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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Leukemia, Lymphoma

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Trial Information

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


- 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.

Inclusion Criteria


- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall response including complete response, clinical complete response, nodular response, and partial response

Outcome Time Frame:

Prior to cycle 4 and after completion of all therapy

Safety Issue:


Principal Investigator

Renier Brentjens, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2005

Completion Date:

July 2013

Related Keywords:

  • Leukemia
  • Lymphoma
  • B-cell chronic lymphocytic leukemia
  • Waldenstrom macroglobulinemia
  • recurrent mantle cell lymphoma
  • recurrent small lymphocytic lymphoma
  • refractory chronic lymphocytic leukemia
  • recurrent marginal zone lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma



Memorial Sloan-Kettering Cancer Center New York, New York  10021