Hairy Cell LeukemiaPhase 2NCT01059786
Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia
A Phase 2 study testing Pentostatin, Rituximab and Bendamustine in people with Hairy Cell Leukemia, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Researchers are attempting to develop new treatments for hairy cell leukemia (HCL) that has not responded well to or has recurred after standard HCL therapies. One nonstandard treatment for HCL is rituximab, an antibody that binds to the cancer cells and helps the immune system destroy them. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hairy Cell Leukemia
- What is being tested?
- Pentostatin, Rituximab and Bendamustine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 69 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jul 2010to 30 Jun 2031
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Evidence of Hairy Cell Leukemia (HCL) by flow cytometry of blood or a solid (lymph node) mass, confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), including positivity for cluster of Differentiation 19 (CD19), cluster of differentiation-22 (CD22), cluster of differentiate 20 (CD20), and Integrin, alpha X (CD11c). Patients with flow cytometry consistent with hairy cell leukemia-variant (HCLv) are eligible, including those with cluster of Differentiation 25 (CD25) and/or cluster of differentiation 103 (CD103) negative disease.
- bone marrow biopsy (BMBx) or bone marrow aspiration (BMA) consistent with HCL, confirmed by National Institutes of Health (NIH) Laboratory of Pathology, NCI, or the Department of Laboratory Medicine, Clinical Center, NIH, unless the diagnosis can be confirmed from a solid (lymph node) mass.
- 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 cladribine 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).
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- 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.
- Increasing lytic bone lesions
- 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.
- One of the following:
- At least 2 prior courses of purine analog
- 1 prior course of purine analog plus greater than or equal to1 course of rituximab if the response to the course of purine analog lasted less than 1 year.
- Diagnosis of HCL variant (HCLv)
- Unmutated (>98% homology to germline) immunoglobulin heavy variable 4-34 (IGHV4-34+) expressing hairy cell leukemia (HCL)/HCLv
- Eastern Cooperative Oncology Group (ECOG) performance status (102) of 0-3
- Patients must be able to understand and give informed consent.
- Creatinine less than or equal to 1.5 or creatinine clearance greater than or equal to 60 ml/min.
- Bilirubin less than or equal to 2 unless consistent with Gilbert's (total/direct greater than 5), alanine transaminase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x 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, unless progressive disease more than 2 months after cladribine is documented.
- 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.
- 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.
Who cannot join
- Presence of active untreated infection
- Uncontrolled coronary disease or New York Heart Association (NYHA) class III-IV heart disease.
- Known infection with human immunodeficiency virus (HIV), hepatitis B or C.
- 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.
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- Presence of central nervous system (CNS) disease
- Patients with history of non-response to both pentostatin plus rituximab and to bendamustine plus rituximab.
- 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. 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Background:
- Researchers are attempting to develop new treatments for hairy cell leukemia (HCL) that has not responded well to or has recurred after standard HCL therapies. One nonstandard treatment for HCL is rituximab, an antibody that binds to the cancer cells and helps the immune system destroy them. By combining rituximab with other anti-cancer drugs, researchers hope to determine whether the combined drugs are successful in treating HCL.
- Pentostatin and bendamustine are two anti-cancer drugs that have been used to treat different kinds of blood and immune system cancers. Bendamustine is approved to treat other kinds of leukemia and lymphoma, but it has not been used to treat HCL. Pentostatin has been used for more than 20 years to treat HCL, but it has not been combined with rituximab in official clinical trials.
Read more
Objectives:
- To determine whether rituximab with either pentostatin or bendamustine is a more effective treatment for HCL than rituximab alone.
- To determine whether pentostatin or bendamustine is a more effective treatment for HCL when combined with rituximab.
Eligibility:
- Individuals at least 18 years of age who have been diagnosed with hairy cell leukemia that has not responded well to or has relapsed after standard HCL therapies.
Design:
- The study will last for four treatment cycles of 28 days each.
- Prior to the study, participants will be screened with a full medical history and physical exam, bone marrow biopsy (if one has not been performed in the last 6 months), computed tomography (CT) or ultrasound scan, tumor measurements, and other tests as required by the researchers. Participants will provide blood and urine samples at this time as well.
- Rituximab with bendamustine: Participants will receive rituximab on Days 1 and 15 of each cycle and bendamustine on Days 1 and 2 of each cycle, for a total of four cycles.
