Cellular Infusions in Patients With Recurrent or Persistent Hematologic Malignancies After Allogeneic Stem Cell Transplant
Phase: NA
Conditions: Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes
Sponsor: Roswell Park Cancer Institute

Rev. 8/27/12, V.13
Page 1 of 28
Roswell Park Cancer Institute Treatment Protocol
Protocol Number:
I 00703
Protocol Title:
Cellular Infusions in Patients with Recurrent or Persistent 
Hematologic Malignancies After Allogeneic Stem Cell 
Transplant.
 Principal Investigator:
Philip L. McCarthy, Jr., M.D.
APPROVED RPCI IRB
8/7/2017
AMENDMENT V.13
NCT# NCT00534118
NCT# NCT00534118

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 2 of 28
Table of Contents
 Section 
Page No.
APPROVED RPCI IRB
8/7/2017
1.0 
INTRODUCTION........................................................3
2.0 
OBJECTIVES...............................................................6
3.0 
RECIPIENT ELIGIBILITY CRITERIA..................6
4.0
EXCLUSION CRITERIA...........................................9
5.0
DONOR ELIGIBILITY CRITERIA..........................9
6.0
PROCEDURES............................................................10
7.0 
DISEASE RESPONSE TO DLI..................................15
8.0 
TREATMENT RESPONSE........................................16
9.0
TREATMENT OF GVHD...........................................16
10. 
REMOVALOF PATIENTS FROM PROTOCOL
AND ADVERSE EVENT REPORTING...................18
11.
STATISTICAL CONSIDERATIONS........................18
12.
ENDPOINTS.................................................................19
13.  
DATA AND SAFETY MONITORING PLAN..........19 
REFERENCES..............................................................................21
APPENDIX I      Bearman Criteria for Toxicity Grading........24
APPENDIX II    Criteria for Acute GVHD................................25
APPENDIX III  Clinical Grading of Chronic GVHD...............27
APPENDIX IV   Karnofsky Performance Status.......................28

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 3 of 28
1.0) INTRODUCTION:
1.1) An anti-leukemic effect of allogeneic lymphocytes was described nearly 50 years ago
 (1).  
The existence of a graft-versus-leukemia effect was shown by studies in which 
leukemic mice treated with irradiation and allogeneic bone marrow were more likely to 
be cured of leukemia than mice treated with irradiation and syngeneic marrow.  
Numerous studies over the years have further documented the existence of this effect 
and delineated its mechanisms in animal models
 (2,3).  
Data accumulated in the late 1970’s and 1980’s strongly suggested the existence of this 
effect in human BMT
 (4-6). Substantially higher relapse rates were observed in 
recipients of syngeneic grafts as opposed to allogeneic grafts; among recipients of 
allografts, relapse rates were higher if GVHD did not occur or if grafts were T-Cell 
depleted.  Horowitz et al., in an analysis of 2,254 patients with AML in first remission, 
ALL in first remission, or CML in chronic phase for the International Bone Marrow 
Transplant Registry (IBMTR), gave strong support to this concept6.  These 
investigators studied four groups in detail: recipients of non-T-cell depleted allografts 
without GVHD, recipients of non-T-cell depleted allografts with GVHD, recipients of 
T-cell depleted allografts, and recipients of syngeneic transplants.  The relative risk of 
relapse in AML patients was higher in syngeneic transplant recipients than in 
allogeneic transplant recipients.  Among allograft recipients, GVHD was associated 
with a significantly lower relative risk of relapse in patients with ALL, AML, and 
CML.  CML patients who received T-cell depleted allografts had a higher risk of 
relapse.  T-cell depletion did not result in increased relapse rates in patients with ALL 
or AML.  Further data analysis suggested different anti-leukemia mechanisms:  (1) An 
anti-leukemia effect of GVHD (decreased risk of relapse in non-T-cell depleted allo-
graft recipients with GVHD as compared with recipients of non-T-cell depleted allo-
grafts without GVHD);  (2) An anti-leukemic effect of allogeneic grafts independent of 
GVHD (increased risk of relapse in AML patients who received syngeneic transplant 
compared to recipients of allografts without GVHD);  (3) An anti-leukemia effect 
independent of GVHD that is altered by T-cell depletion (CML recipients of T-cell 
depleted transplants with or without GVHD had higher probabilities of relapse than 
recipients of non-T-cell depleted allo-grafts without GVHD).  Thus these data provided 
strong but indirect evidence of a powerful GVL effect in humans.  Additionally, 2 
groups have reported higher relapse rates in patients with Non-Hodgkin’s lymphoma or 
Hodgkin’s disease receiving similar chemo/radiotherapy regimens after autologous 
transplant (45%) as compared to allogeneic transplant (15%) suggesting a potential 
anti-tumor effect associated with infusion of allogeneic marrow 
(7,9).
Further evidence of a human GVL effect was provided by the observation of remission 
after discontinuation of immunosuppression and development of GVHD in patients 
with post-allo-graft relapse (10-11)
APPROVED RPCI IRB
8/7/2017
.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 4 of 28
Based on the apparent power of the clinical GVL effect, and the presumed mediation of 
the effect by donor immune cells (T-cells and/or NK cells), several groups have 
investigated infusion of buffy coat cells obtained from the original bone marrow donor 
as a means of inducing a GVL effect in patients who have relapsed after allogeneic 
BMT (12-26). Results obtained from several single-institution studies and two large 
retrospective multi-center studies can be summarized as follows:
a. 
The majority of patients with CML who relapse after allogeneic transplant 
(approximately 65%) have a complete response to donor buffy coat infusion.  In 
almost all complete responders evaluated by PCR, molecular remissions have 
been documented. Responses are more likely in patients with chronic phase or 
cytogenetic relapse than accelerated or blastic disease.  Multivariate analyses of 
two large data sets have not demonstrated an additive role of alpha-interferon in 
the development of complete response
 (23,27).
b. 
The median time to response is 3 months, with a range of 1 to 11 months.
c. 
Most responses in CML have been long lasting with the longest disease-free 
follow-up described 3+ years.
d. 
Approximately 60% of patients have developed GVHD.  Although fatal GVHD is 
uncommon, significant GVHD develops in the majority of long-term responders, 
and the requirement for prolonged immunosuppression with associated morbidity 
and mortality is a major problem.
e. 
Pancytopenia has been observed in approximately 20% of patients.  Many patients 
developing pancytopenia have had minimal donor engraftment by RFLP analysis 
at the time of buffy coat administration.  It is postulated that in these patients 
infused donor lymphocytes eradicate recipient leukemic hematopoiesis; in the 
absence of sufficient donor hematopoietic cells, hematopoiesis does not recover.  
However, this explanation remains hypothetical.  Pancytopenia has been transient 
in most patients, recovering without any intervention or after a short course of 
colony stimulating factor.  However, a second stem cell infusion may be necessary 
in patients who have pancytopenia lasting beyond 28 days.
  
