Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia
- Conditions
- Hairy Cell Leukemia
- Interventions
- Procedure: BMbxDiagnostic Test: MRIDiagnostic Test: EKGDiagnostic Test: EchocardiogramDiagnostic Test: Abdominal/splenic ultrasoundProcedure: Stress test
- Registration Number
- NCT00923013
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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)
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 175
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 1/Cladribine with immediate Rituximab Cladribine Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab Rituximab Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab BMbx Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab MRI Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab EKG Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab Echocardiogram Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab Abdominal/splenic ultrasound Cladribine with immediate Rituximab. 1/Cladribine with immediate Rituximab Stress test Cladribine with immediate Rituximab. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine Cladribine Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine Rituximab Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine BMbx Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine MRI Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine EKG Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine Echocardiogram Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine Abdominal/splenic ultrasound Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine Stress test Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected. 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab Cladribine Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab Rituximab Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab BMbx Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab MRI Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab EKG Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab Echocardiogram Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab Abdominal/splenic ultrasound Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1). 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab Stress test Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1).
- Primary Outcome Measures
Name Time Method Response Rate Comparing Minimal Residual Disease (MRD) at 6 Months After Start of Treatment in Comparison Groups Restaged 6 months after the start of treatment Participants with newly diagnosed Hairy Cell Leukemia (HCL) and once relapsed HCL were split and both groups were randomized to receive either simultaneous treatment with Cladribine and Rituxan or Cladribine with Rituxan given no earlier than 6 months after cladribine as needed. Outcome measured by Bone Marrow and Blood Flow cytometry and histochemistry of the core biopsy at the 6 months after start of treatment time point. If all three were negative for hairy cells participants were in a minimal residual disease status (MRD). And were considered without HCL disease at that time point.
- Secondary Outcome Measures
Name Time Method Minimal Residual Disease (MRD)-Free Survival After Cladribine and up to 2 Courses of Rituximab Testing done 6 months post first dose of treatment, then yearly x2 years and then every 2 years after cladribine indefinitely Compare Cladribine + Rituxan vs cladribine alone in terms of MRD-free survival. MRD free survival time is the time until relapsing from MRD to -free to Complete response. Measured by blood and bone marrow flow cytometry, complete blood count (CBC), and bone marrow immunohistochemistry.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States