- Rituximab with pentostatin: Participants will receive rituximab on Days 1 and 15 of each cycle and pentostatin on rituximab on Days 1 and 15 of each cycle, for a total of four cycles.
- Participants will have regular tests during the treatment cycles, including bone marrow biopsies and CT or ultrasound scans. Participants will also provide regular blood and urine samples to assess the results of treatment.
Read the detailed description
Background:
- Hairy cell leukemia (HCL) is highly responsive to purine analogs cladribine and pentostatin, without evidence of cure. Neither is standard after 2 courses, due to cumulative marrow and T-cell toxicity and declining remission rates and durations. Once resistant, patients after multiple relapses can die of disease-related cytopenias.
- Rituximab alone in 51 patients from 5 trials who had cytopenias and at least 1 prior purine analog resulted in 10 complete + 10 partial remissions (complete response (CR) + partial response (PR) = overall response rate (ORR 39%).
- Rituximab with cladribine gives high CR rates in 1st or 2nd line but is not standard.
- While cladribine use is more common for 1st and 2nd line, pentostatin is often used for subsequent treatment because of < 100% cross-resistance.
- Retrospective published data for pentostatin plus rituximab in HCL include 7 of 7 responses with 6 (86%) CRs, and there are no prospective data.
- Recombinant immunotoxins targeting cluster of Differentiation 25 (CD25) (LMB-2) and cluster of differentiation-22 (CD22) (CAT-3888 (BL22) and R490A (HA22) are highly active in purine analog resistant HCL. Palliative pentostatin-rituximab is often used off-protocol for patients with immunogenicity needing more therapy.
- Bendamustine is approved for early treatment of chronic lymphocytic leukemia (CLL) and is effective with rituximab for relapsed/refractory CLL. Its use in HCL is unreported.
- CRs with minimal residual disease (MRD) by immunohistochemistry (IHC) of bone marrow biopsy (BMBx IHC), can relapse early. 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 MRD test in HCL is real-time quantitative PCR using sequence-specific primers (real-time quantitative polymerase chain reaction (RQ-PCR).
- Of 5 HCL-specific trials listed on Cancer.gov, 2 are phase II trials of cladribine + rituximab in 1st and 2nd line (1 randomized at National Institutes of Health (NIH), 1 non-randomized at MDA), and 3 NIH phase I-II trials of recombinant immunotoxins BL22, HA22 and LMB-2.
Objectives:
-Primary:
--To determine if pentostatin + rituximab and bendamustine + rituximab are each associated with adequate response rates (ORR=PR+CR) in patients with relapsed HCL, and, if so, to select which combination is likely to be superior.
Eligibility:
- HCL needing therapy, either greater than or equal to 2 prior courses of purine analog, 1 course purine analog plus greater than or equal to 1 course rituximab if < 1 year response to the 1 course purine analog, diagnosis of HCL variant (HCLv), or unmutated immunoglobulin heavy variable 4-34 (IGHV4-34+) expressing HCL/HCLv.
- Prior treatment, ineligibility for, or patient refusal of recombinant immunotoxin.
Design:
- Rituximab 375 mg/m^2 on day 1, 15 for 6 x 28-day cycles (all 72 patients).
- Initial tolerability study: 12 patients receive rituximab + bendamustine (nonrandom), including 6 at 70 mg/m^2 and 6 at 90 mg/m^2 of bendamustine.
- Randomize: 1) 28 patients to bendamustine 90 mg/m^2/day, days 1 and 2 each cycle 2) 28 patients to pentostatin 4 mg/m^2 days 1 and 15 of each cycle.
- Non-randomized: up to 4 patients to receive either bendamustine 90 mg/m^2P2P/day, days 1 and 2 each cycle or pentostatin 4 mg/m^2P2P days 1 and 15 of each cycle.
- Statistics: If > 14/28 respond, can conclude with 90% power that response > 40% in that arm. >80% probability of selecting the better arm if true response probability is approximately 40-50% on the inferior arm and >15% higher on the superior arm.
- Stratify to equalize the % of patients/arm refractory to last course of purine analog.
