Clinical trial NCT01319981
Conditions: Leukemia
Keywords: Acute Lymphoblastic Leukemia ALL Lymphoblastic lymphoma Cytoxan Neosar Mesnex Liposomal Vincristine Vincristine Sulfate Liposomes Injection Marqibo Dexamethasone Adriamycin Rubex Cytarabine Cytosar DepoCyt Cytosine Arabinosine Hydrochloride Imatinib Mesylate Gleevec ST1571 NSC-716051 Filgrastim Neupogen
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-03-05; Completion date: 2020-11-11
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.

The goal of this clinical research study is to learn if intensive chemotherapy (hyper-CVAD therapy) given in combination with liposomal vincristine (Marqibo), in addition to rituximab for patients who are CD20 positive and/or imatinib, dasatinib, or ruxolitinib for patients with the Philadelphia (Ph) chromosome, can help to control ALL or lymphoblastic lymphoma. The safety of this treatment will also be studied. CD20 is a protein "marker" that is found in leukemia or lymphoma cells.

This is an investigational study. Liposomal vincristine is FDA approved for the treatment of patients with CLL who have relapsed at least 2 times. All of the other study drugs used in this study are FDA approved and commercially available. The combination of liposomal vincristine with the other study drugs is also being used in research only.

Up to 65 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed description:
The Study Drugs:

Adriamycin (doxorubicin) is designed to stop the growth of cancer cells, which may cause the cells to die.

Cyclophosphamide is designed to disrupt with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Cytarabine (Ara-C) is designed to insert itself into DNA (the genetic material of cells) of cancer cells and stop the DNA from repairing itself.

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body.

Methotrexate is designed to disrupt cells from making and repairing DNA and "copying" themselves.

Vincristine is designed to disrupt the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Liposomal Vincristine (Marqibo) is designed to help vincristine stay in the bloodstream for a longer time, more specifically target tumor tissue, and deliver more of the drug to a tumor site over a longer period of time. This may increase how effective the drug is and lower the risk of possible side effects in healthy, non-tumor tissue.

Rituximab is a monoclonal antibody that is designed to attach to leukemia cells and activate a series of events that may cause the cancer cells to die.

Tyrosine Kinase Inhibitors (TKI--Imatinib, Dasatinib, or Ruxolitinib) Imatinib is a drug designed to block cancer cells from growing and dividing.

Dasatinib and ruxolitinib are designed to block a protein that cancer may need to grow, survive, or spread.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 groups, based on your already performed diagnostic test for a certain protein, called CD20.

* If you test positive for CD20, you will receive hyper-CVAD therapy plus rituximab.
* If you test negative for CD20, you will receive hyper-CVAD therapy only.

In addition, patients with the Philadelphia chromosome (considered Philadelphia-positive or Ph+) will receive imatinib or dasatinib in either group. Patients with Philadelphia chromosome-like disease will receive dasatinib or ruxolitinib. The study doctor will decide which drug these participants will receive.

Study Drug Administration:

Hyper-CVAD therapy is a combination of 7 chemotherapy drugs: the combination of adriamycin (doxorubicin), cyclophosphamide, and liposomal vincristine, alternating with the combination of cytarabine (Ara-C), dexamethasone, methotrexate, and liposomal vincristine. You will receive the 2 different study drug combinations over 21-28 day "courses." You will begin with Course A treatment and alternate with the Course B treatment every other course. You will stay overnight in the hospital for the first 4-5 days of each course.

For Course A of treatment, you will receive cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone.

For Course B of treatment, you will receive methotrexate, cytarabine, and liposomal vincristine.

Courses of treatment on this study will continue to alternate or switch between the Course A study drug combination for all odd number courses (3, 5, and 7) and the Course B study drug combination for all even number courses (4, 6, and 8) for a total of up to 8 courses.

While you are on study, all doses of study drug combinations will be given through a central venous catheter (CVC). A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

Course 1:

On Days 1, 2, and 3 you will receive cyclophosphamide by vein over about 24 hours, mesna by vein continuously over 24 hours, and liposomal vincristine by vein over 1 hour +/- 30 minutes (Day 1 only). Mesna is given to help prevent blood in the urine, which is sometimes caused by cyclophosphamide.

On Days 2 and 7, methotrexate then cytarabine will be given by intrathecal (IT) infusion directly into your spinal fluid to lower the risk of the disease spreading to the brain.

On Day 4, you will receive doxorubicin by vein over 24 hours.

On Day 5 or 6, G-CSF will be injected under the skin to help with the recovery of bone marrow cells recovery 24 hours after the dose of study drugs.

On Day 8, you will receive liposomal vincristine by vein over 1 hour +/- 30 minutes.

On Days 1-4 and Days 11-14, dexamethasone will be given by mouth with a glass of water or by vein as a short infusion.

CD20 positive patients only will also receive rituximab by vein over 6 hours, on Days 1 and 8, in addition to receiving all study drugs, as described above. If you are CD20 negative, you will not receive rituximab.

Ph+ participants will receive imatinib by mouth with breakfast and a large glass of water (about 8 ounces) or dasatinib by mouth on Days 1-14 during Course 1.

Patients with Philadelphia chromosome-like disease will receive dasatinib 1 time each day or ruxolitinib 2 times each day on Days 1-14 during Course 1.

Course 2:

On Day 1, you will receive methotrexate by vein over 24 hours.

On Days 2 and 3, you will receive cytarabine by vein over 2 hours every 12 hours for a total of 4 doses. You will also be given citrovorum factor (leucovorin) by vein or by mouth to help prevent the possible side effects of methotrexate.

On Day 5 or 6, G-CSF will be injected under the skin to help with bone marrow recovery 24 hours after the dose of study drugs.

On Days 5 and 8, cytarabine then methotrexate will be given by IT infusion to lower the risk of the disease spreading to the brain.

CD20 positive patients only will also receive rituximab by vein over 4 hours, on Days 1 and 8, in addition to receiving all study drugs, as described above. If you are CD20 negative, you will not receive rituximab.

Ph+ participants will receive imatinib by mouth with breakfast and a large glass of water (about 8 ounces) every day during Courses 2-8. Dasatinib will be given by mouth every day during Courses 2-8.

Patients with Philadelphia chromosome-like disease will receive dasatinib 1 time each day or ruxolitinib 2 times each day.

Course 1 Study Visits:

* Blood (about 5 teaspoons each time) will be drawn weekly for routine tests.
* During Week 2 and 3 or 4, a bone marrow aspirate will be performed to check the status of the disease.
* At the end of Course 1, if the study doctor thinks it is needed, a chest X-ray or CT scan will be performed to check the status of the disease.

If the study doctor thinks it is needed, any of these tests may be repeated at any time while you are receiving the study drug combination.

Radiation Treatment:

If you have lymphoblastic lymphoma and you have enlarged lymph glands in the chest, you may receive radiation treatment to the chest after completing 8 courses of therapy and before you begin maintenance therapy. If you are to receive radiation therapy to the chest, the study doctor will discuss this procedure and its known risks with you in more detail, and you will be given a separate consent form to sign.

Maintenance Therapy -- Non-Ph+ Participants

After completing 8 courses of the study drug combinations, you will begin maintenance therapy for a total of 30 months, and will be interrupted by 2 periods of intensive chemotherapy consolidation courses.

Every month during maintenance therapy:

* You will take 6-mercaptopurine every day by mouth.
* You will receive methotrexate by vein or mouth 1 time every week.
* You will receive liposomal vincristine by vein over 1 hour +/- 30 minutes on Day 1.
* You will take dexamethasone by mouth on Days 1-5 each month.

First intensive chemotherapy consolidation courses:

* Six (6) months after you begin maintenance therapy, you will receive two months of intensive chemotherapy courses.
* First, you will receive cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone (similar to Course 1) for Month 6 of therapy.
* About one (1) month later, you will receive methotrexate by vein (at a lower dose than given during Course 2) on Day 1 and pegylated asparaginase by vein over about 2 hours on Day 2. You will be given each drug 1 time each week for a total of 4 weeks for Month 7 of therapy.

About eighteen (18) months after you begin maintenance therapy, you will repeat the intensive chemotherapy courses just described.

Maintenance Therapy -- Ph+ Participants and Participants with Ph-like Disease:

After completing 8 courses of the study drug combinations, you will begin maintenance chemotherapy plus TKI (imatinib or dasatinib if you have Ph+ disease; or dasatinib or ruxolitinib if you have Ph-like disease). Maintenance chemotherapy will be given for a total of 24 months, and will be interrupted by 2 periods of intensive chemotherapy courses and the TKI at 6 and 13 months from the start of maintenance. You will continue receiving the TKI every day from that point on, unless intolerable side effects occur.

Every month during maintenance therapy:

* You will take imatinib, dasatinib, or ruxolitinib every day by mouth.
* You will receive liposomal vincristine by vein over 1 hour +/- 30 minutes on Day 1.
* You will take dexamethasone by mouth on Days 1-5 each month.

Intensive chemotherapy consolidation courses:

°At six (6) and eighteen (18) months after you begin maintenance therapy, you will receive two months of intensive chemotherapy courses. You will receive cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone with the TKI (similar to Course 1). If the disease is CD20 positive, you may receive rituximab.

Blood Tests:

During maintenance therapy and the intensive consolidation therapy, you will have blood (about 5 teaspoons) drawn every 4 weeks +/- 4 weeks for routine tests.

After intensive chemotherapy consolidation, for as long as you continue to receive maintenance therapy, blood (about 5 teaspoons) will be drawn every 4 weeks +/- 4 weeks, until maintenance therapy is completed:

Additional Tests while on Study:

Every 3-6 months:

* You will have a bone marrow biopsy performed to check the status of the disease.
* If you have mediastinal disease, you will have a chest x-ray or CT scan.

Length of Study:

You will receive up to 8 courses of therapy. If you are not Ph+, you will continue to receive maintenance therapy for up to 30 months. If you are Ph+, you will continue to receive maintenance therapy for up to 24 months, followed by imatinib or dasatinib alone indefinitely. You will be taken off the study if disease gets worse, you experience intolerable side effects, or the study doctor thinks it is in your best interest.

Additional Information:

If you are 60 years or older, you will receive Course 1 chemotherapy in a protective isolation room to decrease the risk of any infection(s) that you may be exposed to while receiving the Course 1 treatment.

Arms: arm 1: Odd Courses 1, 3, 5, 7: Rituximab 375 mg/m2 IV Day 1 \& 8 Courses 1 \& 3; Imatinib oral 600 mg days 1-14 Course 1 then continuously; Cyclophosphamide 300 mg/m2 IV every; 12 hours for 6 doses; Mesna 600 mg/m2/day IV Days 1-3; Doxorubicin 50 mg/m2 IV CVC Day 4; VSLI 2.25 mg/M2 IV Day 1 \& 8; Pegfilgrastim 6 mg/kg after chemotherapy + G-CSF 10 µg/kg/day; Dexamethasone 40 mg IV or P.O. daily days 1-4 and days 11-14 +/- 3 days. arm 2: Courses 2, 4, 6, 8: Rituximab 375 mg/m2 IV Day 1 \& 8 Courses 2 \& 4; Imatinib oral 600 mg; Methotrexate 200 mg/m2 IV over 2 hours followed by 8-0- mg/m2 over 22 hours on Day 1; Solu-Medrol 40 mg IV hours approximately every 12 hours +/- 2 hours for 6 doses days 1-3 +/- 3 days; Decadron 40 mg IV or orally 4 times Days 1-4; Ara-C 3 gm/m2 IV every 2 hours, 4 doses on Days 2-3; Pegfilgrastim 6 mg/kg after chemotherapy + G-CSF 10 mg/kg/day.
Interventions: intervention 1: Rituximab intervention 2: Imatinib intervention 3: Cyclophosphamide intervention 4: Doxorubicin intervention 5: Mesna intervention 6: VSLI intervention 7: Solu-Medrol intervention 8: Methotrexate intervention 9: Ara-C intervention 10: G-CSF intervention 11: Pegfilgrastim intervention 12: Dexamethasone
Intervention descriptions: intervention 1: In CD20-positive patients, 375 mg/m2 by vein on day 1 and 8 for Courses 1 and 3; and day 1 and 8 of Courses 2 and 4. intervention 2: 600 mg by mouth daily days 1-14 for course 1 and continuously on all other courses for patients who are Philadelphia chromosome positive (Ph+). intervention 3: 300 mg/m2 by vein over 3 hours every 12 hours x 6 doses days 1, 2, 3 (total dose 1800 mg/m2) for courses 1, 3, 5, 7 intervention 4: 50 mg/m2 by vein over 24 hours on day 4 after last dose of Cyclophosphamide for courses 1, 3, 5, 7 intervention 5: 600 mg/m2 by vein continuous infusion daily for 24 hours days 1-3 for courses 1, 3, 5, 7 intervention 6: 2.0 mg/m2 by vein on day 1 and day 8 for courses 1, 3, 5, 7 intervention 7: 40 mg by vein every 12 hours for 6 doses days 1-3 for courses 2, 4, 6, 8. intervention 8: 200 mg/m2 IV over 2 hrs followed by 800 mg/m2 over 22 hrs on day 1 beginning after the completion of rituximab for Courses 2, 4, 6, and 8. intervention 9: 3 gm/m2 by vein over 2 hours every 12 hours for 4 doses on days 2, 3 for Courses 2, 4, 6, and 8. intervention 10: 10 µg/kg/day (rounded) given subcutaneously until neutrophil recovery to 1 x 10\^9/L or higher can be substituted or can be added if neutrophils have not recovered to 1 x 10\^9/L by day 21. intervention 11: 6 mg/kg (rounded) within 72 hrs after completion of chemotherapy. intervention 12: 40 mg by vein or by mouth daily days 1-4 and days 11-14 for courses 1, 3, 5, 7

