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Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive Ph+ Acute Leukemia - a Multi-Center Trial


Phase 2
N/A
70 Years
Open (Enrolling)
Both
Adult Acute Lymphoblastic Leukemia in Remission, Blastic Phase Chronic Myelogenous Leukemia, Childhood Acute Lymphoblastic Leukemia in Remission, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Relapsing Chronic Myelogenous Leukemia

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Trial Information

Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive Ph+ Acute Leukemia - a Multi-Center Trial


PRIMARY OBJECTIVES:

I. To determine whether the rate of leukemia relapse can be decreased for patients with
chronic myelogenous leukemia in blast crisis (CML-BC) and philadelphia chromosome positive
acute lymphoblastic leukemia (Ph+ ALL) responsive to imatinib mesylate (or either dasatinib
or nilotinib for patients who have imatinib-resistant disease or who are intolerant of
imatinib) followed by nonmyeloablative hematopoietic stem cell transplantation (HSCT)
compared to historical controls given high-dose conventional allogeneic HSCT or
chemotherapy.

II. To determine whether the rate of transplantation-related mortality (TRM) can be
decreased for patients with CML-BC and Ph+ ALL responsive to imatinib mesylate (or dasatinib
or nilotinib) followed by nonmyeloablative HSCT compared to historical controls given
high-dose conventional allogeneic HSCT or chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate whether donor lymphocyte infusion (DLI) can be safely used in patients with
mixed or full donor chimerism as preemptive therapy to eliminate minimal residual disease.

OUTLINE:

INDUCTION THERAPY: Patients continue to receive imatinib mesylate orally (PO), dasatinib PO,
or nilotinib PO once or twice daily until day -2 and resume on day 14 or when blood counts
recover after peripheral blood stem cell (PBSC) transplantation.

NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine intravenously (IV) on days -4 to
-2; and undergo TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSC transplantation on day 0.

GRAFT-VERSUS-HOST-DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil (MMF)
PO every 12 hours on days 0-27 (related donor recipients) or every 8 hours on days 0-96 with
taper on day 40 (unrelated donor recipients). Patients also receive cyclosporine IV or PO
every 12 hours on days -3 to 56, followed by taper on days 57-180 (related donor recipients)
or on days -3 to 100, followed by taper on days 101-177 (unrelated donor recipients).

DONOR LYMPHOCYTE INFUSION: Patients with persistent disease and no GVHD after stopping GVHD
prophylaxis receive donor lymphocyte infusion IV over 30 minutes once every 28 days for 3
doses.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed up periodically for 2 years and then annually thereafter for 5 years.


Inclusion Criteria:



- Patients =< 12 years of age must be approved by Fred Hutchinson Cancer Research
Center (FHCRC) principal investigator (PI) in advance

- Patients with a history of Ph+ ALL or CML-BC who, after receiving imatinib mesylate,
(or either dasatinib or nilotinib) have < 15% blasts on morphologic marrow
evaluation; patients with no detectable Ph+ ALL by morphologic or molecular assays
(complete remission) will be accepted

- An appropriately human leukocyte antigen (HLA) matched related or unrelated donor
must be prospectively identified who will be available to donate filgrastim (G-CSF)
mobilized stem cells

- RELATED DONOR:

- Related donor who is HLA genotypically identical at least at one haplotype and
may be genotypically or phenotypically identical at the allele level at HLA-A,
-B, -C, -DRB1, and -DQB1;

- Donor must consent to G-CSR administration and leukapheresis;

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

- HLA-MATCHED UNRELATED DONOR:

- FHCRC matching allowed will be Grades 1.0 to 2.1; Unrelated donors who are
prospectively matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing;
only a single allele disparity will be allowed for HLA-A, B, or C as defined by
high resolution typing

