Clinical trial NCT00074282
Conditions: Leukemia
Keywords: refractory chronic lymphocytic leukemia B-cell chronic lymphocytic leukemia
Sponsor: Eastern Cooperative Oncology Group
Start date: 2005-04-14; Completion date: 2018-05-06
Enrollment: 102 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as pentostatin, cyclophosphamide, and CAMPATH-1H work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies, such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with monoclonal antibody therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well pentostatin, cyclophosphamide, rituximab, and CAMPATH-1H work in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia.

Detailed description:
OBJECTIVES:

Primary

* Determine the objective response rate (complete remission, partial remission \[PR\], or nodular PR) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL) treated with pentostatin, cyclophosphamide, and rituximab (PCR) followed by CAMPATH-1H .
* Determine the presence of minimal residual disease in patients treated with this regimen who achieve a CR or nPR

Secondary

* Determine the toxicity of this regimen in these patients.
* Determine the overall and progression-free survival of patients treated with this regimen.
* Evaluate the number of patients who after PCR (or during PCR for PD), only achieve a PR, SD, or PD and who subsequently convert to a higher response category after CAMPATH-1H .

Exploratory

* Assess the angiogenic profile (i.e., secretion levels of pro- versus anti-angiogenic molecules) of CLL B cell clones as well as bone marrow angiogenesis (i.e., vascular density by immunohistochemistry) at baseline, after PCR, after CAMPATH-1H, every six months (serum only), and at time of response assessment (marrow).
* Determine the V\_H gene mutation status and CD38 expression of the B-CLL clones at study entry and at the end of the therapy and assess the association between the VH gene mutation status and CD38 expression and clinical outcome.
* Determine surface phenotype (by flow cytometry) and genetic defects (by CLL FISH panel) information on CLL-B cell clones and associate with clinical outcome.
* Monitor the T-cell status by repertoire and flow cytometry analysis to determine the nature and extent of T-cell deficiency induced by the PCR and CAMPATH-1H treatment and assess any association with clinical outcome and toxicities.

Arms: arm 1: Treatment consisted of 6 cycles of pentostatin, cyclophosphamide, and rituximab (PCR) given every 28 days.

Rituximab administered as follows: For the first infusion, all patients receive 100 mg dose (regardless of weight/BSA). For subsequent infusions, all patients receive rituximab 375 mg/m2.

Pentostatin and cyclophosphamide administered as follows: Pentostatin given at 4 mg/m2 either as an IV push or IV over 10-30 minutes in 250 mL NS or D5W on day 1 every 4 weeks of cycles 1-6. Cyclophosphamide given at 600 mg/m2 IV over 30-60 minutes in 250 mL NS on day 1 every 4 weeks of cycle 1-6. arm 2: Patients who achieved a confirmed CR or nPR, were registered to receive Alemtuzumab (Arm B). When the patient was registered to Arm B, the drug was administered three times a week for four weeks. The dose was 30 mg per dose. A twelve-week treatment-free period had to elapse before CAMPATH-1H began following completion of PCR for Arm B patients arm 3: For those patients not achieving a CR or nPR (thus patients either achieved PR, SD, or PD), Alemtuzumab (Arm C) was administered three times a week for eighteen weeks at a dose of 30 mg TIW. For PR, SD and PD patients, the timing of CAMPATH-1H was left to the discretion of the investigator, and treatment could begin earlier but no less than two weeks and no longer than eight weeks after the completion of the last PCR course. Patients determined to have PD during treatment with PCR did not need to complete all 6 cycles of PCR to go on to Arm C, however, completing a minimum of 2 cycles was required.
Interventions: intervention 1: rituximab intervention 2: cyclophosphamide intervention 3: pentostatin intervention 4: Alemtuzumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
 
E2903 
1 
Phase II Trial of Pentostatin, Cyclophosphamide and 
Rituximab (PCR) Followed By Campath-1H For 
Previously Treated Relapsed or Refractory Patients With 
Chronic Lymphocytic Leukemia 
STUDY CHAIR: 
Sanford J. Kempin, M.D. 
STUDY CO-CHAIR: 
Neil E. Kay, M.D. 
STATISTICIAN: 
Zhuoxin Sun, Ph.D. 
LABORATORY CO-CHAIRS: 
Neil E. Kay, M.D. 
Elisabeth Paietta, Ph.D. 
COMMUNITY CO-CHAIR: 
Joseph Mazza, M.D. 
CYTOGENETIC CO-CHAIR: 
Rhett Ketterling, M.D. 
LEUKEMIA COMMITTEE CHAIR: 
Martin S. Tallman, M.D. 
Version Date:  April 25, 2014 
NCI Update Date:  May 25, 2011 
 
 
ACTIVATION DATE 
 
 
December 16, 2004 
Addenda #1, #2, #3, and Update #1 submitted 
prior to activation. 
 
 
Addendum #4, 3/05 
 
 
Addendum #5, 6/05 
 
 
Addendum #6, 8/05 
 
 
Addendum #7, 12/05 
 
 
 
Addendum #8, 12/05 
 
 
 
Addendum #9, 5/06 
 
 
 
Addendum #10, 7/07 
 
 
 
Update #2, 7/07 
 
 
 
Addendum #11, 1/09 
 
 
 
Addendum #12, 5/10 
 
 
 
Addendum #13, 6/10 
 
 
 
Update #3, 5/11 
 
 
 
Addendum #14, 1/14 
 
 
 
Addendum #15, 6/14 
 
Rev. 12/05 
Rev. 1/09. 1/14 
Rev. 6/14 


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Table of Contents 
Schema ...................................................................................................................... 5 
1. Introduction ........................................................................................................ 6 
1.1 Demographics, Natural History and Previous Treatments ....................... 6 
1.2 Biochemistry of Purine Nucleosides ......................................................... 6 
1.3 Purine Analogs in Combination Chemotherapy of CLL ............................. 8 
1.4 Antibody Therapy of CLL ........................................................................... 8 
1.5 Combination of Chemotherapy and Immunotherapy of CLL .................. 12 
1.6 Rationale For Current Clinical Study ....................................................... 13 
1.7 Rationale for Ancillary Studies ................................................................ 14 
1.8 Gender and Ethnicity Statement ............................................................. 15 
2. Objectives ......................................................................................................... 16 
2.1 Clinical Objectives ................................................................................... 16 
2.2 Laboratory Objectives ............................................................................. 16 
3. Selection of Patients ......................................................................................... 17 
3.1 Step 1: Induction Eligibility Requirements .............................................. 17 
3.2 Step 2 : Eligibility Requirements For Re-registration to CAMPATH-1H .. 19 
4. Registration Procedures.................................................................................... 21 
4.1 Step 1: Induction (Arm A) ........................................................................ 22 
4.2 Step 2: Re-registration Procedures to Campath-1H (Arm B and Arm C) 23 
5. Treatment Plan ................................................................................................. 24 
5.1 Step 1 (Arm A):  Rituximab, pentostatin, and cyclophosphamide .......... 24 
5.2 Step 2 (Arm B and Arm C): CAMPATH-1H ............................................... 32 
5.3 ADVERSE EVENT REPORTING REQUIREMENTS ....................................... 34 
5.4 Duration of Therapy ................................................................................ 47 
5.5 Duration of Follow-up ............................................................................. 47 
6. Measurement Of Effect .................................................................................... 48 
6.1 Assessment of Clinical Response ............................................................ 48 
7. Study Parameters .............................................................................................. 51 
7.1 Therapeutic Parameters.......................................................................... 51 
7.2 Biological Sample Submissions ............................................................... 55 
8. Drug Formulation and Procurement ................................................................. 56 
8.1 Cyclophosphamide .................................................................................. 56 
8.2 Pentostatin .............................................................................................. 59 
8.3 Rituximab ................................................................................................ 61 
8.4 CAMPATH-1H .......................................................................................... 65 
9. Statistical Considerations .................................................................................. 68 
9.1 Primary Endpoints ................................................................................... 68 
9.2 Accrual ..................................................................................................... 70 
9.3 Early Stopping for Excessive Toxicity ...................................................... 71 
9.4 Secondary Endpoints............................................................................... 71 


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9.5 Laboratory Endpoints .............................................................................. 72 
9.6 Gender and Ethnicity .............................................................................. 75 
9.7 Safety Monitoring ................................................................................... 75 
10. [Section 10 Deleted in Addendum #9, 5/06] .................................................... 76 
11. Correlative Studies ............................................................................................ 77 
11.1 Immunophenotype and Molecular Genetics .......................................... 77 
11.2 FISH Studies (99) ..................................................................................... 79 
11.3 Additional Laboratory Studies ................................................................. 81 
11.4 Sample Inventory Submission Guidelines ............................................... 83 
11.5 Lab Data Transfer Guidelines .................................................................. 83 
12. Records To Be Kept ........................................................................................... 84 
13. Patient Consent And Peer Judgment ................................................................ 84 
14. References ........................................................................................................ 84 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #14] ............................................................ 92 
[Appendix II Deleted in Addendum #9, 5/06] ......................................................... 93 
Appendix III  Neupogen® Information ..................................................................... 94 
Appendix IV  Patient Thank You Letter .................................................................... 97 
Appendix V  Grading Scale for Hematologic Toxicity in CLL Studies ....................... 98 
Appendix VI  Rai Staging System for CLL ................................................................. 99 
Appendix VII  Treatment Evaluation...................................................................... 100 
Appendix VIII  Specimen Kit: Packaging and Shipping Instructions ....................... 101 
Appendix IX  Specimen Kit: Patient Information Form.......................................... 102 
 


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STUDY CHAIR 
Sanford J. Kempin, M.D. 
Saint Vincent’s Comprehensive Cancer Center 
325 West 15th Street 
New York, NY 10011 
Phone: (212) 604-6010 
Fax: (212) 604-6038 
E-mail: skempin@aptiumoncology.com 
STUDY CO-CHAIR 
Neil E. Kay, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Phone: (507) 266-0523 
Fax: (507) 266-4972 
E-mail: kay.neil@mayo.edu 
STUDY CHAIR LIAISON (SCL) 
Lori Megherian, CCRC 
Saint Vincent’s Comprehensive Cancer Center 
325 West 15th Street 
New York, NY 10011 
Phone: (212) 367-1729 
Fax: (212) 604-6074 
E-mail: lmegherian@aptiumoncology.com 
 
Rev. 6/05, 8/05 
Rev. 6/05, 8/05 


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Schema 
Accrual = 110 patients
a) 
The dose of Rituximab (day 1 of week 1) will be 100 mg. The dose of Rituximab will be increased to 375 mg/m2 on days 3 and again on 5 of week 1 (see Section 5.1.1 to 5.1.3 for
rituximab infusion information). 
b) 
See Sections 5.1.1, 5.1.2 and 5.1.4 for details regarding premedication and supportive care.
c)
Serum creatinine will be determined within 14 days of PCR treatment. Serum creatinine must not be > 2mg/dl. 
There are no safe guidelines for administration of pentostatin in patients with a creatinine clearance of < 30ml/min. This will be the minimum clearance for patients 
on this study therefore, any patients whose clearance is < 30ml/min will discontinue protocol therapy. 
See Section 5.1.3.1.1.
d)
A 12-week treatment free period following the completion of PCR will elapse before registering to Arm B.
e)
Patients who have PR or stable disease when evaluated at the end of PCR have a treatment free period of no less than 2 or no more than 8 weeks before registering to Arm C.
If  progressive disease is determined during PCR treatment, the patient is not required to complete 6 cycles of PCR before going on to Arm C CAMPATH-1H for 18 weeks. However, 
completing a minimum of 2 cycles is required.
f)
See Section 5.1.4 and 5.2 for details regarding premedication and support care.
R
E
G
I
S
T
R
A
T
I
O
N
ARM A (a-c)
• 
RITUXIMAB IV (a)
-   375 mg/m2 on wks 1, 5, 9, 13, 17, and 
21 (a total of six 28-day cycles). For 
week 1,  rituximab to be given 3 days/week. 
For weeks 5-21, rituximab to be given 1 day/
week.
PENTOSTATIN IV (c)
-   4 mg/m2  x 1 day on wks 1, 5, 9, 13, 17, 
and  21 (a total of six 28-day cycles).
• 
CYCLOPHOSPHAMIDE IV
- 600 mg/m2 /day x 1 on wks 1, 5, 9, 
13, 17, and 
21 (a total of six 28-
day cycles).
Rev. 7/07    
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
Step 1
COMPLETE REMISSION
OR
NODULAR PARTIAL 
REMISSION
ARM B (d)
CAMPATH-1H
30 mg sc TIW x 4 wks
(week 1 dose escalation - 
see Section 5.2.3)
Rev. 1/09
D
I
S
E
A
S
E 
-
E
V
A
L
U
A
T
I
O
N
PARTIAL REMISSION
OR
LESS THAN PARTIAL 
REMISSION
OR
PROGRESSIVE 
DISEASE (e)
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
ARM C (e)
CAMPATH-1H
30 mg sc TIW x 18 wks 
(week 1 dose escalation - 
see Section 5.2.3)
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
Rev. 1/09
 


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1. 
Introduction 
1.1 
Demographics, Natural History and Previous Treatments 
B-cell chronic lymphocytic leukemia (CLL) is one of the most common types of 
leukemia diagnosed in the United States (1). The median age at diagnosis is 60 
years old with a 2:1 male to female sex ratio (82,83). Most patients are 
diagnosed incidentally during routine blood work. For protocol study purposes, 
the National Cancer Institute (NCI) Working Group on CLL recommends an 
absolute lymphocyte count threshold value of > 5,000/µl (2). Laboratory 
diagnosis is achieved through demonstration in the blood smear of “mature” 
appearing small lymphocytes and immunophenotyping by flow cytometry 
showing co-expression of CD5 and B cell markers with dim expression of surface 
immunoglobulin. (2) 
Despite the greater than 10-year life expectancy in early stage patients, CLL 
remains an incurable illness (3-6). Patients progressing onto or diagnosed with 
more advanced stage CLL have a median survival between 18 months to 3 
years. Patients with low-risk, early stage CLL can be followed closely, as there is 
no survival benefit associated with early intervention (6). With disease symptoms 
or progressive cytopenias, patients previously were treated with oral alkylating 
agents with or without prednisone (7-11). Responses to alkylating agents are not 
durable, and only rarely are associated with morphologic complete remission. 
With the clinical introduction of the purine analogs (pentostatin, cladribine and 
fludarabine), treatment of CLL has changed from primary alkylators as front line 
treatment to purine analogs as front line treatment (12,13). 
1.2 
Biochemistry of Purine Nucleosides 
2-chlorodeoxyadenosine (2-CDA) and pentostatin (deoxycoformycin, DCF), 
analogs of the naturally occurring deoxypurine nucleoside, deoxyadenosine 
(dAdo), are effective for the treatment of CLL (13,14,15,24,87). Their primary 
mechanism of action is promoting the intracellular accumulation of 
deoxynucleotides by inhibiting the function of adenosine deaminase (ADA), an 
enzyme that normally degrades deoxypurine nucleotides. Inhibition of adenosine 
deaminase leads to the accumulation of metabolites inhibiting ribonucleotide 
reductase. This leads to a depletion of the nucleotide pool with resultant inhibition 
of DNA synthesis. 
1.2.1 
Purine Analogs for the Treatment of CLL 
Pentostatin, produced by Streptomyces antibioticus, was the first 
purine analog to enter clinical trials in CLL (13,14).  Cladribine (15) 
and fludarabine (16-19) were introduced in the clinic soon after and 
yielded impressive clinical results in alkylator-refractory CLL.  
Specifically, treatment with fludarabine yields a 31-57% response rate 
in alkylator-resistant CLL patients, and a 63-79% response rate in 
untreated patients (88).  The addition of prednisone did not add 
significant benefit (19).  These data have elevated fludarabine to an 
acceptable front-line therapeutic option in the treatment of 
symptomatic CLL.  Monoallelic p53 gene deletion (detected in 12% of 
CLL patients) is predictive for nonresponse to therapy with purine 
analogs (fludarabine) and poor survival (96).  Likewise, 17p deletion 
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(17% of patients) is also associated with resistance to purine analogs, 
which may be overcome with alemtuzumab therapy (97). 
1.2.2 
Pentostatin trials were not subjected to extensive schedule 
optimization despite demonstrated efficacy and lack of significant 
myelosuppression as compared to other purine analogs.  Extensive 
phase I evaluation was performed (20) and these early studies were 
notable for remarkable inter-patient variability in toxicity, especially at 
high doses given for five days.  Significant renal, pulmonary, and 
central nervous system (CNS) toxicity was encountered (21-24).  
Patients with indolent lymphoid malignancies developed 
lymphocytopenia at doses producing little toxicity, such as 5 mg/m2/d 
for 2 days or 4 mg/m2 every 1 or 2 weeks. In addition renal 
insufficiency and poor performance status were predictive of toxicity, 
even at lower doses of pentostatin (4 mg/m2).  In the phase II studies 
using 4 mg/m2 weekly or less frequently, the incidence of mild, 
reversible creatinine elevation was less than 5%, and no patient 
developed overt renal failure.  CNS toxicity appeared to be schedule-
dependent, and could develop with repeated low doses in patients 
with normal renal function (21).  Early clinical trials also revealed 
adenosine deaminase inhibition resulted in immunosuppression, and 
may increase the patient’s risk of infection during the treatment period 
(89).  Additional side effects include reversible hepatitis, 
keratoconjunctivitis, nausea, and vomiting (24-26).  
1.2.3 
In phase II studies, pentostatin has demonstrated activity in patients 
with relapsed CLL, refractory to alkylating agents.  In the largest 
study, conducted by the Cancer and Leukemia Group B (CALGB) 
(24), 36 evaluable patients were treated with pentostatin at a dose of 
4mg/m2 three times per week, and then every other week.  Among 
these patients, ten (26%) demonstrated a response: 1 complete 
response and 9 partial responses. The European Organization for 
Research and Treatment of Cancer (EORTC) phase II study (25) 
showed 7 of 26 patients (27%) developed a partial response.  In a 
study of 17 CLL patients at the Royal Marsden Hospital, 35% 
achieved a response (26). Toxicities documented in these phase II 
studies with pentostatin show most patients tolerated the treatment 
well, with mild nausea and vomiting and minor skin rashes being the 
most common complaint.  The most significant toxicity was infection.  
These included bacterial as well as opportunistic infections that are 
known to occur in patients receiving purine analog therapy.  Virtually 
all infectious complications occurred within six weeks of initiating 
therapy with pentostatin. There was worsening of anemia and 
thrombocytopenia in 23% and 26% of patients, respectively.  This was 
more frequent in those patients who had very low hemoglobin levels 
and platelet counts when they started treatment. Neither of the two 
large multicenter trials reported any nephrotoxicity. Three patients 
(7%) developed grade 3-4 CNS toxicity in the CALGB study, while no 
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1.3 
Purine Analogs in Combination Chemotherapy of CLL 
Preclinical justification of combining pentostatin and cyclophosphamide comes 
from a report by Johnson and colleagues (27) where CLL cells were incubated in 
vitro with an alkylating agent and a nucleoside analog. The cyclophosphamide 
analog, 4-hydroperoxycyclophosphamide (4-HC), which does not require 
microsomal activation and is converted to the same alkylating agent was utilized.  
This study demonstrated that combination therapy with 4-HC, pentostatin, and 
deoxyadenosine produces at least additive cell kill in vitro. Preclinical data 
demonstrated that a combination of a DNA damaging agent (cyclophosphamide) 
can synergize with the nucleoside analogs fludarabine, pentostatin, or cladribine.  
Recent reports demonstrated significant activity of a combined pentostatin-
cyclophosphamide regimen (28-31). Previously treated patients were required to 
have “high-risk” or “active intermediate risk” disease. Weiss et al. recently 
published the results of a Phase II study of pentostatin (4mg/m2) and 
cyclophosphamide (600-900 mg/m2) in twenty-three previously treated patients 
with chronic lymphocytic leukemia. Therapy was administered every three 
weeks. The response rate was 77% in fludarabine-refractory patients. There 
were four complete responses. Grade 3/4 neutropenia and thrombocytopenia 
were seen in 35% and 30% respectively. There was relative sparing of 
thrombopoiesis (1/23 patients with a platelet count > 20,000 x 106/L required 
platelets). All patients received filgastrim, sulfamethioxazole/trimethaprim, and 
acyclovir prophylactically (31). Fludarabine and cyclophosphamide combinations 
have been developed with similar efficacy (32-34). Previous combinations of 
fludarabine and chlorambucil demonstrated efficacy but significant toxicity 
(35,36). 
1.4 
Antibody Therapy of CLL  
1.4.1 
Rituximab Therapy of CLL 
Immunotherapy with unconjugated monoclonal antibodies represents 
a new mode of therapy for CLL.  Of the many antibodies tested in 
CLL, rituximab and Campath-1H have the highest reported success 
rates to date (37-49). In contrast, rituximab is directed at a B-cell 
specific antigen and therefore is associated with much less 
immunosuppression. While initial studies of the chimeric anti-CD20 
antibody rituximab demonstrated disappointing results in small-cell 
lymphocytic lymphoma (SLL) and CLL (41-43), subsequent studies 
directed at overcoming the adverse pharmacokinetic parameters have 
led to improving efficacy in this disease (40).  Down-regulation of mcl-
1 and XIAP occurred in most patients irrespective of response (49).  
As pre-treatment mcl-1 levels have been associated with lack of 
complete response to treatment in CLL, this may represent the 
mechanism by which rituximab chemosensitizes tumor cells to 
chemotherapy. Given the lack of overlapping toxicity between 
standard therapy (e.g. alkylator and purine analog-based therapy), 
combination approaches with rituximab appear warranted. 


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1.4.2 
CAMPATH-1H Therapy with CLL 
CAMPATH-1H is a humanized antilymphocyte monoclonal antibody 
(MAB) engineered by grafting the rodent hypervariable 
complementarity determining regions (CDR) into a human 
immunoglobulin variable framework region (51).  It is one of a series 
of MABs directed against the CD52 surface antigen, expressed on 
lymphocytes at nearly all stages of differentiation. 
The Campath-1 antigen (designated CD52 by the Fourth International 
Workshop on Human Leukocyte Differentiation Antigens in 1989) is a 
heavily glycosylated, non-modulating glycoprotein of molecular weight 
21-28kD which in humans is predominantly expressed on peripheral 
blood lymphocytes, monocytes, and macrophages. It is estimated that 
peripheral blood lymphocytes have approximately 5x105 antibody 
binding sites per cell (52). Antibodies raised against this antigen 
efficiently lyse lymphocytes in the presence of human complement. 
However, they do not appear to lyse monocytes (53). 
1.4.2.1 
In the three Phase I trials (001,002,003) by Burroughs 
Wellcome (BW), CAMPATH-1H showed evidence of 
activity in patients with CLL, especially in reducing the 
number of circulating leukemia cells, splenomegaly and 
bone marrow infiltration. Many patients entering these trials 
had previously received treatment with alkylators and/or 
fludarabine. In two Phase II studies (005 and 009), 
CAMPATH-1H produced a response rate (based on intent 
to treat analysis) of 33% in 76 patients, including 42 who 
were previously treated with fludarabine (91-95). 
Of the 16 major responses (50% or greater reduction in 
disease), 8 occurred in patients with CLL or prolymphocytic 
leukemia (PLL). Forms of non-Hodgkins lymphoma (NHL) 
in which responses were observed included small 
lymphocytic lymphoma (2 cases), lymphoplasmacytoid 
follicular (1 case), small cleaved cell (1 case), diffuse small 
cleaved cell (2 cases), diffuse mixed cell (1 case), and 
mycosis fungoides (2 cases). 
The majority of patients experienced at least 50% 
reduction of high lymphocyte count. Clearance of bone 
marrow infiltration and reduction in splenomegaly was also 
achieved in a number of patients. CAMPATH-1H had less 
effect in reducing lymphadenopathy, particularly bulky 
areas, possibly due to poor access of the antibody to sites 
of bulky disease and inadequate effector mechanisms at 
such locations.  
Rawston et al reported on 10 patients with CLL who were 
refractory to conventional therapy, including fludarabine, 
who were treated with CAMPATH-1H (54). The regimen 
was 30 mg given three times a week for 6 weeks. Patients 
were treated with co-trimoxazole and fluconazole 
prophylactically. Six of the 10 patients have received a full 


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course. Most patients experienced some minor infusion-
related symptoms, such as rigors, during therapy. While 
Campath-1H is active in the treatment of CLL, the 
immunosuppression produced by this agent can be 
profound (47-49). 
Osterborg et al have published efficacy and safety results 
for previously treated CLL patients (45). Twenty-nine 
patients who had relapsed after an initial response (n=8) or 
were refractory (n=21) to chemotherapy were treated with 
CAMPATH-1H 30 mg administered as a 2-hour IV infusion 
three times weekly for a maximum of 12 weeks. Of them, 8 
had been previously treated with chlorambucil and 
prednisone only, 3 with prior fludarabine, 14 with CHOP or 
similar regimens, and 7 with various single-agents. There 
was 1 CR and 11 PRs, for an overall 42% (95% CI: 23%-
61%) response rate. Three of the 8 patients (38%) with a 
relapse and 9 of 21 refractory patients (43%) responded to 
CAMPATH-1H therapy. CLL cells were rapidly eliminated 
from the blood in 28 of 29 patients (97%). CR in the bone 
marrow was obtained in 36% and splenomegaly resolved 
completely in 32%. Lymphadenopathy was normalized in 
only 2 patients (7%). 
1.4.2.2 
Bowen et al reported on the subcutaneous administration 
of CAMPATH-1H in fludarabine-resistant/relapsed CLL and 
B-PLL (46).  Seven patients with B-cell leukemia (6 with 
CLL and 1 with B-PLL) were treated with CAMPATH-1H 
subcutaneously (SC) three times a week for 6-12 weeks. 
The initial dose was 10 mg with further injections of 30 mg 
given on an outpatient basis. Previously, four of the 
patients were resistant to fludarabine and three had a PR 
before relapsing. The patient with B-PLL achieved a CR 
and three of the CLL patients achieved a PR (two of these 
patients were retreated). The three remaining patients 
were non-responders. Three patients were transfusion 
dependent before CAMPATH-1H, and all three became 
transfusion independent after treatment. Cytomegalovirus 
(CMV) reactivation occurred in 3/7(43%). 
1.4.2.3 
Lundin et al. recently updated the experience of the 
Karolinska group utilizing subcutaneous administration of 
CAMPATH-1H for previously untreated patients with CLL 
(55).  CAMPATH-1H was administrated three times a week 
(TIW) subcutaneously for 12-18 weeks to forty-one 
patients the majority of whom had advanced disease. The 
initial dose was 3 mg, but was escalated rapidly to 30 
mg/ml/TIW. The medication was self-administered at home 
after week 2. Acyclovir, fluconazole, co-trimoxazole, and 
allopurinol were given concomitantly. Responses were 
seen in 81% of the patients (17% CR, 64% PR). Although 
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(79-97%), the medication was most successful in blood 
and least successful in lymph nodes.  The maximum 
response in blood was rapid, those in nodal, splenic, and 
marrow less rapid. Most side effects occurred as “first dose 
reactions”. Non-hematologic side effects, apart from fever, 
were significantly reduced by SQ administration versus IV 
administration. Systemic reactions included rigors (17%), 
fever (68%), and fatigue (3 patients – grade II-III). No 
episodes of rash/urticaria, bronchospasm, hypotension, or 
nausea were observed. Local skin reactions (88% of 
patients) were grade 0-II and generally disappeared during 
continued CAMPATH-1H treatment. These consisted of 
erythema/edema, pruritis, and slight pain. However, three 
patients were withdrawn from the study because of severe 
local reactions (pain) or systemic symptoms (fever, 
fatigue). Hematologic toxicity was still significant with 21% 
of patients developing transient grade IV neutropenia. Five 
patients (13%) developed two or more episodes of grade 
IV neutropenia successfully treated with a “few” injections 
of G-CSF.  No patients developed febrile neutropenia. 
CMV reactivation occurred in 4/41(10%). 
1.4.2.4 
Albitar et al, while studying the pharmacokinetics of 
CAMPATH-1H, in the setting of minimal residual disease 
(MRD), suggested that CLL patients with higher levels of 
residual disease may require higher doses of CAMPATH-
1H to eradicate disease and that detectable plasma levels 
of CAMPATH-1H may be necessary for achieving CR (98). 
The dose of CAMPATH-1H on the present study is 
considerably higher and, hopefully, will overcome 
resistance to eradication of MRD. 


ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
12 
1.5 
Combination of Chemotherapy and Immunotherapy of CLL 
1.5.1 
CALGB performed a randomized phase II trial of sequential versus 
concurrent rituximab (50). All patients fulfilled the NCI definition of B-
CLL and requirement for therapy. Patients on the sequential arm 
(fludarabine then rituximab) received fludarabine (25 mg/m2 dl-d5 
repeated monthly x6) induction followed by rituximab (375 mg/m2 
repeated weekly x4). Patients on the concurrent arm (fludarabine and 
rituximab) received therapy identical to the sequential arm except 
rituximab (375 mg/m2) was also administered (day 1 and 4 of cycle 1; 
day 1 of cycles 2 of 6) with fludarabine induction therapy. A total of 
104 patients have been enrolled. Fludarabine plus rituximab induction 
toxicity included neutropenia (grade 3 or 4, 77%), thrombocytopenia 
(grade 3 or 4, 20%) and infection (grade 3 or 4, 18%). Fludarabine 
induction toxicity included neutropenia (grade 3 or 4, 41%), 
thrombocytopenia (grade 3 or 4, 12%), and infection (grade 3, 21%). 
There was no increase in the frequency of opportunistic infections 
noted in the concurrent (15%) versus the sequential arm (26%). 
Overall consolidation was tolerated well in both arms. Response data 
using the NCI criteria are: 
Treatment 
No. Patients 
No. CR (%) 
No. PR (%) 
No. OR(%) 
Fludarabine plus R 
51 
24 (47) 
22(43) 
46 (90) 
Fludarabine then R 
53 
15 (28) 
26 (69) 
41 (77) 
Key:  R= Rituximab, CR=complete response, PR=partial response, OR overall 
response 
The FCR combination (fludarabine 25 mg/m2/d x3), 
cyclophosphamide 250 mg/m2/d x3, rituximab 375 mg/m2/day 1) 
was recently reported to induce 67% CR, 19%nPR, and 18% PR in 
135 CLL patients when used as initial therapy.  RT-PCR testing 
for MRD was performed on bone marrow at the end of therapy 
(usually 6 cycles) using CD5+ 19+ coexpression. None of the 
MRD negative patients by RT-PCR have had a clinical or flow 
relapse (57). 
1.5.2 
We have recently begun a study of pentostatin, cyclophosphamide 
and rituximab (PCR) as a collaborative effort with the James Cancer 
Center (Ohio State) for patients with untreated B-cell chronic 
lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Toxicity 
has been modest. Weiss et al (personal communication) have treated 
approximately 23 previously treated patients (MSKCC; Cleveland 
Clinic). A full analysis of response and toxicity has not been 
published. However, one patient suffered grade 5 pulmonary toxicity 
(MSKCC) and several patients were removed from study at the 
Cleveland Clinic.  No further details are available.  Data on the use of 
pentostatin and rituximab have been published in abstract form.  
There were 19/60 patients (low grade (NHL)) with the diagnosis of 
small lymphocytic lymphoma. Specific responses in this group were 
not published. However, there was a 70% overall response 
percentage. There were two deaths on study (COPD, TTP). Toxicities 


ECOG-ACRIN 
E2903 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
13 
included neutropenia (6%), fever, shingles, headache (3.3%), anemia, 
atrial fibrillation, bronchospasm, chills, dehydration, febrile 
neutropenia, hypotension, mucositis, pneumonia, increased SGOT, 
and vertigo (1.7%)(93). 
 
 
1.6 
Rationale For Current Clinical Study 
We wish to combine an effective combination chemotherapy regimen that is 
associated with a high complete response rate with immunotherapy (Rituximab 
and CAMPATH-1H) for chemosensitization and eradication of minimal residual 
disease (MRD). Multiparameter immunophenotypic analysis detecting aberrant 
phenotypes has been successful as a probe to detect MRD and will be used as 
part of this study (see Section 2.0)(96). These results appear similar to 
quantitative molecular monitoring utilizing allele-specific oligonucleotide PCR 
(ASO-PCR) (97).  The combination of fludarabine and rituximab has 
demonstrated promising results, but a high rate of grade 3 and 4 neutropenia 
(56). Similarly, addition of rituximab to the fludarabine/cyclophosphamide 
combination piloted by MD Anderson has resulted in high responses but required 
lowering the chemotherapy doses (57,58).  CAMPATH-1H in combination with 
fludarabine has shown significant activity in refractory CLL (59). Rituximab has 
been combined with pentostatin in a Phase 2 study (61). The results have been 
published in abstract form (61,93). Of 54 evaluable patients, 18 (33.3%) achieved 
an objective response 5.5% CR, 3.7% CRn, 16.7% PR, 7.4% nPR.  Response 
rates were similar in previously treated and untreated patients (33.4% and 33.3% 
respectively). Grade ≥ 3 toxicities occurred in 27 patients (neutropenia (29%), 
febrile neutropenia (1.6%), leukopenia (8.1%), thrombocytopenia (5.3%), 
pulmonary (3.2%), gastrointestinal (3.2%), and infection (3.2%)). One death was 
reported as “treatment-related pneumonia”. The preliminary results of the 
combination of pentostatin, cyclophosphamide, and rituximab in previously 
treated patients have been communicated to us (Weiss, personal 
communication), but have not been officially analyzed. Toxicity is described in 
Section 1.5.2. A study of previously untreated CLL patients utilizing PCR is being 
undertaken at Mayo Clinic. Preliminary toxicity results are outlined in Section 
1.5.2. The addition of rituximab, an agent that favorably down-modulates mcl-1 
and XIAP in CLL B cells, may chemosensitize these cells to the effects of 
pentostatin and cyclophosphamide. Recently both rituximab and CAMPATH-1H 
have been combined demonstrating significant activity (61,62). As discussed in 
Sections 1.4.2.2 and 1.4.2.3, the SC administration of CAMPATH-1H would 
appear to have a better therapeutic index with less side effects.  Therefore, its 
incorporation in this study would likely result in less adverse events than might be 
expected with IV administration. For those patients who achieve a partial 
response or progress on therapy, a conventional course of CAMPATH-1H (18 
weeks) may offer a reasonable option for response and clinical benefit, as there 
are few treatment alternatives in the setting of third line options. In conjunction 
with this unique combination therapy, we hope to examine a variety of relevant 
correlative endpoints (detailed in the following sections) that will allow us to 
distinguish features of leukemic cell biology that relate to resistance and patient 
outcome to the chemoimmunotherapy of our clinical protocol. 
Rev. 7/07 
Rev. 7/07 


ECOG-ACRIN 
E2903 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
14 
1.7 
Rationale for Ancillary Studies 
We intend to study critical biologic events in the CLL cells of patients entered 
onto this protocol. Cytogenetic analysis of CLL cells has been undertaken by 
numerous investigators and has been related to stage of disease, overall 
prognosis, and sensitivity to therapy (65-67, 75-81). 
We will also determine the Ig variable region sequence of the CLL B cells in 
order to determine if they are either germline or somatic mutation type clones. 
This is relevant since recent data (63-66) demonstrates CLL patients with 
germline type clones have a worse clinical outcome compared to somatic 
mutation type clones. In addition to the apparent predictive value of lg V heavy 
chain region sequence to clinical outcome, the germline clones had genetic 
defects that were dissimilar from the somatic type clones. A retrospective 
analysis on frozen CLL cells for patients entered on 3 North Central Cancer 
Treatment Group (NCCTG) clinical trials has shown a trend towards longer time 
to progression for CLL patients with somatic type clones compared to germline 
type clones (66). We will examine the presence of germline or somatic type 
clones and evaluate this combination of genetic data to clinical outcomes on this 
trial. Genetic analysis for determination of therapeutic efficacy of monoclonal 
antibodies (67,69) will be incorporated in these studies. The techniques for Ig V 
heavy chain region sequencing have been established at the Mayo Clinic (66). 
We have recently determined that abnormal angiogenesis exists in B-CLL (68).  
Increased marrow blood vessels appear to be positively associated with 
increasing stage of disease.  The mechanism for this abnormal angiogenesis is 
unclear but preliminary work by us has shown that CLL cells produce both pro-
and anti-angiogenic factors. The balance of these two types of vascular growth 
factors are likely to be critical to the induction of tumor related angiogenesis. 
However we have also shown that CLL B cells express mRNA for VEGFR1 and 
VEGFR2 (vascular endothilial growth factor receptor) thus raising the possibility 
of an autocrine pathway for VEGF (vascular endothilial growth factor receptor) 
that could impact on CLL B cells. The levels of pro and anti-angiogenic factors in 
CLL patients progressing through this clinical protocol will be studied. The 
change in both the levels and ratios of angiogenesis factors will be compared to 
their clinical responses. 
Since CLL patients have deficient T cell repertoire with the expanded CLL B cell 
clone it is important to know if this immunodeficiency parameter can be restored 
with therapy. We are particularly interested in knowing if the extent of T cell 
repertoire deficiency and changes induced by treatment can be associated with 
clinical responses and/or toxicities of the treated CLL patients. Therefore we 
intend to study the T cell repertoire by flow cytometry at patient entry to the study 
and then at various times after completion of the chemoimmunotherapy protocol. 
Recent studies have been able to identify patients who are poorly responsive to 
CAMPATH-1H (69) and these studies will be incorporated into the protocol.  
Theoretically, relapse of CLL after treatment evolves from the proliferation of 
“minimal residual disease (MRD)” progenitors. Techniques established for the 
detection of MRD (70-74) will be incorporated into these studies. These will 
include flow cytometric and real-time PCR assays. 


ECOG-ACRIN 
E2903 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
15 
1.8 
Gender and Ethnicity Statement 
1.8.1 
Entry to this study is open to both men and women, and to persons of 
any national or ethnic group. ECOG’s previous CLL studies enrolled 
approximately 70% men, 30% women, 82% white, 12% black, and 6% 
other ethnic backgrounds. We anticipate that entry of women and 
minorities to this study will show similar proportions. We are aware of 
no literature citing differential treatment effects by gender or ethnicity 
in relapse and refractory CLL and therefore have not incorporated 
separate accrual targets for such patient groups. 
 


ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
16 
2. 
Objectives 
2.1 
Clinical Objectives 
2.1.1 
Primary Objectives 
2.1.1.1 
To evaluate the objective (complete remission = CR, 
nodular partial remission = nPR, partial remission = PR) 
response rate of pentostatin, cyclophosphamide, and 
rituximab (PCR) in patients with previously treated B-cell 
chronic lymphocytic leukemia (CLL). 
2.1.1.2 
To assess the presence of minimal residual disease (MRD) 
at the completion of the PCR regimen and after Campath-
1H in patients who achieve a CR or nPR. 
2.1.2 
Secondary Objectives 
2.1.2.1 
To evaluate the toxicity of the combined therapy, PCR with 
CAMPATH-1H, in patients with previously treated B-CLL. 
2.1.2.2 
To evaluate the overall survival and progression-free 
survival of patients treated with pentostatin, 
cyclophosphamide, and rituximab with CAMPATH-1H 
(PCR  CAMPATH-1H). 
2.1.2.3 
To evaluate the number of patients who after PCR (or 
during PCR for PD), only achieve a PR, SD, or PD and 
who subsequently convert to a higher response category 
after Campath-1H. 
2.2 
Laboratory Objectives 
2.2.1 
To assess the angiogenic profile (i.e. secretion levels of pro versus 
anti-angiogenic molecules) (100) of CLL B cell clones as well as bone 
marrow angiogenesis (i.e. vascular density by immunohistochemistry) 
(68) at baseline, after PCR, after Campath-1H, every six months 
(serum only), and at time of response assessment (marrow).  
2.2.2 
To determine the VH gene mutation status and CD38 expression of 
the B-CLL clones at study entry and at the end of the therapy and 
assess the association between the VH gene mutation status and 
CD38 expression and clinical outcome. 
2.2.3 
To acquire surface phenotype (by flow cytometry) and genetic defects 
(by CLL FISH panel) (99) information on CLL-B cell clones. This latter 
information will be studied for association with clinical outcome. 
2.2.4 
The T cell status will also be monitored by repertoire and flow 
cytometry analysis to determine the nature and extent of T cell 
deficiency induced by the PCR and Campath treatment in our patient 
cohort. This latter information will be studied for association with 
clinical outcome and toxicities of the CLL cohort. 
 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
17 
3. 
Selection of Patients 
Each of the criteria in the following checklist must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. _________________________________ 
Patient’s Initials (L, F, M) ____________________________ 
Physician Signature and Date ________________________ 
NOTE: 
All questions regarding eligibility should be directed to the ECOG-ACRIN 
Operations Office - Boston at (617) 632-3610. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration by the treating 
physician. 
3.1 
Step 1: Induction Eligibility Requirements 
3.1.1 
Patients must have a diagnosis of B-CLL, as defined by the NCI 
criteria below (2).  All three criteria must be met: 
3.1.1.1 
Patients must have a peripheral blood absolute 
lymphocyte count of > 5,000/mm3 obtained within 2 weeks 
prior to registration. 
Count:  ______________ Date of Test:  ______________ 
3.1.1.2 
The lymphocytosis must consist of small to moderate size 
lymphocytes, with ≤ 55% prolymphocytes, atypical 
lymphocytes, or lymphoblasts morphologically. 
3.1.1.3 
Patients must have phenotypically characterized B-CLL 
defined as: 1) the predominant population of cells share B-
cell antigens with CD-5 in the absence of other pan-T-cell 
markers (CD-3, CD-2, etc.); 2) B-cell expresses either  
κ and λ light chains; and 3) surface immunoglobulin (slg) 
with low-cell surface density expression. 
NOTE: 
Splenomegaly, hepatomegaly, or 
lymphadenopathy are not required for the 
diagnosis of CLL. However, if palpable 
adenopathy is present, bidimensional 
measurements are required pretreatment and 
at scheduled disease assessments in order to 
determine response. (Provide measurements 
on a minimum of 2 of the largest nodes but no 
more than 5.) 
Rev. 8/05 
Rev. 8/05 
________ 
Rev. 6/05 
Rev. 7/07 
Rev. 6/05 


ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
18 
3.1.2 
Patients must require chemotherapy. The last administration of 
chemotherapy must have been completed ≥ 6 weeks prior to study 
treatment. Any of the indications below for chemotherapy must be 
met: 
3.1.2.1 
One or more of the following disease-related symptoms: 
a. Weight loss ≥ 10% within the previous 6 months (grade 
2 or higher) 
b. Extreme fatigue (grade 3 or higher) 
c. Fevers > 100.5oF for 2 weeks without evidence of 
infection (grade 1 or higher) 
d. Night sweats without evidence of infection (drenching) 
3.1.2.2 
Evidence of progressive marrow failure as manifested by 
the development of or worsening anemia (≤ 10 g/dl) and/or 
thrombocytopenia (≤ 100,000/mm3). 
3.1.2.3 
Massive (i.e. > 6 cm below left costal margin) or 
progressive splenomegaly. 
3.1.2.4 
Massive nodes or clusters (i.e. > 10 cm in longest 
diameter) or progressive adenopathy. 
3.1.2.5 
Progressive lymphocytosis with an increase of > 50% over 
2 month period, or an anticipated doubling time of less 
than 6 months. 
3.1.3 
Patients must have either: (1) demonstrated progression after at least 
one cycle of either an alkylating agent-based or purine nucleoside 
based (i.e. fludarabine) regimen, (2) failed to achieve a meaningful 
response, or (3) relapsed after prior therapy. Patients who have 
relapsed with a pentostatin-based regimen may be eligible if the 
response was greater than 12 months. 
3.1.4 
Patients may have received prior Rituximab therapy but at least eight 
weeks should have elapsed between the last Rituximab dose and 
registration. 
3.1.5 
Patients must not have had previous CAMPATH-1H therapy prior to 
entering the study. Patients may have had previous PCR therapy or 
components thereof, however, they must have completed pentostatin 
and cyclophosphamide ≥ 1 year from date of registration. 
3.1.6 
Serum creatinine must not be greater than 2 mg/dl obtained ≤ 2 
weeks prior to registration. If serum creatinine is greater than 1.5 
mg/dl but less than 2mg/dl, the creatinine clearance calculated from a 
24 hour urine collection must be ≥ 30 ml/min. 
NOTE: 
May be calculated using the Cockcroft-Gault Equation: 
(140-age)*wt(kg)/([Cr]*72). For women, the calculation may 
be multiplied by 0.85. 
Serum creatinine:  ______________ Date of Test:  ______________ 
________ 
________ 
________ 
________ 
________ 
Rev. 5/06 
Rev. 7/07 
Rev. 7/07 
Rev. 1/09 
Rev. 6/05 
Rev. 7/07 


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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
19 
3.1.7 
Bilirubin must be ≤ 2 mg/dl, unless secondary to tumor or hemolysis, 
obtained ≤ 2 weeks prior to registration.   
Bilirubin:  ________________ Date of Test:  ________________ 
NOTE: 
Patients with Gilbert’s syndrome will be eligible for study. 
3.1.8 
Patients with active infections requiring oral or intravenous antibiotics 
are not eligible for entry onto the study until resolution of the infection 
and completion of antibiotics. 
3.1.9 
Age ≥ 18 years. 
3.1.10 
Women must not be pregnant or breast feeding because it is unknown 
what effect these drugs will have on a fetus or child. 
All females of childbearing potential must have a blood test or urine 
study ≤ 2 weeks prior to registration to rule out pregnancy. 
Woman of childbearing potential? _____ (Yes or No) 
Date of Test:  ______________ 
3.1.11 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception. 
3.1.12 
Patients must have ECOG performance status of 0-2. 
3.1.13 
Patients with a second malignancy other than squamous/basal cell 
carcinoma of the skin or in situ carcinoma of the cervix are not eligible 
unless the tumor was curatively treated at least two years previously. 
3.1.14 
Patients with grade III or IV heart failure according to the New York 
Heart Association functional classification are not eligible. 
3.1.15 
Patients whose marrow function is attributable to dysplasia related to 
prior therapy are not eligible. 
3.1.16 
Patients must be tested for hepatitis B virus infection. Those who are 
carriers of the virus or who test positive for the virus will be allowed to 
enter the study, but will be closely monitored for clinical and laboratory 
signs of active HBV infection and hepatitis (see Section 7). 
Result of test:  ________________ Date of Test:  ________________ 
3.2 
Step 2 : Eligibility Requirements For Re-registration to CAMPATH-1H  
NOTE:  
Response to Step 1 must be determined before registration to Step 2. 
To be registered to Arm B, patients must 
• 
meet all criteria for clinical CR response 
• 
have first post-treatment BM BX at 8 weeks after all criteria are first met for 
clinical CR 
• 
start treatment approximately 12 weeks after last dose (6th cycle) of PCR on 
Step 1 
• 
be free of symptoms as specified in 3.1.2.1 
________ 
________ 
________ 
________ 
________ 
________ 
________ 
________ 
________ 
________ 
Rev. 7/07 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
20 
To be registered to Arm C, patients must 
• 
meet all criteria for PR, SD or PD 
• 
have completed 6 cycles of PCR, unless determined to have progressive 
disease on PCR treatment 
• 
if determined to have progressive disease, stop treatment with PCR and 
begin treatment for Arm C CAMPATH-1H 30 mg SQ TIW for 18 weeks, 
beginning CAMPATH-1H no sooner than 2 weeks and no later than 8 weeks 
after the last dose of PCR 
3.2.1 
Patients must have an ECOG performance status of 0-2. 
3.2.2 
Serum creatinine must not be greater than 2.0 mg/dl obtained ≤ 2 
weeks prior to re-registration. If serum creatinine is greater than 1.5 
mg/dl, the creatinine clearance calculated from a 24 hour urine 
collection must be ≥ 40 ml/min. 
Serum creatinine:  ______________ Date of Test:  ______________ 
Creatinine clearance (if required): ____________ 
3.2.3 
Bilirubin must be ≤ 2 mg/dl, unless secondary to tumor or hemolysis, 
obtained ≤ 2 weeks prior to re-registration. 
Bilirubin:  ________________ Date of Test:  ________________ 
NOTE: 
Patients with Gilbert’s syndrome will be eligible for study. 
3.2.4 
Patients with active infections requiring oral or intravenous antibiotics 
are not eligible for entry onto step 2 until resolution of the infection 
and completion of antibiotics. 
 
