EPOCH and Rituximab to Treat Non-Hodgkin's Lymphoma in Patients With HIV Infection

• Toxicity during and 1 year after completion of study treatment. [ Designated as safety issue: Yes ]
• Response rate and duration at completion of study treatment and 5 years later. [ Designated as safety issue: No ]
• Ability of positron emission tomography (PET) scans to predict freedom from relapse at completion of study treatment and 5 years later. [ Designated as safety issue: No ]
• Effects of short course etoposide, vincristine, cyclophosphamide, doxorubicin, and rituximab (SC-EPOCH-R) on CD4 cell depletion and recovery at completion of study treatment and 18 months later. [ Designated as safety issue: No ]
• Response to antiretroviral therapy following SC-EPOCH-R 18 months after completion of study treatment. [ Designated as safety issue: No ]

Background:

• HIV-infected patients have a weakened immune system, and chemotherapy, which is used to treat lymphoma, probably causes further damage to the immune system.
• Limiting the amount of immune damage due to chemotherapy might decrease the number of infections and the risk of developing cancer in the future in HIV-infected patients with non-Hodgkin's lymphoma.

Objectives:

• To determine whether reducing the total amount of chemotherapy using a specific combination of drugs called EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide and rituximab) will rid the body of lymphoma quickly while decreasing the risk of infections and future cancers.
• To determine whether the lymphoma will remain undetectable for at least one year if treatment is stopped one cycle after the patient enters remission.

Eligibility:

-Patients with non-Hodgkin's lymphoma and HIV infection 4 years of age and older who have not been treated previously with rituximab or cytotoxic chemotherapy.

Design:

• Patients receive EPOCH-R in 3-week treatment cycles for at least three and no more than six cycles.
• The lymphoma is evaluated using CT and PET scans at the end of treatment cycles 2 and 3. A bone marrow biopsy is repeated after cycle 2 if a biopsy was initially positive on screening for participation in the study.
• Anti-HIV therapy is stopped before chemotherapy begins and is restarted when EPOCH-R treatment ends.
• Patients are monitored for treatment response with blood tests and imaging scans at baseline, when treatment ends, 2 months after treatment ends and then every 3 to 6 months for a total of 24 months following chemotherapy.

Background:

This is a study to investigate in a preliminary fashion the feasibility of short course chemotherapy to patients with HIV-associated non-Hodgkin's lymphoma (HIV-NHL).

This study will investigate if the paradigm for treatment can be successfully changed from a standard of 6 cycles to one cycle beyond complete remission with 6 total allowable cycles.

Objectives:

To assess with 90 percent probability that at least 50 percent of patients treated with short-course EPOCH-R will be progression free at one year.

Assess toxicity of SC-EPOCH-R.

Assess response rate and duration of SC-EPOCH-R.

Assess the utility of PET scans to predict freedom from relapse with SC-EPOCH-R.

Assess effects SC-EPOCH-R on CD4 cell depletion and recovery.

Assess response to antiretroviral therapy following SC-EPOCH-R.

Eligibility:

Aggressive CD20 positive DLBCL.

HIV+ serology.

All stages (I-IV) of disease.

ECOG Performance status 0-4.

NHL previously untreated with cytotoxic chemotherapy.

Age greater than or equal to 4 years.

May not be pregnant or nursing.

May not have received previous rituximab.

Design:

Patients will be treated every three weeks with a combination of EPOCH and rituximab for one cycle beyond CR/CRu by CT scan of all detectable tumors for a minimum of three and maximum of six cycles. Following cycle 2, CT, positron emission tomography scans (PET), and bone marrow biopsies (if initially positive) will be performed.

At the conclusion of the study, we will estimate whether the number of cycles can be reduced using the paradigm. If the cumulative number of patients to relapse exceeds 25 percent by 6 months, the study will be closed.

