Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia
-Hairy cell leukemia (HCL) is highly responsive to purine analogs cladribine and
pentostatin, without evidence of cure. Neither is standard after 2 courses, due to
cumulative marrow and T-cell toxicity and declining remission rates and durations.
Once resistant, patients after multiple relapses can die of disease-related cytopenias.
- Rituximab alone in 51 patients from 5 trials who had cytopenias and at least 1 prior
purine analog resulted 10 complete + 10 partial remissions (CR+PR= ORR 39%).
- Rituximab with cladribine gives high CR rates in 1st or 2nd line, but is not standard.
- While cladribine use is more common for 1st and 2nd line, pentostatin is often used for
subsequent treatment because of < 100% cross-resistance.
- Retrospective published data for pentostatin plus rituximab in HCL include 7 of 7
responses with 6 (86%) CRs, and there are no prospective data.
- Recombinant immunotoxins targeting CD25 (LMB-2) and CD22 (BL22 and HA22) are highly
active in purine analog resistant HCL. Palliative pentostatin-rituximab is often used
off-protocol for patients with immunogenicity needing more therapy.
- Bendamustine is approved for early treatment of CLL, and is effective with rituximab
for relapsed/refractory CLL. Its use in HCL is unreported.
- CRs with minimal residual disease (MRD) by immunohistochemistry of bone marrow biopsy
(BMBx IHC), can relapse early. Tests for HCL MRD in blood or marrow include flow
cytometry (FACS) or PCR using consensus primers. The most sensitive MRD test in HCL is
real-time quantitative PCR using sequence-specific primers (RQ-PCR).
- Of 5 HCL-specific trials listed on Cancer.gov, 2 are phase II trials of cladribine +
rituximab in 1st and 2nd line (1 randomized at NIH, 1 non-randomized at MDA), and 3 NIH
phase I-II trials of recombinant immunotoxins BL22, HA22 and LMB-2.
--To determine if pentostatin + rituximab and bendamustine + rituximab are each
associated with adequate response rates (ORR=PR+CR) in patients with relapsed HCL, and,
if so, to select which combination is likely to be superior.
- To compare rituximab plus either pentostatin or bendamustine in terms of MRDfree
survival and disease-free survival, and toxicity, including to CD4+ T-cells.
- To determine if MRD levels and tumor markers (soluble CD25 and CD22) correlate
with response and clinical endpoints, and could possibly replace BMBx.
- To study HCL biology by cloning, sequencing and characterizing monoclonal
immunoglobulin rearrangements, and other genes.
HCL needing therapy, either greater than or equal to 2 prior courses of purine analog, or 1
course purine analog plus greater than or equal to 1 course rituximab if less than 1 year
response to the 1 course purine analog.
Prior treatment, ineligibility for, or patient refusal of recombinant immunotoxin.
- Rituximab 375 mg/m(2) on day 1, 15 for 6 x 28-day cycles (all 68 patients).
1. 28 patients to bendamustine 90 mg/m(2)/day, days 1 and 2 each cycle
2. 28 patients to pentostatin 4 mg/m(2) days 1 and 15 of each cycle.
- Initial tolerability study: 12 patients receive rituximab + bendamustine (nonrandom),
including 6 at 70 mg/ m(2) and 6 at 90 mg/ m(2) of bendamustine.
--If > 14/28 respond, can conclude with 90% power that response > 40% in that arm. >
80% probability of selecting the better arm if true response probability is
approximately 40-50% on the inferior arm and > 15% higher on the superior arm.
- Stratify to equalize the % of patients/arm refractory to last course of purine analog.
- Accrual Ceiling: 74, including 0-6 nonrandomized patients/arm with prior noresponse to
the other regimen. Allow crossover after failure of either regimen.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine if pentostatin + rituximab and bendamustine + rituximab are each associated with adequate response rates (ORR=PR+CR) in patients with relapsed HCL, and, if so, to select which combination is likely to be superior.
5-6 months after beginning the protocol
Robert J Kreitman, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|