Clinical trial NCT00003816
Conditions: Chronic Myeloproliferative Disorders Leukemia Lymphoma Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases Nonmalignant Neoplasm Unspecified Adult Solid Tumor, Protocol Specific Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: recurrent childhood acute lymphoblastic leukemia recurrent cutaneous T-cell non-Hodgkin lymphoma Burkitt lymphoma Waldenstrom macroglobulinemia recurrent childhood lymphoblastic lymphoma recurrent childhood acute myeloid leukemia recurrent adult acute myeloid leukemia recurrent adult acute lymphoblastic leukemia relapsing chronic myelogenous leukemia refractory chronic lymphocytic leukemia chronic phase chronic myelogenous leukemia accelerated phase chronic myelogenous leukemia blastic phase chronic myelogenous leukemia adult acute myeloid leukemia in remission adult acute lymphoblastic leukemia in remission childhood acute myeloid leukemia in remission childhood acute lymphoblastic leukemia in remission polycythemia vera essential thrombocythemia refractory anemia refractory anemia with excess blasts refractory anemia with excess blasts in transformation chronic myelomonocytic leukemia T-cell large granular lymphocyte leukemia acute undifferentiated leukemia recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse large cell lymphoma recurrent adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma recurrent adult Burkitt lymphoma recurrent adult T-cell leukemia/lymphoma secondary acute myeloid leukemia de novo myelodysplastic syndromes previously treated myelodysplastic syndromes secondary myelodysplastic syndromes prolymphocytic leukemia intraocular lymphoma recurrent childhood small noncleaved cell lymphoma recurrent childhood large cell lymphoma recurrent mantle cell lymphoma angioimmunoblastic T-cell lymphoma anaplastic large cell lymphoma recurrent mycosis fungoides/Sezary syndrome primary myelofibrosis childhood chronic myelogenous leukemia atypical chronic myeloid leukemia myelodysplastic/myeloproliferative disease, unclassifiable recurrent marginal zone lymphoma recurrent small lymphocytic lymphoma extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone B-cell lymphoma splenic marginal zone lymphoma adult acute myeloid leukemia with t(8;21)(q22;q22) adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with 11q23 (MLL) abnormalities adult acute myeloid leukemia with t(15;17)(q22;q12) childhood myelodysplastic syndromes aplastic anemia unspecified adult solid tumor, protocol specific unspecified childhood solid tumor, protocol specific
Sponsor: Roswell Park Cancer Institute
Start date: 1998-10-19; Completion date: 2019-07-12
Enrollment: 361 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Giving chemotherapy drugs and total-body irradiation before a donor stem cell helps stop the growth of cancer or abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known which combination chemotherapy regimen is most effective when given before a donor stem cell transplant in treating aplastic anemia or hematologic cancer.

PURPOSE: This phase II/III trial is studying different combination chemotherapy regimens to compare how well they work when given before donor stem cell transplant in treating patients with aplastic anemia or hematologic cancer.

Detailed description:
OBJECTIVES:

* Compare the morbidity, mortality, and overall outcome of patients with severe aplastic anemia or hematologic malignancy treated with standard vs novel conditioning regimens followed by allogeneic stem cell transplantation.
* Examine the influence of donor histocompatibility on outcome by comparing matched/related, mismatched/related (with or without T-cell depletion), and matched/unrelated transplants with stratification for type of preparative regimen.
* Ensure that patients with uncommon diagnoses will be treated in a uniform fashion with the best therapy available.

OUTLINE: Patients are stratified according to risk of relapse (standard-risk: acute leukemia in first complete remission, chronic myelogenous leukemia in first chronic phase, lymphoma in sensitive first relapse or second remission, primary or untreated myelodysplastic syndromes, or untreated severe aplastic anemia vs high-risk: all others).

Patients are assigned to one of the following conditioning regimens based on diagnosis, risk of relapse, and donor relatedness:

* Regimen 1: Patients receive busulfan IV over 2 hours every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.
* Regimen 2: Patients receive cyclophosphamide IV over 2 hours on days -5 to -2 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -3.
* Regimen 3: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and total-body irradiation (TBI) twice daily on days -3 to -1.
* Regimen 4: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 1 hour on days -3 and -2.
* Regimen 5: Patients receive etoposide IV over 26 hours beginning on day -5, cyclophosphamide IV over 2 hours on day -4, and TBI twice daily on days -3 to -1.
* Regimen 6: Patients receive cyclophosphamide IV over 24 hours, carboplatin IV over 24 hours, and thiotepa IV over 24 hours on days -7 to -4.
* Regimen 7: Patients receive fludarabine IV over 30 minutes on days -5 to -1 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -2.
* Regimen 8: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4, TBI twice daily on days -3 to -1, and anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.
* Regimen 9: Patients receive busulfan IV over 2 hours every 6 hours and anti-thymocyte globulin IV over 4-8 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.

All patients then receive donor stem cell infusions on day 0. Some patients may undergo involved-field radiotherapy 4-8 weeks after transplant.

Patients will be taken off study after a minimum of 4 years of follow up.

PROJECTED ACCRUAL: At least 405 patients will be accrued for this study within 5 years.

Arms: arm 1: Patients receive busulfan IV over 2 hours every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. arm 2: Patients receive cyclophosphamide IV over 2 hours on days -5 to -2 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -3. arm 3: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and total-body irradiation (TBI) twice daily on days -3 to -1. arm 4: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 1 hour on days -3 and -2. arm 5: Patients receive etoposide IV over 26 hours beginning on day -5, cyclophosphamide IV over 2 hours on day -4, and TBI twice daily on days -3 to -1. arm 6: Patients receive cyclophosphamide IV over 24 hours, carboplatin IV over 24 hours, and thiotepa IV over 24 hours on days -7 to -4. arm 7: Patients receive fludarabine IV over 30 minutes on days -5 to -1 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -2. arm 8: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4, TBI twice daily on days -3 to -1, and anti-thymocyte globulin IV over 4-8 hours on days -3 to -1. arm 9: Patients receive busulfan IV over 2 hours every 6 hours and anti-thymocyte globulin IV over 4-8 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.
Interventions: intervention 1: anti-thymocyte globulin intervention 2: busulfan intervention 3: carboplatin intervention 4: cyclophosphamide intervention 5: etoposide intervention 6: fludarabine phosphate intervention 7: melphalan intervention 8: thiotepa intervention 9: total-body irradiation
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV intervention 8: Given IV intervention 9: Given twice daily for 3 days

Protocol documents:
Prot_SAP_000.pdf: 
Protocol No. RP 98-15
Rev September 27 2018
 Page 1 of 33
Protocol Number:
RP 98-15
Protocol Title:
ALLOGENEIC BLOOD OR MARROW TRANSPLANTATION FOR 
HEMATOLOGIC MALIGNANCY AND APLASTIC ANEMIA
NCT00003816
Principal Investigator:
Philip McCarthy, M.D. 
Roswell Park Cancer Institute 
Elm and Carlton Streets 
Buffalo, New York 14263
Amendment of September 27, 2018
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 Institute). 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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Protocol Number:
RP 98-15
Protocol Title:
ALLOGENEIC BLOOD OR MARROW TRANSPLANTATION FOR 
HEMATOLOGIC MALIGNANCY AND APLASTIC ANEMIA
Table of Contents
Page
Protocol Summary
  3
1.0
Introduction
  5
2.0
Objectives
10
3.0
Eligibility Criteria
12
4.0
Registration
14
5.0
Treatment Plan
14
6.0
Drug Formulation
17
7.0
Potential Toxicity
17
8.0
Data and Safety Monitoring Plan
20
9.0
Removal of Patients from Protocol
21
10.0
Required Data
22
11.0
Response Criteria
23
12.0
Statistical Considerations
23
References
25
Appendices
1.
Calculation of Ideal and Adjusted Body Weight
28
2.
Bearman Criteria for Grading Toxicity
29
3  
Criteria for Acute Graft-vs-Host Disease
30
4    IPSS for MDS
31
5.
Calculation of Body Surface Area and KPS/Lansky Scores
32
                    6.    Definitions:  On/Off Study dates, On/Off Treatment dates
33
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Protocol Summary
Patient Eligibility
1.
Diagnosis of aplastic anemia or histologically documented hematologic malignancy
2.
The new World Health Organization (WHO) criteria will be gradually adopted for use in 
classification of hematologic malignancies.
3.
Disease Status
Aplastic Anemia 
severe disease indicated by marrow cellularity:  <25% (or 25-50% cellularity with 
<30% of remaining cells hematopoietic in origin), or 
abnormal peripheral blood counts (2 of 3 values):  reticulocytes <1% (corrected 
for hematocrit), platelets <20 x 109/L, neutrophils <0.5 x 109/L.
Acute Leukemia
resistant or recurrent disease after combination chemotherapy with at least one 
standard regimen
first remission patients at high risk of relapse
AML - antecedent myelodysplastic syndrome, secondary AML, high risk cytogenetic 
abnormalities
ALL - high risk cytogenetic abnormalities
patients in first remission without adverse prognostic factors may be transplanted after 
discussion and agreement of the transplant team. 
Chronic Myeloid Leukemia (CML)
Chronic or accelerated
Patients in blast phase should be treated with TK (Tyrosine Kinase Inhibitors) as first 
line therapy and/or one standard chemotherapy regimen
Myeloproliferative and Myelodysplastic Syndromes:  Myelofibrosis, Refractory Anemia, 
Refractory Anemia with Excess Blasts, Refractory Anemia with Excess Blasts in 
Transformation, Chronic Myelomonocytic Leukemia.  Patients with P. Vera or Essential 
Thrombocytosis will be eligible for transplant only if they are in transformation to AML or 
MDS.
Lymphoproliferative diseases: 
Waldenstrom's Macroglobulinemia, low-grade Non Hodgkin Lymphoma -  recurrent 
or persistent, symptomatic disease after first-line chemotherapy.
CLL patients with <20% marrow involvement pretransplant will be treated on 
appropriate non-myeloablative transplant protocols.  CLL patients with >20% marrow 
involvement pretransplant will be eligible for this protocol and receive full-ablative 
therapy.
Multiple Myeloma patients will be treated on appropriate non-myeloablative transplant 
protocols.
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Non-Hodgkin Lymphoma: intermediate and high grade
resistant or recurrent disease after combination chemotherapy with one standard regimen
first remission lymphoblastic or small, non-cleaved cell lymphoma at high risk of relapse
CNS disease, or BM disease and LDH >300
4.
Histocompatible donor identified.  For unrelated donors, the compatibility criteria of the National 
Marrow Donor Program must be satisfied.  If a compatible cord blood (CB) donor is identified 
and there is no suitable unrelated donor, the patient may receive a CB transplant (CBT) .  For 
CBT patients, that acute leukemia patients should be in remission.
5.
Autologous marrow transplant not possible (or not desirable)
history of marrow tumor (a relative contraindication to autologous transplantation)
inadequate marrow dose
abnormal marrow histology or function prior to storage
thrombocytopenia, leukopenia
marrow cellularity <20%
6.
Zubrod performance status 0-2 (Karnofsky > 70%)
For myeloablative regimens