- Accrual Ceiling: 72 evaluable participants
- Conditions
- Hairy Cell Leukemia
- Being tested
- Pentostatin, Rituximab, Bendamustine, Acetaminophen, Diphenhydramine
- Keywords
- Monoclonal Antibody, Purine Analog, Soluble CD25, Minimal Residual Disease MRD, CD20
- Medical subject headings
- Leukemia, Hairy Cell, Neoplasm, Residual
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PentostatinDrug
Also called Nipent
28 participants to pentostatin 4 mg/m^2 days 1 and 15 of each cycle.
RituximabDrug
Also called Rituxan
Rituximab 375 mg/m^2 on day 1, 15 for 6 x 28-day cycles
BendamustineDrug
Also called Bendeka, Treanda
1-4 participants to bendamustine 90 mg/m^2/day, days 1 and 2 each cycle
AcetaminophenDrug
Also called Tylenol
Treatment of infusion-related symptoms with acetaminophen is recommended.
DiphenhydramineDrug
Also called Benadryl
Treatment of infusion-related symptoms with diphenhydramine is recommended.
EpinephrineDrug
Also called Adrenaline
Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.
AntihistaminesDrug
Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.
CorticosteroidsDrug
Also called Corticoid
Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.
BronchodilatorsDrug
Also called Broncholytic
Additional treatment with bronchodilators may be indicated.
Intravenous (IV) SalineOther
Additional treatment with intravenous (IV) saline may be indicated.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab | Experimental | Rituximab + Bendamustine at 70 mg/m^2 for initial tolerability study (closed) Receives: Drug: Rituximab; Drug: Bendamustine; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Epinephrine; Drug: Antihistamines; Drug: Corticosteroids; Drug: Bronchodilators; Other: Intravenous (IV) Saline |
| Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab | Experimental | Rituximab + Bendamustine at 90 mg/m^2 for initial tolerability study (closed) Receives: Drug: Rituximab; Drug: Bendamustine; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Epinephrine; Drug: Antihistamines; Drug: Corticosteroids; Drug: Bronchodilators; Other: Intravenous (IV) Saline |
| Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab | Active comparator | Rituximab + Bendamustine (at the tolerated dose) Receives: Drug: Rituximab; Drug: Bendamustine; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Epinephrine; Drug: Antihistamines; Drug: Corticosteroids; Drug: Bronchodilators; Other: Intravenous (IV) Saline |
| Arm 4 - Randomized to Pentostatin-Rituximab | Active comparator | Rituximab + Pentostatin Receives: Drug: Pentostatin; Drug: Rituximab; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Epinephrine; Drug: Antihistamines; Drug: Corticosteroids; Drug: Bronchodilators; Other: Intravenous (IV) Saline |
| Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab | Experimental | After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab Receives: Drug: Pentostatin; Drug: Rituximab; Drug: Bendamustine; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Epinephrine; Drug: Antihistamines; Drug: Corticosteroids; Drug: Bronchodilators; Other: Intravenous (IV) Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Receiving Pentostatin + Rituximab and Bendamustine + Rituximab Who Achieve a Complete Remission (CR) + Partial Response (PR)
Number of participants receiving pentostatin + rituximab and bendamustine + rituximab who achieve a CR +PR measured by the following response criteria. Complete remission is all of the following for at least 4 weeks: absolute neutrophil count ≥ 1500/mm^3, platelets ≥ 100,000/mm^3, hemoglobin ≥ 11g/dl, spleen non-palpable below the costal margin, or not below costal margin on computed tomography, and circulating hairy cell leukemia (HCL) cells either non-visible on Wright stain or < 1% by flow cytometry. Partial response is all of the following for at least 4 weeks: neutrophils ≥ 1,500/µL or 50% improvement over baseline, platelets ≥100,000/µL or 50% improvement over baseline, hemoglobin ≥ 11.0 g/dL or 50% improvement over baseline, ≥ 50% decrease in circulating malignant HCL count from the pretreatment baseline, ≥ 50% reduction in sum of products of perpendicular diameters or decrease to ≤ 2 cm in evaluable (> 2cm) lymphadenopathy.
Measured: At end of treatment, approximately 6 months
Secondary outcomes (10)
Pentostatin + Rituximab and Bendamustine + Rituximab in Crossover When Used After Failure of the 1st Regimen
Compare the 2 regimens - pentostatin + rituximab and bendamustine + rituximab in crossover when used after failure of the 1st regimen.
