Clinical trial NCT00345865
Conditions: Lymphoma
Keywords: Hodgkin lymphoma non-Hodgkin lymphoma HIV-associated lymphoma
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2005-08-24; Completion date: 2019-06-28
Enrollment: 473 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as ifosfamide, etoposide, and carboplatin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving colony-stimulating factors, such as G-CSF, helps stem cells move from the patient's bone marrow to the blood so they can be collected and stored for peripheral stem cell transplant. Giving more chemotherapy, such as cyclophosphamide, carmustine, and etoposide, and total-body irradiation prepares the patient's bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and radiation therapy. More radiation therapy is given after transplant to kill any remaining cancer cells.

PURPOSE: This phase II trial is studying how well autologous peripheral stem cell transplant works in treating patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma.

Detailed description:
OBJECTIVES:

Primary

* Determine the disease-free survival and overall survival of patients with non-Hodgkin's or Hodgkin's lymphoma treated with autologous peripheral blood stem cell transplantation (PBSCT).
* Verify the safety and efficacy of autologous PBSCT in patients with HIV disease and relapsed lymphoma.

Secondary

* Evaluate immune reconstitution in HIV-positive patients undergoing autologous PBSCT and compare to immune reconstitution in HIV-negative patients.
* Predict the adequacy of peripheral blood stem cell (PBSC) harvest prior to flow analysis of a PBSC yield.
* Determine the time to engraftment for neutrophils and platelets.

OUTLINE:

* Peripheral blood stem cell (PBSC) mobilization with filgrastim (G-CSF) alone: Patients not requiring further disease reduction receive G-CSF subcutaneously (SC) once daily on days 1-8. Patients undergo PBSC collection by leukapheresis on days 5-8. Patients who do not adequately mobilize with G-CSF alone proceed to chemo-mobilization.
* Chemo-mobilization: Patients requiring further disease reduction receive 1 of 2 chemo-mobilization regimens.

  * Patients with CD20+ non-Hodgkin's lymphoma (NHL) or lymphocyte predominant Hodgkin's lymphoma: Patients receive rituximab intravenously (IV) over 6-8 hours on day 1, ifosfamide IV over 2 hours and etoposide IV over 30 minutes on days 2-4, and carboplatin IV over 1 hour on day 2. Patients receive G-CSF SC once daily beginning on day 5 and continuing until leukapheresis is completed. Patients undergo PBSC collection by leukapheresis on days 12-15.
  * All other patients: Patients receive ifosfamide IV over 2 hours and etoposide IV over 30 minutes on days 1-3 and carboplatin IV over 1 hour on day 1. Patients receive G-CSF SC once daily beginning on day 4 and continuing until leukapheresis is completed. Patients undergo PBSC collection by leukapheresis on days 12-15.
* Autologous PBSC transplantation (PBSCT) (Patients with NHL undergoing irradiation): Patients receive cyclophosphamide IV over 2 hours on days -7 and -6. Patients undergo total body irradiation (TBI) twice daily on days -4 to -1. Patients undergo autologous PBSCT on day 0. Patients receive G-CSF SC once daily beginning on day 5 and continuing until blood counts recover.
* Autologous PBSCT (Patients with Hodgkin's lymphoma or NHL not undergoing irradiation and cyclophosphamide): Patients receive camustine IV over 2 hours on days -6, etoposide IV over 2 hours twice daily on days -5 to -2, and melphalan over 1 hour on day -1. Patients undergo autologous PBSCT on day 0. Patients receive G-CSF SC once daily beginning on day 5 and continuing until blood counts recover.
* Autologous PBSC transplantation (PBSCT) (Patients with HL not undergoing irradiation): Patients receive cyclophosphamide IV over 2 hours on days -6 to -3, camustine IV over 2 hours on day -6, and etoposide IV over 4 hours twice daily on days -6 to -4. Patients undergo autologous PBSCT on day 0. Patients receive G-CSF SC once daily beginning on day 5 and continuing until blood counts recover.
* Post-transplant irradiation: Patients undergo post-transplant irradiation beginning on day 28. Persisting nodal masses ≥ 2 cm are treated with additional localized external beam irradiation.
* Post-transplant Rituximab therapy: patients with CD20+ NHL may undergo Rituximab maintenance starting between day +45 and +90 and being repeated at day +180 ± 14 days.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Arms: arm 1: Non Hodgkin's Lymphoma patients treated with cyclophosphamide, total body irradiation therapy, peripheral blood stem cell transplantation and G-CSF. arm 2: Patients with Hodgkin's lymphoma treated with cyclosphosphamide, carmustine, etoposide, peripheral blood stem cell transplantation and G-CSF. arm 3: Non Hodgkin's Lymphoma patients infected with HIV, treated with cyclophosphamide, total body irradiation therapy, peripheral blood stem cell transplantation and G-CSF. arm 4: Patients with Hodgkin's lymphoma treated with cyclosphosphamide, carmustine, etoposide, peripheral blood stem cell transplantation and G-CSF. arm 5: Patients with non Hodgkin's lymphoma ineligible to receive total body irradiation because of prior radiation and are not candidates for high dose cyclophosphamide will be treated with carmustine, etoposide, cytarabine, and melphalan followed by peripheral blood stem cell transplantation and G-CSF (called BEAM conditioning).
Interventions: intervention 1: carmustine intervention 2: cyclophosphamide intervention 3: etoposide intervention 4: peripheral blood stem cell transplantation intervention 5: irradiation therapy intervention 6: G-CSF intervention 7: Cytarabine
Intervention descriptions: intervention 1: Day -6, 300 mg/m\^2 over 2 hour intervention 2: NHL with radiation: Cyclophosphamide 60 mg/kg intravenous (IV) over two hours daily x 2 days.

HL without radiation: Cyclophosphamide, Days - 6 through -3, 1.5 gm/m\^2 over 2 hours daily x 4 days.

Cyclophosphamide will be dosed based on actual body weight (ABW) unless the patient is 20% or more of ideal body weight (IBW). If more than 20% of ideal body weight, an adjusted ideal body weight (AIBW) will be used for dosing. intervention 3: NHL without radiation and cyclophosphamide: Etoposide 100 mg/m2 IV over 2 hours twice daily on Day -5 through -2.

HL without radiation: 150 mg/m\^2 intravenously over 4 hours every 12 hours for 6 total doses on Days -6 through -4. intervention 4: Day 0 infuse PBSC. All patients will have PBSC collected by leukapheresis. Mobilization will be done with G-CSF alone (filgrastim) or using ifosfamide/carboplatin/etoposide and with or without rituximab. Leukapheresis is to begin on Day 5. intervention 5: Patients undergo total body irradiation (TBI) twice daily on days -4 to -1.

* \> 1000 cGy to whole lung, kidney, or abdominal bath.
* \> 3000 cGy to spinal cord, myocardium, mediastinum, lumbar periaortic lymph nodes.
* \> 3600 cGy to whole brain. intervention 6: Day 5: Begin G-CSF 5μg/kg/day subcutaneously (SQ) rounded to the nearest vial size.

Continue G-CSF until absolute neutrophil count (ANC) \> 1500/μl x 3 consecutive days.

If ANC falls \<1000/μL, restart G-CSF. intervention 7: 100 mg/m\^2 over one hour BID on days -6 through -2 of BEAM conditioning regimen.

Protocol documents:
Prot_SAP_000.pdf: 
MT2004-24: Auto PBSCT in Lymphoma
1
UNIVERSITY OF MINNESOTA BONE MARROW TRANSPLANTATION PROGRAM
Autologous Peripheral Blood Stem Cell Transplant for Patients with Lymphoma
CPRC# 2005LS048
MT 2004-24
Study Committee:
Veronika Bachanova, MD (Chair)
Linda Burns, MD
Daniel Weisdorf, MD
Jeffrey Miller, MD
Kathryn Dusenbery, MD
David McKenna, MD
Jo-Anne Young, MD
Qing Cao, MS (biostatistician)
Version Date: January 16, 2014
Confidential


MT2004-24: Auto PBSCT in Lymphoma
2
TABLE OF CONTENTS
1
OBJECTIVES....................................................................................................5
2
BACKGROUND AND RATIONALE .......................................................................5
3
ELIGIBILITY AND EXCLUSION CRITERIA...........................................................7
4
SUBJECT REGISTRATION...............................................................................11
5
TREATMENT PLAN .........................................................................................11
6
REQUIRED OBSERVATIONS (APPENDIX V) ....................................................20
7
ENDPOINTS...................................................................................................22
8
TRANSPLANT RELATED TOXICITIES AND COMPLICATIONS .............................22
9
ADVERSE EVENT REPORTING ........................................................................28
10
DATA AND SAFETY MONITORING...................................................................30
11
EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS........................30
12
ESTIMATION OF CELLS..................................................................................33
13
ADMINISTRATIVE PROCEDURES ....................................................................34
14
REFERENCES.................................................................................................34


MT2004-24: Auto PBSCT in Lymphoma
3
Revision History
date
Revision details
Consent change/
version date
08/23/05
original
1/30/07
1. Clarification of minimum cell dose required for individuals requiring
bone marrow harvest.
2. Addition of Rituximab therapy post-transplant for CD20+ NHL
3. Addition of risk of JC virus with progressive multifocal
leukoencephalopathy due to Rituximab.
2/15/2007
Revised eligibility (p.7) and cell collection sections (p.11) to allow for
identical twin donor
8/10/2007
Revised mobilization to allow for patients who have already failed
(R)ICE to use an alternate conditioning regimen.
7/15/2009
Dr. Bachanova replaces Dr Tomblyn as PI
4/1/2010
Standardized the cytoxan dosing in obesity (sections 5.3.1 and 12.2)
9/23/2010
Changed upper age eligibility to 75
Deleted Trec blood draws and analysis
05/17/2013
Add BEAM as an alternative preparative regimen for patients unable to
received additional radiation therapy and/or high dose
cyclophosphamide
update registration, event reporting and toxicity sections
Yes
8/5/2013
Fixed cut & paste error in the BEAM appendix – toxicity chart for
BCNU
Yes
1/16/2014
Fixed additional cut & paste error in the BEAM appendix – toxicity
chart for BCNU; correct BCNU (carmustine) infusion time – over 2
hours, not 1 hour
Yes


