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

This pilot, phase II trial studies the side effects of giving bortezomib together with combination chemotherapy and to see how well it works in treating young patients with relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

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 nuclear factor (NF)-kappa (k)-B activity in leukemia patients.

OUTLINE:

REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; prednisone orally (PO) twice daily (BID) on days 1-28; bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) or IV over 1-2 hours 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 15-30 minutes on days 1-5; bortezomib IV over 3-5 seconds 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 over 24 hours on day 22; and leucovorin calcium PO 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 BID 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.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis

  * Pre-B ALL in first early (\< 36 months from diagnosis) isolated bone marrow (BM) or combined BM/extramedullary relapse; or
  * T-cell ALL in first isolated BM or combined relapse; or
  * T-LL in first relapse
* Patients with leukemia must have had histologic verification of the malignancy at relapse, including immunophenotyping to confirm diagnosis
* Patients with lymphoblastic lymphoma must have measurable disease documented by clinical, radiographic, or histologic criteria; patients must have relapsed or become refractory to conventional therapy
* 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
* Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study
* 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
* No evidence of active graft-vs-host disease (GVHD) and \>= 4 months must have elapsed; must not be receiving GVHD prophylaxis
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:

  * 1 month to \< 6 months (0.4 male, 0.4 female)
  * 6 months to \< 1 year (0.5 male, 0.5 female)
  * 1 to \< 2 years (0.6 male, 0.6 female)
  * 2 to \< 6 years (0.8 male, 0.8 female)
  * 6 to \< 10 years (1 male, 1 female)
  * 10 to \< 13 years (1.2 male, 1.2 female)
  * 13 to \< 16 years (1.5 male, 1.4 female)
  * \>= 16 years (1.7 male, 1.4 female)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 3 x ULN for age, unless elevation due to leukemia infiltration
* Shortening fraction of \>= 27% by echocardiogram, or
* Ejection fraction of \>= 50% by gated radionuclide study
* No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \>= 94% at sea level (\> 90% if at high altitude)
* No evidence of acute pulmonary infiltrates on chest radiograph
* Patients with seizure disorder may be enrolled if on allowed anticonvulsants and well controlled; benzodiazepines and gabapentin are acceptable
* Central nervous system (CNS) toxicity =\< grade 2
* Peripheral nervous system (PNS) toxicity \< grade 3
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, FDA, and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

* Patients with Philadelphia chromosome positive ALL are not eligible unless refractory to at least one tyrosine kinase inhibitor (TKI) therapy; patients that are unable to tolerate TKI therapy due to toxicity are eligible
* Patients with mature B-cell ALL, ie, leukemia with B-cell (soluble immunoglobulin \[sIg\] positive and kappa or lambda restricted positivity) ALL, with French-American-British (FAB) L3 morphology and/or a myc translocation, are not eligible
* Extramedullary disease status: patients with isolated CNS disease or isolated testicular disease are not eligible
* Patients with known optic nerve and/or retinal involvement are not eligible; patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, an magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
* Patients with concomitant genetic syndrome: patients with Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome are not eligible
* Cumulative prior anthracycline exposure must not exceed 400 mg/m\^2
* Patients taking anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible; benzodiazepines and gabapentin are acceptable
* Patients who have previously received bortezomib or other proteasome inhibitors are not eligible
* Patients who have a known allergy to doxorubicin, cytarabine, both etoposide and etopophos, boron, mannitol or bortezomib are not eligible
* Patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or other toxicity) are not eligible; patients who initially receive asparaginase, but must discontinue due to toxicity, remain eligible; patients with clinically significant prior allergies to pegaspargase are eligible if Erwinia L-asparaginase can be substituted
* Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective birth control method
* Patients must not have received any prior re-induction attempts and must not have received treatment for prior extramedullary relapse; patients with primary induction failure are not eligible