Following the completion of chemotherapy, restaging will be performed 2 months following the end of treatment, then every 3 months for one year, every 6 months for one year, then every 12 months until relapse, death, or loss to follow up.

Anti-HIV therapy will be suspended prior to initiation of the chemotherapy and optimum therapy will be reinitiated after all the cycles have been administered.

To study the effects of treatment approach on parameters of HIV disease, measurements of CD4 cells and viral loads will be made at baseline and at the completion of therapy, and then 2 months following the end of treatment, and then every 3-6 months for a total of 24 months following chemotherapy.

• AIDS Related Lymphoma
• HIV Infection

• Biological: Rituximab
  N/A
• Biological: filgrastim
  N/A
• Drug: cyclophosphamide
  N/A
• Drug: doxorubicin hydrochloride
  N/A
• Drug: etoposide
  N/A
• Drug: vincristine sulfate
  N/A

• Kaplan LD, Straus DJ, Testa MA, Von Roenn J, Dezube BJ, Cooley TP, Herndier B, Northfelt DW, Huang J, Tulpule A, Levine AM. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997 Jun 5;336(23):1641-8.
• Tirelli U, Spina M, Vaccher E, Errante D, Tavio M, Simonelli C, Sinicco A, Gastaldi R, Rossi G, Rizzardini G, et al. Clinical evaluation of 451 patients with HIV related non-Hodgkin's lymphoma: experience on the Italian cooperative group on AIDS and tumors (GICAT). Leuk Lymphoma. 1995 Dec;20(1-2):91-6.
• Levine AM. Epidemiology, clinical characteristics, and management of AIDS-related lymphoma. Hematol Oncol Clin North Am. 1991 Apr;5(2):331-42. Review.

• INCLUSION CRITERIA:

Aggressive CD20 positive Diffuse Large B-cell lymphoma confirmed by Laboratory of Pathology, NCI.

HIV + serology.

All stages (I-IV) of disease.

ECOG Performance status 0-4

NHL previously untreated with cytotoxic chemotherapy.

Age greater than or equal to 4 years

Laboratory tests (unless impairment due to respective organ involvement by tumor):

-Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than or equal to 50 ml/min

Pediatric patients: Age-adjusted normal serum creatinine according to the following table or a creatinine clearance greater than 60 ml/min/1.73 m(2).

Less than or equal to 5 age (years), 0.8 Maximum serum creatinine

Greater than 5, less than or equal to 10 age (years), 1.0 Maximum serum creatinine

Greater than 10, less than or equal to 15 age (years), 1.2 Maximum serum creatinine

Greater than 15 age (years), 1.5 Maximum serum creatinine

• Bilirubin less than 2.0 mg/dl, or total bilirubin less than or equal to 4.5 mg/dl with direct fraction less than or equal to 0.3 mg/dl in patients for whom these abnormalities are felt to be due to protease inhibitor therapy
• AST and ALT less than or equal to 3x ULN (AST and ALT less than or equal to 6x ULN for patients on hyperalimentation for whom these abnormalities are felt to be due to the hyperalimentation)
• ANC greater than or equal to 1000/mm(3)
• Platelet greater than or equal to 75,000/mm(3) (unless impairment due to ITP)

Ability of patient or parent/guardian to provide informed consent.

EXCLUSION CRITERIA:

Previous rituximab

Pregnancy or nursing.

• Doxorubicin, etoposide, vincristine and cyclophosphamide are teratogenic and may be excreted in milk.
• Antiretroviral therapy is indicated during pregnancy and nursing.

Current clinical heart failure or symptomatic ischemic heart disease.

Serious underlying medical condition or infection other than HIV that would contraindicate SC-EPOCH-R.

• Examples include, but are not limited to:
• Severe AIDS-related wasting
• Sever intractable diarrhea
• Active inadequately treated opportunistic infection of the CNS

Concurrent anti-retroviral therapy during EPOCH therapy.

Primary CNS lymphoma.

Adolescents who do not freely assent