MT2004-24: Auto PBSCT in Lymphoma
4
SCHEMA
NHL, including
HIV infected
Mobilization by either:
Peripheral
Transplant using:
1)
another protocol, if eligible
Stem Cell
CTX plus TBI (NHL)
Post-transplant F/U &
2)
G-CSF alone
Collection
CTX, BCNU, VP-16 (HL or
immune reconstitution
3)
ICE +/- Rituximab
(NHL with prior RT)
studies
4)
Alternative conditioning if
BEAM
ineligible for 1,2, or 3.
Hodgkin’s
Lymphoma
Other related Activities: For calculation of PBSC harvest
Record each day of leukapheresis:

the pbCD34/µL prior to collection,

the total number of CD34+ cells harvested,

the volume of apheresis plus the patient’s height and weight
Evaluations for immune reconstitution
Quantitative Immunoglobulins and CD4 and CD 8 –prior to mobilization, day + 100 and then q 3 mon for 1 yr
For HIV-positive patients, CD4 and CD8 analysis at d+28 and d+60 as well.
R
E
G
I
S
T
E
R


MT2004-24: Auto PBSCT in Lymphoma
5
1.0
OBJECTIVES
Autologous hematopoietic stem cell transplant (HSCT) is appropriate care for
many patients with Hodgkin (HL) and non-Hodgkin Lymphomas (NHL).
1.1
Primary Objective
1.1.1 To determine the disease free survival and overall survival after
autologous HSCT for NHL and HL
1.1.2 To verify the safety and efficacy of autologous PBSC HSCT in
patients with HIV disease and relapsed lymphoma
1.2
Secondary Objectives
1.2.1 To evaluate immune reconstitution in HIV positive patients
undergoing autologous HSCT and compare to immune
reconstitution in HIV negative patients
1.2.2 To predict the adequacy of PBSC harvest prior to flow analysis of
a PBSC yield (see Section12.2)
1.2.3 To determine the time to engraftment for neutrophils and platelets
2.0
BACKGROUND AND RATIONALE
The role of high-dose chemotherapy and HSCT in the treatment of relapsed
lymphoma is well established1,2.
Since that time, continued improvements in
survival, supportive management and transplant techniques have developed.
Consequently, it is important to continue to scientifically study issues related to
autologous HSCT for patients with lymphomas.
Peripheral blood stem cells (PBSC) are now used almost exclusively as the source
of hematopoietic reconstitution for patients treated with autologous HSCT for both
NHL and HL. The use of PBSC instead of bone marrow has resulted in more rapid
hematopoietic engraftment3,4. A limitation to autologous HSCT is sufficient harvest
of the 2 x 106 CD34+ cells/kg minimum threshold considered necessary for
satisfactory engraftment 5. Optimal estimation of harvest yield prior to the actual
collection is difficult. Surrogate markers have been studied including the white
blood cell and platelet counts on the day of leukapheresis and the numbers of


MT2004-24: Auto PBSCT in Lymphoma
6
circulating CD34+ cells6,7. The most useful marker to date is the peripheral blood
CD34+ cells/µL8.
Even with this surrogate marker, some patients do not mobilize adequate numbers
of PBSC to proceed with transplant and alternative means of hematopoietic stem
cell harvest must be undertaken or alternative therapy sought. In a previous study
of 175 patients with lymphoma undergoing PBSC harvest and autologous HSCT at
the University of Minnesota, 41 (23%) had inadequate PBSC collections defined as
total collection of less than 2 x 106 CD34+/kg. Twenty-eight of these patients went
on to bone marrow harvest9.
With a reliable means to predict the harvest yield,
these patients may have been spared treatment delay and the morbidity and
expense of additional leukaphereses. Instead there may have been consideration
for initial bone marrow harvest or allogeneic transplant.
The kinetics and yield of mobilization are dependent upon the volume of apheresis
and the collection efficiency as well as the peripheral blood CD34+ cells/µL 10,11.
Consequently, even with sufficient circulating peripheral blood CD34+ cells, patients
still may not harvest well due to poor collection efficiency. It would be valuable to
have a means to estimate stem cell yield accurately to determine if the minimum
threshold of PBSC could be obtained with further collection procedures rather than
aborting the whole process.
A previously published retrospective analysis conducted by Gidron et al found that,
even in the setting of a low peripheral blood CD34+ cell count, adequate PBSC
could be harvested if the collection efficiency and numbers of harvests was
adequate12. They retrospectively reviewed 485 PBSC harvests where the
peripheral blood CD34+ count was known. In 104 harvests, the circulating
peripheral blood CD34+ cells were < 5/µL, a cut-off thought indicative of poor
collection. However, over 60% of these harvests contained more than 0.3 x 106
CD34/kg such that a person undergoing leukapheresis for 6-7 days would obtain
an adequate graft to move forward to transplant. Using this data, they determined
an equation useful to estimate the PBSC harvest based on collection efficiency,
volume of leukapheresis, the peripheral blood CD34+ cell count/µL, and the
patient’s ideal body weight (IBW). This study will attempt to validate that formula in
a prospective study. That validation will allow for better estimates of stem cell
harvest for patients planned for autologous HSCT for the management of
lymphoma.
Lymphoma is a frequent complication of HIV disease. With the advent of highly
active anti-retroviral therapy (HAART), transplant is being investigated for patients
with HIV and lymphoma13-15. A small case series (n=9) from the City of Hope
demonstrated adequate engraftment similar to non-HIV infected patients16. All
patients had either NHL or HL and were on HAART therapy. Patients were
conditioned with cyclophosphamide, BCNU, and etoposide (CBV). The median
time to neutrophil and platelet engraftment was 11 and 10 days, respectively.
Furthermore, despite a transient decrease in CD4+ counts to a nadir of 138/µL at


MT2004-24: Auto PBSCT in Lymphoma
7
two months post-transplant, the majority recovered pre-transplant CD4+ levels at a
median of 14 months post-transplant. Infections during the neutropenic period
included bacteremias, Clostridium difficile colitis, and an episode of culture negative
sepsis. Three patients subsequentely developed opportunistic infections including
zoster, cytomegalovirus viremia, and Pneumocystis carinii pneumonia in a patient
who stopped his prophylactic antimicrobials. Re and colleagues published another
small series (n=16) with similar results17. In both series, there were no deaths due
to treatment or opportunistic infection. Furthermore, in the series from Krishan et
al, seven of the nine patients were in remission at a median of 19 months after
transplant. While the literature supports the safety and benefit of transplantation,
the impact on immune reconstitution in HIV patients is unclear.
3.0 ELIGIBILITY AND EXCLUSION CRITERIA
3.1 Age: All patients must be less than 75 years of age at the time of enrollment
in the study.
3.2 Karnofsky performance status: >80% (>60% if poor performance status is
related to lymphoma) [Appendix I]
3.3 Life expectancy: Greater than 8 weeks.
3.4 No evidence of serious organ dysfunction that is not attributable to tumor
including:
3.4.1
Renal: Creatinine ≤ 2.0 mg/dl or creatinine clearance > 50 ml/min. 
3.4.2
Hepatic: No history of severe prior or ongoing chronic liver disease.
Total bilirubin ≤ 2.0 mg/dl, AST and alkaline phosphatase <5x 
upper limit of normal.
3.4.3
Cardiac: Patients must be free of symptoms of uncontrolled cardiac
disease including unstable angina, decompensated congestive
heart failure, or arrhythmia. The ejection fraction by gated cardiac
blood flow scan (MUGA) must be >45%.
3.4.4
Pulmonary: Patients must have no significant obstructive airways
disease (FEV1 must be ≥ 50%) and must have acceptable diffusion 
capacity (corrected DLCO > 50% of predicted).
3.4.5
Hematologic: Patients must have (1) hemoglobin > 8 gm/dL
without transfusion and off erythropoietin for 14 days or Aranesp
for 21 days; (2) WBC > 2.5 x 109/L with an ANC > 1.5 x 109/L off G-
CSF or GM-CSF for 10 days or Neulasta for 21 days; (3) Platelets
> 100 x 109/L without transfusion; (4) Bone marrow cellularity of >
20% with <10% involvement with tumor
3.4.6
Central nervous system: Patients with a history of CNS involvement
by lymphoma or with relapsed primary CNS lymphoma will be


MT2004-24: Auto PBSCT in Lymphoma
8
eligible. Patients with active CNS disease are eligible if they have
completed a standard treatment for CNS lymphoma and have no
evidence of progressive CNS disease at the time of enrollment.
3.4.7
Infection: Patients with serious uncontrolled infections at the time
of transplant will be excluded
3.5
Patients must be at least 4 weeks from previous chemotherapy; 6 weeks from
nitrosoureas.
3.6
Hepatitis B: Patients who are carriers of Hepatitis B will be included in this
study. These patients are not eligible to receive rituximab as a component of
their chemotherapy mobilization18.
3.7
HIV disease
Patients with HIV disease are eligible for this study provided that:
3.7.1
Patients will be seen in the infectious disease(ID)/HIV clinic prior to
enrollment on study for the purpose of determining eligibility and for
local coordination of HIV care during the peri-transplant period.
3.7.2
Must be on a maximally active anti-HIV regimen to control disease
as determined appropriate by the ID/HIV physicians. For the
majority of patients, this will be a highly active anti-retroviral
therapy (HAART)-type therapy including a protease inhibitor.
3.7.3
CD4+ ≥ 50/µL 
3.7.4 HIV RNA viral load ≤ 100,000 copies per mL on each of samples 4 
weeks apart. The most recent level must be within one month of
enrollment.
3.8
Non-Hodgkin’s lymphoma (NHL)
Patients with chemo-sensitive histologically confirmed NHL will be eligible for
this treatment protocol contingent on histologic subclassification.
NHL patients with resistant or refractory lymphoma (no PR following up to
three cycles of combination chemotherapy) will be ineligible for transplant in
this trial.
3.8.1 Precursor B-cell or Precursor T-cell NHL
3.8.1.1
Lymphoblastic lymphoma

All patients will be eligible in second or greater complete
remission (CR) or first or subsequent partial remission (PR).

