Clinical trial NCT00866749
Conditions: Lymphoblastic Leukemia Lymphoblastic Lymphoma
Keywords: acute lymphoblastic leukemia acute lymphoblastic lymphoma Leukemia ALL 6-Thioguanine Cyclophosphamide Cytarabine Daunorubicin Doxorubicin Methotrexate PEG-L-Asparaginase Vincristine Intrathecal Methotrexate Mercaptopurine
Sponsor: M.D. Anderson Cancer Center
Start date: 2006-09-12; Completion date: 2018-07-26
Enrollment: 120 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Objectives:

A. Primary objective:

1 To assess the feasibility and the effectiveness of pediatric type therapy (augmented BFM) in patients age 12 through 40 with untreated precursor-B or T acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL).

B. Secondary objective:

1. To evaluate the prognostic significance of minimal residual disease in bone marrow samples at the end of induction and at the end of consolidation in this group of patients.
2. To prospectively evaluate gene hypermethylation status in this group of patients.
3. To prospectively analyze asparaginase activity and anti-asparaginase antibody formation in this population of patients.

Detailed description:
Induction:

During Induction, you will receive augmented Berlin-Frankfurt-Munster chemotherapy, which is made up of a combination of Cerubidine®, Daunorubicin Hydrochloride (daunorubicin), Oncovin® (vincristine), prednisone, dexamethasone, Oncaspar® (PEG Asparaginase), and MTX amethopterin (methotrexate). All of these drugs are designed to interfere with the multiplication of cancer cells to cause them to die and to keep the cancer from coming back.

If you are found to be eligible to take part in this study, on Day 1 or during the spinal tap procedure, you will be given cytarabine as an injection in your spinal fluid. Within 3 days, you will begin the Induction course, which will last for 4 weeks.

Daunorubicin and vincristine will be given through a needle in your vein on Days 1, 8,15, and 22. During the first week of therapy, you will be given 1 infusion of PEG Asparaginase by vein. You will take prednisone by mouth on Days 1-28. Methotrexate will be injected into your spinal fluid on Weeks 2 and 5 during your spinal tap. Cerebrospinal fluid (CSF) studies will be sent with each spinal tap to test the fluid for leukemia. If there is disease in your spinal fluid before starting the treatment, you will be given additional methotrexate doses once a week until there is no disease present. You will continue to receive methotrexate in spinal taps every other week for 8 doses, then monthly for 6 doses.

Blood (about 3 teaspoons) will be drawn multiple times during the study for routine tests. You will have a bone marrow aspirate or biopsy on Days 15 and 29 and then as needed to confirm remission.

If you have less than 5% immature cells in the bone marrow, 1 week after Induction, you will continue treatment with Consolidation 1. If you achieved remission after 4 weeks of Induction treatment, you will then have treatment with Consolidation 1, which will be discussed in a separate informed consent document.

If you have LL and had no bone marrow involvement at screening, you will have a chest x-ray, CT scans, and PET scans to measure the disease. Consolidation 1 and other phases of chemotherapy will be discussed in a separate informed consent document.

If you still have more than 5% leukemia cells in the bone marrow after Induction therapy, you will receive 2 extra weeks of therapy called "Extended Induction" before going to the next phase of therapy. You will receive daunorubicin by vein on Day 1. You will receive vincristine on Weeks 1 and 2 by vein. You will take prednisone by mouth on Days 1-14. You will receive PEG Asparaginase by vein in the first week of the Extended Induction. Blood (about 3 teaspoons) will be drawn weekly during the Extended Induction period for routine tests.

At the end of the Extended Induction period, you will have a physical exam and a bone marrow aspirate or biopsy to learn your response to treatment.

After Extended Induction, if the disease is in remission, then you will have 1 course of Consolidation 1, 2 courses of Consolidation 2, and 2 courses of Consolidation 3 before proceeding to Maintenance therapy. A separate discussion and informed consent document for Consolidation and Maintenance will be provided.

Length of Study:

You may remain on study for as long as you are benefiting. However, if after Extended Induction, the disease is not in remission, you will be taken off study, and your doctor will discuss other treatment options with you.

You may be taken off study if the disease gets worse or comes back during treatment, intolerable side effects occur, new information becomes available to your study doctor, if your doctor thinks it is in your best interest, or if you do not attend your appointments, which are scheduled at least once every 3 months.

This is an investigational study. The chemotherapy drugs used in this study are FDA approved and commercially available. Up to 125 patients will take part in this study. All will be enrolled at MD Anderson.

Consolidation and Maintenance:

During Consolidation, you will receive cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, PEG asparaginase, methotrexate, doxorubicin, 6-thioguanine, and dexamethasone. During Maintenance, you will receive, vincristine, dexamethasone, 6-mercaptopurine, and methotrexate. All of these drugs are designed to interfere with the multiplication of cancer cells to cause them to die and to keep the cancer from coming back.

If you achieved remission after 4 weeks of induction treatment, you will have treatment with Consolidation 1, Consolidation 2, Consolidation 3 (Parts A and B), and then you will proceed to Maintenance therapy.

If the level of blast cells in your blood is above a certain level at Day 15 of Induction but you achieved complete remission by Day 29, or if you achieved remission after 6 weeks of induction plus extended induction, then you will receive 1 course of Consolidation 1, 2 courses of Consolidation 2, 2 courses of Consolidation 3 (Parts A and B), and then you will proceed to maintenance therapy.

Consolidation 1 will last for 8 weeks (2 months). You will receive cyclophosphamide through a needle in your vein on Weeks 1 and 5. Cytarabine will be given as an injection just beneath the skin or by vein on or around Days 1-4 and Days 8-11 of each month. 6-Mercaptopurine will be taken by mouth on Days 1-14 of each month. Vincristine will be given by vein on Weeks 3-4 of each month. PEG Asparaginase will be given by vein on Week 3 and 6 of each month. You will receive methotrexate through a needle through your spine weekly during Month 1 only. Blood (about 3 teaspoons) will be drawn for routine tests. You will have a spinal tap with spinal fluid tests during the intrathecal methotrexate dose. A spinal tap (also called a lumbar puncture) is when a special needle is inserted into the lower back through the space between the bones to draw a sample of the fluid that surrounds the spinal cord. You will have a bone marrow aspiration at the end of Month 2. To collect a bone marrow aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle.

Consolidation 2 will last for 7 weeks. You will receive vincristine and methotrexate by vein every 10 plus or minus 2 days for 5 doses. You will receive PEG Asparaginase by vein in Weeks 1 and 4. You will receive intrathecal methotrexate in Weeks 1 and 5. You will have a spinal tap with spinal fluid tests during the intrathecal methotrexate dose. Blood (about 3 teaspoons) will be drawn every 2 weeks for routine tests.

Consolidation 3 (Part A) will last for 4 weeks. You will receive vincristine and Doxorubicin by vein in Weeks 1, 2 and 3. Dexamethasone will be taken by mouth on Days 1-7 and Days 15-21. You will receive PEG Asparaginase by vein on Week 1. You will receive intrathecal methotrexate in Week 1.

Consolidation 3 (Part B) will last for 4 weeks. You will receive cyclophosphamide by vein in Week 1. You will receive cytarabine by vein or as an injection for 4 days in a row in Weeks 1-2. You will take 6-Thioguanine by mouth every day for the first 2 weeks. You will receive intrathecal methotrexate in Weeks 1 and 2. You will receive vincristine by vein on Weeks 3 and 4. You will receive PEG Asparaginase by vein on Week 3.

During Consolidation 3 (Part A and B), blood (about 3 teaspoons) will be drawn at least weekly for routine tests. Spinal fluid tests will be sent with each intrathecal methotrexate dose. Spinal taps will be done during each intrathecal chemotherapy dose

Once you finish Consolidation, you will proceed to maintenance therapy.

