Leukemia & Lymphoma, June 2011; 52(S2): 82–86
Recombinant immunotoxins and other therapies for relapsed/refractory hairy cell leukemia
ROBERT J. KREITMAN1, EVGENY ARONS1, MARYALICE STETLER-STEVENSON2, DAVID J. P. FITZGERALD1, WYNDHAM H. WILSON3, & IRA PASTAN1
1Laboratory of Molecular Biology, 2Laboratory of Pathology, and 3Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Abstract Standard treatment for hairy cell leukemia (HCL) is markedly effective, but the constant decrease in disease-free survival, together with the presence of minimal residual disease (MRD), suggests that few if any are cured. HCL cells in MRD are
always strongly CD20þand CD22þ, and also CD25þunless the patient has the poor-prognosis variant HCLv. To target relapsed/refractory HCL, immunotherapy has been developed using anti-CD25 and anti-CD22 recombinant immunotoxins, or the anti-CD20 monoclonal antibody (mAb) rituximab alone or combined with purine analogs. The recombinant immunotoxins contain an Fv fragment of a mAb fused to a truncated form of Pseudomonas exotoxin called PE38. BL22 targeting CD22, in phase I and II testing of relapsed/refractory HCL, achieved 47–61% complete remissions (CRs), several of them ongoing after 9–10 years. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 12% of patients, several of whom could later achieve a partial remission (PR) or CR with LMB-2 targeting CD25. A higher-affinity version of BL22, termed HA22, CAT-8015, or moxetumomab pasudotox, developed to more effectively treat other hematologic malignancies, also achieves CRs in HCL, and with only non-dose-limiting HUS. In separate randomized trials, rituximab is undergoing phase II testing with cladribine for early HCL and with bendamustine or pentostatin for multiply relapsed HCL.
Keywords: Monoclonal, bendamustine, cladribine, pentostatin, rituximab, LMB-2, BL22, Moxetumomab pasudotox
Need for alternative approaches in hairy cell leukemia
The purine analogs cladribine and pentostatin are each markedly effective in achieving long-term complete remissions (CRs) in patients with hairy cell leukemia (HCL), with CR rates of *70–90%, most still in CR at 8 years [1,2]. However, despite 20 years of follow-up, there remains no plateau on the disease-free survival curves, suggesting lack of cure with this approach. In fact, only a small percentage of patients followed for 12–28 (median 18) years after diagnosis were reported negative for minimal resi- dual disease (MRD) [3], suggesting that most if not all will relapse given sufficient time. Although third and fourth CRs are achieved with repeated courses of purine analogs, CR rates decrease significantly with each successive course, despite crossing over to the other purine analog [1,4]. Thus, for at least young patients, alternative strategies are needed for relapsed HCL. Moreover, new approaches for first- or
second-line treatment are needed, which might in younger patients offer less chance of eventual relapse without effective options.
Intoxication of cells by immunotoxins
Recombinant immunotoxins contain an Fv fragment of a monoclonal antibody (mAb) fused to a toxin, to target enzymatic cell-killing activity to the cell surface receptors, initiating internalization, and eventually producing cell death [5]. Agents with efficacy reported for relapsed/refractory HCL include BL22 (CAT-3888), targeting CD22, and LMB-2, targeting CD25. The Fv in each molecule is fused to a truncated form of Pseudomonas exotoxin called PE38, containing amino acids 253–364 and 381–613 of the toxin. Studies indicate that these molecules kill HCL cells by: (1) binding to their cell-surface antigen, (2) undergoing internalization, (3) unfolding at low pH, (4) undergoing proteolytic cleavage between amino acids 279 and 280 and before the carboxy terminal
Correspondence: Robert J. Kreitman, 9000 Rockville PK 37/5124b, Bethesda, MD 20892, USA. Tel: 301-496-6947. E-mail:
kreitmar@mail.nih.gov
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.565843
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