f. 
GVHD is closely associated with disease response.  Nearly all compete responders 
have had GVHD and the statistical correlation of acute and chronic GVHD with 
complete remission was highly significant in one large analysis (p value 
<0.00001)(27).
g. 
In AML, ALL and MDS response rates are lower, being observed in 
approximately 20% of evaluable patients.(23,27)
APPROVED RPCI IRB
8/7/2017
. A large percentage of patients 
with these diagnoses die of progressive disease within a few weeks of DLI, 
suggesting that large disease bulk/rapid growth may explain in part the lower 
response rate in these patients.  Therefore, chemotherapy has been administered 
before DLI is some instances in an attempt to de-bulk tumor; however, too few 
patients have been treated in this way to allow a definitive assessment of its 

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 5 of 28
usefulness.  Another potential approach to this problem is to treat certain patients 
with molecular or cytogenetic relapse, in whom detection of disease-specific 
abnormalities may predict for subsequent development of hematologic disease 
(28,29); this approach has been tested in only a few patients.
h.  
A few complete responses have been reported in multiple myeloma (21,25,27) but 
very few patients have been treated. In addition, confounding variables (such as 
potential anti-myeloma effects of concomitant alpha-interferon and of steroids 
used to treat GVHD) limit interpretation of responses in myeloma.  Lastly, no 
responses have been reported in non-Hodgkin’s lymphoma or Hodgkin’s Disease 
but very few patients have been treated.
An issue that remains unsettled about DLI is the appropriate cell dose.  A single 3-
hour apheresis generally yields approximately 1-2 x 108 mononuclear cells/kg 
(containing approximately 50-60% T-cells).  The median cell dose in most reports 
has been approximately 4.0 x 108 mononuclear cells/kg. Responses have been 
reported at lower cell doses.  In patients with cytogenetic relapse of CML, 
Mackinnon et al reported responses at CD3+ T-cell doses as low as 1.0 x 10
7/kg 
(20,26).  Other CML patients, however, seemed to require cell doses as high as 5 x 10
8 
CD3+ T-cells/kg.  The degree of minor histocompatibility antigen disparity probably 
differs among different donor-recipient pairs; thus, if the target antigen is a minor 
histocompatibility antigen, then the cell dose resulting in effective GVL might also 
be expected to differ among different pairs.  Cell dose might be especially critical in 
DLI using mismatched family members or unrelated donors.  Infusion from these 
donors of cell doses comparable to the doses given by HLA-matched siblings might 
be more likely to cause severe GVHD. Thus, additional study is needed to assess 
safe doses in the setting of greater HLA-disparity.  The doses and criteria for relapse 
and therapy of CML are listed in the eligibility criteria.  These are based on 
guidelines used by the University of Oregon and the Department of Hematology, San 
Martino Hospital, Genova, Italy (R Maziarz, A Bacigalupo Personal 
Communication).  We will also be using IBMTR criteria (http://www.ibmtr.org/).
The mechanism of response to DLI is uncertain (3). Potential mediators include T 
cells with  T cell receptors, T cells with  receptors, NK cells, and cytokines 
released as a consequence of GVH reactions.  Potential targets include minor 
histocompatibility antigens shared between leukemic and normal host tissue, and 
antigens unique to leukemia cells. Data in the literature do not allow definitive 
conclusions regarding the potential mediators and targets of the anti-tumor activity 
of DLI.  The close correlation of response with GVHD may suggest that GVL is 
mediated by alloreactive T cells directed to minor histocompatibility antigens shared 
between normal and leukemic tissue; however this observation does not rule out 
other explanations, including the mediation of specific GVL by a separate effector 
population. It is likely that appropriate effector cell-target cell interaction involves 
target cell expression of certain cell surface molecules such as MHC class I and II, 
costimulatory molecules, adhesion molecules, and FAS
(30)
APPROVED RPCI IRB
8/7/2017
.  Conceivably assessment 

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 6 of 28
of expression of such cell surface molecules by malignant cells may predict for 
response or lack of response to DLI.
 
Allogeneic cellular therapies such as DLI are associated with life-threatening 
toxicities.  These usually result from the development of GVHD, which results from 
the donor cells recognizing recipient tissues as foreign.  This GVHD reaction can 
result in the need for immunosuppression that can result in infectious complications 
that can lead to mortality.  Thus, this form of therapy must be given in a standard 
way so that results and outcomes of this therapy can be monitored prospectively.  
The protocol is designed and written so that a standard approach to the treatment of 
patients requiring DLI and that the toxicities and outcomes from DLI can be 
monitored.  Toxicity monitoring is mandated for these types of potentially dangerous 
therapies.  A Standard Operating Procedure (SOP) provides a template for how to 
perform tasks; however it does not carry the force and rigor that is required for 
protocol adherence.  The results of DLI are reported to a transplant registry, the 
International Blood and Marrow Transplant Registry (IBMTR) in Wisconsin.  
Patient consent is required for the reportage of clinical outcome information to the 
IBMTR. 
2.0) OBJECTIVES:
2.1)     The primary objective is to determine if the complete response rate exceeds 10%.     
2.2) Estimate the CR response rate.
2.3) To assess toxicity of cellular therapy.
2.4) We will accrue approximately 50 patients over 10 years.
3.0) RECIPIENT ELIGIBILITY CRITERIA:
APPROVED RPCI IRB
8/7/2017
3.1) Age <76.
3.2) Recipients must have an expected survival of at least 8 weeks.
3.3) Patient is not a candidate for repeat allogeneic transplant
3.4) Patients not candidates for repeat allogeneic transplant, chimerism status is not 
necessary for determining DLI eligibility
3.5)
For those patients, eligible for allogeneic BMT but for whom DLI is offered as the
 
first option, the patient should have full donor chimerism at relapse or after 
therapy for relapsed disease.  
3.6) Original hematopoietic progenitor stem cell donor must be available
       for cell donation.
3.7) Minimal or no active GVHD (acute or chronic).