The Maintenance period for ALL patients will last for 24 months. If you have ALL, you will receive vincristine by vein every month. You will take dexamethasone by mouth for 5 days every month. You will take 6-Mercaptopurine by mouth once daily. You will take methotrexate by mouth every week. You will receive intrathecal methotrexate every 3 months for the first 12 months of maintenance. You will have a spinal tap with spinal fluid tests during the intrathecal methotrexate dose.

Maintenance for patients with LL will also last for 24 months. If you have LL, you will receive vincristine by vein every month. You will take dexamethasone by mouth for 5 days every month.

You will take 6-Mercaptopurine by mouth once daily. You will take methotrexate by mouth every week.

During the Maintenance period, all participants will have blood samples (about 1 to 3 teaspoons each time) drawn every 3 months for routine tests.

If you have LL, you will have an additional positron emission tomography (PET) scan and computed tomography (CT) scan at the end of the Maintenance period.

Follow-Up Visits:

Your study doctor will inform you of your follow-up visits in the clinic. At each follow-up visit there will be a physical exam and complete blood count. You will be followed-up for the next 3 years after your the last dose of your chemotherapy.

Length of Study:

You may remain on study for as long as you are benefiting. You may be taken off study if the disease gets worse or comes back during treatment, intolerable side effects occur, new information becomes available to your study doctor, if your doctor thinks it is in your best interest, or if you do not attend your appointments, which are scheduled at least once every 3 months.

This is an investigational study. The chemotherapy drugs used in this study are all FDA approved and commercially available. Up to 125 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Induction + Maintenance: Daunorubicin, Vincristine, PEG-asparaginase, Intrathecal Methotrexate, Cyclophosphamide, Cytarabine, Mercaptopurine, Doxorubicin, Thioguanine
Interventions: intervention 1: Daunorubicin intervention 2: Vincristine intervention 3: PEG-asparaginase intervention 4: Intrathecal Methotrexate intervention 5: Cyclophosphamide intervention 6: Cytarabine intervention 7: Mercaptopurine intervention 8: Methotrexate intervention 9: Doxorubicin intervention 10: Thioguanine
Intervention descriptions: intervention 1: Starting Dose 25 mg/m\^2 by vein weekly intervention 2: Starting Dose 2 mg by vein weekly intervention 3: Starting Dose 2000 International units/m2 by vein in week 1 intervention 4: Starting Dose 12 mg on week 2 and week 5 injected into spinal fluid intervention 5: Starting Dose 1g/m2 by vein in weeks 1 and 5 intervention 6: 75 mg/m2 subcutaneous or by vein for four consecutive days on days 1-4 and days 8-11 of both months intervention 7: Starting Dose 60 mg/m2 by mouth on days 1-14 of each month intervention 8: Starting Dose at 100 mg/m2 by vein and escalating by 50 mg/m2/dose every 10

+/- 2 days for 5 doses to toxicity (e.g myelosuppression or mucositis grade 3 intervention 9: 25 mg/m2 by vein in weeks 1, 2 and 3 intervention 10: 60 mg/m2 by mouth daily for two weeks

Protocol documents:
Prot_SAP_000.pdf: 
2006-0375
February 18, 2014
Protocol Page
Augmented Berlin-Frankfurt-Munster therapy for adolescents/young adults with 
acute lymphoblastic leukemia or lymphoblastic lymphoma
2006-0375
Core Protocol Information
Short Title 
Augmented BFM therapy for your adolescent /young adults with acute lymphoblastic leukemia 
or acute lymphoblastic lymphoma
Study Chair: 
Michael E. Rytting
Additional Contact:
Kurt D. Schroeder
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-4855
Unit:
087
Full Title: 
Augmented Berlin-Frankfurt-Munster therapy for adolescents/young adults with acute 
lymphoblastic leukemia or lymphoblastic lymphoma
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 07/30/2018
Version:
29
Submitted by:
Vicky H. Zoeller--6/27/2018 4:47:59 PM
OPR Action:
Accepted by:  Julie Arevalo -- 7/2/2018 10:23:17 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2006-0375
February 18, 2014
Protocol Body
1.0 Objectives
 Primary objective:
1.1      To assess the feasibility and the effectiveness of pediatric type therapy 
(augmented BFM) in patients age 12 through 30 with untreated precursor-B or T acute 
lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL).
  Secondary
1.1.2    To evaluate the prognostic significance of minimal residual disease in bone 
marrow   samples at the end of induction and at the end of consolidation in this  group 
of patients. 
1.1.3    To prospectively evaluate gene hypermethylation status in this group of   
patients.
1.1.4    To prospectively analyze asparaginase activity and anti-asparaginase antibody 
formation in this population of patients.
2.0 Background
2.1    Pediatric ALL Trials
Pediatric patients with ALL historically have been grouped into high and standard risk 
categories according to age and presenting white blood cell count (WBC). Patients over 
age 10, patients with a presenting WBC >50,000, and patients with T-lineage disease 
are  regarded as high risk patients. Prior to 1981, this group had an EFS of 
approximately 40%. Recently, Children's Cancer Group study CCG-1961 has shown an 
improvement in EFS to over 80% in high risk patients who respond rapidly to initial 
treatment (1). This treatment, known as augmented BFM therapy,  uses intensified 
therapy with increased asparaginase and vincristine as well as escalating methotrexate 
therapy during the interim maintenance phase (consolidation 3 in this protocol) of 
chemotherapy.
2.2    Adult ALL Trials
Prognosis in adult ALL is influenced by age, performance status, and organ function as 
well as presenting WBC. In addition, high risk cytogenetic abnormalities such as the 
Philadelphia chromosome are more likely to be present in adults with ALL than in 
pediatric patients (2). More favorable prognostic features such as high hyperdiploidy 
and the presence of the TEL-AML translocation are found less often in adult ALL 
patients than in pediatric patients (3). Survival rates in adult ALL patients continues to 
lag behind that seen in pediatric patients at least partly due to these findings, with long 
term EFS in adult ALL and LL patients ranging from 40-50% (4,5,6).
2.3    Adolescents and Young Adults with ALL on Pediatric or Adult Trials
Patients between the ages of 15 and 21 years of age with ALL may be treated on 
pediatric treatment regimens or adult treatment regimens depending on referral 


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patterns. In retrospective reviews comparing survival in this age group treated often in 
very disparate fashions, pediatric regimens have produced survival rates superior to 
adult treatment regimens in this age group (3,7,8). Further analysis of two large adult 
series report that the survival rates for patients age 21 through 29 are essentially the 
same as that seen in patients age less than 21 (3,5). In these retrospective 
comparisons, patient characteristics in the pediatric trials and in the adult trials have 
been very similar. The most obvious difference between the two groups of patients is 
therapy; pediatric regimens in general use higher doses of vincristine, asparaginase and 
methotrexate than adult regimens. 
 Recently, the results of the Children’s Cancer Group trial, CCG-1961, were analyzed 
specifically for patients age 16 to 21 (1). These patients were treated with so called 
“augmented BFM” therapy with a single phase of delayed intensification if they were in 
remission by day 14 of therapy. The event free survival (EFS) rate at five years was 
81.3% and the overall survival (OS) rate at five years was 84.2% for rapid early 
responders treated with augmented therapy. Patients who were not in remission by day 
14 were treated with augmented therapy and received two blocks of delayed 
intensification and two blocks of interim maintenance therapy before proceeding on to 
maintenance chemotherapy. The results for CCG-1961 are comparable to the survival 
rates obtained in other pediatric group trials for high-risk patients, including teen-aged 
patients (9,10,11,12). We propose to use the same therapy as used for patients aged 
16-21 on CCG-1961 in adult patients with ALL age 12 to 35. If pediatric-type therapy is 
the cause for the improved survival rates seen for teens and young adults in pediatric 
trials, then similar improvements might be expected in patients aged 18 to 21 treated at 
MDACC using this regimen, and improved survival rates in patients aged 22 to 30 could 
perhaps also be realized. 
An obvious question will be whether older adults will have excess toxicity using this 
regimen, but this seems unlikely. Older adults are currently treated with the Hyper 
CVAD regimen, a regimen that uses intensively timed blocks of high dose 
corticosteroids, cytarabine, adriamycin, methotrexate,  and cyclophosphamide as well 
as standard doses of vincristine. In addition, the current adult regimen uses a very 
similar maintenance phase as that in pediatric trials. Toxicity has not been reported to 
be excessive in adults treated with this regimen (6). The University of California-Los 
Angeles and the Dana Farber Cancer Institute are attempting to give pediatric based 
ALL therapy to adults, with the DFCI study including patients up to age 50. So far, 
excessive toxicity has not limited therapy at these centers.
2.4    Lymphoblastic Lymphoma (LL)
The vast majority of lymphoblastic lymphomas are of T-cell phenotype. T 
cell-lymphoblastic leukemia and T-cell lymphoblastic lymphoma are indistinguishable in 
terms of malignant cell morphology, histology and phenotype. The pediatric approach to 
therapy is very similar  to that used in ALL with the exception that the duration of 
therapy for LL is shorter (13). In general, the long-term survival results for adults with LL 
“fall short” of the result seen in children with LL (14). Hyper CVAD therapy used in 
patients with lymphoblastic lymphoma has produced a DFS of 66% (15). In general, 