________ 
________ 
________ 
________ 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
21 
4. 
Registration Procedures 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific regulatory 
documents must be submitted to the CTSU Regulatory Office at the following address: 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
3. A. CTSU IRB Certification Form. 
 
Or 
B. HHS 310 Form. 
 
Or 
 
C. IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed at 
http//www.ctsu.org/rss2_page.asp. If you have questions regarding regulatory 
document submission, please telephone the CTSU Help Desk at 1-888-823-5923 or 
E-mail CTSUContact@westat.com. 
Patients must not start protocol treatment prior to registration. 
Treatment should start within three working days after registration 
Institutions may register eligible patients to this study via the ECOG webpage 24 
hours a day, 7 days a week, using the Web-based Patient Registration Program 
(https://webreg.ecog.org). If you need assistance or have questions, please 
telephone the Central Randomization Desk at the ECOG-ACRIN Operations Office 
Rev. 1/14 


ECOG-ACRIN 
E2903 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
22 
- Boston at (617) 632-2022, Monday through Friday 9:00am-5:00 pm Eastern Time. 
Please note that a password is required to use this program. The following 
information will be requested: 
4.1 
Step 1: Induction (Arm A) 
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification 
4.1.2.1 
Institution name and/or affiliate 
4.1.2.2 
Investigator's name 
4.1.3 
Patient Identification 
4.1.3.1 
Patient's initials and chart number 
4.1.3.2 
Patient's Social Security number 
4.1.3.3 
Patient Demographics 
4.1.3.3.1 
Sex 
4.1.3.3.2 
Birthdate (MM/YYYY) 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.4 
Nine-digit zip code 
4.1.3.5 
Method of payment 
4.1.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.0. An eligibility checklist has been appended to the protocol. A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.1.5 
Additional Requirements 
4.1.5.1 
Patient must provide signed and dated written informed 
consent. 
4.1.5.2 
Correlative study samples should be submitted as outlined 
in Section 11.0. 
NOTE: 
Institutions outside of the United States and 
Canada are not required to submit fresh 
samples because of the costs and problems 
associated with international shipping. 
[Section 4.1.5.3 deleted in Addendum #9, 5/06] 
4.1.6 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment 
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
according to the E2903 Forms Packet. Document the reason for not 
starting protocol treatment on one of the baseline forms. 
Rev. 6/05 
Rev. 8/05 
Rev. 6/05, 5/06 


ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
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4.2 
Step 2: Re-registration Procedures to Campath-1H (Arm B and Arm C)  
If patient achieves confirmed CR or nPR upon re-evaluation, patient will be 
registered to receive CAMPATH-1H for four weeks (Arm B). If patient achieves 
PR, stable disease or PD upon re-evaluation, patient will be registered to receive 
CAMPATH-1H for eighteen weeks (Arm C). 
4.2.1 
Protocol Number 
4.2.2 
Investigator Identification 
4.2.2.1 
Institution name and/or affiliate 
4.2.2.2 
Investigator's name 
4.2.3 
Patient Identification 
4.2.3.1 
Patient's initials and chart number 
4.2.3.2 
Patient's Social Security number 
4.2.3.3 
Patient Demographics 
4.2.3.3.1 
Sex 
4.2.3.3.2 
Birth date (MM/YYYY) 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit zip code 
4.2.3.4 
Method of payment 
4.2.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.2. An eligibility checklist has been appended to the protocol. A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.2.5 
Additional Requirements 
4.2.5.1 
Correlative study samples should be submitted as outlined 
in Section 11.0. 
NOTE: 
Institutions outside of the United States and 
Canada are not required to submit fresh 
samples because of the costs and problems 
associated with international shipping. 
[Section 4.2.5.2 deleted in Addendum #9, 5/06] 
4.2.6 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment 
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
according to the E2903 Forms Packet.  Document the reason for not 
starting protocol treatment on one of the baseline forms. 
 
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Rev. 7/07 
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5. 
Treatment Plan 
NOTE: 
For G-CSF administration, either Neupogen® or Neulasta® may be used. 
NOTE: 
Doses based on actual body weight. 
5.1 
Step 1 (Arm A):  Rituximab, pentostatin, and cyclophosphamide 
5.1.1 
Pre-medication 
During the first week of therapy, Tylenol 650 mg PO and 
diphenhydramine (Benadryl) 50 mg IV should be administered 30 
minutes prior to rituximab to prevent infusion-related toxicity.  
Allopurinol will be required on days 0-14 of cycle 1. Allopurinol will be 
given at 300 mg/day PO x 15 days.  
Antiemetic medications such as Kytril 2 mg PO should be given 1 
hour to thirty minutes prior to chemotherapy and 12 hours after 
chemotherapy if necessary. Additional prophylactic antiemetic therapy 
will be left to the discretion of the treating physician.  Steroids are 
discouraged. 
Patients should be encouraged to drink fluids the night before 
treatment and will receive approximately 1-liter IV hydration over 1 
hour prior to chemotherapy – hydration on days with rituximab but 
without chemotherapy is left to the discretion of the investigator. 
5.1.2 
Rituximab, Pentostatin, and Cyclophosphamide 
Treatment will consist of 6 cycles of pentostatin, cyclophosphamide, 
and rituximab (PCR) given every 28 days. See Table 5.1.2a and 
Sections 5.1.2.1 and 5.1.2.2 for dosing instructions.  
Patients will be assessed with physical examination, assessment of 
liver/spleen and measurement of lymphadenopathy, CBC, and 
chemistries prior to each cycle. Patients meeting criteria for prohibitive 
toxicity or progressive disease will not receive further PCR treatment 
on study.  However, patients demonstrating progressive disease, 
stable disease or partial response will then be given CAMPATH-1H as 
per protocol (see Section 6.0). 
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Table 5.1.2.a: PCR (Pentostatin, Cyclophosphamide, Rituximab) Dose Schedule 
 
Agent 
Dose 
Route 
Cycles 
Rx day(s) 
Frequency 
Rev 3/05 
Rituximab** 
Day 1 of therapy 100 mg IV over 
4 hours (25 mg/hr) 
Day 3 of therapy 375 mg/m2 IV at 
50 mg/hr (if no prior reaction on 
day 1). Increase rate by 50mg/hr 
every 30 minutes, if no reaction, 
to a maximum of 400 mg/hr. 
Day 5 of therapy 375 mg/m2 IV at 
100 mg/hr for the first 30 minutes. 
Increase rate by 100mg/hr every 
30 minutes, if no reaction, to a 
maximum of 400 mg/hr. 
IV in 250-
500 mL NS 
1 
1, 3, 5 
This 
schedule 
for the first 
week only 
Rev. 5/06 
Rituximab** 
375 mg/m2 will be repeated as a 
single IV infusion Day 1 of Week 
5, 9, 13, 17 and 21. 
IV 
2-6 
1 
Q 4 weeks 
Rev. 5/06, 
1/09 
Pentostatin** 
4 mg/m2  on Day 1 of each cycle 
IV over 10-
30 minutes 
in 250 mL 
NS or D5W 
1-6 
1 
Q 4 weeks 
Rev. 5/06, 
1/09 
CTX** 
600 mg/m2  on Day 1 of each 
cycle 
IV over 30-
60 minutes 
in 250-500 
mL NS 
1-6 
1 
Q 4 weeks 
** The order of drug treatment is as follows in this sequence of administration: (1) Rituximab,  
(2) Pentostatin, (3) cyclophosphamide. 
Table 5.1.2b G-CSF* Dose Schedule 
 
Agent 
Dose 
Route 
Cycles 
Rx day(s) 
Frequency 
Rev. 1/09 
G-CSF* 
5 mcg/kg 
SQ 
All 
3-12  
(see Section 
5.1.4.4) 
Each 
Treatment 
Cycle 
* Neulasta, at a dose of 6 mg SQ on day 1 post chemo, Q 4 weeks, may be substituted 
for G-CSF at physician’s discretion. See Section 5.1.4.4. 
NOTE: 
Patients may have their infusions via the following methods:  
Port-a-cath, central line, PIC, peripheral line, or Hickman. 
5.1.2.1 
Rituximab will be administered as follows: 
During the first week of therapy, Tylenol 650 mg PO and 
diphenhydramine (Benadryl) 50 mg IV should be 
administered 30 minutes prior to rituximab to prevent 
infusion-related toxicity.   
Shortness of breath, rigors, and other infusion-related 
toxicity has been noted more frequently during the first 
several treatments. Rarely, pulmonary failure with 
infiltrates and edema resulting in fatalities has been 
observed. Vital signs are recommended to be measured 
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every 15 minutes for the first 2 hours with the first dose of 
rituximab, with each dose escalation and then as clinically 
indicated. Temperature should be taken prior to each 
treatment and repeated as clinically indicated throughout 
each infusion.  The treatment area should be sufficiently 
prepared to allow easy access to supportive care 
medications and measures, such as Demerol for IV push, 
O2 supplementation and nebulized albuterol, warm 
blankets, IV fluid for bolus, and access to crash cart 
(84.85). 
5.1.2.1.1 
For the first infusion: 
All patients will receive diphenhydramine 50 
mg IV and Tylenol 650 mg po 30 minutes 
prior to initiation of rituximab. 
All patients will receive a 100 mg dose 
(regardless of weight/BSA) of rituximab. The 
infusion rate will be 25 mg/hr throughout 
day 1 treatment (the rate will NOT be 
escalated on this day). 
If rigors occur, rituximab administration 
should cease temporarily and meperidine 
25 mg IVP and promethazine 12.5 mg IVP 
should be administered. 
If transient bronchospasm occurs, 
rituximab administration should be 
interrupted. If these symptoms persist, 
consideration should be given to 
administering hydrocortisone 100 mg and 
an albuterol (or other B2 agonist) inhaler. 
Once this has returned to grade 1 in 
severity, rituximab administration can 
resume. 
5.1.2.1.2 
For the second and subsequent infusions: 
All patients will receive diphenhydramine 50 
mg IV and Tylenol 650 mg PO 30 minutes 
prior to initiation of rituximab.  
All patients will receive rituximab 375 
mg/m2. For the second administration of 
cycle 1 (Day 3) the rituximab will be 
administered at an initial rate of 50 mg/hr 
and increased by 50 mg/hr every 30 
minutes, if there are no reactions, to a 
maximum of 400 mg/hr. For the third 
administration of cycle 1 (Day 5) and for all 
subsequent administrations (cycles 2-6) the 
rituximab infusion will begin at 100 mg/hr 
with 100 mg/hr increments every 30 
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minutes, if there are no reactions, to a 
maximum of 400 mg/hr.  
If rigors occur, rituximab administration 
should cease temporarily and meperidine 
25 mg IV and promethazine 12.5 mg IV 
should be administered. 
If transient bronchospasm occurs, 
rituximab administration should be 
interrupted. If this persists, consideration to 
administering hydrocortisone 100 mg and 
an albuterol (or other B2 agonist) inhaler 
should be given. Once this has returned to 
grade 1 in severity, rituximab administration 
can resume. 
5.1.2.1.3 
In patients with high leukocyte counts, 
close observation for potential toxicities 
should occur (84,85). If marked reduction in 
circulating lymphocytes is noted, close 
attention to the possibility of acute tumor 
lysis should occur. As treatment with 
rituximab may result in acute but temporary 
reduction in platelets, patients with baseline 
platelet counts ≤ 20,000/µL should receive 
platelet transfusion prior to rituximab 
therapy. Patients should be encouraged to 
drink abundant fluid prior to the first 
treatment. Additional measures for 
hydration should be considered in patients 
with bulky adenopathy or leukocytes  
> 50,000/µL. Physicians are encouraged to 
contact the Study Chair with any questions 
regarding these supportive care issues. 
5.1.2.2 
Pentostatin and cyclophosphamide will be administered as 
follows: 
Pentostatin to be given at 4 mg/m2 either as an IV push or 
IV over 10-30 minutes in 250 mL NS or D5W on day 1 
every 4 weeks of cycles 1-6. 
Cyclophosphamide to be given at 600 mg/m2 IV over 30-60 
minutes in 250 mL NS on day 1 every 4 weeks of cycle 1-
6. 
5.1.3 
Dose Modification Based on Toxicity:  
All toxicities should be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
The CTCAE version 4.0 is identified and located on the CTEP 
website at http://ctep.cancer.gov. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. 
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If multiple toxicities are seen, administer dose based on greatest 
reduction required for any single toxicity observed. Reductions apply 
to treatment given in the preceding cycle and are based on toxicities 
observed since the prior dose. 
5.1.3.1 
Dose Modifications for Rituximab 
No dose modifications for Rituximab. If grade 4/5 
toxicity occurs (see CTCAE v4.0), please contact the 
principal investigator for further guidelines.  
Dose modifications for Pentostatin and Cyclophosphamide (CTX) 
TOXICITY 
AGENT 
DOSAGE CHANGE 
Pentostatin or CTX 
 
 
At time of retreatment cycles 2-6 
 
 
ANC ≥ 1,000, or PLT ≥ 50,000 
Pentostatin and 
Cyclophosphamide 
Rx @ 100% doses for 
Pentostatin and CTX. 
ANC ≤ 1,000, or PLT ≤ 50,000 
Pentostatin and 
Cyclophosphamide 
Delay Rx 1 week.  If 
counts > these levels, 
resume Rx @ 100% 
dose level. 
After 1 week delay 
 
 
ANC 500 – 1,000 or PLT 30,000-50,000 
Pentostatin and 
Cyclophosphamide 
↓ pentostatin to 1 
mg/m2 and resume. ↓ 
CTX to 300 mg/m2 and 
resume. 
ANC ≤ 500 or PLT ≤ 30,000 
Pentostatin and 
Cyclophosphamide 
Discontinue Rx and go 
to event monitoring. 
Non-hematologic: Grade 3 organ  
toxicity (except fever, hyperglycemia, 
GI, infection) Grade 4 GI 
Discontinue treatment 
and go to event 
monitoring. 
There are no pentostatin or cyclophosphamide modifications for interval toxicity 
5.1.3.1.1 
Serum creatinine will be determined within 
14 days of PCR treatment. Serum creatinine 
must not be > 2mg/dl. (If it is > 2mg/dl, cycle 
should be delayed until creatinine level 
returns to ≤ 2 mg/dl. If creatinine level 
remains above 2 mg/dl for longer than 2 
weeks, the patient will come off study 
treatment with the choice of subsequent 
treatment to be decided by the treating 
physician). If the creatinine level is > 1.5 
mg/dl, but ≤ 2mg/dl, a creatinine clearance 
will be obtained. No dose reduction will be 
made for a creatinine clearance ≥ 60 
ml/min. For a creatinine < 60 ml/min, a dose 
reduction of 50% in the pentostatin dose will 
be made. 
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NOTE: 
May be calculated using the 
Cockcroft-Gault Equation: (140-
age)*wt(kg)/([Cr]*72). For 
women, the calculation may be 
multiplied by 0.85. 
There are no safe guidelines for 
administration of pentostatin in patients with 
a creatinine clearance of < 30 ml/min.  This 
will be the minimum clearance for patients 
on this study and so any patients whose 
clearance is < 30 ml/min will discontinue 
protocol therapy. 
5.1.3.2 
Patients who suffer grade 4 toxicity unrelated to the 
leukemia, using the CTCAE, will be removed from study. 
This may occur either during the PCR phase or during 
Campath-1H consolidation (or treatment for PR, PD and 
SD patients). This includes allergic manifestations, blood 
and bone marrow suppression unrelated to the leukemia, 
and cardiovascular, dermatologic, renal, gastrointestinal 
and neurologic events. For grade 4 infection/febrile 
neutropenia, removal from study will be left to the 
discretion of the investigator. If a patient develops grade 2 
or greater thrombocytopenia during CAMPATH-1H 
administration, the medication will be withheld until this 
resolves. Both myelosuppression and immune-mediated 
mechanisms have been implicated. Myelosuppression and 
drug-induced immune thrombocytopenia should resolve 
once the CAMPATH-1H is stopped (up to four weeks for 
recovery). If immune-mediated thrombocytopenia (ITP) 
occurs, more aggressive measures are to be taken (as 
have been reported) and these are left to the discretion of 
the investigators. Once thrombocytopenia resolves, 
independent of the mechanism, further administration of 
CAMPATH-1H will be decided upon by the treating 
physician and the Study Chair and Co-Chair (Dr. Sanford 
Kempin and Dr. Neil Kay). 
5.1.3.3 
The toxicity profile in the two studies (Weiss et al; Kay et 
al) in which PCR has been used has been modest (see 
1.5.2). There has been one grade 5 pulmonary toxicity in 
the Weiss study and several patients were removed from 
study (no further details available). The maximum toxicities 
in the Kay study were grade 3 and no patient has been 
removed from study. Therefore, it is not anticipated that a 
significant number of patients will be removed from study 
during the first phase. Nonetheless, the study toxicity 
monitors will be notified of any grade 5 event who will then 
recommend either continuation or stopping of the study. In 
the studies utilizing the subcutaneous administration of the 
drug, discontinuation during therapy has been reported. 
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Discontinuation, however, did not result from grade 4 
neutropenia (13%), but rather from severe local reactions 
(pain) or systemic symptoms (fever, fatigue). Therefore, it 
is unlikely that the consolidation phase will be prematurely 
stopped. The main concern on this study is that of 
microbial infection, particularly CMV reactivation. In view of 
this, surveillance for CMV will be undertaken at the 
beginning of each cycle of PCR and every two weeks 
during CAMPATH-1H. Discovery of reactivation, either 
because of a clinical syndrome or a laboratory finding, will 
result in cessation of therapy and treatment of the CMV. A 
decision to resume therapy after treatment of a CMV event 
is the responsibility of the principle investigators. If less 
than grade 4 toxicity has been documented, the protocol 
may be resumed. If grade 4 toxicity occurs the patient will 
be removed from study. 
5.1.4 
Supportive Care Treatment 
5.1.4.1 
All supportive measures consistent with optimal patient 
care will be given throughout the study. 
5.1.4.2 
For step 1: All patients must receive daily allopurinol (300 
mg/day PO) unless they are allergic and should be well 
hydrated before the first cycle of PCR treatment is started. 
All patients will be given PO allopurinol 300 mg/day from 
day 0 to day 14 (a total of 15 days) for the first month of 
therapy. Use of allopurinol after this period is discouraged 
unless the patient has been on this medication chronically. 
The duration of allopurinol and the need for allopurinol 
beyond the first cycle is left to the discretion of the treating 
physician. 
5.1.4.3 
For step 1 and step 2: Bactrim DS 1 BID on 
Monday/Wednesday/Friday AND acyclovir 800 mg po BID 
(or equivalent, including gancyclovir and valgancyclovir) 
during chemoimmunotherapy (PCR) and immunotherapy 
(CAMPATH-1H) and for 6 months after completion of this 
chemoimmunotherapy protocol. 
5.1.4.4 
For step 1 and step 2: During the induction phase (step 1), 
G-CSF 300 mcg for patients < 70 kg and 480 mcg for 
patients > 70 kg will be administered subcutaneously daily 
beginning two days after each treatment. Neulasta may be 
used in place of G-CSF, at a dose of 6 mg SQ on day 1 
post chemo, Q 4 weeks. At the start of the consolidation 
(CR, nPR) phase, the absolute neutrophil number is 
expected to be > 1,000 x 106/L. Patients will not be given 
G-CSF or neulasta routinely unless neutropenia (< 1,000 x 
106/L) is documented during the weekly follow-up studies. 
G-CSF or neulasta may be started and maintained to 
achieve an absolute neutrophil number of > 1,000 x 106/L. 
In the case of G-CSF or neulasta it can be stopped with 
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two consecutive neutrophil counts of > 1,000 x 106/L. For 
those patients receiving CAMPATH-1H as salvage (PR or 
PD), the absolute neutrophil number at the start of therapy 
may be less than 1,000 x 106/L and G-CSF or neulasta is 
recommended to maintain the absolute neutrophil number 
> 1,000 x 106/L during the CAMPATH-1H administration.(If 
neutropenia persists beyond day 12, G-CSF should be 
continued until the ANC is > 1 x109/L for 2 consecutive 
blood counts. G-CSF may be discontinued prior to day 12 
if ANC is > 1x 109/L for 2 consecutive blood counts.) 
5.1.4.5 
For step 2: Although no fatal toxicity has been seen with 
SC administration of CAMPATH-1H, life-threatening and 
fatal CMV disease has been reported with Campath-1H 
therapy, especially when Campath-1H was used following 
nucleoside analogs. 
Development of rapid methods to diagnose CMV infection 
before onset of clinical disease has been the main focus of 
attention in stem cell transplantation. The frequency of 
infection after cytotoxic therapy utilizing purine analogs 
and immunologic targets warrants a similar approach. In 
the transplant setting, older age, the use of purine analogs 
or monoclonal antibodies directed against T-cells and 
seropositivity prior to transplantation, are important risk 
factors for CMV disease and are likely to be operative in 
the elderly prior-treated CLL population. Various 
methodologies have been used to diagnose infection. The 
shell vial culture technique coupled with 
immunofluorescence assays enables diagnosis within 
several days. Broncheoalveolar lavage has a sensitivity 
and specificity of 90%. Blood tests including CMV pp65 
antigenemia and PCR techniques detect virus in the blood 
several weeks before onset of disease, but the former can 
be quite subjective. 
Attempts to prevent infection will depend upon the 
serologic status of the patient prior to immunosuppressive 
therapy. For seronegative patients, CMV negative blood 
products, if needed, are recommended. In seropositive 
patients, prophylactic use of gancyclovir in the transplant 
setting has been successful in preventing clinical infection. 
We do not propose to use this latter strategy in the present 
protocol. Rather, each patient will remain on acyclovir 
prophylaxis for the total treatment time and for six months 
thereafter. Pre-emptive therapy, by serial patient 
monitoring from the beginning of PCR to the completion of 
CAMPATH-1H, will be used. For purposes of this study, 
testing will be performed at the beginning of each cycle of 
PCR and every two weeks during CAMPATH-1H, utilizing 
the current methodology at each center (either pp65 
antigenemia or CMV DNA by RTPCR). CMV serology must 
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be obtained as part of baseline studies. Individual centers 
may define active infection by their own guidelines. In 
general a positive pp65 result, or a greater than 400-copy 
result by PCR will define active CMV infection. For patients 
developing active infection but no clinical sequel, a course 
of either gancyclovir or valgancyclovir is recommended. 
Duration of therapy will be left to each individual center. 
Individual centers have used three weeks to 12 weeks as 
duration of therapy. The protocol at each center will be 
used. Therapy will be interrupted during this period of time. 
Once monitoring determines absence of active infection, 
both therapy and continuing monitoring will be resumed.  
5.1.5 
The potential for toxicity during the induction and 
consolidation/salvage phases demands prophylactic antibacterial, 
antifungal and antiviral therapy, monitoring for viral occurrence and 
provision for stopping therapy if too toxic. Prophylactic antibacterial 
and antiviral therapy are discussed in Sections 5.1.4. CMV 
reactivation during both the induction and consolidation/salvage 
phase will be monitored and verified by polymerase chain reaction 
assays (86). 
5.2 
Step 2 (Arm B and Arm C): CAMPATH-1H  
5.2.1 
Allopurinol will not be administered to patients who have achieved a 
confirmed CR or nPR. Allopurinol (300 mg/d) will be administered to 
those patients who have achieved only a PR or SD (or PD) after the 
PCR regimen. The duration of allopurinol administration will be left to 
the discretion of the investigator. 
5.2.2 
For those patients achieving a confirmed CR or nPR, they will be 
registered to receive CAMPATH-1H (Arm B). When the patient is 
registered to Arm B, the drug will be administered three times a week 
for four weeks. The dose will be 30 mg per dose. A twelve-week 
treatment-free period will elapse before CAMPATH-1H begins 
following completion of PCR for Arm B patients. Patients will be 
assessed with physical examination, CBC, chemistries, and CMV 
monitoring (see Section 7). 
For those patients not achieving a CR or nPR (thus patients have 
either achieved PR, SD, or PD), CAMPATH-1H (Arm C) will be 
administered three times a week for eighteen weeks at a dose of 30 
mg TIW. For PR, SD and PD patients, the timing of CAMPATH-1H will 
be left to the discretion of the investigator, and treatment may begin 
earlier but no less than two weeks and no longer than eight weeks 
after the completion of the last PCR course. Patients determined to 
have PD during treatment with PCR do not need to complete all 6 
cycles of PCR to go on to Arm C, however, completing a minimum of 
2 cycles is required. Patients will be assessed with physical 
examination, CBC chemistries, and CMV monitoring (see Section 7). 
Rev. 7/07 
Rev. 12/05 
Rev. 12/05, 1/09 
Rev. 7/07 
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5.2.3 
CAMPATH-1H will be administered subcutaneously in a volume of 1.5 
ml (55). CAMPATH-1H will be initially administered at a dose of 3 mg 
by subcutaneous injection in the thigh (day 1).  The dose will be 
increased to 10 mg on day 3 and then raised to 30 mg on day 5. If > 
grade 2 toxicity occurs do not increase dose until toxicity returns to 
grade 1 or less. 
Agent 
Dose 
Route 
Initial Response 
Duration 
Frequency 
CAMPATH-1H 
30 mg 
SQ 
CR/nPR 
4 weeks 
TIW 
CAMPATH-1H 
30 mg 
SQ 
PR/PD 
18 weeks 
TIW 
5.2.4 
Premedications will consist of acetaminophen 650 mg po and 
diphenhydramine 50 mg PO 30 minutes prior to each injection during 
the first week. Thereafter, acetaminophen and diphenhydramine will 
be administered according to the discretion of the investigator. 
Additional therapy will be left to the discretion of the treating physician 
but should not include corticosteroids. 
5.2.5 
During the period of CAMPATH-1H administration, anti-infective 
prophylaxis is essential. Trimethoprim/sulfamethoxazole (Bactrim) DS 
1 (BID) Monday, Wednesday and Friday, and acyclovir 800 mg BID 
will be administered for the 4-week and 18-week course of treatment 
and for six months after completion of treatment. For patients allergic 
to Trimethoprim/sulfamethoxazole (Bactrim), Dapsone may be used 
instead at a dose of 100 mg PO QD. 
5.2.6 
For those patients entering the consolidation phase in CR or nPR, the 
absolute neutrophil number is expected to be above 1,000 x106/L. 
Patients will not be given G-CSF (or neulasta) routinely unless 
neutropenia (≤ 1,000 x106/L) is documented during the weekly follow-
up studies. G-CSF (or neulasta) may be started and maintained to 
achieve a neutrophil number > 1,000 x106/L. For those patients 
receiving CAMPATH-1H in PR, SD, or during PD (salvage phase), the 
absolute neutrophil number may be less than 1,000 x106/L and G-
CSF (or neulasta) is recommended to maintain the neutrophil number 
> 1,000 x106/L during the CAMPATH-1H administration. 
5.2.7 
Although grade 4 toxicity, other than myelosuppression is not 
expected to occur during the CAMPATH-1H administration, the 
following side effects should be considered by the investigator as 
possible causes of removal from study:  prolonged neutropenia, 
severe febrile course, severe eczema and the appearance of 
autoimmune phenomena (thyroiditis, anemia, thrombocytopenia).  
5.2.8 
There will be no dose modification for CAMPATH-1H. However, if 
grade 4 non-hematologic toxicity occurs due to CAMPATH-1H the 
investigator may remove the patient from study if the risks outweigh 
the benefits (see 5.2.7). Grade 4 hematologic toxicity is unusual but 
may result in such morbidity that the investigator feels the subject 
should be removed from the study. The decision to remove a patient 
from study in these circumstances should be discussed with the 
principal investigator prior to removal. 
Rev. 12/05, 1/09 
Rev. 12/05 
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5.3 
ADVERSE EVENT REPORTING REQUIREMENTS 
5.3.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E2903 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting). Additionally, certain adverse events must be reported in an 
expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.3.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 will be 
utilized until June 30, 2011 for AE reporting.  CTCAE version 
4.0 will be utilized beginning July 1, 2011. All appropriate 
treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
Step 2: Grade the event using the NCI CTCAE version 4.0. 
Step 3: Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the 
severity of the event is NOT listed in: 
• 
Arm A, B, and C – the drug package insert or protocol 
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Step 5: Review Section 5.3.6 for E2903 and/or ECOG-ACRIN 
specific requirements for expedited reporting of specific 
adverse events that require special monitoring. 
NOTE: 
For general questions regarding expedited 
reporting requirements, please contact the AEMD 
Help Desk at aemd@tech-res.com  or 301-897-
7497. 
5.3.3 
Reporting methods 
Arm A B or C - This study requires that expedited adverse event 
reporting use CTEP’s Adverse Event Reporting System (CTEP-
AERS). CTEP’s guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov.  A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the FDA (1-800-FDA-1088) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617 632 2990), 
Attention: AE within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.3.4 
When to report an event in an expedited manner 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.3.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.3.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.3.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
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5.3.5 
Other recipients of adverse event reports 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
The drug supporter is obliged to forward reported AEs to the FDA.  A 
drug supporter representative may call a site for additional information 
regarding a serious adverse event.  Any additional written AE 
information requested by the drug supporter MUST be submitted to 
BOTH ECOG-ACRIN and the drug supporter. 
5.3.6 
Expedited reporting for commercial agents 
Commercial reporting requirements are provided below. The 
commercial agents used in arms A, B, and C of this study are 
Pentostatin, Cyclophosphamide, Rituximab, and Campath-1H. 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial 
agents only – Arm A, B and C 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN 
and Protocol-
Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. 
NOTE: 
Any death that occurs > 30 days after the last dose of treatment and is attributed 
possibly, probably, or definitely to the treatment must be reported within 7 calendar 
days of learning of the event. 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
Serious Events: 
Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported 
via CTEP-AERS within 7 calendar days of learning of the event. For instructions 
on how to specifically report these events via CTEP-AERS, please contact the 
AEMD Help Desk at aemd@tech-res.com  or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
Hepatitis B Virus: All cases of Hepatitis B Virus (HBV) reactivation with fulminant hepatitis and 
hepatic failure must be reported via CTEP-AERS within 7 calendar days of 
learning of the event. 
Protocol Specific Reporting Requirements 
All ≥ Grade 3 events felt to be possibly, probably or definitely related to protocol treatment 
(regardless of expectedness) must be reported via CTEP-AERS within 7 calendar 
days of learning of the event. 
Rev. 5/06 
Rev.1/09 
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5.3.7 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
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pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 


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5.3.8 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Alemtuzumab (NSC 715969) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. They are developed and continuously monitored by the 
CTEP Investigational Drug Branch (IDB). The information listed in the 
CAEPR(s) below, as well as the other resources described in the 
'Determination of reporting requirements' part of the Adverse Event 
Reporting section in this protocol, can be used to determine 
expectedness of an event when evaluating if the event is reportable 
via CTEP-AERS. Frequency is provided based on 346 patients. Below 
is the CAEPR for alemtuzumab. 
Version 2.1, March 23, 20101 
Adverse Events with Possible Relationship to Alemtuzumab 
(CTCAE 4.0 Term) 
[n= 346] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
 
 
Blood and lymphatic system 
disorders - Other (bone marrow 
aplasia) 
 
Disseminated intravascular coagulation 
 
 
Febrile neutropenia 
 
 
 
Hemolysis 
CARDIAC DISORDERS 
 
Atrial fibrillation 
 
 
Cardiac arrest 
 
 
 
Left ventricular systolic dysfunction 
 
Myocardial infarction 
 
 
Sinus tachycardia 
 
 
Ventricular arrhythmia 
 
 
Ventricular tachycardia 
 
ENDOCRINE DISORDERS 
 
Hyperthyroidism 
 
 
Hypothyroidism 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Constipation 
 
 
Diarrhea 
 
 
Dyspepsia 
 
 
Mucositis oral 
 
Nausea 
 
 
 
Small intestinal mucositis 
 
Vomiting 
 
 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
 
 
 
Edema limbs 
 
Fatigue 
 
 
Fever 
 
 
 
Flu like symptoms 
 
 
Injection site reaction 
 
 
Non-cardiac chest pain 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
Autoimmune disorder 
 
 
Cytokine release syndrome 
 
 
Serum sickness 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
Infections and infestations – Other 
(Opportunistic infection with 
≥Grade 2 Lymphopenia) 
 
 
INVESTIGATIONS 
 
Alkaline phosphatase increased 
 
 
Aspartate aminotransferase increased 
 
Lymphocyte count decreased 
 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Hypoalbuminemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthritis 
 
 
Back pain 
 
 
Generalized muscle weakness 
 
 
Myalgia 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Dysgeusia 
 
 
Headache 
 
 
Peripheral sensory neuropathy 
 
PSYCHIATRIC DISORDERS 
 
Insomnia 
 


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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Allergic rhinitis 
 
 
Bronchospasm 
 
 
Cough 
 
 
Dyspnea 
 
 
Hypoxia 
 
 
Pneumonitis 
 
 
Pulmonary edema 
 
 
Stridor 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Pruritus 
 
 
Purpura 
 
 
Rash acneiform3 
 
 
Urticaria 
 
VASCULAR DISORDERS 
 
Flushing 
 
 
Hypertension 
 
 
Hypotension 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 Also may include desquamation. 
4 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
5 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
6 Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, Esophageal ulcer, Gastric 
ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under the GASTROINTESTINAL 
DISORDERS SOC. 
Also reported on alemtuzumab trials but with the relationship to alemtuzumab still 
undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (lymphadenopathy) 
CARDIAC DISORDERS - Pericarditis 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Endocrine disorders - Other (aggravated diabetes mellitus) 
EYE DISORDERS - Optic nerve disorder 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Gastrointestinal hemorrhage4; 
Gastrointestinal perforation5; Gastrointestinal ulcer6; Pancreatitis 


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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait 
disturbance; General disorders and administration site conditions - Other (Goodpasture's 
syndrome); General disorders and administration site conditions - Other (Guillain-Barre 
syndrome); General disorders and administration site conditions - Other (Hemophagocytic 
syndrome); General disorders and administration site conditions - Other (Syndrome of 
Inappropriate Antidiuretic Hormone Secretion [SIADH]) 
INVESTIGATIONS - Blood bilirubin increased; Creatinine increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperglycemia; Hypocalcemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Joint range of motion 
decreased; Musculoskeletal and connective tissue disorder - Other (muscle atrophy); Myositis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia cerebrovascular; 
Leukoencephalopathy; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Depression; Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(toxic nephropathy); Urinary frequency; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Reproductive 
system and breast disorders - Other (cervical dysplasia); Reproductive system and breast 
disorders - Other (ovarian failure) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Bronchial obstruction; Bronchopulmonary hemorrhage; Pulmonary fibrosis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme 
VASCULAR DISORDERS - Vascular disorders - Other (increased capillary fragility); Vascular 
disorders - Other (splenic infarction) 
NOTE: 
Alemtuzumab in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 


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NCI Update Date: May 25, 2011 
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5.3.9 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Rituximab (NSC 687451) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system.  They are developed and continuously monitored by the 
CTEP Investigational Drug Branch (IDB).  The information listed in the 
CAEPR(s) below, as well as the other resources described in the 
'Determination of reporting requirements' part of the Adverse Event 
Reporting section in this protocol, can be used to determine 
expectedness of an event when evaluating if the event is reportable 
via CTEP-AERS. Frequency is provided based on 986 patients. Below 
is the CAEPR for Rituximab. 
Version 2.1, March 19, 20101 
Adverse Events with Possible 
Relationship to Rituximab 
(CTCAE 4.0 Term) 
[n= 986] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Blood and lymphatic system disorders - 
Other (Hyperviscosity: Waldenstrom’s) 
 
 
Febrile neutropenia 
 
CARDIAC DISORDERS  
 
Myocardial infarction 
 
 
Sinus tachycardia 
 
 
Supraventricular tachycardia 
 
GASTROINTESTINAL DISORDERS  
 
Abdominal pain 
 
 
Diarrhea 
 
 
Nausea 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
Fever 
 
 
Infusion related reaction 
 
 
 
Pain 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis 
 
Serum sickness 
 
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INFECTIONS AND INFESTATIONS 
 
Infection2 
 
 
Infections and infestations - Other 
(Activation of Hepatitis B, C, CMV, 
parvovirus B19, JC virus, varicella 
zoster, herpes simplex, West Nile virus) 
 
 
Infections and infestations - Other 
(Infection in HIV Positive Patients) 
 
INVESTIGATIONS 
Lymphocyte count decreased  
 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS  
 
Hyperglycemia 
 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Myalgia 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
Tumor pain 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
Lethargy 
 
 
 
Nervous system disorders - 
Other (progressive multifocal 
leukoencephalopathy) 
 
Seizure 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Adult respiratory distress 
syndrome 
 
Allergic rhinitis 
 
 
Bronchospasm 
 
 
Cough 
 
 
Dyspnea 
 
 
Hypoxia 
 
 
Pneumonitis 
 
 
Sore throat 
 


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SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Erythema multiforme 
 
Hyperhidrosis 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Skin and subcutaneous tissue disorders 
- Other (angioedema) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 
Urticaria 
 
VASCULAR DISORDERS 
 
Flushing 
 
 
Hypertension 
 
 
Hypotension 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, 
Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal 
obstruction under the GASTROINTESTINAL DISORDERS SOC. 
4 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
Also reported on rituximab trials but with the relationship to rituximab still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (cyanosis); 
Left ventricular systolic dysfunction; Sinus bradycardia; Ventricular fibrillation 
EYE DISORDERS - Conjunctivitis; Eye disorders - Other (ocular edema); Uveitis; Watering 
eyes 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; Gastrointestinal 
obstruction3; Gastrointestinal perforation4; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; 
Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic infection 
associated with >=Grade 2 Lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine 
increased; Investigations - Other (hyperphosphatemia); Investigations - Other (LDH increased); 
Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoglycemia; Hypomagnesemia; 
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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis 
NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial Neuropathy 
NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; Pyramidal tract syndrome; 
Reversible posterior leukoencephalopathy syndrome; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; 
Pharyngolaryngeal pain; Pleural effusion; Pulmonary edema; Respiratory, thoracic and 
mediastinal disorders - Other (bronchiolitis obliterans) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and subcutaneous tissue 
disorders - Other (paraneoplastic pemphigus) 
VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis 
NOTE: 
Rituximab in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 


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5.4 
Duration of Therapy 
5.4.1 
There is a significant potential for this regimen to be exceedingly 
immunosuppressive and toxic. For that reason careful monitoring of 
side effects and prophylaxis against microbial infection is essential 
(see Section 5.1.4).  
5.4.2 
Patients achieving a clinical CR will not have a confirmed CR or nPR 
until the initial post treatment bone marrow biopsy and aspirate is 
done 8 weeks after determining a clinical CR.  Patients with a 
confirmed CR or nPR at 12 weeks after 6 cycles PCR treatment, will 
be treated with Campath-1H 30 mg, TIW for 4 weeks (see Section 7). 
5.4.3 
Patients achieving PR or those who achieve less than a PR after 6 
cycles of PCR will receive a full 18 week course of CAMPATH-1H at 
30 mg SQ TIW. 
5.4.4 
Patients demonstrating progression while on PCR can register for the 
full 18 week course of CAMPATH-1H, Arm C. They do not have to 
complete all 6 cycles of PCR but must have completed at least 2 
cycles. 
5.4.5 
Patients will receive protocol therapy unless: 
5.4.5.1 
Extraordinary Medical Circumstances: If at any time the 
constraints of this protocol are detrimental to the patient’s 
health, protocol treatment should be discontinued. In this 
event submit forms according to the E2903 Forms Packet. 
5.4.5.2 
Patient withdraws consent. 
5.4.5.3 
If treatment is discontinued due to patient refusal or 
noncompliance, unacceptable toxicity or intercurrent illness 
that makes treatment assessment difficult, patients will be 
observed until they relapse and require chemotherapy. 
5.4.5.4 
If disease progression occurs during the CAMPATH-1H 
treatment, treatment will be discontinued. 
5.4.5.5 
Active HBV infection or hepatitis develops. 
5.5 
Duration of Follow-up 
5.5.1 
For this protocol, all patients, including those who discontinue protocol 
therapy early, will be followed for response until progression and for 
survival for 5 years from the date of registration. 
 
Rev. 7/07 
Rev. 7/07 
Rev. 7/07 
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6. 
Measurement Of Effect 
(See Appendix VII) 
6.1 
Assessment of Clinical Response 
The major criteria for determination of the response to therapy in patients with B-
CLL include physical examination and evaluation of peripheral blood and bone 
marrow (if evaluating for CR). It is recommended that the laboratory and physical 
exam findings, which are abnormal prestudy, be repeated to document the 
degree of maximal response. 
Measurements of the largest palpable lymph nodes (provide measurements on a 
minimum of 2 of the largest nodes but no more than 5) should be selected at 
baseline to be followed for response. These lymph nodes should be clearly 
measurable in two perpendicular dimensions and should be selected from each 
of the following sites, if involved: cervical, supraclavicular, axillary, inguinal, 
femoral. 
6.1.1 
A clinical complete remission requires all of the following for a period 
of at least 8 weeks: 
6.1.1.1 
Absence of lymphadenopathy by physical examination. 
6.1.1.2 
No hepatomegaly or splenomegaly. Spleen and/or liver, if 
considered enlarged at baseline, should not be palpable, 
due to disease, on physical exam. 
6.1.1.3 
Absence of constitutional symptoms, as described in 
Section 3.1.2.1. 
6.1.1.4 
Normal CBC as exhibited by: 
6.1.1.4.1 
Polymorphonuclear leukocytes > 1500 x 
106/L 
6.1.1.4.2 
Platelets > 100,000 x 106/L 
6.1.1.4.3 
Hemoglobin > 11.0 gm/dl (untransfused) 
6.1.1.4.4 
Peripheral blood lymphocytes  
≤ 4000 x 106/L 
 
6.1.2 
Confirmed Complete Remission or nPR 
Confirmed complete remission requires all of Section 6.1.1 and a 
normal bone marrow as defined below.  
One marrow aspirate and biopsy should be performed no sooner than 
8 weeks after clinical CR has been documented.  The marrow sample 
must be at least normocellular with <30% of nucleated cells being 
lymphocytes. If it is hypocellular, a repeat determination should be 
made in 2 weeks.  Samples are to be analyzed by a pathologist and 
the presence or absence of nodules noted.   
A patient who is in CR, but has nodules, will be considered to have 
nodular PR (nPR) and recorded separately. 
Rev. 7/07 
Rev. 7/07 
Rev. 7/07 
Rev. 7/07 
Rev. 7/07 
Rev. 7/07 
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If no confirmatory bone marrow biopsy is done in the specified time 
period, or if the bone marrow biopsy shows evidence of disease, the 
response will be PR.  
Any other laboratory assays (e.g. quantitative immunoglobulins) will 
not be used currently as an index for response but will be recorded for 
clinical correlations. 
6.1.3 
Partial Response or PR 
To be considered in PR, the patient must exhibit the features in 
Sections 6.1.3.1 – 6.1.3.3 and one or more of the following features in 
Section 6.1.3.4 – 6.1.3.6 for at least 8 weeks.  In addition to the 
parameters listed below, the presence or absence of constitutional 
symptoms will be recorded. Because the PR can be defined during 
the course of treatment, it is necessary to document a physical exam 
including assessment of liver and spleen, measurement of 
lymphadenopathy and hematologic evaluation (CBC, differential and 
platelet count) every cycle during treatment. 
6.1.3.1 
>50% decrease in peripheral blood lymphocyte count from 
the pretreatment baseline value. 
6.1.3.2 
> 50% reduction in lymphadenopathy. 
6.1.3.3 
No increase in size of liver and/or spleen. 
6.1.3.4 
Polymorphonuclear leukocytes > 1500 x 106/L or 50% 
improvement over baseline. 
6.1.3.5 
Platelets >100,000 x 106/L or 50% improvement over 
baseline. 
6.1.3.6 
Hemoglobin >11.0 gm/dl or 50% improvement over 
baseline without transfusions. 
NOTE: 
Patients in clinical complete remission but with 
evidence of disease in the bone marrow will be 
a PR. 
6.1.4 
Progressive disease (PD) will be characterized by at least one of the 
following: 
6.1.4.1 
> 50% increase in the sum of the products of at least 2 
lymph nodes on 2 consecutive examinations 2 weeks apart 
(at least 1 node must be > 2 cm). Appearance of new 
palpable lymph nodes > 1 cm. 
6.1.4.2 
Increase in the size of liver and/or spleen, as determined 
by physical exam, below the respective costal margin; 
appearance of palpable hepatomegaly or splenomegaly, 
which was not previously present. 
6.1.4.3 
> 50% increase in the absolute number of circulating 
lymphocytes. 
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6.1.4.4 
Transformation to a more aggressive histology (e.g. 
Richter’s syndrome or prolymphocytic leukemia with >55% 
prolymphocytes). 
6.1.4.5 
In the absence of progression as defined above, the 
presence of a > 2 gm/dl decrease in hemoglobin, or > 50% 
decrease in platelet count and/or absolute granulocyte 
count will not exclude a patient from continuing on study.  
Bone marrow aspirate and biopsy are strongly encouraged 
to better define the cause of the suppressed counts. 
6.1.4.6 
Patients who have not achieved a CR, nPR or PR or who 
have not exhibited findings consistent with Progressive 
disease will be considered as having Stable Disease. 
 


