Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia

    Not Recruiting
  • End date
    Dec 31, 2025
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 18 August 2023


  • 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.
  • 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.
  • 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.
  • 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.


  • 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 (CR+PR= 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 CD25 (LMB-2) and CD22 (BL22 and 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 CLL, and is effective with rituximab for relapsed/refractory CLL. Its use in HCL is unreported.
  • CRs with minimal residual disease (MRD) by immunohistochemistry of bone marrow biopsy (BMBx IHC), can relapse early. Tests for HCL MRD in blood or marrow include flow cytometry (FACS) or PCR using consensus primers. The most sensitive MRD test in HCL is real-time quantitative PCR using sequence-specific primers (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 NIH, 1 non-randomized at MDA), and 3 NIH phase I-II trials of recombinant immunotoxins BL22, HA22 and LMB-2.


--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.

  • 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 IGHV4-34+expressing HCL/HCLv.
  • Prior treatment, ineligibility for, or patient refusal of recombinant immunotoxin.
  • 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/m2/day, days 1 and 2 each cycle 2) 28 patients to pentostatin 4 mg/m2 days 1 and 15 of each cycle.
  • Non-randomize: 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

Condition Hairy Cell Leukemia
Treatment Rituximab, pentostatin, Bendamustine
Clinical Study IdentifierNCT01059786
SponsorNational Cancer Institute (NCI)
Last Modified on18 August 2023

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