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Originally published as JCO Early Release 10.1200/JCO.2005.11.437 on August 1 2005 © 2005 American Society of Clinical Oncology. Phase I Trial of Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22) in Patients With B-Cell MalignanciesFrom the Laboratory of Molecular Biology, Laboratory of Clinical Pathology, and Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD Address reprint requests to Robert J. Kreitman, MD, National Cancer Institute, National Institutes of Health, Bldg 5124b, 9000 Rockville Pike, Bethesda, MD 20892; e-mail: kreitmar{at}mail.nih.gov
PURPOSE: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 µg/Kg every other day x 3 doses.
RESULTS: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at CONCLUSION: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.
Standard treatment of indolent lymphomas and leukemias is rarely curative, necessitating the development of novel treatment. A number of treatments with novel mechanisms have been developed and include targeted immunotherapy with monoclonal antibodies (MAbs) or growth factors which are either unlabeled1-4 or conjugated to radionuclides,5-7 chemotherapy drugs,8,9 or protein toxins.10-13 Several clinical trials have previously been reported with immunotoxins containing deglycosylated ricin A chain conjugated to either the anti-CD22 antibody RFB414,15 or its Fab fragment,16 resulting in partial response rates of up to 38%.14-16 CD22 is a 135 kDa phosphoglycoprotein adhesion molecule which is expressed on normal B cells and in 70% to 90% of B-cell malignancies.16,17 We have developed a novel targeted therapeutic approach in which a bacterial toxin is fused to the Fv portion of an antibody.10 To target CD22, a recombinant immunotoxin, BL22, was developed containing the variable domains of the anti-CD22 MAb RFB4 fused to a 38 kDa portion of Pseudomonas exotoxin A.18 To stabilize the recombinant immunotoxin, the cloned variable domains of RFB4 were joined with a disulfide bond by engineering cysteine residues into the framework regions of VH and VL.18-20 The VH domain is fused to PE38, which contains the translocating and ADP ribosylating domains of the toxin, but not the binding domain which binds to normal cells.21-27 BL22 is cytotoxic toward fresh CD22+ B-cell leukemic cells from patients and produces complete remissions (CRs) in mice-bearing human CD22+ lymphoma xenografts.28,29 A phase I trial was undertaken in patients with B-cell hematologic malignancies. Of the first 31 patients enrolled onto the trial, 16 patients had hairy cell leukemia (HCL). A high response rate to BL22 was documented in these 16 patients in an interim report,30 including 11 CRs (69%) and two partial responses (13%; PRs). The following is a report of all 46 patients enrolled onto the phase I study, including a total of 31 patients with HCL.
Patients The phase I protocol was approved by the National Cancer Institute's (NCI) Investigators' Review Board. Three patients were initially enrolled at each dose level. If no patient developed a dose-limiting toxicity (DLT), subsequent patients were enrolled at the next dose level. However, if one patient developed DLT, dose escalation did not proceed until at least three additional patients without DLT were enrolled at the current dose level. The maximum-tolerated dose (MTD) was defined as the highest dose level on cycle 1 where zero to one patient of six had DLT. To be eligible, patients had to have CD22 documented on tumor cells either by flow cytometry, immunohistochemistry, or radiolabeled binding assay. Patients with HCL required prior treatment with a purine analog if they had a CR of less than a year or lower response to the last course. Patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) were eligible after failure of standard chemotherapy, and patients with aggressive NHL required failure of, refusal, or ineligibility for transplantation. All patients had to have disease requiring treatment, adequate pulmonary, renal, and hepatic function, and lack high levels of neutralizing antibodies to BL22 in the serum. Prior chemotherapy within 3 weeks or MAb therapy within 3 months before beginning BL22 was not allowed. Patients received BL22 diluted in 50 mL of saline containing 0.2% human serum albumin over a period of 30 minutes every other day for three doses (QOD x 3). Patients without progressive disease or high neutralizing antibody levels were eligible for re-treatment at 3 to 6 week intervals. The re-treatment dose level could be changed to the highest one that was considered safe. Patients with reversible grade 3 DLT could be re-treated at a lower dose level. Toxicity was graded by the NCI Common Toxicity Criteria version 2.0. DLT was defined as grade 3-4 toxicity except for transient grade 3 transaminase elevations fever, neutropenia, and thrombocytopenia. Response was assessed by computed tomography (CT) and analysis of peripheral blood and bone marrow. CR was defined as an absence of visible HCL by CT, Wright stains of peripheral blood, and hemotoxylin/eosin stains of bone marrow. PR was defined as a reduction in tumor burden by at least 50% by standard criteria with no mass increasing in size. CR and PR were assessed at least 4 weeks after the last dose of BL22. The criteria for major response lacked the need for reversal of cytopenias, which is required by chemotherapy trials31,32 because patients were heavily pretreated. However, hematologic remission (HR) was still tracked and was defined by neutrophil and platelet counts of at least 1.5 and 100 cells/L x 10–9, respectively, and hemoglobin of at least 11 g/dL. Duration of response was measured from the first time point at which patients met all criteria to the first time point of relapse. Marginal response (MR) was defined as a reduction of any lesion by at least 25% without any lesion showing a significant increase. Progressive disease (PD) was defined by at least a 25% increase in any measurable lesion, or more than a 50% increase in leukemic cell count. Stable disease (SD) was defined as the absence of either a response or PD. Of the 46 patients enrolled, 31 patients had HCL, 11 patients had CLL, and four patients had NHL. The first 16 HCL patients (patients 2, 4, 9, 14, 15, 17, 18, 20, 23, 25, and 26 to 31; Table 1) were included in a previous publication30 as patients 1 to 16.