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however, reported survival rates for adults with LL are approximately 45-50%, as seen 
in ALL. The long-term event free survival rates in children with lymphoblastic lymphoma  
reported by pediatric groups have generally been around 75% (16,17). Recently 
published results using BFM therapy, similar to that proposed in this trial, show a 
five-year event free survival for T-LL that is 90%  (15). Similarly, Cairo et al. reported 
that therapy similar to the augmented BFM treatment used in pediatric ALL is effective 
in LL, with long-term overall survival of 85%-90% in localized disease and 65-85% in 
advanced disease (18).Since the results have been excellent using BFM-type therapy 
for LL, and since this is the proposed therapy for patients on this study, young adult 
patients with LL will also be enrolled on this study. Some differences in therapy between 
LL patients and ALL patient will be maintained: 1) stage I and II patients will not receive 
maintenance intrathecal therapy and 2) total treatment duration will be two years for all 
the LL patients.
2.4.1 Radiation and LL
Locoregional radiation therapy to the mediastinum has been shown to reduce local 
failures in adult patients with LL(19, 20). Pediatric LL patients treated with current 
intensive chemotherapy regimens do not show any benefit from local radiation (21). 
Since the chemotherapy regimen is duplicating that used in teens and young adults by 
the Children’s Cancer Group, radiation therapy will not be used routinely to the 
mediastinum. In the event of persistent, active disease at day 35 either by PET scan or 
biopsy, then surgical removal of disease is performed followed by continued 
chemotherapy. This approach has been utilized by the German pediatric oncology 
group with excellent results (15). 
2.6    Minimal Residual Disease (MRD)
MRD status during therapy has been reported to highly predict prognosis in pediatric 
ALL using both molecular or flow-cytometric methods for disease detection 
(22,23,24,25). These studies and others all clearly indicate that low MRD levels, 
especially measured early during therapy, indicate a favorable prognosis.  Data on the 
presence of MRD at the end of induction and during therapy shows a similar prognostic 
value in adult patients (26,27) Current studies in the COG are assessing the prognostic 
and therapeutic value of MRD in both ALL and LL. A secondary objective of this trial will 
be to collect data on the presence of MRD and its prognostic significance in young 
adults treated with pediatric type therapy. 
2.7   Hypermethylation
Promoter gene hypermethylation is found in virtually every type of cancer and is 
associated with transcriptional silencing of genes. Aberrant methylation is a mechanism 
of gene inactivation in tumors and is at least as common as more classic mechanisms 
of tumor suppressor gene disruption such as translocation (28). Recently, promoter 
gene hypermethylation has been reported to be a prognostic factor in ALL (28, 29). 
Increased gene methylation is a plausible explanation for the decreased survival seen in 


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young adults with ALL compared to children. An aim of this study will be to accumulate 
further data on gene hypermethylation in young adults with ALL.
2.8 Asparaginase 
Asparaginase is an important component in the therapy of acute lymphoblastic leukemia 
and of lymphoblastic lymphoma in children. The asparaginases deplete asparagine in 
leukemic cells which results in leukemic cell death (30). PEG-asparaginase, a 
long-acting formulation of asparaginase appears to be at least as effective in depleting 
asparagine as other forms of asparaginase and may be less immunogenic (31, 32). This 
is important since the formation of anti-asparaginase antibodies results in low levels of 
asparaginase activity and may neutralize the effect of the asparaginases (33). While 
clinical studies have reported on antibody formation and asparagine levels in children, 
little data is available for the adult population. An aim of this study will be to examine 
asparaginase activity and anti-asparaginase antibody formation in the young adults 
treated on this protocol. 
3.0 Clinical Pharmacology
4.0 Background Drug Information
1.  PEG Asparaginase (Pegaspargase, Oncaspar)
THERAPEUTIC CATEGORY
Antineoplastic Agent; Enzyme
FORMULATION
Supplied in preservation-free isotonic sterile solution ready for injection containing 750 
IU/mL (3750 IU/vial).  No reconstitution necessary. 
STABILITY AND STORAGE
Keep refrigerated.  Do not freeze. Do not use if cloudy or if precipitate is present. Avoid 
excessive agitation.  DO NOT SHAKE.  Keep refrigerated.   Do not use if stored at room 
temperature for more than 48 hours. Do not use if product has been frozen.
MECHANISM OF ACTION
Pegaspargase is a modified version of asparaginase. Leukemic cells, especially 
lymphoblasts, require exogenous asparagine; normal cells can synthesize asparagine. 
Asparaginase contains L-asparaginase amidohydrolase type EC-2 which inhibits protein 
synthesis by deaminating asparagine to aspartic acid and ammonia in the plasma and 
extracellular fluid and therefore deprives tumor cells of the amino acid for protein 
synthesis. Asparaginase is cycle-specific for the G1 phase of the cell cycle.
TOXICITIES
Systemic anaphylactoid reactions, and local allergic reactions.  Pancreatitis.  


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Hyperglycemia with glucosuria.  Hypoalbuminemia, hypofibrinogenemia, and 
hypercoagulable state.
STATUS
Commercially available
2.  Cyclophosphamide (Cytoxan, Neosar)
THERAPEUTIC CATEGORY
Alkylating Agent; Antineoplastic Agent; Nitrogen Mustard 
FORMULATION
Supplied as Intravenous Powder for Solution:  100 mg, 200 mg, 500 mg, 1 g, and 2 g of 
Cytoxan per vial or  Tablets of 25 mg and 50 mg.
RECONSTITUTION
For IV:  reconstitute each vial with Sterile or Bacteriostatic Water for Injection, USP, to a 
final concentration of 20 mg/ml.  No data is available concerning compatibility with KC1 
or NaHCO3.
STABILITY AND STORAGE REQUIREMENTS
Reconstituted solution is stable for 24 hours at room temperature, or 6 days if 
refrigerated.  Solution reconstituted without preservation should be discarded after 6 
hours. 
MECHANISM OF ACTION
Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking 
DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. 
Cyclophosphamide also possesses potent immunosuppressive activity. 
Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the 
liver.
TOXICITIES
Myelosuppression.  Anorexia, nausea and vomiting.  Alopecia.  Hemorrhagic cystitis, 
and bladder fibrosis.  Acute congestive heart failure.  Syndrome of inappropriate 
antidiuretic hormone (SIADH).  Oligospermia or a zoospermia, amenorrhea, sterility.  A 
small but potential risk of developing secondary AML.
STATUS
Commercially available
3.  Cytosine Arabinoside (Ara-C, Cytarabine, Cytosar-U)
THERAPEUTIC CATEGORY
Antimetabolite Antineoplastic; Antineoplastic Agent; Pyrimidine Analog 
FORMULATION
Supplied as lyophilized powder, 100 mg, 500 mg, 1 g, and 2 g of Ara-C per vial.