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 7 of 28
APPROVED RPCI IRB
8/7/2017
3.8) The following test results must be reported within 30 days of DLI.  (It is 
recommended that testing be done within 30 days and reported within 7 days):
Absolute exclusion:  
HIV 1 + II antibody
All others will be evaluated by BMT Director:
Hepatitis, B (sAg), and C
HTLV I +
 II
RPR
ABO/Rh and CMV IgG/IgM status must be known
3.9)
Recipient must be able to give informed consent.
3.10) Creatinine must be less than 3mg/dl.
3.10a
Criteria for HLA matching to determine DLI dosing are as
 follows:  
A & B Antigen & DRBI Allele matching qualifies as matched.
Any A, B Antigen or DRBI Allele mismatching is mismatched.
C & DQBI are not considered in the matching Algorithm.
3.11) A patient who has relapse of underlying disease after transplant and achieves 
remission after chemotherapy will be considered for DLI
3.12) Recipients with refractory EBV lymphoproliferative disorders or refractory
 EBV 
infection with associated pancytopenia are eligible for this protocol.  Patients must 
be at least 30 days post allogeneic stem cell transplant.  Conventional therapy 
includes acyclovir and immunoglobulin treatment.  DLI may be given
 with or 
without Rituximab.
3.13) Recipient must be in relapse or have persistent malignancy (see
 below).  For each 
of the hematologic conditions, any of the listed markers for relapse or persistent  
malignancy would be sufficient for relapse or
 persistent disease. For example, in a 
patient with CML, molecular relapse or cytogenetic relapse, or relapse with 
chronic phase/accelerated phase would be sufficient for relapse or persistent 
disease.  These inclusion criteria are standard criteria for “relapse and persistent 
malignancy”.
CML
a) 
molecular relapse- May be treated with Imatinib (Gleevec®). Prior 
to DLI  may go onto DLI without
 Imatinib therapy.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 8 of 28
APPROVED RPCI IRB
8/7/2017
BMT was non-T-cell depleted, a negative bcr/abl by PCR has been 
documented post-allogeneic stem cell transplant and bcr/abl is now 
detectable by 2 consecutive PCR determinations greater than 30 
days apart.
BMT was non-T cell depleted, and bcr/abl is detectable by PCR 
determination at any time after day 180 post-allogeneic stem cell 
transplant.
If patient received Imatinib, the patient should be monitored at 
least 3 months before DLI is given. 
b) 
cytogenetic relapse, after failing
 3-6 months of Gleevec®.
c) 
relapse with chronic-phase, accelerated-phase,
or blastic-phase disease, after failing 3-6 months of Gleevec®.  
Patient must be in chronic or accelerated phase only.  Blastic phase 
patients must attain a second chronic phase.
AML, ALL, or MDS
 (No DLI before day +60 post allogeneic transplant)
molecular relapse evidenced by: 
Less than 5% blasts in the bone marrow 
Patient’s leukemia-specific molecular abnormality is detectable by 
PCR analysis
cytogenetic relapse evidenced by:
Less than 5% blasts in the bone marrow  
Patient’s leukemia-specific chromosome abnormality detectable by 
standard cytogenetics at any time greater than day 60 post-
transplant.
hematologic relapse evidenced by >20% blasts in bone marrow, or soft 
tissue recurrence:
must be treated with chemotherapy before DLI.
Multiple Myeloma (No DLI before
 day +60 post allogeneic transplant)
a)
relapse or recurrence of M-protein after previous post-transplant 
documentation of disappearance of M protein by immunofixation
after Thalidomide or other salvage treatment failure.  
b) 
residual or progressive disease
c)
Rising M-protein level at any time post- transplant at a 3-month 
interval.
Original M-protein detectable at 6 months postransplant
Residual (>5%) plasma cells in bone marrow.
d) 
IPEP is required to show that M-component is the same on day +60 
as pre-transplant

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 9 of 28
Non-Hodgkin’s Lymphoma or Hodgkin’s Disease (No DLI before day +60 after 
Allo SCT)
a) 
relapse or progression of disease must be evidenced within 3 
months prior to a donor lymphocyte
 infusion by physical exam, 
radiographic studies, or molecular studies.  If possible, tumor 
should be re-biopsied to determine histology.  Peripheral blood 
must be assayed for the EBV genome by means of EBV DNA 
testing by PCR, done within 30 days of DLI, if EBV lymphoma is 
suspected.
Epstein-Barr Virus Infection
a)  
viremia associated with pancytopenia
Persistent or refractory pancytopenia accompanied by EBV 
genome detected by PCR in the peripheral blood.  Refractory 
pancytopenia is defined as  poorly responsive to growth factors 
and/or transfusions.
Epstein-Barr Virus Lymphoproliferative
 Disorder
a)  
clonal lymphadenopathy that is refractory to standard therapy with 
acyclovir and immunoglobulin.  
DLI may be given with 
Rituximab.
4.0) EXCLUSION CRITERIA: 
4.1) Pregnant or lactating women.
4.2) KPS less than 60%
4.3) CNS recurrence that is not cleared by standard chemotherapy.  CNS remission 
status must be maintained for two weeks
4.4) Life expectancy of
 less than 8 weeks
4.5) Patients who fail to engraft following allogeneic SCT are not eligible for DLI.
5.0) DONOR ELIGIBILITY CRITERIA
5.1) Original stem cell donor.
 
5.2)
Must be in good general health by history and physical examination and fulfill 
donor criteria as per FACT standards. 
APPROVED RPCI IRB
8/7/2017
We will prefer to use a RPCI clinician for 
donor evaluation and clearance.  The criteria for donation are listed in the BMT 
standard operating procedures. 
(http://internal.roswellpark.org/document_426_317.html)