Protocol documents:
Prot_SAP_ICF_000.pdf: 
2008-0598
March 23, 2017
Page 1
Protocol Page
Hyper-CVAD with Liposomal Vincristine (Hyper-CMAD) in Acute Lymphoblastic 
Leukemia
2008-0598
Core Protocol Information
Short Title 
Hyper-CVAD with Liposomal Vincristine in ALL
Study Chair: 
Elias Jabbour
Additional Contact:
Jhinelle L. Graham
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7543
Unit:
428
Full Title: 
Hyper-CVAD with Liposomal Vincristine (Hyper-CMAD) in Acute Lymphoblastic Leukemia
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated 09/13/2017
Version:
23
Submitted by:
Vicky H. Zoeller--6/20/2017 2:51:22 PM
OPR Action:
Accepted by:  Yadira L. Cortez -- 7/11/2017 11:43:31 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2008-0598
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Protocol Body
1.0 Objectives
To determine the CR rate at 1 year of hyper-CVAD plus liposomal vincristine (Marqibo) in newly 
diagnosed acute lymphoblastic leukemia (ALL).
To determine CR duration, toxicity and overall survival of hyper CVAD with liposomal vincristine 
(Marqibo) in newly-diagnosed ALL.
2.0 Background
Marqibo has been FDA approved for patients with second or greater relapsed ALL.
2.1 Acute Lymphoblastic Leukemia (ALL) and Hyper-CVAD 
Following the treatment patterns in childhood ALL, results of intensive chemotherapy in 
adult ALL have improved outcome.
1-6 With hyper-CVAD (fractionated cyclophosphamide, 
vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate and 
cytarabine), a dose-intensive regimen developed at MD Anderson, the results were 
encouraging.
7,8 From 1992 until 2000, 288 patients were treated. Their median age was 40 
years; 59 patients (20%) were 60 years or older; 17% had Ph-positive ALL; 13% had T-cell 
ALL. The CR rate was 92%; induction mortality was 5%. The 5-year CR and survival rates 
were 38%. Patients with Ph-positive ALL have an improved outcome with hyper-CVAD + 
imatinib.
9 Patients with mature B cell ALL also have a better outcome with hyper-CVAD + 
rituximab.
10 Both groups are treated on separate protocols. Other improvements to the 
regimens have included the use of the protected environment in patients aged >/= 60 years 
(mortality 16%, now reduced to < 5%), adding rituximab in CD20-positive cases (CD20 
positivity associated with worse prognosis), prolonging POMP maintenance therapy to 3 
years with intensifications, and reducing CNS prophylaxis to 8 intrathecals for high risk 
disease. 
2.2 Liposomal Vincristine (Marqibo)
Liposomal Vincristine was designed to reduce the neurotoxicity associated with regular 
vincristine. Dose-intensity of vincristine has been correlated with increased cure rates with 
MOPP in Hodgkin's disease. Liposomal Vincristine has produced impressive response 
rates of 45% in aggressive lymphoma salvage.
11 CHOP + Liposomal Vincristine in frontline 
lymphomas produced CR rates of 90%, overall response rates of 100%, and 2-year 
survival and EFS rates above 90%.
12 Phase I-II studies of Liposomal Vincristine in ALL 
relapse have shown encouraging response rates of 15% to 30%.
13,14 The phase II dose of 
Liposomal Vincristine is 2.25 mg/m
2 weekly for up to 12 doses. We propose to replace 
regular vincristine with Liposomal Vincristine in the hyper-CMAD regimen to evaluate 
long-term toxicity and efficacy of the new regimen in newly diagnosed ALL.
3.0 Background Drug Information
The background drug information for the following agents is attached as an appendix to the back 
of this protocol (Appendix G). 
doxorubicin 

cyclophosphamide

methotrexate 

ara-C (cytarabine)



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MESNA 

Liposomal vincristine sulfate 

6-mercaptopurine 

filgrastim (G-CSF)

pegfilgrastim 

3.1
Background 
The dose limiting toxicity of vincristine sulfate is virtually always neurological. Neurological 
toxicity is dose dependent and symmetrical and is manifested as both peripheral sensory 
and motor neuropathy. Cranial nerve damage or encephalopathies are rare. Loss of deep 
tendon reflexes is the first sign of neurotoxicity. Distal parasthesias in the hands or feet and 
dysethesias are common if symptoms occur. With continuing administration of the drug, 
this can progress to severe muscle pain, weakness, gait disturbance and sensory 
impairment, severe weakness with foot and wrist drop. Vincristine sulfate induced 
peripheral neuropathies are generally reversible. 
Other toxicities associated with vincristine sulfate include hyponatremia and the syndrome 
of inappropriate antidiuretic hormone (SIADH), constipation, colicky abdominal pain, and 
ileus. 
Cranial nerves may be affected. Extravasation of vincristine sulfate can result in painful 
local inflammation. 
3.2
Rationale for use of Liposomal Vincristine (Marqibo) in Cancer Therapy 
Due to the relatively low specificity of the interaction of cytotoxic agents with tumor tissue.  
Compared to healthy tissue, severe toxicities are often experienced at doses required to 
achieve a substantial antitumor response. Investigations over the past two decades have 
demonstrated that liposomal drug carriers are capable of increasing the therapeutic index 
of anticancer drugs by altering the drug's pharmacological behavior.
Liposomes do not accumulate in many of the tissues susceptible to vincristine-related 
toxicities. Consequently, liposome-encapsulated vincristine is effectively sequestered from 
these sites. A murine model of drug extravasation demonstrated that vincristPh-ine-induced 
dermal toxicity was significantly reduced by liposomal encapsulation.
16 Toxicities associated 
with peak blood levels and high volume of distribution of free vincristine are expected to be 
ameliorated by liposomal encapsulation as this provides for low blood levels over extended 
time periods via slow release of vincristine from the liposomes in the circulation. 
In a variety of GLP and non-GLP toxicology studies comparing free vincristine with 
Liposomal Vincristine, there were no patterns of toxicity or unexpected toxicities due to the 
liposomal drug. Clinical studies have suggested that Liposomal Vincristine may be 
administered safely at doses exceeding those of free vincristine. 
Pharmacokinetic studies in mice indicated that free vincristine given intravenously is rapidly 
removed from the circulation with 0.5 - 2.5% remaining in the blood compartment 1 hour 
after administration. With Liposomal Vincristine, 70% of the drug remained in the circulation 
after the same time period. 
In murine and human tumor models (L1210 and P388 leukemia, B16/BL6 melanoma and 
human A431 solid tumor xenografts), unencapsulated vincristine had negligible antitumor 
activity. Liposomal Vincristine in the same tumor models had significantly greater 
dose-dependent, antitumor activities. The increased antitumor efficacy of Liposomal 
Vincristine is consistent with liposome-mediated delivery of vincristine to the tumor site and 


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subsequent sustained release of the drug. 
A comprehensive summary of nonclinical efficacy and safety studies is included in the 
Investigator's Brochure. 
3.3
Clinical Studies with Liposomal Vincristine 
Four clinical trials (one Phase I and three Phase II) have been conducted with Liposomal 
Vincristine in solid 
tumors (pancreas, colorectal) and in lymphoma.
The MTD and recommended dose for further Phase II development were 2.0 - 2.4 mg/m
2 
every 2 to 3 weeks. Toxicities were generally non-hematologic: myalgias, peripheral 
neuropathy, constipation, and fever. 
Pharmacokinetic analysis suggested that Liposomal Vincristine protects the drug from 
rapid elimination. 
In the Phase II relapsed/refractory lymphoma study (DM97-162), patients with lymphoma 
(intermediate grade, low grade, and transformed lymphoma) were treated with a 1-hour 
infusion of Liposomal Vincristine 2 mg/m
2 IV every 2 weeks.
11 Liposomal Vincristine was 
well tolerated. The overall response rate was 32% (26 responses in 81 evaluable patients). 
In patients with diffuse large cell lymphoma, 46% had a complete or partial response. 
A recent study by Rodriguez et al
12 at MD Anderson Cancer Center combined CHOP 
substituting Liposomal Vincristine 2 mg/m
2 for VCR in newly diagnosed non-Hodgkin's 
lymphoma. The overall response rate was 100%; the CR rate was above 90%. The 
estimated 2-year survival rate was above 90%, which is extremely encouraging. 
In the original Phase II protocol conducted in lymphoma-leukemia (DM97-162), 16 patients 
with relapsed or refractory ALL were treated with Liposomal Vincristine 2.0 mg/m
2 every 2 
weeks.
13 Of 13 evaluable patients, one patient with refractory Philadelphia-positive ALL 
achieved CR. A second case with refractory Ph-positive ALL achieved PR. Both had been 
previously treated with hyper-CVAD. Significant reductions in marrow leukemia infiltrates 
were observed in 4 other patients. 
A Phase I-II trial of liposomal vincristine weekly and pulse dexamethasone in refractory or 
relapsed ALL (and lymphoblastic lymphoma) also showed a response rate of 30% to 40%.
14 
The Liposomal Vincristine MTD was 2.25 mg/m
2 IV weekly (up to 12 doses). 
3.4
Other drug information of Liposomal Vincristine 
Clinical Formulation 
Spectrum Pharmaceuticals will supply Liposomal Vincristine (Marqibo) 
Liposomal Vincristine consists of a three-component system designed for entrapment of  
vincristine sulfate at the clinical site at the time of use. The vehicle consists of 
sphingomyelin/cholesterol (SM/Chol) liposomes.  The final drug product is prepared on site 
from the components in the Marqibo Kit. After preparation, each single-dose vial of Marqibo 
(vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine 
sulfate (Package Insert)


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Storage, Handling, Preparation, and Administration:
See Appendix I for details. 
Drug Destruction and Handling:
All chemotherapy preparation should follow institutional guidelines for handling and 
destruction. Used kits will be destroyed per institutional policy. Unused kits will be 
destroyed according to the institutional policy at the time of expiration or study closure. 
4.0 Patient Eligibility
Inclusion:
4.1
Newly diagnosed, previously untreated ALL or lymphoblastic lymphoma  18 years old. 
Allow urgent administration of cytarabine/hydrea/atra prior to starting treatment on protocol. 
Allow previous administration of up to one course of Hyper-CVAD and/or FDA approved 
TKI.
4.2
Zubrod performance status </= 3. 
4.3
Adequate liver function (bilirubin </= 3.0 mg/dl, unless considered due to tumor), and renal 
function (creatinine </= 3.0 mg/dl, unless considered due to tumor). 
4.4
No active co-existing malignancy with life expectancy less than 12 months due to that 
malignancy.
4.5
All men and women of childbearing potential who are participating in the study must agree 
to use effective forms of birth control throughout the duration of their treatment.
4.6
Adequate cardiac function as assessed clinically
Exclusion:
4.7
Pregnant or lactating women. Women of childbearing potential (WOCB) must have a blood 
or urine pregnancy test within 7 days prior to administration of the study drug.  (WOCB is 
defined as a woman who has not undergone hysterectomy or bilateral oophorectomy and 
has not been naturally postmenopausal for at least 24 consecutive months).
4.8
Active Grade III-IV cardiac failure as defined by the New York Heart Association criteria, 


2008-0598
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uncontrolled angina or MI within 6 months.
4.9
Patients with medical conditions that compromise their ability to complete the study or 
confound interpretation of study results.
5.0 Treatment Plan
5.1
All patients will be registered through CORE. 
5.2
General Considerations 
 
The hyper-CMAD (odd courses) will alternate with high-dose methotrexate/ara-C 

(even courses) administered on 21 day schedules or later to allow for recovery 
from myelosuppression or infection; or earlier if count recovery allows.
Pegfilgrastim (Neulasta) 6 mg (flat dose) within 72 hours after completion of 

chemotherapy. G-CSF 10 g/kg/day (rounded) until neutrophil recovery to 1 x 10
9/L or 
higher can be substituted or can be added if neutrophils have not recovered to 1 x 10
9
/L by day 21.
Months of administering early and/or late Intensification maintenance courses may 

vary based  on physician’s clinical judgment and if discussed with and approved by PI.
Next course may be started when granulocytes >/= 1.0 x 10
9/L and platelets >/= 50 x 

10
9/L.  These courses (Course 2 and on) may be started  with or without dose 
reduction based on  physician’s clinical judgment  if believed to be in the best interest 
of the patient when ANC <1.0 x 10
9/L and/or PLTs<50 x 10
9/L  if discussed with and 
approved by PI.
Rituximab 375 mg/m
2 will be given on days 1 and 8 +/- 3 days for the first 4 courses 

for a total of 8 doses in patients who are CD20-positive (>/= 20% expression by flow 
cytometry for ALL or any positivity by immunostain for lymphoblastic lymphoma). 
Missed doses of rituximab may be given with later courses to complete 8 doses. 
Prophylactic antibiotics will vary based on tolerance and allergy status. Suggestions 

include: 
-- Levofloxacin 500 mg p.o. daily (or other quinolone), trimethoprim-sulfamethoxazole 
double strength one tablet p.o. twice daily, or other appropriate antibacterial agent. 
Antibacterial antibiotics should be rotated with each cycle of intensive 
chemotherapy as feasible. 
-- Voriconazole 200 mg p.o. twice daily, itraconazole 200 mg p.o. twice daily, or other
appropriate antifungal agent.  Azole antifungal prophylaxis should be held the day 
before, the day of, and the day after the dose of liposomal vincristine as feasible. 
-- Valacyclovir 500 mg p.o. daily, or acyclovir 200 mg p.o. twice daily, or other 
appropriate antiviral agent. 
Patients identified to have Philadelphia chromosome positive (Ph+) disease will 

receive imatinib 600 mg daily or dasatinib 100 mg once daily on days 1 to 14 +/- 5 
days of induction (course 1). On all subsequent courses the tyrosine kinase inhibitor 
will be given daily without interruption (imatinib 600 mg or dasatinib 70 mg). 
Maintenance therapy will be monthly Liposomal Vincristine and dexamethasone and 
continuous daily imatinib or dasatinib (no 6-MP or MTX). 
Patients identified to have Philadelphia chromosome-like disease [evaluated by 



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flow-cytometry and/or Fluorecent in situ hybridization (FISH) for CRLF2] will receive 
tyrosine kinase inhibitors (TKI) dasatinib 100 mg once daily or ruxolitinib 10-25 mg 
twice daily on days 1 to 14 +/- 5 days of induction (course 1). On all subsequent 
courses the tyrosine kinase inhibitor will be given daily without interruption. 
Maintenance therapy will be monthly Liposomal Vincristine and dexamethasone and 
continuous daily TKI.
Maintenance chemotherapy is planned for all patients as described later. Patients 

may move to the maintenance therapy prior to completion of 8 cycles if they develop 
side effects prohibiting further intensive chemotherapy. 
Patients with mediastinal lymphoblastic lymphoma and bulky mediastinal disease 