2006-0375
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RECONSTITUTION
For IM, IV push, and SQ: reconstitute each vial with enclosed diluent as recommended.  
For high dose IV Ara-C infusion, do not use enclosed diluent; use NS without 
preservative.  For IT: reconstitute with preservative free Lactated Ringer’s, or Normal 
Saline.  Ara-C is compatible with KC1 and NaHCO3.
STABILITY AND STORAGE
Reconstituted solution is stable for 48 hours at room temperature.  Solution 
reconstituted without preservative should be discarded after 8 hours.  Discard solution if 
light haze develops. Store at room temperature
MECHANISM OF ACTION
Inhibition of DNA synthesis. Cytosine gains entry into cells by a carrier process, and 
then must be converted to its active compound, aracytidine triphosphate. Cytosine is a 
purine analog and is incorporated into DNA; however, the primary action is inhibition of 
DNA polymerase resulting in decreased DNA synthesis and repair. The degree of 
cytotoxicity correlates linearly with incorporation into DNA; therefore, incorporation into 
the DNA is responsible for drug activity and toxicity. Cytarabine is specific for the S 
phase of the cell cycle.
TOXICITIES
Myelosuppression.  Anorexia, nausea and vomiting, diarrhea, and mucosal ulceration.  
Transient liver function abnormalities.  Alopecia.  “Ara-C syndrome: “fever, myalgia, 
bone pain, occasional chest pain, maculopapular rash, conjunctivitis, malaise.  After 
high doses: confusion, somnolence, seizures, ataxia, and slurred speech.
STATUS
Commercially available
4.  Daunomycin Hydrochloride (Cerubidine®, Daunorubicin Hydrochloride)
THERAPEUTIC CATEGORY
Anthracycline; Antineoplastic Agent; Antitumor Antibiotic 
FORMULATION
Supplied as lyophilized powder in 20 mg vials 
RECONSTITUTION
Reconstitute with 4 ml of Sterile Water for Injection.  Agitate gently until the material has 
completely dissolved.
Avoid extravasation or severe local tissue necrosis may result.
STABILITY AND STORAGE
Stable for 24 hours at room temperature and 48 hours under refrigeration.  Protect from 
exposure to sunlight. store product at  15 – 25º C.
MECHANISM OF ACTION


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Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs and by 
steric obstruction. Daunomycin intercalates at points of local uncoiling of the double 
helix. Although the exact mechanism is unclear, it appears that direct binding to DNA 
(intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result in 
blockade of DNA and RNA synthesis and fragmentation of DNA
TOXICITIES
Locally necrotizing if extravasated, alopecia, nausea and vomiting, bone marrow 
depression, serious myocardial toxicity may be seen as the total dose approaches 550 
mg/m2.
STATUS
Commercially available
5  Dexamethasone (Decadron®)
THERAPEUTIC CATEGORY
Adrenal Corticosteroid; Antiemetic; Corticosteroid, Nasal; Corticosteroid, Ophthalmic; 
Corticosteroid, Topical 
FORMULATION
Supplied  as tablets of 0.25 mg, 0.5 mg, 0.75 mg, 1.5 mg, 4 mg and 6 mg and  Injection 
solution with 4 mg/ml or 24 mg/ml.
RECONSTITUTION
Premixed
STABILITY AND STORAGE
Note expiration date on vial or bottle. Store in  room temperature.  Protect vials from 
light.
MECHANISM OF ACTION
Decreases inflammation by suppression of neutrophil migration, decreased production 
of inflammatory mediators, and reversal of increased capillary permeability; suppresses 
normal immune response. Dexamethasone's mechanism of antiemetic activity is 
unknown
TOXICITIES
Salt or fluid retention, hypertension, potassium loss.  Muscle weakness, loss of muscle 
mass, severe arthralgia, aseptic necrowsis of femoral humeral heads, osteoporosis.  
Peptic ulcer, Pancreatitis, abdominal distention, ulcerative esophagitis.  Impaired wound 
healing, thin fragile skin, striae, bruises, facial erythema.  Convulsion, headache, 
increased intracranial pressure.  Cushingoid state, suppression of growth in children.  
Posterior subcapsular cataracts, increased intraocular pressure.  Fatigue, 
psychosomatic complaints.
STATUS


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Commercially available.
6.  Doxorubicin (Adriamycin)
THERAPEUTIC CATEGORY
Anthracycline; Antineoplastic Agent; Antitumor Antibiotic Formulation
FORMULATION
Supplied as lyophilized red-orange powder: 10 mg, 20 mg, 50 mg, and 150 mg of 
Adriamycin per vial, or 10 mg/5 ml, 20 mg/10 ml, 50 mg/25 ml, and 20 mg/100 ml liquid 
reconstituted single-use vials.
RECONSTITUTION
For powder vials: use NS without preservatives to attain a concentration of 2 mg/ml 
(add 5 ml to 10 mg vial; 10 ml to 20 mg vial; 25 mg ml to 50 mg vial; 75 ml to 150 mg 
vial).  Single-use liquid vials are already in solution.  No data is available concerning 
compatibility with KCl or NaHCO3.
STABILITY AND STORAGE
Reconstituted powder vials are stable for 24 hours at room temperature and 48 hours 
under refrigeration and protected from light.  The reconstituted single-use vials have no 
preservative, but are stable for 24 hours at room temperature.Store at room 
temperature protected from light, for powder vials.  Refrigerate liquid vials and protect 
from light.
MECHANISM OF ACTION
Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs by 
inhibition of topoisomerase II and by steric obstruction. Doxorubicin intercalates at 
points of local uncoiling of the double helix. Although the exact mechanism is unclear, it 
appears that direct binding to DNA (intercalation) and inhibition of DNA repair 
(topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and 
fragmentation of DNA. Doxorubicin is also a powerful iron chelator; the iron-doxorubicin 
complex can bind DNA and cell membranes and produce free radicals that immediately 
cleave the DNA and cell membranes
TOXICITIES
Myelosuppression.  Anorexia, mucositis, nausea and vomiting.  Alopecia, 
hyperpigmentation of nail beds and dermal creases may occur.  Several soft tissue 
damage with extravasation.  Transient liver function abnormalities.  Drug-induced 
congestive heart failure when the cumulative dose exceeds 450 mg/m2.
STATUS
Commercially available.
7.  6-Mercaptopurine (6-MP, Purinethol®)
THERAPEUTIC CATEGORY
 Antimetabolite Antineoplastic; Antineoplastic Agent; Purine Analog 
FORMULATION


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Supplied in 50 mg tablets.
STORAGE
Store at room temperature.
MECHANISM OF ACTION
Purine antagonist which inhibits DNA and RNA synthesis; acts as false metabolite and 
is incorporated into DNA and RNA, eventually inhibiting their synthesis; specific for the 
S phase of the cell cycle
TOXICITIES
Myelosuppression.  Nausea and vomiting, diarrhea.  Hepatocellular or obstructive liver 
disease.  Mild atopic dermatitis.
8.  Methotrexate(MTX, Amethopterin)
THERAPEUTIC CATEGORY
Antifolate; Antimetabolite Antineoplastic; Antineoplastic Agent; Folate Antagonist
FORMULATION
Oral – 2.5 mg tablets.  Lyophilized powder, 20 mg, 50 mg, 100 mg, 200 mg and 1 gm 
per vial.  Liquid with preservative, 25 mg/ml, 2 ml (50 mg) and 10 ml (250 mg) per vial.  
Liquid without preservative, 50 mg, 100 mg, 200 mg, 250 mg per vial.
RECONSTITUTION
Reconstitute powder vials with sterile water, NS or D5W.  Reconstitute the 20 mg and 
50 mg vials to a concentration no greater than 25 mg/ml.  The 1 gm vial should be 
reconstituted with 19.4 ml NS or D5W to a concentration of 50 mg/ml.  Further dilution 
with D5W or NS is acceptable.  No data is available fro KC1 compatibility, but is 
compatible with NaHCO3.  For IT use, mix Methotrexate WITHOUT PRESERVATIVE 
with preservative-free Lactated Ringer’s or Normal Saline.
STABILITY AND STORAGE
Reconstituted solutions without preservatives should be discarded after 8 hours.  
Solutions with preservative stored at room temperature maintain 90% of label potency. 
Store at room temperature.  Protect from light.
MECHANISM OF ACTION
Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate 
irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, 
and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid 
synthesis. Methotrexate is cell cycle specific for the S phase of the cycle. 
TOXICITIES
Myelosuppression.  Anorexia, stomatitis, nausea and vomiting.  Transient liver function 
abnormalities.  Alopecia, rashes, photosensitivity, depigmentation or hyperpigmentation 
of skin.  Drowsiness, blurred vision, leukoencephalopathy, paresis.  Interstitial 
pneumonitis.  Osteoporosis.  Fever.  Defective zoogenesis, or spermatogenesis, 
transient oligospermia, menstrual dysfunction and infertility.


