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Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02566395
Recruitment Status : Recruiting
First Posted : October 2, 2015
Last Update Posted : May 17, 2019
New York Blood Center
Information provided by (Responsible Party):
Joel Brochstein, Northwell Health

Brief Summary:
This clinical pilot trial is intended to evaluate the feasibility, efficacy and safety of hematopoietic stem cell transplantation (HSCT) from Human Leukocyte Antigen (HLA)-mismatched related donors for children and young adults with hematologic malignancies who lack a suitably matched related or unrelated donor. The methodology will be one that has been successfully utilized in adult patients at Thomas Jefferson University.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Acute Myelogenous Leukemia Myelodysplastic Syndrome Chronic Myelogenous Leukemia Non-Hodgkin Lymphoma Hodgkin Lymphoma Radiation: Radiation Drug: Cyclophosphamide Biological: Donor Lymphocyte Infusion (DLI) Biological: Haploidentical Stem Cell Transplantation Phase 3

Detailed Description:

Allogeneic HSCT is a potentially curative therapy for a number of malignancies. A barrier to the institution of this potentially curative strategy in hematologic malignancies is the availability of donors. Only 30% of patients in North America or Europe who may benefit from allogeneic HSCT will have an available HLA matched sibling donor. The ability to find a matched sibling donor is proportional to the number of children in the family. Because of the decreasing size of nuclear families, it is becoming less likely for patients to have an HLA identical matched sibling. Registries can provide a matched unrelated allogeneic stem cell graft for an additional 30% of patients. However this is not an option for patients who do not have a match in the registry, or whose disease status precludes them from waiting to identify an appropriate unrelated donor. The ability of finding a well matched unrelated donor is even more limited for segments of the population with mixed race ancestry as well as for African Americans who, because of a higher degree of HLA diversity, will be unlikely to find an unrelated donor who matches their HLA type.

In these settings it is easier and faster to identify a partially HLA-matched (or haploidentical) family member as a stem cell donor. The use of haploidentical donors broadens the application of HSCT because it is not as limited by family size or racial/ethnic HLA diversity. Because parents and children, as well as siblings can be used as haploidentical donors, this type of transplant enfranchises almost every segment of the population.

Since, in this study, the donor lymphoid and stem cell portions of the graft are collected and administered at different time points during the conditioning regimen, this approach to haploidentical HSCT is referred to as a 2 Step regimen. The approach does not involve ex vivo T cell depletion, but uses cyclophosphamide to tolerize donor lymphocytes within the framework of a myeloablative conditioning regimen. Preliminary experience with this approach in adult patients at Thomas Jefferson University for myeloablative haploidentical HSCT dates back to 2005 with the first trial using myeloablative conditioning formally launched in 2006. That initial trial met its accrual goals and the current trial is one of the successor trials derived from that experience.

The conditioning regimen includes total body irradiation (TBI) (1.5 Gray x 8) and CY (60 mg/kg x 2). Tacrolimus and Mycophenolate Mofetil (MMF) are used as post-transplant immunosuppression in relatively standard fashion.

The novel aspect of the regimen is in the administration of the graft. If one considers that a standard allograft consists of two components, a lymphoid portion and a stem cell portion, what is unique here is the administration of these two portions separately, at different time points during the conditioning regimen rather than together. The lymphoid portion, including a fixed dose of CD3+ cells/kg is administered prior to cyclophosphamide while the hematopoietic stem cell (HSC) portion of the graft is administered after cyclophosphamide has been metabolized and eliminated. Thus, the transplant occurs in 2 steps.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies
Study Start Date : December 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Arm Intervention/treatment
Experimental: Haploidentical Stem Cell Transplantation
Subjects will receive pretransplantation conditioning of total-body irradiation (1,200 cGy delivered in 8 fractions over 4 days [Days -9 through -6] and cyclophosphamide (60 mg/kg IV daily x 2 on Days -3 and -2). Donor lymphocyte infusion will occur on day -6; donor CD34+ cells will be infused on Day 0.
Radiation: Radiation
1,200 cGy, delivered in 8 fractions of 150 cGy bid x 4 days
Other Name: Total Body Irradiation

Drug: Cyclophosphamide
Cyclophosphamide 60 mg/kg IV daily x 2 consecutive days
Other Name: Cytoxan

Biological: Donor Lymphocyte Infusion (DLI)
DLI containing 1 x 10E8/kg donor T-cells

Biological: Haploidentical Stem Cell Transplantation
2-10 x 10E6/kg donor CD34+ selected cells

Primary Outcome Measures :
  1. Hematopoietic engraftment [ Time Frame: Day +30 post-transplantation ]
    Absolute neutrophil count >500/microliter x 3 consecutive days

Secondary Outcome Measures :
  1. 2-Year disease-free survival [ Time Frame: 2 years post-transplantation ]
    Alive and free of disease at 2 years post-transplantation

  2. Grade II-IV GvHD [ Time Frame: Day +100 post-transplantatation ]
    Proportion of subjects with Grade II-IV acute graft-versus-host disease

  3. Grade III-IV GvHD [ Time Frame: Day +100 post-transplantation ]
    Proportion of subjects with Grade III-IV acute graft-versus-host disease

  4. Relapse rate [ Time Frame: 2 years post-transplantation ]
    Proportion of subjects who have experienced disease relapse by 2 years post-transplantation

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Acute lymphoblastic leukemia
  • Acue myelogenous leukemia
  • Myelodysplastic syndrome
  • Non-Hodgkin lymphoma
  • Chronic myelogenous leukemia
  • Adequate lung, liver, renal, cardiac function
  • Performance status >70
  • Available related donor who is mismatched at ≥ 2 HLA alleles

Exclusion Criteria:

  • Available HLA-identical related donor
  • HIV positive
  • Active uncontrolled infection
  • Pregnancy
  • Performance status ≤70

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02566395

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Contact: Nan Werther, CPNP 718-470-3620
Contact: Joel A Brochstein, MD 718-470-3460

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United States, New York
Cohen Children's Medical Center Recruiting
New Hyde Park, New York, United States, 11040
Contact: Joel A Brochstein, MD    718-470-3460   
Contact: Nan Werther, CPNP    718-470-3620   
Sponsors and Collaborators
Northwell Health
New York Blood Center
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Principal Investigator: Joel A Brochstein, MD Cohen Children's Medical Center

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Responsible Party: Joel Brochstein, Associate Chief for Cellular Therapy, CCMC, Northwell Health Identifier: NCT02566395     History of Changes
Other Study ID Numbers: 14-551
First Posted: October 2, 2015    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: May 2019
Keywords provided by Joel Brochstein, Northwell Health:
Stem Cell Transplantation
Haploidentical Donors
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Myeloproliferative Disorders
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists