Chemotherapy and a Donor Natural Killer Cell Infusion in Treating Patients With Relapsed or Persistent Leukemia or Myelodysplastic Syndrome After a Donor Stem Cell Transplant

OBJECTIVES:

Primary

- Determine the anti-leukemic efficacy of allogeneic HLA-haploidentical related natural
killer (NK) cell infusion following a cytoreductive regimen with cyclophosphamide and
fludarabine in patients with acute myeloid leukemia (AML), myelodysplastic syndromes
(MDS), or blastic CML who have relapsed following allogeneic hematopoietic stem cell
transplant, where efficacy is defined as the achievement of complete or partial
remission at one year following NK cell infusion.

Secondary

- To assess treatment efficacy, as defined by achievement of complete or partial
remission, at 3 and 6 months following HLA-haploidentical related NK cell infusion.

- To assess the effects of an HLA-haploidentical related NK cell infusion on the
sustained engraftment and recovery of an HLA-matched stem cell allograft.

- To assess the risk of inducing graft-vs-host disease (GVHD) or altering its severity.

- To provide preliminary evidence that specific donor KIR-recipient HLA ligand
combinations relating to missing self-MHC class I ligand or missing class I ligand are
associated with higher NK alloreactivity and improved outcome.

- To monitor the extent and duration of NK cell donor chimerism.

- To monitor NK cell reconstitution through NK receptor cell surface phenotyping
(CD94/NKG2A, ILT-2, KIR expression) and function (intracellular IFN-γ, cytotoxicity) on
day 15, 30, 60, 100, and 200 following the NK infusion and to correlate with outcome.

- To correlate the magnitude of NK effect with disease and known survival risk factors
(time from allogeneic HSCT to relapse; < 6 months vs > 6 months).

Subject Inclusion Criteria:

Diagnosis and Status

- Patients with a pathologically confirmed diagnosis of relapsed or persistent
resistant AML, MDS, or blastic CML following HSCT and who have been deemed ineligible
for second HSCT after consideration of adequacy of their physical function, extent of
disease, and prior treatment-related toxicities.

Eligible patients have evidence of disease with ≥5% bone marrow involvement detected by
morphology or abnormal cytogenetics (by karyotype or FISH). Patients with molecular
detection of markers characteristic of the patient's disease from two consecutive bone
marrow biopsies are also eligible. Following diagnosis of relapsed disease, treatment to
reduce leukemic burden is allowed prior to protocol therapy without the need for
additional disease documentation prior to cyclophosphamide and fludarabine.

- Patients with extramedullary relapse are eligible except for those with CNS
involvement.

- Patients must have received an allogeneic HSCT.

- Patient must not be pregnant and must be using adequate form of birth control.

- Patients must have a Karnofsky (adult) or Lansky (pediatric) Performance Status ≥
60%.

- Hospitalization does not preclude enrollment, as long as the patient's performance
status is ≥ 60% according to the KPS grading scale.

- Patients must have adequate physical function measured by :

Cardiac: asymptomatic and LVEF at rest must be > 50%. Hepatic: < 2x ULN ALT and < 1.5
total serum bilirubin, unless liver is involved with disease, there is congenital benign
hyperbilirubinemia, or other reversible causes of hepatic abnormalities are documented.

Renal: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range,
then CrCl > 50 ml/min Pulmonary: Patient cannot be oxygen-dependent.

- Patients with documented GVHD are not excluded from this trial, but either must not
have used systemic immunosuppression for two weeks, or during immunosuppression taper
have documented two subtherapeutic levels at least one week apart. Immunosuppressive
agents include but are not limited to systemic steroids, calcineurin inhibitors,
MTOR-inhibitors, Budesonide, anti-thymocyte globulin. The maximal allowable dose of
corticosteroids is the equivalent of 10 mg/day prednisone.

- Patients with grade I/II acute GVHD or limited chronic GVHD and receiving localized
GVHD therapy (e.g. topical steroids) are not excluded from this trial.

- Patients having received previous adoptive cellular therapy such as donor lymphocyte
infusion (DLI) are not excluded from this trial as long as their disease has been
documented to progress within two months of receiving DLI or if the patient has not
received DLI within two months of NK cell infusion.

- Patients who have received cytoreductive therapy following documentation of relapse
and prior to enrollment are not excluded from this trial. The interval between
standard reinduction chemotherapy and start of protocol chemotherapy should be a
minimum of 2 weeks, and all induction chemotherapy-related toxicities should be
documented to be completely resolved. For patients receiving nonintensive
chemotherapies such as hydroxyurea or low-dose cytarabine, nonintensive
chemotherapies should be discontinued upon initiation of protocol chemotherapy.

- Each patient must be willing to participate as a research subject and must sign an
informed consent form. Parents or legal guardians of patients who are minors may sign
the informed consent form

- Patients must have an eligible NK donor.

- There are no age restrictions to this protocol.

NK Cell Donor Eligibility

- Donor is blood-related and HLA-haploidentical to the recipient.

- Donor has undergone serologic testing for transmissible diseases as per blood banking
guidelines for organ and tissue donors. Tests include but are not limited to:
HepBsAg, HepBsAb, HepBcAb, HepC antibody, HIV, HTLV I and II, VZV, CMV and VDRL, and
West Nile Virus . Donor must have normal negative test results for HIV, HTLV I and
II, and West Nile Virus. Donor exposure to other viral pathogens will be discussed on
a case-by-case basis by the Transplant team.

- Donor has a CXR and EKG performed.

- Donor must be able to undergo leukopheresis for total volume of 10-15 liters.

- Donor is not pregnant.

- Donor does not have concurrent malignancy or autoimmune disease.

- There is no age restriction for the donor.

Subject Exclusion Criteria:

- Patients on systemic immunosuppression with therapeutic drug levels. Patients whose
immunosuppression is being actively tapered and have documentation of subtherapeutic
drug levels one week apart are not excluded from enrollment. For patients receiving
corticosteroids, the maximal allowable dose of corticosteroids is the equivalent of
10 mg/day prednisone.

- Patients with untreated or uncontrolled active infection. Infections that are
controlled or being appropriately treated does not exclude a patient from enrollment.

NK Cell Donor Exclusion

- Donor has cardiac risk factors precluding ability to undergo leukopheresis.

- Donor has evidence of concurrent malignancy or autoimmune disease.

- Donor is pregnant.