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STATUS
Commercially available.
9.  Prednisone
THERAPEUTIC CATEGORY
Adrenal Corticosteroid
FORMULATION
Supplied as tablets of 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 50 mg.  Oral 
solution with 5 mg/ml.
STORAGE
Room temperature.
MECHANISM OF ACTION
Decreases inflammation by suppression of migration of polymorphonuclear leukocytes 
and reversal of increased capillary permeability; suppresses the immune system by 
reducing activity and volume of the lymphatic system; suppresses adrenal function at 
high doses. Antitumor effects may be related to inhibition of glucose transport, 
phosphorylation, or induction of cell death in immature lymphocytes. Antiemetic effects 
are thought to occur due to blockade of cerebral innervation of the emetic center via 
inhibition of prostaglandin synthesis.
TOXICITIES
Salt or fluid retention, hypertension, potassium loss.  Muscle weakness, loss of muscle 
mass, severe arthralgia, aseptic necrosis of femoral/humeral heads, osteoporosis.  
Peptic ulcer, Pancreatitis, abdominal distention, ulcerative esophagitis.  Impaired wound
healing, thin fragile skin, striae, bruises, facial erythema.  Convulsions, headache, 
increased intracranial pressure.  Cushingoid state, suppression of growth in children.  
Posterior subcapsular cataracts, increased intraocular pressure.  Fatigue, 
psychosomatic complaints.
STATUS
Commercially available.
10.  6-Thioguanine (6-TG)
THERAPEUTIC CATEGORY
 Antimetabolite Antineoplastic; Antineoplastic Agent; Purine Analog 
FORMULATION
Supplied as tablets of 40 mg.
STORAGE
Store at room temperature.


2006-0375
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MECHANISM OF ACTION
Purine analog that is incorporated into DNA and RNA resulting in the blockage of 
synthesis and metabolism of purine nucleotides
TOXICITIES
Myelosuppression.  Nausea and vomiting, anorexia, stomatitis, diarrhea.  
Veno-occulusive disease.  Increased skin sensitivity to sun, mild atopic dermatitis.  Loss 
of vibration sensitivity and unsteady gait.
STATUS
Commercially available.
11.  Vincristine (Oncovin®)
THERAPEUTIC CATEGORY
Antineoplastic Agent; Vinca Alkaloid
FORMULATION
Supplied as clear liquid, 1 mg 2 mg, and 5 mg vials.
STABILITY AND STORAGE
Keep refrigerated.  Protect from light. Multiple-dose containers with preservatives are 
stable 30 days after opening if refrigerated.
MECHANISM OF ACTION
Binds to tubulin and inhibits microtubule formation; therefore arresting the cell at metaphase by 
disrupting the formation of the mitotic spindle; it is specific for the M and S phases. Vincristine 
may also interfere with nucleic acid and protein synthesis by blocking glutamic acid utilization
TOXICITIES
Neuromuscular effects, jaw pain, constipation, loss of deep tendon reflexes, foot and 
wrist drop, paresthesia, alopecia, convulsion (rare).  Alopecia.  Hyponatremia (SIADH).  
Severe soft tissue damage if extravasated. 
STATUS
Commercially available.
5.0 Patient Eligibility
5.1  Inclusion Criteria
1. Patients must have precursor-B or T-lymphoblastic leukemia or lymphoblastic 
lymphoma.
2. Patients must be untreated or have had only one prior chemotherapy regimen for ALL 
or LL . Previously treated patients will be analyzed separately.
3. Age between 12 to 40 years old


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4. Patients with CNS disease or testicular disease are eligible.
5. Intrathecal therapy with cytarabine is allowed prior to registration for patient 
convenience. This is usually done at the time of the diagnostic bone marrow or venous 
line placement to avoid a second lumbar puncture. Systemic chemotherapy must begin 
within 72 hours of the first intrathecal treatment.
6. Signed informed consent prior to the start of systemic therapy. In the event of 
enrollment of a minor patient, an attempt to obtain assent from the patient must be 
documented, and parental consent must be signed.
7. Echocardiogram should be done within 72 hours of starting therapy if there are 
cardiac risk factors (e.g., history of hypertension or of myocardial infarction)
8. Creatinine should be < 3 mg/dL bilirubin < 3 mg/dl unless felt to be due to disease 
9. Zubrod Performance status of <3
10. Patients who received steroids more than 72 hours prior to study enrollment are 
eligible but will be analyzed separately.
5.2  Exclusion Criteria
1. Age less than twelve years of age or greater than 40 years. 
2. More than one prior treatment regimen for ALL or LL.
3. The patient is pregnant or unwilling to practice appropriate birth control.
4. Presence of the Philadelphia chromosome t(9;22)
6.0 Evaluation During Study
6.1  Pre-treatment
History and physical examination  with bone marrow aspirate and biopsy (optional). 
Further testing is as per standard new leukemia patient evaluation. 
Echocardiogram should be done within 7 days hours of starting therapy if there are 
cardiac risk factors (e.g., history of hypertension or of myocardial infarction)
For patients with lymphoblastic lymphoma:
Lymphoma patients will have standard imaging as per new lymphoblastic lymphoma 
patients. 
6.2  During Treatment


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6.2.1 Induction: Bone marrow evaluation at day 15 +/- 2days and bone marrow 
aspiration at day 29+/- 2 days for morphology and minimal residual disease testing.
Extended Induction:  A bone marrow aspiration is required after 2 weeks of extended 
induction. 
6.2.2 Consolidation 1
A bone marrow aspiration is performed at the end of consolidation 1 for morphology and 
minimal residual disease testing. 
6.3 During Maintenance
Once the patient has entered maintenance, they should be monitored for event free 
survival. 
7.0 Treatment Plan
All patients must begin therapy with an intrathecal treatment using cytarabine 100 mg. 
Induction chemotherapy must begin within 3 days of the intrathecal cytarabine dose.  
Patients with less than or equal to 5% blasts in the bone marrow by day 15  will be 
considered rapid early responders (RER) and will receive augmented BFM therapy with  
single delayed intensification and will continue treatment with consolidation 1, 2 and 3 
parts A and B  followed by maintenance therapy . 
Patients with more than 5% blasts in the bone marrow after two weeks of induction 
therapy will be considered slow early responders (SER) and will receive augmented 
BFM with double delayed intensification. Patients with > 5% blasts and <25% blasts in 
the bone marrow after  induction will receive 2 weeks of extended Induction therapy. If 
the patient has a bone marrow showing remission by week 6, patient will continue 
treatment with  two courses of consolidation 2 and two courses of consolidation 3  parts 
A and B before proceeding to maintenance therapy. Patients who do not have a bone 
marrow remission after 6 weeks of therapy will be taken off protocol.
Parameters to begin next phase of therapy include absolute neutrophil count of >750 L 
K/UL and platelets >75 K/UL. 
In Consolidation 1, pause therapy at day 29 (week 5) until the absolute neutrophil 
count is >750 and platelets are >75 K/microliter. 
For all  vincristine dose, If  body surface area (BSA) is less than 1.3 m2 then the dose  
will be calculated using BSA with a maximum dose of 2 mg.
Treatment assignment
CNS therapy:   If the CSF is positive for  blasts at the start of therapy, then the following 
intrathecal schedule is to be followed: Methotrexate 12 mg IT weekly until negative for 


