Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

PRIMARY OBJECTIVES:

I. To estimate the toxicity, second complete response (CR2) rate at the end of Block 1
therapy, and 4-month event-free survival (EFS) for pediatric and young adult patients with
relapsed acute lymphoblastic leukemia (ALL) treated with bortezomib in combination with
intensive re-Induction chemotherapy.

II. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination
regimen.

SECONDARY OBJECTIVES:

I. To assess minimal residual disease (MRD) in bone marrow following completion of each
therapy block.

II. To assess the feasibility of measuring leukemia initiating cells (LIC) in patient
samples before and after chemotherapy.

III. To discover biologic pathways associated with response and drug resistance using gene
and protein expression profiles at baseline and following initial exposure to chemotherapy.

IV. To determine if bortezomib inhibits lymphoblast NF-kappa-B activity in leukemia
patients.

OUTLINE:

REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine
sulfate IV on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1;
oral prednisone twice daily on days 1-29; bortezomib IV on days 1, 4, 8, and 11; and
pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22. Patients with central nervous
system (CNS)-negative disease (CNS1 or CNS2) also receive methotrexate IT on days 15 and 29;
patients with CNS-positive disease (CNS3) receive triple intrathecal therapy (TIT)
comprising methotrexate, hydrocortisone, and cytarabine IT on days 8, 15, 22, and 29. After
completion of reinduction block 1, patients with ALL and M2 or M3 bone marrow proceed
directly to reinduction block 2. Patients with ALL and M1 bone marrow or lymphoblastic
lymphoma proceed to reinduction block 2 after blood counts recover. Patients with persistent
cerebral spinal fluid (CSF) blasts after 6 doses of TIT or patients with progressive
lymphoblastic lymphoma are removed from the study.

REINDUCTION BLOCK 2: Patients receive etoposide phosphate IV over 1-2 hours on days 1-5;
cyclophosphamide IV over 1 hour on days 1-5; bortezomib IV on days 1, 4, and 8; filgrastim
(G-CSF) subcutaneously (SC) or IV daily beginning on day 6 and continuing until blood counts
recover*; high-dose methotrexate IV on day 22; and leucovorin calcium orally or IV every 6
hours on days 23 and 24. Patients with CNS-negative disease also receive methotrexate IT on
days 1 and 22; patients with CNS-positive disease receive TIT on days 1 and 22. After
completion of reinduction block 2, patients proceed to reinduction block 3 immediately or
when blood counts recover. Patients with disease progression are removed from the study.

NOTE: *Patients do not receive G-CSF on day 8.

REINDUCTION BLOCK 3: Patients receive cytarabine IV over 3 hours twice daily on days 1, 2,
8, and 9; L-asparaginase IM on days 2 and 9; and G-CSF SC or IV daily beginning on day 10
and continuing until blood counts recover.

After completion of study treatment, patients are followed every 6 months for 3 years and
then annually for 2 years.

Inclusion Criteria:

- Diagnosis of 1 of the following:

- Pre-B acute lymphoblastic leukemia (ALL) in first early (< 36 months from
diagnosis) isolated bone marrow or combined bone marrow/extramedullary relapse
as documented by histology and immunophenotyping

- T-cell ALL in first isolated bone marrow or combined relapse as documented by
histology and immunophenotyping

- T-cell lymphoblastic lymphoma in first relapse as documented by histology

- Measurable disease as documented by clinical, radiographic, or histologic
criteria

- Relapsed or refractory to conventional therapy

- No Philadelphia chromosome-positive (Ph+) ALL unless refractory to ≥ 1 tyrosine
kinase inhibitor therapy

- Patients who are unable to tolerate tyrosine kinase inhibitor therapy due to
toxicity are eligible

- No mature B-cell ALL (i.e., sIg positive and kappa or lambda restricted positivity)
with French-American-British Cooperative Group (FAB) L3 morphology and/or myc
translocation

- No known optic nerve and/or retinal involvement

- Patients presenting with visual disturbances should have an ophthalmological
exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic
nerve or retinal involvement

- No extramedullary disease (i.e., isolated CNS disease or isolated testicular disease)

- No concurrent genetic syndrome (e.g., Down syndrome, Fanconi anemia, Kostmann
syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome)

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients ≤ 16 years of age

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
maximum serum creatinine based on age/gender as follows:

- 0.4 mg/dL (for patients 1 to 5 months of age)

- 0.5 mg/dL (for patients 6 to 11 months of age)

- 0.6 mg/dL (for patients 1 year of age)

- 0.8 mg/dL (for patients 2 to 5 years of age)

- 1 mg/dL (for patients 6 to 9 years of age)

- 1.2 mg/dL (for patients 10 to 12 years of age)

- 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)

- 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age)

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

- Serum glutamate pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) < 3
times ULN for age (unless elevation due to leukemia infiltration)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by gated
radionuclide study

- Pulse oximetry ≥ 94% at sea level (> 90% if at high altitude)

- No evidence of dyspnea at rest or exercise intolerance

- No evidence of acute pulmonary infiltrates on chest radiograph

- No known allergy to doxorubicin, cytarabine, etoposide, etoposide phosphate, boron,
mannitol, or bortezomib

- No CNS toxicity > grade 2

- Seizure disorder allowed provided patient is on anticonvulsants (e.g.,
benzodiazepines or gabapentin) and it is well controlled

- Able to receive asparaginase (i.e., no prior severe pancreatitis, stroke, or other
toxicity)

- Patients who initially receive asparaginase but discontinue drug due to toxicity
are eligible

- Patients with prior allergies to pegaspargase that are clinically significant
are eligible provided Erwinia L-asparaginase can be substituted

- Patients who relapse on therapy other than standard ALL maintenance therapy must have
fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study

- At least 14 days since the completion of cytotoxic therapy with the exception of
hydroxyurea, which is permitted up to 24 hours prior to the start of protocol
therapy

- At least 7 days since the completion of therapy with a biologic agent or donor
lymphocyte infusions (DLI); for agents that have known adverse events occurring
beyond 7 days after administration, this period must be extended beyond the time
during which adverse events are known to occur

- Stem cell transplant or rescue: no evidence of active graft-vs-host disease
(GVHD) and ≥ 4 months must have elapsed; must not be receiving GVHD prophylaxis

- No prior cumulative anthracycline exposure > 400 mg/m²

- No prior bortezomib or other proteasome inhibitors

- No prior reinduction attempts or treatment for prior extramedullary relapse

- Patients with primary induction failure are not eligible

- No concurrent anticonvulsants known to activate the cytochrome p450 system (e.g.,
phenytoin, carbamazepine, and phenobarbital)

- Concurrent benzodiazepines or gabapentin allowed

- No concurrent corticosteroids (including steroids as antiemetics) except as treatment
or prophylaxis for anaphylactic reactions OR treatment for pulmonary toxicity

- No other concurrent anticancer chemotherapy or immunomodulating agents

- Patients who relapse while receiving standard ALL maintenance chemotherapy will not
be required to have a waiting period before entry onto this study