No KPS requirement for failure to engraft transplants and Reduced Intensity Conditioning 
with FluMel
7.
Age > 4, < 70 years.
8.
No serious concomitant medical or psychiatric illness 
9. 
Not pregnant
10.
Informed consent
Required Laboratory Data (see section 3.0 for full eligibility criteria)
1.
DLCO ≥50% predicted, corrected for HgB or DLVA alveolar ventilation
2.
Cardiac ventricular ejection fraction (MUGA scan or echocardiogram) ≥ 50%
3.
Bili, Alk phos, SGOT < 3 x normal, unless due to disease
4.
Creatinine clearance (CrCl) is > 50 ml/min by 24 hour urine collection or by CrCl calculation 
5.
HIV screening negative, according to current RPCI Blood Bank Criteria
6.
CMV and  hepatitis status known
7.
If evidence of active viral infection, infectious disease clearance is required
Study Outline
1.
Registration:  Contact the BMT Coordinator at extension 8963, 3868, 8927, 4192, or 8205 to 
register patient.  
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2.
Preliminary cytoreductive chemotherapy, if indicated
3.    Involved-field radiation, if indicated 
4. Transplant Regimens: (Abbreviations:  C or Cy – Cyclophosphamide; T or TBI - Total Body 
Irradiation; Bu – Busulfan; M – Melphalan; Flu – Fludarabine; V or VP-16 - Etoposide; ATG – 
Antithymocyte Globulin) (See section 5 for details)
a.
CATG
b. FluM
c.
FluATG
1.
INTRODUCTION
1.1.
Since its introduction into clinical practice in 1968, bone marrow transplantation (BMT) has become 
the treatment of choice for severe aplastic anemia (SAA) and chronic myelocytic leukemia (CML), 
and it plays an important role in the management of other hematologic malignancies offering the 
possibility of long-term remission or cure for patients who have failed first-line therapy and are 
unlikely to be cured by other means (1).  For all indications, more than 48,000 transplants have been 
reported to the International Bone Marrow Transplant Registry through 6/1/96. (2)
1.2.
SAA is fatal in 80% of cases treated with supportive measures alone (3).  Immunosuppressive therapy 
with antithymocyte globulin leads to complete recovery in approximately 20% of patients and partial 
recovery (without the need for further transfusions) in a similar number; overall 5-yr. survival is 60% 
(4).  Survival after allogeneic BMT is age dependent (5-7):
Age (yrs)
Survival  
 < 20 
   75%
  20-30
   60%
 >30
   40%
The chief complication of BMT for SAA is graft vs. host disease (GvHD) which is  fatal (or leads to 
fatal infection) in approximately 20% of patients.  Other problems are graft rejection (which can 
occur in up to 20% of cases), infection (without GvHD), and hemorrhage.  The best results reported 
for BMT indicate a 10-yr. survival of 82% in  a group of untransfused patients (age 3-32 years) (5).  
The improvement in outcome for untransfused patients is largely due to reduced risk of marrow graft 
rejection.  For patients with prior transfusions similar results may be achieved by the addition of total 
lymphoid irradiation (TLI) or total body irradiation (TBI) to the usual high-dose cyclophosphamide 
regimen (7,8).  With these approaches rejection has become less frequent in the group of patients who 
have had multiple transfusions and survival has improved to 60-70%.  Although the addition of 
radiation may reduce the incidence of the rejection, there are other associated risks.  Irradiation may 
cause late cancers (8a,8b) as well as problems with growth, development and fertility (8c).  Recently 
published data suggest that Cyclophosphamide combined with antithymocyte globulin (ATG) may be 
a more effective regimen than Cyclophosphamide alone in patients who have received multiple 
transfusions without the attendant risks associated with irradiation.  In a report from the Seattle group, 
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39 patients who received the combination of Cyclophosphamide and ATG had a 3 year survival  of 
92% vs. 72% in historically treated patients who received Cyclophosphamide alone (8d).  The 
incidence of chronic graft versus host disease of 32% and the low incidence of graft failure (7%) are 
similar to values seen in patients who are untransfused.
This is a rare disease and we are unlikely to see more than 2 transplant candidates per year.  However, 
the International Bone Marrow Transplant Registry sponsors a study which examines the use of 
cyclophosphamide alone versus cyclophosphamide plus anti-thymocyte globulin for conditioning 
before allogeneic fully HLA matched transplant.  Either regimen has been associated with long-term 
survival approaching 80%.  Accordingly, we will participate in this study. If the study is not open or 
the patient is ineligible for randomization, we plan to deliver the best available BMT care for these 
patients using a standardized approach, without a research question.  Cyclophosphamide/ATG will be 
given as standard conditioning for all patients with aplastic anemia.  Consecutive patients will be 
reported to the International Bone Marrow Transplant Registry, and outcome also will be compared to 
published results from other centers.  In addition, these patients may participate in ancillary studies 
which go across diagnoses and are designed to reduce transplant-related complications (e.g., GvHD, 
CMV infection, etc.).  Patients with aplastic anemia in need of an unrelated transplant will be treated 
as a standard AML patient.  This is due to the need for a more aggressive conditioning regimen to 
prevent graft rejection.
1.3.
CML has been considered a universally fatal disease with a median survival of 4 years from 
diagnosis.  Gleevec® (Imatinib) has changed the standard treatment of CML (9a).  Currently, it is not 
clear when allogeneic transplant should be performed for CML patients.  Currently Oregon Health 
Sciences Center has reported that patients who do not respond to Gleevec within 6 months with a 
major cytogenetic response will not at further time points after treatment (Richard Maziarz, Brian 
Druker Personal Communication (9b)).    Thus, these patients should be considered for allogeneic 
transplant.  In addition, patients under the age of 30 can be considered candidates for allogeneic BMT 
because of a lower mortality than older CML patients.  Allogeneic BMT, performed during the 
chronic phase of the disease, results in 60% disease-free survival (DFS) beyond 5 years (9).  
Preliminary results indicate that if BMT is performed within the first year of diagnosis DFS is further 
improved to approximately 80%.  Conversely, if BMT is delayed until accelerated or blast phase, DFS 
is reduced to 15-25% due to resistant leukemia.  Patients should be considered for BMT within one 
year of diagnosis since evolution to blast phase is unpredictable (approximately 25%/year after the 
first year) and markedly increases the probability of relapse after transplantation.  
1.4.
Extensive experience with BMT for recurrent acute leukemia and lymphoma indicates that 50-60% of 
patients can be expected to achieve a complete remission, and half of these will remain free of disease 
more than 5 years after marrow transplantation (and are probably cured) (10-12).  In comparison, fewer 
than 10% of these patients can be cured with conventional therapy.  The results of allogeneic BMT 
for acute leukemia and lymphoma in first remission are more difficult to interpret.  Disease-free 
survival of 50-60% is typically reported, and although this is superior to the results of chemotherapy, 
it may not be superior to chemotherapy followed by BMT for those patients who relapse (10, 11, 13, 14).
1.5.
The problems associated with BMT fall into two broad categories, treatment-related toxicity and 
resistant disease.  
1.5.1. Treatment-related mortality is typically 20-25%, and includes regimen-related toxicities 
(especially infections, interstitial pneumonitis, and hepatic veno-occlusive disease) and 
complications of graft vs. host disease (GvHD).  Patient age and donor histocompatibility are 
the most important determinants of GvHD mortality which ranges from < 10% for patients 
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under the age of 20 with an HLA-genotypically identical donor, to >30% for patients over the 
age of 40, or with partially matched donors (15, 16).  Post-transplant immunosuppression with 
cyclosporine, usually combined with methotrexate or methylprednisolone, reduces the 
incidence and severity of GvHD (6).  Removal of T-lymphocytes from the donor marrow is one 
of the most effective ways to prevent GvHD, but depletion of more than 99% of T-cells (2 
logs) increases the risk of graft rejection (17,18).  A variety of methods for T-cell depletion has 
been employed; the most popular has been the use of antibodies to T-lineage surface antigens, 
however separation in centrifugal fields (elutriation) and in vitro exposure of marrow to 
cytotoxic drugs (e.g., methylprednisolone, etoposide) also has been used.  Factors that increase 
the risk of regimen-related organ toxicity are incompletely defined but include extent of prior 
therapy, performance status at the time of BMT, presence of organ dysfunction prior to BMT, 
and intensity of the transplant regimen.  
Cytomegalovirus infection is an important 
complication, which was responsible for a 10-20% mortality rate after allogeneic BMT.  
Several recent developments have reduced the risk of fatal CMV infection, including the use 
of seronegative blood products (and marrow donors when possible) for CMV-negative 
patients, administration of prophylactic acyclovir and intravenous immunoglobulin (IVIG), 
treatment of CMV infections with gancyclovir plus IVIG, and the use of blood products that 
have been filtered.
1.5.2. The frequency of failure due to resistant malignancy depends both on the diagnosis and the 
timing of the transplant.  For example, the relapse rate is approximately 70% after BMT for 
refractory acute leukemia or CML in blast crisis, compared to 20% for patients with acute 
leukemia in first remission or CML in the chronic phase (2).  Another factor influencing 
relapse rate is GvHD; patients who survive despite significant acute GvHD (grade 2 or 
greater) or chronic GvHD have a reduced risk of leukemic relapse (19).  Of particular 
importance is the finding of a strikingly high relapse rate for patients with chronic phase CML 
who received T-depleted marrow.  Autologous BMT would be expected to be inferior to 
allogeneic BMT due to lack of graft vs. tumor effect as well as possible reinfusion of tumor 
cells (hidden) in the transplanted marrow.  On the positive side, autologous BMT avoids the 
complications of GvHD and marrow rejection.
1.6.
It is often difficult to determine the optimum timing for BMT.  Balancing anticipated toxicity against 
tumor response requires consideration of multiple factors, including diagnosis, response to previous 
(conventional) therapy, age, and donor compatibility.  In general, allogeneic BMT is the preferred 
treatment for any patient under the age of 50 with a hematologic malignancy, whenever alternative 
therapies have a predicted probability of cure < 20%, and an HLA-matched related donor is available.  
BMT also may be indicated in other circumstances depending on the specific disease in question.  
The appropriate timing for SAA and CML is less problematic and has already been discussed (sec. 
1.2, 1.3).
1.6.1. Acute Myeloblastic Leukemia (AML).  BMT is considered standard therapy for patients in 
their first chemotherapy-induced complete remission since it results in 50% long-term disease-
free survival, compared to 20% for typical chemotherapy regimens.  However, the best results 
from recent reports of chemotherapy indicate a similar disease-free survival to BMT (20, 21).  In 
addition, if BMT is delayed until the first sign of relapse, approximately 30% of patients still 
can be salvaged.  Based on these considerations we believe that BMT is best performed at the 
initial relapse, rather than first remission, unless prognostic factors at diagnosis indicate a high 
risk of relapse.  Adverse prognostic factors include secondary AML, antecedent hematologic 
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disorder, deletion of chromosome 5 or 7 (in whole or in part), trisomy 8, and certain 
chromosomal translocations, e.g., t(9;22).  Patients in a second chemotherapy-induced 
remission (and those with more advanced disease) have little chance of  cure and should  be 
considered for BMT (22).  
The most commonly used transplant regimens combine 
cyclophosphamide with TBI or busulfan, however, the high relapse rate (40% or more) 
following BMT for advanced leukemia indicates the need for more effective chemotherapy 
and immune modulation.
1.6.2. Acute Lymphoblastic Leukemia (ALL).  Current results of initial chemotherapy for ALL 
suggest that 80-90% of children and 40-50% of adults may be cured (13,23).  Many patients who 
relapse will respond to further chemotherapy, however, patients in a second chemotherapy-
induced remission (and those with more advanced disease) have little chance of  cure.  A 
possible exception is patients who relapse after an initial remission of >18 months; of those 
who achieve a second complete remission 50% may be cured (24).  Based on these 
considerations we believe that BMT is best performed in first relapse, or second remission of 
ALL, unless prognostic factors at diagnosis indicate a high risk of relapse.  Karyotype is the 
most important risk factor with the presence of any balanced translocation indicating an 
adverse prognosis (13,25).  Patients in a second relapse (and those with more advanced disease) 
have little chance of cure and also should  be considered for BMT.  The results of BMT for 
recurrent ALL indicate that 30-50% of patients can be expected to achieve long-term disease-
free survival (11,26).  Again, the high relapse rate following BMT indicates the need for more 
effective chemotherapy and immune modulation.
1.6.3. Myelodysplastic Syndrome (MDS), and Myeloproliferative Disorders.  BMT is the only 
therapy with the potential (although experience is still limited) for cure.  Patients should be 
considered for BMT when the disease progression causes life-threatening complications (27,28).
1.6.4. Lymphoma (including Hodgkin Disease and Intermediate or High-grade Non-Hodgkin 
Lymphomas).  Conventional therapy is not effective for patients who fail aggressive 
combination chemotherapy for lymphoma, but approximately 25% can apparently be cured by 
BMT (12).  Many different BMT regimens have been used, without clear superiority of any one 
approach.  The most frequent cause of failure is resistant disease.  Patients who are refractory 
to standard therapy (having never achieved a complete remission) fare less well after BMT 
than patients who relapse from an initial response, and the best results are achieved in patients 
who relapse, but are still responsive to conventional agents.  For patients like these, with 
"sensitive relapse", long-term disease-free survival can be expected in  more than 40% (29).  
Most of the lymphoma experience involves the use of autologous marrow, however some 
patients are not good candidates for autologous BMT because of poor marrow function, prior 
pelvic irradiation, or marrow lymphoma.  In this situation allogeneic BMT may be the best 
choice.  Thus for most patients BMT is recommended at the time of relapse from first-line 
combination chemotherapy.  
For patients with high-grade Non-Hodgkin lymphoma 
(lymphoblastic and small non-cleaved cell) prognostic factors have been identified that 
indicate a high risk of relapse (presence at diagnosis of bone marrow involvement 
accompanied by elevated serum LDH) and can be used to select patients who may benefit 
from BMT during first remission.  
1.6.5. Chronic Lymphocytic Leukemia, Waldenstrom's Macroglobulinemia, Low-grade Non-
Hodgkin Lymphoma (NHL).  These are chronic lymphoproliferative disorders for which 
there is no proven curative therapy, and despite their usually indolent course, most patients 
ultimately die of disease-related complications.  There is limited experience with BMT in 
these disorders, but preliminary results are promising (30-32).  BMT should be considered for 
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younger patients (age < 55) with progressive or symptomatic disease after conventional 
therapy.
1.6.6
Patients with malignancies who would be treated with an autologous stem cell transplant but 
have a syngeneic donor.
1.7.
Donors can be classified arbitrarily as "well-matched" or "partially-matched" based on the post-
transplant risk of GvHD.  Considering the three most important serologically-defined HLA loci (A, B, 
D) there are 6 possible alleles that can be matched.  The DR locus has been further defined by 
molecular typing such that this technique has replaced serologic typing of the D region.  DRB1 and 
DQB1 are two of the more defined regions that can be analyzed and matched for on a molecular basis.  
(33)
Well-matched donors carry the least risk of GvHD and are represented primarily by genotypically 
matched siblings (HLA 6/6).  Although experience is more limited, similar results have been obtained 
with 5/6 HLA-matched family members and fully-matched (HLA 6/6) unrelated donors (34-36).
Partially-matched donors carry a greater risk of fatal GvHD (and possibly of graft rejection) and their 
use is only considered if no well-matched donor is available, autologous BMT is not possible, and the 
patient's underlying disease warrants the added risk.  Included in this category are unrelated donors 
who are matched for class II specificities (HLA DRB and DQ), but mismatched for 1 HLA-A or B 
specificity, as well as family-member donors who are matched for 3 or 4 (of 6) HLA-A,B,D 
specificities. Patients who are <25 years of age may be considered for an unrelated transplant using a 
donor who is singlely mismatched at a Class I antigen.  All other patients who do not have a fully 
matched unrelated donor will be treated on an appropriate cord blood protocol.  The specifics 
matching criteria are contained in the BMT Standards of Therapy that are updated yearly.
For this study, bone marrow or blood progenitor cells (BPC) will be the primary source of 
hematopoietic stem cells .  Bone marrow will be used for all standard risk patients, and blood 
progenitor cells will be used for all high risk patients with a fully-matched related donor, including 
MDS patients with > 10% blasts in the marrow (37-39).  Stem cells from an unrelated donor may be 
either bone marrow or blood progenitor cells, although it is preferred that standard risk patient receive 
bone marrow and high risk patients receive blood progenitor cells.
A syngeneic donor would be considered to have the same risk as an autologous stem cell transplant 
patient but because the donor is another individual, the patient would be treated on this protocol.
1.8.
Transplant Conditioning Regimens (preparative regimens) – (see Section 5.2 for full dosing schema)
1.8.1. CATG. Published BMT data support the use cyclophosphamide 200 mg/kg and ATG 90 
mg/kg for the treatment of aplastic anemia patients.
FluM.  Recent evidence has shown that fludarabine at a dose of 125 mg/m2 over 5days plus 
melphalan at a dose of 140 mg/m2 over 2 days is a safe and potentially less toxic conditioning 
regimen in allogeneic transplant.  Patients who are at higher risk for transplant-related toxicity 
will be treated with this regimen including older patients. (54, 55).
1.8.2. Patients who have undergone allogeneic or autologous transplant and fail to engraft or 
experience prolonged graft failure may be considered for a reinfusion of either:  1)  donor 
lymphocytes, 2) previously harvested and stored stem cells, or 3) stem cells harvested from a 
suitably matched donor.  In the third situation, the patient should receive additional 
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immunosuppression with Fludarabine 25 mg/m2 intravenously every day for 5 days, and ATG 
10 mg/kg/day intravenously every day for 4 days.
2.
OBJECTIVES
2.1.
The 2 major objectives are:  1) To study the morbidity, mortality and overall outcome of standard and 
novel conditioning regimens for the treatment of diseases by allogeneic BMT, and 2) To ensure that 
patients with uncommon diagnoses will be treated in a uniform fashion with the best therapy 
available.   
2.2
For purposes of analysis, patients will be stratified into two groups (standard and high risk), since 
accrual of patients to some of the individual disease/status strata will be slow.  The assignment of risk 
is as follows: (also, see section 4.3)
Standard risk:
Acute leukemia, 1st CR
Lymphoma, sensitive 1st relapse or 2nd remission
CML, 1st CP  
MDS, untreated or Primary MDS with IPSS low or Intermediate 
grade 1 (see Appendix 6)
AA with no co-morbidities *
High risk definition: 
Leukemia and lymphoma
2nd CR or greater
Resistant 1st relapse 
Primary refractory to standard chemotherapy (considered 
to be at highest risk)
Previously treated MDS, Secondary MDS, or MDS converted to 
AML without induction therapy; with IPSS intermediate 
2 or high risk (see Appendix 6)
CML other than chronic phase 1
High grade NHL in 1st CR
AA with co-morbidities *
Solid Tumors
*Co-morbidity is defined as a life threatening medical condition that is controlled with therapy (see 
Section 3.7)
2.3.
Influence of donor histocompatibility on outcome will be examined by comparison of 
matched/related, mismatched/related (with or without T-cell depletion), and matched/unrelated 
transplants with stratification for type of preparative regimen.
2.4.
Regimen selection will be based on criteria as indicated in the following table:
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All patients with refractory disease will be treated as a first choice with FluM.  If for any reason a 
patient is unable to be treated according to the table, the default will be FluM
Disease
Risk
Age
HLA Match1
Regimen
Stem Cells3
MDS
High
51-60
6/6 related
FluM
PBSC
High
< 60
Unrelated
FluM
PBSC/BM
High 
< 50
5/6 related
FluM
BM
Either
61-70
Related or Unrelated
FluM
PBSC/BM
Either
>50
Syngeneic
FluM
PBSC/BM
AML
High
51-60
6/6 related
FluM
PBSC/BM
High
31 -  60
Unrelated
FluM
PBSC/BM
High
< 50
5/6 related
FluM
BM
Either
61-70
Related or Unrelated
FluM
PBSC/BM
Either
>50
Syngeneic
FluM
PBSC/BM
ALL
High
51-60
6/6 related
FluM
PBSC/BM
High
17-50
5/6 related
FluM
BM
High
< 41 - 60 Unrelated
FluM
PBSC/BM
Either
60-70
Related or Unrelated
FluM
PBSC/BM
Either
>50
Syngeneic
FluM
PBSC/BM
CML
High
< 60
Unrelated
FluM
PBSC/BM
High
< 50
5/6 related
FluM
BM
Either
60-70
Related or Unrelated
FluM
PBSC/BM
Either
>50
Syngeneic
FluM
PBSC/BM
HD
High
< 70
6/6 related
FluM
PBSC/BM
High
< 70
Unrelated
FluM
PBSC/BM
High
< 50
5/6 related
FluM
BM
Either
< 50
4/6
BuCATG 
CB4
Either
<70
Syngeneic
FluM
PBSC/BM
NHL
High
< 60
6/6 related
FluM
PBSC/BM
High
< 60
Unrelated
FluM
PBSC/BM
High
< 60
5/6 related
FluM
BM
Either
60-70
Related or Unrelated
FluM
PBSC/BM
Either
>50
Syngeneic
FluM
PBSC/BM
CLL
High
< 60
6/6 related
FluM
PBSC/BM
High
< 50
5/6 related
FluM
BM
High 
< 60
Unrelated
FluM
PBSC/BM
Either
60-70
Related or Unrelated
FluM
PBSC/BM
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Disease
Risk
Age
HLA Match1
Regimen
Stem Cells3
Either
<70
Syngeneic
FluM
PBSC/BM
AA
Either
< 60
6/6 related
CATG
PBSC/BM
Either
60-70
Related or Unrelated
FluM
PBSC/BM
Either
<60
Syngeneic
CATG
PBSC/BM
Either
>60
Syngeneic
FluM
PBSC/BM
1 An unrelated HLA A, B,or C mismatch, BM preferred over PBSC. Patients with single or greater HLA Antigen or 
Allele mismatch (at A, B, C, or DRB1) over 30 receive FluMel and Marrow as preferred conditioning regimen and stem 
cell source respectively.  CB units should be 4/6 matches and preferably matched at HLA-DRB1.
FluM is the preferred regimen if there is any medical contraindication to a higher intensity regimen for PB or BM 
transplants.   Patients must be transplanted from and identical twin sibling and be <60 years. 
3 BM is preferred stem cell source for patients under the age of 18.  If HLA-mismatched at HLA A or B antigen, Bone 
marrow is preferred.  In HLA matched patients, PB is preferred for high risk BMT patients.
4 The CB cell dose must be 2 x 10^7 NC per kg minimum dose for a single unit.  Cord Blood could be used as stem cell 
source with FluMel.
3.0
GENERAL ELIGIBILITY GUIDELINES
3.1.  
Diagnosis
3.1.1. severe aplastic anemia
3.1.2. chronic myelocytic leukemia
3.1.3. hematologic malignancy in first remission with high risk of relapse
3.1.4. hematologic malignancy in second or subsequent remission
3.1.5. hematologic malignancy, relapsed or refractory after first-line combination chemotherapy
3.1.6
myelodysplastic syndrome, untreated 
1) with features of neutropenia and or blood product transfusion dependence
2) unfavorable cytogenetics
3) converted to AML without induction therapy
4) Intermediate 1 or higher IPSS (see Section 2.2, Appendix 5)
3.1.7
Solid tumor patients who would otherwise be treated on DS 91-15 (or equivalent autologous 
stem transplant protocol and have a syngeneic donor).
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3.1.8
For myeloablative regimens
3.1.9
No KPS requirement for failure to engraft transplants and Reduced Intensity Conditioning 
with FluMel
3.2.
Age  > 4, < 70 
3.3 
Not pregnant 
3.4.
Required initial laboratory data  
1.  Pulmonary function tests (DLCO or DLVA) ≥50% predicted; DLCO to be corrected for 
hemoglobin or alveolar ventilation.  (See Section 10.0 for pediatric requirements.)
2.  
Cardiac ventricular ejection fraction ≥50% by radionucleotide ventriculogram or 
echocardiogram.  
3.  Bili, Alk phos, SGOT < 3 x normal, unless due to disease
   4. Creatinine clearance is > 50 ml/min. (See Section 10.0 for pediatric requirements.)
5.  HIV antibody negative
6.  CMV and  hepatitis status known; HBsAg negative
3.5.
No serious organ dysfunction unless it is caused by the underlying disease; exclusion criteria 
include the following:
1. Uncontrolled or severe cardiovascular disease, including recent (< 6 months) myocardial 
infarction, congestive heart failure, symptomatic angina, life-threatening arrhythmia or 
hypertension
2. Uncontrolled bacterial, viral, or fungal infection
3. Uncontrolled peptic ulcer disease
4. Uncontrolled diabetes mellitus
5.  Any severe pulmonary, hepatic, or renal disease, or any other condition which, in the opinion of 
the transplant director, would make this protocol unreasonably hazardous for the patient. 
3.6.
Compatible donor identified 
3.6.1. Autologous BMT not possible or not desirable.
3.6.2. Well-matched donor: family member matched for 5 of 6 HLA specificities (A, B, DR); 
unrelated donor matched for HLA A, B,  and DRB1 antigens.  Patients may be singly 
mismatched at the A, B, C loci when using FluMel.  Identical twin sibling.
3.6.3. All other patients are considered too highly mismatched and will be considered for cord 
blood transplant. CB must be a minimum of 2 x 10^7 NC per kg patient wt.
3.6.4. For this study, bone marrow or blood progenitor cells will be the primary source of 
hematopoietic stem cells. 
3.7.
Informed Consent:  Patients must be aware of the neoplastic nature of their 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.  There must be no other 
serious medical or psychiatric illness that would prevent informed consent.
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4.
REGISTRATION AND DATA SUBMISSION
4.1.
Registration - to register patients, contact the BMT Coordinator.  Transplant regimens will be 
assigned as per protocol guidelines by the BMT team.
4.2.
Data pertaining to this protocol will be collected by the BMT research nurse, and/or any other 
persons 
assigned by the BMT department head.
4.3.
Stratification by risk - for overall analysis of toxicity and response, patients will be assigned to one 
of two risk groups (refer to Section 2.2)
4.4
Reference Appendix 7 for definitions of On/Off Study Dates, Start/Stop Treatment Dates.
5.
TREATMENT PLAN    
5.1.
Pretransplant cytoreductive chemotherapy may be administered to patients with relapsed or 
refractory disease in an attempt to demonstrate sensitivity to therapy and reduce bulky disease.  The 
decision to treat and the choice of specific therapy to be used will be made on an individual case 
basis.
5.1.1. Involved-field radiation therapy:  For all patients for whom radiation therapy is planned, it 
is recommended that radiation begin no sooner than 4 weeks and no greater than 8 weeks after 
transplant.  
5.1.2. Regimen selection depends on diagnosis and prior therapy as defined in eligibility criteria 
(refer to table in Section 2.4)
5.1.3. Stem Cell Infusion:  Day 0 is the day on which the stem cells are infused.  As required by 
scheduling, the stem cells may be infused on the same day after the last fraction of TBI is given.  
The described scheduling for each regimen is the preferred timing.  However, it is recognized that 
situations may arise that require variation in scheduling.  Any such deviation from described 
scheduling should be discussed with the Study Chair first.
The procedure of infusing stem cell products may be performed by the physician or qualified nurse 
under the direct supervision of a BMT physician.  The 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 diphenhydramine, epinephrine, and corticosteroids will be available for use in 
appropriate doses.  No other blood products should be given on the day of transplant, especially 
within 8 hours of planned infusion time.  
Patients will be pre-medicated with the following medications (doses must be adjusted for 
pediatric patients):
 
