Pentostatin, Cyclophosphamide, Rituximab, and Mitoxantrone in Treating Patients With Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Cancer

Conditions:Blood Cancer, Lymphoma, Leukemia
Therapuetic Areas:Oncology
Age Range:Any
Start Date:July 2005

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A Phase I-II Study of Pentostatin, Cyclophosphamide, Rituximab, and Mitoxantrone in Previously Treated Patients With Chronic Lymphocytic Leukemia and Other Low Grade B-Cell Neoplasms

RATIONALE: Pentostatin may stop the growth of cancer cells by blocking some of the enzymes
needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and
mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing
the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can
block cancer growth in different ways. Some block the ability of cancer cells to grow and
spread. Others find cancer cells and help kill them or carry cancer-killing substances to
them. Giving pentostatin together with combination chemotherapy and rituximab may kill more
cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of mitoxantrone
when given together with pentostatin, cyclophosphamide, and rituximab and to see how well it
works in treating patients with chronic lymphocytic leukemia or other low-grade B-cell


- To determine the dose of mitoxantrone hydrochloride that can be safely administered
with pentostatin, cyclophosphamide, and rituximab in patients with previously treated
chronic lymphocytic leukemia or other low-grade B-cell malignancies.

- To characterize the toxicity of this regimen in these patients.

- To determine the response rate in patients treated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of mitoxantrone hydrochloride followed by
a phase II study.

- Phase I: Patients receive pentostatin IV, cyclophosphamide IV, and mitoxantrone
hydrochloride IV on day 1. Patients also receive rituximab IV on day 1 beginning in
course 2. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

- Phase II: Patients receive pentostatin, cyclophosphamide, rituximab, and mitoxantrone
hydrochloride (at the maximum tolerated dose determined in phase I) as in phase I.

All patients receive either pegfilgrastim subcutaneously (SC) on days 1-4 following each
course or filgrastim or sargramostim SC beginning 2 days after each course until blood
counts recover.

Patients undergo blood collection and bone marrow biopsy periodically for assessment of
therapy response by biomarker and laboratory studies. Samples are analyzed for molecular
genetics for IgH arrangement by PCR and for response by immunoelectrophoresis. Some samples
are analyzed for response by flow cytometry or fluorescence in situ hybridization (FISH).

After completion of study treatment, patients are followed every 3 months for 1 year.

PROJECTED ACCRUAL: A total of 63 patients (18 patients for phase I and 45 patients for phase
II) will be accrued for this study.


- Diagnosis of 1 of the following diseases confirmed by a Memorial Sloan-Kettering
Cancer Center (MSKCC) pathologist:

- Chronic lymphocytic leukemia meeting the following risk criteria as defined by
the three-stage Rai system:

- Intermediate-risk disease meeting the following criteria for active disease
as defined by the NCI Working Group:

- Weight loss

- Fatigue

- Fevers

- Evidence of progressive marrow failure

- Splenomegaly

- Progressive lymphadenopathy

- Progressive lymphocytosis with a rapid doubling time, defined as
doubling time less than 6 months and absolute lymphocyte count >

- High-risk disease

- Other low grade B-cell neoplasms, including any of the following:

- Small lymphocytic lymphoma

- Follicular lymphoma

- Waldenstrom macroglobulinemia

- Marginal zone lymphomas

- Mantle cell lymphomas

- Transformed lymphoma

- Previously treated disease

- Must have received prior cytotoxic therapy

- Malignant lymphocytes must demonstrate B-cells via immunophenotypic or
immunohistochemical analysis NOTE: A new classification scheme for adult
non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or
"aggressive" lymphoma will replace the former terminology of "low", "intermediate",
or "high" grade lymphoma. However, this protocol uses the former terminology.


- Karnofsky performance status 60-100%

- Life expectancy > 8 weeks

- Total bilirubin ≤ 2.0 mg/dL (patients with Gilbert disease or autoimmune hemolytic
anemia should have an evaluation for other causes of hyperbilirubinemia, but if none
are found, may be enrolled regardless of serum bilirubin)

- Total creatinine ≤ 2.0 mg/dL OR creatinine clearance > 50 mL/min

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Normal cardiac ejection fraction ≥ 50% (increased ejection fraction [at least 5% over
rest]) required for study eligibility

- Borderline (40-50%) ejection fraction must undergo a stress echocardiogram or
MUGA scan

- Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are eligible
for treatment

- Must have undergone consultation with the primary investigator or his/her designee
prior to study entry

- No significant active infections

- No ongoing hepatitis B infection, specifically hepatitis B antigen or surface antigen

- Hepatitis B antibody-positive patients are eligible


- See Disease Characteristics

- The following concurrent medications are allowed:

- Intravenous immunoglobulin (IVIG)

- Erythropoietin, darbepoetin, filgrastim, or sargramostim

- Cyclosporine (only for patients with cellular immune cytopenias [i.e., pure red
cell aplasia]), with required consultation of the principle investigator or

- Concurrent prednisone allowed provided it is used as brief courses (≤ 7 days) for
inflammatory conditions unrelated to CLL

- No concurrent chemotherapy or radiotherapy
We found this trial at
1275 York Avenue
New York, New York 10065
Memorial Sloan-Kettering Cancer Center Memorial Sloan-Kettering Cancer Center — the world's oldest and largest private...
New York, NY
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