Patients with any high-risk features will be eligible in first
complete remission

High risk features include:

Stage IV;


MT2004-24: Auto PBSCT in Lymphoma
9

LDH >2x normal;
 
≥ 2 extranodal sites. 
3.8.2 Mature B-cell Lymphomas
3.8.2.1
Small lymphocytic lymphoma (SLL) or Chronic Lymphocytic
Leukemia (CLL)
 
Patients will be eligible in ≥ CR1 with molecularly 
negative disease

Patients in CR with molecularly positive disease or in
PR will be excluded from autologous transplant.
3.8.2.2
Follicular Lymphoma
 
Patients will be eligible in ≥ first CR/PR (if treatment is 
delayed until clinically required).
Patients who are treated at diagnosis (without clinical
symptoms necessitating treatment, such as B symptoms,
bulky disease, marrow or other organ compromise) will be
eligible in ≥ second CR/PR. 
3.8.2.3
Diffuse Large B-cell Lymphoma
 
All patients will be eligible in ≥ CR2 or ≥ PR1.  
 
Patients with a high intermediate or high IPI (≥ 2 for 
age-adjusted IPI or ≥3 for IPI) at diagnosis will be 
eligible in first CR.
3.8.2.4
Mantle Cell Lymphoma

All patients will be eligible in first or greater CR or PR.
3.8.2.5
Burkitt’s/Burkitt’s like

All patients except localized lymphoma will be eligible
anytime after initial therapy (after achievement of first
complete remission), or in partial remission if they fail
to achieve CR.

Patients with localized (stage I or Ziegler stage A) will
be eligible only if they fail to achieve CR1 or after
relapse
3.8.3
Mature T-cell lymphoma

T-cell lymphomas including Primary T-cell not
otherwise specified, angioimmunoblastic, and ALK-


MT2004-24: Auto PBSCT in Lymphoma
10
positive anaplastic large cell, will be eligible after
initial therapy, whether or not CR is achieved.

Mycosis fungoides/Sezary syndrome will be eligible in
≥CR2/PR2 
3.9
Hodgkin's lymphoma (HL)
Patients with histologically proven HL will be eligible for transplantation after
failing prior therapy.
Patients with resistant disease (initial or at relapse): those who fail to
achieve an objective partial response to three cycles of combination non-
cross resistant chemotherapy will be ineligible for transplant in this trial.
3.9.1
For stage I/II patients treated with primary radiation, they must
have failed (no CR or progression after CR) at least one salvage
combination chemotherapy treatment regimen.
3.9.2
For advanced (stage III/IV) Hodgkin's disease, patients must have
failed an adriamycin containing regimen (ABVD) or an alternative
non-cross resistant regimen (eg MOPP).
3.9.3
Patients with any high-risk features will also be eligible, including
those who:

Fail to achieve complete remission with initial combination
chemotherapy

Patients with bulky disease after initial therapy
(chemotherapy or radiation) defined as residual mediastinal
mass ≥ 5 cm or other residual mass ≥ 10 cm accompanied 
by other features of persisting disease (e.g., Gallium or PET
scan positive; high LDH; enlarging on serial x-rays or biopsy
positive) will be eligible. If possible, persistent disease
should be proven by biopsy.
3.9.4
Patients should receive chemotherapy to attempt to achieve CR or
minimal disease state for all patients pre-transplantation. The use of
up to three cycles of non-cross resistant combination chemotherapy
is advised.
3.9.5
Residual areas of limited disease should receive radiotherapy
following and not prior to transplantation (See Section 5.4).
3.10 All responses are to be determined using the Response Criteria for Non-
Hodgkin’s Lymphoma19(Appendix II) and will include PET/CT prior to HCT.
3.11 All participating patients must exercise informed voluntary consent and sign a
consent form approved by the University of Minnesota Committee on the
Use of Human Subjects in Research.


MT2004-24: Auto PBSCT in Lymphoma
11
3.12 Patients may be transplanted under this protocol using a syngeneic
(identical) twin donor.
3.13 Exclusions
3.13.1
Patients eligible for any higher priority transplant protocols
3.13.2
Women who are pregnant or breast feeding
3.13.3
Patients with chemotherapy resistant disease
4.0 SUBJECT REGISTRATION
Patients will be registered to this study in OnCore at the time of consent signing.
5.0 TREATMENT PLAN
5.1 Peripheral Blood Stem Cell (PBSC) Mobilization
All patients will have PBSC collected by leukapheresis. Patients may be
eligible and enrolled on other higher priority PBSC mobilization studies.
Patients not requiring further disease reduction (i.e. in CR or very good PR
after salvage chemotherapy) can be mobilized with G-CSF alone at a dose
of 10µg/kg/day sub-cutaneously (see Appendix III) 9.

CR or CRu: definition per Appendix II

Very good PR: defined as minimal residual disease with all nodal sites
≤2 cm and no morphologic bone marrow involvement 
Patients with stage IV disease at the time of diagnosis or more than 1 year
from time of diagnosis to planned harvest should be considered for
chemotherapy priming if not eligible for alternative PBSC mobilization
studies 9.
If patients have progressed through the (R)ICE regimen, then an alternative
conditioning regimen will be used at the discretion of the treating physician.
One suggestion is to use Cyclophosphamide 4000mg/m2 as per protocol
MT2003-13. R-DHAP and Gemcitabine based regimen (Gemcitabine,
Vinorelbine, Dexamethasone) are also permitted. Rituximab 375mg/m2 may
be co-administered if the patient has a CD20+ lymphoma.


MT2004-24: Auto PBSCT in Lymphoma
12
5.1.1
Mobilization with G-CSF alone
G-CSF 10µg/kg/day subcutaneously q day each morning (prior to harvest on days
of apheresis) until completion of harvest
Leukapheresis will begin on day 5 of G-CSF administration
If patients do not adequately mobilize with G-CSF alone, they will then receive
chemo-mobilization (see 5.1.2)
5.1.2
Chemo-mobilization using ICE ± Rituximab (R-ICE)
Patients requiring further disease reduction (i.e. PR after salvage chemotherapy)
or others eligible will receive chemo-mobilization using Ifosfamide, Carboplatin,
and Etoposide (ICE) ± Rituximab (R-ICE). This may be administered either as an
inpatient or outpatient.
Patients with CD20+NHL or lymphocyte predominant HL will have Rituximab
included in their mobilization chemotherapy. Patients who are carriers of Hepatitis
B are not eligible to receive Rituximab regardless of their disease type.
Chemotherapy for mobilization will be administered as follows:
Day
Drug
Administration
1
Rituximab
(CD20+ NHL or
lymphocyte predominant
HL pts. only)
375mg/m2 on day 1 infused over 6-8 hours. Infusion should start
at 50mg/hr and increase by 50mg/hr every 30 minutes as
tolerated to a maximal infusion rate of 400mg/hr
Premedication with acetaminophen 650mg and benadryl 50mg
orally. Hydrocortisone 50mg IV may be administered if
necessary for infusion reactions.
Day 2
Ifosfamide
1665 mg/m2/day IV over 2 hours
MESNA
1665 mg/m2/day IV over 2 hours given concomitantly with
Ifosfamide
Etoposide (VP-16)
100mg/m2/day IV over 30 minutes after Ifosfamide
Carboplatin
AUC 5 (max dose 350mg/m2; see Appendix III) IV over 1 hour
after Etoposide
Day 3, 4
Ifosfamide
1665 mg/m2/day IV over 2 hours
MESNA
1665 mg/m2/day IV over 2 hours given concomitantly with
Ifosfamide
Etoposide (VP-16)
100mg/m2/day IV over 30 minutes after Ifosfamide


MT2004-24: Auto PBSCT in Lymphoma
13
Start
Day 5
G-CSF
10µg/kg/day SQ (dosed per appendix III) until completion of
leukapheresis
Ifosfamide will be dosed based on actual body weight (ABW)
unless the patient is 20% or more of ideal body weight (IBW) [See
section 12.2 for IBW formula]. If more than 20% of ideal body
weight, an adjusted ideal body weight (AIBW) will be used for
dosing. This is calculated as:
AIBW = IBW + 1/3(ABW - IBW)
Leukapheresis will begin the first day after the ANC ≥ 1.0 x 109/L.
This will likely be between day +12 and day +15 after the initiation
of chemotherapy.
5.1.3 Supportive Care during Chemotherapy mobilization
5.1.3.1
IV Hydration: All patients will be given a minimum of 1
Liter of Normal Saline daily (days 1 – 4) during
chemotherapy mobilization. Additional IV hydration can
be given at the physician’s discretion.
5.1.3.2
Prophylactic antiemetics will be administered as follows:
day 2 (prior to Ifosfamide, VP-16, and Carboplatin):
Ondansetron 32mg IV and dexamethasone 20mg IV plus
lorazepam 1mg po/IV 30 minutes before chemotherapy.
days 3 and 4: Ondansetron 8mg oral dissolving tablet
(ODT) every 8 hours and dexamethasone 10 mg IV 30
minutes before chemotherapy. Lorazepam and
prochlorperazine can be given IV/PO every 6 hours as
needed.
5.1.3.3
For patients with uric acid > 5.0 mg/dl on the first day of
chemotherapy, add allopurinol 300 mg/d or 150 mg/M2/d
po for 7 days or longer if hyperuricemia (> 10 mg/dl)
persists.
5.1.3.4
Beginning day 5 of mobilization, patients will be
monitored closely (at least q 48h but daily if medically
necessary) with careful observation for fever, infection, or
anemia or thrombocytopenia needing transfusion
support.
5.1.3.5
All blood products administered must be irradiated before
infusion and if the patient is CMV seronegative, must be
CMV-safe (CMV-seronegative or leukocyte depleted by
filtration).
5.1.3.6
Antibiotic prophylaxis starting on the first day of
chemotherapy will include Levofloxacin 500mg po daily
and Fluconazole 200mg po daily. Acyclovir 400mg po
TID should be given to if patient’s are seropositive for


MT2004-24: Auto PBSCT in Lymphoma
14
HSV.  Antibiotic prophylaxis will continue until the ANC ≥ 
1.0 x 109/L
5.1.3.7
Neutropenic fever or signs of infection should be
investigated promptly and treated empirically with broad
spectrum IV antibiotics.
5.1.3.8
CBC differential and platelets shall be monitored at least
q 48 hours
5.2 Peripheral Blood Stem Cell Collection
5.2.1 Patients must have satisfactory venous access using appropriate
large bore vascular access catheters suitable for repeated
leukapheresis. (Hickman/Leonard types are not acceptable;
Quinton or Davol double lumen subclavian 13.5 French dialysis
catheters are required.)
5.2.2 Collection starts on the first day after the ANC ≥ 1.0 x 109/L after
R-ICE or on day 5 of G-CSF if not chemo-mobilized
A peripheral blood CD34+ (pbCD34) cell count/µL will be drawn in
clinic daily prior to apheresis starting the first day of leukapheresis
and continuing through the entire period of leukapheresis
5.2.3 Peripheral blood stem cell collection proceeds for a minimum of 3
days regardless of the measured pre-collection pbCD34/µL unless
the goal (5 x 106 CD34+/kg) collection is met (see Section 5.2.4).
However, if patients do not collect a minimum of 0.1 x 106 CD34+
cells/kg on the first day of apheresis or a total of 0.3 x 106 CD34+
cells/kg by the completion of day 2 of apheresis, the leukapheresis
procedure will be aborted and alternative means of hematopoietic
stem cell collection will be determined as defined below
Decisions regarding continued PBSC collection beyond 3 days
should be based on the following:
5.2.3.1
If the pbCD34/µL is continuing to increase and the goal of
5 x 106 CD34+cells/kg has not been reached, then further
collections should proceed. This increase should be by
at least 1/µL/day to continue as long as the minimum
pbCD34/µL is ≥5.   