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1)  Diphenhydramine (Diphenhydramine) 25 mg IV, 30 minutes prior to infusion of stem 
cells.
 2) Lorazepam 0.5 mg IV, 30 minutes prior to infusion of stem cells.
For Recipients who are ABO incompatible with their donors, premedication will include:
1) Hyperhydration of 150 mls/m2 per hour beginning 6-12 hours prior to infusion
2) Hydrocortisone 100 mg IV 15 minutes prior to infusion, and
3) Diphenhydramine 50 mg IV 15 minutes prior to infusion
Treatment of a transfusion reaction will include the following:
1) Stop infusion and give hydrocortisone 100 mg
2) Restart infusion as soon as patient is clinically stable
5.2.
Transplant Conditioning Regimens (preparative regimens)
5.2.1.  Cyclophosphamide, ATG summary: 
Day
-5 
-4 
-3
-2
-1
0
C 50 mg/kg/2hr
X
X
X
X
   (total 200mg/kg)
ATG* 30mg/kg/qd 
X
X
X
   (total 90 mg/kg)
Stem Cell Infusion
X
*ATG is given 4-8 hours after Cyclophosphamide, given via central line
Cyclophosphamide  Diphenhydramine 25-50 mg IV should be given 30 minutes prior to the 
administration of all cyclophosphamide doses (adjusted for pediatric dosing).  A minimum of 12 
hours prior to first dose,  begin IV hydration at 150 ml/m2hr (see appendix 6).  Cyclophosphamide, 
50 mg/kg (ideal body weight or actual whichever is less) in 500ml D5W or NS, is given by 2-hr IV 
infusion (1200 -1400 hrs) days -5,-4,-3, and -2 (total dose 200 mg/kg).  To calculate dose use IBW 
(see Appendix 1 for table of IBW by height) or actual weight, whichever is less.  Hyperhydration is 
continued until 24 hrs. after the last cyclophosphamide dose.  Lasix, 10-20 mg IV, will be given 2 
hrs after each cyclophosphamide dose and then q4 hrs. prn to maintain urine flow >100ml/hr.
Antithymocyte Globulin (ATG) Prior to infusion of ATG patients will be premedicated with 
diphenhydramine 50 mg IV (adjust for pediatric dosing) and methylprednisolone 2 mg/kg IV .  Four 
to eight hours after the completion of the first, second and third doses of Cyclophosphamide, ATG 
30 mg/kg (actual body weight) will be given intravenously over 4-8 hours.  
5.2.2.  Fludarabine, Melphalan summary:
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Day
-6
-5
-4
-3
-2
-1
0
Flu 25 mg/m2  qdx5
X
X
X
X
X
 (total 125 mg/m2) 
M 70 mg/m2 qd x2
X
X
 (total 140 mg/m2)
Stem Cell Infusion
X
Fludarabine.  A minimum of 1 hour prior to first dose, begin IV hydration.  Fludarabine, 25 mg/m2 
(see appendix 6) (actual body weight) in 100 ml D5W or NS, is given by 30-minute IV infusion 
days -6, -5, -4, -3, and -2 (total dose 125 mg/m2).  
Melphalan.  Prepare melphalan 70 mg/m2 BSA (see appendix 6) (actual body weight) in diluent 
provided at a final concentration not to exceed 5 mg/ml to infuse over 1/2 hr following fludarabine, 
day -3 and -2 (total dose 140 mg/m2).  On day -3 hydrate 150cc/m2/hr IV hydration 1 hour prior to 
Melphalan.  Hyperhydration is continued until 24 hrs. after last melphalan dose.
 