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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
1. Chest x-rays should be done ≤ 30 days before registration. 
2. Prestudy CBC with differential, LFTs should be done ≤ 2 weeks before registration. 
3. All required prestudy chemistries should be done ≤ 2 weeks before registration - unless specifically required on Day 
1 as per protocol. If abnormal, they must be repeated within 48 hours prior to registration. 
4. Prestudy Hgb, Hct, WBC, Plt should be done ≤ 2 weeks before registration. 
NOTE: 
When recording prestudy results on the baseline data form, please make sure that ALL relevant dates 
are clearly given. Do not put all the results under the date for Day 1 of protocol treatment unless they 
were actually done that day. Record the actual dates. 
Table 7.1.1 
Test Schedule:  Pre-treatment and during treatment with PCR (Arm A) 
 
Test/procedures 
PRETREATMENT 
DURING TREATMENT-PCR 
(Arm A) 10 
Rev. 1/09 
Within 30 days prior to 
registration 
Within 14 days  
prior to registration 
Day 1, 
Cycle 1 
Subsequent 
cycles 
8 weeks After 
Cycle 6 
Rev. 7/07 
History and exam, height,6 weight, PS 
X 
 
X 
X 
X 
Rev. 8/05, 
7/07 
Tumor Measurement by PE 
X3 
 
 
X3 
X3 
Rev. 6/05, 
8/05, 5/06 
CBC/diff/blood smear 
 
X 
Day 18,  
End of Weeks 1-4 
Day 18, 
End of  
Week 2 
X 
Rev. 6/05, 
1/09 
Rev. 6/05 
Chem group (SGOT, t bili, creat11, glucose, calcium, 
alk phos, albumin, electrolytes, BUN, LDH, uric acid) 
 
X 
Day 18 
Day 18 
X 
 
Chest x-ray 
X 
 
 
 
X 
 
Screening of patients for HBV infection 
X7 
 
 
 
 
Rev. 7/07 
[Deleted in Addendum #10] 
 
 
 
 
 
 
Bone Marrow BX/Aspirate 
X2 
 
 
 
X5 
 
Pregnancy test 
 
X1, 4 
 
 
 
 
Immunofixation-Beta-2-microglobulin 
X 
 
 
 
X 
 
Coombs, serum Immunoglobulins 
X 
 
 
 
X 
Rev. 8/05 
CMV testing 
 
 
X9 
X9 
 
Rev. 8/05 
Rev. 8/05 
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1. For women of childbearing potential.   
2. Bone marrow biopsy is required.   
3. Tumor measurements to be taken at pretreatment, after each cycle through cycle 6. For each visit, physical examination should  record the two 
perpendicular dimensions for each of the palpable lymph nodes assessed at baseline. (Provide measurements on a minimum of 2 of the largest 
nodes but no more than 5.) Physical exam should also document splenomegaly and hepatomegaly. 
4. Only required at on-study. 
5. As indicated to assess complete response. CR demonstrated by bone marrow biopsy must be done no sooner than 8 weeks after clinical CR 
has been documented to confirm that a complete remission has been achieved and sustained. 
6. Start of protocol only. 
7. LFTs will be monitored monthly until 12 months from the last rituximab dose for patients who test positive for HBV at pretreatment. 
8. To be obtained within 24 hours prior to each cycle of treatment. 
9. CMV testing to be performed at the beginning of each treatment cycle of PCR and every two weeks during CAMPATH-1H. 
10. If patient does not go onto Step 2, CMV testing will be done every 6 months for one year after completion of treatment. 
11. Refer to Sec. 5.1.3.1.1 if creatinine clearance is greater than 1.5 but ≤ 2 mg/dl. 
 
Rev. 6/05 
Rev. 8/05
Rev. 7/07 
Rev. 7/07 
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Table 7.1.2 
Test Schedule:  During and Post-Treatment with CAMPATH-1H  - CR/nPR (Arm B)1 
 
Test/procedures 
CAMPATH – 1H (CR/nPR)1 (Arm B) 
Rev. 8/05, 
7/07 
 
Within 14 
days prior 
to re-
registratio
n 
Q 2 
weeks 
until 
completio
n 
Q 4 
weeks 
Post-
treatment at 
6 weeks after 
Day 1 
(CR/nPR) 
Post-
treatment to 
5 years from 
study entry3 
Rev. 1/09 
History and exam, weight, PS 
X 
 
X 
X 
X 
Rev. 8/05, 
7/07, 1/09 
Tumor Measurement by PE 
X2 
 
X2 
X2 
X2 
Rev. 7/07, 
1/09 
CBC/diff/blood smear 
X 
 
X 
X 
X 
Rev. 8/05, 
12/05, 
7/07, 1/09 
Chem group (SGOT, t billi, creat, 
glucose, calcium, alk phos, 
albumin, electrolytes, BUN, LDH, 
uric acid) 
X 
 
X 
X 
X 
Rev. 8/05, 
7/07 
[Deleted in Addendum #10] 
 
 
 
 
 
Rev. 8/05 
CMV testing 
 
X6 
 
 
X7 
 
Chest x-ray 
 
 
 
X 
X4 
Rev. 7/07 
[Deleted in Addendum #10] 
 
 
 
 
 
Rev. 7/07 
Rev. 1/09 
Bone Marrow  
BX/Aspirate 
 
 
 
X 
X5 
 
Immunofixation-Beta-2-
microglobulin 
 
 
 
X 
X4 
 
Coombs, serum Immunoglobulins 
 
 
 
X 
X4 
1. See Section 5.2 describing the time frame of Campath-1H. 
2. For each visit, physical examination should record the two perpendicular dimensions for each of 
the palpable lymph nodes assessed at baseline. (Provide measurements on a minimum of 2 of the 
largest nodes but no more than 5.) Physical exam should also document splenomegaly and 
hepatomegaly. 
3. To begin after the 6-week post-treatment tests: Every 3 months if patient is ≤ 2 years from study 
entry and every 6 months if patient is 2-5 years from study entry. No specific requirements if 
patient is more than 5 years from study entry. 
4. To be done yearly to 5 years from study entry. 
5. Every 6 months from completion of study.  If at any time prior to the 6-month follow-up an 
abnormality is noted, either clinically (lymphadenopathy, splenomegaly) or by blood tests 
suggesting relapse (lymphocytosis), a bone marrow study will be performed. 
6. CMV testing to be performed at the beginning of each treatment cycle of PCR and every two weeks 
during CAMPATH-1H. 
7. CMV testing will be done every 6 months for one year after completion of treatment. 
 
NOTE: 
LFTs will be monitored until 12 months from the last rituximab dose for patients who 
test positive for HBV at pretreatment (see table 7.1.1) 
 
Rev. 6/05, 
7/07, 1/09 
Rev. 8/05 
Rev. 7/07 
Rev. 7/07 
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Table 7.1.3 
Test Schedule: During and Post-Treatment with Campath-1H – PR/SD/PD (Arm C) 1 
 
 
CAMPATH-1H – (PR/SD/PD)1 (ARM C) 
Rev. 8/05 
Test/procedures 
Within 14 
 days prior 
to re-
registration 
Q 2 weeks 
until 
completion 
Q 4 weeks 
until 
completion 
Post-
treatment 
at 6 weeks 
after Day 1 
(CR/nPR) 
Post-
treatment 
to 5 years 
from study 
entry3 
Rev. 1/09 
History and exam, weight, PS 
X 
 
X 
X 
X 
Rev. 8/05, 
1/09 
Tumor Measurement by PE 
X2 
 
X2 
X2 
X2 
Rev. 1/09 
CBC/diff Blood smear 
X 
 
X 
X 
X 
Rev. 8/05, 
12/05, 
1/09 
Chem group (SGOT, t billi, 
creatinine7, glucose, calcium,  
alk phos, albumin, electrolytes, 
BUN, LDH, uric acid) 
X 
 
X 
X 
X 
Rev. 8/05, 
12/05, 
7/07 
[Deleted in Addendum #10] 
 
 
 
 
 
 
Chest x-ray 
X 
 
 
X 
X4 
Rev. 7/07 
[Deleted in Addendum #10] 
 
 
 
 
 
Rev. 7/07 
Rev. 1/09 
Bone marrow asp/bx 
 
 
 
X 
X5 
 
Immunofixation – Beta-2-
microglobulin 
X 
 
 
X 
X4 
 
Coombs, Serum 
Immunoglobulins 
X 
 
 
X 
X4 
Rev. 8/05 
CMV testing 
 
X5 
 
 
X6 
1. See Section 5.2 describing the time frame of CAMPATH-1H. 
2. For each visit, physical examination should record the two perpendicular dimensions for each of the 
palpable lymph nodes assessed at baseline. (Provide measurements on a minimum of 2 of the 
largest nodes but no more than 5.) Physical exam should also document splenomegaly and 
hepatomegaly. 
3. Every 3 months if patient is ≤ 2 years from study entry and every 6 months if patient is 2-5 years from 
study entry. No specific requirements if patient is more than 5 years from study entry. 
4. Every 6 months from completion of study.  If at any time prior to the 6-month follow-up an abnormality 
is noted, either clinically (lymphadenopathy, splenomegaly) or by blood tests suggesting relapse 
(lymphocytosis), a bone marrow study will be performed. 
5. CMV testing to be performed at the beginning of each treatment cycle of PCR and every two weeks 
during CAMPATH-1H. 
6. CMV testing will be done every 6 months for one year after completion of treatment. 
7. NOTE: May be calculated using the Cockcroft-Gault Equation: (140-age)*wt(kg)/([Cr]*72) For women 
the calculation may be multiplied by 0.85. 
NOTE: 
LFTs will be monitored until 12 months from the last rituximab dose for patients who 
test positive for HBV at pretreatment (see table 7.1.1) 
 
Rev. 6/05,  
7/07, 1/09 
Rev. 1/09 
Rev. 7/07 
Rev. 7/07 
Rev. 8/05 
Rev. 7/07 
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7.2 
Biological Sample Submissions 
1. Submission of peripheral blood for immunophenotypic diagnostic review is 
mandatory. Failure to submit the materials may render the patient 
unevaluable. See Section 11.1 
2. Samples for the optional correlative studies and banking should be submitted 
as outlined in Sections 11.2 and 11.3. Collection of samples should be limited 
to those patients who have given written informed consent to participate in 
the correlative studies. 
 
NOTE: 
An informed consent MUST be signed prior to the submission of any 
material for any correlative study, including mandatory diagnostic 
reviews. Samples for optional correlative studies should be submitted 
only from patients who have given written consent for the use of their 
samples for these purposes. 
NOTE: 
For patients who consent to the laboratory studies, please submit ALL 
sequential blood specimens at ALL time points. 
Parameters 
Baseline 
After 
PCR 
After 
CAMPATH-1H 
or 
Discontinuation 
of Protocol 
Treatment 
Q 6 
months2 
Time of 
Response 
assessment 
Ship to: 
Peripheral Blood 
(green top)1 
2 tubes1 
 
 
 
 
Dr. Paietta 
(Section 11.1) 
Peripheral Blood 
(red top) 
1 tube 
Peripheral Blood 
(green top) 
1 tube 
1 tube 
1 tube 
 
 
Cytogenetics 
Lab 
(Section 11.2) 
Peripheral Blood 
(green top) 
10 tubes 
5 tubes 
5 tubes 
5 tubes 
 
Mayo Clinic 
(Section 11.3) 
Peripheral Blood 
(red top) 
1 tube 
1 tube 
1 tube 
1 tube 
 
Marrow 
Slides/Tissue3 
X 
X 
X 
 
X3 
Rev. 5/06 
 
 
1. Submission mandatory for diagnostic review. Samples should be submitted as indicated in Section 
11.1. Samples should be collected after registration prior to beginning therapy. 
2. Samples are requested at baseline, after completion of PCR, after completion of Campath, and every 
six months following therapy for 5 years from start of therapy. 
3. Bone marrow block or 8-10 unstained, positively charged slides are requested.  Sample should be 
submitted at any time a BM is performed to assess response. 
 
Rev. 5/06 
Rev. 1/09 
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8. 
Drug Formulation and Procurement 
8.1 
Cyclophosphamide 
8.1.1 
Other Names 
Cytoxan, Neosar, CTX, CPM 
8.1.2 
Classification 
Cyclophosphamide is a prodrug biotransformed to active alkylating 
metabolites by a mixed function microsomal oxidase system. 
8.1.3 
Mode of Action 
Cyclophosphamide metabolites are thought to disrupt cell division 
primarily by cross-linking DNA strands.  Cyclophosphamide is 
considered cell cycle phase non-specific. 
8.1.4 
Storage and Stability 
Injectable powder are stored at room temperature 25°C (77°F). The 
temperature is not to exceed 30°C (90 F°). Reconstituted parenteral 
solutions are stable for 24 hours at room temperature for 6-14 days if 
refrigerated. 
8.1.5 
Dose Specifics 
600 mg/m2/day on day 1 of weeks 1, 5, 9, 13, 17, and 21. 
8.1.5.1 
Dosage in Renal or Hepatic Failure 
Cyclophosphamide dosage adjustment for patients with 
renal or hepatic failure has not been adequately evaluated. 
8.1.6 
Preparation 
Dissolve the 100 mg, 200 mg, 500 mg, 1 gm, and 2 gm vials in 5, 10, 
25, 50, and 100 ml of sterile water, respectively, resulting in a solution 
of 20 mg/ml.  Shake vials vigorously and warm slightly in lukewarm 
water to facilitate dissolution.  The lyophilized form is more easily 
solubilized. 
Reconstituituted solutions may be further diluted in D5W, D5W/NS, 
D5W/Ringer’s Injection, Lactated Ringer’s Injection, and ½ NS. 
8.1.7 
Administration 
To be given by IV. 
8.1.8 
Compatibilities 
Numerous compatibility studies have been published.  For specific 
details refer to handbook on injectable drugs by Lawrence A. Trissel 
(sec. 8.1.13). 
8.1.9 
Availability 
Cyclophosphamide is commercially available for parenteral injection 
as 100 mg, 200 mg, 500 mg, 1 g, and 2 g vials. 
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8.1.10 
Side Effects – Please refer to package insert. 
Side effects vary significantly based on the specific dose and duration 
of cyclophosphamide.  
8.1.10.1 
Incidence More Frequent (> 5%) 
1. Anemia, leukopenia (usually asymptomatic; less 
frequently fever and/or chills)  
2. Thrombocytopenia (usually asymptomatic; less 
frequently unusual bleeding or bruising; black tarry 
stools; blood in urine or stools; pinpoint red spots on 
skin). Nadir counts usually occur 7 to 12 days after 
administration and recovery usually compete by day 17 
to 21. 
3. Alopecia 
4. Anorexia, nausea and vomiting 
5. Gonadal suppression (azoospermia, missed menstrual 
periods) resulting in infertility. Return of normal gonadal 
function and fertility occurs with time in many younger 
men and women. 
6. Hemorrhagic cystitis 
8.1.10.2 
Incidence Less Frequent (1-5%) 
1. Stomatitis 
8.1.10.3 
Incidence Rare (1%) 
1. Anaphylaxis (tachycardia, shortness of breath, 
wheezing, tightness in throat) 
2. Flushing or redness of face 
3. Diarrhea 
4. Skin rash 
5. Pneumonitis or interstitial pulmonary fibrosis 
6. Syndrome of inappropriate antidiuretic hormone (siadh) 
7. Chemical phlebitis (redness, swelling or pain at site of 
injection) 
8. Secondary malignancies 
9. Blurred vision, cardiac toxicity presenting as congestive 
heart failure 
10. Hemorrhagic myocarditis 
11. Cardiac necrosis 
12. Pericarditis (seen with high dose regimens used with 
bone marrow transplantation) 
8.1.11 
Drug Interactions 
8.1.11.1 
Digoxin 
Several studies conducted in lymphoma patients receiving 
combination chemotherapy including cyclophosphamide 
revealed a 20–50% reduction in digoxin absorption when 


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digoxin tablets were administered.  When digoxin capsules 
were administered no significant decrease in digoxin 
absorption occurred.  To avoid decreased serum digoxin 
levels the use of digoxin in liquid form (liquid or capsules 
containing liquid digoxin) instead of tablets is 
recommended. 
8.1.11.2 
Pentostatin 
Two case reports describe fatal cardiac toxicity in patients 
receiving cyclophosphamide  6.4 g/m² over 4 days and 
pentostatin 4 mg/m² over 4 hours on day 3.   
8.1.11.3 
Succinylcholine 
Cyclophosphamide may prolong the effects of 
succinylcholine by irreversibly inhibiting the enzyme 
pseudocholinesterase.  Limited clinical observations and in 
vitro  studies suggest that prolonged apnea might result 
when  succinlycholine is administered to some patients 
also receiving cyclophosphamide. Management options 
include avoiding concurrent therapy or if concurrent 
therapy can not be avoided, to monitor for prolonged 
succinlycholine effect in patients receiving both drugs. If 
cyclophosphamide has been administered within 10 days 
of succinylcholine, extreme caution should be used after 
succinylcholine administration.  The anesthesiologist 
should be informed of the potential for succinylcholine-
induced apnea and appropriate precautions and 
monitoring should be implemented. 
8.1.11.4 
Trastuzumab 
In early clinical trials the concurrent administration of 
cyclophosphamide and trastuzumab increased the 
incidence and severity of cardiac dysfunction.  Until 
additional data from clinical trials demonstrate the safety of 
concurrent use of these drugs concurrent administration is 
not recommended. 
8.1.12 
Nursing/Patient Implications 
1. Monitor CBC, platelet count.  Advise patients of increased risk of 
infection with absolute neutrophil count less than 500 cells/mm³ 
and increased risk of bleeding with platelet counts less than 
20,000 cells/ mm³.  Advise patients to call the clinic if they develop 
a fever above 101°F or notice any easy bruising,  petechiae 
(pinpoint red spots on skin), or prolonged bleeding. 
2. Advise patient of possible alopecia.  Instruct how to obtain wig, 
hairpiece, etc. 
3. Assess hydration and fluid balance.  Patients receiving larger 
doses should force fluids up to 2 liters above normal intake for 72 
hours after administration.  Instruct patients to void more 


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frequently to minimize occurrence of hemorrhagic cystitis.  For 
high-dose therapy MESNA may be used. 
4. Premedicate with antiemetics. 
5. Observe for possible phlebitis at injection site. 
6. Administer antiemetics as indicated. 
8.1.13 
References 
American Hospital Formulary Service 99 – Drug Information; 832-837. 
Cytoxan Package Insert, Princeton, NJ: Mead Johnson Oncology 
Products 1998; July Micromedex Inc. Vol. 101; 1999. 
USPDI Volume 1 1999; 1128-1134. 
Trissel L.A, Handbook on injectable drugs (8th Ed), Bethesda, MD: 
American Society of Hospital Pharmacists, 1994, Pp. 287-295. 
Cazin B, Gorin NC, Laporte JP. Cardiac complications after bone 
marrow transplantation: A report of a series of 63 consecutive 
transplants. Cancer 1986; 57:2061-2069. 
Gryn et. al. Pentostatin increases the acute toxicity of high dose 
cyclophosphamide. Bone Marrow Transplantation 1993; 12:217-220. 
Pedersen-Bjergaard J, Ersboll J, Sorenson HM. Risk of acute 
nonlymphocytic leukemia and preleukemia in patients treated with 
cyclophosphamide for Non-Hodgkin’s lymphoma. Ann Intern Med 
1985; 103:195-200. 
Stillwell TJ, Benson RJ. Cyclophosphamide-induced hemorrhagic 
cyctitis: A review of 100 patients. Cancer 1988; 61:451-457. 
Zucchero FJ, Ed. Evaluation of drug interactions. St. Louis: 
Professional Drug Systems, 1997; 2/35, 12/21. 
Hansten Pd, Ed. Drug interactions analysis and management. Applied 
Therapeutics, Inc., Vancouver, WA 1998; 185-186. 
Trastuzumab Package Insert, South San Francisco, CA  Genentech, 
Inc. 1998; September. 
Date/Reviewer: July 1999/Robert K. Sylvester, PharmD (701) 234-
5154. 
8.2 
Pentostatin  
8.2.1 
Other Names 
Nipent, 2'-Deoxycoformycin, dCF, Co-Vidarabine, NSC # 218321. 
8.2.2 
Classification  
Adenosine deaminase inhibitor (antimetabolite). 
8.2.3 
Mode of Action 
Adenosine deaminase (ADA) is an enzyme that is essential for the 
metabolism of purine nucleosides. Pentostatin irreversibly inhibits 
ADA activity resulting in intracellular accumulation of adenosine and 


