Randomized Trial of Cladribine (CdA) With Simultaneous or Delayed Rituximab to Eliminate Hairy Cell Leukemia Minimal Residual Disease
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.
Purine analogs cladribine and pentostatin have similar efficacy for HCL, both inhibiting DNA
synthesis selectively in HCL cells. Cladribine is effective after just 1 cycle. 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
In studies with limited follow-up, MRD detected by tests other than RQ-PCR can be eliminated
by rituximab after cladribine in > 90% of patients, but MRD rates after purine analog 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 Cancer.gov: 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 or pentostatin 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. Also may repeat for
those with blood-MRD relapse at least 6 months after delayed rituximab.
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 HCL patients with 0 and 62 with 1 prior course of purine analog
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.)
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine if hairy cell leukemia (HCL) minimal residual disease (MRD) differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine.
Robert J Kreitman, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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