5.2.3. Fludarabine, ATG summary:  (FOR GRAFT FAILURE ONLY)
Day
-5
-4
-3
-2
-1
0
FLU 25 mg/m2  qdx5
X
X
X
X
X
 (total 125 mg/m2) 
ATG 10 mg/kg/day qdx4
X
X
X
X
 (total 40 mg/kg)*
Stem Cell Infusion
X
steroid premedication of 2 mg/kg/day medrol (pre ATG)
Fludarabine.  A minimum of 1 hour prior to first dose, begin IV hydration.  Fludarabine, 25 mg/m2 
(actual body weight) in 100 ml D5W or NS, is given by 30-minute IV infusion days -5, -4, -3, -2, -1 
(total dose 125 mg/m2).  
Antithymocyte Globulin (ATG) Prior to infusion of ATG patients will be premedicated with 
diphenhydramine 25-50 mg IV and methylprednisolone 2 mg/kg IV.  ATG will be given within one 
hour of the completion of the first, second, third, and fourth doses of Fludarabine, ATG 10 mg/kg 
(actual body weight) will be given intravenously over 4-8 hours.  
6.
DRUG FORMULATION, AVAILABILITY AND PREPARATION
6.1.
Cyclophosphamide is commercially available in 100, 200, 500, 1000, 2000 mg vials.  Dilute with 
5, 10, 25, 50 ml, or 100 ml respectively, of NS (normal saline) for Injection, yielding a 
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concentration of 20 mg/ml which is stable for 24 hours at room temperature.  Give the appropriate 
IV dose by 2 hour IV infusion after further dilution to 500 ml with D5W.
6.2.
Antithymocyte globulin (ATGAM, Upjohn) is commercially available in 5 ml ampules containing 
50 mg of horse gamma globulin/ml.  It should be stored in a refrigerator  (2-8°C).  It should be 
diluted in 0.9% NaCl to a concentration not exceeding 4 mg/ml, and is stable for 24 hours when 
diluted.  The final product is filtered.  ATG should be administered alone.
6.3.
Melphalan is commercially available in 50 mg vials.  It is to be admixed just prior to intravenous 
administration and is stable for 90 minutes.  The dose of melphalan will be diluted with the diluent 
that is provided with the product to a final concentration of 5 mg/ml and protected from light.
6.4
Fludarabine is commercially available in 50 mg vials.  It is reconstituted by adding 2 ml of sterile 
water   for injection to provide a solution containing 25 mg/ml which is stable for 8 hours at room 
temperature.
7.0
POTENTIAL TOXICITY - MANAGEMENT AND DOSE MODIFICATIONS
7.1.
Toxicity Grading - The Bearman Toxicity Criteria, Appendix 2) will be used for the grading and 
reporting of all toxicities.  Grade 4 hematosuppression does not have to be reported for agents 
known and expected to cause hematosuppression at the dose used. Bearman Toxicity Criteria refers 
to regimen-related toxicity only. GvHD grading is located in Appendix 4 .
7.2.
Hematologic:  Two to four weeks of severe pancytopenia (PMN < 500/µL, Platelets < 20,000/µL) 
are expected, and rarely patients may fail to engraft.  All blood products will be irradiated (2500 
cGy) to prevent graft vs. host disease.  Despite optimal antibiotics, 10-15% of patients treated with 
intensive chemotherapy may die as a result of infection.  Infection prophylaxis and treatment will be 
given according to standard accepted medical practice.  On rare occasion, we may transfuse 
granulocytes from an acceptable donor for the purpose of treating a life-threatening infection in a 
neutropenic patient.  With prophylactic platelet transfusions, the risk of death from hemorrhage is 
<5%.  Use of T-depleted marrow may delay recovery and increase the risk of graft failure to as 
much as 10%.
7.3.
Hepatic: Moderate toxicity is common.  More severe, possibly fatal, liver toxicity can occur, 
usually in the form of veno-occlusive disease. With the study regimens the incidence of fatal liver 
toxicity should be < 10%.  Management of liver toxicity is with standard supportive and 
symptomatic measures. Avoid exposure of patients to other hepatotoxic agents whenever possible.
7.4.
Pulmonary:  Idiopathic interstitial pneumonitis (IP) is possible after high dose alkylating agent 
therapy or TBI.  With the study regimens the risk of fatal idiopathic IP is felt to be < 10%. Patients 
with diffuse pulmonary infiltrates often present a difficult diagnostic and management problem.  
Whenever possible, histologic confirmation of the diagnosis should be attempted by bronchoalveoar 
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lavage, or transbronchial or open-lung biopsy to exclude infectious causes, including 
cytomegalovirus.
7.5.
Cardiac:  High-dose cyclophosphamide can produce fatal hemorrhagic pancarditis.  The risk of 
fatal cardiac toxicity with the study regimens is <5%.  Patients who develop signs of congestive 
heart failure not attributable to fluid overload should be evaluated for signs of carditis before 
additional Cyclophosphamide is given.  Studies should include ECG (to compare voltage to 
pretreatment ECG), radionuclide ventriculogram, and/or echocardiography.  
If evidence of 
pericarditis, pericardial effusion or impaired myocardial function (decreased ejection fraction) is 
found, no further chemotherapy will be administered. In this situation patients must be watched 
carefully for signs of pericardial tamponade; pericardiectomy may be required.
7.5.1. Fludarabine can cause weakness, paresthesias or peripheral neuropathies, visual or auditory 
impairment, and/or mental status changes such as confusion, agitation, depression, or coma. 
7.5.2
Some antibiotics, which may be needed to treat infections during the period of low white 
blood cell counts, can cause eighth cranial nerve damage resulting in hearing loss (especially 
high-frequency tones) and dizziness which may be permanent. To minimize this possibility, 
antibiotic levels will be monitored.
 