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blasts, then Methotrexate 12 mg IT every other week for 8 doses, then Methotrexate 12 
mg IT monthly for 6 doses. If CSF is negative for blasts at the start of therapy, then 
follow IT methotrexate schedule indicated for each cycle.
CNS 3: Augmented BFM therapy with double delayed intensification and additional 
radiation therapy will be as per  attending physician's discretion following discussion 
with the study principal investigator
Testicular involvement: Augmented BFM with double delayed intensification and 
additional radiation therapy will be as per  attending physician's discretion following 
discussion with the study principal investigator
LL: Augmented BFM with a single delayed intensification; treatment length of 24 months
LL with CNS involvement:   Augmented BFM with a single delayed intensification and  
cranial radiation during consolidation as per  attending physician's discretion following 
discussion with the study principal investigator
7.1 Induction ( 4 weeks)
Daunorubicin 25 mg/m2 IV weekly x 4 doses.
Vincristine 2 mg IV weekly x 4 doses.
Prednisone 60 mg/m2/day, maximum dose of 120 mg/day in divided doses (BID or TID) 
PO on days 1-28.
PEG-asparaginase 2000 international units (IU)/m2 (maximum dose 3750 IU) IV in 
week 1.
Intrathecal Methotrexate 12 mg on week 2 and week 5. 
7.1.2 Extended Induction ( 2 weeks)
Daunorubicin 25mg/m2 IV in week 5
Vincristine 2 mg IV on weeks 5 and 6
Prednisone 60 mg/m2/day, maximum dose of 120 mg/day in divided PO daily in weeks 
5 and 6
PEG-asparaginase 2000 IU/m2 (maximum dose 3750 IU) IV in week 5.
7.2 Consolidation 1 ( 8 weeks)
Cyclophosphamide 1 g/m2  IV in weeks1 and  5.
Cytarabine 75 mg/m2 SC or IV on days 1-4 and days 8-11 of both months.     
Mercaptopurine 60 mg/m2/d PO on days 1-14 of each month.
Vincristine 2 mg IV in week 3 and 4 of each month.
PEG-asparaginase 2000 IU/m2 (maximum dose 3750 IU) IVIV in weeks 3 and 6.
Intrathecal Methotrexate 12 mg weekly for the first month only.
7.3 Consolidation 2 (7 weeks)


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Vincristine 2 mg IV every 10 days +/- 2 days for 5 doses. 
Methotrexate IV over 15 minutes, starting at 100mg/m2 and escalating by 50 
mg/m2/dose every 10 +/- 2 days for 5 doses to toxicity (e.g myelosuppression or 
mucositis grade 3). 
PEG-asparaginase 2000 IU/m2 (maximum dose 3750 IU) IV in week 1 and week 4.
Intrathecal Methotrexate 12 mg week 1 and week 5.
7.4 Consolidation 3- Part A ( 4 weeks )
Vincristine 2 mg IV in weeks 1, 2 and 3
Dexamethasone 10 mg/m2/d  PO  in divided   doses on days 1-7 and days 15-21
Doxorubicin 25 mg/m2 IV in weeks 1, 2 and 3.
PEG-asparaginase 2000 IU/m2 (maximum dose 3750 IU) IV in week 1 
Intrathecal Methotrexate 12 mg in week 1.
7.5 Consolidation 3- Part B (4 weeks)
Cyclophosphamide 1 g/m2 IV in week 1.
Cytarabine 75 mg/m2 SQ or IV for four consecutive days in weeks 1 and 2  
Thioguanine 60 mg/m2 days PO daily  for two weeks 
Intrathecal Methotrexate 12 mg in weeks 1 and 2
Vincristine  2mg IV on  weeks 3 and 4
PEG-Asparaginase 2000 IU/m2 (maximum dose 3750 IU) on week 3
NOTE: Slow early responders repeat consolidation 2 and consolidation 3, A and B, prior 
to maintenance chemotherapy.
7.6 Maintenance for patients with ALL (24 months)
Vincristine 2 mg IV every month.
Dexamethasone 6 mg/m2/d in divided doses PO for 5 days every month
Mercaptopurine 75 mg/m2/d PO daily.
Methotrexate 20 mg/m2  PO every week.
Intrathecal methotrexate 12 mg every 3 months for the first 12 months of maintenance.
7.7 Maintenance for patients with LL (maintenance stops two years from the start 
of chemotherapy)
Vincristine 2 mg IV every month.
Dexamethasone 6 mg/m2/d in divided doses PO for five days every month.
Mercaptopurine 75 mg/m2/d PO daily.
Methotrexate 20 mg/m2  PO every week.


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8.0 Supportive Care
 Patients should start Bactrim prophylaxis for Pneumocystis by week 2 of 
induction. During induction and delayed intensification, additional prophylactic 
anti-bacterial, anti-viral and anti-fungal therapies are at the discretion of the attending 
physician. 
Prophylactic antibiotics may be given with each course until neutrophil recovery 
500/microliter or greater and  will vary according to the patient's tolerance and allergies. 
Suggested medications for supportive care include: 
Levaquin 500 mg daily (or other quinolone) or trimethoprim/sulfamethoxazole double 
strength b.i.d. on Monday-Wednesday and Friday. 
Fluconazole 200 mg daily or itraconazole 200 mg b.i.d. or other appropriate antifungal 
agent
Valacyclovir 500 mg daily or acyclovir 200  mg b.i.d. or other appropriate antiviral agent
For metabolic support, induction therapy should include intravenous alkalinization and 
hyperhydration along with oral allopurinol. Uricozyme may be substituted for allopurinol 
at the investigators discretion
9.0 Dose Modifications for Toxicities
Intrathecal Cytarabine (Day 0 of Induction)
Do not hold dose.
1. Steroid
Steroids should not be held for hypertension unless the hypertension is severe. In cases 
of severe hypertension, reduce the dose by 33%. Steroids should not be altered for 
diabetes or pancreatitis. For psychosis, administer half the dose. If myopathy develops, 
measure the serum CPK and consider EMG studies. Omit further steroids if avascular 
necrosis develops. Steroids should be held during active varicella zoster infection 
except during induction. 
2. Vincristine 
Hold one dose for seizures. Hold doses for severe foot drop, paresis, abdominal pains, 
obstipation or ileus. Resume at one-half the dose when symptoms improve and 
escalate to full dose as tolerated. If the total bilirubin is greater than 2 mg/dL, then 
fractionate the bilirubin. If the direct bilirubin is greater than 1 mg/dL, then hold 
vincristine. Also hold vincristine if the AST/ALT is greater than 1000 U/l on two 
evaluations at least one week apart or if the PT is prolonged above normal.
3. PEG-Asparaginase
Discontinue for systemic allergic reaction to PEG-asparaginase. Discontinue in the 
presence of pancreatitis documented by an elevated serum amylase or lipase or 


