Phase I Study of Adoptive Immunotherapy With CD8 Minor Histocompatibility (H) Antigen-Specific CTL Clones for Patients With Relapsed of AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant
Phase I Study of Adoptive Immunotherapy With CD8 Minor Histocompatibility (H) Antigen-Specific CTL Clones for Patients With Relapsed of AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant
RATIONALE: Biological therapies, such as cellular adoptive immunotherapy, stimulate the immune system in different ways and stop cancer cells from growing.
PURPOSE: This phase I trial is studying the side effects of cellular adoptive immunotherapy in treating patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes that relapsed after donor stem cell transplant.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a pilot, open-label, nonrandomized study.
Leukapheresis: Patients undergo leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) before transplantation. Donors undergo leukapheresis to obtain PBMCs to use as feeder cells for generating adoptive immunotherapy. Patient PBMCs are combined with donor PBMCs and expanded in vitro to generate CD8-positive minor histocompatability antigen-specific cytotoxic T-lymphocytes (CTLs) for adoptive immunotherapy.
Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation. Patients with a morphologic or flow cytometric relapse on or after day 100 post-transplantation proceed to cytoreductive chemotherapy. Patients with a molecular or cytogenetic relapse on or after day 100 post-transplantation proceed directly to adoptive immunotherapy. Patients with relapsed disease before day 100 post-transplantation are eligible to receive adoptive immunotherapy at a later date provided the patient continues to relapse and CTLs are available.
Cytoreductive chemotherapy: The chemotherapy regimen for each patient is determined after consideration of prior chemotherapy, type of leukemia, and other clinical parameters. Two regimens to consider are:
Adoptive immunotherapy: Within 2-3 days after completion of cytoreductive chemotherapy, patients receive CTLs IV over 1-2 hours on days 0, 4, 11, 21, and 28 in the absence of unacceptable toxicity. Patients with evidence of persistent disease on or after day 35 OR relapsed disease after an initial response to CTLs receive a sixth infusion of CTLs followed, no more than 24 hours later, by interleukin-2 subcutaneously once daily for up 14 total doses in the absence of unacceptable toxicity. Patients with subsequent relapsed disease after day 48 may be eligible for retreatment.
After completion of study treatment, patients are followed with bone marrow aspiration every 3 months for 1 year.
PROJECTED ACCRUAL: A total of 25-30 patients (10-15 with acute myeloid leukemia or myelodysplastic syndromes AND 10-15 with acute lymphoblastic leukemia) will be accrued for this study within 3 years.
DISEASE CHARACTERISTICS:
Undergoing allogeneic hematopoietic stem cell transplantation* from a major histocompatability complex (MHC)-identical related donor for 1 of the following:
Primary refractory acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL)
AML or ALL beyond first remission
Therapy-related AML at any stage
Philadelphia chromosome (bcr-abl)-positive p190-positive ALL at any stage
Acute leukemia at any stage arising from myelodysplastic syndromes or myeloproliferative disorders, including any of the following:
Refractory anemia with excess blasts
Refractory anemia with excess blasts in transformation NOTE: *Patients must be enrolled on study prior to undergoing transplantation
Relapsed disease post-transplantation, as evidenced by 1 of the following criteria:
Morphologic relapse, as defined by 1 or more of the following:
Flow cytometric relapse, as defined by the appearance of cells with abnormal immunophenotype consistent with leukemia relapse in the peripheral blood or bone marrow (detected before transplantation)
Cytogenetic relapse, as defined by the appearance in 1 or more metaphases from bone marrow or peripheral blood cells of either a non-constitutional cytogenetic abnormality detected in at least 1 cytogenetic study performed before transplantation OR a new abnormality known to be associated with leukemia
Molecular relapse, as defined by 1 of the following:
No grade III or IV acute graft-versus-host disease (GVHD)**
No extensive chronic GVHD** NOTE: **At time of post-transplant relapse
PATIENT CHARACTERISTICS:
Age
Performance status
Life expectancy
Hematopoietic
Hepatic
Renal
Other
PRIOR CONCURRENT THERAPY:
Biologic therapy
Chemotherapy
Endocrine therapy
Concurrent immunosuppressive steroid therapy for GVHD allowed provided both of the following are true:
Radiotherapy
Surgery