Measured: 4 years
Response Rate
Response rate between participants who received rituximab plus either pentostatin or bendamustine measured by the following response criteria. Complete remission is all of the following for at least 4 weeks: absolute neutrophil count ≥ 1500/mm^3, platelets ≥ 100,000/mm^3, hemoglobin ≥ 11g/dl, spleen non-palpable below the costal margin, or not below costal margin on computed tomography, and circulating hairy cell leukemia (HCL) cells either non-visible on Wright stain or < 1% by flow cytometry. Partial response is all of the following for at least 4 weeks: neutrophils ≥ 1,500/µL or 50% improvement over baseline, platelets ≥100,000/µL or 50% improvement over baseline, hemoglobin ≥ 11.0 g/dL or 50% improvement over baseline, ≥ 50% decrease in circulating malignant HCL count from the pretreatment baseline, ≥ 50% reduction in sum of products of perpendicular diameters. Progressive disease is appearance of new evaluable lymph nodes >2cm. Stable disease is none of the above
Measured: 4 years
Mechanism of Thrombocytopenia
The mechanism of thrombocytopenia after purine analog plus rituximab.
Measured: 4 years
Hairy Cell Leukemia (HCL) Biology
HCL biology was determined by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements, and other genes.
Measured: 4 years
Correlation of Measurable Residual Disease (MRD) Levels and Tumor Markers With Response
Determine if MRD levels and tumor markers (soluble cluster of Differentiation 25 (CD25) and cluster of differentiation-22 (CD22), and real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) correlate with response and clinical endpoints, and if bone marrow magnetic resonance imaging (MRI) signal correlates with bone marrow biopsy (BMBx) results, and whether these tests could in some cases possibly replace BMBx.
Measured: 4 years
Measurable Residual Disease (MRD)-Free Survival
MRD-free survival is defined by the Response criteria.
Measured: 4 years
Disease-free Survival (DFS)
Disease-free survival is the time from start of treatment to documented evidence of disease progression measured by the following response criteria. Progressive disease ≥50% increase in sum of products of perpendicular diameters of evaluable (> 2cm) lymphadenopathy or appearance of new evaluable lymph nodes >2cm.
Measured: time from start of treatment to documented evidence of disease progression
Overall Survival
OS is the time between the first day of treatment to the day of death.
Measured: time between the first day of treatment to the day of death
Grade 3 and/or 4 Toxicity
Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). 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.
Measured: 4 years
Cluster of Differentiation 4 (CD4+) T-cells
Cluster of differentiation 4 (CD4+) T-cells assessed by analysis.
Measured: 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Feb 2010 (estimated)
- Study start1 Jul 2010
- Primary completion15 Dec 2022
- Study completion30 Jun 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Hairy Cell LeukemiaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 69 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Robert Kreitman, M.D., National Cancer Institute (NCI)
- Investigators
- Robert J Kreitman, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01059786
- Sponsor's protocol ID
- 100025
- Other IDs
- 10-C-0025
- Status last verified
- Sep 2026
- First submitted
- 29 Jan 2010
- Last updated
- 15 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
Publications
Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12.
PubMed 7820038Kreitman 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.
PubMed 11399570Jemal 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.
PubMed 17237035Schroeder B, Yuan C, Wang HW, Mohindroo C, Zhou H, Raffeld M, Xi L, Arons E, Feurtado J, James-Echenique L, Calvo KR, Maric I, Kreitman RJ. Phase 2 trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia. Blood. 2026 Feb 12;147(7):725-738. doi: 10.1182/blood.2025031243.
PubMed 41060318
Study at a glance
From the registry record, last updated by the sponsor on 15 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia
- ClinicalTrials.gov ID
- NCT01059786
- Acronym / sponsor ID
- 100025
- Conditions
- Hairy Cell Leukemia
- Keywords
- Monoclonal Antibody, Purine Analog, Soluble CD25, Minimal Residual Disease MRD, CD20
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 69 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 1 Jul 2010 (actual)
- Primary completion
- 15 Dec 2022 (actual)
- Study completion
- 30 Jun 2031 (estimated)
- First posted
- 1 Feb 2010 (estimated)
- Results
- Posted 1 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Researchers are attempting to develop new treatments for hairy cell leukemia (HCL) that has not responded well to or has recurred after standard HCL therapies. One nonstandard treatment for HCL is rituximab, an antibody that binds to the cancer cells and helps the immune system destroy them. By combining rituximab with other anti-cancer drugs, researchers hope to determine whether the combined drugs are successful in treating HCL.
