Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

NCT00923013 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 2 other identifiers: 09000509-C-0005
• Study Type: interventional
• Target: 175
• Locations: 1 country
• Sites: 1

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.)

Conditions

Hairy Cell Leukemia

Keywords

Hairy Cell Leukemia; Cladribine; Rituximab; Minimal Residual Disease; Leukemia

Outcome Measures

Primary Outcomes (1)

• Response Rate Comparing Minimal Residual Disease (MRD) at 6 Months After Start of Treatment in Comparison Groups

  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.

  Restaged 6 months after the start of treatment

Secondary Outcomes (1)

• 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

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAEv3.0)

  From first study intervention,Study Day 1, Cycle 1-30 days after study agent up to day 35 for participants receiving cladribine only, up to day 80 for participants receiving cladribine+rituximab, &up to day 80 for participants receiving delayed rituximab.

Study Arms (3)

1/Cladribine with immediate Rituximab

EXPERIMENTAL

Cladribine with immediate Rituximab.

Drug: Cladribine; Drug: Rituximab; Procedure: BMbx; Diagnostic Test: MRI; Diagnostic Test: EKG; Diagnostic Test: Echocardiogram; Diagnostic Test: Abdominal/splenic ultrasound; Procedure: Stress test

2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine

ACTIVE COMPARATOR

Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected.

Drug: Cladribine; Drug: Rituximab; Procedure: BMbx; Diagnostic Test: MRI; Diagnostic Test: EKG; Diagnostic Test: Echocardiogram; Diagnostic Test: Abdominal/splenic ultrasound; Procedure: Stress test

3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

EXPERIMENTAL

Non-randomized group receiving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1).

Drug: Cladribine; Drug: Rituximab; Procedure: BMbx; Diagnostic Test: MRI; Diagnostic Test: EKG; Diagnostic Test: Echocardiogram; Diagnostic Test: Abdominal/splenic ultrasound; Procedure: Stress test

Interventions

Cladribine DRUG

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).

Also known as: Mavenclad

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

Rituximab DRUG

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).

Also known as: Rituxan

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

BMbx PROCEDURE

Baseline and week 5.

Also known as: Bone marrow biopsy

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

MRI DIAGNOSTIC_TEST

Baseline and week 5.

Also known as: Magnetic resonance imaging

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

EKG DIAGNOSTIC_TEST

Baseline and week 5.

Also known as: Electrocardiogram

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

Echocardiogram DIAGNOSTIC_TEST

Baseline.

Also known as: Echo

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

Abdominal/splenic ultrasound DIAGNOSTIC_TEST

Baseline and week 5.

Also known as: Abdominal/splenic U/S

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

Stress test PROCEDURE

Baseline.

1/Cladribine with immediate Rituximab; 2/Cladribine with Rituximab Delayed by at Least 6 months After Cladribine; 3/Non-randomized Group Receiving Cladribine with Immediate Rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Evidence of Hairy Cell Leukemia (HCL) by flow cytometry, reviewed by the Laboratory of Pathology, National Cancer Institute (NCI), including positivity for Cluster of Differentiation 19 (CD19), Cluster of Differentiation 22 (CD22), cluster of differentiation 20 (CD20), and integrin alpha X (CD11c).
• 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.

You may not qualify if:

• Presence of active untreated infection
• 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.
• Pregnant or lactating women.
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12.

  PMID: 7820038 BACKGROUND

• 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.

  PMID: 11399570 BACKGROUND

• 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.

  PMID: 17237035 BACKGROUND

• 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.

  PMID: 34607348 DERIVED

• 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.

  PMID: 32109194 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia, Hairy Cell; Neoplasm, Residual; Leukemia

Interventions

Cladribine; Rituximab; Magnetic Resonance Imaging; Electrocardiography; Echocardiography; Caves; Exercise Test

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Electrodiagnosis; Cardiac Imaging Techniques; Ultrasonography; Geological Phenomena; Physical Phenomena; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Environment and Public Health; Respiratory Function Tests; Diagnostic Techniques, Respiratory System; Ergometry; Investigative Techniques

Results Point of Contact

• Title: Dr. Robert Kreitman
• Organization: National Cancer Institute

kreitmar@mail.nih.gov

301-648-7375

Study Officials

• Robert J Kreitman, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: October 20, 2008
• Primary Completion: July 15, 2024
• Study Completion (Estimated): January 31, 2030
• Last Updated: August 8, 2025
• Results First Posted: August 8, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)