1.5 ×109/L or 50% improvement over baseline

Platelets > 100 ×109/L or 50% improvement over baseline

Hemoglobin > 11 g/dL or 50% improvement over baseline
Stable Disease (SD)
Not meeting the definition of complete response, partial response, or progressive disease.
Progressive Disease (PROG)/Relapse
One or more of the following:

≥ 50% increase in the sum of the products of ≥ 2 lymph nodes (≥ 1 lymph node must be ≥ 
2 cm) or new nodes

≥ 50% increase in liver or spleen size, or new hepatomegaly or splenomegaly

≥ 50% increase in absolute lymphocyte count to ≥ 5 ×109/L

Transformation to a more aggressive histology
Bone Marrow Failure Disorders, including Aplastic Anemia
Complete Response:

At least 20% cellularity in the bone marrow with neutrophil and platelet engraftment (ANC 
>500 and Platelets >20)
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No Response:

Does not meet definition of CR
Other Non-Malignant Hematologic Disorders, Immune Disorders
Complete Response:

Disappearance of signs/symptoms and absence of evidence of the presence of the 
underlying disease
No Response:

Persistence of the underlying disease
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Appendix N
Myelofibrosis, Polycythemia Vera, and CMML Post-Transplant Response 
Criteria
Myelofibrosis (82)
CCR: For those patients in CR at baseline, continued CR.
Complete 
remission (CR)
All of the following criteria should be met:

Complete resolution of disease-related symptoms and signs 
including palpable hepatosplenomegaly

Peripheral blood count remission (hemoglobin ≥ 11 g/dL, platelets ≥ 
100 x109/L, neutrophils ≥ 1.0 x109/L), all 3 blood counts should also 
be no higher than upper limit of normal

Normal white cell differential including absence of nucleated red 
cells, blasts, and immature myeloid cells on the blood film, in the 
absence of splenectomy (1)

Histologic remission on bone marrow trephine: normocellular for 
age, ≤ 5% myeloblasts, and osteomyeloﬁbrosis grade ≤ 1 (2)
Partial 
remission (PR)
All CR criteria met except bone marrow histologic remission
Clinical 
improvement 
(CI)
At least one of the following for at least 8 weeks, in the absence of 
progressive disease, or complete or partial remission:

≥ 2 g/dL increase in hemoglobin or achievement of transfusion 
independence (only applies to patients with baseline hemoglobin ≤ 
10 g/dL) (3)

≥ 50% reduction in palpable splenomegaly (if spleen ≥ 10 cm at 
baseline) OR spleen no longer palpable (if 5 - 10 cm at baseline) (4)

≥ 100% increase in platelet count AND platelet count ≥ 50 x109/L 
(only applies to patients with baseline platelet count < 50 x109/L)

≥ 100% increase in neutrophil count AND neutrophil count ≥ 0.5 
x109/L (only applies to patients with baseline neutrophil count < 1.0 
x109/L)
Progressive 
disease (PD)
At least one of the following: (5)

Progressive splenomegaly: palpable splenomegaly > 5 cm below left 
costal margin if no prior palpable splenomegaly, OR ≥ 100% 
increase in palpable splenomegaly if baseline 5 - 10 cm, OR ≥ 50% 
increase if baseline splenomegaly > 10 cm