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 10 of 28
5.3) The following tests must be collected and reported  within 7 days of each
 DLI 
collection:
Absolute Exclusion:
HIV 1 + II antibody
All others will be evaluated by BMT Director:
Hepatitis B (sAg), and C
HTLV I +
 II
RPR
CMV IgG
IgM
ABO/Rhstatus must be known.
All stem cell products will be collected per current FDA Guidances.  Current FDA 
Guidances may be referenced at the following website:
http://www.fda.gov.
5.4)
Must have CBC within normal limits.
5.5)
Must be able to give informed consent.
5.6) Must have negative serum pregnancy test for female donors
 of childbearing age.
5.7) Syngeneic donors are not eligible.
5.8) Must have good peripheral venous access, or be willing to have central venous 
line placement for cell collection.
6.0 
PROCEDURES:
6.1)
DLI Calculation Timeline:  Some patients have cellular infusions on more than 
one day.  A single DLI is defined as all infusions given within a 6 week period 
starting from the date of the first DLI > 60 days following a HSCT or 6 weeks 
post prior DLI.  Separate DLIs are given after this
 6-week period.  For example:
HSCT
           1
st DLI                                                           2nd DLI                                                                         3rd DLI                      
                 0         
                          Weeks       6                      12                         18                      24
  ↔
   > 60 days   |   |   |   |   |  |   |   |    |   |   |    |     |    |    |
  |   |    |   |   |
  |   |    |   |    |
              ⌂  ⌂  ⌂                                     ⌂                                                       ⌂              ⌂
                                 These 3 infusions are                         This infusion is                                                                 These 2 infusions are 
                                 considered  one DLI .                         a second DLI.                                                                    counted as one DLI, 
                                                                                                                                                                                      and  are DLI  #3
                                                                                                                                                                                      in  the Series.
In this example, 6 Infusions = 3 DLI accruals = 3 consents.
Infusions given ≤
APPROVED RPCI IRB
8/7/2017
 6 weeks apart are included as one DLI (one consent).
Infusions > 6 weeks apart will require reconsent and re-enrollment on study.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 11 of 28
6.2) Protocol Date Definitions:
6.3) GvHD Prophylaxis:  Recipients will stop cyclosporine or tacrolimus. Steroids will 
be tapered off over 1-4 weeks as clinically indicated. A period of 2-4 weeks after 
discontinuation of all immunosuppression will be observed before cellular therapy is 
given.  If GVHD flares during this period to >grade II acute GVHD, grade I acute 
GVHD requiring systemic treatment, or any extensive chronic GVHD, the patient should 
not receive cellular therapy for at least one month to evaluate clinical response to new 
GVHD.
6.4  Cellular Therapy:  Cell doses for each infusion are disease-specific.  Please check 
disease categories when determining cell dose and method of collection (see section 
6.3).
6.4.1Phlebotomy will be used for patients receiving low cell doses (1 to 5 x106 
CD3+ cells/kg) Phlebotomy is performed by standard procedures with collection 
into sterile syringe or donor collection blood bags.
The first collection will be approximately 5-20 ml based on peripheral 
blood CD3 determination.
The second collection will be approximately 50-200 ml based on 
peripheral blood CD3 determination.
6.4.2 Leukapheresis procedure will be used for higher cell doses (1 x107 to 1 
x108 CD3+ cells/kg
Donor will sign leukapheresis consent
Peripheral venous access is preferred, but an indwelling pheresis catheter 
may be indicated
As many collections as needed will be done to achieve target dose.
In cases where low cell doses are stipulated by protocol, but it is 
anticipated subsequent doses may be required or the donor may not be 
available, a higher dose may be collected and cryopreserved for potential 
later use, at the physician’s discretion.  
On-Study
 Date
Start Treatment 
Date
Stop Treatment
Date
Off-Study
Date
Date of first DLI 
infusion
Date of first DLI 
infusion
For multiple infusions given <6 weeks 
apart, date of the last infusion in the 
series
Date of disease restaging (~50-100 days 
after the last DLI infusion) or date of 
death due to any cause or date of onset 
of grade 3-4 acute GVHD, whichever 
comes first
APPROVED RPCI IRB
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I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 12 of 28
If the original donor was from the NMDP, the NMDP cellular therapy 
protocol will be used for collection, and the product will be procured and 
given as per RPCI standards.
6.4.3 Cells are not irradiated. If donor and recipient are ABO incompatible, 
RBC packed volume infused should not exceed >3 ml/kg.
6.4.4 Cell Infusion
a. Flow cytometry
 will be done on the product to calculate the CD3
+ (or, T-
cell) dose. 
b. The cell dose will be reviewed with the Transplant Director or designee 
prior to infusion of cells.
c. Cells will be infused according to standard operating procedure, using 
standard blood filter tubing.
d.If necessary, cells can be held overnight at room temperature before 
infusion, kept in autologous plasma as per Processing Laboratory 
standards.
6.4.5 Recipient will not receive post-cellular therapy immunosuppression for 
GVHD prophylaxis.
6.4.6 After the first or subsequent infusion, subsequent DLI will not be given if 
the recipient is in remission without detectable disease and has had clinical 
or pathologic evidence of GVHD within 2 months of the infusion.
6.5)
Disease specific parameters for determining cell dose and content, pre-DLI 
chemo, and timing of infusions:
6.5.1CML 
a.  pre-DLI chemo:   
None required.  Patient may be given Gleevec or 
interferon to induce remission.
b. Cell dose: HLA-matched sib or matched unrelated donor (See 3.10a)
First infusion:  1X106 CD3+ cells/kg
Second infusion:  One month later, if no response, 5x106 CD3+ cells/kg
Third infusion:  One month later, if no response (two months from first 
DLI), 1x107 CD3+ cells/kg
Fourth infusion:  One month later, if no response (three months from first 
DLI), 5x107 CD3
+ cells/kg
c. Cell Dose: HLA-mismatched sib or mismatched unrelated (See 3.10a)
First infusion:  5x105 
APPROVED RPCI IRB
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CD3+ cells/kg

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 13 of 28
Second infusion:  One month later, if no response, 1x106 CD3
+ cells/kg
Third infusion:  One month later, (two months from first DLI), if no 
response,  5x10
6 CD3
+ cells/kg
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 1x10
7 CD3
+ cells/kg.
6.5.2AML, ALL or
 MDS
a. Pre-DLI chemo:  Recipients with molecular or cytogenetic relapse will not 
receive pre-DLI
 chemotherapy.  Patients who are in remission from 
salvage chemotherapy may receive DLI.  Transplant candidates should be 
considered for a second transplant if incomplete donor chimerism present.  
If not a transplant candidate, chimerism status should be know but degree 
of chimerism is not an eligibility criterion.
b. Recipients with hematologic relapse will receive pre-DLI chemotherapy or 
radiation therapy for localized recurrence.  The attending physician will 
determine chemotherapy.  Optimally, DLI will be planned for reinfusion 
10-18 days after the chemotherapy has begun, i.e., when the recipient has 
nadired.  
c. Recipients and donors must meet all eligibility criteria for DLI prior to the 
recipient receiving chemotherapy. 
 
d. Recipients may receive G-CSF post chemo.
e. Cell dose: HLA-matched sib or matched unrelated (See 3.10a)
First infusion:  1x107 CD3
+ cells/kg
Second infusion:  One month later, if no response 5x107 CD3+ cells/kg
Third infusion:  One month later, if no response (two months from first 
DLI), 1x108 CD3+ cells/kg
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 1 x10
8 CD3
+ cells/kg.
f. Cell Dose: HLA-mismatched family or mismatched unrelated (See 
3.10a)
First infusion:  1X106 CD3+ cells/kg
Second infusion:  One month later, if no response,  5X106 CD3
+ cells/kg
Third infusion:  One month later, (two months from first DLI), if no 
response,  1x10
7 CD3
+
APPROVED RPCI IRB
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 cells/kg

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 14 of 28
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 5 x10
7 CD3
+ cells/kg
g.  Infusion day for recipients receiving
 pre-DLI chemo:
Day+10 to 18 after beginning of chemotherapy (consider t1/2 of 
chemotherapy agents to ensure chemotherapy not in system at time of 
DLI).  The first day of pre-DLI chemotherapy is
 counted as day +1.
 
