Background:

• Studies conducted at the National Cancer Institute suggest that certain chemotherapy drugs may be more effective if given by continuous infusion into the vein rather than by the standard method of rapid intravenous injection. One combination of six chemotherapy drugs, known as etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), has had a high degree of effectiveness in people with certain kinds of cancer.
• Recent evidence also indicates that the effects of chemotherapy may be improved by combining the treatment with monoclonal antibodies, which are purified proteins that are specially made to attach to foreign substances such as cancer cells. A monoclonal antibody called campath (alemtuzumab) has been manufactured to attach to a protein called Campath-1 antigen (CD52) that may target tumor cells or the surrounding inflammatory cells.
• Researchers are interested in developing new treatments for large B-cell lymphoma or Hodgkin lymphoma that can best be treated with chemotherapy. This protocol is specifically for people with diffuse large B-cell or Hodgkin lymphomas that have not responded to standard treatments.

Objectives:

- To test whether giving campath (alemtuzumab) in combination with continuous infusion EPOCH-R chemotherapy will improve the outcome of lymphoma treatment.

Eligibility:

- Individuals 18 years of age and older who have large B-cell lymphoma or Hodgkin lymphoma that has not responded well to standard treatments.

Design:

• During the study, patients will receive standard EPOCH-R chemotherapy, which includes the following drugs: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. The additional drug, campath, will be given by intravenous (IV) infusion on the first day of treatment over several hours.
• When the campath IV infusion and rituximab IV infusion are complete, the drugs doxorubicin, etoposide, and vincristine will each be given by continuous IV infusion over the next 4 days (that is, continuously for a total of 96 hours). Cyclophosphamide will be given by IV infusion over several hours on Day 5. Prednisone will be given by mouth twice each day for 5 days.
• Patients may be given other drugs to treat the side effects of chemotherapy, to prevent possible infections, and to improve white blood cell counts.
• The campath-EPOCH-R therapy will be repeated every 21 days, as a cycle of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles (approximately weeks 12 and 18) of campath-EPOCH-R treatment, study researchers will perform blood tests and computed tomography (CT)/magnetic resonance imaging (MRI) scans on all patients to assess their response to the treatment.

Background:

Two signatures of the microenvironment were recently identified that are predictive of outcome in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone (R-CHOP). These signatures, called stromal 1 and stromal 2, are associated with genes expressed by infiltrating mononuclear cells. The stromal 2 signature, which includes genes associated with angiogenesis, is predictive of an inferior outcome. Based on these observations, we are interested in targeting the reactive cells in the microenvironment as a therapeutic strategy in patients with relapsed and refractory DLBCL. Along the same principles, we are also including patients with relapsed Hodgkin lymphoma (HL). The surrounding reactive cells around Hodgkin Reed Sternberg (HRS) cells are now not thought to be bystander cells and they appear to provide important survival signals to HRS cells.

• Campath-1 antigen (CD52) is one such promising target that is highly expressed in most of these infiltrating cells and on most DLBCL although not on HRS cells specifically. Anti-CD52 antibodies may have therapeutic value by depleting reactive B and T cells, and monocytes from the microenvironment.
• The dose of alemtuzumab in combination with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH) is 30 mg intravenous (IV), as determined by a prior study done in patients with untreated peripheral T-cell lymphoma. The main toxicities of this combination are myelosuppression and opportunistic infections.
• An important component of this study will be to obtain tumor tissue for gene expression profiling and to assess microenvironment signatures and look at other molecular signatures and targets before treatment and in patients who progress and ultimately correlate response and outcome with these various end-points.

Objectives:

- Assess response, progression free survival (PFS) and overall survival (OS) in relapsed/refractory DLBCL and Hodgkin Lymphoma.

Eligibility:

• Previously treated or refractory classical large B-cell lymphomas, Grey-zone lymphoma and Hodgkin lymphoma, including Lymphocyte predominant Hodgkin Lymphoma (LPHL).
• Age greater than or equal to 18 years with adequate organ functions.
• Human immunodeficiency virus (HIV) negative and no active central nervous system (CNS) lymphoma.

Study Design:

• Patients will receive 30mg of Alemtuzumab on day 1 of therapy, followed by Rituximab on day 1 and dose-adjusted EPOCH chemotherapy days 1-5, up to six cycles of therapy.
• Tumor biopsies will be done before treatment, after 1 cycle of therapy and at relapse.
• It is anticipated that up to 10-15 patients per year may be enrolled onto this trial. Thus, accrual of up to 52 patients is expected to require approximately 4-5 years.

• INCLUSION CRITERIA:

  1. Previously treated or refractory classical large B-cell lymphomas, Grey-zone lymphoma and Hodgkin lymphoma, including Lymphocyte predominant Hodgkin Lymphoma (LPHL).
  2. Confirmed pathological diagnosis by the Laboratory of Pathology, National Cancer Institute (NCI).
  3. Age greater than or equal to 18 years.
  4. Eastern Cooperative Oncology Group (ECOG) performance 0-2
  5. Laboratory tests: absolute neutrophil count (ANC) greater than or equal to 1000/mm(3), platelet greater than or equal to 75,000/mm(3). Creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 ml/min; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal (ULN). Total bilirubin < 2.0 mg/dl except < 5mg/dL in patients with Gilbert's (as defined as > 80% unconjugated hyperbilirubinemia without other known cause); unless impairment due to organ involvement by lymphoma.

EXCLUSION CRITERIA:

1. Active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. If echocardiogram (ECHO) is obtained, the left ventricular ejection fraction (LVEF) should exceed 40%.
2. Human immunodeficiency virus (HIV) positive, because of the unknown effects of combined therapy with chemotherapy and an immunosuppressive agent on HIV progression.
3. Female subject of child-bearing potential not willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and two years beyond treatment completion.
4. Female subject pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotrophin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for women without childbearing potential.
5. Male subject unwilling to use an acceptable method for contraception for the duration of the study and one year beyond treatment completion.
6. Invasive or active malignancy in past 2 years.
7. Serious concomitant medical illnesses that would jeopardize the patient s ability to receive the regimen with reasonable safety.
8. Active central nervous system (CNS) lymphoma. These patients have a poor prognosis and because they frequently develop progressive neurological dysfunction that would confound the evaluation of neurological and other adverse events.
9. Systemic cytotoxic therapy within 3 weeks of treatment.

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Clinical data will be available during the study and indefinitely.

Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).