- Pentostatin and bendamustine are two anti-cancer drugs that have been used to treat different kinds of blood and immune system cancers. Bendamustine is approved to treat other kinds of leukemia and lymphoma, but it has not been used to treat HCL. Pentostatin has been used for more than 20 years to treat HCL, but it has not been combined with rituximab in official clinical trials.
Objectives:
- To determine whether rituximab with either pentostatin or bendamustine is a more effective treatment for HCL than rituximab alone.
- To determine whether pentostatin or bendamustine is a more effective treatment for HCL when combined with rituximab.
Eligibility:
- Individuals at least 18 years of age who have been diagnosed with hairy cell leukemia that has not responded well to or has relapsed after standard HCL therapies.
Design:
- The study will last for four treatment cycles of 28 days each.
- Prior to the study, participants will be screened with a full medical history and physical exam, bone marrow biopsy (if one has not been performed in the last 6 months), computed tomography (CT) or ultrasound scan, tumor measurements, and other tests as required by the researchers. Participants will provide blood and urine samples at this time as well.
- Rituximab with bendamustine: Participants will receive rituximab on Days 1 and 15 of each cycle and bendamustine on Days 1 and 2 of each cycle, for a total of four cycles.
- Rituximab with pentostatin: Participants will receive rituximab on Days 1 and 15 of each cycle and pentostatin on rituximab on Days 1 and 15 of each cycle, for a total of four cycles.
- Participants will have regular tests during the treatment cycles, including bone marrow biopsies and CT or ultrasound scans. Participants will also provide regular blood and urine samples to assess the results of treatment.
Detailed description
Background:
- Hairy cell leukemia (HCL) is highly responsive to purine analogs cladribine and pentostatin, without evidence of cure. Neither is standard after 2 courses, due to cumulative marrow and T-cell toxicity and declining remission rates and durations. Once resistant, patients after multiple relapses can die of disease-related cytopenias.
- Rituximab alone in 51 patients from 5 trials who had cytopenias and at least 1 prior purine analog resulted in 10 complete + 10 partial remissions (complete response (CR) + partial response (PR) = overall response rate (ORR 39%).
- Rituximab with cladribine gives high CR rates in 1st or 2nd line but is not standard.
- While cladribine use is more common for 1st and 2nd line, pentostatin is often used for subsequent treatment because of < 100% cross-resistance.
- Retrospective published data for pentostatin plus rituximab in HCL include 7 of 7 responses with 6 (86%) CRs, and there are no prospective data.
- Recombinant immunotoxins targeting cluster of Differentiation 25 (CD25) (LMB-2) and cluster of differentiation-22 (CD22) (CAT-3888 (BL22) and R490A (HA22) are highly active in purine analog resistant HCL. Palliative pentostatin-rituximab is often used off-protocol for patients with immunogenicity needing more therapy.
- Bendamustine is approved for early treatment of chronic lymphocytic leukemia (CLL) and is effective with rituximab for relapsed/refractory CLL. Its use in HCL is unreported.
- CRs with minimal residual disease (MRD) by immunohistochemistry (IHC) of bone marrow biopsy (BMBx IHC), can relapse early. 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 MRD test in HCL is real-time quantitative PCR using sequence-specific primers (real-time quantitative polymerase chain reaction (RQ-PCR).
- Of 5 HCL-specific trials listed on Cancer.gov, 2 are phase II trials of cladribine + rituximab in 1st and 2nd line (1 randomized at National Institutes of Health (NIH), 1 non-randomized at MDA), and 3 NIH phase I-II trials of recombinant immunotoxins BL22, HA22 and LMB-2.
Objectives:
-Primary:
--To determine if pentostatin + rituximab and bendamustine + rituximab are each associated with adequate response rates (ORR=PR+CR) in patients with relapsed HCL, and, if so, to select which combination is likely to be superior.
