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Induction Of Mixed Hematopoietic Chimerism Using Fludarabine, Low Dose TBI , PBSC Infusion And Post-Transplant Immunosuppression With Cyclosporine And Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion In Patients With Chronic Myeloid Leukemia in Chronic and Accelerated Phases: A Multi-Center Study.


Phase 2
N/A
74 Years
Open (Enrolling)
Both
Accelerated Phase Chronic Myelogenous Leukemia, Childhood Chronic Myelogenous Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, Relapsing Chronic Myelogenous Leukemia

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Trial Information

Induction Of Mixed Hematopoietic Chimerism Using Fludarabine, Low Dose TBI , PBSC Infusion And Post-Transplant Immunosuppression With Cyclosporine And Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion In Patients With Chronic Myeloid Leukemia in Chronic and Accelerated Phases: A Multi-Center Study.


PRIMARY OBJECTIVES:

I. To determine if mixed hematopoietic chimerism can be safely established using a
non-myeloablative conditioning regimen in patients > 65 years of age with CML in chronic or
accelerated phase who have human leukocyte antigen (HLA) identical related donors.

II. To determine if mixed chimerism, established with non-myeloablative conditioning
regimens, can be converted to full donor hematopoietic chimerism by infusions of donor
lymphocytes (DLI), and thereby produce an immunologic cure of the malignancy.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4
to -2 and undergo low-dose total-body irradiation (TBI) on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation
(PBSCT) on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV BID or
thrice daily (TID) on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil
PO or IV BID on days 0-27.

DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor
cluster of differentiation (CD)3+ T cells and no evidence of graft-versus-host disease
(GVHD) receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at
increasing cell doses in the absence of GVHD.

After completion of study treatment, patients are followed up periodically for 5 years.


Inclusion Criteria:



- Patients with Philadelphia chromosome positive (Ph+) CML in first and second chronic
and first accelerated phases

- Patients =< 65 years old who are at high risk of regimen related toxicity through
pre-existing chronic disease affecting liver, lungs, and/or heart, or others who wish
to be treated on this protocol, will be considered on a case-by-case basis;
transplants should be approved for these inclusion criteria by both the participating
institutions' patient review committees such as the Patient Care Conference (PCC) at
the Fred Hutchinson Cancer Research Center (FHCRC) and by the principal investigators
at the collaborating centers; patients =< 65 years of age who have received previous
high-dose transplantation do not require patient review committee approvals; all
children < 12 years must be discussed with the FHCRC principal investigator (PI)
(Brenda Sandmaier, MD 206-667-4961) prior to registration

- HLA genotypically identical related donor willing to undergo leukapheresis initially
for collection of peripheral blood stem cell (PBSC) and subsequently for collection
of peripheral blood mononuclear cell (PBMC)

- Patients treated with alpha interferon must have discontinued drug at least 1 month
prior to transplant

- DONOR: HLA genotypically identical family member (excluding identical twins)

- DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis

- DONOR: Donor must have adequate veins for leukapheresis or agree to placement of
central venous catheter (femoral, subclavian)

Exclusion Criteria:

- GROUP 1: (PATIENTS AGED > 65 AND < 75 YEARS)

- Patients who are human immunodeficiency virus positive (HIV+)

- Patients unwilling to use contraceptive techniques during and for 12 months following
treatment

- Presence of circulating leukemic blasts (in the peripheral blood) detected by
standard pathology for patients with CML

- Patients in an interferon induced complete or partial cytogenetic remission

- Organ dysfunction:

- Patients with renal failure are eligible, however patients with renal compromise
(Serum creatinine greater than 2.0) will likely have further compromise in renal
function and may require hemodialysis (which may be permanent) due to the need
to maintain adequate serum cyclosporine levels

- Cardiac ejection fraction < 40%; ejection fraction is required if the patient
has a history of anthracyclines or history of cardiac disease

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted

- Liver function tests including total bilirubin, serum glutamic pyruvate
transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2x the
upper limit of normal unless proven to be due to the malignancy

- Karnofsky score < 70

- Patients with poorly controlled hypertension

- GROUP 2 (PATIENTS AGED =< 65)

- Patients who are HIV+

- Presence of circulating leukemic blasts (in the peripheral blood) detected by
standard pathology for patients with CML

- Females who are pregnant

- Patients unwilling to use contraceptive techniques during and for 12 months following
treatment

- Patients in an interferon induced complete or partial cytogenetic remission

- Organ dysfunction:

- Patients with renal failure are eligible, however patients with renal compromise
(Serum creatinine greater than 2.0) will likely have further compromise in renal
function and may require hemodialysis (which may be permanent) due to the need
to maintain adequate serum cyclosporine levels

- Cardiac ejection fraction < 40% or a history of congestive heart failure;
ejection fraction is required if the patient has a history of anthracyclines or
history of cardiac disease

- Severe defects in pulmonary function testing as defined by the pulmonary
consultant (defects are currently categorized as mild, moderate and severe) or
receiving supplementary continuous oxygen; DLCO < 50% of predicted

- Liver function tests: total bilirubin > 2x the upper limit of normal, SGPT and
SGOT 4x the upper limit of normal

- Karnofsky score < 50

- Patients with poorly controlled hypertension

- DONOR: Age less than 12 years

- DONOR: Pregnancy

- DONOR: Infection with HIV

- DONOR: Inability to achieve adequate venous access

- DONOR: Known allergy to G-CSF

- DONOR: Current serious systemic illness

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety of establishing mixed chimerism using this non-lethal conditioning regimen, in terms of development of GVHD, myelosuppression, infections, and treatment-related mortality

Outcome Description:

All unexpected toxicities will be summarized and reported.

Outcome Time Frame:

Within the first 65 days

Safety Issue:

Yes

Principal Investigator

Brenda Sandmaier

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Federal Government

Study ID:

1209.00

NCT ID:

NCT00003145

Start Date:

August 1997

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Childhood Chronic Myelogenous Leukemia
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Phase Chronic Myelogenous Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase

Name

Location

Stanford UniversityStanford, California  94305
Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
University of ColoradoDenver, Colorado  80217
Baylor University Medical CenterDallas, Texas  75246
VA Puget Sound Health Care SystemSeattle, Washington  98101
City of Hope Medical CenterDuarte, California  91010