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

Study Overview
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Brief Summary
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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
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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 (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. 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 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/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

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

Conditions
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Hairy Cell Leukemia

Intervention / Treatment
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* Drug: Pentostatin
* Drug: Rituximab
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Evidence of HCL by flow cytometry of blood or a solid (lymph node) mass, confirmed by the Laboratory of Pathology, NCI, including positivity for CD19, CD22, CD20, and CD11c. Patients with flow cytometry consistent with HCL variant (HCLv) are eligible, including those with CD25 and/or CD103 negative disease. BMBx or BMA consistent with HCL, confirmed by 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 (ANC less than 1000 cells/microl). Anemia (Hgb less than 10g/dL). Thrombocytopenia (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 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) IGHV4-34+expressing HCL/HCLv 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), ALT and 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 investigator s 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 NYHA class III-IV heart disease. Known infection with 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. Presence of 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 patient s 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Rituximab + bendamustine at 70 mg/m2 for initial tolerability study (closed) | Drug: Rituximab<br>* Rituximab 375 mg/m2 on day 1, 15 for 6 x 28-day cycles (all 72 patients)<br>Drug: Bendamustine<br>* 28 patients to bendamustine 90 mg/m2/day, days 1 and 2 each cycle<br>|
| Experimental: Arm 2<br>Rituximab +bendamustine at 90 mg/m2 for initial tolerability study (closed) | Drug: Rituximab<br>* Rituximab 375 mg/m2 on day 1, 15 for 6 x 28-day cycles (all 72 patients)<br>Drug: Bendamustine<br>* 28 patients to bendamustine 90 mg/m2/day, days 1 and 2 each cycle<br>|
| Experimental: Arm 3<br>Rituximab + Bendamustine (at the tolerated dose) | Drug: Rituximab<br>* Rituximab 375 mg/m2 on day 1, 15 for 6 x 28-day cycles (all 72 patients)<br>Drug: Bendamustine<br>* 28 patients to bendamustine 90 mg/m2/day, days 1 and 2 each cycle<br>|
| Active Comparator: Arm 4<br>Rituximab + Pentostatin | Drug: Pentostatin<br>* 28 patients to pentostatin 4 mg/m2 days 1 and 15 of each cycle.<br>Drug: Rituximab<br>* Rituximab 375 mg/m2 on day 1, 15 for 6 x 28-day cycles (all 72 patients)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR(PR+CR)) | Proportion of patients receiving pentostatin + rituximab and bendamustine + rituximab who achieve response | time of progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| two regimens crossover | compare the 2 regimens in crossover when used after failure of the 1st regimen | 4 years | 
| response rate | compare rituximab plus either pentostatin or bendamustine in terms of MRD-free survival, disease-free survival, overall survival and toxicity, including to CD4+ T-cells. | 4 years | 
| mechanism of thrombocytopenia | study the mechanism of thrombocytopenia after purine analog plus rituximab | 4 years | 
| HCL biology | study HCL biology by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements, and other genes | 4 years | 
| correlation of MRD levels and tumor markers with response | determine if MRD levels and tumor markers (soluble CD25 and CD22, and RQ-PCR) correlate with response and clinical endpoints, and if bone marrow MRI signal correlates with BMBx results, and whether these tests could in some cases possibly replace BMBx | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD20, Monoclonal Antibody, Purine Analog, Soluble CD25, Minimal Residual Disease MRD