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ultrasound abnormalities. Do not re-start if there is a prior history of asparagninase 
induced pancreatitis. Do not modify the dose for hyperglycemia. Hold if there is 
ketonemia not controlled by insulin. Hold for significant thrombosis until the thrombus 
resolves. Coagulopathy without bleeding is not an indication to withhold asparaginase. 
Replace fibrinogen with cryoprecipitate and replace AT III with fresh frozen plasma. For 
transaminases >200, obtain a total bilirubin. Hold asparaginase if the total bilirubin is 
>1.9 mg/dL. Administer half the dose if the total bilirubin is 1.5-1.9 mg/dL. Erwinia 
chrysanthemi L-aparaginase ( Erwinase) may be used as a substitute  in case of 
systemic allergic reaction to  Peg-Asparaginase. Follow manufacturer's 
recommendation on dosage and timing of administration. Consult Principal Investigator  
prior to ordering the drug.
4. Daunomycin
Do not administer if there is congestive heart failure. Hold if the total bilirubin is > 7 
mg/dL; if 5-7, give 6.25 mg/m2; if 3-5, give 12.5 mg/m2; if < 3 mg/dL, give the whole 
dose. The third or fourth dose may be delayed or omitted for severe infection or 
mucositis. Upon recovery, full doses are given.
5. Intrathecal Methotrexate
Do not reduce the dose for systemic toxicity. Leucovorin may be used as a single 10 
mg/m2 dose to reduce the risk of already existent myelosuppression (ANC < 500/ 
microliter) and mucositis. Do not use leucovorin for myelosuppression alone. For 
seizures, paresis or organic brain syndrome attributed to methotrexate, omit 
methotrexate intrathecally and substitute cytarabine. 
6. Oral Methotrexate
a. Neutropenia and thrombocytopenia: ANC < 1000 and > 750
Do not modify the dose, but recheck the CBC in one week. If the CBC shows an ANC 
<1000 and > 750, continue at full dose. Hold doses if the ANC <500/microliter and 
re-start at 50% dose when the ANC > 1000/microliter.
b. ANC < 750 and > 500 
Reduce the dose by 50%. Re-check the CBC weekly and increase in 25% increments to 
full dose when the ANC recovers to greater than 1000. 
Platelets < 100k and >75k, modify as for ANC <1000/microliter and >750/microliter.
Platelets <75k and >50k, modify as for ANC <750/microliter and >500/microliter.
Platelets <50k, modify as for ANC < 500/microliter.
c. Severe diarrhea or persistent vomiting.
Discontinue methotrexate. Re-start at 50% of the original dose and escalate as clinically 
appropriate. Reduce the dose to 50% if grade 3 mucositis develops. Hold the 
methotrexate if grade 4 mucositis develops and restart at 50% of the prior dose with 
gradual dose escalation. 
d. Liver dysfunction
Obtain a total bilirubin if the transaminase (GPT or GOT) is greater than 200 U/L.  


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Monitor the GPT or GOT along with the bilirubin every 2 weeks during consolidation and 
every 4 weeks during maintenance. Continue full dose therapy unless the bilirubin is 
greater than 2 mg/dL or the GPT or GOT is over 1000 U/L on two determination at least 
2 weeks apart. If either of these occur, hold the methotrexate and monitor labs weekly. 
Re-start at full dose when the transaminase is less than 200 U/L if the bilirubin is 
normal. 
e. Nephrotoxicity
For grade 2-4 nephrotoxicity, omit the methotrexate until the problem has resolved 
(grade 0).
7.  IV Methotrexate
a. Liver Dysfunction 
Omit until grade 0-2 toxicity, then re-start at half dose. Escalate by 25% at two week 
intervals if grade 3-4 toxicity does not recur. 
b. Kidney Dysfunction
Hold IV methotrexate until toxicity has resolved (grade 0). Resume at 100% dose.
c. Mucositis
Decrease the dose by 30% for grade 2 mucositis that persists for 3 days. Hold the drug 
for grade 3-4 stomatitis and resume at 50% with subsequent escalations by 25% to full 
dose.
d. Neutropenia
During the escalation of IV methotrexate, only methotrexate should be held for 
ANC<750/microliter or platelets <75K. Upon recovery of the ANC>750 and platelets 
>75K, the next methotrexate dose should be reduced by 20%. If there is no recovery of 
the ANC or platelet count despite holding two doses of IV methotrexate, Please contact 
study PI and schedule a  bone marrow aspiration.
8. Mercaptopurine
Do not modify in consolidation for low counts. 
a. Neutropenia and thrombocytopenia
Do not change the dose for ANC >750 or platetets > 75,000. For an ANC >500 but 
<750, reduce by 50% until ANC > 1000 and the platelets >75,000. Escalate the dose by 
25% to full dose as peripheral blood counts allow.
b. For an ANC <500 or platelets <50,000, 
Discontinue the drug and resume when the ANC >1000 and the platelets >75,000. 
Escalate the mercaptopurine by 25% in weekly intervals as the peripheral blood counts 
allow. 
c. Liver Dysfunction
Same as for oral methotrexate.


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d. Mucositis Same as for oral methotrexate. 
9. Doxorubicin
The drug is contraindicated in congestive heart failure. 
a. Hyperbilirubinemia
Same as for Daunorubicin. 
b. Neutropenia
The 3rd dose of doxorubicin in consolidation 3A may be omitted for fever and presumed 
severe infection or for severe mucositis preventing oral intake (grade 3-4). The 
subsequent dose should be given at full dose. If the delay exceeds one week, notify the 
PI and do not give the 3rd dose. Therapy with cyclophosphamide will begin on day 28 
provided blood count criteria are met. 
10. Cyclophosphamide
a. Gross hematuria or prior microscopic hematuria
Hydrate for 24 hours after the dose and use MESNA 360 mg/m2 pre, hour 4, 7 and 11.
b. SIADH
Manage with saline and lasix. 
d. Therapy with cyclophosphamide will begin on day 28 provided blood count criteria 
ANC >750 and platelets > 75,000/microliter are met. 
11. Cytarabine
a. Cytarabine syndrome
Do not hold the dose for fever if the fever is likely due to cytarabine. For rash or 
conjunctivitis grade 3-4, hold the drug until the toxicity resolves. 
b. Liver Dysfunction 
Same as for oral methotrexate. Re-start when the transaminase is less than 200 U/L 
and the bilirubin is normal .
12. Thioguanine
Do not modify the dose for low blood counts. 
a. Liver Dysfunction
Monitor GPT or GOT and total bilirubin before each 4 day course of cytarabine while the 
patient is receiving thioguanine. Modify as per oral methotrexate guidelines. 
13. Escalation of Mercaptopurine (MP) and Methotrexate (MTX) during 
Maintenance Therapy
The oral doses of MP and MTX should be adjusted to maintain the ANC between 


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750/microliter and 1500/microliter and the platelet count >75,000/microliter. 
a.  If the ANC is > 1500/microliter on Day 0 of any maintenance course, and the ANC 
was > 1500/microliter on days ), 28 and 56 of the preceding maintenance course, then 
the MP dose should be increased by 25%. Subsequently, if the monthly ANC is:1) >750 
and <1500, then make no change
b. If the  ANC  is <750 and >500 or platelets <75,000, then reduce the MP dose to 50% 
of the original dose and increase the MP dose by 25% to full dose when the ANC>750, 
3) 
c. If the ANC is >1500 and platelets >75,000, then increase the methotrexate dose by 
25%. Continue to increase the MP dose at day 0 of each maintenance course as above 
it the ANC persists >1500/microliter. There is no maximum dose for the MP or oral MTX.
10.0 Reporting Requirements
10.1 Adverse Events
Expected events related to the study are described in section 3, in appendix  A 
guidelines for reporting adverse events (ADR’s) to the Institutional Review Board (IRB) 
and  in appendix E leukemia guidelines for Adverse events reporting.These events will 
be scored  using the  NCI toxicity scoring system in appendix B
10.2 Reporting Requirements
Serious and unexpected adverse events occuring during the treatment phase up to 30 
days post treatment will be reported accordingly to MD Anderson guidelines 
11.0 Criteria for Response
11.1 Complete Remission- ALL and LL
For ALL, an absolute neutrophil count greater than 1000/mm3 and platelet count 
>100k/mm3 and bone marrow with 5% or less blasts. Resolution of extramedullary 
disease is required for complete remission. 
For LL, complete response is complete disappearance of all lesions by physical exam, 
by imaging studies and in the bone marrow or CNS (if involved at the onset of therapy). 
Or, in the event of persistent masses, the largest tumors must show >55% decrease in 
the products of the two greatest perpendicular diameters of up to 6 of the largest 
masses. In addition, the PET scan must be negative to designate a CR. 
11.2 Partial Remission
For ALL, as above with 6-25% marrow blasts.
For  LL, greater than a 30% decrease in the products of the greatest perpendicular 
masses of up to six of the largest tumors but not satisfying the criteria for CR. Any 
morphologic evidence of CNS or marrow disease must resolve.
11.3 CNS Leukemia


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CNS leukemia will be defined as >/= 5 WBC/microliter and a cytocentrifuge specimen 
showing leukemic blasts. CNS leukemia may also be diagnosed if the CSF WBC is 
normal but clinical signs of CNS involvement are present. 
11.3.1 If there are leukemia cells in the peripheral blood and the lumbar puncture is 
traumatic with >/= 5 WBC/microliter, then the following algorithm is used:  if CSF WBC/ 
CSF RBC >Blood WBC/Blood RBC, then the patient has CNS leukemia. 
11.4 Testicular Leukemia
Unilateral or bilateral testiculomegaly. Biopsy is required if the physical exam is 
equivocal.
 
