Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    177
  • sponsor
    National Cancer Institute (NCI)
Updated on 13 June 2021

Summary

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.)

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: 177 patients (155 HCL, 2 extra HCL if needed, and 20 HCLv)

Details
Condition Hairy Cell Leukemia
Treatment Rituximab, cladribine
Clinical Study IdentifierNCT00923013
SponsorNational Cancer Institute (NCI)
Last Modified on13 June 2021

Eligibility

Yes No Not Sure

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
-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
Clear my responses

How to participate?

Step 1 Connect with a site
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar
Name

Primary Contact

site
Name

0/250
Preferred Language
Other Language
Please verify that you are not a bot.

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note