6.5.3NHL or HD
a. Recipients and donors must meet all eligibility criteria for DLI prior to the 
recipient receiving chemotherapy or
 radiation for localized recurrence.
b. Cell dose: HLA-matched sib or matched unrelated (See 3.10a)
First infusion:  1x10
7 CD3
+ cells/kg
Second infusion:  One month later, if no response 5x107 CD3+ cells/kg
Third infusion:  One month later, if no response (two months from first 
DLI), 1x108 CD3+ cells/kg
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 5 x10
8 CD3
+ cells/kg.
c. Cell Dose: HLA-mismatched family or mismatched unrelated (See 
3.10a)
First infusion:  1x106 CD3+ cells/kg
Second infusion:  One month later, if no response,  5x106 CD3
+ cells/kg
Third infusion:  One month later, (two months from first DLI),if no 
response,  1x10
7 CD3
+ cells/kg
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 5 x10
7 CD3
+ cells/kg.
d.Infusion day: 
Day +10 to 18 after beginning of chemotherapy (consider t1/2 of 
chemotherapy agents to ensure chemotherapy not in system at time of 
DLI).  The first day of pre-DLI chemotherapy is
 counted as day +1.
6.5.4Multiple Myeloma
a. Pre-DLI chemo:  None if disease controlled.  Otherwise, may be given 
salvage chemotherapy and cells infused on day + 10 to 18 after the 
beginning of chemotherapy.
b. Cell dose: HLA-matched sib or matched unrelated (See 3.10a)
First infusion:  1x107 CD3
+ cells/kg
Second infusion:  One month later, if no response 5x107 CD3+
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I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
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Page 15 of 28
Third infusion:  One month later, if no response (two months from first        
DLI), 1x108 CD3+ cells/kg
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 5 x10
8 CD3
+ cells/kg.
c. Cell Dose: HLA-mismatched family or mismatched unrelated (See 
3.10a)
First infusion:  1x106 CD3+ cells/kg
Second infusion:  One month later, if no response, 5x106 CD3
+ cells/kg
 Third infusion:  One month later, (two months from first DLI), if no 
response,  1X10
7 CD3+ cells/kg
Fourth infusion:  One month later, (3 months from first DLI) if no 
response, 5 x10
7 CD3
+ cells/kg.
7.0) DISEASE RESPONSE TO DLI:  The response to therapy will be based on the 
response of the underlying disease and not on the basis of the development of 
GVHD.  Disease response for all diseases is defined by the International Bone 
Marrow Transplant Registry (IBMTR) standards as
 follows:  
7.1) CML: 
Hematologic Remission . is described as control of the WBC count.
Cytogenetic Remission, is described when the 9;22 translocation 
becomes undetectable by FISH. 
Molecular Remission, is described when the 9;22chromosome becomes 
undetectable by PCR.
7.2) AML, ALL, MDS:
Complete Remission requires that the following be maintained for at least 4 
weeks.:
The peripheral blood neutrophil count should be >1.5 x 109/L, and 
platelets >100 x 10 9/L.
Bone Marrow Cellularity should be >20% and should contain less than 
5% blast cells.
Extramedullary leukemia, such as CNS or soft tissue involvement, may 
not be present.  
7.3)    NHL or HD:
Complete Remission- Complete disappearance of all known disease.
Complete Remission undetermined
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- as above with the exception of 
persistent scan abnormalities of unknown significance.
7.4)   Multiple myeloma:

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
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Page 16 of 28
CR= Complete Response requires all of the following:
Absence of the original monoclonal paraprotein in serum and urine by 
routine electropheresis and by immunofixation maintained for a minimum 
of 6 weeks. The presence of a new monoclonal band consistent with 
oligoclonal immune reconstitution does not exclude CR.
< 5% plasma cells in bone marrow aspirate and also on trephine bone 
biopsy, if biopsy is performed. If absence of monoclonal protein is 
sustained for 6 weeks it is not necessary to repeat the bone marrow unless 
the patient has had non-secretory myeloma.
No increase in size or number of lytic bone lesions on radiological 
investigations, (development of a compression fracture does not exclude 
response). 
Disappearance of soft tissue plasmacytomas
For plasma cell leukemia, absence of plasma cells in blood.
(Patients in whom some, but not all, the criteria for CR are fulfilled are classified as PR, 
providing the remaining criteria satisfy the requirements for PR. This includes patients whom 
routine electrophoresis is negative but in whom immunofixation has not been performed.)
8.0) TREATMENT RESPONSE:  
Patients are monitored at approximately 2week intervals as clinically indicated
 for:
 
evidence of GVHD 
Disease response , including tumor measurements where indicated
toxicities 
infection 
second malignancies 
survival
9.0)  TREATMENT OF GVHD
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A biopsy of the affected organ should be obtained before initiation of therapy especially for 
cutaneous disease.  In the event that a liver or GI tract biopsy cannot be safely obtained or 
obtained with 48 hours, therapy may start for higher stage and grade GVHD as defined 
below.
For stages and grades of GVHD, topical steroids or tacrolimus may be used for initial 
treatment without delay.
9.1) AGVHD Gr I
 Monitor without systemic therapy 