Eligibility:
- HCL needing therapy, either greater than or equal to 2 prior courses of purine analog, 1 course purine analog plus greater than or equal to 1 course rituximab if < 1 year response to the 1 course purine analog, diagnosis of HCL variant (HCLv), or unmutated immunoglobulin heavy variable 4-34 (IGHV4-34+) expressing HCL/HCLv.
- Prior treatment, ineligibility for, or patient refusal of recombinant immunotoxin.
Design:
- Rituximab 375 mg/m^2 on day 1, 15 for 6 x 28-day cycles (all 72 patients).
- Initial tolerability study: 12 patients receive rituximab + bendamustine (nonrandom), including 6 at 70 mg/m^2 and 6 at 90 mg/m^2 of bendamustine.
- Randomize: 1) 28 patients to bendamustine 90 mg/m^2/day, days 1 and 2 each cycle 2) 28 patients to pentostatin 4 mg/m^2 days 1 and 15 of each cycle.
- Non-randomized: up to 4 patients to receive either bendamustine 90 mg/m^2P2P/day, days 1 and 2 each cycle or pentostatin 4 mg/m^2P2P days 1 and 15 of each cycle.
- Statistics: If > 14/28 respond, can conclude with 90% power that response > 40% in that arm. >80% probability of selecting the better arm if true response probability is approximately 40-50% on the inferior arm and >15% higher on the superior arm.
- Stratify to equalize the % of patients/arm refractory to last course of purine analog.
- Accrual Ceiling: 72 evaluable participants
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab | Experimental | Drug: Rituximab, Drug: Bendamustine, Drug: Acetaminophen, Drug: Diphenhydramine, Drug: Epinephrine, Drug: Antihistamines, Drug: Corticosteroids, Drug: Bronchodilators, Other: Intravenous (IV) SalineRituximab + Bendamustine at 70 mg/m^2 for initial tolerability study (closed) |
| Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab | Experimental | Drug: Rituximab, Drug: Bendamustine, Drug: Acetaminophen, Drug: Diphenhydramine, Drug: Epinephrine, Drug: Antihistamines, Drug: Corticosteroids, Drug: Bronchodilators, Other: Intravenous (IV) SalineRituximab + Bendamustine at 90 mg/m^2 for initial tolerability study (closed) |
| Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab | Active comparator | Drug: Rituximab, Drug: Bendamustine, Drug: Acetaminophen, Drug: Diphenhydramine, Drug: Epinephrine, Drug: Antihistamines, Drug: Corticosteroids, Drug: Bronchodilators, Other: Intravenous (IV) SalineRituximab + Bendamustine (at the tolerated dose) |
| Arm 4 - Randomized to Pentostatin-Rituximab | Active comparator | Drug: Pentostatin, Drug: Rituximab, Drug: Acetaminophen, Drug: Diphenhydramine, Drug: Epinephrine, Drug: Antihistamines, Drug: Corticosteroids, Drug: Bronchodilators, Other: Intravenous (IV) SalineRituximab + Pentostatin |
| Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab | Experimental | Drug: Pentostatin, Drug: Rituximab, Drug: Bendamustine, Drug: Acetaminophen, Drug: Diphenhydramine, Drug: Epinephrine, Drug: Antihistamines, Drug: Corticosteroids, Drug: Bronchodilators, Other: Intravenous (IV) SalineAfter initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Evidence of Hairy Cell Leukemia (HCL) by flow cytometry of blood or a solid (lymph node) mass, confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), including positivity for cluster of Differentiation 19 (CD19), cluster of differentiation-22 (CD22), cluster of differentiate 20 (CD20), and Integrin, alpha X (CD11c). Patients with flow cytometry consistent with hairy cell leukemia-variant (HCLv) are eligible, including those with cluster of Differentiation 25 (CD25) and/or cluster of differentiation 103 (CD103) negative disease.
- bone marrow biopsy (BMBx) or bone marrow aspiration (BMA) consistent with HCL, confirmed by National Institutes of Health (NIH) Laboratory of Pathology, NCI, or the Department of Laboratory Medicine, Clinical Center, NIH, unless the diagnosis can be confirmed from a solid (lymph node) mass.
- 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 cladribine and no less than 4 weeks after other prior treatment, if applicable.
- 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.
- One of the following:
Key exclusion criteria (9 listed)
- Presence of active untreated infection
- Uncontrolled coronary disease or New York Heart Association (NYHA) class III-IV heart disease.