7.6.
Genitourinary:
7.6.1. Urinary metabolites of cyclophosphamide can produce hemorrhagic cystitis.  Microscopic 
hematuria is common following high-dose Cyclophosphamide regimens and up to 20% of 
patients may have gross hematuria or symptoms.  Vigorous hydration of patients (3,000 
ml/m2/day) prior to beginning Cyclophosphamide and continuing until 24 hours after the 
final Cyclophosphamide dose produces a dilute urine and reduces the likelihood of severe 
cystitis.  The risk of life-threatening cystitis is estimated to be <1%.  For patients with a 
history of previous cyclophosphamide induced hemorrhagic cystitis, MESNA may be used.
7.7.
Renal:   All these agents in high doses can produce renal toxicity that can be minimized by vigorous 
hydration and avoidance of concomitant exposure to other nephrotoxic agents.  Kidney damage is 
usually reversible, but severe cases may require dialysis.  Carboplatin in high doses can produce 
renal toxicity which can be minimized by vigorous hydration and avoidance of concomitant 
exposure to other nephrotoxic agents.
7.8.
Gastrointestinal:
7.8.1. Nausea/Vomiting - Many patients will experience moderate to severe toxicity.  All patients 
should receive vigorous antiemetic treatment 
7.8.2. Stomatitis/Dysphagia - Many patients will experience severe toxicity.  Adequate pain relief 
often requires parenteral narcotics. 
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7.8.3. Diarrhea - Most patients will experience moderate-severe diarrhea which responds to 
standard symptomatic therapy.  Appropriate studies are needed to exclude infectious causes 
of diarrhea, especially C. difficile.
7.9.
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.
7.10.
Hair:  All patients will experience total (reversible) alopecia.
7.11.
Graft vs. Host Disease:  Approximately 80% of patients will exhibit some manifestation of GvHD.  
Severe GvHD may occur in up to 40% of patients with an overall mortality of 20% due to GvHD 
and its complications.  The risk of severe or fatal GvHD is increased for older patients and for 
patients receiving marrow from  partially matched donors.  A chronic form of GvHD is expected to 
occur in up to 40% of patients who survive beyond 3 months;  10% may experience significant 
disability due to chronic GvHD that persist for months to years post-transplant.  Measures for 
prevention and treatment of GvHD will be followed as per standard practice.  Acute GVHD should 
be treated according to existing BMT SOPs 
(http://internal.roswellpark.org/files/1_2_1/Internal/patient_care/bmt/2002Clinical/CP2002.03.doc)
7.12
Allergy:  Antithymocyte globulin may be associated with a serum sickness like reaction consisting 
of rash, hives, pruritis, joint aches.  More severe anaphylactic like reactions with the development of 
bronchospasm and anaphylactic shock are uncommon but reported after the use of ATG.  Prior to 
administration patients should be premedicated with Diphenhydramine and Methylprednisolone.  
Epinephrine and resuscitation equipment must be available during administration of ATG.  Other 
chemotherapeutic agents may be associated with mild allergic reactions including rash, hives, 
itching nasal stuffiness, sinus congestion, sneezing, watery eyes, and running nose occur 
occasionally; more severe reactions with low blood pressure and wheezing are rare.
 
