Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia
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.

 Deoxycytidine kinase phosphorylates cladribine to CdATP, which incorporates into DNA, leading
 to DNA strand breaks and inhibition of DNA synthesis. 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 greater than 90 percent of patients, but MRD rates after
 cladribine 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).

 Objectives:

 Primary:

 To determine if HCL MRD differs at 6 months after cladribine with or without rituximab
 administered concurrently with cladribine.

 Secondary:

 -  To compare cladribine plus rituximab vs cladribine alone in terms of 1) initial MRD-free
 survival and disease-free survival, and 2) response to delayed rituximab for relapse, to
 determine if early rituximab compromises later response.

 -  To determine if MRD levels and tumor markers (soluble CD25 and CD22) after cladribine
 and/or rituximab correlate with response and clinical endpoints.

 -  To determine, using MRD and tumor marker data, when BMBx can be avoided.

 -  To compare response and MRD after the 1st and 2nd courses of cladribine.

 -  To evaluate the effects of cladribine and rituximab on normal T- and B-cells.

 -  To enhance the study of HCL biology by cloning, sequencing and characterizing monoclonal
 immunoglobulin rearrangements.

 Eligibility:

 HCL with 0-1 prior courses of cladribine 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).

 Stratification: 68 patients with 0 and 62 with 1 prior course of cladribine.

 Statistics: 80% power to discriminate rates of MRD of 5 vs 25%, or 10 vs 35%

 Non-randomized arm: 20 with HCLv will begin rituximab with cladribine.

 Accrual Ceiling: 152 patients (130 HCL, 2 extra HCL if needed, and 20 HCLv.)
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, and

 bone marrow aspirate FACS, 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) attributed to HCL. Patients FACS-negative in both blood and bone marrow
 aspirate are considered MRD-negative complete response (CR) 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

 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 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.