For example, if on day 2, the pbCD34/µL is 5 and on day
3, the pbCD34/µL is 6, then, if necessary, the collection
could proceed to day 4. If the pbCD34/µL on day 4 has
declined or reached a plateau, a fifth day of harvest
would not be done. However, if the pbCD34/µL is 7, then
apheresis could continue if necessary.

See Section 12.1 for formula to calculate pbCD34/µL


MT2004-24: Auto PBSCT in Lymphoma
15
5.2.3.2
If the patient was mobilized with G-CSF alone, then
growth factor should be stopped and the patient should
proceed to chemo-mobilization (see 5.2.4)
5.2.3.3
If the patient was chemo-mobilized, then a recovery
period of 1 – 2 weeks should be given and decision made
for alternative means of harvest (see 5.2.4)
5.2.4 Targets
Goal collection: 5 x 106 CD34/kg actual body weight
Minimal peripheral blood collection to proceed to transplant: 2 x
106 CD34/kg actual body weight.
Minimum collection to proceed to transplant if patient requires a
bone marrow harvest (see below): 1 x 106 CD34/kg actual body
weight.
If < 2 x 106 CD34/kg actual body weight are collected, alternative
harvesting procedure after ANC>1.5 x 109/L and Plt > 100 x 109/L
off G-CSF will be performed
If patient had previously undergone G-CSF mobilization,
then chemotherapy mobilization using ICE ± Rituximab per
5.1.2
If patient had previously undergone chemotherapy
mobilization then, if bone marrow biopsy is ≥20% cellular 
and without morphologic evidence of lymphoma, patients
will be given GM-CSF at 10µg/kg/day for 5 days. On day 5,
patients will undergo a 1.5L bone marrow harvest. For
patients requiring a bone marrow harvest, the minimum
CD34+ cell/kg dose is 1 x 106 CD34/kg actual body weight.
If patients do not achieve the minimal collection goal with
combination of growth factor and chemotherapy
mobilization and do not meet the bone marrow biopsy
criteria to move forward with bone marrow harvest, they will
be removed from the transplant portion of the study. Data
collected for harvest will be used in the evaluation of
appropriate secondary endpoints.
5.2.5
Syngeneic (identical) twin donors will be mobilized according to
standard clinical practice (as outlined in allogeneic protocol
MT2001-02)


MT2004-24: Auto PBSCT in Lymphoma
16
5.3 Transplant Admission
5.3.1 Non-Hodgkin’s lymphoma including irradiation
For patients who have had greater than the following pre-
transplant radiotherapy limits, treatment will be per section 5.3.2:
i) > 1000 cGy to whole lung, kidney, or abdominal bath.
ii) > 3000 cGy to spinal cord, myocardium, mediastinum, lumbar
periaortic lymph nodes.
iii) > 3600 cGy to whole brain.
Day
Procedure
Day -8
Admission
Day -7, -6
Cyclophosphamide 60 mg/kg i.v. over two hours daily x 2 days (total 120 mg/kg).
Day -5
Rest
Day -4, -3, -2, -1
Total body irradiation (TBI) 165 cGy b.i.d. x 4 days (total 1320 cGy).
Day 0
Reinfuse all previously collected PBSC.
Day +5
Begin G-CSF 5µg/kg/day SQ rounded to the nearest vial size.
Continue G-CSF until ANC > 1500/μl x 3 consecutive days. 
If ANC falls <1000/µL, restart G-CSF.
Cyclophosphamide dosing is calculated based on ABW (actual
weight) unless ABW is > 150% of IBW (Ideal Body Weight). In
this case the dose should be computed using adjusted body
weight.
Ideal body weight is calculated using:
50kg + [2.3kg x (height in inches - 60)] for men
45.5kg + [2.3kg x (height in inches -60)] for women
Adjusted body weight = IBW + 0.5(ABW - IBW)
TBI will be given by 6, 18, or 24 MV x-ray beams through right
and left lateral fields prescribed at the umbilicus at midplane.
Aluminum compensators will be used as necessary to deliver a
uniform dose within ±10% of the prescribed dose.
A beam
spoiler will be used to prevent skin sparing.
The dose rate will
be 10-19 cGy/min. Total dose will be 1320 cGy administered in 8


MT2004-24: Auto PBSCT in Lymphoma
17
fractions over 4 days. The interval between fractions should be at
least 6 hours.
5.3.2 Non-Hodgkin’s Lymphoma. Radiation-free and
Cyclophosphamide-free regimen
For patients with NHL

ineligible to receive total body irradiation because of prior
radiation (as above) to central nervous system, lungs, or
heart in excessive doses, or

patients who are not candidates for high dose
cyclophosphamide due to excessive risk of toxicity, the
following conditioning regimen will be used.
Treatment will be administered per current institutional guidelines.
Day
Procedure
Day -7
Admission
Day -6
BCNU 300 mg/m2 IV over 2 hours
Day -5
Etoposide 100 mg/m2 IV over 2 hours BID
AraC 100 mg/m2 IV over 1 hour BID
Day -4
Etoposide 100 mg/m2 IV over 2 hours BID
AraC 100 mg/m2 IV over 1 hour BID
Day -3
Etoposide 100 mg/m2 IV over 2 hours BID
AraC 100 mg/m2 IV over 1 hour BID
Day -2
Etoposide 100 mg/m2 IV over 2 hours BID
AraC 100 mg/m2 IV over 1 hour BID
Day -1
Melphalan 140 mg/m2 IV over 1 hour
Day 0
Re-infuse all previously collected PBSC
Day +5
Begin G-CSF 5µg/kg/day SQ rounded to the nearest vial size.
Continue G-CSF until ANC > 1500/μl x 3 consecutive days. 
If ANC falls <1000/µL, restart G-CSF.
BEAM conditioning regimen can be used for HL patients only if they are ineligible
for CBV (detailed below).


MT2004-24: Auto PBSCT in Lymphoma
18
5.1.3 Hodgkin’s Lymphoma Without Irradiation
For patients with HL the following conditioning regimen will be used.
Day
Procedure
Day -7
Admission
Day -6, -5, -4, -3
Cyclophosphamide 1.5 gm/M2 over 2 hours at 10 a.m. daily x 4 days. (Total dose
of cyclophosphamide 6 gm/M2)
Day -6
BCNU (carmustine) 300 mg/M2 over 2 hours, 9 am.
Day -6, -5, -4
Etoposide (VP-16) 150 mg/M2 intravenously over 4 hours every 12 hours starting
at 6AM and 6PM, for 6 total doses. (Total dose: 900 mg/M2)
Day -2, -1
Rest
Day 0
Reinfuse all previously collected PBSC
Day +5
Begin G-CSF 5µg/kg/day SQ rounded to the nearest vial size.
Continue G-CSF until ANC > 1500/μl x 3 consecutive days. 
If ANC falls <1000/µL, restart G-CSF.
Cyclophosphamide will be dosed based on actual body weight
(ABW) unless the patient is 20% or more of ideal body weight
(IBW) [See section 12.2 for IBW formula]. If more than 20% of
ideal body weight, an adjusted ideal body weight (AIBW) will be
used for dosing. This is calculated as:
AIBW = IBW + 1/3(ABW - IBW)
5.1.4 Supportive Care
5.1.4.1
All patients with uric acid > 5.0 mg/dl will receive
allopurinol (300 mg/d or 150 mg/M2/d po) beginning on
admission and continuing to Day -1 unless
hyperuricemia (>10 mg/dl) persists. Allopurinol may be
stopped when uric acid ≤ 5mg/dL. 
5.1.4.2
Vigorous intravenous hydration (2000-3000 ml/m2/day)
should be given from 4 hours before the first
cyclophosphamide dose until 24 hours past the second
dose. Adequate diuretics should be given and patients
urged to urinate every 1-2 hours to ensure urinary
output of at least 200 ml every two hours and to
maintain appropriate fluid balance. Patients should be
weighed b.i.d. during cyclophosphamide administration
to aid in managing fluid balance. Mesna should be given
totaling the same number of milligrams as the
cyclophosphamide dose each day. See MT(S)9006 for
Mesna dosing.


MT2004-24: Auto PBSCT in Lymphoma
19
5.1.4.3
Prior to infusion of PBSC on day 0, patients will receive
6 hours of hydration with D5 1/2NS + 20mEq KCL/L at a
rate of 150ml/hr. Patients will be administered
acetaminophen 650mg po and diphenhydramine 50mg
po 30 minutes prior to PBSC infusion
5.1.4.4
Patients will be eligible for additional supportive care
study protocols including, but not limited to, those
related to prophylaxis and treatment of infection,
mucositis, transfusions, nutritional support, graft failure,
and/or post-transplant therapy or immune reconstitution.
5.1.4.5
All blood product support will be irradiated to prevent
inadvertent blood donor lymphoid engraftment.
Standard BMT protocol blood product support
techniques will be used, including packed red cell
transfusions to maintain hemoglobin > 8.0 g/dl, platelet
transfusion support to maintain platelet counts
>10,000/μl. Leukocyte transfusions can be used if 
clinically indicated.
5.1.4.6
HIV positive patients will remain on optimized
antiretroviral medication regimen, which will usually be
HAART therapy. As there are no IV alternatives,
HAART therapy will be held if patient is unable to
tolerate oral medications and re-instituted as soon as
the patient can tolerate oral therapies.
5.1.4.7
All patients will receive standard antimicrobial
prophylaxis per institutional protocols (See Infection
Prophylaxis and Therapy Guidelines for BMT Recipients
at UMMC)
5.1.4.8
All patients will receive antiemetic support per
institutional protocols (see Antiemetic Guideline for BMT
Recipients at UMMC).
5.2
Post Transplant Irradiation
Patient’s will be eligible and should receive post-transplant irradiation after
disease re-staging at Day +28 per Appendix III and when ANC > 1500/µL
and Plts are > 100,000/µL.  Persisting nodal masses ≥ 2 cm will be treated 
with additional localized external beam irradiation with a target treatment of
2000 – 3600 cGy given as 150 – 200 cGy/day 5 days/week. Sites
suspicious for neoplastic involvement but <2 cm and potentially amenable
to radiation should have biopsy confirmation of neoplastic involvement
before treatment.


MT2004-24: Auto PBSCT in Lymphoma
20
5.3
Post Transplant Rituximab Therapy
Patients with CD20+ NHL will be eligible for post-transplant Rituximab
therapy if they have recovered from transplant. Particularly patients with
mantle cell lymphoma with high risk features prior to transplant (high MIPI
and positive preHCT PET or marrow MRD positive) may benefit from
Rituximab maintenance. Treatment will be started between day + 45 and day
+90 after transplant and will be repeated at day +180 ± 14 days.
5.3.3 Indications for Rituximab therapy
5.3.3.1
Hematologic: ANC > 1500/µL and Plts are >
100,000/uL
5.3.3.2
Recovery from all other transplant toxicity
5.3.3.3
Absence of active uncontrolled infections
5.3.4 Dosing
5.3.4.1
Rituximab 375mg/m2 once every 2 months..
Rituximab is administered on day 1 infused over 6-8 hours.
Infusion should start at 50mg/hr and increase by 50mg/hr every 30
minutes as tolerated to a maximal infusion rate of 400mg/hr.
Premedication with acetaminophen 650mg and benadryl 50mg
orally for each infusion. Hydrocortisone 50mg IV may be
administered if necessary for infusion reactions.
6
REQUIRED OBSERVATIONS (APPENDIX V)
In addition to complete history and physical examination with detailed recording
of initial sites and characteristics of disease at diagnosis, immunophenotyping
(molecular biologic or cytogenetic studies as available) as well as previous
chemotherapy and radiation and the clinical responses to this treatment, patients
will undergo multi-organ screening to assess their eligibility for initiation into the
study treatment protocol. An attempt should be made to obtain the scheduled
activity as close as possible to the scheduled date. However, scheduling
difficulties (for procedures and around weekends) may make this difficult.
Therefore the scheduled activity will be obtained within 14 days of that schedule.


MT2004-24: Auto PBSCT in Lymphoma
21
6.1
Staging studies prior to enrollment to define the extent of disease will
include unilateral bone marrow aspiration and bone marrow biopsy, PET/CT
scans of chest, abdomen, pelvis (and neck if indicated), serum protein
electrophoresis, LDH, β2-microglobulin.
6.1.3 If patient has previous PET negative disease, then PET scan is not
required for eligibility or follow-up
6.1.4 If patient has had no prior bone marrow involvement, then bone
marrow biopsies will be performed to determine eligibility, at
day+100, and then at 1 year unless otherwise clinically indicated.
6.2
PBSC collection data: For each day of leukapheresis, the pbCD34/µL prior
to collection, the total number of CD34+ cells harvested, the patient’s actual
weight, the amount of CD34+ cells/kg of actual body weight and the volume
of apheresis will be recorded. The patient’s ideal body weight will be
calculated and included in the database.
6.3
Disease staging will be performed prior to enrollment in study; at Day +28,
at Day +100, at Day +180, at 1 year and then at 6 month intervals in the
second post-transplant year.
6.4
All diagnostic bone marrow aspiration and biopsy studies (at study entry
and thereafter) shall include a unilateral aspirate and bilateral bone marrow
biopsies for light microscopic morphologic studies; aspirate for
immunophenotyping (lymphoma panel, Cell Marker Lab); aspirate to
Molecular Diagnostics lab for gene rearrangement studies (if appropriate);
and cytogenetic studies to evaluate for development of myelodysplasia.
6.5
HIV-positive patients should have HIV disease assessed (HIV viral load and
CD4 count) prior to stem cell mobilization, at day +28, day +60, day +100
and then q 3 months during the first post-transplant year and then at 6
month intervals in the second and third post-transplant years, and then
yearly thereafter. If there is evidence of an increasing HIV viral load, the
patient’s HIV physician will be consulted
6.6
Evaluations for immune reconstitution
6.6.1 Quantitative Immunoglobulins (IgG, IgM, IgA) should be measured
prior to mobilization and post-transplant at day +100, day +180,
and at 1 year.
6.6.2 Evaluation of CD4 and CD8 cells should be measured prior to
mobilization and post-transplant at day +100, day +180, and 1
year.
For HIV-positive patients, CD4 and CD8 analysis will be
performed at day +28 and day +60 as well.


MT2004-24: Auto PBSCT in Lymphoma
22
7
ENDPOINTS
7.1Primary Endpoints
7.1.1 The percent of patients achieving complete response, the duration
of response and, ultimately, progression free and overall survival
will be evaluated.
7.1.2 Safety and outcomes of autologous transplant in the management
of lymphoma in HIV-positive patients with adequate control of HIV
disease.
7.2Secondary Endpoints
7.2.1 Prospective validation of the previously published formula used to
estimate targeted collection of PBSC (Section 12.0).
7.2.2 Evaluation of immune reconstitution post-transplant in patients with
HIV disease compared to HIV negative patients.
7.2.3 The time to hemopoietic recovery after transplantation (first of three
consecutive days of ANC ≥ 0.5 x 109/L; time to red cell transfusion-
independence [no transfusions for 30 days]; time to platelet
independence of 20 x 109/L and 50 x 109/L [no transfusions for 15
days]).
8 TRANSPLANT RELATED TOXICITIES AND COMPLICATIONS
8.1G-CSF
G-CSF
Common
Less Common
Rare
none

bone or muscle pain

injection site reaction
(redness, pain, or swelling)
allergic reaction
spleen enlargement or rupture
serious lung problems (ARDS)
coughing up blood
8.2Side Effects Of The Chemotherapy For Mobilization
Ifosphamide
Common
Less Common
Rare

nausea

vomiting

hair loss

bladder irritation and
pain or inflammation where the
drug was injected
low platelet count with
increased risk of bleeding
tiredness (fatigue)
confusion
sleepiness
seizures


MT2004-24: Auto PBSCT in Lymphoma
23
Ifosphamide
Common
Less Common
Rare
bleeding, blood in the urine

frequent or painful urination

abnormal kidney function

poor appetite

diarrhea

low white blood cell count
with increased risk of
infection
agitation
dizziness
constipation
hallucinations (seeing or
hearing things that aren't there)
severe kidney damage or
kidney failure
allergic reaction
abnormal heart rhythm
death due to effects on the
brain or other causes
Carboplatin
Common
Less Common
Rare
low white blood cell count with
increased risk of infection
low platelet count with
increased risk of bleeding
low red blood cell count
(anemia), which can make
you tired, dizzy, or easily out
of breath
brittle hair
kidney function can be altered
at high doses
fetal abnormalities if taken
while pregnant
nausea
vomiting
loss of appetite
diarrhea
constipation
taste changes
allergic reaction
sensation of pins and needles
in hands and/or feet related to
nerve irritation
temporary or permanent
infertility (inability to have
children)
confusion
changes in vision or vision
loss (which improves after
drug is stopped)
ringing in ears or hearing loss,
which may be permanent
rash
dehydration
sores in the mouth or throat
severe allergic reaction*
kidney damage (may go away
when drug is stopped)
liver problems
hair loss or thinning, including
face and body hair
dizziness
death due to allergic reaction,
infection, or other causes
Etoposide
Common
Less Common
Rare

low white blood cell count with
increased risk of infection

low blood platelet count with
increased risk of bleeding

nausea and/or vomiting

loss of appetite

hair loss, including face and
body hair
constipation
diarrhea
fever and chills
lowered red blood cell count
(anemia)
low blood pressure while drug
is being given
sores in mouth and throat
changes in how foods taste
rash, which can become
serious
itching
numbness and tingling in
hands and/or feet
allergic reactions (may include
chills, fever, rapid heart rate,
trouble breathing, dizziness)
increased risk of a second
cancer


MT2004-24: Auto PBSCT in Lymphoma
24
Rituximab
Common
Less Common
Rare
mild allergic reaction with first
infusion (may include fever,
headache, chills, itching,
hives, nausea, shortness of
breath)
allergic reaction with second
and later infusions
low white blood cell count with
increased risk of infection
cough
rash, itching
nausea
vomiting
diarrhea
muscle aches
runny nose
sinus infection
serious allergic reaction, with
hives, trouble breathing,
tightness in the chest or throat,
heart attack, or shock
serious skin reaction
kidney damage
low platelet count with
increased risk of bleeding
blockage or hole in the bowel,
with abdominal (belly) pain
low red blood cell count
(anemia) with tiredness and
weakness
death due to allergic reaction,
infection, lung damage, tumor
lysis syndrome, serious skin
rash, bowel obstruction, liver
failure from reactivated
hepatitis B, and other causes
8.3Peripheral Blood Stem Cell Collections
Risks to the apheresis process including:
1) bruising and/or bleeding where the needles are inserted for the apheresis,
2) reaction to citrate
3) loss of platelets with the of stem cells collection.
4) loss of blood (up to ½ pint) if the tubing breaks – this is very rare
8.4Side Effects Of The Preparative Agents For Transplantation
8.4.1 Cyclophosphamide, BCNU and Etoposide
Cyclophosphamide
Common
Less Common
Rare
low white blood cell count with
increased risk of infection
hair loss or thinning, including
face and body hair (usually
grows back after treatment)
nausea
vomiting
loss of appetite
sores in mouth or on lips
bleeding from bladder, with
blood in urine
allergic reaction with second
and later infusions
low white blood cell count with
increased risk of infection
cough
rash, itching
nausea
vomiting
diarrhea
muscle aches
low platelet count (mild) with
heart problems with high
doses, with chest pain,
shortness of breath, or
swollen feet
severe allergic reactions
skin rash
scarring of bladder
kidney damage (renal tubular
necrosis) which can lead to
kidney failure
heart damage, with trouble
getting your breath, swelling


