NCT00923013

Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

Randomized Trial of Cladribine (CdA) With Simultaneous or Delayed Rituximab to Eliminate Hairy Cell Leukemia Minimal Residual Disease

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 175 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Background: 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 interleukin 2 (IL-2) receptor (CD25)-negative hairy cell leukemia variant (HCLv) respond poorly to initial cladribine but do respond to rituximab in anecdotal reports. Deoxycytidine kinase phosphorylates cladribine to chlorodeoxyadenosine triphosphate (CdATP), which incorporates into deoxyribonucleic acid (DNA), leading to DNA strand breaks and inhibition of DNA synthesis. Rituximab is an anti-cluster of differentiation 20 (CD20) monoclonal antibody which induces apoptosis and either complement or antibody dependent cytotoxicity (antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (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 fluorescence-activated cell sorting (FACS) or polymerase chain reaction (PCR) using consensus primers. The most sensitive HCL MRD test is real-time quantitative PCR using sequence-specific primers real-time quantitative reverse transcriptase polymerase chain reaction (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 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 cluster of differentiation-22 (CD22) (BL22, HA22) and CD25 (LMB-2). Objectives: Primary: To determine if HCL MRD differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine. Secondary: * 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 bone marrow biopsy (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. Eligibility: HCL with 0-1 prior courses of cladribine and treatment indicated. Design: Cladribine 0.15 mg/Kg/day times 5 doses each by 2hour(hr) intravenous (i.v.) infusion (days 1-5) Rituximab 375 mg/m\^2/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 Clinical Laboratory Improvement Amendments (CLIA) certified. Blood MRD relapse is defined as FACS positivity or low blood counts (ANC less than 1500/microl, platelet (Plt) less than 100,000/microl, or hemoglobin (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.)

Detailed description

Background: 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 interleukin 2 (IL-2) receptor (CD25)-negative hairy cell leukemia 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 deoxyribonucleic acid (DNA) synthesis selectively in HCL cells. Cladribine is effective after just 1 cycle. Rituximab is an anti-cluster of differentiation 20 (CD20) monoclonal antibody which induces apoptosis and either complement or antibody dependent cytotoxicity (antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (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 fluorescence-activated cell sorting (FACS) or polymerase chain reaction (PCR) using consensus primers. The most sensitive HCL MRD test is real-time quantitative PCR using sequence-specific primers real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR). 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 cluster of differentiation-22 (CD22) (BL22, HA22) and CD25 (LMB-2). Objective: To determine if HCL MRD differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine. Eligibility: HCL with 0-1 prior courses of cladribine or pentostatin and treatment indicated. Design: Cladribine 0.15 mg/Kg/day times 5 doses each by 2hour(hr) intravenous (i.v.) infusion (days 1-5) Rituximab 375 mg/m\^2/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, and bone marrow aspirate FACS, all Clinical Laboratory Improvement Amendments (CLIA) certified. Blood MRD relapse is defined as FACS positivity or low blood counts (absolute neutrophil count (ANC) less than 1500/microl, platelet (Plt) less than 100,000/microl, or hemoglobin (Hgb) less than 11) attributed to HCL. Patients FACS-negative in both blood and bone marrow aspirate are considered MRD-negative complete response (CR) regardless of blood counts. Randomization: 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 HCLv arm: 20 patients with HCLv will begin rituximab with cladribine. Non-randomized HCL arm: 25 newly diagnosed patients will be enrolled to receive rituximab beginning day 1, but beginning before the 1st dose of cladribine, rather than after. Accrual ceiling: 175 evaluable patients (155 HCL and 20 HCLv)

Conditions

• Hairy Cell Leukemia

Interventions

Type	Name	Description
DRUG	Cladribine	Cladribine 0.15 mg/Kg/day by 2-hour intravenous (i.v.) infusion days 1-5. The infusion time may be changed to 1 hour at the discretion of the principal investigator (PI).
DRUG	Rituximab	Rituximab 375 mg/m\^2 intravenous (i.v.) infusion every week x8, begin day 1 in half of randomized patients and in all hairy cell leukemia variant (HCLv) patients, and then again in all patients at least 6 months later when hairy cell leukemia (HCL) is detected by blood fluorescence-activated cell sorting (FACS).
PROCEDURE	BMbx	Baseline and week 5.
DIAGNOSTIC_TEST	MRI	Baseline and week 5.
DIAGNOSTIC_TEST	EKG	Baseline and week 5.
DIAGNOSTIC_TEST	Echocardiogram	Baseline.
DIAGNOSTIC_TEST	Abdominal/splenic ultrasound	Baseline and week 5.
PROCEDURE	Stress test	Baseline.

Timeline

• Start date: 2008-10-20
• Primary completion: 2024-07-15
• Completion: 2030-01-31
• First posted: 2009-06-18
• Last updated: 2025-08-08
• Results posted: 2025-08-08

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study