(defined as >/= 7 cm) or residual mediastinal lymphadenopathy may be considered for 
consolidative mediastinal irradiation prior to the maintenance phase of therapy.
Other dosage adjustments are allowed if they are judged to be in the best interest of the 
patient, don’t exceed the maximums dosages described in the protocol, and the adjustments 
are discussed with the study PI. 
5.3
Patients aged >/= 60 years with newly diagnosed active disease, or with poor performance 
status, (at the discretion of the treating physician) may be induced in the protective 
environment. Protective environment is optional. Dosing may also be adjusted. See Section 
5.7 for suggested dose modifications by age and performance status.
5.4
Central Nervous System Management 
Total number of prophylactic intrathecal treatments for newly diagnosed patients (in the 
absence of CNS disease) will be 8 (2 intrathecals of methotrexate on day 2  3 days and 
cytarabine day 7  3 days with each course of chemotherapy until total number reached).  
Missed intrathecals (e.g., related to failed procedure attempts, scheduling issues, patient 
social situations) can be made up with subsequent courses of chemotherapy. 
High-risk disease: 8 intrathecals 

Serum lactate dehydrogenase (LDH) > 1400 U/L
Lymphoblastic lymphoma with/without marrow involvement
Burkitt or Burkitt-like (treated with 16 intrathecals on separate protocol)
Patients with Philadelphia (Ph) positive ALL will receive 12 intrathecals, 2 per cycle, 

for the first 6 cycles.  Missed intrathecals may be made up at later cycles.  
Low-risk disease: 8 intrathecals

LDH </=1400 U/L
Indeterminate risk:  8 intrathecals

None of these parameters met (de novo LDH level unknown)
If the patient has had prior intrathecal therapy or prior CNS disease, discuss 

management of CNS prophylaxis/therapy with the Principal Investigator. 
If active CNS disease: consider intrathecal methotrexate alternating with ara-C twice 

weekly until CSF clear twice; then once weekly for 4 weeks, then back to prophylactic 
schedule. Consider XRT to the base of the skull, if cranial nerve root involvement. 
Alternative methods and intratheral schedules of treating CNS disease are allowed if 
appropriate for the patient. 
5.5
Hyper-CMAD (Courses 1, 3, 5, 7): 
Rituximab 375 mg/m
2 IV on days 1 and 8 +/- 3 days for courses 1 and 3 in patients 

who are CD20-positive.
Imatinib 600 mg PO daily or dasatinib 100 mg PO daily or ruxolitinib 10-25 mg twice 



2008-0598
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daily days 1-14 +/- 5 days on course 1 and continuously (imatinib 600 mg PO or 
dasatinib 70 mg PO or ruxolitinib 10-25 mg twice daily) daily starting day 1 of course 2 
for patients who are Ph+ or Philadelphia chromosome-like disease. 
Cyclophosphamide (CTX) 300 mg/m
2 IV over 3 +/- 1 hours approximately every 12 

hours x 6 doses days 1, 2, 3 (total dose 1800 mg/m
2) 
MESNA 600 mg/m
2/d IV continuous infusion daily for 24 hours days 1-3. 

Doxorubicin 50 mg/m
2 IV over 24 +/- 2 hours via central venous catheter on day 4 

after last dose of CTX given (infuse over 48 +/- 4 hours in patients with reduced 
ejection fractions <50%). May be given by shorter infusion if difficulty with central 
venous access.
Liposomal Vincristine 2.0 mg/m
2 IV (cap at 4.0 mg total dose) over 1 hour +/- 30 

minutes on days 1 and day 8 +/- 2 days.
Dexamethasone 40 mg IV or P.O. daily days 1-4 and days 11-14 +/- 3 days. 

Pegfilgrastim (Neulasta) 6 mg (flat dose) within 72 hours after completion of 

chemotherapy. G-CSF 10 g/kg/day (rounded) until neutrophil recovery to 1 x 10
9/L or 
higher can be substituted or can be added if neutrophils have not recovered to 1 x 10
9
/L by day 21.
The next course may be started when granulocytes >/= 1.0 x 10
9/L and platelets >/= 

50 x 10
9/L. Therapy may start earlier or later depending on the clinical situation, with a 
minimum of  14 days between cycles.  Courses may be started with dose reductions 
prior to full platelet recovery, if the treatment is delayed (e.g., >/= 28 days from the last 
course). 
CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg if via Ommaya reservoir) 

day 2 +/- 3 days and ara-C 100 mg intrathecally day 7 +/- 3 days. 
Tumor lysis prophylaxis (e.g. allopurinol, intravenous alkalinization, oral bicarbonate) if 

indicated. Urate oxidase may substitute for allopurinol. 
5.6
High-dose methotrexate and ara-C (Courses 2, 4, 6, 8): 
Rituximab 375 mg/m
2 IV on days 1 and 8 +/- 3 days for courses 2 and 4 in patients 

who are CD20-positive. 
Imatinib 600 mg PO daily or dasatinib 70 mg PO daily or ruxolitinib 10-25 mg twice 

daily without interruption for patients who are Ph+ or Philadelphia chromosome-like 
disease.  
Methotrexate (MTX) 200 mg/m
2 IV over 2 +/- 1 hours followed by 800 mg/m
2 IV over 

22 +/- 2 hours on day 1 beginning after the completion of rituximab, if given. 
Solu-Medrol 40 mg IV approximately every 12 hours +/- 2 hours for 6 doses days 1-3 

+/- 3 days.
Ara-C 3 gm/m
2 IV over 2 +/-1 hours approximately every 12 hours for 4 doses on days 

2, 3. 
-- Reduce to 1 gm/m
2 IV over 2 +/- 1 hours approximately every 12 hours for 4 doses 
on days 2, 3 for: 
 o  Age >/= 60 years. 
 o  Creatinine >/= 1.5 mg/dl. 
    o  MTX > 20 µM at time "0" (see below), confirmed on repeat sample. 
    o  Neurotoxicity (grade 2 reversible cerebellar toxicity or other ara-C related CNS 
toxicity) with previous courses. 
-- Consider reduction to 1 gm/m
2/day IV continuous infusion days 2, 3 for 
grade 2 reversible cerebellar toxicity related to ara-C 1 gm/m2, or 
grade 3 reversible cerebellar toxicity related to any dose of ara-C. 
Citrovorum rescue 50 mg IV followed by 15 mg IV approximately every 6 hours for 8 

doses or until methotrexate level < 0.1M beginning 12 hours +/- 2 hours post MTX 


2008-0598
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Page 9
completion. Additional rescue allowed as indicated for elevated levels or delayed 
methotrexate clearance. 
-- Check MTX levels around time 0h, 24h and 48h post completion of MTX 
unless cleared (e.g. 0.15 µM or less). 
o if > 20 µM at time "0", hold ara-C and repeat level; if continues to be > 20 
reduce ara-C to 1 gm/m
2 IV over 2 +/-1 hours approximately every 12 hours 
for 4 doses on days 2, 3. 
o if > 1 µM at 24 hours or > 0.1 µM at 48 hours, increase citrovorum rescue until 
serum methotrexate level is < 0.1 µM. Clearance to levels 0.15 µM or less 
is acceptable in patients with normal renal function.
Consider oral acetazolamide 250 mg p.o. b.i.d. to promote MTX excretion if the urine 

pH is < 7.0. 
Pegfilgrastim (Neulasta) 6 mg (flat dose) within 72 hours after completion of 

chemotherapy. G-CSF 10 g/kg/day (rounded) until neutrophil recovery to 1 x 10
9/L or 
higher can be substituted or can be added if neutrophils have not recovered to 1 x 10
9
/L by day 21.
The next course may be started when granulocytes >/= 1.0 x 10
9/L and platelets >/= 

50 x 10
9/L. Therapy may start earlier or later depending on the clinical situation, with a 
minimum of 14 days between cycles. Courses may be started with dose reductions 
prior to full platelet recovery, if the treatment is delayed (e.g., >/= 28 days from start of 
last course). 
CNS prophylaxis:Ara-C 100 mg intrathecally day 5 +/-3 days and Methotrexate 12 mg 

intrathecally (6 mg if via Ommaya reservoir) day 8 +/- 3 days. 
5.7
Suggested Dose Modifications 
      Suggested Dose Modifications Based on Age and Performance Status
< 60 yrs
60 – 74 yrs
PS 0–2
>74 yrs
> 60, PS 3–4
Cyclophosphamide (mg/m
2)
300
250
200
Doxorubicin (mg/m
2)
50
37.5
  25
Liposomal vincristine (mg/m
2)
2.0
1.6
1.2
Dexamethasone (mg)
40
20
20
Methotrexate (mg/m
2)
200
800
100
400
  50
100
Cytarabine (g/m
2)
3
1
0.5
Note:  Age 60 – 64 with PS 0-1 may be treated with full doses (except for reduction of 
cytarabine to 1 g/m2 as per design) at the discretion of the treating physician  
Ara-C 1 gm/m
2 IV over 2 hours every 12 hours for 4 doses on days 2, 3: 
Creatinine >/= 1.5 mg/dl. 

Time "0" MTX level > 20 µM (on repeat level). 

In older patients scheduled to receive 1 g/m
2 reduce to 0.5 gm/m
2
Creatinine >/= 1.5 mg/dl

Time "0" MTX level > 20 µM (on repeat level).

Grade 2 reversible cerebellar toxicity related to high dose ara-C. 

Ara-C 1 gm/m
2/day IV continuous infusion days 2, 3 for: 
Grade 2 reversible cerebellar toxicity related to ara-C 1 gm/m
2 or grade 3 reversible 

cerebellar toxicity related to ara-C. 


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Page 10
Liposomal Vincristine -- reduce by 50% for bilirubin > 1.5 mg/dl and </= 3.0 mg/dL or grade 
2 persistent peripheral neuropathy. 
Eliminate Liposomal Vincristine for grade 3-4 neurotoxicity, including ileus suspected 

to be related to vincristine, bilirubin > 3.0 mg/dL, or grade 3-4 peripheral neuropathy. 
When improved to Grade 0 or 1 resume at 50% of level.
Doxorubicin: 
Reduce by 50% for bilirubin >/= 2 and </= 3 mg/dl, reduce by 75% for bilirubin > 3 and 

</= 5 mg/dl. Eliminate if bilirubin level > 5 mg/dl. 
Administer over 48 +/- 12 hours or longer for patients with borderline/reduced (<50%) 

ejection fractions. 
Methotrexate: 
Reduce by 25%-50% for grade 3 or worse mucositis with previous methotrexate 

course. 
Reduce by 50% for calculated creatinine clearance 10-50 ml/min; if < 10 ml/min, hold 

methotrexate. 
Reduce by 25% to 75% for delayed excretion and/or nephrotoxicity with previous 

methotrexate course. 
Reduce by 50% for pleural effusion or ascites (drain effusion if possible). 

5.8
Imatinib/Dasatinib dose adjustments:
Grade III-IV hepatoxicity (bilirubin > 3 x upper limit normal or elevation transaminases 

> 5.0 x upper limit normal)
Consider holding until grade I or less.

May resume at dose -1 level for grade III hepatotoxicity; consider discontinuing if 

> grade II hepatotoxicity recurs.
Consider decrease by one dose level (e.g., imatinib 400 mg PO daily or dasatinib 50 

mg PO daily) for bilirubin 1.5 - 3.0 x upper limit normal or elevation transaminases > 
2.5 - 5.0 x upper limit normal.
During intensive phase of chemotherapy, consider holding imatinib or dasatinib if ANC 

not > 1.0 x 10
9/L or platelet count not > 30,000 by day 21 of the cycle. Resume 
imatinib or dasatinib upon recovery to ANC  1.0 x 10
9/L and platelet count  50,000 
(without need for G-CSF or platelet transfusions) if able to tolerate. Resume imatinib 
or dasatinib at prior dosing if time to recovery < 2 weeks. Resume imatinib or 
dasatinib with dose reductions if time to recovery > 2 weeks.
Imatinib or dasatinib should be interrupted for clinically significant fluid retention 

syndrome and/or pericardial/pleural effusions.  Imatinib and dasatinib may be 
resumed with dose reductions according to the guidelines for resolution provided for 
recovery from myelosuppression. 
Dose modifications for imatinib and dasatinib are guidelines only. The treatment is not 

required to be held if the treating physician feels it is in the patients best interest to 
continue treatment. Difficult cases should be discussed with the Principal Investigator. 
5.9
Maintenance, intensifications, and post-remission therapy 
A.
Maintenance (non Ph+ positive)
Maintenance chemotherapy with 6-mercaptopurine (6-MP), methotrexate (MTX), 

Liposomal Vincristine and dexamethasone (DOMP) for approximately 30 months 
(except for consolidations with hyper-CMAD followed by methotrexate/L-asparaginase 
[or vice versa] beginning at months 6 and 18) beginning at level 0 (or lower dose level 
if previous toxicity warrants): 


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-- 6-MP 50 mg tablets P.O. t.i.d. daily 
-- Methotrexate 20 mg/m
2 (rounded) IV or P.O. weekly 
-- Liposomal Vincristine 2.0 mg/m
2 IV (cap at 4.0 mg total dose) over 1 hour +/- 30 
minutes approximately every 28 days 
-- Dexamethasone  6 mg/m
2 mg P.O. daily (rounded to the nearest pill size, in divided 
doses twice or three times daily) days 1-5, approximately every 28 days,  starting 
with Liposomal Vincristine (if given). Prednisone 200 mg PO daily days 1 to 5 may 
be substituted at the discretion of the treating physician if intolerant of 
dexamethasone.
Suggested maintenance chemotherapy dose adjustments as below: 

Level
    MTX (mg/m2)
(Rounded)
6-MP 
(mg/day)
Liposomal 
Vincristine
    (mg/m2)
Dexamethasone
(mg/m2)
Prednisone 
(mg)
 0
20
150
2.0
6
200
-1
15
100
1.6
4
100
-2
10
50
1.4
2
  50
-3
 5
50
1
0
   0
Note:  Doses lower and less frequent than specified in this table and combinations of 
these dose modifications are permitted. 
Dose adjustments for myelosuppression include methotrexate and 6-MP, but not 