MT2004-24: Auto PBSCT in Lymphoma
25
Cyclophosphamide
Common
Less Common
Rare
diarrhea
long-term or short-term
infertility (inability to have
children) in women and men
increased risk of bleeding
darkening of nail beds
acne
tiredness
infection
fetal changes if you become
pregnant while taking
cyclophosphamide
of feet, rapid weight gain
scarring of lung tissue, with
cough and shortness of
breath
second cancer, which can
happen years after taking this
drug
death from infection, bleeding,
heart failure, allergic reaction,
or other causes
BCNU (Carmustine)
Common
Less Common
Rare

low white blood cell count
with increased risk of
infection

low platelet count with
increased risk of bleeding

nausea

vomiting

loss of appetite

diarrhea

headache

pain along vein while the
drug is being given

irritation of vein used for
giving the drug

fetal abnormalities if
pregnancy occurs while
taking this drug

scarring of lung tissue, with
cough and shortness of
breath, which can happen
years after treatment

flushing of skin

redness of the eyes (just after
infusion)

tiredness (fatigue)

loss or thinning of hair
(including hair on the face
and body)

low red blood cell counts
(anemia) causing tiredness
and other symptoms

temporary kidney damage

hardening of vein used for
injection

liver abnormalities, which
usually get better when the
drug is stopped

death due to lung damage or
other problems
Etoposide
Common
Less Common
Rare

low white blood cell count with
increased risk of infection

low blood platelet count with
increased risk of bleeding

nausea and/or vomiting

loss of appetite

hair loss, including face and
body hair
constipation
diarrhea
fever and chills
lowered red blood cell count
(anemia)
low blood pressure while drug
is being given
sores in mouth and throat
changes in how foods taste
rash, which can become
serious
itching
numbness and tingling in
hands and/or feet
allergic reactions (may include
chills, fever, rapid heart rate,
trouble breathing, dizziness)
increased risk of a second
cancer


MT2004-24: Auto PBSCT in Lymphoma
26
8.4.2 BEAM
BCNU (Carmustine)
Common
Less Common
Rare

low white blood cell count
with increased risk of
infection

low platelet count with
increased risk of bleeding

nausea

vomiting

loss of appetite

diarrhea

headache

pain along vein while the
drug is being given

irritation of vein used for
giving the drug

fetal abnormalities if
pregnancy occurs while
taking this drug

scarring of lung tissue, with
cough and shortness of
breath, which can happen
years after treatment

flushing of skin

redness of the eyes (just after
infusion)

tiredness (fatigue)

loss or thinning of hair
(including hair on the face and
body)

low red blood cell counts
(anemia) causing tiredness
and other symptoms

temporary kidney damage

hardening of vein used for
injection

liver abnormalities, which
usually get better when the
drug is stopped

death due to lung damage or
other problems
Total Body Irradiation (TBI)
Common
Less Common
Rare
nausea and vomiting
diarrhea
cataracts
sterility
endocrinopathies
growth failure
intestinal cramps
mucositis

parotitis

interstitial pneumonitis

generalized mild erythema

veno-occlusive disease
dysphagia
vertebral deformities
nephropathy
risk of 2nd malignancy years
later (when given along with
chemotherapy)


MT2004-24: Auto PBSCT in Lymphoma
27
Etoposide
Common
Less Common
Rare

low white blood cell count with
increased risk of infection

low blood platelet count with
increased risk of bleeding

nausea and/or vomiting

loss of appetite

hair loss, including face and
body hair
constipation
diarrhea
fever and chills
lowered red blood cell count
(anemia)
low blood pressure while drug
is being given
sores in mouth and throat
changes in how foods taste
rash, which can become
serious
itching
numbness and tingling in
hands and/or feet
allergic reactions (may include
chills, fever, rapid heart rate,
trouble breathing, dizziness)
increased risk of a second
cancer
Ara-C
Common
Less Common
Rare

low white blood cell count with
increased risk of infection

low platelet count with
increased risk of bleeding

low red blood cell count
(anemia) with symptoms like
weakness, tiredness,
shortness of breath

nausea

vomiting

stomach pain

tiredness (fatigue)

sores in mouth or on lips

diarrhea

loss of appetite

rash

hair loss or thinning (may
include face and body hair)

fever

muscle and bone aches

liver damage

blood clots and inflammation
of the vein where the drug
was given
red or swollen eyes
sleepiness
muscle weakness
trouble walking
trouble writing
slurred speech
kidney damage
fetal changes that may lead to
birth defects, prematurity, or
serious illness in the newborn
if you become pregnant while
taking this drug
allergic reaction with itching,
dizziness, trouble breathing,
or swelling of the face, mouth,
or throat
death due to infection,
bleeding, or other causes
Melphalan
Common
Less Common
Rare

nausea (at higher doses)

vomiting (at higher doses)

low white blood cell count
with increased risk of
infection

low platelet count with
increased risk of bleeding

anemia (low red blood cell
count) with symptoms like
tiredness, paleness, or

short-term or long-term
infertility (inability to have
children)

weakness

severe allergic reaction

loss of appetite

scarring (fibrosis) or
inflammation of lungs

hair loss, including face and
body hair

rash

itching

second type of cancer (may


MT2004-24: Auto PBSCT in Lymphoma
28
Melphalan
Common
Less Common
Rare
trouble catching breath
happen years after
treatment)

death from lung damage or
other causes
8.5Possible Risks of Autologous Transplant:
During the cell infusion: nausea, chills
During the post-transplant period:

low blood counts increasing the risk of infection and bleeding

suppression of the immune system

risks of cancer recurrence
9
ADVERSE EVENT REPORTING
Toxicity and adverse events will be classified according to NCI's Common
Terminology Criteria for Adverse Events V 3.0 (CTCAE) and reported on the
schedule below. A copy of the CTCAE can be downloaded from the CTEP home
page
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev
3.pdf).
9.1
Definitions
The following definitions are based on the Code of Federal Regulations
Title 21 Part 312.32 (21CFR312.32(a)).
Adverse Event:
Any untoward medical occurrence associated with the
use of a drug in humans, whether or not considered drug related.
Suspected Adverse Reaction:
Any adverse event for which there is a
reasonable possibility that the drug caused the adverse event.
Life-Threatening
Adverse
Event
Or
Life-Threatening
Suspected
Adverse Reaction: An adverse event or suspected adverse reaction is
considered “life-threatening” if, in the view of either the investigator or
sponsor, its occurrence places the patient or subject at immediate risk of
death.


MT2004-24: Auto PBSCT in Lymphoma
29
Event Attribution Categories:
CTCAE does not define an AE as necessarily ‘caused by a therapeutic
intervention.’ The clinical investigator must assign attribution for an
adverse event after naming and grading of the event.
Attribution
Description
Unrelated
The AE is clearly NOT related to the intervention
Unlikely
The AE is doubtfully related to the intervention
Possible
The AE may be related to the intervention
Probable
The AE is likely related to the intervention
Definite
The AE is clearly related to the intervention
Unanticipated (unexpected) adverse event or unexpected suspected
adverse reaction as defined by the University Of Minnesota IRB are
those that are not already described as potential risks in the consent form,
not listed in the Investigator’s Brochure or not part of an underlying
disease.
Expedited
(Rapid)
Reporting:
Certain
events
may
require
rapid
notification to entities providing patient safety oversight (e.g. IRB) as
detailed in section 9.2.
9.2
Adverse Event Reporting Requirements
The reporting period for this study is from initiation of study treatment
through engraftment or day 42, whichever occurs earlier; however after
this time point, the investigator must report upon knowledge any study
treatment related event meeting the expedited reporting criteria below.
The SAE Coordinator will provide the Cancer Center’s Data and Safety
Monitoring Council (DSMC) with the SAE in an appropriate format
depending on the individual SAE (as reported or in a summary format).
Agency
Criteria for reporting
Timeframe
Form to Use
Submission
address/ fax
numbers
Copy AE to:
U of MN
IRB
UPIRTSO: any event which is
unanticipated, involved new or
increased risk to subjects, and was at
least possibly related to study
procedures through engraftment or day
42, whichever occurs earlier
10 Working
Days
UMCC SAE
MMC 820
MCC SAE
Coordinator
mcc-
saes@umn.edu
Other Problems or Events meeting
the definition of UPIRTSO
UPIRTSO
Form
MCC SAE
Coordinator
Any event that counts toward a study
stopping rule (see section 11.2.2)
Upon
reporting
Study
stopping rule
form


MT2004-24: Auto PBSCT in Lymphoma
30
10 DATA AND SAFETY MONITORING
The study’s Data and Safety Monitoring Plan will be in compliance with the
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan
(DSMP),
which
can
be
accessed
at
http://www.cancer.umn.edu/exfiles/research/dandsmplan.pdf.
For the purposes of data and safety monitoring, this study is classified as moderate
risk. Therefore the following requirements will be fulfilled:

The PI will complete and submit a quarterly Trial Progress Report to
the Masonic Cancer Center Data and Safety Monitoring Council (DSMC) with the
understanding the Cancer Protocol Review Committee (CPRC) may require more
frequent reporting.

The PI will comply with at least twice yearly monitoring of the project by
the Masonic Cancer Center monitoring services.

