Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia
NCT ID: NCT00923013
Last Updated: 2025-08-08
Study Results
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View full resultsBasic Information
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ACTIVE_NOT_RECRUITING
PHASE2
175 participants
INTERVENTIONAL
2008-10-20
2030-01-31
Brief Summary
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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.)
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Detailed Description
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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
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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1/Cladribine with immediate Rituximab
Cladribine with immediate Rituximab.
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).
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).
BMbx
Baseline and week 5.
MRI
Baseline and week 5.
EKG
Baseline and week 5.
Echocardiogram
Baseline.
Abdominal/splenic ultrasound
Baseline and week 5.
Stress test
Baseline.
2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine
Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected.
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).
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).
BMbx
Baseline and week 5.
MRI
Baseline and week 5.
EKG
Baseline and week 5.
Echocardiogram
Baseline.
Abdominal/splenic ultrasound
Baseline and week 5.
Stress test
Baseline.
3/Non-randomized Group Receiving Cladribine with Immediate 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).
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).
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).
BMbx
Baseline and week 5.
MRI
Baseline and week 5.
EKG
Baseline and week 5.
Echocardiogram
Baseline.
Abdominal/splenic ultrasound
Baseline and week 5.
Stress test
Baseline.
Interventions
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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).
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).
BMbx
Baseline and week 5.
MRI
Baseline and week 5.
EKG
Baseline and week 5.
Echocardiogram
Baseline.
Abdominal/splenic ultrasound
Baseline and week 5.
Stress test
Baseline.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Bone marrow biopsy (BMBx) consistent with HCL, reviewed by Laboratory of Pathology, NCI. BMBx may be negative in hairy cell leukemia variant, (HCLv) in patients with increasing peripheral blood HCLv cells and spleen size.
Treatment indicated based on demonstration of at least one of the following, no more than 4 weeks from the time of enrollment, and no less than 6 months after prior purine analog and no less than 4 weeks after other prior treatment, if applicable.
* Neutropenia (absolute neutrophil count (ANC) less than 1000 cells/microl).
* Anemia (hemoglobin (Hgb) less than 10g/dL).
* Thrombocytopenia (Platelet (Plt) less than 100,000/microl).
* Absolute lymphocyte count (ALC) of greater than 5,000 cells/microL
* Symptomatic splenomegaly.
* Enlarging lymph nodes greater than 2cm.
* Repeated infections requiring oral or intravenous (i.v.) antibiotics.
* Patients who have eligible blood counts within 4 weeks from enrollment will not be considered ineligible if subsequent blood counts prior to enrollment fluctuate and become ineligible up until the time of enrollment.
No prior purine analog therapy except up to 1 prior course of cladribine.
No prior rituximab unless HCLv patient.
Eastern Cooperative Oncology Group (ECOG) performance status (78) of 0-3.
Patients must be able to understand and give informed consent.
Women of child-bearing age and all men must use birth control of any type until at least 12 months after the last dose of therapy.
Creatinine less than or equal to 1.5 or creatinine clearance greater than or equal to 60 ml/ml.
Bilirubin less than or equal to 2 unless consistent with Gilbert's (total/direct greater than 5), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 times upper limits of normal.
No other therapy (i.e. chemotherapy, interferon) for 4 weeks prior to study entry, or cladribine for 6 months prior to study entry.
Age at least 18
Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
Subject has provided written informed consent
Patients must be willing to co-enroll in the investigators companion protocol 10-C-0066 titled Collection of Human Samples to Study Hairy Cell and other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment.
Exclusion Criteria
Uncontrolled coronary disease or New York Heart Association Classification (NYHA) class III-IV heart disease.
Known infection with HIV. Hepatitis B is allowed only if viral load is undetectable and if on anti-hepatitis B therapy like Entecavir. Hepatitis C is allowed only if viral load is undetectable, and if the patient has received curative therapy.
Patients with documented history of no response to cladribine, and without 50% improvement in platelets, hemoglobin or granulocytes. This exclusion does not apply to HCLv. These patients are eligible regardless of prior response to chlorodeoxyadenosine (CDA)
Pregnant or lactating women.
Presence of active 2nd malignancy requiring treatment. 2nd malignancies with low activity which do not require treatment (i.e. low-grade prostate cancer, basal cell or squamous cell skin cancer) do not constitute exclusions.
Inability to comply with study and/or follow-up procedures.
Presence of central nervous system (CNS) disease, which is symptomatic.
At the Investigators discretion, receipt of a live vaccine within 4 weeks prior to randomization. Efficacy and/or safety of immunization during periods of B-cell depletion have not been adequately studied. It is recommended that a patients vaccination record and possible requirements be reviewed. Per the investigator's discretion, the patient may have any required vaccination/booster administered at least 4 weeks prior to the initiation of study treatment. Review of the patient s immunization status for the following vaccinations is recommended: tetanus; diphtheria; influenza; pneumococcal polysaccharide; Varicella; measles, mumps and rubella (MMR); and hepatitis B. Patients who are considered to be at high risk for hepatitis B virus (HBV) infection and for whom the investigator has determined that immunization is indicated should complete the entire HBV vaccine series at least 4 weeks prior to participation in the study.
18 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Responsible Party
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Robert Kreitman, M.D.
Principal Investigator
Principal Investigators
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Robert J Kreitman, M.D.
Role: PRINCIPAL_INVESTIGATOR
National Cancer Institute (NCI)
Locations
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National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Countries
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References
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Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12.
Kreitman RJ, Cheson BD. Malignancy: Current Clinical Practice: Treatment of Hairy Cell Leukemia at the Close of the 20th Century. Hematology. 1999;4(4):283-303. doi: 10.1080/10245332.1999.11746452.
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
Chihara D, Arons E, Stetler-Stevenson M, Yuan C, Wang HW, Zhou H, Raffeld M, Xi L, Steinberg SM, Feurtado J, James-Echenique L, Tai CH, Patel KP, Braylan RC, Calvo KR, Maric I, Dulau-Florea A, Kreitman RJ. Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant. Blood Adv. 2021 Dec 14;5(23):4807-4816. doi: 10.1182/bloodadvances.2021005039.
Chihara D, Arons E, Stetler-Stevenson M, Yuan CM, Wang HW, Zhou H, Raffeld M, Xi L, Steinberg SM, Feurtado J, James L, Wilson W, Braylan RC, Calvo KR, Maric I, Dulau-Florea A, Kreitman RJ. Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. J Clin Oncol. 2020 May 10;38(14):1527-1538. doi: 10.1200/JCO.19.02250. Epub 2020 Feb 28.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form: Cohort Eligibility Screening Consent
Document Type: Informed Consent Form: Cohort Non-Randomized, Classic Hairy Cell Consent
Document Type: Informed Consent Form: Cohort Non-Randomized Consent
Document Type: Informed Consent Form: Cohort Randomized Consent
Related Links
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NIH Clinical Center Detailed Web Page
Other Identifiers
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09-C-0005
Identifier Type: -
Identifier Source: secondary_id
090005
Identifier Type: -
Identifier Source: org_study_id
NCT00781235
Identifier Type: -
Identifier Source: nct_alias
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