7.13.
Bone marrow and/or blood stem cell infusion of a previously frozen product:
In certain cases, stem cells may have been previously cyropreserved for use. Products are protected 
from damage during freezing with DMSO (dimethylsulfoxide). DMSO produces a garlic-like odor 
on the breath that lasts for 1 to 2 days. In rare instances, severe allergic reaction to DMSO may 
occur. Red coloration of urine may be noticed for 1 to 2 days after the reinfusion due to the release 
of hemoglobin from blood cells in the marrow damaged by freezing.
7.14.
Secondary malignancy:  Exposure to alkylating agents and radiation increases the risk of 
developing leukemia or a second cancer.  
7.15In summary, overall day 100 transplant related mortality is expected to be approximately 20-30% 
due to graft failure, regimen-related organ toxicity, infection, hemorrhage, and graft versus host disease.  
Risk factors associated with higher transplant related mortality include increased patient age, prior 
chemotherapy, poor performance status, unrelated donor transplant, and more intensive transplant 
regimens. 
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8.0  
DATA AND SAFETY MONITORING PLAN
The Principal Investigator (PI) will be responsible for continuous monitoring of the safety of 
the study. (see section 12.3.2 for stopping rules)  
Patient Outcomes Rounds are held weekly on the transplant unit, at which time all BMT 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 xrays.

a properly signed and dated transplant consent.

compliance issues that could compromise patient safety; pretransplant, a conference is held for all 
allogeneic 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.  In addition, psychosocial evaluations are completed on all allogeneic and high-risk 
autologous transplant patients prior to transplant, to identify any compliance issues.

other aspects of safety monitoring as prescribed 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, Tobramycin, Cyclosporine).  
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.

Assignment of KPS/Lansky Score  (Appendix 6)
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

