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Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplantation From a Haploidentical Donor for Patients With Acute Leukemia and Myelodysplasia


Phase 1
N/A
50 Years
Open (Enrolling)
Both
Leukemia, Myelodysplastic Syndromes

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Trial Information

Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplantation From a Haploidentical Donor for Patients With Acute Leukemia and Myelodysplasia


OBJECTIVES:

Primary

- Establish the feasibility of delayed infusion of ex vivo anergized donor peripheral
blood mononuclear cells (PBMC) after CD34-selected megadose haploidentical
hematopoietic stem cell transplantation (HSCT) in patients with hematopoietic cancers
or other diseases.

- Determine the feasibility of collecting parental allogeneic stimulator cells to induce
anergy to the nonshared donor-recipient haplotype in these patients.

- Determine the feasibility of collecting donor PBMC as a source of T cells for ex vivo
anergization.

- Determine the number of transplanted individuals who meet the criteria for proceeding
to delayed infusion of ex vivo anergized donor PBMC.

- Establish the safety of delayed infusion of ex vivo anergized donor PBMC by
establishing the maximum number of donor T cells that can be infused without
unacceptable graft-versus-host disease.

Secondary

- Evaluate, in vitro, the induction and specificity of alloantigen hyporesponsiveness in
donor PBMC after ex vivo anergization.

- Assess, in vitro, the function of immune cells engrafted in these patients.

- Assess, in vitro, whether alloantigen hyporesponsive donor T cells are present in these
patients.

- Develop, preliminarily, in vitro data on the extent of pathogen-specific immunity and
its rate of recovery.

- Describe the patterns of opportunistic infections in these patients.

OUTLINE: This is a multicenter, dose-escalation study of ex vivo anergized allogeneic
peripheral blood mononuclear cells (PBMC). Patients who are treated on any dose level except
dose level 1 are stratified according to age (under 17 [pediatric] vs 17 and over [adult]).

- Myeloablative conditioning regimen: Patients undergo total-body irradiation twice daily
on days -11 to -9. Patients also receive thiotepa IV over 4 hours on days -8 and -7,
fludarabine phosphate IV over 30 minutes on days -7 to -3, and anti-thymocyte globulin
IV over 8 hours and methylprednisolone IV over 15-30 minutes on days -6 to -3.

- Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo
CD34-selected PBSCT on day 0.

- Ex vivo anergized allogeneic PBMC infusion: If cells have engrafted and patients are
free of active uncontrolled infection and graft-vs-host disease, patients undergo
allogeneic or autologous PBMC infusion on day 35 or 42.

Cohorts of 3-8 patients receive escalating doses of ex vivo anergized allogeneic PBMCs until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of
5 or 3 of 8 patients experience dose-limiting toxicity.

After completion of study, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of 1 of the following:

- Acute lymphocytic leukemia

- In ≥ second complete remission (CR), defined as < 5% blasts in bone marrow
(BM) and no active extramedullary disease OR in first CR with any of the
following high risk features:

- History of induction failure

- Philadelphia chromosome positive

- t(4;11) by cytogenetic analysis

- Any infant with MLL rearrangements on cytogenetic analysis

- No relapse with isolated extramedullary disease after completion of prior
treatment

- Acute myeloid leukemia

- Failed induction therapy after < 3 courses

- In ≥ second CR, defined as < 5% blasts in BM and no active extramedullary
disease OR in first CR with any of the following high-risk features:

- History of induction failure = 5q- or monosomy 7 cytogenetic findings

- Any of the following myelodysplastic syndromes:

- Refractory anemia (RA) with excess blasts (RAEB) with a high International
Prognostic Scoring System (IPSS) score or score of intermediate-1(INT-1) or
intermediate-2 (INT-2)

- RAEB in transformation with INT-1, INT-2, or high IPSS score

- RA with INT-2 score

- Patients must have a healthy, related donor who is at least genotypically HLA-A, B,
C, and DR haploidentical to the patient

- No suitably matched family donor defined by genotypic or phenotypic identity for
≥ 5/6 A, B, or DR loci

- No immediately available genotypically matched (6/6) unrelated marrow donor

- No immediately available umbilical cord blood donor with suitable cell dose
after a search ≥ 2 months

- Patients whose medical condition is at high risk of deteriorating or whose
disease is at high risk of progression during a donor search are eligible

- Has a parent with a haplotype that is disparate from that of the donor for the
haplotype shared by the patient and parent, but not shared by the patient and donor
OR patient is able to donate sufficient autologous cells by peripheral blood draw or
unstimulated leukapheresis

- No active CNS disease

PATIENT CHARACTERISTICS:

- Room air O_2 saturation > 95% unless the lungs are involved with disease

- No clinical evidence of pulmonary insufficiency unless the lungs are involved with
disease

- AST and ALT < 3 times upper limit of normal (ULN)*

- Bilirubin < 2.0 mg/dL*

- Creatinine < 2 times ULN OR creatinine clearance or glomerular filtration rate > 50%
of the lower limit of normal

- LVEF > 45% OR shortening fraction > 20%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No active infection, defined as absence of an infectious diagnosis or (in patients
who have had a recent positive infectious diagnosis) the resolution of fever,
documentation of negative cultures or antigen testing, continuation or completion of
a course of appropriate therapy, and presence of stable to resolving clinical
symptoms

- No evidence of HIV infection OR known HIV positivity NOTE: *Does not apply if liver
is involved with disease

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior stem cell transplantation

- No other concurrent immunosuppressive therapy

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Feasibility

Safety Issue:

No

Principal Investigator

Eva Guinan, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

Unspecified

Study ID:

CDR0000491633

NCT ID:

NCT00376480

Start Date:

March 2005

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • refractory anemia with excess blasts in transformation
  • adult acute lymphoblastic leukemia in remission
  • refractory anemia with excess blasts
  • refractory anemia
  • adult acute myeloid leukemia in remission
  • childhood acute lymphoblastic leukemia in remission
  • childhood acute myeloid leukemia in remission
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary acute myeloid leukemia
  • 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)
  • secondary myelodysplastic syndromes
  • childhood myelodysplastic syndromes
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
Childrens Hospital Los AngelesLos Angeles, California  90027
M. D. Anderson Cancer Center at University of TexasHouston, Texas  77030-4009
Massachusetts General HospitalBoston, Massachusetts  02114-2617
Children's Hospital BostonBoston, Massachusetts  02115