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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 1
14 Years
N/A
Not Enrolling
Both
Leukemia, Myelodysplastic Syndromes

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Trial Information

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


OBJECTIVES:

Primary

- Determine the toxic effects of adoptive immunotherapy comprising CD8-positive minor
histocompatability antigen-specific cytotoxic T-lymphocytes in patients with acute
myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes that
relapsed after allogeneic hematopoietic stem cell transplantation.

Secondary

- Determine the persistence of adoptively transfused T cells in vivo and assess their
migration to the bone marrow in these patients.

- Determine the anti-leukemic activity of this therapy in these patients.

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:

- Mitoxantrone IV and etoposide IV on days -6 to -2

- High-dose cytarabine IV over 2 hours twice daily on days -6, -4, and -2 Patients
achieving a complete remission after completion of cytoreductive chemotherapy
proceed to adoptive immunotherapy.

- 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.

Inclusion Criteria


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:

- Chronic myelomonocytic leukemia

- Chronic myelogenous leukemia

- Polycythemia vera

- Essential thrombocytosis

- Agnogenic myeloid metaplasia with myelofibrosis

- 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:

- Peripheral blasts in the absence of growth factor therapy

- Bone marrow blasts > 5% of nucleated cells

- Extramedullary chloroma or granulocytic sarcoma

- 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:

- 1 or more positive polymerase chain reaction (PCR) assays for clonotypic
immunoglobulin heavy chain or T-cell receptor gene rearrangement in
patients transplanted for B- or T-cell ALL respectively

- 1 or more positive post-transplantation reverse transcription PCR assays
for p190 BCR-ABL mRNA fusion transcripts in patients transplanted for
Philadelphia chromosome-positive p190-positive ALL

- 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

- 14 and over (patients < 14 years of age may be eligible if they are deemed to be of
sufficient height and weight by the pediatric attending physician)

Performance status

- Karnofsky 60-100% (at time of post-transplant relapse)

Life expectancy

- Not specified

Hematopoietic

- Not specified

Hepatic

- Not specified

Renal

- Not specified

Other

- No preexisting major nonhematopoietic organ toxicity ≥ grade 3 (at time of
post-transplant relapse)

PRIOR CONCURRENT THERAPY:

Biologic therapy

- Not specified

Chemotherapy

- Not specified

Endocrine therapy

- Concurrent immunosuppressive steroid therapy for GVHD allowed provided both of the
following are true:

- Able to taper steroid dose to < 0.5 mg/kg/day

- No increase of > 1 grade in acute GVHD OR progression of chronic GVHD within 14
days after dose change

Radiotherapy

- Not specified

Surgery

- Not specified

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity

Safety Issue:

Yes

Principal Investigator

Edus H. Warren, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center

Authority:

United States: Federal Government

Study ID:

1334.00

NCT ID:

NCT00107354

Start Date:

December 1998

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • recurrent adult acute lymphoblastic leukemia
  • recurrent adult acute myeloid leukemia
  • recurrent childhood acute lymphoblastic leukemia
  • recurrent childhood acute myeloid leukemia
  • secondary acute myeloid leukemia
  • refractory anemia with excess blasts in transformation
  • refractory anemia with excess blasts
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • T-cell adult acute lymphoblastic leukemia
  • T-cell childhood acute lymphoblastic leukemia
  • B-cell adult acute lymphoblastic leukemia
  • B-cell childhood acute lymphoblastic leukemia
  • childhood myelodysplastic syndromes
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109