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deoxyadenosine, leading to cell death.  Other proposed mechanisms 
of cytotoxicity include depletion of adenosine triphosphate (reducing 
cellular energy levels and cyclic adenosine monophosphate 
formation), incorporation of the triphosphate of pentostatin into DNA, 
and formation of DNA strand breaks. 
8.2.4 
Storage and Stability 
Unreconstituted drug vials are stored in the refrigerator.  
Reconstituted solutions (2 mg/ml) are chemically stable at room 
temperature for at least 72 hours.  Dilute solutions (10 mg/500 ml) are 
chemically stable at room temperature for 24 hours in 5% dextrose, 
48 hours in normal saline or lactated Ringer's.  Refrigerated solutions 
are chemically stable for at least 96 hours. 
8.2.5 
Dose Specifics 
4 mg/m²/day on day 1 of weeks 1, 5, 9, 13, 17, and 21. 
8.2.6 
Preparation 
The 10 mg vial is reconstituted with 5 ml of normal saline, resulting in 
a 2 mg/ml solution.  The desired dose is further diluted to 
concentrations of 1 mg/ml or less in normal saline, lactated Ringer's 
or 5% dextrose. 
8.2.7 
Administration 
Pentostatin is usually administered by IV bolus, over 2 minutes or 
longer. Patients should be hydrated with 500-1000 ml fluid (D5W, 
0.5NS, or equivalent), prior to administration, and another 500 ml 
should be administered afterward. 
8.2.8 
Incompatibilities 
No information available. 
8.2.9 
Availability 
Pentostatin, 10 mg/vial, is commercially available. 
8.2.10 
Side Effects – Please refer to package insert. 
1. Hematologic:  Leukopenia, thrombocytopenia, lymphopenia, 
anemia, infections. 
2. Dermatologic:  Rash, dry skin. 
3. Gastrointestinal:  Nausea, vomiting, stomatitis, diarrhea, anorexia, 
altered taste. 
4. Hepatic:  Elevated liver enzymes, rarely hepatitis, elevated LDH, 
hyperbilirubinemia. 
5. Neurologic:  Lassitude, confusion, expressive aphasia, slurred 
speech, depression, hallucinations, agitation, cerebral edema, 
seizures, coma; dose-limiting in phase I studies, but the more 
severe toxicities occur rarely with conventional doses (i.e., 4 
mg/m2 every 2 weeks). 
6. Pulmonary:  Cough, shortness of breath, respiratory insufficiency, 
pulmonary infiltrates on chest X-ray. 
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7. Renal:  Elevated serum creatinine; acute tubular necrosis; renal 
failure. 
8. Other:  Keratoconjunctivitis, photophobia, fever, arthralgia, 
myalgia; severe and fatal infections have been reported. 
8.2.11 
Nursing/Patient Implications 
1. Monitor CBC, platelet counts. 
2. Administer antiemetics as indicated. 
3. Assess for neurologic toxicities. 
4. Monitor for symptoms of pulmonary toxicity. 
5. Observe for rash, dry skin. 
6. Monitor for diarrhea, stomatitis, and treat symptomatically.  
8.2.12 
References 
Grever MR, Leiby JM, Kraut EH, et al.  Low-dose deoxycoformycin in 
lymphoid malignancy.  J Clin Oncol 1985; 3: 1196-1201. 
O'Dwyer PJ, Wagner B, Leyland-Jones B, et al.  2'-Deoxycoformycin 
(pentostatin) for lymphoid malignancies.  Rational development of an 
active new drug.  Ann Intern Med 1988; 108: 733-743. 
Johnston JB, Eisenhauer E, Corbett WEN, et al.   Efficacy of 2'-
deoxycoformycin in hairy-cell leukemia:  A study of the National 
Cancer Institute of Canada Clinical Trials Group.  J Natl Cancer Instit 
1988; 80: 765-769. 
Spiers ASD, Moore D, Cassileth PA, et al.  Remissions in hairy-cell 
leukemia with pentostatin (2'-deoxycoformycin).  N Engl J Med 1987; 
316: 825-830. 
O'Dwyer PJ, Spiers AS, Maisoni S.  Association of severe and fatal 
infections and treatment with pentostatin.  Cancer Treat Rep 1986; 
70: 1117-20. 
8.3 
Rituximab 
8.3.1 
Other Names 
IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituximab, 
NSC# 687451. 
8.3.2 
Classification 
Antibody. 
8.3.3 
Mode of Action 
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal 
antibody (Chinese hamster ovary [CHO] transfectoma).  It recognizes 
the CD20 antigen expressed on normal B cells and most malignant B-
cell lymphomas.  It binds with high affinity to CD20-positive cells, 
performs human effector functions in vitro, and depletes B cells in 
vivo.  The Fab domain of rituximab binds to the CD20 antigen on B-


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lymphocytes and the Fc domain recruits immune effector functions to 
mediate B-cell lysis in vitro.  The biological effect is manifested by B-
cell depletion in peripheral blood, lymph nodes, and bone marrow. 
8.3.4 
Storage And Stability 
Rituximab vials are stored at refrigerated temperatures 2Ε to 8ΕC 
(36Ε to 46ΕF). Protect vials from direct sunlight.  Diluted drug product 
at a concentration of 0.5 to 4 mg/ml in polyvinylchloride or polyolefin 
IV bags containing normal saline or dextrose 5% can be stored for up 
to 24 hours at 2Ε to 8ΕC, and at room temperature for an additional 
12 hours. 
8.3.5 
Dose Specifics 
375 mg/m2 on weeks 1, 5, 9, 13, 17, and 21. Cycle 1 (week 1) dose 
varies. Please see Section 5.1 for specific doses and dosing 
procedures for Cycle 1.  
8.3.6 
Preparation 
Withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1 to 4 mg/ml into an infusion bag containing either 
0.9% Sodium Chloride or 5% Dextrose in Water. Gently invert the bag 
to mix the solution. Caution should be taken during the preparation of 
the drug, as shaking can cause aggregation and precipitation of the 
antibody. 
8.3.7 
Administration 
Rituximab is administered intravenously. An in-line filter is not 
required. The initial rate is 50 mg/hr for the first hour. If no toxicity is 
seen, the rate may be escalated gradually in 50 mg/hour increments 
at 30-minute intervals to a maximum of 300mg/hr.  If the first dose is 
well tolerated, the initial rate for subsequent dose is 100mg/hr, 
increased gradually in 100 mg/hr increments at 30-minute intervals, 
not to exceed 400 mg/hr. If the patient experiences fever and rigors, 
the antibody infusion is discontinued. The severity of the side effects 
should be evaluated. If the symptoms improve, the infusion is 
continued initially at one-half the previous rate. Following the antibody 
infusion, the intravenous line should be maintained for medications as 
needed. If there are no complications after one hour of observation, 
the intravenous line may be discontinued. 
Oral pre-medication (two 325 mg tablets of acetaminophen and 50 to 
100 mg diphenhydramine) may be administered 30 to 60 minutes 
prior to starting each infusion of rituximab. The patient should be 
treated according to the best available local practices and procedures.  
The use of dexamethasone or other glucocorticoids should be 
discouraged. 
8.3.8 
Compatibility/Incompatibilities 
Do not mix or dilute rituximab with other drugs. No incompatibilities 
between rituximab and polyvinylchloride or polyethylene bags have 
been observed. 
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8.3.9 
Availability 
Commercial: Preservative-free injection 10 mg/ml, in 10 and 50 ml 
single-unit vials. 
8.3.10 
Side Effects – Please refer to package insert. 
WARNINGS: 
General:  Rituximab is associated with hypersensitivity reactions 
which may respond to adjustments in the infusion rate. Hypotension, 
bronchospasm, and angioedema have occurred in association with 
rituximab infusion as part of an infusion-related symptom complex. 
Rituximab infusion should be interrupted for severe reactions and can 
be resumed at a 50% reduction in rate when symptoms have 
completely resolved. Medications for the treatment of hypersensitivity 
reactions, e.g., epinephrine, antihistamines and corticosteroids should 
be available for immediate use in the event of a reaction during 
administration. 
Cardiovascular:  Infusions should be discontinued in the event of 
serious or life-threatening cardiac arrhythmias.  Patients who develop 
clinically significant arrhythmias should undergo cardiac monitoring 
during and after subsequent infusions of rituximab.  Patients with 
preexisting cardiac conditions including arrhythmias and angina have 
had recurrences of these events during rituximab therapy and should 
be monitored throughout the infusion and immediate post-infusion 
period. 
Tumor Lysis Syndrome (84,85):  Rituximab rapidly decreases benign 
and malignant CD20 positive cells. Tumor lysis syndrome has been 
reported to occur within 12 to 24 hours after the first rituximab infusion 
in patients with high numbers of circulating malignant lymphocytes. 
Patients with high tumor burden (bulky lesions) may also be at risk. 
Patients at risk of developing tumor lysis syndrome should be followed 
closely and appropriate laboratory monitoring performed. Appropriate 
medical therapy should be provided for patients who develop tumor 
lysis syndrome. Following treatment for and resolution of tumor lysis 
syndrome, subsequent rituximab therapy was administered in 
conjunction with prophylactic therapy for this syndrome in a limited 
number of cases. 
Hepatitis B Virus: Hepatitis B virus (HBV) reactivation with fulminant 
hepatitis, hepatic failure, and death has been reported in some 
patients with hematologic malignancies treated with rituximab. The 
majority of patients received rituximab in combination with 
chemotherapy. The median time to the diagnosis of hepatitis was 
approximately 4 months after the initation of rituximab and 
approximately one month after the last dose. 
HIV-associated lymphoma: A report in the literature described an 
increase in fatal infection in HIV-related lymphoma patients when 
Rituximab was used in combination with CHOP chemotherapy as 
compared to CHOP alone. 
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Hematologic: In patients with Waldenstrom’s macroglobulinemia, 
following initiation of Rituximab therapy, transcient increases in serum 
lgM levels have been observed which may result in hyperviscosity 
syndrome requiring plasmapheresis. 
8.3.10.1 
Incidence more frequent (> 5%) 
Fever, chills, rigors, asthenia, headache, angioedema, 
hypotension, myalgia, dizziness, fatigue, throat irritation, 
abdominal pain, nausea, vomiting, leukopenia, 
thrombocytopenia, neutropenia, rhinitis, bronchospasm, 
pruritus, rash, urticaria. 
8.3.10.2 
Incidence less frequent (1-5%) 
Flushing, arthralgia, diarrhea, anemia, cough increase, 
hypertension, lacrimation disorder, pain, hyperglycemia, 
back pain, peripheral edema, paresthesia, dyspepsia, 
chest pain, anorexia, anxiety, malaise, tachycardia, 
agitation, insomnia, sinusitis, conjunctivitis, abdominal 
enlargement, postural hypotension, LDH increase, 
hypocalcemia, hyperesthesia, respiratory disorder, 
shortness of breath, tumor pain, pain at injection site, 
bradycardia, hypertonia, tachycardia, nervousness, 
bronchitis and taste perversion. 
8.3.10.3 
Incidence rare (< 1%) 
Anaphylaxis, severe infusion-related adverse events which 
may result in death.  Tumor Lysis Syndrome: Patients with 
a high tumor burden or with a high number (> 50,000/mm3) 
of circulating malignant cells may be at higher risk of 
severe infusion-related events. 
When treated with Rituximab, some patients with a history 
of Hepatitis B may experience a reactivation of their 
hepatitis that may be life-threatening. 
8.3.11 
Nursing/Patient Implications 
1. Monitor blood pressure, pulse, respiration, and temperature every 
15 minutes x 4 or until stable and then hourly until the infusion is 
discontinued. 
2. Have epinephrine for subcutaneous injections, diphenhydramine 
for intravenous injection, and resuscitation equipment for emergency 
management of anaphylactoid reactions available. 
3. Monitor and alter infusion rates in the presence of toxicities. 
4. Carriers of hepatitis B should be closely monitored for clinical and 
laboratory signs of active HBV infection and for signs of hepatitis 
throughout study participation. 
Rituximab shows no significant effect on bone marrow reserve and no 
apparent increased rate of infections in heavily pretreated, relapsed 
lymphoma patients. 
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Prophylaxis for Tumor Lysis Syndrome (TLS) should be used in 
patients with high tumor burden, particularly with markedly elevated 
numbers of circulating malignant cells.  Precautionary hospitalization 
should be made available for patients who experience severe 
infusional symptoms which do not resolve after discontinuation or 
completion of the infusion. 
References 
Product Information: Rituximab. IDEC Corporation, December, 1998. 
Reff ME et al. Depletion of B cell in vivo by a chimeric mouse human 
monoclonal antibody to CD20. Blood  1994; 83:435-45. 
Demidem A et al. Chimeric anti-CD20 antibody (IDEC-C2B8) is 
apoptotic and sensitizes drug resistant human B cell lymphomas and 
AIDS related lymphomas to the cytotoxic effect of CDDP, VP-16, and 
toxins. FASEB  1995; J9:A206. 
Maloney DG et al. Phase I clinical trial using escalating single dose 
infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2D8) in 
patients with recurrent B-cell Lymphoma. Blood  1993; 82(Suppl 
1):445a. 
Maloney DG et al. Initial report in a phase I/II multiple dose clinical 
trial of IDEC-C2B8 (chimeric anti-CD20) in relapsed B-cell lymphoma. 
Proc Am Soc Clin Oncol 1994; 13:993. 
Facts and Comparisons, March, 1998. 
Date/Reviewer: February, 1999/Darryl Grendahl, R.Ph. (507) 284-
2701 
8.4 
CAMPATH-1H 
8.4.1 
Other Names 
CAMPATH-1H monoclonal antibody, Alemtuzumab. 
8.4.2 
Classification 
CAMPATH-1H is a humanized antilymphocyte monoclonal antibody 
engineered by grafting the rodent hypervariable complementarity 
determining regions into a human immunoglobulin variable framework 
region.  CAMPATH-1H is expressed in recombinant CHO cells. It is 
directed against the CD52 surface antigen expressed on lymphocytes 
at nearly all stages of differentiation. 
8.4.3 
Mode of Action 
The CAMPATH -1 antigen in humans is predominantly expressed on 
peripheral blood lymphocytes, monocytes, and macrophages.  
CAMPATH -1H causes the lysis of lymphocytes by fixing to CD52, a 
highly expressed, non-modulating antigen on the surface of 
lymphocytes.  CAMPATH -1H antibodies elicit cell lysis through 
effector mechanisms including opsonization, complement (C’) fixation 
and antibody dependent cell-mediated cytotoxicity (ADCC) as well as 
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8.4.4 
Storage and Stability 
Intact ampules are to be stored at refrigerated temperature and 
protected from direct sunlight. 
8.4.5 
Dose Specifics 
30 mg sc tiw for 4 weeks (Arm B) or 30 mg sc tiw for 18 weeks (Arm 
C) depending on patient randomization. 
8.4.6 
Preparation 
Not applicable. 
8.4.7 
Route of Administration 
For subcutaneous injection, CAMPATH-1H should be withdrawn into 
the syringe using sterile, low protein binding, non-fiber releasing 5-
micron filter. The appropriate dose of CAMPATH-1H may be 
administered undiluted in up to three divided doses with no more than 
1 mL per injection.  
8.4.8 
Compatibilities 
No information available. 
8.4.9 
Availability 
Commercial: CAMPATH-1H is supplied in glass ampoules containing 
30 mg of antibody in 3 ml of sterile phosphate buffered saline 
(concentration of 10 mg/ml) with 0.05 mm EDTA.  Tween 80 is added 
to a concentration of 0.01%.  Ampoules are supplied in boxes of 10 
ampoules/box.  Ampoules must be used on a per patient, single use 
basis. 
8.4.10 
Side Effects – Please refer to package insert. 
Adverse Events 
Please refer to CAEPR Section 5.3.9. 
Contraindications 
CAMPATH-1H is contraindicated in those patients who are 
hypersensitive to this drug or its components.  CAMPATH-1H is 
contraindicated in patients who have serious infections.  CAMPATH-
1H is contraindicated during pregnancy and lactation. 
Incidence more frequent (> 5%) 
Rigors, fever, fatigue, skin reactions (erythema/edema, pruritis, and 
slight pain), neutropenia, and CMV reactivation. 
CAMPATH-1H is a potent lymphocyte-depleting agent. Neutropenia 
and thrombocytopenia emerge on treatment in approximately 10-20% 
of patients.  
Incidence rare (< 1%) 
Overdoses of up to 240 mg CAMPATH-1H have been given without 
any significant additional toxicity being observed.  There is no known 
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specific antidote for CAMPATH-1H overdose. Treatment consists of 
drug discontinuation and supportive therapy. 
 
 
8.4.11 
Nursing/Patient Implications 
Patients should be premedicated with 50 mg diphenhydramine and 
650 mg of acetaminophen 30 minutes prior to the first CAMPATH-1H 
injection. The premedication is to be given with the first dose and 
thereafter if clinically indicated. 
Careful hematologic and non-hematologic (including infection) 
monitoring is indicated for patients receiving CAMPATH-1H. 
Infections resulting from CAMPATH-1H induced immunosuppression 
are the major type of adverse event occurring outside the CAMPATH-
1H administration period.  The most commonly reported infections are 
mucocutaneous herpes simplex, CMV, and candidiasis.  If a patient 
develops a serious infection while receiving CAMPATH-1H, therapy 
should not be administered until complete resolution of the infection. 
CAMPATH-1H may then be reinstituted at the previous dose. 
CAMPATH-1H is contraindicated in those patients who are 
hypersensitive to this drug or its components.  CAMPATH-1H is 
contraindicated in patients who have serious infections. CAMPATH-
1H is contraindicated during pregnancy and lactation. 
8.4.12 
References 
Dyer MVS, Hale G, Hayhoe FGJ, Waldmann H. Effects of CAMPATH-
1 Antibodies in vivo in patients with lymphoid malignancies: influence 
of antibody isotype. Blood 1989 73:1431-9. 
Personal Communication. Ilex Oncology Services, Inc. December 
1998. 
 