Bearman and CTC toxicity grades 3 and 4

Variances in the delivery of standard care

Readmissions prior to day +100 post transplant

Deaths occurring prior to day +100 post transplant

Engraftment
Followup on all transplant patients is continued even after they have returned to the care of the 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), and/or the 
National Marrow Donor Program (NMDP).  Registry reports are reviewed internally prior to 
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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 the NMDP.
9.
REMOVAL 
OF 
PATIENTS 
FROM 
PROTOCOL 
THERAPY 
AND 
TOXICITY 
REPORTING:
9.1.Removal from protocol.  If the constraints of this protocol are detrimental to the patient's health, the 
patient will be removed from the protocol.  In this event the reason for withdrawal will be 
documented.  Patients will be taken off study after a minimum of 4 years of follow up.
9.2.Toxicity Reporting
9.2.1. Expected toxicity (recorded in protocol consent form or manufacturer's literature).  Within 
10 days of occurrence written reports should be submitted to the IRB and the protocol 
chairman in the following circumstances (Bearman and CTC toxicity)
9.2.2. Unexpected toxicity
All instances of Bearman grade 3-4 will be reported to the IRB and the protocol 
chairman immediately by telephone and followed by a written report
Grade 3-4 acute GVHD will be reported by written notification. 
Failure to engraft (defined as a patient alive on day 45 with no ANC recovery)
Graft failure (defined as a patient who had initial ANC recovery but subsequently had 
a decline in ANC that required additional stem cell support)
         Death due to any cause
Readmission due to any reason up to 100 days post BMT.
10.
REQUIRED DATA
Record on the flow sheets: 
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1.
Important hematologic recovery endpoints
day PMN >500/µL, >1000/µL; Plt >25K, >100K; Hb >10gm%
day of last Plt transfusion, last RBC transfusion
2.
day(s) of occurrence of severe toxicity (gr3)
§ 
d 0 is day of marrow transplant; studies to be obtained as close to indicated time as possible
*    
Obtain cytogenetics if previously abnormal 
**
Non-invasive studies including:  (1) measurement (perpendicular diameters) of palpable disease,
(2) CT scan of chest, abdomen, pelvis, (3) Whole-body Ga scan (SPECT, if available)
***
Post therapy is defined as until engraftment and /or discharge from hospital.
Intervals shown are the minimum requirement
****Not required in pediatric patients <5 years, 5-8 years to be done at WCOB, >8 years to be done at RPCI.
*****In pediatric patients, only if CARBO Regimen or Serum creatinine – Abnormal.
******Not required for Pediatric patients unless has pulmonary problems for pneumonia.
Test/Observations
Pre-Rx
Post-Rx***
Post-Disch
Signed Consent Form
x
--
--
Ht/Wt/BSA
x
--
--
Ideal Body Wt/Adjusted Body Wt 
(if applicable)
x
--
--
Serology (Infectious disease 
screening)
x
--
--
HLA–Class I and II typing
x
--
--
Cr Clearance*****
x
--
--
PFT’s/DLCO/DLVA****
x
--
--
MUGA or ECHO
x
--
--
EKG
x
--
--
Quantitative IG’s
x
--
--
BM aspirate, biopsy*
x
d+100 for all
d+30 for any not in marrow 
remission prior to transplant
as clinically indicated
Prophylactic IT Chemo
x
after d+100
as clinically indicated
Staging profile**
x
repeat positive studies d+100 
and d+360; then as clinically 
indicated
repeat positive studies 
d+100 and d+360; then 
as clinically indicated
Flow cytometry analysis  testing 
on donor and recipient
x
Chimerism (obtain samples from 
donor and recipient pre-
transplant)
x
Lymphoid and myeloid chimerism
x
d+30, d 60, d 100
as clinically indicated
Flow Cytometry BMT Standard of 
Care
x
d+30, d 100, d 180, d 360
as clinically indicated
CBC/Plt
x
q day to PMN>500, 
Plt>20K, then as clinically 
indicated
q wk to day 30
Urinalysis
x
as clinically indicated
--
PT-INR
x
as clinically indicated
--
Full Chemistry Panel
x
biw
as clinically indicated
Chest X-ray******
x
as clinically indicated
--
Performance Status
x
qwk
as clinically indicated
Toxicity (Bearman and CTC)
--
weekly
q l mo until d 100
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11.
RESPONSE CRITERIA
11.1
Complete Response:  
11.1.1. Lymphoma.  Disappearance of all measurable disease, signs, symptoms, and biochemical 
changes related to the tumor, for >4 weeks, during which no new lesions may appear.
Complete Response Undetermined (CRU):  Complete disappearance of all known 
disease for >4 weeks, with the exception of persistent scan abnormalities of unknown 
significance.
11.1.2. Leukemia:  Remission marrow status with no evidence of prior disease.  Patients with a 
cytogenetic abnormality  must also have normal karyotype.
11.2. Partial Response:
11.2.1. Lymphoma: A reduction of > 50% in the sum of the products of the perpendicular 
diameters of all measurable lesions lasting > 4 weeks, during which no new lesions may 
appear and no existing lesion may enlarge.
12.
STATISTICAL CONSIDERATIONS
12.1. Study Design:  
This is a phase II-III study of high dose therapy and allogeneic blood or marrow transplantation for 
patients with severe aplastic anemia, and patients with hematologic malignancy who have failed 
standard first-line chemotherapy or who are in their first remission, but are at  high risk of relapse.  
Patients will be stratified into two groups in the following manner:  (1) High risk -  patients with 
progressive disease at the time of transplant, including those who failed to achieve a complete 
remission with first-line therapy, and those who have relapsed and failed to respond to further 
treatment (2) Standard risk - leukemia patients transplanted in first remission, lymphoma patients 
transplanted in sensitive first relapse or second remission, patients with CML in chronic phase, 
untreated aplastic anemia patients, and untreated or primary MDS patients.  Response rates for each 
regimen will be determined separately for the two strata. Patients with solid tumors will be 
evaluated in an exploratory fashion. 
12.2. Endpoints:  
The primary objective of this study is to determine the activity of the proposed blood or marrow 
transplant regimens.  Response rates and toxicities will be reported using descriptive statistics.  The 
Kaplan-Meier method will be used to construct progression-free, and overall survival curves.  
Patients will be stratified into standard vs. high-risk groups.  The BMT conditioning regimens will 
be compared within each risk group on toxicity, efficacy, progression-free survival and overall 
survival.  Toxicity criteria for premature termination autologous SCT will be applied for syngeneic 
transplants.  
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12.3. Sample Size: 
12.3.1. Patients will be differentially accrued to two risk strata: high-risk and standard-risk for 
disease relapse.  It is expected that the standard-risk stratum will have an overall efficacy 
rate (post-BMT CR rate) of 70% and the high-risk strata will have an overall efficacy rate 
(post-BMT CR rate) of 50%.  The two-sided alpha error is set at 0.02 to correct for multiple 
comparisons.  For the standard-risk strata, 55 patients will be registered for each regimen to 
be able to detect a 20% difference in efficacy between regimens with power>0.90.  For the 
high-risk strata, 70 patients will be registered for each regimen to be able to detect a 20% 
difference in efficacy between regimens with power>0.90.  Accrual is expected at 55 
patients per regimen times 5 regimens for the standard-risk strata and 70 patients per 
regimen times 5 regimens for the high-risk strata, yielding a total protocol accrual of 625 
patients.  Approximately 100 patients will be accrued every three years.
12.3.2. Entry of patients will be terminated before full accrual if treatment-related deaths occur at an 
unacceptable rate.  A sequential stopping rule will be used.  If the number of toxic deaths 
(regimen-related) exceeds the number in the table below at any given point, accrual will be 
suspended for that regimen and the toxicity will be deemed unacceptable. This stopping rule 
is based on a sequential probability ratio test with one-sided type I and type II error rates set 
at alpha = 0.01 and beta = 0.01, and the null and alternative toxicity rates set at Po < 0.20 
and P1 > 0.20.  If the observed number of toxic deaths is greater than or equal to the number 
in the table, then one may conclude with 99% power that the toxic death rate is greater than 
an unacceptable rate of 20% and the study should be stopped. 
No. Patients
6
12
18
24
Unacceptable No.      4            6          8        11
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REFERENCES
1.
Thomas, E.D.  Am. J. Med Sci. 2: 75-79 ('87)
2.
Personal communication, International Bone Marrow Transplant Registry, January 1998
3.
Camitta BM, Thomas ED, Nathan DG, et al.  Severe aplastic anemia: A prospective study of the 
effect of early marrow transplantation on acute mortality. Blood 48: 63-70, 1976.
4.
Bacigalupo A, Hows J, Gluckman E, et al. Bone marrow transplantation (BMT) versus 
immunosuppression for the treatment of severe aplastic anemia (SAA): a report of the IBMT SAA 
working party. Brit J Haematol 70: 177-182, 1988.
5.
Anasetti C, Doney KC, Storb R, et al. Marrow transplantation for severe aplastic anemia: Long-term 
outcome in fifty "untransfused" patients. Ann Int Med 104: 461-466, 1986.
6.
Storb R, Deeg HJ, Farewell V, et al. Marrow transplantation for severe aplastic anemia: 
Methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention 
of acute graft-versus-host disease. Blood 68: 119-125, 1986.
7.
McGlave PB, Haake R, Miller W, et al. Therapy of severe aplastic anemia in young adults and 
children with allogeneic bone marrow transplantation. Blood 70: 1325-1330, 1987.
8.
Feig SA, Champlin R, Arenson E, et al.  Improved survival following bone marrow transplantation 
for aplastic anemia. B J Haematol 54:509, 1983.
8a.  Witherspoon RP, Fisher LD, Schoch G, Martin P, Sullivan KM, Sanders J, Deeg HJ, Doney K, 
Thomas D, Storb R, Thomas ED:  Secondary cancers after bone marrow transplantation for 
leukemia or aplastic anemia.  N Eng J Med 321:710,1989.  
8b.  Socie G, Henry-Amar M, Cosset JM, Devergie A, Girinsey T, Gluckman E:  Increased incidence of 
solid malignant tumors after bone marrow transplantation for severe aplastic anemia.  Blood 78: 
277, 1991.
8c.
Sanders JE, and the Seattle Marrow Transplant Team:  The impact of marrow transplant preparative 
regimens on subsequent growth and development.  Semin Hematol 29: 244, 1991.
8d. 
Storb R, Etzioni R, Anasetti C, Applebaum FR, Buckner CD, Bensinger W, Bryant E, Clift R, Deeg 
HJ, Doney K, Flowers M, Hansen J, Martin P, Pepe M, Sale G, Sanders J, Singer J, Sullivan KM, 
Thomas ED, Witherspoon RP:  Cyclophosphamide Combined With Antithymocyte Globulin in 
Preparation for Allogeneic Bone Marrow Transplants in Patients With Aplastic Anemia. Blood 84: 
941-49, 1994.
 9a
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, 
Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O'Brien SG, 
Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, 
Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, 
Baccarani M, Morra E; The International STI571 CML Study Group. Hematologic and cytogenetic 
responses to imatinib mesylate in chronic myelogenous leukemia.  N Engl J Med 2002 Feb 
28;346(9):645-52
9b.
Maziarz, R, Druker B, Personal Communication.
9c.
Thomas ED, Clift RA. Indications for marrow transplantation in chronic myelogenous leukemia.  
Blood 73: 861-864, 1989.
10.
Santos GW. Marrow transplantation in acute non-lymphocytic leukemia.  Blood 74: 901-908, 1989.
11.
Ramsey, N.  Blood 75: 815, 1990
12.
Armitage, J.O. Marrow transplantation in the treatment of patients with lymphoma.  Blood 73: 
1749-1758, 1989.
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Protocol No. RP 98-15
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13.
Champlin, R.  Blood 73: 2051-2066, 1989
14.
Appelbaum, F.  Blood 72: 179, 1988
15.
Gale RP, Brit J Haematol 67: 397, 1987
16.
Ferrara JLM, Deeg HJ. Graft-versus-host disease. New Eng J Med 324: 667-674, 1991.
17.
Martin PJ. The role of donor lymphoid cells in allogeneic marrow engraftment. Bone Marrow 
Transpl 6: 283-289, 1990.
18.
Butturini A, Gale RP. New strategies for T-cell depletion. Bone Marrow Transpl 6: 225-227, 1990.
19.
Horowitz MM, Blood 75: 555, 1990.
20.
Wolff, S.  J. Clin. Oncol. 7: 1260. 1989.
21.
Grier, H.  J. Clin. Oncol. 7: 1026, 1987.
22.
Schiffer CA, Lee EJ. Approaches to the therapy of relapsed acute myeloid leukemia. Oncology 3: 
23-27, 1989.
23.
Clavell, L.  New Eng. J. Med. 315: 657, 1986.
24.
Rivera, G.  New Eng. J. Med. 315: 273, 1986.
25.
Hoelzer, D.  Blood 71: 123, 1988.
26.
Brochstein, J.A.  New Eng. J. Med. 317: 1618, 1987.
27.
Cheson, B.  Ann. Int. Med. 112: 932, 1990.
28.
Appelbaum, F. Ann. Int. Med. 112: 590, 1990.
29.
Philip, T.  New. Eng. J. Med. 316: 1493, 1987.
30.
Takvorian, T.  New. Eng. J. Med. 316: 1499-1505, 1987.
31.  
Hansen J, Peterdorf E, Martin P, Anasetti C.  Hematopoietic stem cell transplants from unrelated 
donors.  Immunological Reviews 157: 141-151, 1997.
32.
Hansen J. Donor selection for marrow transplantation. HLA polymorphism and matching. In Gale 
RP, Champlin RE (eds.), Bone Marrow Transplantation: Current controversies. Alan R. Liss, New 
York, 1989, pp 607-618.
33.
Beatty PG, Anasetti CA, Thomas ED, et al. Marrow transplantation from relatives other than HLA-
identical siblings. In Gale RP, Champlin RE (eds.), Bone Marrow Transplantation: Current 
controversies. Alan R. Liss, New York, 1989, pp 619-624.
34.
Ash RC, Casper J, Menitove J, et al. Evolving role of the closely HLA-matched unrelated marrow 
donor:  HLA matching considerations for alternative donor transplantation. In Gale RP, Champlin 
RE (eds.), Bone Marrow Transplantation: Current controversies. Alan R. Liss, New York, 1989, pp 
629-640.
35.
Powles R, Mehta J, Kulkarni S, Treleaven J, et al.  Allogeneic blood and bone marrow stem-cell     
transplantation in haematological malignant diseases:  a randomised trial.  The Lancet Vol 355, 
4/8/00
36a.
Russell JA, Brown C, Bowen T, et al.  Allogeneic blood cell transplants for haematological 
malignancy;   preliminary comparison of outcomes with bone marrow transplantation.  Bone 
Marrow Transplant 1996; 17; 703-08.
36b.
Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson EM, Woolfrey AE, 
Hansen JA. Optimizing outcome after unrelated marrow transplantation by comprehensive 
matching of HLA class I and II alleles in the donor and recipient. Blood 1998 Nov 15;92(10):3515-
20
37
Bensinger W, Martin P, Clift R, et al.  A prospective, randomised trial of peripheral blood stem 
cells (PBSC) or marrow (BM) for patients undergoing allogeneic transplantation for hematologic 
malignancies.  Blood 1999; 94 (suppl 1):  368a (abstr.)
38
von Bueltzingsloewen A, Belanger R, Perreault C, Bonny Y, Roy DC, Boileau J, Kassis J, Lavallee 
R, Lacombe M, Gyger M.  Allogeneic bone marrow transplantation following busulfan-
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cyclophosphamide with or without etoposide conditioning regimen for patients with acute 
lymphoblastic leukaemia.  Br J Haematol 85:706-13, 1993. 
39
Copelan EA, Biggs JC, Avalos BR, Szer J, Cunningham I, Klein JP, Atkinson K, Kapoor N, Klein 
JL, Downs K, et al.  Radiation-free preparation for allogeneic bone marrow transplantation in adults 
with acute lymphoblastic leukemia.  J Clin Oncol 10:237-42, 1992 
40
Avalos BR, Klein JL, Kapoor N, Tutschka PJ, Klein JP, Copelan EA.  Preparation for marrow 
transplantation in Hodgkin's and non-Hodgkin's lymphoma using Bu/CY.  Bone Marrow Transplant 
12:133-8, 1993.
41
Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L, Parkkali T, Lenhoff S, 
Sallerfors B, Ljungman P, et al.  A randomized trial comparing busulfan with total body irradiation 
as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic 
Bone Marrow Transplantation Group.  Blood 83:2723-30, 1994.
42
Santos GW.  Busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation 
for marrow transplantation in chronic myelogenous leukemia--a review.  Leuk Lymphoma 
11(S1):201-4, 1993. 
43
von Bueltzingsloewen A, Belanger R, Perreault C, Bonny Y, Roy DC, Lalonde Y, Boileau J, Kassis 
J, Lavallee R, Lacombe M, et al.  Acute graft-versus-host disease prophylaxis with methotrexate 
and cyclosporine after busulfan and cyclophosphamide in patients with hematologic malignancies.  
Blood 81:849-55, 1993. 
44
Bandini G, Belardinelli A, Rosti G, Calori E, Motta MR, Rizzi S, Benini C, Tura S.  Toxicity of 
High-dose Busulfan and Cyclophosphamide as Conditioning Therapy for Allogeneic Bone Marrow 
Transplantation in Adults with Haematological Malignancies.  Bone Marrow Transplant 13:577-81, 
1994.
45
Beelen D, Quabeck K, Graeven U, Sayar H, Mahmoud H, Schaefer U.  Acute Toxicity and First 
Clinical Results of Intensive Postinduction Therapy Using a Modified Busulfan and 
Cyclophosphamide Regimen With Autologous Bone Marrow Rescue in First Remission of Acute 
Myeloid Leukemia.  Blood vol 74 no 5:  1507-16, 1989.
46
Burnett A, Pendry K, Rawlinson P, Blesing N, Green R, Hann I, McDonald G, Robertson A, Gibson 
B.  Autograft to Eliminate Residual Disease in  AML First Remission - Update on the Glasgow 
Experience.  Bone Marrow Transplantation, 6:59-60, 1990.
51.
Lowenburg B, Verdonck L, Dekkar A, et al.  Autologous Bone Marrow Transplantation in Acute 
Myeloid Leukemia in First Remission:  Results of a Dutch Prospective Study.  Journal of Clinical 
Oncology 8: 287-94, 1990.
52.
Willemze R, Fibbe W, Kluin 0, Nelemans J, et al.  Bone Marrow Transplantation or Chemotherapy 
as Post-Remission Treatment of Adult Acute Myelogenous Leukemia.  Annals of Hematology 62: 
59-63, 1991. 
53.
Stewart P, Buckner C, Bensinger W, et al.  Autologous Marrow Transplantation in Patients With 
Acute Nonlymphocytic Leukemia in First Remission.  Exp Hematology 13:267-72, 1985.
54.
Giralt S, Thall PF, Khouri I, Wang X, et al.  Melphalan and purine analog-containing preparative 
regimens: reduced intensity conditioning for patients with hematologic malignancies undergoing 
allogeneic progenitor cell transplantation.  Blood, 97:631-637, 2001.   
55.
 Personal communication, S Giralt.
56.
Schuler US, Ehrsam M, Schneider A, Schmidt H, Deeg J, Ehninger G. Pharmacokinetics of 
intravenous busulfan and evaluation of the bioavailability of the oral formulation in conditioning for 
hematopoietic stem cell transplantation. Bone Marrow Transplant 1998 Aug;22(3): 241-4
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Appendix 1
Calculation of Ideal and Adjusted Body Weight
To calculate ideal body weight for men:
50 + 0.91x(height in cm – 152) 
To calculate ideal body weight for women:
45 + 0.91x(height in cm – 152)
 