Liposomal Vincristine or dexamethasone. Titrate to keep granulocytes > 0.75 x 10
9/L 
and platelet count >/= 50 x 10
9/L. 
Methotrexate 
Decrease by one dose level for mucositis > grade 2 

Decrease by one dose level for bilirubin > 2.5 mg/dL or elevation transaminases 

>/= 5 x upper limit normal 
Hold if granulocyte count nadir < 0.5 x 10
9/L or platelets < 30 x 10
9/L, resume 

with decrease in one dose level or lower depending on duration of cytopenias. 
6-mercaptopurine 
Decrease by one dose level for bilirubin > 2.5 mg/dL or elevation transaminases 

>/= 5 x upper limit normal 
Hold if granulocyte count nadir < 0.5 x 10
9/L, or platelets < 30 x 10
9/L, resume with 

decrease in one dose level or lower depending on duration cytopenias. 
Liposomal Vincristine 


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Page 12
Reduce by 50% for bilirubin > 1.5 mg/dL, hold for bilirubin > 3.0 mg/dL.
The dose adjustments of DOMP are guidelines, and the dosing needs to be 
individualized to the patient, as differential toxicities between 6-MP and methotrexate 
may be difficult to discern. Continued antiviral prophylaxis to prevent herpes zoster is 
encouraged. Consider antifungal prophylaxis days of prednisone. Consider PCP 
prophylaxis.
B.
Maintenance: Philadelphia Chromosome Positive ALL or Philadelphia Chromosome-like 
ALL
Imatinib 800 mg PO daily or dasatinib 100 mg PO daily or ruxolitinib 10-25 mg twice 

daily indefinitely (or best tolerated dose).
Liposomal Vincristine 2.0 mg/m
2 IV (cap at 4.0 mg total dose) over 1 hour +/- 30 

minutes approximately every 28 days for 24 months
Dexamethasone  6 mg/m
2 mg P.O. daily (rounded to nearest pill size, in divided doses 

twice or three times daily) days 1-5 approximately every 28 days for 24 months, 
starting with Liposomal Vincristine (if given). Prednisone 200 mg PO daily days 1 to 5 
may be  substituted at the discretion of the treating physician if intolerant of  
dexamethasone.
Early and late intensifications with hyper-CMAD (and rituximab if CD20 positive) at 

months 6 and 18 as per intensive phase (see Section 5.5).  May be omitted (with 
continuation of at the discretion of the treating physician if intolerant to intensive 
chemotherapy or if in complete molecular remission. 
Continued antiviral prophylaxis to prevent herpes zoster is encouraged. Consider 
antifungal prophylaxis days of prednisone. Consider PCP prophylaxis. 
C.
Intensifications at 6 and 18 months of DOMP (Philadelphia Chromosome Negative ALL)
Early and late intensifications interrupting maintenance phase as follows: 


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Two courses of chemotherapy months 6 (hyper-CMAD) and 7 (methotrexate and 

pegylated asparaginase) of maintenance, repeated at months 18 and 19.
-- hyper-CMAD may precede or follow methotrexate and pegylated asparaginase 
Methotrexate 100 mg/m2 day 1 IV over 2 hours and pegylated asparaginase at a dose 

of 2000 IU/m2 on day 2 by IV over 2 hours and this dose will be reduced to 1000 
IU/m2 on day 2 by IV over 23 hours on patients older than 60 years of age.
Hyper-CMAD (with rituximab for CD20 positive patients)

-- (See Section 5.5) 
The length of listed medication infusion times are approximate and may run longer than 
described in the protocol to allow for flushing of infusion tubing and/or due to each patient's 
clinical situation and shall not be counted as deviations to the protocol.  
5.10 Monitoring Plan 
The hyper-CVAD regimens have been conducted since 1992, and have accrued over 

500 patients on similar induction-consolidation-maintenance phases. The treatment 
associated side-effects, both myelosuppressive and extramedullary, are well-known. 
Known and anticipated side effects of this regimen will not be reported as individual 
ADRs according to the Code of Federal Regulations and ICH guidelines-CGP Section 
4.11.1, p. 24. This also complies with the NCI CTEP -CTC guidelines which state that 
for expected events "grade 4 myelosuppression or other grade 4 events that do not 
require expedited reporting will be specified in the protocol" (see Section 12.0 
Reporting Requirements).
6.0 Pretreatment evaluation
Pretreatment evaluations should be completed within 30 days prior to start of drug except for 
pregnancy test which should be completed within 7 days of start of treatment.
6.1
History and physical examination. 
6.2
CBC, platelet count, differential, creatinine, bilirubin. 
6.3
Bone marrow aspirate and cytogenetics. 
6.4
In patients with mediastinal disease chest x-ray or CT of the chest will be performed at 
baseline. 
6.5
12-lead EKG
6.6
Blood or urine pregnancy test (if applicable)
6.7
Echocardiogram or MUGA to assess pretreatment ejection fraction in patients with 
cardiac risk factors prior to the doxorubicin infusion.
7.0 Evaluation During Study
7.1
Weekly  2 days CBC, platelet count and differential (when granulocytes > 1.0 x 10
9/L) 
for course 1, then every 2 weeks  2 daysduring courses 2-8 of chemotherapy, then 
every 4 weeks +/- 4 weeks during maintenance therapy and the intensive 
consolidation therapy. 


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7.2
Bilirubin, creatinine weekly  2 daysfor course 1, then every 2 weeks  2 daysduring 
courses 2-8, then every 4 weeks +/- 4 weeks during maintenance therapy and the 
intensive 
consolidation therapy.
7.3
Bone marrow aspiration for course 1 day 14 +/- 5 days and 1-2 weeks +/- 5 days later to 
confirm response. Bone marrow aspiration will then be done every 3-6 months to monitor 
disease as feasible.  Omitted or missed bone marrow aspirations will not be considered 
protocol deviations. 
7.4
Follow up Chest x-ray or CT scan in patients with mediastinal disease to document CR 
after cycle 1 of therapy and then as indicated every 3 to 6 months. 
8.0 Criteria for Response
8.1
Complete Remission: Normalization of the peripheral blood and bone marrow with 5% or 
less blasts in a normocellular or hypercellular marrow with a granulocyte count of 1 x 
10
9/L or above and platelet count of 100 x 10
9/L or above. Complete resolution of 
extramedullary disease. 
8.1.1 
Complete remission with incomplete platelet recovery (CRp).  As per CR but 
platelet count < 100 x 10
9/L.
8.1.2
Complete remission with incomplete recovery (CRi).  As per CR but platelet 
count < 100 x 10
9/L or absolute neutrophil count < 1 x 10
9/L.
8.2 
Partial Remission (PR): As above for CR except for the presence of 6-25% marrow 
blasts or for lymphoblastic lymphoma without marrow disease, >/= 50% decrease in 
tumor size.
9.0 Evaluation of Toxicity
9.1
The CTEP Version 4 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized for AE reporting. The CTEP Version 4 of the CTCAE is identified 
and located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have acccess to a copy of the CTEP Version 4 
of CTCAE.
10.0 Criteria for Removal from the Study
10.1
Progressive disease 
10.2
Non-compliance by the patient with protocol requirements. 
10.3 
Patient's request to be removed from the study. 
11.0 Statistical Considerations
This is a single-arm, open-label, phase II clinical trial to evaluate the efficacy and safety of liposomal 
vincristine (Marqibo), replacing standard vincristine in the Hyper-CVAD (HCVAD) regimen, for the 
treatment of newly diagnosed, previously untreated acute lymphoblastic leukemia (ALL) or lymphoblastic 
lymphoma. 


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Since liposomes do not accumulate in many tissues susceptible to vincristine-related toxicities, the 
toxicity profile of Liposomal Vincristine, especially neurotoxicity is improved relative to standard 
vincristine. Thus the potential for increasing dose intensity and hopefully cure exists.  Since neurotoxicity 
is the dose limiting toxicity with vincristine, grade 3 or 4 neurotoxicity at 6 months will be monitored in this 
study. Since the dose intensity of Liposomal Vincristine is higher than for standard vincristine, we will 
simultaneously monitor the complete remission rate at one year.  Accrual is estimated at 1 to 2 patients 
per 6 months.  A maximum of 65 patients will be enrolled in this study on an intent-to-treat basis; total 
study duration is thus estimated as 4 to 5 years.
Sample Size and Endpoint Monitoring
The Bayesian approach of Thall et al. (1995, 1996) with the extension by Thall and Sung (1998) will be 
used to simultaneously monitor CR rate at one year and 6-month grade 3 or 4 neurotoxicity.  264 ALL 
patients treated with HCVAD experienced a 95% induction CR rate.  At 1, 2, and 3 years the CR rates 
were 70%, 55%, and 46%. The 6-month neurotoxicity rate in this population is approximately 15%.  For 
the prior distribution of HCVAD with standard vincristine, we assumed a simple Dirichlet distribution and 
independence between 1-year CR rate and neurotoxicity in 132 patients.  The parameters for this prior 
distribution are presented in table 1.  
A flat Dirichlet prior distribution for HCVAD with Liposomal Vincristine was chosen reflective of 
information from the equivalent of 2 patients with the same marginal distributions as for HCVAD alone 
(e.g., 1-year CR rate of 70% and neurotoxicity rate of 15%).
This regimen of HCVAD with Liposomal Vincristine will be considered worthy of further investigation if it 
elicits an increase in 1-year CR rate to 80% with acceptable toxicity.  A 25% 6-month grade 3 or 4 
neurotoxicity rate is considered unacceptable.  Thus, interim monitoring rules, assuming the prior 
distributions above, were constructed as below. The trial will be stopped if,
The monitoring rule for 6-month grade 3 or 4 neurotoxicity, based on these assumptions and monitoring 
conditions is found in table 2.  For example, accrual will cease if 3 patients experience grade 3 or 4 
neurotoxicity in the first 6 months of treatment among the first 3 to 6 patients treated.


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Monitoring 1 Year CR rate will be based on the Table 3.  For example, accrual will cease if 5 or fewer 
patients are in CR at one year in the first 10 patients treated or if there are 26 or fewer CRs at one year 
for the first 40 patients.
Simulation (10,000 replicates) was used to evaluate the performance of these stopping rules on the 
conduct of the study. The operating characteristics of the stopping rules are listed in the following table. 
Analysis Plan
The primary end point is the CR rate at one year for the hyper-CVAD plus liposomal vincristine in newly 


2008-0598
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Page 17
diagnosed ALL. 
Secondary endpoints include CR duration, overall survival and toxicities.
Since the CR rate at one year by the standard HCVAD is 70%, the new regime of HCVAD with Liposomal 
Vincristine will be considered worthy of further investigation if it elicits an increase in 1-year CR rate to 
80% with acceptable toxicity.  A lower than 25% 6-month grade 3 or 4 neurotoxicity rate is considered 
acceptable. The CR rate at one year will be calculated as the total number of patients who are in CR at 
one year divided by the total number of patients who received at least one dose of HCVAD with 
Liposomal Vincristine. Patients who dropped out before one year will be counted as failures. Logistic 
regression analysis will be conducted for the primary end point, i.e., CR at one year. More analysis details 
are described below.
Continuous variables (e.g., age, hematology values) will be summarized using the mean (s.d.) or median 
(range).  Frequency tables will be used to summarize categorical variables.  Logistic regression will be 
used to assess the impact of patient characteristics (e.g., low/high LDH) on 6-month neurotoxicity rates 
and CR rates.  The distribution of time-to-event endpoints (e.g., CR duration, overall survival) will be 
estimated using the method of Kaplan and Meier.  Comparison of time-to-event endpoints by important 
subgroups of patients will be made using the logrank test.  Cox (proportional hazards) regression will be 
used to evaluate multivariable predictive models of time-to-event outcomes.
References 
Thall, PF, Simon, R, Estey, EH: Bayesian sequential monitoring designs for single-arm clinical trials with 
multiple outcomes. Statistics in Medicine 14:357-379, 1995. 
Thall, PF, Simon, R, Estey, EH: New statistical strategy for monitoring safety and efficacy in single-arm 
clinical trials. J. Clinical Oncology 14:296-303, 1996. 
Thall, PF and Sung, H-G: Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Statistics in Medicine 17:1563-1580, 1998.
12.0 Reporting Requirements
12.1
Adverse events will be documented in the medical record and entered into PDMS/CORE 
according to Appendix D. The investigator is responsible for determining the attribution of 
adverse events to study drug(s). 
12.2
Adverse Events Requiring Expedited Reporting: Serious unexpected adverse events 
(SAEs) considered associated therapy should be reported to the Principal Investigator. 
All AEs should be reported to the study nurse. 
12.3
Events include those known toxicities or side effects related to the components of the 
chemotherapy. Grade 4 or less events that are known toxicities or known side effects 
related to the components of the chemotheray or supportive therapy will not be reported 
as individual SAEs, but will be summarized in the annual report to the IRB:. 
12.4
Events not considered to be serious events are hospitalization for the routine treatment 
or monitoring of the studied indication, not associated with any deterioration in condition. 
Treatment, which was elective or pre-planned, for a pre-existing condition that did 

not worsen. 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the 

definitions of serious given above and not resulting in hospital admission. 


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12.5
Leukemia/myelosuppression related events. [from other protocols] 
12.6
Serious Adverse Event Reporting (SAE)
An adverse event or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes:
Death

A life-threatening adverse drug experience - any adverse experience that places 

the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death.
Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant disability/incapacity - a substantial disruption of a 

person's ability to conduct normal life functions.
A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32).
Important medical events as defined above, may also be considered 

serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office.
All events occurring during the conduct of a protocol and meeting the definition of 

a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy on Reporting Serious Adverse Events”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event).
All life-threatening or fatal events, that are unexpected, and related to the 

study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.
The MDACC “Internal SAE Report Form for Prompt Reporting” will be used 

for reporting to the IND Office. 
Serious adverse events will be captured from the time the patient signs 

consent until 30 days after the last dose of drug. Serious adverse events 
must be followed until clinical recovery is complete and laboratory test 
have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event.
Additionally, any serious adverse events that occur after the 30 day time 

period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy.