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
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Page 17 of 28
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9.2 
AGVHD Gr II
Monitor for 1 week after onset of symptoms.  
If Gr II persists for 1 week or worsens, treat with tacrolimus or cyclosporine to 
maintain a whole blood level of 5 to 10 ng per ml for tacrolimus and 200 to 350 ng 
per ml for cyclosporine.
If Gr II persists for 1 week or worsens, add intravenous methylprednisolone at 1 to 2 
mg per kg or the equivalent of oral methylprednisolone, prednisone or other 
glucocorticoid.
9.3 
AGVHD gr III and IV
Treat with methylprednisolone 2 mg/kg/d with tacrolimus or cyclosporine to 
maintain a whole blood level of 5 to 20 ng per ml for tacrolimus and 200 to 450 ng 
per ml for cyclosporine.
AGVHD not responding to initial therapy may be treated as per institutional SOP.
9.4
CGVHD-limited or extensive without GI tract or liver involvement
Treat with tacrolimus or cyclosporine to maintain a whole blood level of 5 to 10 ng 
per ml for tacrolimus and 200 to 350 ng per ml for cyclosporine.
If Gr II persists for 2-4 week or worsens, add intravenous methylprednisolone at 1 
to 2 mg per kg or the equivalent of oral methylprednisolone, prednisone or other 
glucocorticoid.
9.5 
CGVHD-extensive- (with GI tract or Liver involvement)
Treat with tacrolimus or cyclosporine to maintain a whole blood level of 5 to 10 ng 
per ml for tacrolimus and 200 to 350 ng per ml for cyclosporine and intravenous 
methylprednisolone at 1 to 2 mg per kg or the equivalent of oral 
methylprednisolone, prednisone or other glucocorticoid.
CGVHD not responding to initial therapy may be treated as per institutional SOP.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
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Page 18 of 28
10.0)  REMOVAL OF PATIENTS FROM PROTOCOL AND ADVERSE EVENT 
          REPORTING (AER):
10.1) Removal from protocol:  
If the patient experiences uncontrolled Graft Versus Host Disease, CTC Grade 
4 toxicity and/or the patient no longer wishes to continue protocol therapy, the 
patient will be removed from the protocol.  In this event the reason for 
withdrawal will be documented and the patient will be followed for survival. 
Any patient with rapid disease progression will not receive subsequent DLI.   
10.2) Toxicity Reporting:
10.2.1) Expected toxicity: (recorded in protocol consent form or there is no 
literature).
Within 10 days of occurrence, written reports should be submitted to 
the IRB and the protocol chairman in the following circumstances 
(Bearman toxicity).
Any fatal toxicity.
Any non-hematologic grade 3 toxicity
For AML, ALL, MDS recipients:  slow count recovery post 
chemotherapy will be documented.
Acute GVHD, Grade 3 - 4    
10.2.2) Unexpected toxicity: All instances of Bearman grade 3-4 toxicity will 
be reported to the IRB and the protocol chairman immediately by 
telephone and followed by a written report. 
11.0) STATISTICAL CONSIDERATIONS:
Patients who have multiple DLIs with infusions <6 weeks apart will count as one accrual, 
with one assessment of toxicity and response.  Patients who have multiple DLIs with 
infusions >=6 weeks apart will count as multiple accruals, with each infusion having an 
assessment of toxicity and response. The response to each DLI is independent if the patient 
had an intervening event (disease progression or relapse) that indicated further treatment.
Let p= the proportion of patients from the heterogeneous population (AML, ALL, CML, 
NHL, MM patients) who achieve a complete response, CR.  If it can be determined that 
p>0.1, then continued use of the proposed therapy will be justified.  The binomial 
distribution will be used to test Ho: p = 0.1 versus H
1: p>0.1.  If the probability of 
erroneously concluding H
1 is set to be 0.05 and the probability is at least 0.80 of correctly 
concluding H
1 when p =0.25, then a sample of n =50 patients is required.  That is, if the 
significance level of the test is fixed to be  =0.05 and if the power of the test at 0.25 is 
required to be at least 0.80, then 50 
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patients must be accrued.  Let S = the number patients 

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
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Page 19 of 28
out of 50 that have a CR.  If S > 13, then H
1 will be concluded.  The actual significance 
level and power of this test are 0.05 and 0.815 respectively. 
All 50 patients will be accrued even if the determination that S > 4 is made prior to the 
accrual of the 50
th patient to increase the precision of the estimator of p.  Past accruals at 
RPCI suggest that there will be 6 to 10 DLIs per year available to accrue to this study.  
Based on these data, this study will accrue patients for 6 to 10 years.
12.0)  STUDY ENDPOINTS
12.1) The primary endpoint for the study is evaluating response rate, percent of 
complete responses, and duration of response.
12.2) The secondary endpoint is evaluation of the toxicity of cellular therapy.
13.0) DATA AND SAFETY MONITORING PLAN:
The Principal Investigator (PI) will be responsible for continuous monitoring of the 
safety of the study.  This monitoring is accomplished by the following:
Patient Outcomes Rounds are held weekly on the transplant unit, at which time all BMT 
(patients receiving cellular therapy are followed as BMT patients) patient care is reviewed, 
including:

medications (chemotherapy for conditioning regimens; prophylactic, empiric and 
therapeutic antimicrobials; graft-versus-host disease prophylactic and therapeutic 
medications; and possible drug interactions).

adverse events and/or adverse reactions to any medication, procedure,  or other treatment; 
reports are filed according to RPCI policy and procedure.

regimen-related toxicity, based on Bearman toxicity grading, and/or Common Toxicity 
Criteria (CTC) if the toxicity does not correlate with a Bearman grade.

 indications for additional testing or therapies such as biopsies, scans or x-rays.

a properly signed and dated transplant consent.

compliance issues that could compromise patient safety.

other aspects of safety monitoring as prescribed by the BMT Standards of Care and common 
clinical practice. 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.  

Monitoring will be done according to BMT standard operating procedures: 
http://internal.roswellpark.org/document_426_317.html/
The BMT Quality Assurance plan requires quarterly reporting to the BMT Quality 
Assurance Committee, which in turn reports to the hospital Quality Assurance Committee.  
Indicators for BMT patient safety monitoring include:

Patient complaints

Adverse events and serious adverse events

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Bearman and CTC toxicity grades 3 and 4