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9. 
Statistical Considerations 
9.1 
Primary Endpoints 
The primary endpoints of this Phase II trial of PCR followed by CAMPATH-1H in 
previously treated B-CLL patients are i) to determine the response (CR, nPR, 
PR) rate of PCR in all patients treated with PCR, and ii) to determine the rate of 
molecular complete remission (MCR) after the treatment of CAMPATH-1H in 
patients who achieve a CR or nPR. 
Patients who achieve a CR or nPR, minimal residual disease (MRD) will be 
assessed using both flow cytometry and real-time allele specific oligonucleotide 
polymerase chain reaction (RT-PCR), and response will be further categorized 
as clinical CR or nPR (CCR) with flow positive, CCR with flow negative but RT-
PCR positive, or CCR with flow negative and RT-PCR negative (MCR). 
Response to PCR will be assessed prior to the administration of CAMPATH-1H, 
and MCR will be assessed post PCR administration, post CAMPATH-1H 
administration, and at 3 months post CAMPATH-1H. For patients who continue in 
CR or nPR, their MRD status will be monitored every three months. 
The study is a two-stage design for the response endpoint. PCR will be 
considered promising in this patient population if a true response rate of 50% or 
greater and not worthy if less than a 30% response rate. A total of 100 eligible 
patients will be entered in this study: 26 in the first stage and 74 in the second 
stage. At the end of the first stage of accrual, data will be reviewed to determine 
if the study should be terminated due to lack of activity of the proposed regimen. 
If 9 or fewer patients achieve a response in the first stage, the study will be 
terminated. If 10 or more patients achieve a response, the study will proceed to 
the second stage, accruing an additional 74 patients to yield a total of 100. If 35 
or more responses are observed after the second stage, then PCR will be 
considered promising. Conversely, if less than 35 patients respond, then PCR 
will not be recommended for further investigation. 
With this design, the probability of terminating the study after 26 patients is 0.77 if 
the true but unknown response rate is 30%, but 0.08 if the true but unknown 
response rate is 50%. The probability of concluding the regimen effective is 0.92 
if the true response rate is 50% and 0.08 if the true response rate is 30%. 
Table 1 below summarizes the operating characteristics of two-stage design. 
Table 1 
True Response Rate 
30% 
40% 
50% 
Prob. stopping early 
(≤ 10 responses in 26 
0.77 
0.36 
0.08 
eligible pts) 
Prob. concluding effective 
(>= 35 responses in 100 
0.08 
0.60 
0.92 
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To investigate whether CAMPATH-1H eliminates minimal residual disease 
(MRD) in CR or nPR, MRD will be assessed by both flow cytometry and RT-PCR 
as described above. The proportion of pre-to-post treatment improvement in 
response will be estimated as (total number of samples with a MCR at 3 months 
post CAMPATH-1H) divided by (total number of samples of any changes in 
response), and whether this proportion is different from the random chance 
improvement 0.5 will be tested using McNemar's test. Assuming the study 
proceeds to the second stage and at least 30 eligible patients will achieve a CR 
or nPR after the PCR treatment, Figure 1 shows power for detecting the true pre-
to-post treatment improvement to MCR given any change in response. 
In the study of previously untreated B-CLL patients at Mayo clinic, about 50% of 
patients in the CR or nPR group presented a MCR after PCR and prior to 
CAMPATH-1H. Based on this information, we assume that about 30% of 
previously treated B-CLL patients in the CR or nPR group will have a MCR prior 
to CAMPATH-1H, and an additional 30% or more patients will achieve a MCR at 
3 months post CAMPATH-1H. For example, if there are 9 MCRs prior to 
CAMPATH-1H, the 9 additional patients achieve a MCR at 3 months post 
CAMPATH-1H, and no patient experiences his/her response worsened, there will 
be approximately 97% power to detect this pre-to-post treatment improvement in 
response. If, however, only 8 out of the 9 additional patients with any response 
change achieve a MCR at 3 months post CAMPATH-1H, there will be 
approximately 73% power. Alternatively, if there are 9 MCRs prior to CAMPATH-
1H, 12 experience any change in response, and 11 out of those 12 patients 
achieve a MCR at 3 months post CAMPATH-1H, there will be approximately 91% 
power. This power calculation is based on McNemar's test at the one-sided 0.05 
significance level, using PROC IML in SAS with 10,000 simulations. 
When data are available, whether MRD status is associated with relapse and 
whether MCR suggests any survival implication will be explored using an 
Andersen-Gill type survival analysis to accommodate the time-varying covariate 
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9.2 
Accrual 
Accounting for 10% ineligibility, the overall accrual goal will be 110 patients. The 
previous ECOG study in this patient population (E4996) accrued poorly. 
However, the proposed chemoimmunotherapy, PCR+CAMPATH-1H, is very 
different from the regimen used in E4996 (VAD+PSC) and appears promising in 
literature. Mayo clinic, an ECOG-ACRIN member institution, sees 4-5 previously 
treated B-CLL patients per month. Putting this together, we anticipate that the 
accrual rate will be approximately 60-70 patients per year and the accrual will be 
completed in 1.5 years. 
Although the study is expected to encounter no accrual problem, the feasibility of 
achieving the accrual goal will be monitored closely. If accrual rate is slower (30 
or fewer patients per year) than anticipated, the study will be reviewed for early 
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9.3 
Early Stopping for Excessive Toxicity 
Since this regimen has not been examined in a cooperative setting, all toxicities 
will be monitored closely and reported using ECOG-ACRIN's standard AE 
mechanism. 
The tolerability of the proposed regimen will be initially tested in the first 30 
patients for PCR and in the first 50 patients for CAMPATH-1H separately. Since 
there will be an 8 week treatment-free period between PCR and CAMPATH-1H 
treatment, we assume that PCR related toxicities and CAMPATH-1H related 
toxicities will be independent. 
We will consider PCR or CAMPATH-1H tolerable if 30% or less grade 3 or higher 
regimen related toxicity and intolerable if 50% or higher. If, in the first 30 patients 
treated with PCR, we observe 13 or more patients with grade 3 or higher PCR 
related toxicity, the study will be terminated to further accrual. With this design, 
the probability of terminating the study early is 0.08 if the true but unknown rate 
of grade 3 or higher toxicity is 30%, and the probability of terminating the study 
early is 0.82 if the true but unknown rate of grade 3 or higher toxicity is 50%.  
Toxicity profile for CAMPATH-1H will be evaluated for CR or nPR and for PR or 
less response separately since CAMPATH-1H will be given for 4 weeks for CR or 
nPR and for 18 weeks for PR or less response, and the toxicity profile for these 
two subpopulations may be different. 
In the first 50 patients, we assume about 15 patients will achieve a CR or nPR 
and about 35 patients will have a PR or less response. 
Of these 15 patients with CR or nPR, if we observe 8 or more patients with grade 
3 or higher CAMPATH-1H related toxicity, the study will be terminated to further 
accrual. With this design, the probability of terminating the study early is 0.05 if 
the true but unknown rate of grade 3 or higher toxicity is 30%, and the probability 
of terminating the study early is 0.5 if the true but unknown rate of grade 3 or 
higher toxicity is 50%. 
Of the 35 patients with PR or less response, if we observe 16 or more patients 
with grade 3 or higher CAMPATH-1H related toxicity, the study will be terminated 
to further accrual. With this design, the probability of terminating the study early 
is 0.04 if the true but unknown rate of grade 3 or higher toxicity is 30%, and the 
probability of terminating the study early is 0.75 if the true but unknown rate of 
grade 3 or higher toxicity is 50%. 
9.4 
Secondary Endpoints 
Overall survival (OS) and progression-free survival (PFS) will be assessed for all 
patients and by response category. OS is defined as the time from registration 
until death from any cause. PFS is defined as the time from registration until 
induction failure, institution of non-protocol therapy, relapse or death from any 
cause in the absence of relapse. OS and PFS will be calculated using the 
Kaplan-Meier method, and confidence limits will be calculated using the 
Greenwood formula. 
For about 70 patients who do not achieve CR or nPR, response will be re-
assessed every three months to examine whether CAMPATH-1H improves their 
response and the rate of conversion to a higher response category (call it 
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patients, if we observe 12 or more patients with improvement, CAMPATH-1H will 
be considered promising in this patient population. Deaths without improvement 
of response prior to re-assessment will be regarded as no improvement. With this 
design, the probability of concluding CAMPATH-1H promising is 0.96 if the true 
but unknown improvement rate is 25% and 0.04 if the true but unknown 
improvement rate is 10%. This decision rule is calculated using an exact binomial 
distribution. 
9.5 
Laboratory Endpoints 
The goal of this laboratory study is to investigate new biologic parameters with 
utility as risk stratification parameters (FISH, CD38 expression, IgVH mutational 
status and angiogenesis profiles). Statistical plans for all laboratory correlative 
studies are based on the assumption that the study will proceed to the second 
stage and complete with 100 eligible patients. 
9.5.1 
To investigate the association between angiogenesis profiles and 
clinical outcome, serum levels of VEGF and bFGF, secreted levels of 
both pro- and anti-angiogenic factors from purified CLL B cells and 
levels of bone marrow angiogenesis will be assessed at study entry 
and after treatment. Descriptive statistics (mean, STD, median, range, 
frequency) will be reported for each pro- (e.g., bFGF, VEGF) or anti-
angiogenic (e.g., Thrombospondin-1,) factor. In the report of Kay et al. 
(100), the mean VEGF levels were 6.6 pg/ml (+/- 3.2) for high-risk B-
CLL patients (n=11, Rai stage 3-4) and 2.4 pg/ml (+/- 0.7) for low-risk 
B-CLL patients (n=18, Rai stage 0), and the mean bFGF levels were 
337.9 pg/ml (+/- 254.5) for high-risk patients and 72.1 pg/ml (+/- 25.6) 
for low-risk patients. However, there seem to be little difference in the 
median levels of these angiogenic factors between two patient cohorts 
(see Figure 2 in Kay et al, 2000). On the contrary, in the unpublished 
manuscript of Kay et al. (Angiogenic Status of Blood B Cells in B-
CLL), the mean VEGF levels were 3.9 (+/- 3.8) for Rai stage 3-4 
(previously treated patients), 3.2 (+/- 3.4) for Rai stage 1-2, and 12.4 
pg/ml (+/- 14.8) for Rai stage 0 (previously untreated patients), and 
the mean bFGF levels were 7.5 pg/ml (+/- 2.6) for Rai stage 3-4, 10.4 
pg/ml (+/- 7.2) for Rai stage 1-2, and 11.6 pg/ml (+/- 3.9) for Rai  
stage 0. 
Having this information in mind, we will assess each pro- or anti-
angiogenic factor separately before and after the treatment and 
investigate in a cooperative setting whether the angiogenic factors are 
associated with clinical outcome and whether the treatment affects the 
level of each angiogenic factor. Assuming about 30 patients will be in 
the CR or nPR group and 70 in the PR or less response group, there 
will be approximately 84% power if the mean difference in VEGF level 
at baseline between these two groups is 2 pg/ml with standard 
deviation of the difference 3, and 92% power if the difference is 3 
pg/ml with standard deviation of the difference 4. This power 
calculation is based on the asymptotic power of the Wilcoxon-Rank-
Sum test for normal treatment difference alternative at two-sided 
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The pre-to-post treatment difference of each angiogenic factor will be 
evaluated in each response group. If the mean VEGF levels are 6 
pg/ml at baseline and 4 pg/ml post treatment for patients who achieve 
a CR or nPR, there will be approximately 93% power to detect this 
pre-to-post difference in VEGF level if the standard deviation of the 
difference is 3 and approximately 83% power if the standard deviation 
of the difference is 3.5. This power calculation is based on the 
Wilcoxon signed-rank test at the two-sided 0.05 significance level, 
using PROC IML in SAS with 10,000 simulations. 
When data are available, correlation analysis will be performed to 
explore potential relationship between anti- and pro-angiogenic 
factors, the association between angiogenesis profiles and clinical 
outcome will be summarized descriptively, and logistic regression 
analysis and a survival model will be performed to assess the 
association further. 
9.5.2 
The IgVH gene mutation status will be assessed at study entry and 
the relationship between IgVH mutation status and clinical outcome 
will be investigated. It is anticipated that approximately 40% of 
patients will have IgVH gene mutation (99) at study entry and these 
patients will show better prognosis. With 100 eligible patients, there 
will be approximately 85% power for detecting a 32% difference in 
response rate if response rates are 69% for patients with mutation 
and 37% for patients without mutation, and 79% power if response 
rates are 68% and 38%, respectively. This power calculation is based 
on Fisher's exact test at a two-sided significance level of 0.05 and 
assumes 50% overall response rate. When data are available, 
whether IgVH gene mutation status is associated with CD38 
expression level will be examined using a 2x2 table analysis and a 
Wilcoxon-Rank-Sum test and whether IgVH gene mutation status and 
CD38 expression level are prognostic factors will be examined using a 
survival model, such as proportional hazards model or cure rate 
model. 
To explore whether CD38 expression level is an independent 
prognostic marker for B-CLL, CD38 expression will be measured at 
study entry.  The expression level will be analyzed on a continuous 
scale and will be dichotomized, i.e., CD38+ if CD38 > =30% and 
CD38- if CD38 < 30% (66). Based on the study of Dewald, et al. (99), 
we assume that about 40% of patients will be CD38+ and 60% will be 
CD38-. If response rates for these two groups are 31% and 63%, 
respectively, there will be approximately 85% power to detect this 
difference and 79% power if 32% and 62% response rates, 
respectively. This power calculation is based on Fisher's exact test at 
a two-sided significance level of 0.05 and assumes 50% overall 
response rate. Progression free and overall survival was also reported 
from small clinical trials of previously untreated B CLL patients 
(60,86). Conservatively extrapolating their report to previously treated 
patients, there will be approximately 80% lower if the median 
progression free survival time is 23 months in the CD38- group and 12 
months in the CD38+ group, assuming 60 and 40 patients in the 


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CD38- and CD38+ group, respectively. This power calculation is 
based on the log-rank test at the two-sided significance level of 0.05 
and assumes exponential survival distribution. 
9.5.3 
To investigate whether genetic defects seen in B-CLL patients are 
associated with clinical outcome, the percentage of abnormal nuclei 
with chromosome anomalies, the frequency of anomalies of 
chromosomes 6-, 11-, 12-, 13-, 14- and 17 will be estimated among 
responders and non-responders separately. As described in Dewald, 
et al.(74) a hierarchical risk model of FISH anomalies in B-CLL will be 
used to order anomalies from the most aggressive to the least 
aggressive, and the association between this ordered categorical 
variable and clinical response will be examined using the exact 
Wilcoxon test.  According to Dewald, et al., about 23% of patients with 
progressive disease falls into a high risk FISH category.  Thus, if 23 
out of 100 eligible patients fall into the high-risk category and the 
clinical response rates are 23% in this high-risk category and 58% in 
the intermediate or low-risk group, there will be approximately 81% 
power to detect this difference.  This power calculation is based on 
Fisher's exact test at a two-sided significance level of 0.05 and 
assumes 50% overall response rate.  Kappa analysis will also be 
performed to assess the agreement between two technologists who 
analyze the interphase nuclei. 
9.5.4 
To study whether patients with B-CLL present defects in the T cell 
repertoire (TCR) at study entry and to investigate the impact of the 
proposed chemoimmunotherapy on TCR, peripheral blood samples 
will be collected at pre and post treatment  (after PCR and after 
Campath-1H for responders and after Campath-1Hfor non-
responders) and CD3+ blood lymphocytes will be analyzed by flow-
cytometric Vβ and Vα repertoire analysis. The flow-cytometric Vβ and 
Vα analysis uses monoclonal antibodies directed against 18 specific 
Vβ and Vα chains in two color flow with either CD4 or CD8 reactive 
monoclonal antibodies,  and it covers 70% of the human T cell 
repertoire. In the report of a phase 2 trial for previously untreated CLL 
patients at Mayo clinic, dramatic elevations in blood T cell subsets for 
responding patients were observed and the percent CD3+ was from 
60-86%. Of 11 patients studied in their analysis, the major expansions 
(20-70%) occurred at Vβ3, 7.1, 9, and 17.  Based on this information, 
if there is a 20% difference in a specific Vβ subfamily or in the percent 
CD3+ between responders (CR+ nPR) and non-responders after 
treatment, there will be a 92% power to detect this difference if its 
standard deviation is 15%. This power calculation assumes a 30% 
CR+ nPR rate and is based on Wilcoxon-Rank-Sum test for normal 
group difference alternative at the two-sided significance level of 0.05. 


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9.6 
Gender and Ethnicity 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
6 
9 
Not Hispanic or Latino 
30 
71 
101 
Ethnic Category: Total of all subjects  
33 
77 
110 
Racial Category 
American Indian or Alaskan Native 
1 
2 
3 
Asian 
1 
2 
3 
Black or African American 
4 
8 
12 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
26 
64 
90 
Racial Category: Total of all subjects 
33 
77 
110 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
9.7 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.3. 
 


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10. 
[Section 10 Deleted in Addendum #9, 5/06] 
 
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11. 
Correlative Studies 
NOTE: 
An informed consent MUST be signed prior to the submission of any material 
for any correlative study, including mandatory diagnostic reviews. Samples 
for optional correlative studies should be submitted only from patients who 
have given written consent for the use of their samples for these purposes. 
NOTE: 
Three sample submissions are described for these studies. The collection 
and submission requirements outlined in Section 11.1 are mandatory. 
Samples described in Sections 11.2, and 11.3 are to be submitted from 
patients participating in the optional studies.  
NOTE: 
An E2903 Material Submission Form #1847 must be submitted with each 
submission. All samples, sample treatments, and collection time points are to 
be indicated on the form(s). The original E2903 Material Submission Form 
#1847 should accompany the samples to the central laboratory(ies). Please 
forward a copy of the original form to the ECOG-ACRIN Operations Office - 
Boston (Attn: Translational Sciences) at the same time it is sent to the central 
laboratory. 
11.1 
Immunophenotype and Molecular Genetics  
NOTE: 
Samples are required for diagnostic review. 
Immunophenotyping has become an essential part of the diagnostic work-up of 
all leukemia patients.  In fact, the diagnosis of leukemia without 
immunophenotypic characterization is no longer acceptable.  ECOG-ACRIN has, 
therefore, developed a model system for antigenic data collection that requests 
specimens from all patients entered on ECOG-ACRIN leukemia treatment trials 
be studied by ECOG-ACRIN’s Immunophenotyping Reference Laboratory. In 
addition to establishing the leukemia subtype, this centralized testing and data 
collection has allowed that research questions of clinical relevance to be applied 
to a growing database (e.g., definition of prognostically significant antigen 
expression levels to eventually yield specific treatment subcategories).  
Depending on the study protocol and tissue availability, anti-coagulated (heparin, 
EDTA, ACD) peripheral blood or bone marrow or both are to be submitted to 
ECOG-ACRIN’s Immunophenotyping Reference Laboratory. 
In addition to the study of abnormal hematopoietic cells, the focus of research on 
circulating serum factors in patients with leukemia or myelodysplasia has 
increased. Two tubes of coagulated peripheral blood (red top tubes) are 
requested for future research studies that may aim at identifying pathogenetic, 
diagnostic, or prognostic factors associated with leukemia or myelodysplasia.   
Serum and cells from peripheral blood or bone marrow from patients entered on 
studies of hematologic malignancies are stored in ECOG-ACRIN’s Leukemia 
Tissue Bank for future laboratory studies. The bank provides the scientific 
community a source of leukemia specimens that are collected, processed, and 
maintained following quality control and quality assurance guidelines. The bank 
will accommodate requests from investigators within and outside ECOG-ACRIN 
in a timely and efficient manner, with respect to tissue type, tissue preparation, 
and most importantly, biologic characteristics of specimens.   
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11.1.1 
Sample Submission Schedule 
Samples are to be submitted at the following time points: 
• 
Pretreatment 
Samples are to be shipped on the day they are drawn. If this is not 
possible, call the Immunophenotyping Reference Laboratory. 
If you have questions, contact the Immunophenotyping Reference 
Laboratory (718) 920-9992. 
NOTE: 
Dr. Paietta’s institutional regulations require that she 
receive a copy of the patient consent and a copy of the 
HIPAA authorization form along with samples. 
11.1.2 
Sample Preparation Guidelines  
11.1.2.1 
The following MUST be submitted:  
1. Heparinized peripheral blood (2 green top tubes, 10-20 
mL)  
NOTE: 
Submission of pathologic materials for 
diagnostic review is mandatory in order for 
the patient to be considered evaluable. 
Failure to submit pathologic materials will 
render the case unevaluable. 
An E2903 Material Submission Form (#1847) must be 
submitted with each shipment, listing all sample types, 
collection times, patient’s disease, and patient’s status at 
time of collection (e.g., PR, CR, relapse).   
11.1.2.2 
The following should be submitted to be banked for use in 
future studies: 
One red top serum tube of peripheral blood (10mL) 
NOTE: 
Submission of banking samples is optional. If 
samples designated for banking only are not 
submitted, please note the reason in the 
Comments section of the Material Submission 
Form. 
11.1.3 
Shipping Procedures 
The Immunophenotyping Reference Laboratory must be notified by 
telephone, 24 hours prior to the arrival of a sample. Fax is not 
acceptable. 
Telephone: (718) 920-9992 
Beeper (off hours):  (917) 729-7231 
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Heparinized samples and serum must be sent fresh (on the day of 
collection) on wet/cool packs (do not freeze) by overnight courier 
(preferably Federal Express) to arrive within 24 hours to: 
Elisabeth Paietta, Ph.D. 
Montefiore Northern Division 
Cancer Center 
600 East 233rd Street 
Bronx, NY 10466  
Tel: (718) 920-9992 
The laboratory is open to receive shipments Monday through 
Saturday.  Shipments on Fridays for Saturday delivery must have 
“Saturday Delivery” marked on the overnight courier slip. 
11.1.4 
Banking 
The residuals and/or derivatives of samples collected for this study 
will be retained at the Immunophenotyping Reference Laboratory for 
possible use in ECOG-ACRIN approved future studies.  If future use 
is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. 
11.2 
FISH Studies (99) 
Chromosomal anomalies detected by interphase FISH are among the most 
important factors predicting survival in CLL. We believe that these FISH 
detectable chromosome anomalies are associated with other biological features 
in CLL that also have prognostic value such as antigen expression on leukemic 
B-lymphocytes. The interphase FISH results will be used to classify each patient 
to a FISH risk category for CLL based on 13q- and normal as favorable, and 6q-, 
11q- and/or 17 as unfavorable. We will establish the percentage of abnormal 
nuclei with chromosome anomalies before and after therapy to assess response 
to therapy. The results will help assess the efficacy of the treatments under 
evaluation in this clinical trial. At the end of the clinical trial, the results of FISH 
will be compared with other laboratory and clinical information in an effort to learn 
more about the biology of CLL. Results will be correlated with clinical 
assessments, outcome, gene expression profiles and other biological 
parameters.  
CLL B-cell FISH Analysis:  Analysis by a CLL FISH panel will be done in order to 
determine if the recurring genetic defects seen in B-CLL patients entered onto 
the companion clinical trial are predictive of clinical status and outcome. We will 
perform FISH studies on blood cells isolated from our patients with CLL. The  
"panel FISH test" we have developed is used to detect common chromosome 
abnormalities associated with B-cell neoplasms including B-CLL (99,105). Thus, 
the FISH panel is designed to detect 1) 11;14 translocations that involve cyclin 
D1 (11q13) and IgH (14q32) loci; 2) deletions of MYB (6q21), ATM (11q23), 
D13S319 (13q14) and P53 (17p13.3); and 3) trisomy 12.  The 11;14 probe is 
included in this panel to help assure that our patients represent well­documented 
cases of B-CLL and not Mantle cell lymphoma.  For each blood cell specimen, 
we will score the cells in a blind fashion to avoid knowing whether the specimen 
is from a patient, normal control or pre- or post-therapy specimen.  For each 
specimen and each probe, two independent technologists will each analyze 100 
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interphase nuclei that meet the scoring criteria; thus, a total of 200 nuclei will be 
scored for each specimen.  We have already determined the normal ranges for 
these probes from data from the normal controls (99). The results of the panel 
FISH test will be correlated with treatment and all other biological and clinical 
aspects of patients enrolled in this study (see Section 9.0). 
These analyses will be performed by the ECOG-ACRIN Cytogenetics Laboratory 
under the direction of Dr. Rhett Ketterling. 
11.2.1 
Sample Submission Schedule 
Peripheral blood should be collected and submitted at: 
• 
baseline (prior to therapy)  
• 
after PCR therapy, 
• 
after CAMPATH-1H, or at discontinuation of protocol treatment. 
Samples are to be submitted the day of collection.  Questions 
concerning sample preparation and sample submission should be 
directed to Mr. Gary Hicks, telephone #  (507) 284-2950. 
11.2.2 
Sample Preparation Guidelines 
Peripheral blood (5 ml) should be collected in sodium heparin and 
sent fresh (within 1 to 5 hours of drawing) on wet ice (do not freeze).  
Samples should be labeled with protocol number, patient sequence 
number, patient’s initials and date specimen drawn. 
11.2.3 
Shipment Procedures 
The E2903 Material Submission Form #1847 must be submitted with 
each sample to ensure proper identification and processing of the 
specimen.  Send blood specimens refrigerated (do not freeze) by 
overnight courier to arrive within 24 hours to: 
Mr. Gary Hicks 
Mayo Clinic 
Cytogenetics Laboratory 
970 Hilton Building 
200 Second Street SW 
Rochester, MN 55905 
Ph:  (507) 284-2950 
The Cytogenetics Laboratory will be open to receive shipments 
Monday-Saturday.  Shipments on Friday for Saturday delivery must 
have “Saturday Delivery” marked on the overnight courier slip.  Notify 
Cytogenetics Laboratory prior to shipping samples and to obtain the 
FedEx account number. 
11.2.4 
Banking 
The residuals and/or derivatives of samples collected for this study 
will be retained at the Cytogenetics Reference Laboratory at Mayo for 
possible use in ECOG-ACRIN approved future studies. If future use is 
denied or withdrawn by the patient, the samples will be removed from 
consideration for use in any future study. 
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11.3 
Additional Laboratory Studies 
These studies will be done on serum, malignant cells from the blood of B-CLL 
patients entering this protocol.   
The correlative studies will be performed under the direction of Dr. Neil Kay at 
the Mayo Clinic in Rochester, Minnesota. 
11.3.1 
The studies to be performed: 
11.3.1.1 
Minimal residual disease assessment by ASO-PCR 
Blood samples collected from patients attaining CR or nPR 
will be assessed for MRD by allele specific oligonucleotide-
polymerase chain reaction (ASO-PCR) at time of 
assessment of response, post-CAMPATH-1H 
administration, and every 6 months after CAMPATH-1H. 
The sample collection timing for CR or nPR in this study 
will be different from PR or less response since the 
duration of CAMPATH-1H treatment is different between 
CR and nPR and PR or less response. 
11.3.1.2 
Ig VH mutational analysis 
The VH gene mutation status will be assessed at baseline. 
11.3.1.3 
Angiogenesis studies 
Secretion levels of pro- and anti-angiogenic factors (bFGF, 
VEGF, TSP1, of CLL B-cell clones will be measured at 
study entry, at time of assessment of response, post-
CAMPATH-1H administration, and every 6 months after 
CAMPATH-1H. The sample collection timing for CR or 
nPR in this study will be different from PR or less response 
since the duration of CAMPATH-1H treatment is different 
between CR or nPR and PR or less response. 
11.3.1.4 
CD38+ expression level 
CD38+ expression level will be measured at study entry. 
11.3.1.5 
T cell repertoire 
T cell repertoire will be studied using flow cytometry and 
methodology. These will be measured at study entry, at 
time of assessment of response, post-CAMPATH-1H 
administration, and every 6 months after CAMPATH-1H. 
11.3.1.6 
Sample Submission Schedule 
Peripheral blood and marrow samples are requested at the 
intervals indicated below.  
NOTE: 
For patients who consent to the laboratory 
studies, please submit ALL sequential blood 
specimens at ALL time points. 
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Sample Type 
Baseline 
After 
PCR 
After  
CAMPATH-1H or 
Discontinuation of 
Protocol Treatment 
Q 6 months1 
Time of 
Response 
assessment 
Peripheral Blood 
(green top) 
10 tubes 
5 tubes 
5 tubes 
5 tubes 
 