2008-0598
March 23, 2017
Page 19
Reporting to FDA:
Serious adverse events will be forwarded to FDA by the IND Office according to 

21 CFR 312.32.
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy.
Concomitant medications will not be added to the case report form but will be 
documented in the electronic medical record (Clinicstation).
13.0 References
1.
Faderl S, Jeha S, Kantarjian H. The biology and therapy of adult acute lymphoblastic 
leukemia. Cancer. 2003;98:1337-1354. 
2.
Gokbuget N, Hoelzer D, Arnold R, Bohme A, Bartram CR, Freund M, Gasner A, Kneba M, 
Langer W, Lipp T, Ludwig W-D, Maschmeyer G, Rieder H, Thiel E, Weiss A, Messerer D. 
Treatment of adult ALL according to protocols of the German Multicenter study group for 
adult ALL (GMALL). Hematology/Oncology Clinics of North America, 2000;14(6):
1307-1325. 
3.
Durrant IJ, Richards SM, Prentice HG, Goldstone AH. The Medical Research Council trials 
in adult acute lymphocytic leukemia. Hematology/Oncology Clinics of North America, 
2000;14(6):1327-1352. 
4.
Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Seban C, Lepage E, Thomas 
X, Fiere D. Adult acute lymphocytic leukemia study testing chemotherapy and 
autologous and allogeneic transplantation: A follow-up report of the French protocol LALA 
87. Hematology/Oncology Clinics of North America, 2000;14(6):1353-1365. 
5.
Larson RA. Recent clinical trials in acute lymphocytic leukemia by the Cancer and 
Leukemia Group B. Hematology/Oncology Clinics of North America, 2000;14(6):
1367-1379. 
6.
Garcia-Manero G, Kantarjian H. The Hyper-CVAD regimen in adult acute lymphocytic 
leukemia. Hematology/Oncology Clinics of North America, 2000;14(6):1381-1396. 
7.      Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff 
M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with 
hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 
2000; 18(3):547-561.
8.      Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, 
Shan J, Koller C, Beran M, Keating M, Freireich EJ.  Long-term follow-up results of 
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone 
(Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. 
Cancer. 2004; 101(12):2788-2801.
9.
Thomas D, Faderl S, Cortes J, O’Brien S, Giles F, Kornblau S, Garcia-Manero G, Keating 
M, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin 
R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-Positive Acute 
Lymphocytic Leukemia with Hyper-CVAD and Imatinib Mesylate. Blood, 
2004;103(12):4396-4407. 
10.    Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, 
Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, 
Cabanillas F, Kantarjian H.  Chemoimmunotherapy with hyper-CVAD plus rituximab 
for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic 
leukemia. Cancer. 2006;106(7):1569-1580.
11.    Sarris AH, Hagemeister F, Romaguera J, et al: Liposomal vincristine in 


2008-0598
March 23, 2017
Page 20
relapsed non-Hodgkins's lymphomas: early rsults of an ongoing phase II trial. Ann 
Oncol 2000;11:69.
12.    Rodriguez MA, Sarris A, Dang NH, Fayad L, Goy A, Hagemeister F, McLaughlin P, Pro B, 
Romaguera J, Samaniego F, Younes A, Cabanillas F.  Sphinogosomal vincristine in CHOP 
+/- rituximab is a promising new treatment for patients with high risk untreated aggressive 
non-Hodgkin lymphoma (NHL):  Follow-up results of a phase II study [abstract 4602].  
Blood 
2004;104:234b. 
13.
Thomas DA, Sarris A, O’Brien S, Cortes J, Giles FJ, Faderl S, Keating MJ, Burge C, 
Cabanillas F, Kantarjian H: Phase II study of liposomal vincristine in relapsed or refractory 
adult acute lymphoblastic leukemia. Blood 94:Suppl 1, 4269, 1999. 
14.    Thomas DA, Kantarjian HM, Stock W, Heffner LT, Faderl S, Garcia-Manero G, Ferrajoli A, 
Wierda W, Pierce S, Lu B, Deitcher SR, O'Brien S. Phase 1 multicenter study of vincristine 
sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute 
lymphoblastic leukemia.  Cancer. 2009;115(23):5490-8.
15.
Boman NL, Tron VA, Bally MB et al. Vincristine-induced dermal toxicity is significantly 
reduced when the drug is given in liposomes. Cancer Chemother Pharmacol 1996;37:351.


Informed Consent
Consent Revision Date:  11/11/2016
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN RESEARCH
Hyper-CVAD with Liposomal Vincristine (Hyper-CMAD) in Acute Lymphoblastic Leukemia
2008-0598
Subtitle: Hyper CVAD   
Study Chair: Elias Jabbour
1.
 
Participant’s Name
Medical Record 
Number
You are being asked to take part in this clinical research study at The University of Texas MD Anderson Cancer Center ("MD 
Anderson").  This consent and authorization form explains why this research study is being done and what your role will be if 
you choose to take part.  This form also describes the possible risks connected with being in this study.  After reviewing this 
information with the person responsible for your enrollment, you should know enough to be able to make an informed decision 
on whether you want to take part in the study.
You are being asked to take part in this study because you have acute lymphoblastic leukemia (ALL) or lymphoblastic 
lymphoma.
If you are reading and signing this form on behalf of a potential participant, please note:  Any time the words "you," "your," "I," or 
"me" appear, it is meant to apply to the potential participant. 
2. PURPOSE OF STUDY
The goal of this clinical research study is to learn if intensive chemotherapy (hyper-CVAD therapy) given in combination with 
liposomal vincristine (Marqibo), in addition to rituximab for patients who are CD20 positive and/or imatinib or dasatinib for 
patients with the Philadelphia (Ph) chromosome, can help to control ALL or lymphoblastic lymphoma.  The safety of this 
treatment will also be studied.  CD20 is a protein "marker" that is found in leukemia or lymphoma cells.
3. DESCRIPTION OF STUDY
The Study Drugs
Adriamycin (doxorubicin) is designed to stop the growth of cancer cells, which may cause the cells to die.
Cyclophosphamide is designed to disrupt with the multiplication of cancer cells, which may slow or stop their growth and 
spread throughout the body.  This may cause the cancer cells to die. 
Cytarabine (Ara-C) is designed to insert itself into DNA (the genetic material of cells) of cancer cells and stop the DNA from 
repairing itself. 
Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body.  
Methotrexate is designed to disrupt cells from making and repairing DNA and "copying" themselves.
Vincristine is designed to disrupt the multiplication of cancer cells, which may slow or stop their growth and spread throughout 
the body.  This may cause the cancer cells to die.  
Liposomal Vincristine (Marqibo) is designed to help vincristine stay in the bloodstream for a longer time, more specifically 
target tumor tissue, and deliver more of the drug to a tumor site over a longer period of time.  This may increase how effective 
the drug is and lower the risk of possible side effects in healthy, non-tumor tissue.


Rituximab is a monoclonal antibody that is designed to attach to leukemia cells and activate a series of events that may cause 
the cancer cells to die.
Tyrosine Kinase Inhibitors (TKI--Imatinib or Dasatinib) 
Imatinib is a drug designed to block cancer cells from growing and dividing. Dasatinib is designed to block a protein that 
cancer may need to grow, survive, or spread.
Screening Tests
Signing this consent form does not mean that you will be able to take part in this study.  You will have "screening tests” to help 
the doctor decide if you are eligible to take part in this study.  The following tests and procedures will be performed:
Your complete medical history will be recorded.
You will have a complete physical exam, including measurement of your height, weight, and vital signs (blood pressure, 
breathing rate, heart rate, and temperature).
You will have an electrocardiogram (ECG - a test to measure the electrical activity of the heart).
An echocardiogram (ECHO) or multigated acquisition (MUGA) scan will be performed  to check the pumping function of 
your heart.
Blood (about 7 tablespoons) will be drawn for routine tests.
Blood (about 1 teaspoon) or urine will also be collected for a pregnancy test for women who are able to become 
pregnant.  To take part in this study, the pregnancy test must be negative.
If the study doctor thinks it is needed, computerized tomography (CT) scans of the chest will be performed to check the 
status of the disease.  The study doctor will decide how many scans you will have.
A bone marrow aspirate will be performed to check the status of the disease.  To collect a bone marrow aspirate, an area 
of the hip bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. 
If you have lymphoblastic lymphoma, a chest X-ray will be performed to check the status of the disease.
The study doctor will discuss the screening test results with you.  If the screening tests show that you are not eligible to take part 
in the study, you will not be enrolled.  Other treatment options will be discussed with you.
Study Groups
If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 groups, based on your already performed 
diagnostic test for a certain protein, called CD20.
If you test positive for CD20, you will receive hyper-CVAD therapy plus rituximab. 
If you test negative for CD20, you will receive hyper-CVAD therapy only.
In addition, patients with the Philadelphia chromosome (considered Philadelphia-positive or Ph+) will receive imatinib or 
dasatinib in either group.  The study doctor will decide which drug these participants will receive.
Study Drug Administration
Hyper-CVAD therapy is a combination of 7 chemotherapy drugs: the combination of adriamycin (doxorubicin), 
cyclophosphamide, and liposomal vincristine, alternating with the combination of cytarabine (Ara-C), dexamethasone, 
methotrexate, and liposomal vincristine.  You will receive the 2 different study drug combinations over 21-28 day "courses."  You 
will begin with Course A treatment and alternate with the Course B treatment every other course.  You will stay overnight in the 
hospital for the first 4-5 days of each course.
For Course A of treatment, you will receive cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone.
For Course B of treatment, you will receive methotrexate, cytarabine, and liposomal vincristine. 
Courses of treatment on this study will continue to alternate or switch between the Course A study drug combination for all odd 
number courses (3, 5, and 7) and the Course B study drug combination for all even number courses (4, 6, and 8) for a total of 
up to 8 courses.
While you are on study, all doses of study drug combinations will be given through a central venous catheter (CVC).  A CVC is a 
sterile flexible tube that will be placed into a large vein while you are under local anesthesia.  Your doctor will explain this 
procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.
Course 1:
On Days 1, 2, and 3 you will receive cyclophosphamide by vein over about 24 hours, mesna by vein continuously over 24 hours, 
and liposomal vincristine by vein over 1 hour +/- 30 minutes (Day 1 only).  Mesna is given to help prevent blood in the urine, 
which is sometimes caused by cyclophosphamide. 
On Days 2 and 7, methotrexate then cytarabine will be given by intrathecal (IT) infusion directly into your spinal fluid to lower the 
risk of the disease spreading to the brain.
On Day 4, you will receive doxorubicin by vein over 24 hours.
On Day 5 or 6, G-CSF will be injected under the skin to help with the recovery of bone marrow cells recovery 24 hours after the 
dose of study drugs.
On Day 8, you will receive liposomal vincristine by vein over 1 hour +/- 30 minutes.
On Days 1-4 and Days 11-14, dexamethasone will be given by mouth with a glass of water or by vein as a short infusion.


CD20 positive patients only will also receive rituximab by vein over 6 hours, on Days 1 and 8, in addition to receiving all study 
drugs, as described above.  If you are CD20 negative, you will not receive rituximab.
Ph+ participants will receive imatinib by mouth with breakfast and a large glass of water (about 8 ounces) or dasatinib by 
mouth on Days 1-14 during Course 1.
Course 2:
On Day 1, you will receive methotrexate by vein over 24 hours.
On Days 2 and 3, you will receive cytarabine by vein over 2 hours every 12 hours for a total of 4 doses.  You will also be given 
citrovorum factor (leucovorin) by vein or by mouth to help prevent the possible side effects of methotrexate.
On Day 5 or 6, G-CSF will be injected under the skin to help with bone marrow recovery 24 hours after the dose of study drugs.
On Days 5 and 8, cytarabine then methotrexate will be given by IT infusion to lower the risk of the disease spreading to the 
brain.
CD20 positive patients only will also receive rituximab by vein over 4 hours, on Days 1 and 8, in addition to receiving all study 
drugs, as described above.  If you are CD20 negative, you will not receive rituximab.
Ph+ participants will receive imatinib by mouth with breakfast and a large glass of water (about 8 ounces) every day during 
Courses 2-8.  Dasatinib will be given by mouth every day during Courses 2-8.
Course 1 Study Visits
Blood (about 5 teaspoons each time) will be drawn weekly  for routine tests.
During Week 2 and 3 or 4, a bone marrow aspirate will be performed to check the status of the disease.
At the end of Course 1, if the study doctor thinks it is needed, a chest X-ray or CT scan will be performed to check the 
status of the disease. 
If the study doctor thinks it is needed, any of these tests may be repeated at any time while you are receiving the study drug 
combination.  
Radiation Treatment
If you have lymphoblastic lymphoma and you have enlarged lymph glands in the chest, you may receive radiation treatment to 
the chest after completing 8 courses of therapy and before you begin maintenance therapy.  If you are to receive radiation 
therapy to the chest, the study doctor will discuss this procedure and its known risks with you in more detail, and you will be 
given a separate consent form to sign.
Maintenance Therapy -- Non-Ph+ Participants
After completing 8 courses of the study drug combinations, you will begin maintenance therapy for a total of 30 months, and will 
be interrupted by 2 periods of intensive chemotherapy consolidation courses.
Every month during maintenance therapy:
You will take 6-mercaptopurine every day by mouth.
You will receive methotrexate by vein or mouth 1 time every week.
You will receive liposomal vincristine by vein over 1 hour +/- 30 minutes on Day 1.
You will take dexamethasone by mouth on Days 1-5 each month.
First intensive chemotherapy consolidation courses:
Six (6) months after you begin maintenance therapy, you will receive two months of intensive chemotherapy courses.  
First, you will receive cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone (similar to Course 1) for 
Month 6 of therapy. 
About one (1) month later, you will receive methotrexate by vein (at a lower dose than given during Course 2) on Day 1 
and pegylated asparaginase by vein over about 2 hours on Day 2.  You will be given each drug 1 time each week for a 
total of 4 weeks for Month 7 of therapy.
About eighteen (18) months after you begin maintenance therapy, you will repeat the intensive chemotherapy courses just 
described.
Maintenance Therapy -- Ph+ Participants
After completing 8 courses of the study drug combinations, you will begin maintenance chemotherapy plus imatinib or dasatinib. 
Maintenance chemotherapy will be given for a total of 24 months, and will be interrupted by 2 periods of intensive chemotherapy 
courses and imatinib or dasatinib at 6 and 13 months from the start of maintenance. You will continue receiving imatinib or 
dasatinib every day from that point on, unless intolerable side effects occur.
Every month during maintenance therapy:
You will take imatinib or dasatinib every day by mouth.
You will receive liposomal vincristine by vein over 1 hour +/- 30 minutes on Day 1.
You will take dexamethasone by mouth on Days 1-5 each month.


