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

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 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 > 2 prior courses of purine analog, or 1 course purine
analog plus >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 68 patients).

- 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.

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.

- 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: 74, including 0-6 nonrandomized patients/arm with prior noresponse to
the other regimen. Allow crossover after failure of either regimen.

- INCLUSION CRITERIA:

2.1.1.1. 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.

2.1.1.2.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..

2.1.1.3. 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.

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.

2.1.1.4. 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

2.1.1.5. ECOG performance status (100) of 0-3

2.1.1.6. Patients must be able to understand and give informed consent.

2.1.1.7. Creatinine less than or equal to 1.5 or creatinine clearance greater than or equal
to 60 ml/ml.

2.1.1.8. 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.

2.1.1.9. 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.

2.1.1.10. Age at least 18

2.1.1.11. 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.

EXCLUSION CRITERIA:

2.1.2.1. Presence of active untreated infection

2.1.2.2. Uncontrolled coronary disease or NYHA class III-IV heart disease.

2.1.2.3. Known infection with HIV, hepatitis B or C.

2.1.2.4. Pregnant or lactating women.

2.1.2.5. 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.

2.1.2.6. Inability to comply with study and/or follow-up procedures.

2.1.2.7. Presence of CNS disease

2.1.2.8. Patients with history of non-response to both pentostatin plus rituximab and to
bendamustine plus rituximab.

2.1.2.9. 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.