In this study the investigators investigate a cell therapy strategy that could harness allogeneic effectors that can potentially mediate anti-lymphoma effect. The investigators have designed a novel lymphodepleting conditioning regimen followed by infusion of donor-derived natural killer (NK) cells and interleukin-2 (IL-2) for patients with refractory lymphoid malignancies.

This is a single center phase II trial designated to expand donor NK cells and induce remissions in patients with refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) using chemotherapy followed by haploidentical NK cells and IL2.

Primary Objective is to evaluate the objective response rate (PR+CR) at 2 months post haploidentical NK cell infusion in patients with refractory Non Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

Secondary Objective is to 1) evaluate the safety and tolerability of lymphodepleting chemotherapy, rituximab, and methylprednisone as determined by incidence of serious adverse events; 2) evaluate in vivo expansion of allogeneic donor NK cells at day 14; 3) determine time to progression

Exploratory Objective is to 1) correlate clinical response with frequencies of peripheral blood T reg cells after chemotherapy; 2) correlate clinical response with donor KIR-B-content score determined by genotype; 3) monitor phenotypic and functional characteristics of natural killer cells and regulatory T cells in vivo; 4) correlate clinical response with donor FcR polymorphism.

• Pre-NK cell infusion chemotherapeutic regimen consist of 1) Rituximab 375mg/m2 IV weekly x 4, start day -7; 2) Fludarabine 25 mg/m2 IV day -6 through day -2; 3) Cyclophosphamide 60mg/kg IV day -5; 4) Methylprednisolone 1 mg/kg day -2 through day +9.
• NK cell infusion using IL2 activated donor NK cells 1.5 to 8 x 107 cells/kg IV day 0
• IL2 SC 9 million IU every other day x 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule

Accrual Goal: Up to 17 patients will be enrolled

Inclusion Criteria:

• Patients of any age with diagnosis of:

  • Relapsed/refractory lymphoma (B cell non-Hodgkin) who have lack of objective response to at least two prior chemotherapy regimens
  • Relapsed chronic lymphocytic leukemia with high risk features: lack of objective response or relapse within 6 months following nucleoside-analogue based chemotherapy regimen or patients with 17p deletion CLL who lacked objective response to at least 1 preceding chemotherapy regimen

• Available related HLA haploidentical NK cell donor by at least Class I serologic typing at the A&B locus (age 12-75 years)

• Karnofsky > 70% for patients 16 years and older and Lansky play score > 50 for patients under 16 years of age

• Measurable disease based on modified Response Evaluation Criteria in Solid Tumors (RECIST)

• Have acceptable organ function as defined within 28 days of enrollment:

  • Hematologic: platelets ≥ 80,000 x 10^9/L; hemoglobin ≥ 9 g/dL, unsupported by transfusions within 7 days; absolute neutrophile count (ANC) ≥ 1000 x 10^9/L, unsupported by Granulocyte colony-stimulating factor (G-CSF) or Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) for 10 days or Neulasta for 21 days - the hematologic requirements are waived for patients with inadequate counts due to known bone marrow involvement by disease who are otherwise eligible
  • Renal: calculated glomerular filtration rate (GFR) > 50 ml/min
  • Hepatic: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 x upper limit of normal and total bilirubin ≤3 mg/dl - hepatic requirements are waived for patients with known disease involvement in the liver if otherwise eligible
  • Pulmonary function: >40% corrected Carbon Monoxide Diffusing Capacity (DLCO) and Forced expiratory volume in one second (FEV1) (oxygen saturation [>92%] can be used in child where pulmonary function tests (PFT's) cannot be obtained)
  • Cardiac: no symptoms of uncontrolled cardiac disease, left ventricular ejection fraction ≥ 40%

• Able to be off prednisone or other immunosuppressive medications for at least 3 day prior to Day 0 (excluding denileukin diftitox pre-medications)

• Sexually active women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment.

• Voluntary written consent

Exclusion Criteria:

• Pregnant or lactating. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 14 days prior to enrollment to rule out pregnancy. Women of childbearing age must use appropriate contraceptive method.
• Active central nervous system (CNS) lymphoma/leukemia - Patients with prior CNS involvement are eligible provided that it has been treated and is in remission.
• Active serious infection (pulmonary infiltrates or lesions are allowed only after the appropriate diagnostic testing is negative for infection or appropriate therapy was initiated for probable infection)
• Pleural effusion large enough to be detectable on chest x-ray (CXR)
• Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
• Active concurrent malignancy (except skin cancer)
• Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder
• Positive HBsAg. If HBcAb is positive, Hepatitis B DNA by PCR will be evaluated. Positive anti HBcAb with an undetectable viral load does not exclude the patient.
• Any investigational therapy in the past 30 days
• Patients following allogeneic stem cell transplantation are eligible in the absence of graft versus host disease and are off immunosuppression for at least 30 days
• Known allergy to any of the study agents