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 20 of 28

Variances in the delivery of standard care

Readmissions prior to day +100 post transplant

Deaths occurring prior to day +100 post transplant

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Engraftment
Followup on all transplant patients is continued even after they have returned to the care of 
their referring physicians.  A Long Term Transplant Clinic has been established, which 
provides care for allogeneic patients with chronic complications, as well as assessments to 
identify dental, bone, and psychosocial complications.
All outcomes are reported to the International Bone Marrow Transplant Registry (IBMTR) 
the Autologous Bone Marrow Transplant Registry (ABMTR), and the National Marrow 
Donor Program (NMDP).  Registry reports are reviewed internally prior to submission to 
the respective registry.  These data are also entered into the RPCI BMT Database, from 
which patient outcomes are assessed and reviewed on a regular basis.  Regimen-related 
toxicities reported in this fashion have resulted in a number of changes to transplant 
protocols since 1997, thus decreasing toxicity and improving outcomes in a number of 
patient groups.  
Registry reports also establish the efficacy of treatment as measured by overall best response 
to transplant at day +100 and on subsequent annual reports.  The patients’ medical records 
serve as original source documents for all reporting. Audits are conducted every two to three 
years by the IBMTR and ABMTR, and
 the NMDP.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
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Page 21 of 28
References
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:
1. 
Barnes D, Louti J, Neal F.  Treatment of murine leukemia with x-rays and homologous 
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2.  
Truitt RL, LeFever AV, Shih CC-Y, Jeske JM, Martin TM. Graft-vs-leukemia effect.  In:        
Burakoff SJ, Deeg HJ, Ferrara J, Atkinson K, (eds): Graft-vs-Host Disease. Immunology, 
Pathophysiology, and Treatment. New
 York, NY, Marcel Dekker, Inc., p 177-204, 1990.
3. 
Truitt R, Johnson B. Principles of graft-vs.-leukemia reactivity. Biology of Bone and 
Marrow Transplant 1:61-68, 1995.
4. 
Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, The Seattle Marrow 
Transplant Team: Antileukemic effect of chronic graft-versus-host disease.  Contribution 
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5. 
Gale RP, Champlin RE. How does bone-marrow transplantation cure leukemia? Lancet 
2:28-30, 1984. 
6. 
Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone 
marrow transplantation. Blood 75:555-562, 1990. 
7. 
Jones RJ, Ambinder RF, Piantadosi S, Santos GW:  Evidence of a graft-versus-lymphoma 
effect associated with allogeneic bone marrow transplantation.  Blood 1991, 77(3):649-
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8. 
Ratanatharathorn V, Uberti J, Karanes et al: Prospective comparative trial of autologous 
versus allogeneic bone marrow transplantation in patients with non-Hodgkin’s 
lymphoma.  Blood 84(4):1050-1055, 1994.
9. 
Petersen FB, Applebaum FR, Bigelow CL et al. High-dose cytosine arabinoside, total 
body irradiation and marrow transplantation for advanced malignant lymphoma.  Bone 
Marrow Transplant 1989, 4:483-488.
10. 
Higano CS, Brixey M, Bryant EM et al.  Durable complete remission of acute 
nonlymphocytic leukemia associated with discontinuation of immunosuppression 
following relapse after allogeneic bone marrow transplantation.  A case report of a 
probable graft-versus-leukemia effect. Transplantation 1990, 50:175-177. 
11. 
Collins RH, Rogers ZR, Bennett M, Kumar V, Nikein A, Fay JW.  Hematologic relapse 
of chronic myelogenous leukemia following allogeneic bone marrow transplantation: 
apparent graft-versus-leukemia effect following abrupt discontinuation of 
immunosuppression. Bone Marrow Transplant 1992, 10: 391-395. 

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 22 of 28
12. 
Kolb HJ, Mittermuller J, Clemm C et al. Donor leukocyte transfusions for treatment of 
recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462-
2465, 1990.
 
13. 
Bar BMAM, Schattenberg A, Mesnick EJBM et al.  Donor leukocyte infusions for 
chronic myeloid leukemia after allogeneic bone marrow transplantation. J Clin Oncol 
11:513-519, 1993. 
14. 
Drobyski WR, Keever CA, Roth MS et al.  Salvage immunotherapy using door leukocyte 
infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone 
marrow transplantation: Efficacy and toxicity of a defined T-cell dose. Blood 82:2310-
2318, 1993.
15. 
Hertenstein B, Wiesneth M, Novotny J, Bunjes D, Stefanic M, Heinze B, Hubner G, 
Heimpel H, Arnold R.  Interferon- and donor buffy coat transfusions for treatment of 
relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation.  
Transplantation 56(5):1114-1118, 1993.
16. 
Szer J, Grigg AP, Phillips GL, Sheridan WP.  Donor leucocyte infusions after 
chemotherapy for patients relapsing with acute leukemia following allogeneic BMT. 
Bone Marrow Transplant 11:109-111, 1993. 
17. 
Helg C, Roux E, Beris P et al. Adoptive immunotherapy for recurrent CML after BMT. 
Bone Marrow Transplant 12:125-129, 1993. 
18.
Porter DL, Roth MS, McGarigle C, Ferrara JLM, Antin JH.  Induction of graft-versus-
host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 
330:100-106, 1994. 
19. 
Van Rhee F, Lin F, Cullis JO et al. Relapse of chronic myeloid leukemia after allogeneic 
bone marrow transplant: the case for giving donor leukocyte transfusions before the onset 
of hematologic relapse. Blood 83; 3377-3383, 1994.
20. 
Mackinnon S, Papadopoulos E, Carabasi MH, Reich L, Collins NH, Boulad F, Castro-
Malaspina HC, Childs BH, Gillio AP, Kernan NA, Small TN, Young JW, O’Reilly RJ. 
Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of 
chronic myeloid leukemia after bone marrow transplantation:  separation of graft-versus-
leukemia responses from graft-versus-host disease. Blood 86:1261-1268, 1995.
21. 
Collins R, Pieiro L, Nemunaitis J, Jain V, Waxman D, Miller W, Fay J.  Donor buffy 
coat infusion in the treatment of persistent or recurrent malignancy after allogeneic bone 
marrow transplantation.  Transfusion 35:891-898, 1995.
 22. Giralt S, Hester J, Huh Y, Hirsch-Ginsberg C, Rondn G, Seong D, Lee M, Gajewski J, 
Besien KV, Khouri I, Mehra R, Przepiorka D, Krbling
APPROVED RPCI IRB
8/7/2017
 M, Talpaz M, Kantarjian H, 
Fischer H, Deisseroth A, Champlin R. CD8-depleted donor lymphocyte infusion as 

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 23 of 28
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treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow 
transplantation. Blood 86:4337-4343, 1995.
23. 
Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versus-Leukemia effect of donor 
lymphocyte transfusions in marrow grafted patients.
  Blood 86(5):2041-2050, 1995.
24. 
Slavin S, Naparstek E, Nagler A, et al.  Allogeneic cell therapy with donor peripheral 
blood cells and recombinant human interleukin-2 to treat leukemia relapse after 
allogeneic bone marrow transplantation.  Blood 87:2195-2204, 1996.
25. 
Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-
myeloma effect:  proof of principal. Blood 87(3):1196-1198, 1996.
26. 
Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L, Collins NH, Boulad F, Castro-
Malaspin H. Childs B,Gillio A, Hernan NA, Small T, Young J, O’Reilly RJ. Donor 
leukocyte infusions for molecular or cytogenetic relapse of CML following allogeneic 
BMT:  graft-versus-leukemia responses with minimal toxicity. Blood 86(10):566a, 1995.
27. 
Collins R, Shpilberg O, Drobyski W et al. Donor leukocyte infusion in 140 patients with 
relapsed malignancy after allogeneic bone marrow transplantation. (submitted for 
publication)
28. 
Mackinnon S, Heller G. The polymerase chain reaction is highly predictive of relapse 
following T-cell depleted allogeneic BMT for CML and identifies patients who may 
require immunotherapy with donor leukocytes.  Blood 86(10):292a, 1995.
29. 
Radich JP, Gehly G, Gooley T et al. Polymerase chain reaction detection of the brc-abl 
fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia:  
Results and implication in 346 patients.  Blood 85(9):2632-2638, 1995.
 