The PI will oversee the submission of all reportable events per the
definition of reportable in section 9.2 to the Masonic Cancer Center’s SAE
Coordinator and the University of Minnesota IRB.
At the time of the IRB continuing review, the Principal Investigator will submit to the
CPRC a copy of all documentation submitted to the IRB for continuing review.
11 EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS
11.1 Estimated Accrual
It is estimated that approximately 30 patients per year will be accrued to
this study. Of these 30 patients, approximately 5 per year are expected to
be HIV positive.
11.2 Primary Endpoint analyses
11.2.1 Time-to-event analyses of progression-free and overall survival
Progression-free (PFS) and overall survival (OS) will all be
assessed by time-to-event analyses. Based on the event rate
from prior data collected from this institution on protocol MT1995-
27, the anticipated precision of the PFS estimate is ± 2.5% at 1
year and ± 3.3% at 5 years. For OS, the anticipated precision is
±1.5% at 1 year and ± 3.6% at 5 years.
Kaplan-Meier and cumulative incidence plots will describe the
distribution of event times. For events experienced by greater than
50% of patients, median event times and confidence intervals will


MT2004-24: Auto PBSCT in Lymphoma
31
be reported. Log-rank tests will assess differences between HIV
positive and negative patients
11.2.2
Safety of autologous PBSC HSCT in patients with HIV disease
and relapsed lymphoma
It is estimated that approximately 5 HIV positive patients per year
will be enrolled. Stopping rules will be implemented based on
numbers of unexpected adverse events in the cohort of HIV
positive patients. Based on current available literature for
autologous HSCT in HIV positive patients with lymphoma,
morbidity and mortality are similar to non-HIV infected patients
(i.e. ≤ 5%).  Based on this information, the study would be 
reviewed if the following occur:
2 events in the first 2 patients enrolled
3 events occurring up to and including15 patients enrolled
4 events occurring up to and including 22 patients enrolled
5 events occurring up to and including 30 patients enrolled
These stopping rules control the chance of stopping to 4.9% if the
event rate is at an acceptable 5% while giving an 80.7% chance of
stopping if the event rate is 20%. Other probabilities of stopping
the study are included in the table below.
Event Rate
Probability of Stopping Accrual
Expected number of
subjects enrolled before
stopping
8%
16.5%
28
10%
27.5%
26
15%
57.7%
21
18%
72.9%
18
20%
80.7%
16
25%
93%
13
30%
97.9%
10
11.3 Secondary Endpoint Analysis
11.3.1 Comparison of the actual CD34+ cells collected versus the
collection estimated by the formula (Section 12.2):
The accuracy of the formula’s estimation of CD34+ cell collection
will be assessed by a statistical description of the difference
between actual and estimated daily collection of CD34+ cells. This
difference is the formula’s discrepancy.


MT2004-24: Auto PBSCT in Lymphoma
32
A repeated measures (variance components) model will be used
to account for the correlation of daily differences from the same
patient.
Estimates of the mean daily difference and the standard deviation
of the daily differences both within and between patients will
characterize the formula’s performance.
A criterion of acceptable variation in the formula’s discrepancy is
specified a priori. The lower 95% confidence interval for the
predicted discrepancy shall not fall below zero by more than 1/3
the predicted CD34+ cell collection for CD34+ cell collection levels
in the range (0.3, 1.5) x 106 cells/kg. For example, for a formula-
predicted CD34+ cell collection of 0.5 x 106 cells/kg, the lower end
of the 95% confidence interval around the discrepancy should be
± 0.167, indicating high confidence that actual collection will fall
between 0.33 and 0.67 x 106 cell/kg.
Tests will also be performed to determine if the mean and
standard deviation of the formula’s discrepancy vary by pbCD34,
collection day, disease stage, type of lymphoma, and HIV status.
11.3.2 Assessment of CD34+ cell collection
CD34+ cell collection data will be described by its distribution,
mean, median, range and standard deviation both within patient
and across all patient cohorts.
Regression analysis of CD34+ cell collection will be performed to
estimate potential effects of collection day, pbCD34
measurement, HIV status and patient and lymphoma
characteristics on cell counts.
11.3.3
Immune reconstitution will be compared between HIV negative
and positive patients.
Immune reconstitution will be assessed by the time from
transplant until measured levels return to the lower of a patient’s
pre-transplant level and a clinically normal level. This
assessment will be performed for CD4, CD8, and quantitative
immunoglobulins (IgG, IgM, IgA).
Statistical comparison will be performed by a log-rank test to
compare Kaplan-Meier curves describing time-to-reconstitution
for each measured quantity.
11.3.4 Descriptive statistics for patient and lymphoma characterization


MT2004-24: Auto PBSCT in Lymphoma
33
Patient demographics, clinical history, and attributes of their
lymphomas will be described statistically using means, medians,
ranges, and standard deviations for quantitative variables and
frequencies for categorical variables. Differences between HIV
positive and negative patients will be assessed using t-tests and
chi-squared tests
11.3.5
Time-to-event analyses of engraftment of neutrophils and
platelets
Engraftment will be assessed by time-to-event analyses. Kaplan-
Meier and cumulative incidence plots will describe the distribution
of event times. For events experienced by greater than 50% of
patients, median event times and confidence intervals will be
reported. Log-rank tests will assess differences between HIV
positive and negative patients.
12 ESTIMATION OF CELLS
12.1 Hypothesis: Using a set volume of apheresis and the estimated
collection efficiency (CE) as well as the measured pbCD34/µL and donor
ideal body weight (IBW) in kilograms, the number of pbCD34 collected can
be accurately estimated prior to harvest
12.2 Formulas:
Prediction of CD34 + cells collected:
(Volume of Apheresis) x (CE) x [(pbCD34/µL) / (IBW)]

Volume of apheresis will be recorded by the Donor Center for every
collection

Based on recent analyses of stem cell collections, the estimated
collection efficiency (CE) at the University of Minnesota donor center is
60 ± 0.5%

Peripheral Blood (pb)CD34/µL = WBC count x %CD34
WBC count is reported in the computer x109/L
%CD34 is reported by the Flow cytometry lab as the percentage
of mononuclear cells that are dual positive for CD45 and CD34
The factor 10 corrects for conversion of WBC to cells/µL and the
%CD34 to an absolute number
EXAMPLE: Patient’s WBC is reported as 5.7 x 109/L and the
%CD34 is reported as 0.25% then
pbCD34/µL = 5.7 x 0.25 = 1.425/µL


MT2004-24: Auto PBSCT in Lymphoma
34

Ideal body weight is calculated using:
50kg + [2.3kg x (height in inches - 60)] for men
45.5kg + [2.3kg x (height in inches -60)] for women
Adjusted body weight = IBW + 0.5(ABW - IBW)
13 ADMINISTRATIVE PROCEDURES
13.1 Informed Consent
After the patient is fully evaluated and available clinical data is reviewed by the
attending physician, eligible patients are presented with specific details of the
treatment plan. The recommended therapeutic steps are discussed thoroughly
with the patient and family. The risks of the procedure are outline including the
priming of PBSC chemotherapy plus G-CSF, the peripheral stem cell collections,
the pre-transplant chemotherapy and/or radiation; the transplantation hospital
course; the potential need for local radiation treatment post-transplant and the
need for ongoing follow-up evaluation to monitor the patient's post-transplant
recovery.
The rationale of the study as well as the hazards of these components of
treatment is explained to the patient in full and all questions are answered as
completely as possible. Alternative forms of therapy are presented. After this
presentation, informed consent is obtained using forms approved by the
University of Minnesota IRB: Human Subjects Committee.
13.2 Records Retention
The investigator, through the CTO and BMT research database, will retain study
records, including source data and all study correspondence in a secured facility
for 6 years from the date of the study file closure with the IRB. In addition, the
Clinical Trials Office (CTO) will keep a master log of all patients participating in
the study, with sufficient information to allow retrieval of the medical records for
that patient.
14 REFERENCES
1. Neben K, Hohaus S, Goldschmidt H, Egerer G, Voso MT, Ho AD, Haas R.
High-dose therapy with peripheral blood stem cell transplantation for patients with
relapsed or refractory Hodgkin's disease: long-term outcome and prognostic factors.
Ann Hematol. 2000;79:547-555
2. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D,
Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL. Autologous bone marrow
transplantation as compared with salvage chemotherapy in relapses of chemotherapy-
sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995;333:1540-1545


MT2004-24: Auto PBSCT in Lymphoma
35
3. Chao N, Schriber J, Grimes K, Long G, Negrin R, Raimondi C, Horning S,
Brown S, Miller L, Blume K. Granulocyte colony-stimulating factor "mobilized" peripheral
blood progenitor cells accelerate granulocyte and platelet recovery after high-dose
chemotherapy. Blood. 1993;81:2031-2035
4. Schmitz N, Linch DC, Dreger P, Goldstone AH, Boogaerts MA, Ferrant A,
Demuynck HM, Link H, Zander A, Barge A. Randomised trial of filgrastim-mobilised
peripheral blood progenitor cell transplantation versus autologous bone-marrow
transplantation in lymphoma patients. Lancet. 1996;347:353-357
5. Bensinger W, Appelbaum F, Rowley S, Storb R, Sanders J, Lilleby K, Gooley
T, Demirer T, Schiffman K, Weaver C, et al. Factors that influence collection and
engraftment of autologous peripheral-blood stem cells. J Clin Oncol. 1995;13:2547-
2555
6. Armitage S, Hargreaves R, Samson D, Brennan M, Kanfer E, Navarrete C.
CD34 counts to predict the adequate collection of peripheral blood progenitor cells.
Bone Marrow Transplant. 1997;20:587-591
7. Borbolla J, Najera A, Lopez-Hernandez M, Gonzalez M, Siller A, Rubio B,
Garces O, Delgado J, Collados M. Correlation Coefficients Between Several
Parameters and CD34+ Cell Yield in Peripheral Blood Stem Cell Harvesting by
Apheresis. J Hematother Stem Cell Res. 2001;10:17-18
8. Chapple P, Prince H, Quinn M, Bertoncello I, Juneja S, Wolf M, Januszewicz
H, Brettell M, Gardyn J, Seymour C, Venter D. Peripheral blood CD34+ cell count
reliably predicts autograft yield. Bone Marrow Transplant. 1998;22:125-130
9. Tomblyn M, Rogers T, Arora M, Barker J, Brunstein C, Burns LJ, Kaufman D,
McGlave P, Miller J, Slungaard A, Weisdorf D. Predictive Factors for Adequate
Hematopoietic Stem Cell Mobilization with Hematopoietic Growth Factor Alone in
Patients with Lymphoma. Biol Blood Marrow Transplant. 2005;11:68
10. Benjamin RJ, Linsley L, Fountain D, Churchill WH, Sieff C, Cannon ME, Uhl
L, Gaynes L, Antin JH, Wheeler C. Preapheresis peripheral blood CD34+ mononuclear
cell counts as predictors of progenitor cell yield. Transfusion. 1997;37:79-85
11. Armitage S, Hargreaves R, Samson D, Brennan M, Kanfer E, Navarrete C.
CD34 counts to predict the adequate collection of peripheral blood progenitor cells.
Bone Marrow Transplant. 1997;20:587-591
12. Gidron A, Doyle M, Gordon L, Singhal S, Tallman M, Williams S, Winter J,
Tomblyn M, Verma A, Mehta J. Significance of Low Peripheral Blood CD34+ Cell
Numbers Prior to Leukapheresis: Should the 5/microL Threshold Required for
Apheresis be Changed? Biol Blood Marrow Transplant. 2004;10:15 - 16
13. Gabarre J, Azar N, Autran B, Katlama C, Leblond V. High-dose therapy and
autologous haematopoietic stem-cell transplantation for HIV-1-associated lymphoma.
Lancet. 2000;355:1071-1072
14. Krishnan A, Zaia J, Molina A. Stem cell transplantation and gene therapy for
HIV-related lymphomas. J Hematother Stem Cell Res. 2002;11:765-775
15. Molina A, Krishnan AY, Nademanee A, Zabner R, Sniecinski I, Zaia J,
Forman SJ. High dose therapy and autologous stem cell transplantation for human
immunodeficiency virus-associated non-Hodgkin lymphoma in the era of highly active
antiretroviral therapy. Cancer. 2000;89:680-689


