Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

2014-08-27 03:21:25 | BioPortfolio



- Cladribine is very effective in treating hairy cell leukemia, but it is not known if it can cure the disease.

- Rituximab is a monoclonal antibody that binds to the hairy cells and may kill them either by causing the cells to kill themselves or by getting the immune system to kill the cells. Rituximab is effective in hairy cell leukemia but is not considered standard treatment. Rituximab is approved by the Food and Drug Administration to treat patients with follicular non-Hodgkin's Lymphoma and diffuse large B-cell non-Hodgkin's lymphoma and for certain patients with rheumatoid arthritis.


- To determine if cladribine and rituximab, whether given together or with rituximab given 6 months after cladribine, is effective in treating residual hair cell leukemia (disease that remains after the original treatment).


- Patients 18 years of age and older with hair cell leukemia.

- Patients who have received no more than one prior course of cladribine and no prior treatment with rituximab.


- It is believed that Rituximab may improve the activity of cladribine in cladribine, but it is unknown whether it would help most to add it at the beginning or wait until 6 months when the cladribine has had a full chance to work. Therefore, patients are randomly assigned to receive rituximab at the same time as cladribine or to receive the rituximab at least 6 months after cladribine (and only if hairy cells are present in a blood or bone marrow biopsy).

- Patients receive the initial treatment during a 5- to 7-day hospitalization at the NIH Clinical Center. Cladribine is given by vein over 2 hours every day for 5 days. Rituximab is given through a vein over 2 hours (or longer, if needed) once a week for 8 weeks.

- Patients have several lab tests, including bone marrow biopsies and blood tests, to determine whether they have hairy cells left during or after treatment.

- CT or other imaging study of the spleen and any other site of disease at 1 and 6 months after cladribine; before and 6 months after beginning delayed rituximab, yearly for 4 years while in complete remission, then every 2 years after that while in complete remission.



Hairy cell leukemia (HCL) is highly responsive to but not curable by cladribine (CdA). HCL responds to rituximab, which is not yet standard therapy for HCL.

Patients with the CD25-negative variant (HCLv) respond poorly to initial cladribine but do respond to rituximab in anecdotal reports.

Deoxycytidine kinase phosphorylates cladribine to CdATP, which incorporates into DNA, leading to DNA strand breaks and inhibition of DNA synthesis. Rituximab is an anti-CD20 monoclonal antibody which induces apoptosis and either complement or antibody dependent cytotoxicity (ADCC or CDC).

Patients in complete remission (CR) to cladribine have minimal residual disease (MRD) by immunohistochemistry of the bone marrow biopsy (BMBx IHC), a risk for early relapse. Tests for HCL MRD in blood or marrow include flow cytometry (FACS) or PCR using consensus primers. The most sensitive HCL MRD test is real-time quantitative PCR using sequence-specific primers (RQ-PCR).

In studies with limited follow-up, MRD detected by tests other than RQ-PCR can be eliminated by rituximab after cladribine in greater than 90 percent of patients, but MRD rates after cladribine alone are unknown. Simultaneous cladribine and rituximab might be superior or inferior to delaying rituximab until detection of MRD.

Only 4 HCL-specific trials are listed on a phase II trial of cladribine followed 4 weeks later by 8 weekly doses of rituximab, and phase I-II trials of recombinant immunotoxins targeting CD22 (BL22, HA22) and CD25 (LMB-2).



To determine if HCL MRD differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine.


- To compare cladribine plus rituximab vs cladribine alone in terms of 1) initial MRD-free survival and disease-free survival, and 2) response to delayed rituximab for relapse, to determine if early rituximab compromises later response.

- To determine if MRD levels and tumor markers (soluble CD25 and CD22) after cladribine and/or rituximab correlate with response and clinical endpoints.

- To determine, using MRD and tumor marker data, when BMBx can be avoided.

- To compare response and MRD after the 1st and 2nd courses of cladribine.

- To evaluate the effects of cladribine and rituximab on normal T- and B-cells.

- To enhance the study of HCL biology by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements.


HCL with 0-1 prior courses of cladribine and treatment indicated.


Cladribine 0.15 mg/Kg/day times 5 doses each by 2hr i.v. infusion (days 1-5)

Rituximab 375 mg/m2/week times 8 weeks, randomized half to begin day 1, then repeat for all patients with blood-MRD relapse at least 6 months after cladribine.

MRD tests used for the primary objective will be limited to BMBx IHC, blood FACS or blood consensus PCR, all CLIA certified. Blood MRD relapse is defined as FACS positivity or low blood counts (ANC less than 1500/microl, Plt less than 100,000/microl, or Hgb less than 11).

Stratification: 68 patients with 0 and 62 with 1 prior course of cladribine.

Statistics: 80% power to discriminate rates of MRD of 5 vs 25%, or 10 vs 35%

Non-randomized arm: 20 with HCLv will begin rituximab with cladribine.

Accrual Ceiling: 152 patients (130 HCL, 2 extra HCL if needed, and 20 HCLv.)

Study Design

Allocation: Randomized, Control: Uncontrolled, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


Hairy Cell Leukemia


Cladribine, Rituximab


National Institutes of Health Clinical Center, 9000 Rockville Pike
United States




National Institutes of Health Clinical Center (CC)

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:21:25-0400

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Medical and Biotech [MESH] Definitions

An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia.

A neoplastic disease of the lymphoreticular cells which is considered to be a rare type of chronic leukemia; it is characterized by an insidious onset, splenomegaly, anemia, granulocytopenia, thrombocytopenia, little or no lymphadenopathy, and the presence of "hairy" or "flagellated" cells in the blood and bone marrow.

A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS.

A potent inhibitor of ADENOSINE DEAMINASE. The drug induces APOPTOSIS of LYMPHOCYTES, and is used in the treatment of many lymphoproliferative malignancies, particularly HAIRY CELL LEUKEMIA. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.

A lymphoid leukemia characterized by a profound LYMPHOCYTOSIS with or without LYMPHADENOPATHY, hepatosplenomegaly, frequently rapid progression, and short survival. It was formerly called T-cell chronic lymphocytic leukemia.

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