Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

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 CD25-negative 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 DNA
synthesis selectively in HCL cells. Cladribine is effective after just 1 cycle. Rituximab is
an anti-CD20 monoclonal antibody which induces apoptosis and either complement or antibody
dependent cytotoxicity (ADCC or 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 (FACS) or PCR using consensus primers.
The most sensitive HCL MRD test is real-time quantitative PCR using sequence-specific primers
(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 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 2hr i.v. infusion (days 1-5)

Rituximab 375 mg/m2/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 CLIA certified. Blood MRD relapse is defined as FACS positivity or low
blood counts (ANC less than 1500/microl, Plt less than 100,000/microl, or Hgb less than 11).
Patients FACS-negative in both blood and bone marrow aspirate are considered MRD-negative
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: 177 patients (155 HCL, 2 extra HCL if needed, and 20 HCLv)

- INCLUSION CRITERIA:

Evidence of HCL by flow cytometry, reviewed by the Laboratory of Pathology, NCI, including
positivity for CD19, CD22, CD20, and CD11c.

BMBx consistent with HCL, reviewed by Laboratory of Pathology, NCI. BMBx may be negative in
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 (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.

No prior purine analog therapy except up to 1 prior course of cladribine.

No prior rituximab unless HCLv patient.

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), ALT and 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

EXCLUSION CRITERIA:

Presence of active untreated infection

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

Known infection with HIV. Hepatitis B is allowed only if viral load is undetectable andif
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 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 CNS disease, which is symptomatic.

At the Investigator s 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 patient s 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.