Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

Randomized Trial of Cladribine (CdA) With Simultaneous or Delayed Rituximab to Eliminate Hairy Cell Leukemia Minimal Residual Disease

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.)

Study Overview

• Status: Active, not recruiting
• Conditions: Hairy Cell Leukemia
• Intervention / Treatment: Drug: Cladribine; Drug: Rituximab

Detailed Description

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: 175 evaluable patients (155 HCL and 20 HCLv)

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Julie C Feurtado, R.N.; Phone Number: (301) 480-6186; Email: julie.feurtado@nih.gov
• Study Contact Backup: Name: Robert J Kreitman, M.D.; Phone Number: (301) 480-6187; Email: kreitmar@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Cladribine with immediate Rituximab	Drug: Cladribine; Cladribine 0.15 mg/Kg/day by 2-hour i.v. infusion days 1-5. The infusion time may be changed to 1 hour at the discretion of the PI.; Drug: Rituximab; Rituximab 375 mg/m2 i.v. infusion every week x8, begin day 1 in half of randomized patients and in all HCLv patients, and then again in all patients at least 6 months later when HCL is detected by blood FACS.
Active Comparator: 2; Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected	Drug: Cladribine; Cladribine 0.15 mg/Kg/day by 2-hour i.v. infusion days 1-5. The infusion time may be changed to 1 hour at the discretion of the PI.; Drug: Rituximab; Rituximab 375 mg/m2 i.v. infusion every week x8, begin day 1 in half of randomized patients and in all HCLv patients, and then again in all patients at least 6 months later when HCL is detected by blood FACS.
Experimental: 3; Non-randomized group receving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1)	Drug: Cladribine; Cladribine 0.15 mg/Kg/day by 2-hour i.v. infusion days 1-5. The infusion time may be changed to 1 hour at the discretion of the PI.; Drug: Rituximab; Rituximab 375 mg/m2 i.v. infusion every week x8, begin day 1 in half of randomized patients and in all HCLv patients, and then again in all patients at least 6 months later when HCL is detected by blood FACS.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	Rate of minimal residual disease (MRD) identified in patients 6 months after beginning cladribine for treatment of HCL compared to patients treated with cladribine combined with rituximab	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD-free survival and disease-free survival	percentage of subjects without minimal residual disease or disease after cladribine +/- rituximab	1 and 6 months after cladribine
response to delayed rituximab for relapse	determine if early rituximab compromises later response	1 and 6 months after cladribine
overall response	determine if MRD levels and tumor markers (soluble CD25 and CD22) after cladribine and/or rituximab correlate with response and clinical endpoints	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly
blood MRD-free survival	compare blood MRD-free survival in patients who receive cladribine and up to 2 courses of rituximab, with respect to whether the 1st course of rituximab was used simultaneous with cladribine	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly
evaluation for BMBx	determine, using MRD and tumor marker data, when bone marrow biopsy (BMBx) can be avoided in managing HCL	6 months after cladribine or delayed rituximab, then yearly until 2.5 years, then every other year
Overall response and MRD	compare response and MRD after the 1st and 2nd courses of cladribine	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly
T- and B-cells	evaluate the effects of cladribine and rituximab on normal T- and B-cells	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly
characterization of monoclonal immunoglobulin rearrangements	enhance the study of HCL biology by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly
overall survival	Percentage of subjects alive at different time points particularly in patients with poor-prognosis HCL like HCLv	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly
correlate bone marrow MRI signal with bone marrow biopsy	To correlate bone marrow MRI signal with bone marrow biopsy, patients will obtain cervical and thoracic spine MRI at baseline and at bone marrow restaging time points, when feasible.	Every 3 months after cladribine or delayed rituximab for 1 year, then every 6 months until 2.5 years, then yearly

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert J Kreitman, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
• Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12.
• Kreitman RJ, Cheson BD. Malignancy: Current Clinical Practice: Treatment of Hairy Cell Leukemia at the Close of the 20th Century. Hematology. 1999;4(4):283-303. doi: 10.1080/10245332.1999.11746452.
• Chihara D, Arons E, Stetler-Stevenson M, Yuan C, Wang HW, Zhou H, Raffeld M, Xi L, Steinberg SM, Feurtado J, James-Echenique L, Tai CH, Patel KP, Braylan RC, Calvo KR, Maric I, Dulau-Florea A, Kreitman RJ. Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant. Blood Adv. 2021 Dec 14;5(23):4807-4816. doi: 10.1182/bloodadvances.2021005039.
• Chihara D, Arons E, Stetler-Stevenson M, Yuan CM, Wang HW, Zhou H, Raffeld M, Xi L, Steinberg SM, Feurtado J, James L, Wilson W, Braylan RC, Calvo KR, Maric I, Dulau-Florea A, Kreitman RJ. Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. J Clin Oncol. 2020 May 10;38(14):1527-1538. doi: 10.1200/JCO.19.02250. Epub 2020 Feb 28.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2008
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 17, 2009
• First Submitted That Met QC Criteria: June 17, 2009
• First Posted (Estimated): June 18, 2009

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: January 17, 2024

More Information

Terms related to this study

• Keywords: Rituximab; Leukemia; Cladribine; Minimal Residual Disease; Hairy Cell Leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Leukemia; Leukemia, Hairy Cell; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab; Cladribine
• Other Study ID Numbers: 090005; 09-C-0005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No