Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia
- Conditions
- Hairy Cell Leukemia
- Interventions
- 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 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 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).
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 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 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 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 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 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 \> 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).
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 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, and
bone marrow aspirate FACS, 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) 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
- 203
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 1 Rituximab Cladribine with immediate Rituximab 2 Cladribine Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected 1 Cladribine Cladribine with immediate Rituximab 2 Rituximab Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected 3 Cladribine Non-randomized group receving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1) 3 Rituximab Non-randomized group receving 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 6 months Rate of minimal residual disease (MRD) identified in patients 6 months after beginning cladribine for treatment of HCL compared to patients treated with cladribine combined with rituximab
- Secondary Outcome Measures
Name Time Method overall survival Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly Percentage of subjects alive at different time points particularly in patients with poor-prognosis HCL like HCLv
MRD-free survival and disease-free survival 1 and 6 months after cladribine percentage of subjects without minimal residual disease or disease after cladribine +/- rituximab
response to delayed rituximab for relapse 1 and 6 months after cladribine determine if early rituximab compromises later response
overall response Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly determine if MRD levels and tumor markers (soluble CD25 and CD22) after cladribine and/or rituximab correlate with response and clinical endpoints
blood MRD-free survival Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly compare blood MRD-free survival in patients who receive cladribine and up to 2 courses of rituximab, with respect to whether the 1st course of rituximab was used simultaneous with cladribine
evaluation for BMBx 6 months after cladribine or delayed rituximab, then yearly until 2.5 years, then every other year determine, using MRD and tumor marker data, when bone marrow biopsy (BMBx) can be avoided in managing HCL
Overall response and MRD Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly compare response and MRD after the 1st and 2nd courses of cladribine
T- and B-cells Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly evaluate the effects of cladribine and rituximab on normal T- and B-cells
characterization of monoclonal immunoglobulin rearrangements Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly enhance the study of HCL biology by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements
correlate bone marrow MRI signal with bone marrow biopsy Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly To correlate bone marrow MRI signal with bone marrow biopsy, patients will obtain cervical and thoracic spine MRI at baseline and at bone marrow restaging time points, when feasible.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States