By combining a variety of agents that potentiate Zidovudine (ZDV), the investigators hope to
induce remission in this generally fatal disease. Most therapies for aggressive B cell
lymphomas are based upon intensive chemotherapeutic regimens, expensive modalities (bone
marrow transplant, Rituximab), or experimental approaches (gene therapy, cytotoxic T cell
infusion) that are difficult to implement in heavily pre-treated patients. Therapy for
relapsed aggressive B cell lymphomas is very poor. Even curable lymphomas such as Burkitt
Lymphoma (BL) and Hodgkin lymphoma are extremely difficult to treat in relapse and/or after
stem cell transplant failure. The investigators propose a novel therapeutic approach that
exploits the presence of Epstein-Barr virus (EBV) in lymphomas; antiviral mediated
suppression of NF-kB and disruption of viral latency.
Inclusion Criteria:
1. Any stage, histologically or cytologically documented intermediate to high grade
relapsed or refractory EBV+ non-Hodgkin's (NHL) or Hodgkin's lymphoma (HL), or any
treated or untreated patients with EBV+ lymphoma involving CNS. Patients with relapsed
or refractory monomorphic (monoclonal) post-transplant lymphoproliferative disease
(PTLD) are also eligible.
2. Patients who are HIV+ or negative. Documentation of HIV infection can be done at any
time prior to study entry. Documentation may be serologic (positive ELISA and positive
Western blot), molecular (positive HIV viral RNA), or other federally approved
licensed HIV test. Prior documentation of HIV seropositivity is acceptable.
3. Tumors must be positive for EBV. This may be done either by Epstein-Barr virus-encoded
small RNA (EBER) stain on the original tumor or the biopsy of relapsed disease (if
performed). Biopsy of relapsed disease is desirable but not mandatory. If stains for
Epstein-Barr virus latent membrane protein 1 (LMP1) done outside are positive, EBER
does not need to be done.
4. All patients, except those who have CNS involvement, must have relapsed or progressed
from at least one previous chemotherapy based regimen.
5. Measurable or non-measurable tumor parameter(s). Non-measurable tumor parameter(s) is
defined as not having bi-dimensional measurements (e.g., gastric or marrow
involvement), but can be followed for response by other diagnostic tests such as
gallium scan, Positron emission tomography (PET) imaging and/or bone marrow biopsy.
6. Age ≥ 18 years.
7. Karnofsky performance status (KPS) ≥ 50%/Eastern Cooperative Oncology Group (ECOG)
Performance Score 0, 1, 2.
8. Patients must have adequate end organ and bone marrow function as defined below:
- 8.1 Absolute neutrophil count ≥ 1,500 cells/mm3 and platelets ≥ 75,000 cells/dL
unless cytopenias are secondary to lymphomatous involvement of bone marrow or due
to HIV-related thrombocytopenia. All patients must be off colony stimulating
factor therapy at least 24 hours prior to institution of Cycle 1 chemotherapy.
- 8.2 Adequate hepatic function: Serum glutamic-oxaloacetic transaminase (SGOT) ≤ 5
times the upper limit of normal. Total bilirubin ≤ 2.0 mg/dL (unless elevated
secondary to lymphomatous involvement of liver or biliary system or due to other
HIV medications [e.g., indinavir, tenofovir or atazanavir]). Patients who are
negative for Hepatitis B, or if infected with Hepatitis B, receiving
anti-Hepatitis B therapy are eligible. All subjects will be required to be
screened for Hepatitis B and C. Per Infectious Diseases Society of America (IDSA)
and American Association for the Study of Liver Diseases (AASD) guidelines, those
subjects that show no immunity, defined by the lack of Hepatitis B surface
antibody, and show evidence of chronic infection (i.e. HBsAg+, HBcore+, HBsAB-)
will be required to be on anti-Hepatitis B therapy, during the study, in order to
be eligible. Patients will be permitted to enroll in the study provided liver
function tests meet criteria listed above, and there is no evidence of cirrhosis.
The exact Hepatitis B therapy will be at the discretion of the infection disease
specialist or investigator. However all patients who present with acute hepatitis
B or show normal transaminases and are HBsAg+ and IgM+ for Hepatitis core antigen
will not be eligible for trial enrollment. Subjects who are Hepatitis C antibody
positive, with or without a positive Hepatitis C RNA level, will be permitted to
enroll in the study provided liver function tests meet criteria listed above, and
have no evidence of cirrhosis. Patients diagnosed with Hepatitis C less than 6
months from trial enrollment, will be considered to have Acute Hepatitis C and
will be excluded from study unless Hep C viral load is undetectable.
- 8.3 Creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 60 mL/min unless due to
renal involvement by lymphoma.
9. Concurrent radiation, with or without steroids, for emergency conditions secondary to
lymphoma (CNS tumor, cord compression, etc.) will be permitted.
10. Females with childbearing potential must have a negative serum pregnancy test within 7
days prior of entering into the study. Men and women must agree to use adequate birth
control if conception is possible during the study. Women must avoid pregnancy and men
avoid fathering children while in the study and for 6 months following the last study
drug treatment.
11. Able to give consent.
12. Patients already receiving erythropoietin or Granulocyte-colony stimulating factor
(G-CSF) are eligible, although G-CSF therapy must be discontinued at least 24 hours
prior to receiving chemotherapy.
13. The maximum cumulative dose of doxorubicin allowed is 450 mg/m2. Patients who have
previously received doxorubicin with a cumulative dose of 350 mg/m2 or greater are
eligible but MAY NOT receive doxorubicin under protocol.
Exclusion Criteria:
1. Concurrent active malignancies, with the exception of in situ carcinoma of the cervix,
non-metastatic, non-melanomatous skin cancer, or Kaposi sarcoma not requiring systemic
chemotherapy.
2. Myocardial infarction (MI) within 6 months prior to study entry, New York Heart
Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe,
uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or
electrocardiograph evidence of acute ischemic or active conduction system
abnormalities.
3. Left Ventricular Ejection Fraction (LVEF) that is less than the lower institutional
limits of normal as assessed by Multiple Gated Acquisition (MUGA) scan or
echocardiogram within 6 weeks prior to registration.
4. Subjects with viral hepatitis who do not meet the criteria listed on (8.2) will be not
be eligible. All patients who present with acute hepatitis B including those with
normal transaminases who are HBsAg+ and IgM + for hepatitis core antigen will not be
eligible. Subjects who are Hepatitis B core antibody positive are eligible only if
they start or are on prophylactic therapy. A hepatitis B viral load should be
confirmed negative on all patients who are hepatitis B core antibody positive, but
hepatitis B antigen negative. Patients refusing to take any anti-hepatitis B therapy
during study will also be excluded. Patients diagnosed with Hepatitis C are eligible
if they meet criteria listed on (8.2).
5. Psychological, familial, sociological or geographical conditions that do not permit
treatment and/or medical follow-up required to comply with the study protocol.
6. Patients may not be receiving any other investigational agents.
7. Uncontrolled intercurrent illness 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. Patients with mycobacterium avium will not be excluded.
8. Pregnant or breast-feeding women.