Intensive chemotherapy consolidation courses:
At six (6) and eighteen (18) months after you begin maintenance therapy, you will receive two months of intensive 
chemotherapy courses.  You will receive  cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone with 
imatinib or dasatinib (similar to Course 1). If the disease is CD20 positive, you may receive rituximab.
Blood Tests
During maintenance therapy and the intensive consolidation therapy, you will have blood (about 5 teaspoons) drawn every 4 
weeks +/- 4 weeks for routine tests.  
After intensive chemotherapy consolidation, for as long as you continue to receive maintenance therapy, blood (about 5 
teaspoons) will be drawn every 4 weeks +/- 4 weeks, until maintenance therapy is completed:
Additional Tests while on Study
Every 3-6 months:
You will have a bone marrow biopsy performed to check the status of the disease.
If you have mediastinal disease, you will have a chest x-ray or CT scan.
Length of Study
You will receive up to 8 courses of therapy.  If you are not Ph+, you will continue to receive maintenance therapy for up to 30 
months.  If you are Ph+, you will continue to receive maintenance therapy for up to 24 months, followed by imatinib or dasatinib 
alone indefinitely.   You will be taken off the study if disease gets worse, you experience intolerable side effects, or the study 
doctor thinks it is in your best interest.
Additional Information
If you are 60 years or older, you will receive Course 1 chemotherapy in a protective isolation room to decrease the risk of any 
infection(s) that you may be exposed to while receiving the Course 1 treatment.
This is an investigational study.  Liposomal vincristine is FDA approved for the treatment of patients with CLL who have 
relapsed at least 2  times.  All of the other study drugs used in this study are FDA approved and commercially available.  The 
combination of liposomal vincristine with the other study drugs is also being used in research only.
Liposomal vincristeine will be provided at no cost to you while you are enrolled in this study.  You and/or your insurance provider 
will be responsible for all other drugs that are given to you as part of this study.
Up to 65 patients will take part in this study.  All will be enrolled at MD Anderson.
4. RISKS, SIDE EFFECTS, AND DISCOMFORTS TO PARTICIPANTS
While on this study, you are at risk for side effects.  These side effects will vary from person to person.  The more commonly 
occurring side effects are listed in this form, as are rare but serious side effects.  You should discuss these with the study 
doctor.  You may also want to ask about uncommon side effects that have been observed in small numbers of patients but are 
not listed in this form.  Many side effects go away shortly after treatment is stopped, but in some cases side effects may be 
serious, long-lasting or permanent, and may even result in hospitalization and/or death.
Tell the study staff about any side effects you may have, even if you do not think they are related to the study drug.  
Imatinib, dasatinib, doxorubicin, cyclophosphamide, cytarabine, liposomal vincristine, and rituximab each may cause low blood 
cell counts (red blood cells, platelets, and/or white blood cells): 
A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You may need a blood transfusion. 
A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, and/or digestive system 
bleeding). You may need a platelet transfusion.  
A low white blood cell count increases your risk of infection (such as pneumonia and/or severe blood infection). Infections 
may occur anywhere and become life-threatening. Symptoms of infection may include fever, pain, redness, and/or difficulty 
breathing.
Imatinib Side Effects
Common (occurring in more than 20% of patients)
swelling
fatigue
fever 
headache
skin rash and/or itching
abnormal salts, minerals, and/or acids 
in the blood (possible weakness, 
swelling, fatigue, low blood pressure, 
organ failure, heart problems, changes 
in mental status, and/or seizure)
nausea 
diarrhea 
vomiting 
gas
abdominal pain 
loss of appetite 
weight gain 
upset stomach
low blood cell counts (white, red, 
and/or platelets)
pain
weakness 
cramps
abnormal liver tests (possible liver 
damage)
teary eyes 
abnormal kidney test (possible kidney 
damage)
cough 
difficulty breathing 


Occasional (occurring in 3-20% of patients)
chest pain
irregular heartbeat 
low blood pressure (possible 
dizziness/fainting)
high blood pressure
low oxygen levels in the blood 
(possible light-headedness)
bleeding in the brain 
depression
dizziness 
difficulty sleeping
anxiety
chills/shivering
hair loss (partial or total) 
sweating (possible night sweats)
skin sensitivity to sunlight or lamps
dry skin
high blood sugar (possible diabetes) 
abnormal digestive blood test 
(possible inflammation of the 
pancreas)
constipation 
mouth blisters/sores (possible difficulty 
swallowing)
weight loss 
abdominal swelling
abnormal taste 
digestive system bleeding
inflammation of the stomach and/or 
intestines
abnormal liver tests (possible 
yellowing of the skin and/or eyes)
abnormal liver and bone tests
abnormal sensations (such as pins 
and needles)
blurry vision
painful red eyes
sore throat
runny nose 
build-up of fluid around the lungs
flu-like symptoms
Exact frequency unknown but occurring between 1% to 10%
numbness 
flushing
skin redness
changes in nail color/appearance
heartburn
dry mouth
increase in infection-fighting cells
nerve damage (possible numbness, 
pain, and/or loss of motor function)
bleeding in the tissue lining the eye
dry eyes
nosebleed
Rare but serious (occurring in fewer than 3% of patients)  
chest pain due to heart trouble
tissue swelling
shock caused by heart damage
severe heart problems (such as heart 
attack and/or heart failure)
sudden stopping of the heart
build-up of fluid in the tissue around 
the heart (possible heart failure)
fast heartbeat
blood clot in either the vein or artery 
(possible pain, swelling, and/or 
redness)
increased pressure between the skull 
and brain (possible vision changes 
and/or headaches)
swelling of the brain (possible 
headache and/or mental status 
changes)
seizure
memory loss
fainting
allergic skin reaction
very severe blistering skin disease 
(loss of large portion of skin)
shedding and scaling of the skin 
(possible fatal loss of bodily fluids)
skin condition with fever and skin 
lesion
red, dry, scaly patches of thickened 
skin (psoriasis)
hand-foot syndrome (palms of 
hands/soles of feet having pain, 
swelling, and blistering)
very severe blistering skin disease 
(with ulcers of the skin and digestive 
tract)
blistering skin rash
underactive thyroid gland (possible 
weight gain, heart failure, and/or 
constipation)
stomach ulcer
intestinal blockage
hole in the intestines (possibly leaking 
contents into the abdomen)
vomiting of blood
dehydration
tarry or coffee ground-like blood in the 
stool
fluid in the abdomen
inflammation of the pancreas (possible 
abdominal pain)
heavy/irregular menstrual bleeding
swelling of the scrotum
bleeding ovarian cyst (fluid-filled lump)
blood in the urine
anemia due to destruction of red blood 
cells
blood vessel inflammation (possible 
bleeding and/or bruising)
blood vessel disorder causing painful, 
cold, numb, and discolored fingers 
and/or toes
high blood platelet count (possible 
increased clotting)
bleeding in or from the tumor 
breakdown products of the cancer 
cells entering the bloodstream 
(possible weakness, low blood 
pressure, muscle cramps, kidney 
damage, and/or other organ damage)
blood vessel blockage 
liver damage and/or failure (possibly 
due to inflammation)
breakdown of muscle tissue (possible 
kidney failure)
hip bone destruction
pain in the hip/leg due to loss of blood 
supply
bleeding in the eye
swelling under the central part of the 
retina and/or of the eye nerve 
(possible vision loss)
increased pressure in the eye 
(possible vision loss)
cataracts (clouding of the lens of the 
eye)
hearing loss
kidney failure
high blood levels of uric acid (possible 
painful joints and/or kidney failure)
lung damage and/or inflammation 
(possible difficulty breathing)
bleeding in the lungs and/or airways
increased blood pressure in the lungs 
(possible difficulty breathing and/or 
heart failure)
life-threatening allergic reaction (such 
as difficulty breathing, low blood 
pressure, and/or organ failure)
severe life-threatening infection 
(possible low blood pressure, kidney 
failure, and/or heart failure)
Studies in rats have shown an increased risk of developing tumors of the kidney, bladder, and/or female organs, both non-
cancerous and cancerous, when receiving doses of imatinib mesylate that are 0.5 to 4 times higher than the dose level 
commonly given to humans.  To date, there is no information available on the risk of these events occurring in humans.


If you can become pregnant, imatinib may cause miscarriage and/or birth defects.
Dasatinib Side Effects
Common (occurring in more than 20% of patients) 
swelling
headache 
fatigue
skin rash (possible 
itching, blistering, 
shedding, irritation, 
and/or redness)
hives
allergic skin reaction
white skin bumps
diarrhea 
nausea 
low blood cell counts 
(red, white, platelets)
build-up of fluid in 
and/or around the lungs 
(possible difficulty 
breathing) 
difficulty breathing
Occasional (occurring in 3-20% of patients)
build-up of fluid in the 
tissue around the heart 
decreased blood supply 
to the heart
heart failure
severe heart problems
enlarged heart
fever
central nervous system 
bleeding
constipation
vomiting 
abdominal pain 
digestive system 
bleeding 
abnormal liver tests 
(possible liver damage 
or yellowing of the skin 
and/or eyes) 
pain (joint/bone/muscle)
muscle spasms
abnormal kidney test 
(possible kidney 
damage) 
increased blood 
pressure in the lungs 
(possible difficulty 
breathing and/or heart 
failure)
infection  
Exact frequency unknown but occurring in between 1 and 10% of patients:
irregular/fast heartbeat
chest pain
flushing
high blood pressure 
chills
depression
dizziness
difficulty sleeping
acne
hair loss (partial or total)
eczema (skin 
inflammation)
dry skin
sweating 
high blood levels of uric 
acid (possible painful 
joints and/or kidney 
failure)
abdominal swelling
loss of appetite
upset stomach
inflammation of the 
stomach and/or 
intestines
mouth 
blisters/sores  (possible 
difficulty swallowing)
abnormal taste 
weight loss/gain 
nerve damage (possible 
numbness, pain, and/or 
loss of motor or sensory 
function)
weakness
blurry vision (possible 
loss of vision)
dry eyes
vision problems
ringing in the ears
cough
lung inflammation 
(possible difficulty 
breathing)
severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure)
Rare but serious (occurring in fewer than 3% of patients) 
chest pain due to heart 
trouble
low blood pressure 
(possible 
dizziness/fainting)
heart attack
sudden stopping of the 
heart
enlarged heart
heart and lung failure 
heart inflammation
inflammation of the 
tissue around the heart 
(possible chest pain)
abnormal blood test 
(possible heart 
inflammation of the 
thyroid gland (possible 
tenderness in the neck)
overactive thyroid gland 
(possible weight loss, 
heart rate changes, 
and/or sweating)
underactive thyroid 
gland (possible weight 
gain, heart failure, 
and/or constipation)
high blood levels of fat 
(possible heart disease 
and/or stroke)
low blood levels of 
albumin (possible 
swelling, weakness, 
blood clots in a vein 
(possible pain, swelling, 
and/or redness)
abnormal blood clotting
blockage of the bile 
tract (possible body 
yellowing and/or 
abdominal pain)
liver damage
paralysis of nerves 
controlling the head and 
neck
bone destruction
eye bleeding  
inflammation of an eye 
nerve


problems)
stroke
temporary stroke 
symptoms
seizure
memory loss
dementia (loss of 
mental capacity)
fainting
difficulty walking
inflammation of the fatty 
layer under the skin
skin condition with fever 
and skin lesions
painful skin bumps
hand-foot 
syndrome  (palms of 
hands/soles of feet 
having pain, swelling, 
and blistering)
very severe blistering 
skin disease (with 
ulcers of the skin and 
digestive tract)
and/or fatigue)
diabetes
fluid in the abdomen
dehydration 
gum bleeding 
stomach ulcer
abnormal connections 
or passageways 
between organs or 
vessels
intestinal blockage
gallbladder 
inflammation (possible 
abdominal pain)
severe inflammation of 
the pancreas (possible 
sudden abdominal pain)
blood in the urine
uterine and/or vaginal 
bleeding 
decreased bone 
marrow function and 
inability to make red 
blood cells
blood vessel blockage  
hearing loss
kidney failure
breakdown of muscle 
tissue (possible kidney 
failure)
difficulty breathing due 
to narrowing of the 
airways
blockage in the lung 
(possible pain, 
shortness of breath, 
and/or failure to 
breathe)
coughing up blood
breakdown products of 
the cancer cells 
entering the blood 
stream (possible 
weakness, low blood 
pressure, muscle 
cramps, kidney 
damage, and/or other 
organ damage)
allergic reaction
Dasatinib may cause harm to a fetus if taken during pregnancy. 
Other Instructions about Dasatinib 
Call your doctor at the first sign of diarrhea.  You should keep some Loperamide (Imodium) at home, in case you have 
diarrhea.  You should call your doctor right away or go to the hospital if there are any signs of bleeding from your stomach 
(vomiting bloody or dark stomach contents) or bleeding from the intestines (dark or bloody bowel movements).
Call your doctor right away, and go to a hospital if you have signs of heart problems such as abnormal heartbeat or chest 
discomfort.
Anybody other than the participant should wear protective gloves when handling dasatinib.
You should not eat grapefruit or drink grapefruit juice while taking dasatinib.
Doxorubicin Side Effects 
It is not known how often the side effects of doxorubicin may occur.
irregular, slow, and/or fast heartbeat
abnormal ECG
extra heartbeats
severe heart problems
heart failure
heart inflammation
inflammation of the tissue around the 
heart (possible chest pain) 
fatigue/lack of energy
chills
coma
fever
seizure
shock
nerve damage (possible numbness, 
pain, and/or loss of motor function) 
skin rash
itching
hives
skin sensitivity to sunlight or lamps
severe sunburn-like rash at site of 
previous radiation (called radiation 
recall)
very severe blistering skin disease 
(with ulcers of the skin and digestive 
tract)
very severe blistering skin disease 
(loss of large portion of skin)
hair loss (partial or total)
discoloration of saliva, sweat, urine, or 
tears
darkening of the skin, nail, and/or 
mouth
stopped menstrual cycle
dehydration
inability to have children
problems with production of sperm 
and eggs
high blood levels of uric acid (possible 
painful joints and/or kidney failure) 
abdominal pain
loss of appetite
death of colon tissue
diarrhea
stomach and/or small intestine ulcer
mouth blisters/sores
nausea
vomiting 
low blood cell counts (red and 
platelets)
decreased bone marrow function 
(possible leukemia)
vein hardening
growth failure
abnormal liver tests (possible 
yellowing of the skin and/or eyes) 
liver damage due to inflammation
weakness
painful red and/or teary eyes
eye inflammation
lung damage at the site of prior 
radiation 
infection
injection site pain and/or inflammation 
allergic reaction, which may be life-
threatening (including hives, itching, 
tissue swelling, difficulty swallowing, 
and difficulty breathing)
Doxorubicin may cause you to develop another type of cancer (such as secondary acute myelogenous leukemia, a type of 
blood cancer). 


