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Phase II Study of Reduced-Intensity Allogeneic Stem Cell Transplant for High-Risk Chronic Lymphocytic Leukemia (CLL)


Phase 2
18 Years
69 Years
Open (Enrolling)
Both
Leukemia, Lymphoma

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Trial Information

Phase II Study of Reduced-Intensity Allogeneic Stem Cell Transplant for High-Risk Chronic Lymphocytic Leukemia (CLL)


OBJECTIVES:

Primary

- To determine if reduced-intensity allogeneic stem cell transplantation can improve
2-year progression-free survival (PFS) of patients with chronic lymphocytic leukemia
(CLL) or small lymphocytic lymphoma (SLL) in the early disease cohort compared to
historical controls.

Secondary

- To determine whether 2-year PFS ≥ 50% can be achieved and 2-year PFS ≤ 30% can be
excluded in patients with CLL or SLL in the advanced disease cohort.

- To assess objective response rate.

- To assess the incidence of grade 2-4 and 3-4 acute graft-vs-host disease (GVHD).

- To assess the incidence of extensive chronic GVHD.

- To assess the incidence of treatment-related mortality at 100 days and 1 year after
transplantation.

- To assess overall survival.

- To assess donor chimerism for CD3+ cells at 1 and 2 years after transplantation.

- To investigate the presence of donor antigen-specific T-cell clones before and after
withdrawal of immune suppression.

- To compare the relapse profiles of patients with T-cell responses against CLL to those
whose CLL cells are not reactive.

- To prospectively examine the impact of high-risk genomic features and immune-based
single nucleotide polymorphisms on response, toxicity, and 2-year PFS.

OUTLINE: This is a multicenter study.

- Preparative regimen: Patients receive 1 of 2 preparative regimens at the discretion of
the participating institution.

- Preparative regimen 1: Patients receive rituximab IV on days -7, -1, 7, and 14 and
fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -5
to -2. .

- Preparative regimen 2: Patients receive rituximab IV on days -7, -1, 7, and 14,
fludarabine phosphate IV over 30 minutes on days -5 to -2, and cyclophosphamide IV
over 1-2 hours on days -5 to -3. Patients with matched unrelated donors also
receive anti-thymocyte globulin IV over 4-6 hours on days -6 to -4.

- Graft-vs-host disease (GVHD) prophylaxis: Patients who receive preparative regimen 1
may receive either GVHD prophylaxis regimen 1 or 2; patients who receive preparative
regimen 2 may only receive GVHD prophylaxis regimen 2.

- GVHD prophylaxis regimen 1: Patients receive tacrolimus either orally or IV and
oral sirolimus beginning on day -2 and continuing until day 60, followed by a
taper until day 180. Patients also receive methotrexate IV on days 1, 3, and 6.

- GVHD prophylaxis regimen 2: Patients receive tacrolimus either orally or IV
beginning on day -2 and continuing until day 60, followed by a taper until day
180. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

- Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation
on day 0.

- Maintenance therapy: Patients receive rituximab IV at 3, 6, 9, and 12 months after
transplantation.

Peripheral blood and bone marrow aspirate samples may be collected periodically for
correlative laboratory studies.

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

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of B-cell chronic lymphocytic leukemia or B-cell small lymphocytic lymphoma
according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008
criteria

- Meets 1 of the following criteria:

- Early disease cohort:

- Meets ≥ 1 of the following criteria:

- FISH showing deletion 17p in ≥ 20% of cells (either at diagnosis or
any time before study entry) either alone or in combination with other
cytogenetic abnormalities

- FISH showing deletion 11q in ≥ 20% of cells (either at diagnosis or
any time before study entry) either alone or in combination with other
cytogenetic abnormalities, unless the patient has achieved a complete
remission, according to IWCLL 2008 criteria which includes CT scan,
bone marrow morphology, and flow cytometry

- Failed to achieve a partial response to initial therapy but lack of
disease progression (may receive a second therapy to improve response
before transplant)

- Received ≥ 2 courses of induction therapy (it is expected that patients
will receive ≥ 4 months of therapy prior to enrollment, but this is not
required)