Leukemic transformation conﬁrmed by bone marrow blast count ≥ 
20%

≥ 20% increase in peripheral blood blast percentage lasting for ≥ 8 
weeks
Stable disease
None of the above
Relapse
Patient previously meeting criteria CI, PR or CR no longer meets criteria for 
CI
Notes
(1) Because peripheral blood film analysis is subjective, CR does not require absence of 
morphologic abnormalities of red cells, platelets, and neutrophils
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(2) In patients with CR and a pre-existing cytogenetic abnormality, complete cytogenetic response 
is deﬁned as failure to detect the abnormality in at least 20 metaphases. Partial cytogenetic 
response is deﬁned as ≥ 50% reduction in abnormal metaphases. Major molecular response is 
deﬁned as absence of a previously-positive speciﬁc disease-associated mutation in peripheral 
blood.
(3) Transfusion-dependence is deﬁned as a transfusion of at least 2 units of red blood cells in the 
previous month for a hemoglobin < 8.5 g/dL not due to clinically overt bleeding. During therapy 
within clinical trials, transfusions for a hemoglobin ≥ 8.5 g/dL is therefore discouraged unless 
clinically indicated.
(4) In splenectomized patients, palpable hepatomegaly is substituted, with the same measurement 
criteria.
(5) Worsening cytopenias were not included as a criterion for progressive disease because of the 
difﬁculty differentiating between disease-associated cytopenias and drug-induced 
myelosuppression. However, ≥ 2 g/dL decrease in hemoglobin, ≥ 100% increase in transfusion 
requirement, or new development of transfusion dependence, each lasting for > 3 months after 
discontinuation of protocol therapy, can be considered disease progression.
Polycythemia Vera(60)
Criteria
Complete 
remission
 A
Durable* resolution of disease-related signs including palpable 
hepatosplenomegaly, large symptoms improvement† AND
 B
Durable* peripheral blood count remission, defined as Ht lower than 45% 
without phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 
109/L, AND
 C
Without progressive disease, and absence of any hemorrhagic or 
thrombotic event, AND
 D
Bone marrow histological remission defined as the presence of age-
adjusted normocellularity and disappearance of trilinear hyperplasia, and 
absence of >grade 1 reticulin fibrosis
Partial remission
 A
Durable* resolution of disease-related signs including palpable 
hepatosplenomegaly, large symptoms improvement† AND
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Criteria
 B
Durable* peripheral blood count remission, defined as Ht lower than 45% 
without phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 
109/L, AND
 C
Without progressive disease, and absence of any hemorrhagic or 
thrombotic event, AND
 D
Without bone marrow histological remission defined as persistence of 
trilinear hyperplasia.
No response
Any response that does not satisfy partial remission
Progressive 
disease
Transformation into post-PV myelofibrosis, myelodysplastic syndrome or 
acute leukemia‡
Molecular response is not required for assignment as complete response or partial 
response. Molecular response evaluation requires analysis in peripheral blood 
granulocytes. Complete response is defined as eradication of a preexisting abnormality. 
Partial response applies only to patients with at least 20% mutant allele burden at baseline. 
Partial response is defined as ≥ 50% decrease in allele burden.
WBC, white blood cell.
*Lasting at least 12 wk.
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.10
‡For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria12; for the diagnosis 
of myelodysplastic syndrome and acute leukemia, see WHO criteria.
CMML(61)
Complete response (presence of all of the following improvements)*
Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) 
with normal maturation of all cell lines and return to normal cellularity*
Osteomyelofibrosis absent or equal to "mild reticulin fibrosis" (≤grade 1 fibrosis)¶
Peripheral bloodΔ
WBC ≤10 x 109 cells/L
Hgb ≥11 g/dL
Platelets ≥100 x 109/L; ≤450 x 109/L
Neutrophils ≥1.0 x 109/L
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Blasts 0%
Neutrophil precursors reduced to ≤2%
Monocytes ≤1 x 109/L
Extramedullary disease: Complete resolution of extramedullary disease present before 
therapy (eg, cutaneous disease, disease-related serous effusions), including palpable 
hepatosplenomegaly
Provisional category of CR with resolution of symptoms:Δ CR as described above, and 
complete resolution of disease-related symptoms as noted by the MPN-SAF TSS
Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia*
Complete cytogenetic remission
Resolution of previously present chromosomal abnormality (known to be associated with 
myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN), as seen on 