Cyclophosphamide Side Effects
It is not known how often the following side effects may occur:
hair loss (partial or total)
mouth blisters/sores (possible difficulty 
swallowing)
nausea
vomiting
abdominal pain
loss of appetite
diarrhea
problems with production of sperm 
and eggs
inability to have children
stopped menstrual cycle
low blood counts (red, platelet, white)
bladder inflammation and bleeding 
(possible pain and/or urge to urinate)
infection
Cyclophosphamide may cause you to develop another type of cancer (such as bladder cancer, acute leukemia [a type of blood 
cancer], lymphoma [a type of lymph node cancer], thyroid cancer, cancer of the bone marrow, and/or sarcoma [a type of cancer 
that can start in the soft tissue, bone, or other tissue].
Rare but serious (occurring in fewer than 3% of patients)
irregular heartbeat 
build-up of fluid around 
the heart (possible 
heart failure)
inflammation of the 
heart and/or the tissue 
around the heart 
(possible chest pain 
and/or bleeding)
heart damage/failure, 
death of heart tissue, or 
other severe heart 
problems
blood clots in a vein 
(possible pain, swelling, 
and/or redness)
blood clots in an artery 
(possible organ damage 
such as stroke and/or 
heart attack)
brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision 
loss)
dizziness
very severe blistering 
skin disease (with 
ulcers of the skin and 
digestive tract)
severe sunburn-like 
rash at site of previous 
radiation (called 
radiation recall)
wound healing 
problems
very severe blistering 
skin disease (loss of 
large portion of skin)
low blood levels of 
potassium (possible 
weakness) 
low blood levels of 
sodium (possible 
headache, 
confusion,  seizures, 
and/or coma)
hormonal deficiency 
that affects the body's 
ability to control blood 
pressure and react to 
stress
decreased supply of 
blood to the abdomen
digestive system 
bleeding
enlarged bowel 
(possible abdominal 
pain)
inflammation of the 
intestines (possible 
bleeding)
inflammation of the 
pancreas (possible 
abdominal pain)
liver damage (possibly 
due to blood clots)
jaundice (yellowing of 
skin and/or eyes)
high blood levels of uric 
acid (possible painful 
joints and/or kidney 
failure)
ovarian scarring
urinary tract or bladder 
scarring
decreased testicle size 
and function
blood in the urine
blurry vision
hearing loss
breakdown of muscle 
tissue (possible kidney 
failure)
death of kidney tissue 
(possible kidney failure)
difficulty breathing
lung inflammation 
(possible difficulty 
breathing)
problems with blood 
carrying oxygen 
(possible blue skin)
lung damage due to 
blood clots
increased blood 
pressure in the lungs 
(possible difficulty 
breathing and/or heart 
failure)
multiorgan failure
breakdown products of 
the cancer cells 
entering the blood 
stream (possible 
weakness, low blood 
pressure, muscle 
cramps, kidney 
damage, and/or other 
organ damage) 
life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure)
severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure)
Cytarabine Side Effects
Frequent:
fever 
skin rash
anal and/or rectal inflammation
anal sores
loss of appetite
diarrhea
mouth sores and/or blisters
nausea
vomiting
low blood cell counts (red, white, 
platelet)
abnormal liver tests (possible liver 
damage)
abnormal liver tests (possible 
yellowing of the skin and/or eyes
blood clots in a vein (possible pain, 
swelling, and/or redness) 


Less Frequent:
chest pain
inflammation of the tissue around the 
heart (possible chest pain) 
dizziness
headache
nerve damage (possible dizziness 
and/or headache)
inflammation of nerves (possible pain 
and/or loss of motor or sensory 
function)
hair loss (partial or total)
itching
skin freckling
skin sores
hives 
abdominal pain
death of tissue in the intestines
esophageal sore
throat inflammation
inflammation of the pancreas (possible 
abdominal pain)
sore throat 
inability to urinate 
jaundice (yellowing of skin and/or 
eyes) 
painful red eyes 
decreased kidney function 
difficulty breathing
injection site swelling
allergic reaction (swelling of face, 
mouth, and/or tongue) 
life-threatening allergic reaction (such 
as difficulty breathing, low blood 
pressure, and/or organ failure)
severe life-threatening infection 
(possible low blood pressure, kidney 
failure, and/or heart failure)
Infrequent:
chest pain due to heart trouble
stoppage of heart and lung function
inflammation of the membranes 
around the spinal cord and brain 
(possible headache and/or coma)
mental status change
paralysis
brain damage that may be reversible 
(possible headache, confusion, 
seizures, and/or vision loss)
enlarged bowel (possible abdominal 
pain)
high blood levels of uric acid (possible 
painful joints and/or kidney failure) 
abnormal blood test (possible 
pancreas inflammation and/or 
damage)
liver damage due to blood clots 
breakdown of muscle tissue (possible 
kidney failure)
lung inflammation (possible difficulty 
breathing)
injection site pain and/or swelling
cytarabine syndrome 
(bone/chest/muscle pain, painful red 
eyes, fever, skin rash, and/or 
fatigue/lack of energy)
 
Additional side effects seen only in high dose cytarabine: 
It is not well known how often the following side effects may occur.
enlarged heart
decreased brain function affecting 
movement
coma
nervous system damage (possible 
seizure and/or coma)
nerve damage (possible numbness, 
pain, and/or loss of motor function)
personality change
sleepiness
skin peeling
hair loss (partial or total)
skin rash
stomach and/or small intestine ulcer
abdominal wall inflammation
inflammation of the pancreas (possible 
abdominal pain)
air-filled cysts in the intestines
decreased blood flow to part of the 
bowel (possibly causing death of 
tissue)
pus-filled areas in the liver
liver damage
damage to the surface of the eye 
bleeding in the eye
difficulty breathing
fluid in the lung (possible difficulty 
breathing)
severe life-threatening infection 
(possible low blood pressure, kidney 
failure, and/or heart failure)
When cytarabine is given intrathecally, it may also cause the following side effects: 
decreased brain function (possible 
paralysis and/or coma) 
bladder/bowel dysfunction
paralysis (possibly of the nerves in the 
neck and/or both legs)
blindness 
double vision
difficulty swallowing
cough
hoarseness
voice loss
Dexamethasone Side Effects
It is not well known how often the following side effects may occur.
high blood pressure
irregular/slow heartbeat
sudden stopping of the heart
enlarged heart
heart failure
tearing of the walls of the heart (post-
heart attack)
blood vessel inflammation (possible 
bleeding and/or bruising)
hair loss (partial or total)
hair growth
sweating
tissue death
Cushing's syndrome (possible 
weakness, diabetes, and/or bone 
weakness)
decreased ability to process 
carbohydrates
worsening of existing myasthenia 
gravis (immune response causing 
muscle weakness)
bruising
abnormal blood test (possible kidney 
damage)
enlarged liver
abnormal liver tests (possible liver 
damage)


blood clots in a vein (possible pain, 
swelling, and/or redness)
blood clots in the arteries (possible 
organ damage such as stroke and/or 
heart attack)
swelling (tissue/abdomen)
dizziness
shock
fainting
headache
increased pressure in the skull or 
between the skull and brain (possible 
headache, vision changes, and/or 
mental status changes) 
seizure
depression
mood swings
personality changes
euphoria (unusual feelings of 
happiness or well-being)
difficulty sleeping
fatigue/lack of energy
darkening and/or lightening of the skin
tiny dots on the skin 
wound healing problems
skin rash, redness, and/or dryness
fragile and/or thinning skin
skin tests (such as for TB) may not be 
accurate
stretch marks
hives
acne
high blood sugar (possible diabetes)
diabetes
decreased production of adrenal 
hormones (possible weakness and/or 
low blood pressure)
body-wide loss of proteins (possible 
weakness and/or swelling)
changes in body salts such as sodium, 
potassium, and/or magnesium 
(possible fatigue and/or weakness)
build-up of fat in abnormal areas
pituitary gland failure (possible 
hormone imbalance)
weight gain
increased appetite
digestive system bleeding
esophageal sore
hole in the intestines (possibly leaking 
contents into the abdomen)
nausea
itching near the anus
inflammation of the pancreas (possible 
abdominal pain)
stomach ulcer
changes to the menstrual cycle
problems with production of sperm
weakness
inflammation of nerves (possible pain 
and/or loss of motor or sensory 
function)
joint disease/pain
pain or loss of function of the hips or 
shoulders due to bone death
broken bones
loss of muscle
muscle damage causing weakness
nerve damage (loss of motor or 
sensory function)
abnormal sensation (such as pins and 
needles)
tendon tear
collapse of bones in the spine
bulging eye
increased pressure in the eye 
(possible vision loss, pain, and/or 
blurry vision)
cataracts (clouding of the lens of the 
eye)
hiccups
fluid in the lung (possible difficulty 
breathing)
allergic reaction that may be life-
threatening (such as difficulty 
breathing, low blood pressure, and/or 
organ failure)
infection
Dexamethasone may cause you to develop another type of cancer.
Methotrexate Side Effects
Exact frequency unknown but occurring in more than 10% of patients:
inflammation of the membrane around 
the spinal cord and brain (possible 
headache, vomiting, and fever) 
nerve damage (loss of motor or 
sensory function)
paralysis of nerves controlling the 
head and neck
coma
skin redness 
high blood levels of uric acid (possible 
painful joints and/or kidney failure) 
low sperm count
mouth blisters/sores
swollen tongue
gum disease
nausea
vomiting
diarrhea
hole in the intestines (possibly leaking 
contents into the abdomen)
low blood cell counts (red, white, and 
platelets)
kidney failure
build-up of bodily waste products in 
the blood (possible kidney damage)
sore throat 
Exact frequency unknown but occurring in between 1 and 10% of patients:
blood vessel inflammation (possible 
bleeding and/or bruising)
dizziness
fatigue/lack of energy
decreased brain function (possible 
paralysis and/or coma)
fever
chills 
hair loss (partial or total)
skin rash and/or itching
skin sensitivity to sunlight or lamps
lightening or darkening of skin
diabetes 
bladder inflammation (possible pain 
and/or urge to urinate) 
liver damage due to scarring
scarring of a vein to the liver (possible 
liver damage) 
abnormal liver test (possible live 
damage) 
joint pain 
blurry vision 
decreased kidney function
abnormal blood test (possible muscle 
disorders)
decreased urine output
lung inflammation (possible difficulty 
breathing)
cough
infection
Rare but serious (occurring in less than 1% of patients)
chest pain
low blood pressure (possible 
dizziness/fainting)
heart attack
very severe blistering skin disease 
(with ulcers of the skin and digestive 
tract)
very severe blistering skin disease 
broken bone(s)
paralysis
increase in white blood cells
liver failure


irregular heartbeat
stroke
blood clots in an artery (possible 
organ damage such as stroke and/or 
heart attack)
blood clots in a vein (possible pain, 
swelling, and/or redness)
blood clots in the brain
inflammation of and/or build-up of fluid 
in the tissue around the heart 
(possible chest pain)
decreased blood supply to the heart
brain damage that may be reversible 
(possible headache, confusion, 
seizures, and/or vision loss)
fainting
seizure 
inability to speak
difficulty forming or speaking words
weakness on one side of the body
(loss of large portion of skin) 
shedding and scaling of the skin 
(possible fatal loss of bodily fluids)
red, dry, scaly patches of thickened 
skin (psoriasis)
allergic skin reaction
low blood level of albumin (possible 
swelling, weakness, and/or fatigue) 
decreased supply of blood to the 
abdomen
abdominal pain
vomiting of blood
tarry or coffee ground-like blood in the 
stool
inflammation of the pancreas (possible 
abdominal pain)
blood in the urine
abnormal hole inside the nose
bone destruction and soft tissue death 
of tissue (with radiotherapy)
liver damage due to inflammation
blindness
blood clot inside the eye (possible 
blindness)
difficulty breathing
failure to breathe
lung damage (possible difficulty 
breathing)
blood clots in the lung (possible failure 
to breathe)
life-threatening allergic reaction (such 
as difficulty breathing, low blood 
pressure, and/or organ failure)
severe life-threatening infection 
(possible low blood pressure, kidney 
failure, and/or heart failure)
breakdown products of the cancer 
cells entering the blood stream 
(possible weakness, low blood 
pressure, muscle cramps, kidney 
damage, and/or other organ damage)
Methotrexate may rarely cause you to develop another type of cancer (such as lymphoma, a type of lymph node cancer).
Frequency Unknown
birth defects
miscarriage
Liposomal Vincristine Side Effects
Likely (occurring in more than 20% of patients)
fever
fatigue
difficulty sleeping
constipation
nausea
diarrhea
loss of appetite
low red blood cell count
nerve damage (loss of sensory 
function and/or affecting movement)
Common (occurring in 3-20% of patients)
low blood pressure (possible 
dizziness/fainting)
sudden stopping of the heart
mental status changes
paralysis of the intestines
low blood count (white, platelets)
bacteria in the blood 
abnormal liver test (possible liver 
damage)
weakness
pain (such as abdominal pain)
nerve damage (possible numbness, 
pain, and/or loss of motor function)
difficulty breathing
severe life-threatening infection 
(possible low blood pressure, kidney 
failure, and/or heart failure)
At this time, there are no known serious side effects that occur in fewer than 3% of patients.
It is not known how often the following side effects may occur:
liver damage 
breakdown products of the cancer cells entering the blood 
stream (possible weakness, low blood pressure, muscle 
cramps, kidney damage, and/or other organ damage)
Rituximab Side Effects
Common (occurring in more than 20% of patients)
fever
fatigue
chills
nausea
low blood cell counts (red, white, 
platelet)
weakness
nerve damage (loss of motor or 
sensory function)
infection
Rituximab may commonly cause infusion reactions such as difficulty breathing and/or tissue swelling.  In some cases, life-
threatening reactions such as sudden stopping of the heart and/or shock caused by heart damage may occur.  It is not known 
how often these more serious reactions may occur.
Because rituximab is a mouse antibody that has been changed to make it similar to a human antibody, treatment with rituximab 
may commonly cause the body to make human antibodies to the mouse-based antibody.  These antibodies are called HAMA or 
HACA.  The potential response of your body to rituximab may lead to decreasing the effectiveness of mouse-based antibody 