- Suggested regimens include, but are not limited to, the following:

- Fludarabine phosphate and rituximab

- Fludarabine phosphate, cyclophosphamide, and rituximab

- Pentostatin, cyclophosphamide, and rituximab

- Bendmustine and rituximab

- Alemtuzumab alone or in combination with other agents

- Stable disease or better after most recent therapy (i.e., no prior
progression), according to the revised IWCLL 2008 criteria

- Nodes ≤ 5 cm

- Advanced disease cohort:

- Meets ≥ 1 of the following criteria:

- First disease progression < 24 months after completing (this includes
progression on initial therapy)

- Second or subsequent progression

- Stable disease or better after most recent chemotherapy, according to the
revised IWCLL 2008 criteria

- Nodes ≤ 5 cm

- FISH showing deletion of 17p in ≥ 20% of cells (regardless of interval from
initial therapy) either alone or in combination with other cytogenetic
abnormalities

- Has an HLA-matched related or unrelated donor available

- 6/6 HLA-matched related donor by low-resolution typing at HLA A, B, C, and DR

- 8/8 HLA-matched unrelated donor by molecular typing at both HLA class I and
class II (A, B, C, and DR loci)

- No syngeneic donors

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Serum creatinine < 2 mg/dL

- Calculated creatinine clearance ≥ 40 mL/min

- AST < 3 times upper limit of normal

- Total bilirubin < 2 mg/dL (except for patients with Gilbert syndrome)

- DLCO ≥ 40% predicted

- LVEF ≥ 30% by ECHO or MUGA

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- HIV negative

- Hepatitis B surface antigen negative

- Anti-hepatitis B core antigen negative

- Hepatitis C antibody negative

- No uncontrolled diabetes mellitus or active uncontrolled serious infections

- No history of Richter transformation

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 4 weeks after day 1 of the last course since prior cytotoxic chemotherapy or
alemtuzumab

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

2-year progression-free survival

Safety Issue:

No

Principal Investigator

Edwin P. Alyea, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

Unspecified

Study ID:

CDR0000660555

NCT ID:

NCT01027000

Start Date:

February 2010

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • refractory chronic lymphocytic leukemia
  • stage I chronic lymphocytic leukemia
  • stage II chronic lymphocytic leukemia
  • stage III chronic lymphocytic leukemia
  • stage IV chronic lymphocytic leukemia
  • B-cell chronic lymphocytic leukemia
  • contiguous stage II small lymphocytic lymphoma
  • noncontiguous stage II small lymphocytic lymphoma
  • recurrent small lymphocytic lymphoma
  • stage I small lymphocytic lymphoma
  • stage III small lymphocytic lymphoma
  • stage IV small lymphocytic lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
University of Chicago Cancer Research CenterChicago, Illinois  60637
CCOP - Christiana Care Health ServicesWilmington, Delaware  19899
CCOP - North Shore University HospitalManhasset, New York  11030
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
City of Hope Comprehensive Cancer CenterDuarte, California  91010
Long Island Jewish Medical CenterNew Hyde Park, New York  11040
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
New York Weill Cornell Cancer Center at Cornell UniversityNew York, New York  10021
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Siteman Cancer Center at Barnes-Jewish Hospital - Saint LouisSt. Louis, Missouri  63110
Don Monti Comprehensive Cancer Center at North Shore University HospitalManhasset, New York  11030
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Cancer Institute of New Jersey at Cooper - VoorheesVoorhees, New Jersey  08043
Massachusetts General HospitalBoston, Massachusetts  02114-2617
H. Lee Moffitt Cancer Center and Research Institute at University of South FloridaTampa, Florida  33612
Tunnell Cancer Center at Beebe Medical CenterLewes, Delaware  19958
Monter Cancer Center of the North Shore-LIJ Health SystemLake Success, New York  11042
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer CenterColumbus, Ohio  43210-1240
Union Hospital of Cecil CountyElkton MD, Maryland  21921
Dana-Farber/Brigham and Women's Cancer CenterBoston, Massachusetts  02115