MT2004-24: Auto PBSCT in Lymphoma
36
16. Krishnan A, Molina A, Zaia J, Nademanee A, Kogut N, Rosenthal J, Woo D,
Forman SJ. Autologous stem cell transplantation for HIV-associated lymphoma. Blood.
2001;98:3857-3859
17. Re A, Cattaneo C, Michieli M, Casari S, Spina M, Rupolo M, Allione B,
Nosari A, Schiantarelli C, Vigano M, Izzi I, Ferremi P, Lanfranchi A, Mazzuccato M,
Carosi G, Tirelli U, Rossi G. High-dose therapy and autologous peripheral-blood stem-
cell transplantation as salvage treatment for HIV-associated lymphoma in patients
receiving highly active antiretroviral therapy. J Clin Oncol. 2003;21:4423-4427
18. Rituximab Product Label approved by the FDA. 2004
19. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister
TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W,
Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an
international workshop to standardize response criteria for non-Hodgkin's lymphomas.
NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244


MT2004-24: Auto PBSCT in Lymphoma
37
Appendix I
Karnofsky Performance Status
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%)
CRITERIA
Able to carry on normal activity and to work;
no special care needed.
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
signs or symptoms of disease.
Unable to work; able to live at home and
care for most personal needs; varying
amount of assistance needed.
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 of his
personal needs.
50
Requires considerable assistance
and frequent medical care.
Unable to care for self; requires equivalent
of institutional or hospital care; disease may
be progressing rapidly.
40
Disabled; requires special care and
assistance.
30
Severely disabled; hospital
admission is indicated although
death not imminent.
20
Very sick; hospital admission
necessary; active supportive
treatment necessary.
10
Moribund; fatal processes
progressing rapidly.
0
Dead


MT2004-24: Auto PBSCT in Lymphoma
38
Appendix II
Response Criteria for Non-Hodgkin's Lymphoma
Response Category
Physical
Examination
Lymph
Nodes
Lymph
Node
Masses
Bone Marrow
CR
Normal
Normal
Normal
Normal
CRu
Normal
Normal
Normal
Indeterminate
Normal
Normal
> 75%
decrease
Normal or
indeterminate
PR
Normal
Normal
Normal
Positive
 
Normal 
≥50% 
decrease
50%
decrease
Decrease in
liver/spleen
50%
decrease
50%
decrease
Relapse/progression Enlarging
liver/spleen; new
sites
New or
increased
New or
increased
Reappearance
1. CR:
Complete disappearance of all detectable clinical and radiographic evidence of
disease and disappearance of all disease-related symptoms if present before
therapy, and normalization of biochemical abnormalities (i.e. LDH) attributable
to disease. All lymph nodes and nodal masses must have regressed to
normal size (< 1.5 cm in their greatest transverse diameter for nodes ≥1.5 cm 
before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their
greatest transverse diameter before treatment must have decreased to < 1 cm
in their greatest transverse diameter after treatment. The spleen, if considered
to be enlarged before therapy on the basis of a CT scan, must have regressed
in size and must not be palpable on physical examination. If the bone marrow
was involved by lymphoma before treatment, the infiltrate must be cleared on
repeat bone marrow aspirate and biopsy.
2. CRu: Includes patients who fulfill the criteria for CR but with the following features:
A residual lymph node mass greater than 1.5 cm in greatest transverse
diameter that has regressed by more than 75%. Individual nodes that were
previously confluent must have regressed by more than 75% compared with


MT2004-24: Auto PBSCT in Lymphoma
39
the size of the original mass. Indeterminate bone marrow (increased number
or size of aggregates without cytologic or architectural atypia).
3. PR:
At least 50% regression in diameter of major nodal masses. No increase in
the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must
regress by at least 50%. With the exception of splenic and hepatic nodules,
involvement of other organs is considered assessable and not measurable
disease. Bone marrow assessment is irrelevant for determination of a PR
because it is assessable and not measurable disease; however, if positive, the
cell type should be specified. No new sites of disease.
4. Stable Disease:
This is defined as less than a PR but is not progressive disease.
5. Progressive Disease:
At least a 50% increase from nadir of any previously identified abnormal node.
Appearance of any new lesion during or at the end of therapy.


MT2004-24: Auto PBSCT in Lymphoma
40
Appendix III
Calculation of AUC for Carboplatin dosing using Calvert formula
Carboplatin Dose (mg) = target AUC (mg/mL x min) x [GFR (mL/min) +25]
GFR (mL/min) = (wt in kg) x (140 – age)/ [72 x Creatinine]
** for women, multiply result by 0.85


MT2004-24: Auto PBSCT in Lymphoma
41
Appendix IV
Cell Collection, Storage and Use/Vascular Access for Apheresis
Peripheral blood stem cells will be collected using available apheresis machines.
Currently at the University Hospital, the Fenwal CS3000 is available and will be used. A
standard technique, using a modification of program one, run at 1400 rpm, will be used.
Procedures will be performed using either antecubital veins or 13.5 Fr Quinton/Davol
catheters if antecubital veins are not appropriate for apheresis collection. Peripheral
blood mononuclear cell collections will be performed on weekends only if clinically
appropriate.
Peripheral blood cells will be combined with an equal volume of 20% dimethylsulfoxide
(DMSO) in protein containing media for a final concentration of ≤ 300x106 nucleated
cells per kg and 10% DMSO. The cell concentrate will then be frozen at a controlled
rate in a programmable controlled rate freezer (1°minute through -60°C and 3°minute
through -90°C). The frozen cell concentrates will be stored in the vapor phase of liquid
nitrogen.
Quality control including careful measurement of CD34%, absolute MNC and NC counts
will be performed. The total number of CD34 cells collected (not weight based) as well
as the CD34/kg actual body weight will be reported.
See Section 5.2 for guideline for continuation of poor collections.


MT2004-24: Auto PBSCT in Lymphoma
42
Appendix V
Dosing of G-CSF and Volume of Apheresis based on patient actual body weight
BODY WEIGHT
DOSE OF G-CSF
VOLUME OF APHERESIS
<40 Kg
300 mcg
6 L
40 – 45 kg
300 mcg
6 L
45 – 50 kg
480 mcg
8 L
51 – 55 kg
480 mcg
8 L
56 – 60 kg
600 mcg
10 L
61 – 65 kg
600 mcg
10 L
66 – 70 kg
600 mcg
10 L
71 – 75 kg
780 mcg
12 L
76 – 80 kg
780 mcg
12 L
81 – 85 kg
900 mcg
12 L
86 – 90 kg
900 mcg
12 L
91 – 95 kg
900 mcg
12 L
>95 kg
1260 mcg
15 L


MT2004-24: Auto PBSCT in Lymphoma
29
Appendix VI
Required Observations
within 30
days of
enrollment
Start of
mobilization
Daily
during
apheresis
Prior to
Admit for
transplant
day
+28
day
+60
day
+100
day
+180
1
yr
1
8
m
o
2y
r
Medical History
x
x
x
Physicial Exam
x
x
x
x
x
x
x
x
x
x
x
Weight/Height
x
x
x
x
Performance
status
x
x
x
x
x
x
x
x
x
x
Adverse
Event/toxicity
notation
x
x
x
x
x
x
x
x
x
x
x
Comprehensive
chemistry panel
x
x
x
x
x
x
x
x
x
Hepatic Panel
x
x
x
x
x
x
x
x
x
CBC with diff
x
x
x
x
x
x
x
x
x
x
x
*SPEP
x
x
x
LDH
x
x
x
x
x
x
x
*ß2-
microglobulin
x
x
x
HIV viral load
2
x
x
x
x
x
x
x
x
x
Viral Hepatitis
serologies
x
quantitative
Immunoglobulin
x
x
x
x
pb CD4+
x
x 2
x 2
x
x
x 2
x
x 2
pb CD8+
x
x 2
x 2
x
x
x 2
x
x 2
%CD34 cells
prior to
collection
x
x
Bilateral bm
biopsy
unilateral
aspirate
x
x 1
x
x
x
CT scan –
chest,
abdomen,
pelvis (neck if
indicated)
x
x
x
x
x
x
x
PET scan
x
x
x
Flow cytometry
x
x 1
x
x
x
BM
Cytogenetics
x
x
x
x
CD34+ cells
harvested
(total number)
x
Volume of
apheresis
x
1 Day 28 bone marrow biopsy and flow cytometry to be performed ONLY if prior history of marrow
involvement
2 Only for HIV-positive patients
3 If patient is eligible for post-transplant radiation therapy and has prior PET-positive disease.
* for CLL + low grade lymphomas only


MT2004-24: Auto PBSCT in Lymphoma
30
An attempt should be made to obtain the scheduled activity as close as possible
to the scheduled date. However, scheduling difficulties (for procedures and
around weekends) may make this difficult. Therefore, the scheduled activity will
be obtained within 14 days of that schedule (30 days for dates after day +100).