Cladribine + Rituximab for Hairy Cell Leukemia

Recruiting at 1 trial location

Overseen By Julie C Feurtado, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antiretrovirals, Chemotherapy

Disqualifiers: Active infection, Heart disease, HIV, Pregnancy, CNS disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

203 Participants Needed

Trial Summary

What is the purpose of this trial?

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.)

Will I have to stop taking my current medications?

The trial protocol does not specify whether you must stop taking your current medications. However, it mentions that no other therapy, such as chemotherapy or interferon, should be taken for 4 weeks prior to study entry, and cladribine should not be taken for 6 months prior to study entry.

What data supports the effectiveness of the drug combination Cladribine and Rituximab for treating Hairy Cell Leukemia?

Research shows that Cladribine is highly effective for treating Hairy Cell Leukemia, achieving excellent remission rates, though some patients may relapse. Rituximab has been successful in treating relapsed cases, helping to clear remaining cancer cells and achieve remission again. ^{1 2 3 4 5}

Is the combination of Cladribine and Rituximab safe for treating Hairy Cell Leukemia?

Cladribine and Rituximab have been used separately in treating Hairy Cell Leukemia, with Cladribine showing high response rates and Rituximab being effective in relapsed cases. Some side effects of Rituximab include febrile neutropenia (fever with low white blood cells), and other rare complications, but these treatments are generally considered safe for use in humans. ^{1 3 5 6 7}

How is the drug combination of Cladribine and Rituximab unique for treating hairy cell leukemia?

The combination of Cladribine and Rituximab is unique because Cladribine is a standard first-line treatment that can lead to high remission rates, but often with minimal residual disease (small amounts of cancer cells left), while Rituximab, a monoclonal antibody, can help clear these remaining cells, potentially reducing relapse rates. ^{1 2 5 8 9}

Research Team

Robert J Kreitman, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for adults with Hairy Cell Leukemia (HCL) who have had no more than one prior treatment with cladribine. Participants should not be pregnant, must agree to use birth control, and cannot have untreated infections or certain other health conditions. Those with the variant form of HCL (HCLv) may also join even if they've had rituximab before.

Inclusion Criteria

I can care for myself but may not be able to do heavy physical work.

I understand the study and can agree to participate.

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

Exclusion Criteria

I have symptoms from my brain or spinal cord disease.

I have an active infection that hasn't been treated.

I have not improved after cladribine treatment for my blood condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Cladribine 0.15 mg/Kg/day for 5 days and Rituximab 375 mg/m2/week for 8 weeks, with randomization for immediate or delayed Rituximab

8 weeks

Follow-up

Participants are monitored for MRD-free survival and other outcomes every 3 months for 1 year, then every 6 months until 2.5 years, then yearly

2.5 years

Extension

Participants with blood-MRD relapse may receive additional Rituximab treatment at least 6 months after initial treatment

Treatment Details

Interventions

• Cladribine
• Rituximab

Trial Overview The study tests whether giving rituximab at the same time as cladribine is better than waiting until after cladribine treatment when minimal residual disease (MRD) might be detected. Patients will either receive both drugs simultaneously or just cladribine first, followed by rituximab later if MRD appears.

Participant Groups

Group I: 3 Experimental Treatment 2 Interventions

Non-randomized group receving Cladribine with immediate Rituximab (before rather than after the 1st of the 5 daily doses of cladribine on day 1)

Group II: 1 Experimental Treatment 2 Interventions

Cladribine with immediate Rituximab

Group III: 2 Active Control 2 Interventions

Cladribine with Rituximab delayed by at least 6 months after Cladribine if and when minimal residual disease is detected

Cladribine is already approved in United States, European Union for the following indications:

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

A patient with hairy cell leukemia, who had relapsed after multiple treatments, achieved a complete response after being treated with rituximab.

The treatment resulted in a fourfold reduction of leukemic cells and restored normal blood counts, indicating rituximab's efficacy in this case.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: a useful drug for a repeatedly relapsed hairy cell leukemia patient. Pollio, F., Pocali, B., Palmieri, S., et al.[2015]

Combining cladribine with concurrent rituximab significantly improves the rates of minimal residual disease-free complete remission (MRD-free CR) in hairy cell leukemia patients, with 97% achieving MRD-free CR compared to only 24% with cladribine alone after 6 months.