11.5  Bone Marrow Status
 M1: Less than 5% blasts on bone marrow differential.
 M2: 5-25% blasts on bone marrow differential.
 M3: >25% blasts on bone marrow differential.
11.6 Rapid Early Responder (RER)
Day 14 bone marrow with </= 5% blasts
11.6 Slow Early Responder (SER)
Day 14 bone marrow with > 5% blasts
11.7 Unfavorable Characteristics
a  Philadelphia chromosome present. These patients are not eligible for this protocol.
b  t(4;11) present 
c. Hypodiploidy (</= 44 chromosomes)
Patients with hypodiploidy should be strongly considered for transplant. 
Patients with the t(4;11) should be strongly considered for transplant. 
12.0 Criteria for Removal from the Study
1. Progressive disease
2. M3 marrow at day 28 of induction.
3. Development of CNS leukemia while receiving therapy.
4. Bone marrow, extramedullary or testicular relapse while receiving therapy
5. Unfavorable characteristics are diagnosed.
6.Unacceptable toxicity; grade 4, life threatening toxicities that preclude administration 
of essential chemotherapy.
7. Patient or guardian requests removal from study. 
8. Development of a second malignancy.
9. Physician determines that it is in the patient's best interest to be removed from 
therapy.
10. For patients requiring extended induction, those who do not have </= 5% blasts in 
the bone marrow at the end of 6 weeks of therapy.


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11. Failure to acheive a CR in LL patients by the end of consolidation 1 therapy. 
(histological confirmation of disease, if feasible, is strongly recommended).
12. Upon completion of the study treatment, patients are not required to return for 
follow-up care. Patients should be encouraged to return for a yearly evaluation.
13. Patients will be followed for survival after the completion of therapy even if clinical 
documentation is difficult to obtain from outside offices.
13.0 Number of Patients
Statistical Considerations:
This is a single-arm, open-label, phase II trial. The primary objective of this 
trial is to assess the efficacy and toxicity of the augmented 
Berlin-Frankfurt-Munich (BFM) chemotherapy regimen in untreated acute 
lymphoblastic leukemia (ALL) patients of age 12 through 30. The primary end 
point is 3-year event-free survival (EFS) rate. Current practice in the study 
population yields a 3-year EFS rate of 40-50% with response (defined as CR 
after four weeks of treatment) rate of 90%. The toxicity rate of standard induction 
is 33% when one looks at grade 3-4 infection. The study regimen will be 
considered successful if it exhibits a 3-year EFS rate greater than 60% and 
response rate no less than 90% with Grade III-IV infectious toxicity rate in 
induction no more than 33%. A maximum of 125 patients will be enrolled with 
accrual rate of 2-3/month, thus we estimate this study will be completed in six 
years. 
Sample Size and End Point Monitoring:
The 3-year EFS rate of the study regimen will be compared with historical 
EFS rate of 45%, which is observed in standard treatment for the study 
population. In order to control a two-sided type I error rate of 5%, 125 patients 
are needed to provide power of 99% and 92% if the true EFS rate of the 
augmented BFM regimen is 65% and 60%, respectively. Sample size calculation 
was conducted using exact test for single proportion with nQuery software. 
It is impractical to carry out interim analysis based on the 3-year EFS rate. 
The futility monitoring rule will be based on the CR rate at 4 weeks. Using the 
Bayesian approach of Thall, Simon, Estey (1995, 1996) and the extension by 
Thall and Sung (1998), response and toxicity monitoring will be performed from 
the 10th patient and continue in cohort of 10. The response rate of standard 
regimen is 90% with toxicity rate of 33%. Therefore, the historical probability 
vector of (Response With Toxicity, Response Without Toxicity, No Response 
With Toxicity, No Response No Toxicity) is assumed to follow a Dirichlet 
distribution with parameters (29.7, 60.3, 3.3, 6.7), and the corresponding vector 
for the experimental regimen is assumed to follow a flat Dirichlet distribution with 
parameters (1.188, 2.412, 0.132, 0.268), which has the same response 
probabilities (i.e., response rate of 90%) and toxicity rate (i.e., toxicity rate of 


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33%). This regimen of augmented BFM will be considered worthy of further 
investigation if it elicits no less than 90% response rate and no greater than 33% 
toxicity rate. Thus, monitoring rule, assuming the prior distributions above, was 
constructed that meet the following condition,
Pr(S,Resp < E, Resp | data) < 0.05 for efficacy, and
Pr(S,Tox < E, Tox | data) > 0.85 for toxicity.
E,Resp and S,Resp are the response rates for study regimen and standard care, 
respectively. E,Tox and S,Tox are the toxicity rates for study regimen and 
standard care, respectively. These conditions will stop the study early if the data 
suggest that it is unlikely the response rate with this new treatment is at least as 
good as the standard care or the toxicity rate of new treatment is higher than the 
standard care. 
The stopping boundary for efficacy is listed in Table 1, for example, accrual will 
cease if 14 or fewer responses seen in the first 20 patients.
Table1. Stop accrual if the number of patients with response is less than or equal 
to that indicated (i.e., # response) in the number of patients accrued (i.e., # 
Patients)
#Response 6
14
23
31
39
48
56
#Patients
10
20
30
40
50
60
70
#Response 65
73
81
90
98
#Patients
80
90
100
110
120
The stopping boundary for toxicity is listed in Table 2, for example, accrual 
will cease if 10 or more toxicity observed in the first 20 patients.
Table 2.  Stop accrual if the number patients with toxicity is greater than or 
equal to that indicated (i.e., # Toxicity) in the number of patients accrued (i.e., 
# Patients).
#Toxicity 6
10
14
18
22
25
29
#Patients
10
20
30
40
50
60
70
#Toxicity 33
37
41
45
49
#Patients
80
90
100
110
120
Simulation (10,000 replicates) was used to evaluate the performance of 
the stopping rule on the conduct of the study (Table 3). The probability of 
stopping the study early when true response rate of the study regimen was 80% 
was at least 82%. 
Table 3.  Operating characteristics, based on 10,000 simulations per scenario, of 


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monitoring of response rates for patients treated with augmented BFM regimen.
True Rates of 
Response/Toxicity 
Probability of Early 
Stopping
Achieved Sample 
Size
Quartiles
25th
50th
75t
h
90%/20%
6%
125
125
125
90%/30%
17%
125
125
125
90%/40%
70%
20
50
125
90%/50%
99%
10
20
30
80%/20%
82%
30
40
90
80%/30%
84%
20
40
80
80%/40%
94%
10
30
50
80%/50%
99.8%
10
20
30
70%/20%
99.9%
10
20
30
Analysis Plan
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 the response rate. The 
distribution of time-to-event endpoints (e.g., EFS, 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.
14.0 Protocol Compliance
This study will be conducted as described in this protocol, except for an emergency 
situation in which the protection, safety, and well being of the patient requires immediate 
intervention, based on the judgement of the investigator or his/her designee. In the 
event of a significant deviation from the protocol, the investigator will notify the MDACC 
surveillance committee following the institutional guidelines
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