- A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion;
Donors are excluded when preexisting immunoreactivity is identified that would
jeopardize donor hematopoietic cell engraftment; This determination is based on
the standard practice of the individual institution; The recommended procedure
for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a
panel reactive antibody (PRA) screens to class I and class II antigens for all
patients before HCT; If the PRA shows >10% activity, then flow cytometric or B
and T cell cytotoxic cross matches should be obtained; The donor should be
excluded if any of the cytotoxic cross match assays are positive; For those
patients with an HLA Class I allele mismatch, flow cytometric or B and T cell
cytotoxic cross matches should be obtained regardless of the PRA results

- Patient and donor pairs homozygous at a mismatched allele in the graft rejection
vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the
donor is A*0102, and this type of mismatch is not allowed

- Only G-CSF mobilized PBSC only will be permitted as a HSC source on this
protocol

Exclusion Criteria:

- Central nervous system (CNS) involvement with leukemia refractory to intrathecal
chemotherapy; prior to HSCT (all patients must receive a diagnostic lumbar puncture
(LP) with intrathecal (IT) chemotherapy as per standard practice)

- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following treatment

- Patients with active non-hematologic malignancies (except non-melanoma skin cancers);
this exclusion does not apply to patients with non-hematologic malignancies that do
not require therapy

- Patients with a history of non-hematologic malignancies (except non-melanoma skin
cancers) currently in a complete remission, who are less than 5 years from the time
of complete remission, and have a > 20% risk of disease recurrence; this exclusion
does not apply to patients with non-hematologic malignancies that do not require
therapy

- Females who are pregnant or breastfeeding

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

- Patients with poorly controlled hypertension despite multiple antihypertensives

- Adults: Karnofsky score < 60

- Pediatrics: Lansky Play-Performance Score < 40

- Patients with cardiac ejection fraction < 35% (or, if unable to obtain ejection
fraction, shortening fraction of < 26%); ejection fraction is required if age > 50
years or there is a history of anthracycline exposure or history of cardiac disease;
patients with a shortening fraction < 26% may be enrolled if approved by a
cardiologist

- Diffusing capacity of the lungs for carbon monoxide (DLCO) < 30%

- Total lung capacity (TLC) < 30%

- Forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary
continuous oxygen; the FHCRC PI of the study must approve enrollment of all patients
with pulmonary nodules

- Patients with clinical or laboratory evidence of liver disease would be evaluated for
the cause of liver disease, its clinical severity in terms of liver function, and the
degree of portal hypertension; patients will be excluded if they are found to have
fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension,
alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices,
hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by
prolongation of the prothrombin time, ascites related to portal hypertension,
bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with
total serum bilirubin > 3 mg/dL, or symptomatic biliary disease

- Creatinine levels more than 2.2 X's the upper limit of normal (ULN) at the laboratory
where the analysis was performed

- Patients with active bacterial or fungal infections unresponsive to medical therapy

- For patients receiving dasatinib or nilotinib, baseline QTc (Fridericia's method)
prolongation greater than 500 msec

- RELATED DONORS:

- Identical twin;

- Infection with HIV;

- Inability to achieve adequate venous access;

- Known allergy to G-CSF;

- Current serious system illness;

- Bone marrow (BM) donors

- HLA-MATCHED UNRELATED DONORS:

- BM donors

- Donors who are HIV-positive and/or, medical conditions that would result in
increased risk for G-CSF mobilization and harvest of PBSC

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Rate of relapse

Outcome Time Frame:

Assessed up to 5 years

Safety Issue:

No

Principal Investigator

George Georges

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Federal Government

Study ID:

1581.00

NCT ID:

NCT00036738

Start Date:

July 2001

Completion Date:

Related Keywords:

  • Adult Acute Lymphoblastic Leukemia in Remission
  • Blastic Phase Chronic Myelogenous Leukemia
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Phase Chronic Myelogenous Leukemia
  • Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
  • Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase
  • Philadelphia Chromosome

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
VA Puget Sound Health Care SystemSeattle, Washington  98101
Presbyterian - Saint Lukes Medical Center - Health OneDenver, Colorado  80218