Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Adoptive Immunotherapy and Interleukin-2 in Treating Patients With Recurrent Myeloid Leukemias After Undergoing Allogeneic Stem Cell Transplantation

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Treatment Temporarily closed 75 and under NCI FHCRC-1671.00 5429, NCT00052598

Objectives

Primary

1. Determine the safety and potential toxicities associated with infusing donor CD8+ CTL clones specific for proteinase 3 (myeloblastin) in patients with relapse/progression of high risk myeloid leukemias after transplant.

Secondary

1. Determine the in vivo persistence of transferred T-cells and assess migration to the bone marrow, a predominant site of leukemic relapse.
2. Determine if adoptively transferred PR3-specific T-cells mediate antileukemic activity.

Entry Criteria

Disease Characteristics:

• Diagnosis of 1 of the following high-risk myeloid leukemias:
  • Accelerated phase chronic myelogenous leukemia (CML)
  • Blastic phase CML
  • Acute myeloid leukemia (AML) beyond first remission
  • Primary refractory AML
  • Acute leukemia arising in a patient with an prior diagnosis of a myelodysplastic or myeloproliferative syndrome (including chronic myelomonocytic leukemia, CML, polycythemia vera, essential thrombocytosis, and agnogenic myeloid metaplasia with myelofibrosis)
    • Any stage disease



• Undergoing allogeneic stem cell transplantation



• Patient and donor must be HLA-A2 positive



• Able and willing to provide blood and bone marrow samples for study



• Highest-risk disease group: More than 5% blasts detected in bone marrow or peripheral blood just prior to or at time of transplantation



• Relapsed-disease group: One of the following types of relapsed disease after transplantation:
  • Morphologic relapse defined as at least 1 of the following:
    • Abnormal peripheral blasts in absence of growth factor therapy
    • Abnormal bone marrow blasts more than 5% of nucleated cells
    • Extramedullary chloroma or granulocytic sarcoma
  • Flow cytometric relapse
    • Cells with abnormal immunophenotype in the peripheral blood or bone marrow by flow cytometry and consistent with leukemia relapse or progression
  • Cytogenetic relapse or progression defined by ≥ 1 of the following:
    • Appearance in ≥ 1 more metaphases from bone marrow or peripheral blood cells of either a nonconstitutional cytogenetic abnormality identified in at least 1 cytogenetic study performed prior to transplant or a new abnormality known to be associated with leukemia
    • Increase in the number of Philadelphia chromosome-positive metaphases from bone marrow or peripheral blood between 2 consecutive samples after engraftment in patients with CML
    • Increase in the percentage of bcr/abl+ cells by fluorescence in situ hybridization between 2 consecutive samples after engraftment
  • Molecular relapse or progression
    • Polymerase chain reaction assay of bone marrow or peripheral blood mononuclear cells positive for the presence of the bcr/abl mRNA fusion transcript that quantitatively increases by greater than 1 order of magnitude on a subsequent sample



• No grade III or IV graft-versus-host disease unresponsive to therapy or requiring treatment with any of the following:
  • Anti-CD3 monoclonal antibody
  • Prednisone (or equivalent) more than 0.5 mg/kg/day
  • Other treatments resulting in the ablation or inactivation of T cells (e.g., anti-T-cell monoclonal antibodies)



• No graft rejection or failure

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• No concurrent hydroxyurea

Endocrine therapy

• See Disease Characteristics
• Concurrent immunosuppressive therapy for graft-versus-host disease (GVHD) allowed if 1 of the following:
  • Corticosteroid dose can be tapered to no more than 0.5 mg/kg/day without an increase to grade III or IV acute GVHD or progression of chronic GVHD

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No concurrent agents that may interfere with function or survival of infused cytotoxic T-lymphocyte clones

Patient Characteristics:

Age

• 75 and under

Performance status

• Karnofsky 40-100%

  OR

• Lansky 40-100%

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Not specified

Renal

• Not specified

Other

• No grade 3 or 4 nonhematopoietic organ toxicity

Expected Enrollment

A total of 15-35 patients will be accrued for this study within 3-5 years.

Outcomes

Aplasia

Hematopoietic suppression (neutropenia, lymphopenia, thrombocytopenia, anemia)
Toxicity in any organ system (grade 3 or 4)

Outline

This is an open-label, non-randomized, pilot study.

Donors undergo leukapheresis for the harvest of allogeneic blood mononuclear cells. CD8+ proteinase 3 (PR3)-specific cytotoxic T-lymphocytes (CTLs) are isolated as clones and generated ex vivo.

Patients undergo allogeneic stem cell transplantation.

Patients with relapse/progression (more than 5% leukemic blasts in marrow) after transplantation may receive cytoreductive chemotherapy before adoptive immunotherapy.

After leukemic relapse or progression*, patients receive adoptive immunotherapy comprising allogeneic CD8+ PR3-specific CTLs IV over 1-2 hours on days 0, 7, 14, 28, and 49 and interleukin-2 subcutaneously twice daily on days 28-41 and 49-62. Treatment continues in the absence of unacceptable toxicity.

Patients with disease progression or recurrence after complete or partial response to adoptive immunotherapy may be eligible to repeat treatment.

Blood samples are collected monthly and patients undergo a bone marrow biopsy every 3 months.

After completion of study treatment, patients are followed for up to 2 years.

 [Note: *Patients with > 5% morphologic blasts detectable in bone marrow or peripheral blood just prior to or at the time of transplant will receive therapy phophylactically directly after transplant.]

Trial Contact Information

Trial Lead Organizations

Fred Hutchinson Cancer Research Center

Gunnar Ragnarsson, MD, MSC, Protocol chair		Ph: 206-667-5918 Email: gunnib@u.washington.edu

Registry Information
Official Title		Phase I/II Study Of Adoptive Immunotherapy With CD8+ Proteinase 3 (Myeloblastin)-Specific CTL Clones For HLA-A2+ Patients With Relapse Or Progression Of Disease After Allogeneic Hematopoietic Stem Cell Transplant For High-Risk Myeloid Leukemias
Trial Start Date		2005-08-15
Trial Completion Date		2010-08-15 (estimated)
Registered in ClinicalTrials.gov		NCT00052598
Date Submitted to PDQ		2002-10-09
Information Last Verified		2008-12-28
NCI Grant/Contract Number		CA15704, CA96669, CA18029

Back to Top