Leukemia & Lymphoma, October 2009; 50(S1): 32–37
Approach to the patient after relapse of hairy cell leukemia
ROBERT J. KREITMAN, DAVID J. P. FITZGERALD, & IRA PASTAN
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Abstract
The current hairy cell leukemia (HCL) treatment is excellent, but evidence of cure with purine analogs cladribine and
pentostatin, is lacking. Significant long-term immune suppression, particularly to CD4þT-cells, and declining complete
remission rates with each course, make the identification of new therapies an important goal. The anti-CD20 monoclonal
antibody (Mab) rituximab displays significant activity, and, while causing prolonged normal B-cell depletion, spares T-cells.
Recombinant immunotoxins, containing an Fv fragment of a Mab fused to truncated Pseudomonas exotoxin, have shown
efficacy in HCL resistant to both purine analogs and rituximab. LMB-2 targets CD25 and can induce remission providing
the HCL cells are CD25þ. All HCL cells display CD22. Recombinant anti-CD22 immunotoxin BL22, targeting CD22, has
shown significant efficacy in phase I and II testing, and avoids prolonged suppression of both normal B- and T-cells. An
improved high-affinity version of BL22, termed HA22, is currently undergoing phase I testing.
Keywords: Recombinant immunotoxin, monoclonal antibody, Fv, BL22, LMB-2, HA22
HCL (10–25 patients each, total 97) vary from 10 to
Need for additional therapies
54% [8–13]. However, in the 51 patients from five
The results of therapy with purine analogs cladribine studies who demonstrated a need for treatment based
and pentostatin for hairy cell leukemia (HCL) are on cytopenias and who had at least one prior purine
excellent, with 85–95% of patients achieving com- analog, there were 10 (20%) CRs and 10 (20%)
plete remission (CR), only about 40% of patients partial responses (PRs) [8–12]. In the largest single
relapsing by 10 years [1–3], and 75% achieving trial enrolling 24 such patients, there were 3 (13%)
second CR [1]. However, disease-free survival curves CRs and 3 (13%) PRs [10]. Thus, new treatments
fail to show a plateau even after 10 years, and hence are needed for relapsed HCL which have both high
there is no evidence of cure. Moreover, while third efficacy and lack of cumulative toxicity, particularly
and fourth CRs are common with repeated courses of to T-cells. Recombinant immunotoxins are currently
purine analogs, the CR rates decline significantly being developed to meet this need.
with each successive course, irrespective of whether
the same purine analog is used or not [4,5]. Because
Recombinant immunotoxins
a single course of cladribine or pentostatin is
reported to suppress CD4þlymphocytes below the Protein toxins are among the most potent natural
lower limit of normal for a median of 40 or 54 substances known, in that they act catalytically and
months, respectively [6,7], it may be unsafe to use can therefore kill a cell with a single molecule in its
repeated courses of purine analogs to maintain HCL cytoplasm [14]. Plant toxins inactivate ribosomes by
patients, particularly at short intervals. The use of preventing their association with elongation factor-1
rituximab, while not approved for HCL, is an and -2 (EF-1 and EF-2). Bacterial toxins such as
important advance because this anti-CD20 mono- Pseudomonas exotoxin (PE) and diphtheria toxin
clonal antibody (MAb) spares T-lymphocytes. CR (DT) induce ADP-ribosylation of EF-2. This leads
rates among the six reported rituximab studies in to protein synthesis inhibition in either case, and cell
Correspondence: Robert J. Kreitman, 37/5124b, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. Tel:þ1-301-496-6947. E-mail: kreitmar@mail.nih.gov
ISSN 1042-8194 print/ISSN 1029-2403 online C211 2009 Informa Healthcare USA, Inc.
DOI: 10.3109/10428190903142216
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