Immunotoxins for hairy cell leukemia Agent(s)


Table I. HCL-specific clinical trials at NIH. Trial type


HA22 (CAT-8015 or moxetumomab pasudotox) Phase I Target Eligibility


CD22 Two prior therapies Need for treatment* No/low antibodies Adequate organ function


LMB-2 Phase II


CD25 54 year CR/PR to2nd-line cladribine Need for treatment*


No/low antibodies Adequate organ function


CD25þHCL Prior BL22 or HA22, or ineligible


Cladribineþrituximab


Phase II randomized CD20 0–1 prior courses of cladribine No other purine analog No prior rituximab Need for treatment* HCLv allowed (non-randomized)


Bendamustineþrituximab vs. pentostatinþrituximab Phase II randomized CD20


2 prior courses purine analog Need for treatment*


HCLv allowed


*Need for treatment in HCL is generally defined as at least one of the following: neutrophils51000/mL, hemoglobin510 g/dL, platelets5100 000/mL, lymphocytes420 000/mL, or symptomatic splenomegaly. All trials require adequate organ function. HCL, hairy cell leukemia; NIH, National Institutes of Health; CR, complete remission; PR, partial remission; HCLv, variant HCL.


85


B-cell depletion, compared to if rituximab were added after neutropenia resolves. This trial so far shows an ORR of 100% in 22 evaluable patients, and without immediate rituximab most patients have MRD in the blood 6 months after cladribine.


Bendamustine versus pentostatin combined with rituximab for multiply relapsed hairy cell leukemia


The combination of pentostatin and rituximab is reported to have an ORR of 100% with six (86%) CRs in seven patients treated [4], although a prospective trial has not been carried out with this combination. Bendamustine is approved for CLL and is active with rituximab in several hematologic malignancies [13] including CLL. Although it has a purine analog group similar to cladribine, it also contains alkylator activity and its mechanisms of cell death allow non-cross-resistance with purine analogs.


To evaluate both regimens of pentostatinþrituximab and bendamustineþrituximab in multiply relapsed HCL, a randomized trial has begun whereby each


regimen is evaluated in phase II fashion and the two regimens compared, with a crossover allowed.


Summary


The outlook for patients with HCL dramatically improved after the introduction of purine analogs over 20 years ago, but cure seems elusive for patients young enough to outlive their remissions and become


treatment-refractory. New immunotherapeutic ap- proaches include rituximab combined with purine analog, or recombinant immunotoxin either alone or eventually combined with other agents (Table I). These new approaches may offer eradication of HCL in some patients, or at least a dramatic lengthening of treatment-free intervals sufficient to prevent HCL- related deaths even in young patients.


Acknowledgements


This work was supported in part by the National Cancer Institute, Intramural Program. Work regard- ing moxetumomab pasudotox (HA22 or CAT-8015) and BL22 (CAT-3888) was supported in part by MedImmune, LLC.


Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.


References


1. Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol 2003;21:891–896.


2. Grever MR. Pentostatin: impact on outcome in hairy cell leukemia. Hematol Oncol Clin North Am 2006;20:1099– 1108.


3. Sigal DS, Sharpe R, Burian C, Saven A. Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine. Blood 2010;115:1893–1896.


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