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

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.)

Study Overview

• Status: Active, not recruiting
• Conditions: Hairy Cell Leukemia
• Intervention / Treatment: Drug: Cladribine; Drug: Rituximab; Procedure: BMbx; Diagnostic test: MRI; Diagnostic test: EKG; Diagnostic test: Echocardiogram; Diagnostic test: Abdominal/splenic ultrasound; Procedure: Stress test

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)

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

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.

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:

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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Cladribine with immediate Rituximab; Cladribine with immediate Rituximab.	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).; Other Names: Mavenclad; 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).; Other Names: Rituxan; Procedure: BMbx; Baseline and week 5.; Other Names: Bone marrow biopsy; Diagnostic test: MRI; Baseline and week 5.; Other Names: Magnetic resonance imaging; Diagnostic test: EKG; Baseline and week 5.; Other Names: Electrocardiogram; Diagnostic test: Echocardiogram; Baseline.; Other Names: Echo; Diagnostic test: Abdominal/splenic ultrasound; Baseline and week 5.; Other Names: Abdominal/splenic U/S; Procedure: Stress test; Baseline.
Active Comparator: 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.	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).; Other Names: Mavenclad; 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).; Other Names: Rituxan; Procedure: BMbx; Baseline and week 5.; Other Names: Bone marrow biopsy; Diagnostic test: MRI; Baseline and week 5.; Other Names: Magnetic resonance imaging; Diagnostic test: EKG; Baseline and week 5.; Other Names: Electrocardiogram; Diagnostic test: Echocardiogram; Baseline.; Other Names: Echo; Diagnostic test: Abdominal/splenic ultrasound; Baseline and week 5.; Other Names: Abdominal/splenic U/S; Procedure: Stress test; Baseline.
Experimental: 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).	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).; Other Names: Mavenclad; 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).; Other Names: Rituxan; Procedure: BMbx; Baseline and week 5.; Other Names: Bone marrow biopsy; Diagnostic test: MRI; Baseline and week 5.; Other Names: Magnetic resonance imaging; Diagnostic test: EKG; Baseline and week 5.; Other Names: Electrocardiogram; Diagnostic test: Echocardiogram; Baseline.; Other Names: Echo; Diagnostic test: Abdominal/splenic ultrasound; Baseline and week 5.; Other Names: Abdominal/splenic U/S; Procedure: Stress test; Baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal Residual Disease (MRD)-Free Survival After Cladribine and up to 2 Courses of Rituximab	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.	Testing done 6 months post first dose of treatment, then yearly x2 years and then every 2 years after cladribine indefinitely

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAEv3.0)	Here is the number of participants with serious and/or non-serious adverse events (AE's) assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	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.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert J Kreitman, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2008
• Primary Completion (Actual): July 15, 2024
• Study Completion (Estimated): January 31, 2030

Study Registration Dates

• First Submitted: June 17, 2009
• First Submitted That Met QC Criteria: June 17, 2009
• First Posted (Estimated): June 18, 2009

Study Record Updates

• Last Update Posted (Actual): August 8, 2025
• Last Update Submitted That Met QC Criteria: July 24, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Rituximab; Leukemia; Cladribine; Minimal Residual Disease; Hairy Cell Leukemia
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia; Leukemia, Hairy Cell; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Rituximab; Cladribine
• Other Study ID Numbers: 090005; 09-C-0005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing 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).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes