Intensive Combination Chemotherapy in Treating Patients with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
This partially randomized phase II trial studies how well intensive combination chemotherapy works in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as daunorubicin hydrochloride, cyclophosphamide, vincristine sulfate, prednisone, leucovorin calcium, cytarabine, etoposide, and liposomal cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as rituximab, may induce changes in body’s immune system and may interfere with the ability of cancer cells to grow and spread. Biological therapies, such as mercaptopurine, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Dietary supplements, such as levocarnitine, may reduce the incidence of liver damage. Pegaspargase, methotrexate, dasatinib and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy with, rituximab, mercaptopurine, levocarnitine, pegaspargase, methotrexate, dasatinib and imatinib mesylate may be an effective treatment for acute lymphoblastic leukemia or lymphoblastic lymphoma.
Inclusion Criteria
- Ability to understand and the willingness to sign a written informed consent
- Diagnosis of acute lymphoblastic leukemia or lymphoblastic lymphoma as defined by the World Health Organization
- Untreated disease EXCEPT for corticosteroids, hydroxyurea, leukapheresis, and/or tyrosine kinase inhibitors for up to 2 weeks prior to initiation of study therapy
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Total bilirubin < 2 mg/dL (unless due to acute lymphoblastic leukemia [ALL])
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 times institutional upper limit of normal (unless due to ALL)
- Serum creatinine < 2 mg/dL OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (unless elevated creatinine or creatinine clearance felt by investigator to be acute and reversible)
- Left ventricular ejection fraction >= 50%
- Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
Exclusion Criteria
- Current or anticipated use of other investigational agents during the study
- Known central nervous system mass lesion
- Known additional malignancy except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
- Any prior chemotherapy or radiotherapy for additional malignant or non-malignant condition
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to liposomal cytarabine or other agents used in study inclusive of known allergy to polyethylene glycol
- History of unprovoked venous thrombosis/thromboembolism
- Recurrent or chronic pancreatitis
- Uncontrolled diabetes mellitus
- Uncontrolled intercurrent illness that would limit compliance with study requirements including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant or nursing
- Any condition, in the opinion of the investigator, that significantly compromises compliance with study requirements
- Known human immunodeficiency virus (HIV) positivity
Additional locations may be listed on ClinicalTrials.gov for NCT02043587.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To determine in a randomized fashion if levocarnitine (L-carnitine) administered by intravenous infusion is effective as prophylaxis against pegaspargase (pegylated [PEG]-asparaginase)-induced grade 2-4 hyperbilirubinemia. (Cohort 2)
II. To describe the safety on toxicity of the regimen. (Cohort 1 and 2)
SECONDARY OBJECTIVES:
I. To estimate the 3-year event-free survival (EFS), leukemia-free survival (LFS), and overall survival (OS) in Cohort 2 patients treated with levocarnitine vs placebo.
II. To estimate the 3-year event-free survival (EFS), leukemia-free survival (LFS) and overall survival (OS) in Cohort 1 and Cohort 2.
III. To determine rate and severity of intrathecal liposomal cytarabine and intrathecal methotrexate neurologic toxicities within the context of this regimen, including treatment-related central nervous system (CNS) abnormalities, neuropathies, and rate of arachnoiditis (Cohort 1) and compare to standard intrathecal methotrexate (Cohort 2).
IV. To determine the 3-year CNS relapse rate with the regimen in Cohort 1 and Cohort 2.
V. To evaluate the efficacy of hydrocortisone (hydrocortisone sodium succinate) pre-medication for reducing the incidence of hypersensitivity reactions to PEG-asparaginase in a randomized fashion.
VI. To describe PEG-asparaginase toxicities within the context of this regimen, specifically rates of hypersensitivity reactions, hyperbilirubinemia, non-catheter associated venous thrombosis, insulin usage in non-insulin-dependent diabetics and non-diabetics, lipase elevation and clinical pancreatitis.
VII. To determine the complete remission (CR) rate.
VIII. To determine the overall response rate (CR + CR with incomplete blood count recovery [CRi]).
IX. To determine the non-relapse mortality of this regimen.
X. To evaluate the ability to deliver chemotherapy courses on time as per protocol and correlate with patient factors (age, performance status) and disease factors at study entry as well as 3-year LFS, EFS, and OS.
EXPLORATORY OBJECTIVES:
I. To correlate presence of and level of minimal residual disease after induction and first consolidation with 3-year LFS.
II. To determine the rate of formation of anti-asparaginase antibodies and its correlation with hypersensitivity reactions and efficacy.
III. To measure plasma asparaginase activity during therapy and correlate with anti-asparaginase antibodies and 3-year LFS.
IV. To correlate molecular and cytogenetic aberrations with response and survival.
V. To measure L-carnitine and acyl-L-carnitine levels in the blood of patients treated with L-carnitine or placebo. (Cohort 2)
VI. To evaluate the efficacy of early L-carnitine treatment for PEG-asparaginase-induced hepatoxicity as determined by reduction in the severity and duration of hepatotoxicity (Cohort 2)
OUTLINE:
Course 1A - Induction: Patients are randomized to receive levocarnitine or placebo.