Delayed rituximab treatment after cladribine resulted in lower rates and durability of MRD-free CR, highlighting the importance of timing in treatment for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. Chihara, D., Arons, E., Stetler-Stevenson, M., et al.[2021]

Bendamustine-rituximab (BR) treatment showed a 100% overall response rate in patients with multiply relapsed/refractory hairy cell leukemia, with significant complete remission rates of 50% and 67% for the 70 mg/m² and 90 mg/m² dose groups, respectively.

The treatment was well-tolerated, with no significant dose-related differences in efficacy or toxicity, and the 90 mg/m² dose was selected for future studies due to its effectiveness and manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. Burotto, M., Stetler-Stevenson, M., Arons, E., et al.[2022]

Treatment with purine analogs like 2-chlorodeoxyadenosine (2-CdA) leads to high remission rates and long-term survival in patients with hairy cell leukemia, although many still have minimal residual disease after achieving complete remission.

For patients who relapse, repeat treatment with 2-CdA is effective in achieving a second complete remission, and new agents like rituximab and BL22 have shown promise in treating relapsed and refractory cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

2-CdA in the treatment of hairy cell leukemia: a review of long-term follow-up. Gidron, A., Tallman, MS.[2019]

Cladribine is an effective treatment for hairy cell leukemia (HCL), but up to 37% of patients may experience relapse, especially those who do not respond completely to the initial therapy.

Rituximab, a monoclonal antibody targeting CD20, has shown effectiveness in treating relapsed HCL, as demonstrated by a case of successful multiple re-treatments in a heavily pre-treated patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiply relapsing hairy cell leukemia responsive to repeated courses of rituximab: a case report. Buckstein, R., Patel, H., Chesney, A., et al.[2015]

In a study of 24 patients with relapsed hairy cell leukemia treated with rituximab, only 25% achieved a response, indicating that rituximab has modest efficacy as a single-agent treatment in this context.

The treatment was generally safe, with only a few instances of serious side effects, such as febrile neutropenia and disseminated intravascular coagulation, suggesting that while rituximab may not be highly effective, it is relatively safe for patients who have failed previous cladribine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Nieva, J., Bethel, K., Saven, A.[2021]

In a study of 123 patients with hairy cell leukemia (HCL) diagnosed between 1996 and 2016, cladribine as a first-line treatment resulted in a high hematological complete response rate of 92%, demonstrating its efficacy in managing this rare cancer.

The median overall survival for HCL patients was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%, indicating a favorable long-term prognosis, especially compared to other treatments like IFN-α which had a higher relapse rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population-based study of hairy cell leukemia over a period of 20 years. Wiber, M., Maitre, E., Poncet, JM., et al.[2021]

Cladribine therapy has significantly improved outcomes for patients with hairy cell leukemia, leading to long-lasting remissions in most cases, and can be re-administered effectively for relapsed patients.

Alpha interferon has shown promise as an effective treatment option for selected patients with short remission durations after cladribine, including those who did not respond to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon-alpha is a very effective salvage therapy for patients with hairy cell leukemia relapsing after cladribine: a report of three cases. Hoffman, MA.[2021]

Cladribine (CdA) demonstrated a complete remission rate of 50% and a partial remission rate of 37% in a phase II study involving 861 patients with hairy cell leukemia, indicating its efficacy as a treatment option.

While CdA was generally well tolerated, there is a noted potential increased risk for secondary malignancies, highlighting the need for ongoing monitoring of patients after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients. Cheson, BD., Sorensen, JM., Vena, DA., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Rituximab: a useful drug for a repeatedly relapsed hairy cell leukemia patient. [2015]

2. United States pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

2-CdA in the treatment of hairy cell leukemia: a review of long-term follow-up. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Multiply relapsing hairy cell leukemia responsive to repeated courses of rituximab: a case report. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. [2021]

7. England pubmed.ncbi.nlm.nih.gov

A population-based study of hairy cell leukemia over a period of 20 years. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Interferon-alpha is a very effective salvage therapy for patients with hairy cell leukemia relapsing after cladribine: a report of three cases. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients. [2022]