Haploidentical Transplantation With Early Adoptive Transfer of CD56+CD3- NK Cells

Transplantation of Hematopoetic Stem Cells and Infusion of CD56+CD3- NK Cells From Haploidentical Donors for Patients With Hematological Malignancies

Experimental and clinical data suggest that alloreactive NK cells can reduce the risk of graft-rejection, GvHD and leukemic relapse after HLA-mismatched transplantation. The effectiveness of allogeneic NK cells is a function of HLA-differences between donor and recipient that give rise to NK cell clones which do not express inhibitory receptors matching for the HLA molecules of the recipient. Aim of the study is to evaluate cellular therapy with alloreactive, IL-2 activated NK cells after transplantation of T-cell depleted stem cell grafts from one haplotype mismatched family donors in patients with hematological malignancies.

Study Overview

• Status: Unknown
• Conditions: Acute Myeloid Leukemias; Advanced Hematological Malignancies; Indication for Allogeneic Stem Cell Transplantation; no HLA-identical Donor Available
• Intervention / Treatment: Biological: Haploidentical transplantation with donor NK cells

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Lutz Uharek, MD; Phone Number: 4550 +49308445; Email: lutz.uharek@charite.de
• Study Contact Backup: Name: Birte Friedrichs, MD; Phone Number: 4574 +49308445; Email: birte.friedrichs@charite.de

Study Locations

• Germany
  • Berlin, Germany, 12200
    • Recruiting
    • Charite Campus Benjamin FRanklin, Medical Clinic III, Department of Hematology/Oncology
    • Contact: Lutz Uharek, Prof.; Phone Number: 4550 +49308445; Email: lutz.uharek@charite.de
    • Contact: Birte Friedrichs, Dr.; Phone Number: 4574 +49308445; Email: birte.friedrichs@charite.de
  • Leipzig, Germany, 04103
    • Recruiting
    • Medical Clinic II, Department of Hematology/Oncology, University of Leipzig
    • Contact: Dietger Niederwieser, Prof.; Phone Number: 13050 +4934197; Email: dietger@medizin.uni-leipzig.de
    • Contact: Nadezda Basara, Dr.; Email: Nadezda.Basara@medizin.uni-leipzig.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 54 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with AML or ALL in first CR with the following high risk features:

  1. AML with aberration Del (5q) -5, del (7q) -7, t(9;22) or t(6;9), abn 3q, 9q, 11q, 20q, 21q, 17p;
  2. AML with a complex caryotype;
  3. secondary AML after previous chemo- or radiotherapy or MDS;
  4. Ph-positive ALL
• Patients with AML or ALL after induction failure or in second CR
• Patients with CML in second chronic or accelerated phase

• Patients with malignant Lymphoma and the following high risk features:

  1. relapse after autologous transplantation
  2. primary chemotherapy refractory disease

• All patients must fulfill the following criteria:

  1. lack of a suitable HLA-identical family, unrelated or cord blood donor
  2. no active infection, no severe impairment of cardial, pulmonary, renal and hepatic function
  3. blast count in the marrow < 30%
  4. informed consent

Exclusion Criteria:

• active infection, no severe impairment of cardial, pulmonary, renal and hepatic function
• blast count in the marrow > 30%
• unable or unwilling to sign and/or understand informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: HaploTransplant with NK cells; Haploidentical transplantation of mega-dose CD34+ hematopoetic stem cells with transfer of CD56+CD3-NK cells at day +2

Biological: Haploidentical transplantation with donor NK cells; Pat received a myeloablative conditioning regimen with 12 Gy total-body irradiation in six single doses from day -11 to day -9, thiotepa (5mg/kg/d) on days -8 and -7, fludarabine (40mg/m2/d) from day -6 to day -3, and OKT-3 (5mg/d) from day -5 to day +3. The stem cell graft was aimed to contain > 8 x 10e6 CD34+ cells/kg and < 5 x 10e4 CD3+ cells/kg. A minimum of 1 x 10e7 CD56+CD3- NK cells/kg will be transferred on days +2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate feasibility and safety of alloreactive CD56+/CD3- donor NK cells after one haplotype mismatched transplantation	To evaluate feasibility and safety of cellular immunotherapy with purified alloreactive CD56+/CD3- donor NK cells after one haplotype mismatched hematopoietic stem cell transplantation in patients with high risk hematological malignancies who lack an HLA-identical donor.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
transplant related mortality	The investigation of transplant related mortality (incidence of veno occlusive disease; incidence and type of infectious complications).	1 year
effectiveness	To evaluate the effectiveness of the therapy (relapse rate; disease free survival; MRD monitoring).	2 years
technical aspects of the cell separation procedure	To investigate technical aspects of the cell separation procedure (problems of stem cell mobilization; yield, viability, sterility and purity of the CD34+ and CD56+CD3- cell fraction; log CD3 depletion; in vitro anti-leukemic activity of the CD56+CD3- cell fraction).	7 days
stable engraftment of haploidentical stem cell grafts can be achieved after conditioning with total body irradiation, thiotepa, fludarabine and OKT3 and subsequent transfer of megadoses of positively selected CD34+ stem cells and CD56+CD3- NK-cells.	Graft rejection is defined as neutrophils < 0.5 x 10e9/l on day+28 post transplantation.	28 days

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: University of Leipzig
• Investigators: Principal Investigator: Lutz Uharel, MD, Charité University Medicine; Principal Investigator: Dietger Niederwieser, MD, University of Leipzig

Study record dates

Study Major Dates

• Study Start: July 1, 2001
• Primary Completion (ANTICIPATED): October 1, 2010
• Study Completion (ANTICIPATED): October 1, 2011

Study Registration Dates

• First Submitted: October 13, 2010
• First Submitted That Met QC Criteria: October 13, 2010
• First Posted (ESTIMATE): October 14, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): October 14, 2010
• Last Update Submitted That Met QC Criteria: October 13, 2010
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: BELEHAPLO-1412001