Peripheral Blood 
(red top) 
1 tube 
1 tube 
1 tube 
1 tube 
 
Marrow  
Slides/ Tissue  
X 
X 
X 
 
X2 
1. Samples are requested at baseline, after completion of PCR, after competion of Campath, 
and every six months following therapy for 5 years from start of therapy. 
2. Bone marrow block or 8-10 unstained, positively charged slides are requested.  Samples 
should be submitted at any time a BM is performed to assess response. 
Peripheral blood is to be shipped the day of collection.  
Bone marrow blocks or slides should be submitted within 
one month of collection. Follow the packaging and 
shipping guidelines in Appendix VIII. 
Baseline kits are to be ordered at least one week in 
advance. 
11.3.1.7 
Correlative Studies Kit Instructions 
1. Kits will be supplied through Dr. Neil Kay’s laboratory. 
Participating institutions may obtain kits by contacting 
Charla Secreto at (507) 284-3805. 
2. The appropriate type and number of collection tubes 
will be contained within each specimen collection kit, 
along with the Federal Express Mail Form. 
11.3.2 
Sample Preparation Guidelines 
All specimens are to be clearly labeled with the protocol number 
E2903, the patient’s initials, and sequence number, hospital number 
and date of collection. The Patient Information Form (Appendix IX) 
should be completed at the time of collection of the specimens. 
11.3.2.1 
Peripheral Blood 
1. Baseline Samples: 
• 
Ten (10) 10 mL green top tubes 
• 
One (1) 10mL red top tube 
2. All other time points: 
• 
Five (5) 10mL green top tubes 
• 
One (1) 10 mL red top tube 
11.3.2.2 
Bone Marrow 
Submit a bone marrow block or 8-10 unstained, positively 
charged slides. This sample should be shipped separately. 
Rev. 7/07 
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11.3.3 
Shipping Procedures 
Peripheral blood specimens should be mailed the day they are 
obtained and shipped overnight to arrive during normal working hours.  
Bone marrow blocks and slides, if shipped separately, are to be 
shipped within one month of collection (please include a cold pack 
during warm weather). 
Follow the packaging and shipping guidelines listed in Appendix VIII. 
If samples are sent late in the week and will arrive on the weekend, 
please note “Saturday Delivery” on the Federal Express form. 
FRIDAY AND PRE-HOLIDAY SHIPMENTS SHOULD BE AVOIDED. 
Please call Charla Secreto at (507) 284-3805 when samples are 
being mailed. 
Using the mailer provided in the kit, ship the samples at room 
temperature by overnight Federal Express to: 
Charla Secreto 
Mayo Clinic 
613 Stabile 
200 First Street, SW 
Rochester, MN 55905 
The E2903 Material Submission Form (#1847) must be submitted with 
each sample submission, listing all sample types, collection times, 
and patient’s status at the time of collection (e.g., baseline, 6 months, 
etc.). 
11.3.4 
Banking 
The residuals and/or derivatives of samples collected for the 
correlative studies described in Section 11.3 will be forwarded and 
retained at the Leukemia Translational Studies Laboratory for possible 
use in ECOG-ACRIN approved future studies.  If future use is denied 
or withdrawn by the patient, the samples will be removed from 
consideration for use in any future study. 
11.4 
Sample Inventory Submission Guidelines 
Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory correlative study(ies) will be submitted to the ECOG-ACRIN 
Operations Office - Boston on a quarterly basis.  Inventories will be submitted 
electronically or by diskette by any laboratory holding and/or using any 
specimens associated with this study. Electronic submissions should be 
submitted to ecog.labdata@jimmy.harvard.edu. All other correspondence should 
be addressed to the attention of the Translational Science Team. 
11.5 
Lab Data Transfer Guidelines 
The data collected on the above mentioned correlative study(ies) will be 
submitted to the ECOG-ACRIN Operations Office - Boston by the central 
laboratory(ies) on a quarterly basis. The quarterly cut-off dates are March 31, 
June 30, September 30 and December 31. Data is due at the ECOG-ACRIN 
Operations Office - Boston 1 week after these cut-off dates. Electronic 
submissions should be submitted to ecog.labdata@jimmy.harvard.edu. All other 
correspondence should be addressed to the attention of the Translational 
Science Team. 
Rev. 7/07 
Rev. 1/09 
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12. 
Records To Be Kept 
Please refer to the E2903 Forms Packet for the forms submission schedule and copies 
of all forms. The E2903 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
13. 
Patient Consent And Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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O’Brien S, Kantarjian H, Beran M, et al:  Results of fludarabine and prednisone 
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27. 
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therapy with nucleoside analogs and alkylating agents.  Leukemia Suppl 1:5140-
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Identification of three subgroups of B cell chronic leukemia based upon mutations 
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CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc RIIIa gene.  
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are non-responsive to MabCampathTM.  Blood 98:365a, (abstr 1539), 2001. 
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levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay 
improves the prediction of outcome and can be used to optimize therapy.  Blood 
98:29-35, 2001. 


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71. 
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disease with Campath-1H therapy results in prolonged survival in patients with 
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73. 
Mattson J, Vzunel M, Remberger M, et al:  Minimal residual disease is common 
after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic 
leukemia and may be controlled by graft-versus-host-disease.  Leukemia 14:247-
254, 2000. 
74. 
Pfitzner T, Engert A, Wittor H, et al:  A real-time PCR assay for the quantification of 
residual malignant cells in B-cell chronic lymphatic leukemia.  Leukemia 14:754-
766, 2000. 
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Rai KR, Sawitsky, A.  A review of the prognostic role of cytogenetic, phenotypic, 
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abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations.  
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78. 
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Parker AC, Castoldi GL, Cuneo A, Knuutila S, Elonen E, Gahrton G.  Prognostic 
subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal 
abnormalities.  New Eng J Med 323:720, 1990. 
79. 
Oscier DG, Fitchett M, Hamblin TJ.  Chromosomal abnormalities in B-CLL.  Nouv 
Rev Fr Hematol 30:397, 1988. 
80. 
Golub TR, Slonim DK, Tamayo R, et al:  Molecular classification of cancer: class 
discovery and class prediction by gene expression profiling.  Science 286:531-537, 
1999. 
81. 
Dohner H, Stilgenbauer S, Berman A, et al:  Genomic aberrations and survival in 
chronic lymphocytic leukemia. NEJM 343:1910-1916, 2000. 
82. 
Jaksic B, Vitale B, Hauptmann E, Planinc-Peraica A, Ostojic S, Kusec R.  The 
roles of age and sex in the prognosis of chronic leukemias.  A Study of 373 Cases.  
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83. 
Linet MS, Cartwright RA.  Chronic lymphocytic leukemia: epidemiology and 
etiologic findings.  Nov Rev Fr Hematol 30:353, 1988. 
84. 
Winkler V, Jensen M, Manzke O, et al:  Cytokine-release syndrome in patients with 
B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment 
with an anti-CD20 monoclonal antibody (rituximab, IDECC-2BS).  Blood 94:2217-
2224, 1999. 
85. 
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malignancy patients with circulating blood tumor cells: association with increased 
infusion-related side effects and rapid blood tumor clearance.  J Clin Oncol 17:791-
795, 1999. 


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86. 
Einsele B, Ehminger G, Hebart H:  Polymerase chain reaction monitoring reduces 
the incidence of cytomegalovirus disease and duration and side effects of antiviral 
therapy after bone marrow transplantation.  Blood 86:2815-2820, 1995. 
87. 
Juliussen G, Lilliemark J: High complete remission rate from 2-chloro-2’-
deoxyadenosine in previously treated patients with B-cell chronic lymphocytic 
leukemia: response predicted by rapid decrease of blood lymphocyte count. J Clin 
Oncol 11:679-689, 1993. 
88. 
Keating MJ, O’Brien S, Kantarjian H, et al: Long term follow-up of patients with 
chronic lymphocytic leukemia treated with fludarabine as a single agent.  Blood 
81:2878-2884, 1993. 
89. 
Kraut EH, Neff JC, Bouronde BA, et al:  Immunosuppressive effects of pentostatin. 
J Clin Oncol 8:848-855, 1990. 
90. 
Rai KR, Courtre S, Rizzieri D, et al:  Efficacy and safety of alemtuzumab 
(Campath-1H) in refractory B-CLL patients treated on a compassionate basis. 
Blood 98:365a (abstr 1538), 2001. 
91. 
Rai HR, Freter CE, Mercier RJ, et al:  Alemtuzumab in previously treated chronic 
lymphocytic leukemia patients who also had received fludarabine.  J Clin Oncol 
20:3891-3897, 2002. 
92. 
Keating MJ, Flinn I, Jain V, et al:  Therapeutic role of alemtuzumab (CAMPATH-
1H) in patients who have failed fludarabine: results of a large international study.  
Blood 99:3554-61, 2002. 
93. 
Kay NE. Geyer SM. Call TG. Shanafelt TD. Zent CS. Jelinek DF. Tschumper R. 
Bone ND. Dewald GW. Lin TS. Heerema NA. Smith L. Grever MR. Byrd JC. 
Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and 
rituximab shows significant clinical activity with low accompanying toxicity in 
previously untreated B chronic lymphocytic leukemia. Blood. 109(2):405-411, 2007 
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and non-response to therapy with purine analogs in chronic B-cell leukemias. 
Blood 85:1580-1589, 1995. 
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Stilgenbauer S, DÖhner H:  CAMPATH-1H induced complete remission of chronic 
lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy.  
NEJM 347: 452-53, 2002. 
96. 
Sanchez ML, Almeida J, Vidriales B, et al:  Incidence of phenotypic aberrations in 
a series of 467 patients with B chronic lymphoproliferative disorders:  basis for the 
design of specific four- color stainings to be used for minimal residual disease 
investigation.  Leukemia 16:1460-1469, 2002. 
97. 
Pfitzner T, Reiser M, Barth S, et al:  Quantitative molecular monitoring of residual 
tumor cells in chronic lymphocytic leukemia.  Ann Hematol 81:258-266, 2002. 
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Albitar M, Manshouri T, Giles FJ, Kantarjian H, Keating M, O’Brien S: Correlation 
between Campath-1h and response to therapy in patients with chronic lymphocytic 
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significant biological features of B-cell chronic lymphocytic leukemia.  British 
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102. Rosenwald A. Alizadeh AA. Widhopf G. Simon R. Davis RE. Yu X. Yang LM. 
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expression phenotype to immunoglobulin mutation genotype in B cell chronic 
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NCI Update Date: May 25, 2011 
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Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #14] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #14 and is posted as 
a separate document on the ECOG website. This was removed from the protocol to 
comply with NCI formatting guidelines. 
 


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Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
[Appendix II Deleted in Addendum #9, 5/06] 
 
Rev. 5/06 


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Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
Appendix III 
 
Neupogen® Information 
Reimbursement Support for Neupogen® 
Amgen, the manufacturer of Neupogen® (Filgrastim), has agreed to provide Neupogen® 
reimbursement assistance through its Amgen Reimbursement Hotline for E2903 Phase II 
Randomized Trial of Pentostatin, Cyclophosphamide, Rituximab and CAMPATH-1H for 
Previously Treated Chronic Lymphocytic Leukemia. 
As indicated in Section 5.1.4.4 of the protocol’s treatment plan, Neupogen® should be 
administered at 5 ug/kg/d SC at least 48 hours following the completion of chemotherapy (day 
3) and continued through day 12 or until post-nadir ANC > 10,000/mm3. Filgrastim must be 
stopped 48 hours prior to next cycle of chemotherapy regardless of the ANC. The 
recommended day to start G-CSF is Day 3. These uses of Neupogen® are within approved FDA 
labeling. However, it is anticipated that some insurers may be reluctant or unable to cover 
patients treated with Neupogen® in this trial. Amgen’s Reimbursement Hotline is prepared to 
assist in providing up-to-date claims advice for these situations. The Hotline’s services have 
been expanded specifically for this clinical trial and include: 
1. Reimbursement Support:  The Hotline provides assistance relating to claims filing and 
appeals, and identification of alternative sources of payment (secondary insurer, state 
programs, and charity programs). 
2. Claims Support:  The Hotline provides claims appeal support at several different levels, 
including investigating claims denials, preparing the claims appeal, assisting with letters of 
medical necessity, and providing necessary supporting literature. 
The schema on the following page outlines the options should reimbursement 
assistance be required. 
SHOULD THE HOTLINE VERIFY THE PATIENT HAS NO INSURANCE OR NEUPOGEN® IS 
NOT COVERED, THEY WILL COORDINATE WITH AMGEN THE REPLACEMENT OF 
PRODUCT USED BUT NOT REIMBURSED BY THE INSURER. 
NEUPOGEN® REIMBURSEMENT HOTLINE: 
Reimbursement Hotline: 
1-800-272-9376 
Hours: 
Monday through Friday 9:00 AM – 5:00 PM ET 
Contact: 
Amgen Claims Specialist – Jeanne Pettit 
When calling be prepared with the following information: 
1. Identify yourself as being with the ECOG-ACRIN CLL Trial E2903. 
2. Name and address of physician. 
3. Date of service. 
4. Patient name and ECOG-ACRIN Patient Sequence Number. 
5. Name and address of the insurer. 
6. Insurer’s reason for rejection claim. 
7. Copy of the claim. 


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Provider/Patient 
Contacts 
Reimbursement Hotline 
 
 
Provider/Patient 
Identifies ECOG-ACRIN 
E2903 CLL Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hotline Staff Conducts 
Insurance Verification 
for Neupogen® 
Neupogen covered 
but request denied 
Status of Insurance 
Verification 
Patient has no 
insurance or 
NEUPOGEN® 
not covered 
Hotline Staff explains how 
to bill and code for 
NEUPOGEN® 
Insurance reimburses 
Provider for  
NEUPOGEN® 
Hotline Staff 
Contacts 
NEUPOGEN® 
Manufacturer 
Hotline Staff directs 
provider to Study 
Coordinator, 
 Sanford Kempin, 
MD 
Provider given info 
to appeal denied 
request – template 
letter and articles 
NEUPOGEN® 
Representative 
Coordinates free 
product 
replacement 
Patient has insurance for 
NEUPOGEN® 
Request 
Approved? 
Patient receives 
NEUPOGEN® 
through samples 
Patient not enrolled 
Patient enrolled 
No 
Yes 


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96 
NEUPOGEN® SAMPLE REQUEST 
Date Submitted:  _______________________ 
Requesting Physician: 
 
 
 
 
 
 
 
Prof. 
Name:  ____________________________  
Designation:  _____________________ 
Mailing/Shipping Address: 
__________________________________________________________________________ 
__________________________________________________________________________ 
Telephone:  __________________________ 
FAX: __________________________ 
Hospital/Office/Clinic: 
Name:_____________________________________________________________________ 
Contact Person:  _________________________Title:_________________________________ 
Shipping Address: ________________________________________ 
________________________________________ 
Telephone:  ____________________________FAX:_______________________________ 
DEA#:  ________________________________Expiration Date:  _____________________ 
(Number and Photocopy Required) 
REQUEST AND CERTIFICATION 
I hereby request that AMGEN furnish me with _____ boxes NDC# ________________ at 
the mailing/shipping address listed on this form. I understand and agree that free sample 
units furnished in response to this request will only be used in furtherance of the above 
mentioned trial and are not to be sold, purchased, or traded. I certify that no charge for 
any such units used in the treatment of any patient will be made, and no bill for or 
containing any such charge will be submitted to the patient or any third party. 
Physician Signature:  _______________________________Date: _____________________ 
Physician address (if different from above): 
Understood and agreed to on behalf of hospital/office/clinic by: 
Name:  ______________________ Title:  _____________________ Date:  _______________ 
Telephone:  _______________________ 
for AMGEN Use Only 
Project Manager:  Terry M. Cook Phone No:  _____________  Patient ID#:  ___________ 
cc:  Jeanne Petit, Robert A. Butler 
 


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Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
 
Appendix IV 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important clinical program. Programs like this 
offer a chance to get the best care while helping us make better care available for all 
patients. Many questions remain unanswered in cancer. With the help of people like you 
who participate in these programs, we will achieve our goal of effectively treating and 
ultimately curing cancer. 
We believe this program will provide you with high quality, thorough care. Your 
physicians and research staff will maintain very close contact with you. This is important 
to allow your physician to provide you with the best care while learning as much as 
possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
98 
Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
 
Appendix V 
 
Grading Scale for Hematologic Toxicity in CLL Studies 
Grading Scale for Hematologic Toxicity in CLL Studies1 
Decrease from 
Pretreatment value (%) 
Grade2 
Platelets3 
Grade2 
Hemoglobin4 
No change – 10% 
0 
0 
11-24% 
1 
1 
25-49% 
2 
2 
50-74% 
3 
3 
≥ 75% 
4 
4 
1. A decrease in circulating granulocytes is not being considered since it is not a reliable index 
in CLL. 
2. Grades:  1-mild; 2-moderate; 3-severe; 4-life-threatening. Grade 5 (fatal) toxicity can 
potentially occur at any level of decrease from pretreatment values and will be recorded as 
such. 
3. If, at any level of decrease the platelet count is ≤ 20,000/µL, this will be considered grade 4, 
unless the initial platelet count was ≤ 20,000/µL in which case the patient is inevaluable for 
toxicity referable to platelet counts. 
4. Baseline and subsequent hemoglobin determinations must be immediately prior to any 
given transfusions. 
* Cheson BD, et al:  National Cancer Institute-sponsored working group guidelines for chronic 
lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 
1996. 
 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
99 
Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
 
Appendix VI 
 
Rai Staging System for CLL 
Rai Staging System for CLL (5) 
Stage 0 
Lymphocytosis in blood shown to be monoclonal by immunophenotyping or 
molecular techniques and a morphology consistent with CLL. 
Stage 1 
Same as Stage 0 with lymphadenopathy. 
Stage 2 
Same lymphocytosis as Stage 0 plus enlarged spleen and/or liver. 
Stage 3 
Includes lymphocytosis and anemia defined as Hgb ≤ 11 gm/dL or Hct  
≤ 33%.Physical findings of lymphadenopathy, hepato- or splenomegaly are 
not required. 
Stage 4 
Includes the findings at diagnosis of lymphocytosis as defined in Stage 0, 
with thrombocytopenia ≤ 100,000/µL. 
 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
100 
Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
 
Appendix VII 
 
Treatment Evaluation 
1. Complete remission (CR) requires fulfillment of all physical exam and peripheral blood criteria for a 
duration of > 2 months. A bone marrow aspirate and biopsy are required to document the response 
as a complete (≤ 30% lymphocytes with no nodules). 
2. Nodular partial remission (NPR) is essentially a patient in who it appeared that CR had been obtained 
but nodules are present in the bone marrow. It requires fulfillment of all physical exam and peripheral 
blood criteria for CR; however, when the bone marrow is done to confirm CR, nodules of malignant 
lymphocytes are found. 
3. Partial remission (PR) requires fulfillment of the above noted decrease in circulating lymphocytes, 
regression in adenopathy and/or hepatosplenomegaly, and one other parameter listed above for a 
duration of > 2 months. 
 
 
CR1 
NPR2 
PR3 
PROG 
PHYSICAL EXAM 
Nodes 
None 
None 
50% ↓ 
50% ↑, new 
nodes 
Liver/spleen 
Not palpable 
Not palpable 
50% ↓ 
50% ↑, newly 
palpable 
Symptoms 
None 
None 
N/A 
N/A 
PERIPHERAL BLOOD 
ANC 
1,500/µL 
1,500/µL 
1,500/µL or 50% 
improvement from 
baseline 
 
Platelets 
>100,000/µL 
>100,000/µL 
>100,000/µL or >50% 
improvement from 
baseline 
 
Hemoglobin 
>11.0 g/dL 
without 
transfusion 
>11.0 g/dL 
without 
transfusion 
>11.0 g/dL or >50% 
improvement from 
baseline without 
transfusion 
 
Lymphocytes 
4,000/µL 
4,000/µL 
50% ↓ 
≥ 50% ↑ to at 
least 5,000/µL 
BONE MARROW 
≤ 30% 
lymphocytes; 
No nodules 
Bone marrow 
nodules 
N/A 
N/A 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
101 
Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
Appendix VIII 
 
Specimen Kit: Packaging and Shipping Instructions 
*PLEASE AVOID DRAWING OR SHIPPING SPECIMENS ON FRIDAYS OR PRIOR TO 
HOLIDAYS 
1. Complete Patient Information Form (See Appendix IX Page 2) 
Send CBC and Differential Information (WBC and % Lymphocytes essential) 
Specimen Checklist: 
________ 
Peripheral Blood  -  10 - 10cc Heparin Tubes (Green top) @ Baseline 
5 - 10cc Heparin Tubes (Green top) after Baseline 
________ 
Peripheral Blood  -  1 -10cc Red top tube for serum 
________ 
Bone Marrow Block or 8-10 unstained positively charged Slides 
(Shipped separately) 
Label all tubes with the Patient's Initials and ID# 
Place filled tubes in styrofoam container with absorbent material and put in corrugated mailer 
box 
Place Patient Information Form into the mailing box 
Fill out provided Federal Express Mail Form for No Charge Billing including your name, 
telephone number, address, and date on the left side of the airbill 
Specimens are shipped at ROOM TEMPERATURE 
Notify Jenn Abrahamson or Charla Secreto (507-284-3805) at the Mayo Clinic that samples are 
being sent overnight priority delivery. 
SPECIMENS MUST BE MAILED THE SAME DAY AS COLLECTED 
SHIP SPECIMENS TO: 
 
Charla Secreto 
Mayo Clinic 
613 Stabile 
200 First Street SW 
Rochester, MN 55905 
Rev. 7/07 
Rev. 7/07 
Rev. 1/09 
Rev. 1/09 


ECOG-ACRIN 
E2903 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: May 25, 2011 
102 
Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed By 
Campath-1H For Previously Treated Relapsed or Refractory Patients With Chronic 
Lymphocytic Leukemia 
Appendix IX 
 
Specimen Kit: Patient Information Form 
PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND PRE-HOLIDAYS 
Specimen Date: ________________ 
Time Drawn: _______________ 
Institution/Affiliate: ____________________________________________________________ 
Physician: 
____________________________________________________________________ 
Patient Name: 
_________________________________________________________________ 
Hospital I.D. or Social Security #: _________________________________________________ 
ECOG-ACRIN Protocol #: E2903 
ECOG-ACRIN Sequence #: ______ 
Contact /Coordinating Person: 
Name: ______________________________________________________________________ 
Institution: ___________________________________________________________________ 
Address: ____________________________________________________________________ 
City: _______________________________________________________________________ 
Phone #: ___________________________________________________________________ 
PLEASE INCLUDE A CURRENT WHITE BLOOD COUNT AND DIFFERENTIAL: 
WBC   _______________________________ 
LYMPHOCYTE %   ____________________ 
Study Time Point (circle one): 
1. Baseline 
7. 2 Year 
6. Months 
8. 2-5 Year follow up 
8. Months 
9. Other __________ 
10. Months 
12. Months 
18. Months 
Any questions concerning these samples or to obtain an E2903 Specimen Kit, please contact: 
Charla Secreto 
Hematology Research 
Tel: (507) 284-3805 
* Affiliates who anticipate participating in this study should please call in advance for kits 
Rev. 7/07 
Rev. 1/09