RATIONALE: Aldesleukin may stimulate natural killer cells to kill cancer cells. Treating
natural killer cells with aldesleukin in the laboratory may help the natural killer cells
kill more cancer cells when they are put back in the body. Giving monoclonal antibodies, such
as rituximab, and chemotherapy drugs, such as fludarabine and cyclophosphamide, before a
donor natural killer cell infusion helps stop the growth of cancer cells. It also helps stop
the patient's immune system from rejecting the donor's stem cells.
PURPOSE: This phase I/II trial is studying how well giving rituximab and chemotherapy
followed by a donor natural killer cell infusion that has been treated in the laboratory with
aldesleukin followed by aldesleukin works in treating patients with non-Hodgkin lymphoma or
chronic lymphocytic leukemia.
- To determine if allogeneic natural killer (NK) cells infused following
chemoimmunotherapy can be safely expanded in vivo with aldesleukin.
- To determine if interleukin-15 production at day 0 correlates with NK cells expansion.
- To determine overall response rate at 3 months.
- To determine time to progression and overall survival.
- To characterize the quantitative and qualitative toxicities of this treatment plan.
- To determine the incidence of donor products that do not meet release criteria and the
NK cell numbers infused.
- To correlate clinical response with donor/recipient KIR ligand matching status, FcG
receptor 3A genotype, and NK cells phenotype and function
- To determine pharmacodynamic and pharmacogenomic markers and correlate them with NK cell
expansion and disease response.
- Conditioning regimen: Patients receive rituximab intravenously (IV) over 6-8 hours on
days -8, -1, 6, and 13; fludarabine IV on days -6 to -2; and cyclophosphamide IV on day
- Allogeneic natural killer (NK) cell administration: Patients receive
aldesleukin-activated haploidentical NK cells IV over less than 1 hour on day 0. Within
4 hours after allogeneic NK cell infusion, patients receive aldesleukin subcutaneously
(SC) 3 times a week for 6 doses. Patients also receive filgrastim (G-CSF) SC beginning
on day 14 and continuing until absolute neutrophil count (ANC) is > 2,500/mm³ for 2
Patients who achieve a complete or partial response at 28 days are eligible for allogeneic
stem cell transplantation. Patients who achieve initial response at 3 months, clinically
benefit from treatment, but subsequently relapse are eligible for retreatment provided all
eligibility criteria are met.
Blood samples are collected periodically for correlative laboratory studies. Patients with
chronic lymphocytic leukemia (CLL) also undergo bone marrow aspiration periodically for
correlative laboratory studies.
After completion of study treatment, patients are followed periodically for up to 1 year.
- Patient 18 years or older with a diagnosis of non-Hodgkin Lymphoma or chronic
lymphocytic leukemia (NHL or CLL) and one of the following:
- Progression of NHL following at least 2 prior chemotherapy regimens, (must
contain rituximab for all NHL and fludarabine for follicular NHL) defined as:
- failure to achieve partial remission (PR) with the last chemotherapy
- disease progression within 6 months following last chemotherapy
- Progression of CLL/SLL (small lymphocytic lymphoma) following at least 2 prior
chemotherapy regimens (containing purine analogs ) in stage Rai III or IV or
- Relapsed NHL or CLL following stem cell transplantation for whom the option of
donor lymphocyte infusion is not available or clinically indicated (e.g.
recipients of autologous or umbilical cord blood [UCB] transplants).
- Available related HLA-haploidentical (human leukocyte antigen) natural killer (NK)
cell adult donor by at least Class I serologic typing
- Karnofsky performance status > 60%
- Measurable disease based on modified Response Evaluation Criteria In Solid Tumors
- Have acceptable organ function as defined within 28 days of enrollment:
- Hematologic: platelets ≥ 80,000 x 10^9/L; hemoglobin ≥ 9g/dL, unsupported by
transfusions; absolute neutrophil count (ANC) ≥ 1000 x 10^9/L, unsupported by
granulocyte-colony stimulating factor or granulocyte-macrophage
colony-stimulating factor (G-CSF or GM-CS)F 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 lymphoma who are otherwise eligible
- Renal: glomerular filtration rate (GFR) > 50 ml/min
- Hepatic: alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3 x
upper limit of normal and total bilirubin <3 mg/dl
- Pulmonary function: >50% corrected carbon monoxide diffusing capacity (DLCO) and
Forced Expiratory Volume in the first second (FEV1)
- Cardiac: no symptoms of uncontrolled cardiac disease, left ventricular ejection
- Off prednisone or other immunosuppressive medications for at least 3 days prior to Day
- 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 informed consent before performance of any study-related procedure
not part of normal medical care.
- 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 2 weeks prior to
registration to rule out pregnancy. Women of childbearing age must use appropriate
- Active central nervous system (CNS) lymphoma/leukemia
- 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 the chest x-ray
- Allergy to rituximab or IL-2
- Human immunodeficiency virus (HIV) and associated non-Hodgkins lymphoma (NHL)
- Active concurrent malignancy (except skin cancer) requiring systemic therapy in the
past 2 years
- Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder
- Positive hepatitis B surface antigen (HBsAg). If Hepatitis B core antibody (HBcAb) is
positive, Hepatitis B deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR)
will be evaluated. Positive anti HBcAb and undetectable viral load does not exclude
- Any experimental therapy in the past 30 days
- Related donors (sibling, parent, offspring, parent or offspring of an HLA identical
sibling) ≥ age 18 years
- Able and willing to undergo lymphapheresis
- HLA-haploidentical donor/recipient match. If time permits and multiple donors are
available, preference will be given to the Killer-cell Immunoglobulin-like Receptors
(KIR) ligand mismatched donor (as predicted by HLA typing).
- HIV-1, HIV-2 negative, Human T-lymphotropic virus Type I (HTLV-1), HTLV-2 negative,
West Nile virus (WNV) negative, Hepatitis B and C negative
- Adequate organ function defined as:
- Hematologic: CBC/diff/platelet count near normal limits,
- Hepatic: ALT < 2 x upper limit of normal,
- Not pregnant or lactating
- In general good health as determined by the study physician
- Able to give informed consent