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Reduced Intensity Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Supplemented With Donor Natural Killer (NK) Cell Infusions in Patients With High Risk Myeloid Malignancies Who Are Unsuitable for Fully Myeloablative Transplantation

Phase 1/Phase 2
18 Years
70 Years
Open (Enrolling)
Acute Myelogenous Leukemia

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Trial Information

Reduced Intensity Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Supplemented With Donor Natural Killer (NK) Cell Infusions in Patients With High Risk Myeloid Malignancies Who Are Unsuitable for Fully Myeloablative Transplantation



- To determine the disease-free survival at 6 months and 1 year in patients with
high-risk myeloid malignancies who undergo a reduced-intensity haploidentical
hematopoietic stem cell transplantation (HSCT) supplemented with donor natural killer
(NK) cells.


- To evaluate the in vivo expansion of a donor CD3- CD19- selected NK cell product
administered after a preparative regimen of cyclophosphamide, fludarabine, and total
body irradiation (TBI) and HSCT in these patients.

- To determine the rate of graft failure defined by absolute neutrophil count (ANC) <
500/mm³ by day 28.

- To determine the incidence of grade III-IV acute graft-versus-host disease (GVHD) at 6

- To determine the rate of treatment-related mortality at day 100.

- To determine the incidence of chronic GVHD at 12 months.

- To determine the incidence of disease relapse at 12 months.

- To determine the incidence of post-transplant lymphoproliferative disorder at 12


- To correlate immune reconstitution of the in vivo expanded haploidentical NK cells with
clinical outcomes.

OUTLINE: This is an open-label study.

Patients receive fludarabine intravenous (IV) over 1 hour on days -18 to -14 and
cyclophosphamide IV over 2 hours on days -16 and -15. Patients receive cyclosporin A on Day
-15 through Day -8. Patients undergo total body irradiation on day -13. Patients then
receive an infusion of donor natural killer cells on day -12 and interleukin-2
subcutaneously on alternating days between days -12 to -2. Patients receive thymoglobulin
(ATG) and undergo allogeneic peripheral blood stem cell transplantation on day 0.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study.

Inclusion Criteria:

- 4.2 High risk acute myeloid leukemia (AML) fitting within one of the following
disease groups:

- Primary induction failure defined as no complete remission (CR) after two or
more induction cycles. For primary induction failure (PIF) or refractory AML,
the patient must have <5% circulating blasts (and <1000 absolute circulating
blasts) beyond Day 28 after last chemo. During work-up period if circulating
blasts rise above these levels, the patient is ineligible. The use of hydrea or
other non-induction cytotoxic agents is not allowed to reduce blasts and achieve
this eligibility. If the blasts are higher than these limits, the patient should
be treated on an alternative therapeutic protocol or receive another reinduction
attempt. (See section 7 regarding final check of blast status within 7 days of
preparative regimen start).

- Relapsed AML with low disease burden must have less than 5% marrow blasts at
time of enrollment for patients who did not receive re-induction or measured at
least 28 days from the start of reinduction therapy for patients who did receive
re-induction (maximum of 2 re-induction attempts). Patients who have relapsed
more than 12 months following a prior HCT and did not reach CR following one
re-induction cycle but have less than 10% marrow blasts are eligible.

- CR3 or greater. This will include CRp defined as CR without platelet recovery to

- CR1 or CR2 with high risk features (therapy induced, prior myelodysplastic
syndrome [MDS] or myeloproliferative disease [MPD], high risk cytogenetic or
molecular phenotype) with no available alternate (sibling, unrelated donor [URD]
or umbilical cord blood [UCB]) donors.

Patients with prior central nervous system (CNS) involvement are eligible provided that it
has been treated and CFS must be clear for at least 2 weeks prior to enrollment.

- Available related HLA-haploidentical donor (3-5 of 6 HLA, A, B and DRB1 matched)

- Karnofsky performance status > 50

- Pulmonary Function: oxygen saturation ≥ on room air and diffusion lung capacity for
carbon monoxide (DLCOcor) ≥ 40%

- Cardiac Function: Ejection fraction (EF) ≥ 30%, no uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities.

- Able to be off prednisone or other immunosuppressive medications for at least 3 days
prior to Day 0

- Women of child bearing potential must have a negative pregnancy test within 14 days
prior to study registration and agree to use adequate birth control during study

- Human anti-mouse antibody (HAMA) monitoring: All subjects will be questioned about
prior exposure to antibody therapy (including OKT3, rituximab, trastuzumab, etc).

- For subjects with no prior antibody therapy exposure, no further action will be

- For subjects who have received previous antibody therapies 10 ml of serum will
be drawn before starting therapy. The presence of HAMA will not preclude
proceeding with treatment.

- Voluntary written consent signed before performance of any study related procedure
not part of the normal medical care.

Exclusion Criteria:

- Biphenotypic leukemia

- New or progressive pulmonary infiltrates on screening chest x-ray or chest computed
tomography (CT) scan that has not been evaluated with bronchoscopy, if feasible.
Infiltrates attributed to infection must be stable/improving (with associated
clinical improvement) after 1 week of appropriate therapy (2 weeks for presumed or
documented fungal infections). Surgical resection waives any waiting requirements.

- Uncontrolled bacterial or viral infections. Chronic asymptomatic viral hepatitis is

- Known hypersensitivity to any of the study agents used

- Received other investigational drugs within the 14 days before enrollment

Donor Selection:

- 12-75 years of age

- > 40 kilogram body weight

- In general good health as determined by the evaluating physician

- Donors must be HLA-A, B, DRB1 haploidentical (3-5/6 antigens HLA, A, B, DRB1) match
to recipient. Patients and donors will be typed for HLA-A, B and C using at least
intermediate resolution DNA techniques for DRB1 at high (allele) resolution. KIR B
genotyping will be done on all haploidentical donors, and when feasible, the donor
with the most favorable KIR gene profile will be used.

- Able and willing to have up to 4 separate apheresis collections per formed

- Not pregnant

- Human immunodeficiency virus (HIV): HIV-1, HIV-2 negative; HTLV-1, HTLV-2 negative,
Hepatitis B and C negative

- Voluntary written consent

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival

Outcome Time Frame:

Month 6, 1 Year

Safety Issue:


Principal Investigator

Sarah Cooley, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

January 2005

Completion Date:

January 2015

Related Keywords:

  • Acute Myelogenous Leukemia
  • NK cells
  • natural killer cells
  • immunotherapy
  • hematopoietic cell transplant
  • acute myelogenous leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid



Masonic Cancer Center, University of Minnesota Minneapolis, Minnesota  55455