30. 
Guinan EC, Gribben JG, Boussiotis VA et al. Pivotal role of the B7:CD28 pathway in 
transplantation tolerance and tumor immunity.  Blood 84(10):3261-3282, 1994.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 24 of 28
Appendix no. I
Bearman* criteria for toxicity grading
Grade I
Grade II
Grade III
Cardiac
Mild EKG abnormality, not requiring medical 
intervention; or noted heart enlargement on CXR 
with no clinical symptoms
Moderate EKG abnormalities requiring and 
responding to medical intervention; or 
requiring continuous monitoring without 
treatment; or congestive heart failure 
responsive to digitalis or diuretics
Severe EKG abnormalities with no or only 
partial response to medical intervention; or 
heart failure with no or only minor response 
to medical intervention; or decrease in 
voltage by more than 50%
Bladder
Macroscopic hematuria after 2 days from last 
chemotherapy dose with no subjective symptoms 
of cystitis and not caused by infection
Macroscopic hematuria after 7 days from last 
chemotherapy dose not caused by infection; 
or hematuria after 2 days with subjective 
symptoms of cystitis not caused by infection
Hemorrhagic cystitis with frank blood, 
necessitating invasive local intervention with 
installation of sclerosing agents, nephrostomy 
or other surgical procedure
Renal
Increase in creatinine up to twice the baseline 
value (usually the last recorded before start of 
conditioning)
Increase in creatinine above twice baseline 
but not requiring dialysis
Requirement of dialysis
Pulmonary
Dypsnea without CXR changes not caused by 
infection or congestive heart failure; or CXR 
showing isolated infiltrate or mild interstitial 
changes without symptoms not caused by 
infection or congestive heart failure
CXR with extensive localized infiltrate or 
moderate interstitial changes combined with 
dyspnea and not caused by infection or CHF; 
or decrease of PO2 (>10% from baseline) but 
not requiring mechanical ventilation or > 
50% O2 on mask and not caused by infection 
or CHF
Interstitial changes requiring mechanical 
ventilatory support or >50% oxygen on mask 
and not caused by infection or CHF
Hepatic
Mild hepatic dysfunction with bili > 2.0 mg% 
but  < 6.0 mg %; or weight gain > 2.5 % and 
< 5 % from baseline of noncardiac origin; or 
SGOT increase more than 2-fold but less than 5-
fold from lowest preconditioning
Moderate hepatic dysfunction with bili >6 
mg% < 20 mg %; or SGOT increase with 
> 5-fold from preconditioning; or clinical 
ascites or image documented ascites > 100ml; 
or weight gain > 5% from baseline of 
noncardiac origin
Severe hepatic dysfunction with bili 
> 20 mg %; or hepatic encephalopathy; or 
ascites compromising respiratory function
CNS 
Somnolence but the patient easily arousable and 
oriented after arousal
Somnolence with confusion after arousal; or 
other new objective CNS symptoms with no 
loss of consciousness not more easily 
explained by other medication, bleeding, or 
CNS infection
Seizures or coma not explained by other 
medication, CNS infection, or bleeding
Stomatitis
Pain and/or ulceration not requiring a continuous 
IV narcotic drug
Pain and/or ulceration requiring a continuous 
IV narcotic drug
Severe ulceration and/or mucositis requiring 
preventive intubation; or resulting in 
documented aspiration pneumonia with or 
without intubation
NOTE:  Grade IV regimen-related toxicity is defined as fatal toxicity
*Bearman Sl et al. Regimen Related Toxicity in Patients Undergoing Bone Marrow Transplantation. JCO 1988, 6(10); 1562-15
GI
Watery stools > 500 ml but < 2,000 ml every day 
not related to infection
Watery stools > 2,000 ml every day not 
related to infection; or macroscopic 
hemorrhagic stools with no effect on 
cardiovascular status not caused by infection; 
or subileus not related to infection
Ileus requiring nasogastric suction and/or 
surgery and not related to infection; or 
hemorrhagic enterocolitis affecting 
cardiovascular status and requiring 
transfusion
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Appendix no.  II 
                  
CRITERIA FOR ACUTE GRAFT-VS-HOST DISEASE
Clinical staging of acute graft-vs.-host disease according to organ involvement
STAGE
SKIN
LIVER
INTESTINAL TRACT
0
No rash
Bilirubin
< 2.0 mg/dL
< 34µmol/L
Diarrhea
500 ml/day
+
Maculopapular rash
<25% of body surface
Bilirubin
2-2.9 mg/dL
34-50 µmol/L
Diarrhea
500-1000 ml/day
++
Maculopapular rash
25-50% of body surface
Bilirubin
3.0-6.0 mg/dL
51-102 µmol/L
Diarrhea
1000-1500 ml/day
+++
> 50% body surface
Bilirubin
6.1-15 mg/dL
103-255 µmol/L
Diarrhea
1500 ml/day
++++
Generalized erythroderma
with bullous formation
and desquamation
Bilirubin
> 15 mg/dL
> 255 µmol/L
Severe abdominal pain 
with or without ileus
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Clinical grading of severity of acute graft-vs-host disease
GRADE
DEGREE OF ORGAN INVOLVEMENT
I
+ to ++skin rash; 
no gut involvement; 
no liver involvement; 
no decrease in clinical performance
II
+ to +++ skin rash;
+ gut involvement or
+ liver involvement (or both);
mild decrease in clinical performance
III
++ 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
APPROVED RPCI IRB
8/7/2017
Source:  Thomas et al, N Engl. J Med. 1975; 292, 832

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 27 of 28
Appendix no. III
       Clinical Grading of Chronic GVHD
APPROVED RPCI IRB
8/7/2017
Limited Chronic GVHD:
1. Localized skin involvement,
and/or
2.
Hepatic dysfunction due to chronic GVHD.
Extensive Chronic GVHD:
1.
Generalized skin involvement, or
2. Localized skin involvement and/or hepatic dysfunction due to 
chronic GVHD
Plus
3a. Liver histology showing chronic aggressive hepatitis, bridging 
necrosis, or cirrhosis, or 
3b.Involvement of eye (Schirmer’s test with less than 5 mm 
wetting), or
3c.Involvement of minor salivary glands or oral mucosa 
demonstrated on labial biopsy, or
                             3d.  Involvement of any other
 target organ.

I 00703 Cellular Infusions in Patients with Recurrent or Persistent  Hematologic Malignancies
 After Allogeneic Stem 
Cell Transplant.
Rev. 8/27/12, V.13
Page 28 of 28
Appendix no.  IV
                           Karnofsky Performance Status (KPS)
KPS
DEFINITION
100 Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or
 do active work
60
Requires occasional assistance, but is able to care for most personal needs
50
Requires considerable assistance and frequent medical care 
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
APPROVED RPCI IRB
8/7/2017