To calculate ideal body weight for small children: ages 1-16 and under 5 feet (152.5 cm)
                     (Height in cm) 2 x 1.65                      gives you IBW in kg.  
                                    1000
                           .
To calculate ideal body weight for children:  ages 1 – 16 and 5 feet tall and taller 
 
IBW (male) = 39 + (2.27 X height in inches over 5 feet)
 
IBW (female) = 42.2 + (2.27 X height in inches over 5 feet)
To calculate adjusted ideal body weight for men and women:
Ideal body weight + [0.25 x (actual body weight – ideal body weight)]
The calculation of ideal body weight is referenced in the package insert of Busulfex (busulfan) Injection, 
and also found in the article written by:  Gibbs, JP, Gooley, T, Comeau, B, et al, “The Impact of Obesity 
and Disease on Busulfan Oral Clearance in Adults”, Blood, Vol 93, No 12 (June 15) 1999:  pp 4436-4440. 
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Appendix 2
Regimen Related Toxicity in Patients Undergoing BMT (Bearman*)
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 confustion 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
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
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); 1562-1568
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Appendix 3
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
+++
Generalized erythroderma
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
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
Source:  Thomas et al, N Engl. J Med. 1975; 292, 832
APPROVED RPCI IRB
10/22/2018


Protocol No. RP 98-15
Rev September 27 2018
 Page 31 of 33
Appendix 4
International Prognostic Scoring System (IPSS) For MDS Classification
IPSS Score 
Value
Prognostic 
Variable
0
0.5
1.0
1.5
2.0
BM Blasts (%)
<5
5-10
-
11-20
21-30
Karyotype*
Good
Intermediate
Poor
Cytopenias**
0/1
2/3
* Cytogenetic Classification
Good:
normal,  or –Y alone, del(5q) alone or del(20q) alone
Poor:
complex (≥3 abnormalities) or chromosome 7 anomalies
Intermediate:
other abnormalities, +8
** Cytopenias were defined as:
Hemoglobin
<10 g/dL
ANC
<1,500/μL
Platelet Count
<100,000/ μL 
Scores for risk groups are as follows:
Score
Risk
Median 
Survival
AML Evolution*
0
Low
5.7 yrs
9.4 years
0.5-1.0
Intermediate 1
3.5 yrs
3.3 years
1.5 –2.0
Intermediate 2
1.2 yrs
1.1 years
> 2.5
High
0.4 yrs
0.2 years
* Time until 25% of patients in the risk group developed acute myeloid leukemia. AML, acute myeloid 
leukemia
Adapted from Greenberg P, Cox C, Le Beau MM, et al. International scoring system for evaluating 
prognosis in myelodysplastic syndromes, Blood 89:2079-2088,1997. erratum: Blood 91: 1100, 1998.
APPROVED RPCI IRB
10/22/2018


Protocol No. RP 98-15
Rev September 27 2018
 Page 32 of 33
Appendix 5
Calculation of  Body Surface Area
The “New England Journal” formula for calculating body surface area (BSA) in adults will be the standard 
method at Roswell Park Cancer Institute.  
To calculate Body Surface Area:
Square root ((wt[kg] x ht[cm])/(3600))
Performance Status
Karnofsky Performance Status   (age>=16 years
Lansky Scale (age <16 years)
Able to carry on normal activity; no special care is needed:
Normal Range.
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity
80
   Normal activity with effort
100       Fully active
90
     Minor restriction in physically strenuous play
80
      Restricted in strenuous play, tires more easily, 
             otherwise active
Unable to work; able to live at  home, care 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
60
Requires occasional assistance but is able to care for
   most needs
50
    Requires considerable assistance and frequent 
   medical care
70
       Both greater restrictions of, and less time spent in,
              active play
60
      Ambulatory up to 50% of time, limited active play 
              with assistance/supervision
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
30
   Severely disabled; hospitalization indicated,
   although death is not imminent
20    Very sick; hospitalization necessary
10
   Moribund; fatal process progressing rapidly
40
       Able to initiate quiet activities
30
       Needs considerable assistance for quiet activity
20
       Limited to very passive activity initiated by others
 
 (i.e., TV)
10
Completely disabled, not even passive play
APPROVED RPCI IRB
10/22/2018


Protocol No. RP 98-15
Rev September 27 2018
 Page 33 of 33
Appendix 6
Definitions:  On/Off Study Dates, On/Off Treatment Dates
On-Study Date
Start Treatment Date
Stop Treatment Date
Off-Study Date
Date conditioning 
regimen started
Date conditioning 
regimen started
Date infusion of stem 
cells is complete 
(relevant for patients who 
have more than one 
infusion over 2 or more 
days)
Date of first disease 
progression post-
transplant or date of 
death due to any cause or 
date patient failed to 
engraft
** All >/=2nd BMTs and DLIs count toward accrual, except for planned tandem auto BMTs which count 
once toward accrual
APPROVED RPCI IRB
10/22/2018