therapies for you in the future.  If you receive other drugs in the future that contain mouse proteins, you could develop an 
allergic reaction to those drugs.
Occasional (occurring in 3-20% of patients)
high blood pressure 
low blood pressure (possible 
dizziness/fainting)
swelling (arm/leg/
tissue)
flushing
anxiety
headache
difficulty sleeping
dizziness
skin rash
itching
night sweats
hives
high blood sugar (possible diabetes)
diarrhea
abdominal pain
weight gain 
vomiting
upset stomach
abnormal liver and/or bone tests 
(possible liver damage)
pain (back/joint/muscle)
muscle spasms
difficulty breathing (possibly due to 
narrowing of the airways)
cough
runny nose
nosebleed
sore throat
Rare but serious (occurring in fewer than 3% of patients)
sudden stopping of the heart
fast and/or irregular heartbeat 
chest pain due to heart trouble
heart failure
heart attack
blood vessel inflammation (possible 
bleeding, bruising, and/or rash)
shock caused by heart damage
inflammation of the brain and spinal 
cord (possible altered consciousness)
progressive multifocal 
leukoencephalopathy (PML – a 
disease with brain damage that may 
likely result in paralysis and/or coma, 
which may be permanent, or death)
brain injury that may be reversible 
(possible headache, confusion, 
seizures, and/or vision loss)
severe painful blisters
severe skin rash
very severe blistering skin disease 
(with ulcers of the skin and digestive 
tract)
very severe blistering skin disease 
(loss of large portion of skin)
blockage and/or hole in the intestines 
(possibly leaking contents into the 
abdomen)
anemia due to destruction of red blood 
cells
thick blood (possible blockage of 
blood flow)
condition that looks like lupus (an 
immune system disease)
immune system reaction (possible 
organ damage)
liver damage/failure
muscle inflammation and weakness
abnormal sensation (such as pins and 
needles)
kidney damage/failure
inflammation inside the eye and/or of 
an eye nerve (possible vision 
problems)
bronchiolitis obliterans (damage of the 
small airways with difficulty breathing)
lung inflammation  (possible difficulty 
breathing)
life-threatening allergic reaction (such 
as difficulty breathing, low blood 
pressure, and/or organ failure)
worsening of Kaposi's sarcoma
breakdown products of the cancer 
cells entering the blood stream 
(possible weakness, low blood 
pressure, muscle cramps, kidney 
damage, and/or other organ damage) 
In people who have ever been infected with hepatitis B virus, there is a risk that the virus can flare up during treatment with 
drugs that affect your immune system, such as rituximab.  This could lead to liver failure.  The risk of hepatitis B virus flaring up 
may continue for several months after you stop taking rituximab.  If you become jaundiced (yellowing of the skin and eyes) or 
develop viral hepatitis while taking rituximab or after stopping treatment, you should tell your study doctor right away.  Your 
study doctor will discuss this risk with you and explain what testing is recommended to check for hepatitis.
 
Rituximab may also cause other viruses to reactivate.  This includes JC virus (PML), cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C.
Talk to the study doctor before receiving any vaccines (for example, vaccines for measles, mumps, rubella, or polio).  Receiving 
a vaccine while taking rituximab may increase the risk of serious infection or make the vaccine less effective.
Chemotherapy injected directly into the spinal fluid may cause nausea, vomiting, headaches, and/or irritation of the lining of 
the spinal cord (chemical meningitis). It may lead to infection. If an Ommaya catheter is used for the intrathecal therapy, it may 
leak, bleed, and/or become infected. An Ommaya catheter may lead to a change in the flow of the spinal fluid. 
Using the study drugs together may cause side effects that are not seen when each is given alone.  The study drug 
combination may also increase the frequency and/or severity of the side effects listed above.
Having bone marrow aspirations performed may cause pain, bruising, bleeding, redness, low blood pressure, swelling, and/or 
infection at the site of the collection. An allergic reaction to the anesthetic may occur. A scar may form at the collection site. 
You may experience pain, bleeding, and/or bruising from the blood draws. You may faint and/or develop an infection with 
redness and irritation of the vein at the site where blood is drawn. Frequent blood collection may cause anemia (low red blood 
cell count), which may create a need for blood transfusions.
This study may involve unpredictable risks to the participants.
Pregnancy Related Risks


4a.
Because taking part in this study can result in risks to an unborn or breastfeeding baby, you should not become pregnant, 
breastfeed a baby, or father a child while on this study.  You must use birth control during the study if you are sexually 
active.
Males:  Tell the doctor right away if your partner becomes pregnant or suspects pregnancy.
Females:  If you are pregnant, you will not be enrolled on this study. If you become pregnant or suspect that you are 
pregnant, you must tell your doctor right away.
Getting pregnant will result in your removal from this study.
5. POTENTIAL BENEFITS
This treatment may help to control the disease.  Future patients may benefit from what is learned in this study.   There may 
be no benefits for you in this study.
6. ALTERNATIVE PROCEDURES OR TREATMENTS
You may choose not to take part in this study.   You may choose to receive other standard therapies, such as chemotherapy 
combinations with vincristine, prednisone, asparaginase, and/or cyclophosphamide.  You may choose to receive other 
investigational therapy, if available.  You may choose not to have treatment for cancer at all.  In all cases, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer.


Additional Information
7.
You may ask the study chair any questions you have about this study.  You may contact the study chair, Dr. Elias Jabbour, at 
713-792-7543.  You may also contact the Chair of MD Anderson's Institutional Review Board (IRB - a committee that reviews 
research studies) at 713-792-2933 with any questions that have to do with this study or your rights as a study participant.
8.
Your participation in this research study is strictly voluntary.  You may choose not to take part in this study without any penalty 
or loss of benefits to which you are otherwise entitled.  You may also withdraw from participation in this study at any time 
without any penalty or loss of benefits.  If you decide you want to stop taking part in the study, it is recommended for your 
safety that you first talk to your doctor.  If you withdraw from this study, you can still choose to be treated at MD Anderson.
9.
This study or your participation in it may be changed or stopped at any time by the study chair, Spectrum Pharmaceuticals, the 
U.S. Food and Drug Administration (FDA), the Office for Human Research Protections (OHRP - a regulatory agency that 
oversees research in humans), or the IRB of MD Anderson.
10. You will be informed of any new findings that might affect your willingness to continue taking part in the study.
11. MD Anderson may benefit from your participation and/or what is learned in this study.
12. This study is supported by:  Spectrum Pharmaceuticals.
13. The MD Anderson Conflict of Interest policy states that MD Anderson employees may not serve as the study chair or co-chair 
on a research study if they have received funds that are greater than the amount allowed by the policy or own stock in the 
sponsoring or supporting companies.
The MD Anderson Conflict of Interest policy and the IRB require that you be told about significant financial relationships that the 
study staff and MD Anderson officials may have with the study sponsor(s).
At this time, no significant financial relationships with the study sponsor(s) have been disclosed by any of the study staff.
14. In a medical emergency, you may be cared for by someone who has a financial interest with the study sponsor(s). If you have 
any questions about this, you may call the IRB at 713-792-2933.
STUDY COSTS AND COMPENSATION
If you suffer injury as a direct result of taking part in this study, MD Anderson health providers will provide medical 
care.  However, this medical care will be billed to your insurance provider or you in the ordinary manner. You will not be 
reimbursed for expenses or compensated financially by MD Anderson or Spectrum Pharmaceuticals for this injury.  You may 
also contact the Chair of MD Anderson’s IRB at 713-792-2933 with questions about study-related injuries. By signing this 
consent form, you are not giving up any of your legal rights.
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without cost to you because they are 
for research purposes only.  However, your insurance provider and/or you may be financially responsible for the cost of care 
and treatment of any complications resulting from the research tests, procedures, and/or drugs, including hospitalization, 
nausea, vomiting, low blood cell counts, and dehydration.  Standard medical care that you receive under this research study will 
be billed to your insurance provider and/or you in the ordinary manner.  Before taking part in this study, you may ask about 
which parts of the research-related care may be provided without charge, which costs your insurance provider may pay for, and 
which costs may be your responsibility.  You may ask that a financial counselor be made available to you to talk about the costs 
of this study.
There are no plans to compensate you for any patents or discoveries that may result from your participation in this research.
You will receive no compensation for taking part in this study.
Authorization for Use and Disclosure of Protected Health Information:
A. During the course of this study, the research team at MD Anderson will be collecting and using your protected health 
information.  This information may include personal identifying information about you (such as your name, race, date of birth, 
gender, city, and zip code), your medical history, study schedule, and the results of any of your tests, therapies, and/or 
procedures.  The purpose of collecting and sharing this information is to learn about how the study procedures may affect the 
disease and any study-related side effects. Your doctor and the research team may share your study information with the 
parties named in Section D below.
B. Signing this consent and authorization form is optional. However, if you refuse to provide your authorization to use and disclose 
your protected health information for this study, you will not be able to participate in this research project.
C. MD Anderson will take appropriate steps to keep your protected health information private when possible, and it will be 
protected according to state and federal law.  However, there is no guarantee that your information will remain confidential, and 
it may be re-disclosed at some point. Federal agencies (such as the FDA, OHRP, or National Cancer Institute [NCI]), Spectrum 
Pharmaceuticals, and the IRB of MD Anderson might view or receive your record in order to collect data and/or meet legal, 
ethical, research, and safety-related obligations. In some situations, the FDA could be required to reveal the names of 
participants.
D. Your protected health information may be shared with the following parties: 


Spectrum Pharmaceuticals (and/or any future sponsors of the study)
Federal agencies that require reporting of clinical study data (such as the FDA, NCI, and OHRP)
The IRB of MD Anderson
Officials of MD Anderson
Clinical study monitors who verify the accuracy of the information
Individuals with medical backgrounds who determine the effect that the treatment procedures may have on the disease
Individuals who put all the study information together in report form
E. There is no expiration date for the use of your protected health information.  You may withdraw your authorization to share your 
protected health information at any time in writing.  Instructions on how to do this can be found in the MD Anderson Notice of 
Privacy Practices (NPP).  You may contact the IRB Staff at 713-792-2933 with questions about how to find the NPP.  If you 
withdraw your authorization, you will be removed from the study, and the study chair and staff will no longer use or disclose your 
protected health information in connection with this study, unless the study chair or staff needs to use or disclose some of your 
research-related personal health information to preserve the scientific value of the study.  Data collected about you up to the 
time you withdrew will be used and included in the data analysis. The parties listed in Section D above may use and disclose 
any study data that were collected before you canceled your authorization.
F. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not 
include information that can identify you.  At most, the Web site will include a summary of the results.  You can search this Web 
site at any time.


CONSENT/AUTHORIZATION 
I understand the information in this consent form.  I have had a chance to read the consent form for this study, or have had it read 
to me. I have had a chance to think about it, ask questions, and talk about it with others as needed. I give the study chair 
permission to enroll me on this study.  By signing this consent form, I am not giving up any of my legal rights.  I will be given a 
signed copy of this consent document.
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
SIGNATURE OF 
PARTICIPANT
DATE
LEGALLY AUTHORIZED REPRESENTATIVE (LAR)
The following signature line should only be filled out when the participant does not have the capacity to legally consent to take part 
in the study and/or sign this document on his or her own behalf.
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
SIGNATURE OF LAR
DATE
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
RELATIONSHIP TO PARTICIPANT
WITNESS TO CONSENT
I was present during the explanation of the research to be performed under Protocol 2008-0598.
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
SIGNATURE OF WITNESS 
TO THE VERBAL CONSENT 
PRESENTATION (OTHER 
THAN PHYSICIAN OR 
STUDY CHAIR)
DATE
A witness signature is only required for vulnerable adult participants. If witnessing the assent of a pediatric participant, leave this line blank and sign on the 
witness to assent page instead.
PERSON OBTAINING CONSENT
I have discussed this clinical research study with the participant and/or his or her authorized representative, using language that is 
understandable and appropriate.  I believe that I have fully informed this participant of the nature of this study and its possible 
benefits and risks and that the participant understood this explanation.
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
SIGNATURE OF STUDY 
CHAIR 
OR PERSON AUTHORIZED 
TO OBTAIN CONSENT
DATE


TRANSLATOR
I have translated the above informed consent as written (without additions or subtractions) into _____________________________ 
and assisted the people 
(Name of Language)
obtaining and providing consent by translating all questions and responses during the consent process for this participant.
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
NAME OF 
TRANSLATOR
SIGNATURE OF 
TRANSLATOR
DATE
Please check here if the translator was a member of the research team.  (If checked, a witness, other than the translator, must 
sign the witness line below.)
SAMPLE -- NOT FOR USE IN CONSENTING PATIENTS
SIGNATURE OF WITNESS 
TO THE VERBAL 
TRANSLATION
(OTHER THAN 
TRANSLATOR, 
PARENT/GUARDIAN, OR 
STUDY CHAIR)
DATE