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Nonmyeloablative Conditioning With Pre- and Post-Transplant Rituximab Followed by Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients With Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial


Phase 2
18 Years
N/A
Open (Enrolling)
Both
B-cell Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage III Small Lymphocytic Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Small Lymphocytic Lymphoma, T-cell Large Granular Lymphocyte Leukemia

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Trial Information

Nonmyeloablative Conditioning With Pre- and Post-Transplant Rituximab Followed by Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients With Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial


PRIMARY OBJECTIVES:

I. Determine whether nonmyeloablative conditioning and allogeneic hematopoietic cell
transplantation (HCT) improves survival at 18 months for patients with fludarabine
(fludarabine phosphate)-refractory, fludarabine/cyclophosphamide/rituximab (FCR)-failed, or
del 17p CLL over that of historical controls (45% at 18 months) given CAMPATH-1H
(alemtuzumab).

SECONDARY OBJECTIVES:

I. Estimate the overall response rate (complete remission [CR] + partial remission [PR]) by
standard morphologic, flow cytometric, and molecular techniques.

II. Assess the rate of relapse/progression.

III. Define incidences of regimen-related toxicities (RRT) and infections within the first
200 days and the incidence of transplant-related mortality (TRM) within the first year.

IV. Estimate incidences of grade II-III and III-IV acute graft-versus-host disease (GVHD)
and chronic GVHD.

V. Determine whether the addition of Rituximab to the nonmyeloablative conditioning and
allogeneic HCT improves survival at 18 months over our historical data (57% at 18 months).

VI. Determine the incidence of serious adverse events with the addition of Rituximab in
comparison to historical data of unrelated nonmyeloablative HCT.

VII. Evaluate the pharmacokinetics of Rituximab.

VIII. Evaluate B-cell and T-cell immune reconstitution in comparison to historical data of
unrelated nonmyeloablative HCT.

IX. Describe donor and host polymorphisms of the FCgammaRIIIa receptor and cluster of
differentiation (CD)32 and evaluate their impact on disease response and relapse.

X. Investigate the mechanism of disease resistance in relapsed/nonresponding patients.

XI. Isolate donor cytotoxic T lymphocytes specific for host minor histocompatibility
antigens.

OUTLINE:

Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV)
on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38.

Patients undergo single fraction low-dose total-body irradiation (TBI) on day 0. After
completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation
(HSCT) on day 0. Patients then receive rituximab IV on days 10, 24, and 38.

Patients receive an immunosuppressive regimen comprising cyclosporine orally (PO) twice
daily (BID) on days -3 to 56 followed by a taper to day 180 (related recipients) or on days
-3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive
mycophenolate mofetil PO BID on days 0-27 (related recipients) or three times daily (TID) on
days 0-40 followed by a taper to day 96 (unrelated recipients).

After completion of study treatment, patients are followed up at 6 months, 1 year, and then
annually thereafter.


Inclusion Criteria:



- Patients with a diagnosis of CLL (or SLL) or diagnosis of CLL that progresses to
prolymphocytic leukemia (PLL)

- Patients with B-Cell CLL or PLL who:

- Failed to meet National Cancer Institute (NCI) Working Group criteria 2 for
complete or partial response after 2 cycles of therapy with regimen containing
fludarabine (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin)
or with disease relapse within 12 months after completing therapy with a
fludarabine (or another nucleoside analog) containing regimen

- Failed FCR or pentostatin/cyclophosphamide/rituximab (PCR) combination
chemotherapy at any time point

- Patients with novo or acquired "17p deletion" cytogenetic abnormality; patients
should have received induction chemotherapy but could be transplanted in 1st CR

- Patients who have suitable human leukocyte antigen (HLA)-matched related or unrelated
donors willing to receive filgrastim (G-CSF), undergo leukapheresis to collect
peripheral blood mononuclear cell (PBMC), and to donate stem cells

- RELATED DONORS: When more than one potential donor exists, priority should be given
to donors based on HLA identity > cytomegalovirus (CMV) seronegativity > ABO
compatibility > sex matching

- Donor who is HLA phenotypically or genotypically identical at the allele level
at HLA-A, -B, -C, -DRB1, and -DQB1

- Must consent to G-CSF administration and leukapheresis;

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

- Only G-CSF mobilized PBMC only will be permitted as a hematopoietic stem cell
(HSC) source on this protocol

- UNRELATED DONORS:

- Fred Hutchinson Cancer Research Center (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

- UNRELATED DONORS: 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; recommended procedure
for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
reactive antibody screens to class I and 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; a positive anti-donor cytotoxic crossmatch is an
absolute donor exclusion

- UNRELATED DONORS: 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

- UNRELATED DONORS: Only G-CSF mobilized PBMC will be permitted as a HSC source on this
protocol

Exclusion Criteria:

- Infection with human immunodeficiency virus (HIV)

- Active diagnosis of central nervous system (CNS) involvement with CLL

- Patients unwilling to use contraceptive techniques before and for 12 months after HCT

- Pregnant women or females who are breastfeeding

- The addition of cytotoxic agents for 'cytoreduction' with the exception of tyrosine
kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low
dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of
the initiation of conditioning

- Active bacterial or fungal infections unresponsive to medical therapy

- Performance status: Karnofsky score < 60 for adult patients

- Cardiac ejection fraction < 40%; ejection fraction is required if age > 50 years or
there is a history of prior transplant, anthracycline exposure or history of cardiac
disease; and poorly controlled hypertension despite multiple antihypertensives

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity
(TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40% and/or requiring
continuous supplementary oxygen, or severe deficits in pulmonary function testing as
defined by pulmonary consultant service; and the FHCRC principal investigator (PI) of
the study must approve of 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,
hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a
history of bleeding esophageal varices or hepatic encephalopathy, uncorrectable
hepatic synthetic dysfunction evidenced 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

- 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

- DONOR: Age < 12 years

- DONOR: Identical twin

- DONOR: Pregnancy

- DONOR: Infection with HIV

- DONOR: Inability to achieve adequate venous access

- DONOR: Known allergy to filgrastim (G-CSF)

- DONOR: Current serious systemic illness

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Survival

Outcome Time Frame:

At 18 months

Safety Issue:

No

Principal Investigator

Mohamed Sorror

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Federal Government

Study ID:

1840.00

NCT ID:

NCT00104858

Start Date:

December 2004

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Prolymphocytic Leukemia
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Stage III Chronic Lymphocytic Leukemia
  • Stage III Small Lymphocytic Lymphoma
  • Stage IV Chronic Lymphocytic Leukemia
  • Stage IV Small Lymphocytic Lymphoma
  • T-cell Large Granular Lymphocyte Leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Prolymphocytic
  • Lymphoma
  • Leukemia, Large Granular Lymphocytic

Name

Location

Mayo ClinicRochester, Minnesota  55905
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