classic karyotyping with minimal of 20 metaphases or FISH◊
Partial remission
Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and 
blast equivalents) reduced by 50%, but remaining >5% of cellularity except in cases of 
MDS/MPN with ≤5% bone marrow blasts at baseline
Marrow response
Optimal marrow response: Presence of all marrow criteria necessary for CR without 
normalization of peripheral blood indices as presented above
Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but 
remaining >5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on 
at least two bone marrow evaluations spaced at least two months apart
Clinical benefit
Requires one of the following in the absence of progression or CR/partial response and 
independent of marrow response (cord blood response must be verified at ≥8 weeks) to be 
considered a clinical benefit
Erythroid response
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Hgb increase by ≥2.0 g/dL
TI for ≥8 weeks for patients requiring at least four packed red blood cell transfusions 
in the previous eight weeks
Only red blood cell transfusions given based on physician's judgment for a 
pretreatment Hgb of ≤8.5 g/dL will count in the red blood cell TI response evaluation§
Platelet response
Transfusion independence when previously requiring platelet transfusions of at least a 
rate of four platelet transfusions in the previous eight weeks
Pretreatment ≤20 x 109/L: Increase from <20 x 109/L to >20 x 109/L and by at least 
100%
Pretreatment >20 x 109/L but ≤100 x 109/L: Absolute increase of ≥30 x 109/L§
Neutrophil response
Pretreatment ≤0.5 x 109/L at least 100% increase and an absolute increase ≥0.5 x 109/L
Pretreatment >0.5 x 109/L and ≤1.0 x 109/L at least 50% increase and an absolute 
increase ≥0.5 x 109/L§
Spleen response
Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 
10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes 
not palpable
Symptom response
Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS 
scoring <20 were not considered eligible for measuring clinical benefit¥
CMML: chronic myelomonocytic leukemia; CR: complete response; MDS: 
myelodysplastic syndrome; MPN: myeloproliferative neoplasm; WBC: white blood cell; 
Hgb: hemoglobin; FISH: fluorescence in situ hybridization; TI: transfusion 
independence; MPN-SAF TSS: Myeloproliferative Neoplasm Symptom Assessment 
Form total symptom score; MDS IWG: Myelodysplastic Syndrome International 
Working Group.    
* Presence of dysplastic changes, which may be interpreted within the scope of normal 
range of dysplastic changes, may still exist in the presence of CR as allowed in MDS 
IWG. Marrow should exhibit age-adjusted normocellularity in CR.
¶ If there is no significant fibrosis present on the initial bone marrow biopsy, a second 
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biopsy is not required to prove resolution of fibrosis. Grading of fibrosis in measurement 
of treatment response should be according to the European Consensus System.
Δ Given the current lack of a validated tool to assess complete resolution of symptoms in 
MDS/MPN, "CR with resolution of symptoms" (a complete resolution of disease related 
symptoms as noted by the MPN-SAF TSS in presence of CR) will be a provisional 
category of disease response.
◊ Loss of cytogenetic burden of disease by (via FISH or classic karyotyping) known to 
adversely affect prognosis is required to reach complete cytogenetic remission. Decrease 
in the cytogenetic burden of disease must be by ≥50% (via FISH or classic karyotyping) 
to be indicative of a partial cytogenetic response. Given variability of fluorescent probes 
used in FISH, cytogenetic normalization via FISH will depend on the performance 
characteristics of the specific probes used.
§ Resolution of abnormal peripheral blood counts must persist for at least two separate 
analyses over at least eight weeks. In the case of proliferative MDS/MPN, CR will 
include resolution of thrombocytosis to a normal platelet count (150 to 450 x 109/L) and 
resolution of leukocytosis to WBC ≤10 x 109 cells/L but ≥1.5 x 109/L. Hgb should be 
maintained >11 g/dL and platelets ≥100 x 109/L without the support of transfusions. 
Clinical benefit may occur when these changes occur in absence of other changes 
required for CR or marrow response. Platelet and packed red blood cell TI would be 
considered for clinical benefit, and duration of TI should be monitored. Reduction in 
myeloid precursors (promyelocytes, myelocytes, metamyelocytes, nucleated red blood 
cells) to less than appreciable levels (≤2 to 3%) and/or 1 x 109/L monocytosis in the 
absence of infection, cytokine treatment, or other reactive causes.
¥ MPN-SAF TSS validation among patients with MDS/MPN is currently under way (RA 
Mesa, personal communication, 2014).
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