- Known infection with human immunodeficiency virus (HIV), hepatitis B or C.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PentostatinAlso: Nipent28 participants to pentostatin 4 mg/m^2 days 1 and 15 of each cycle. | Drug | Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| RituximabAlso: RituxanRituximab 375 mg/m^2 on day 1, 15 for 6 x 28-day cycles | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| BendamustineAlso: Bendeka, Treanda1-4 participants to bendamustine 90 mg/m^2/day, days 1 and 2 each cycle | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| AcetaminophenAlso: TylenolTreatment of infusion-related symptoms with acetaminophen is recommended. | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| DiphenhydramineAlso: BenadrylTreatment of infusion-related symptoms with diphenhydramine is recommended. | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| EpinephrineAlso: AdrenalineEpinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab. | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| AntihistaminesAntihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab. | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| CorticosteroidsAlso: CorticoidCorticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab. | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| BronchodilatorsAlso: BroncholyticAdditional treatment with bronchodilators may be indicated. | Drug | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
| Intravenous (IV) SalineAdditional treatment with intravenous (IV) saline may be indicated. | Other | Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab, Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab, Arm 4 - Randomized to Pentostatin-Rituximab, Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab |
Primary outcome
Number of Participants Receiving Pentostatin + Rituximab and Bendamustine + Rituximab Who Achieve a Complete Remission (CR) + Partial Response (PR)
Time frame: At end of treatment, approximately 6 months
Number of participants receiving pentostatin + rituximab and bendamustine + rituximab who achieve a CR +PR measured by the following response criteria. Complete remission is all of the following for at least 4 weeks: absolute neutrophil count ≥ 1500/mm^3, platelets ≥ 100,000/mm^3, hemoglobin ≥ 11g/dl, spleen non-palpable below the costal margin, or not below costal margin on computed tomography, and circulating hairy cell leukemia (HCL) cells either non-visible on Wright stain or < 1% by flow cytometry. Partial response is all of the following for at least 4 weeks: neutrophils ≥ 1,500/µL or 50% improvement over baseline, platelets ≥100,000/µL or 50% improvement over baseline, hemoglobin ≥ 11.0 g/dL or 50% improvement over baseline, ≥ 50% decrease in circulating malignant HCL count from the pretreatment baseline, ≥ 50% reduction in sum of products of perpendicular diameters or decrease to ≤ 2 cm in evaluable (> 2cm) lymphadenopathy.
10 secondary outcomes
Pentostatin + Rituximab and Bendamustine + Rituximab in Crossover When Used After Failure of the 1st Regimen
Time frame: 4 years
Response Rate
Time frame: 4 years
Mechanism of Thrombocytopenia
Time frame: 4 years
Hairy Cell Leukemia (HCL) Biology
Time frame: 4 years
Correlation of Measurable Residual Disease (MRD) Levels and Tumor Markers With Response
Time frame: 4 years
Measurable Residual Disease (MRD)-Free Survival
Time frame: 4 years
Disease-free Survival (DFS)
Time frame: time from start of treatment to documented evidence of disease progression
Overall Survival
Time frame: time between the first day of treatment to the day of death
Grade 3 and/or 4 Toxicity
Time frame: 4 years
Cluster of Differentiation 4 (CD4+) T-cells
Time frame: 4 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 7820038Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12.
- Background: PubMed 11399570Kreitman 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.
- Background: PubMed 17237035Jemal 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.
- Derived from this study: PubMed 41060318Schroeder B, Yuan C, Wang HW, Mohindroo C, Zhou H, Raffeld M, Xi L, Arons E, Feurtado J, James-Echenique L, Calvo KR, Maric I, Kreitman RJ. Phase 2 trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia. Blood. 2026 Feb 12;147(7):725-738. doi: 10.1182/blood.2025031243.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert J Kreitman, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pentostatin, Rituximab and Bendamustine in people with Hairy Cell Leukemia, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 15 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Receiving Pentostatin + Rituximab and Bendamustine + Rituximab Who Achieve a Complete Remission (CR) + Partial Response (PR) (time frame: At end of treatment, approximately 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01059786, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2026; AzTrials last refreshed its copy on 7 Nov 2026.