Patients receive daunorubicin hydrochloride intravenously (IV) over 15-30 minutes once daily (QD) on days 1, 2, and 3 (on day 15 if bone marrow is M2 [5-25% lymphoblasts] or M3 [> 25% lymphoblasts]); cyclophosphamide IV over 60 minutes QD on day 1 and 15 (every 12 hours on days 15 and 16 for patients < 40 years of age if day 14 bone marrow M2 (>= 5% but =< 25% lymphoblasts) or M3 (> 25% lymphoblasts); vincristine sulfate IV over 5-10 minutes QD on days 1, 8, 15, and 22; prednisone orally (PO) QD on days 1-28, rituximab IV QD on days 1 and 15 (precursor B-cell acute lymphoblastic leukemia [ALL] only, administer per institutional protocol); levocarnitine or placebo IV over 2-3 minutes daily on days 1-37; pegaspargase IV over 1-2 hours QD on day 16; and dasatinib or imatinib mesylate PO daily (if breakpoint cluster region [BCR]/abelson murine leukemia viral oncogene homolog 1[ABL] positive [+] and/or t[9;22]).
CNS PROPHYLAXIS: Patients receive methotrexate intrathecally (IT) on days 1 and 15 (omit second dose if CNS-3 disease).
CNS treatment - cerebrospinal fluid (CSF) positive for acute lymphoblastic leukemia (ALL): Patients receive methotrexate IT or intraventricularly twice weekly until CSF clear and/or cranial nerve abnormality, then 4 times weekly, and then 12 times monthly.
Prior to course IB, patients are randomized to receive hydrocortisone sodium succinate IV or placebo IV on day 17.
Course 1B: On day 29 after course 1A, patients receive rituximab IV QD on days 1 and 15 (precursor B-cell ALL only, administer per institutional protocol); methotrexate IV over 15 minutes-36 hours on days 2-3 and 16-17; leucovorin calcium IV over 15-30 minutes or PO every 6 hours for 3 doses; mercaptopurine PO QD on days 2-8 and 16-22; and pegaspargase IV over 1-2 hours on day 18.
Course 1C: On day 29 after course 1B, patients receive cytarabine IV over 2 hours QD and etoposide IV over 3 hours QD on days 1-4, and rituximab IV QD on days 1 and 15 (precursor B-cell ALL only, administer per institutional protocol).
Course 2A: On day 29 after course 1C, patients receive daunorubicin hydrochloride IV over 15-30 minutes QD on days 1, 2, and 3; cyclophosphamide IV over 60 minutes QD on days 1 and 15 (for patients < 40 years of age); vincristine sulfate IV over 5-10 minutes QD on days 1, 8, 15 and 22; prednisone PO QD on days 1-28; rituximab IV QD on days 1 and 15 (precursor B-cell only, administer per institutional protocol); and pegaspargase IV over 1-2 hours on day 16.
CNS prophylaxis (omit if CNS-3 disease): Patients receive methotrexate IT on days 1 and 15.
Course 2B: On day 29 after course 2A, patients receive methotrexate IV over 15 minutes-36 hours on days 1-2 and 15-16; leucovorin calcium IV over 15-30 minutes or PO every 6 hours for 3 doses; mercaptopurine PO QD on days 1-7 and 15-21; and pegaspargase IV over 1-2 hours on day 17.
Course 2C: On 29 day after course 2B, patients receive cytarabine IV over 2 hours QD and etoposide IV over 3 hours QD on days 1-4.
Course 3B: Patients receive methotrexate, leucovorin calcium, mercaptopurine, and pegaspargase as in course 2B.
1st month of maintenance: On day 29 after course 3B, patients receive methotrexate PO once weekly (every 7 days); mercaptopurine PO QD continuously; prednisone PO QD on days 1-5; vincristine sulfate IV over 5-10 minutes on day 1; and pegaspargase IV over 1-2 hours on day 16.
CNS prophylaxis (omit if CNS-3 disease): Patients receive methotrexate IT on day 1.
2nd-12 months maintenance: Patients receive methotrexate PO once weekly (every 7 days); mercaptopurine PO QD continuously; prednisone PO QD on days 1-5; and vincristine sulfate IV over 5-10 minutes on day 1. Treatment repeats monthly for 12 months in the absence of disease progression or unacceptable toxicity.
CNS prophylaxis (omit if CNS-3 disease): Patients receive methotrexate IT on day 1 of months 2, 3, and 4.
13th-24th months of maintenance: Patients receive methotrexate PO once weekly (every 7 days); mercaptopurine PO QD continuously; prednisone PO QD on days 1-5 every other month starting month 14; and vincristine sulfate IV over 5-10 minutes on day 1 every other month starting month 14.
In all courses, treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUC San Diego Medical Center - Hillcrest
Principal InvestigatorMatthew Joseph Wieduwilt
- Primary IDUCSD 130934
- Secondary IDsNCI-2014-02017, 130934, UCHMC1401
- ClinicalTrials.gov IDNCT02043587