Plasma Pharmacokinetics and Serum Antibody Assays To determine levels of BL22, dilutions of plasma were incubated with Raji cells.29 Cytotoxicity assessed by the inhibition of [3H]leucine incorporation was used to interpolate on a standard curve as described.28,29 The plasma level was determined by multiplying the plasma dilution calculated to produce 50% inhibition of protein synthesis by the IC50, the concentration of purified BL22 which caused 50% protein synthesis inhibition. To assay for the presence of neutralizing antibodies, mixtures containing 90% serum and 10% BL22 (final BL22 concentration, 1,000 ng/mL) were incubated at 37°C for 15 to 20 minutes, diluted, cultured with Raji cells at a final BL22 concentration of 10 ng/mL, and % inhibition determined by [3H]leucine incorporation. The percent neutralization was defined as % inhibition in the presence of serum, subtracted from the % inhibition in the presence of 0.2% human serum albumin in phosphate-buffered saline (HSA-PBS), divided by the % inhibition in the presence of HSA-PBS, multiplied by 100%.
Patients As shown in Table 1, patients treated had received a median of four (range, 1 to 11) prior treatments, and had a median Eastern Cooperative Oncology Group performance status of 1 (range, 0 to 2) and a median age of 54 years (range, 30 to 81 years). Among the 42 patients with HCL or CLL, the median circulating leukemic count was 0.53 x 109/L (range, 0 to 600 x 109) cells. Among the 31 HCL patients, three had HCLv, a poor prognosis variant of HCL which responds poorly to even initial chemotherapy.33-36
Dose Levels and DLT
Adjunct Measures Tried to Prevent Toxicity To prevent allergic reactions and fever, patients received prophylactic acetaminophen, hydroxyzine, and ranitidine, and no dose-limiting allergic reactions were observed. Prophylactic anti-inflammatory agents, ultimately judged not to be useful, were administered to most of the first 31 patients enrolled onto the study. As shown in Table 1, these agents consisted of either (1) nonsteroidal anti-inflammatory drugs (NSAIDs) alone, (2) high-dose steroids, or (3) an NSAID plus an anti-TNF  agent (etanercept or infliximab). Some of the first 12 patients enrolled at dose levels of 3 to 20 µg/Kg QOD x 3 had prophylactic NSAIDs, but only during re-treatment, and none had DLT. The six patients enrolled at the 30 µg/Kg QOD x 3 dose each received an NSAID during cycle 1 and some re-treatment cycles; two of these six patients had DLT, one patient had DLT during cycle 1 (HUS), and one patient during cycle 2 (VLS). In an attempt to reduce inflammation leading to VLS, we administered prophylactic high-dose steroids to the seventh patient enrolled at the 30 µg/Kg QOD x 3 dose. However, an inflammatory syndrome and Pneumocystis carinii pneumonia occurred after prednisone was decreased. We therefore tried rofecoxib and infliximab in the next 12 patients enrolled at dose levels 30 (n = 3), 40 (n = 6), and 50 (n = 3) µg/Kg QOD x 3. However, one patient each at dose levels 30 and 50 µg/Kg QOD x 3 developed HUS during cycle 2. Once HUS appeared more serious than inflammatory syndromes, we stopped using anti-inflammatory agents, and began using prophylactic intravenous (IV) fluid to minimize renal toxicity. Using prophylactic fluid, we enrolled patients at dose levels of 30 (n = 3) and 40 (n = 6) µg/Kg QOD x 3. Two patients in the latter group had HUS during cycle 3. In both cases, cycle 3 began only 16 days after the last dose of cycle 2. In an attempt to reduce the risk of HUS, the re-treatment interval was increased to 6 weeks and the dose level was decreased to 30 µg/Kg QOD x 3 on cycle 1 and 20 µg/Kg x 3 on subsequent cycles. Six additional patients were treated at this dose and schedule with prophylactic IV fluid, and no DLT was observed. Since no DLT was observed in 12 of 12 patients during cycle 1 of 40 µg/Kg QOD x 3, this dose level was the cycle 1 MTD, but the safe dose and interval for re-treatment were not defined.
Toxicity
Immunogenicity To determine the immunogenicity of BL22, a bioassay was used to detect neutralizing antibodies to BL22. Eleven of 46 patients presented with neutralizing antibodies after one to eight cycles of BL22 at dose levels of 20 to 50 µg/Kg QOD x 3 (Table 2). BL22 was not immunogenic in B-cell chronic lymphocytic leukemia or NHL, and most patients with HCL received multiple cycles of BL22 without presenting with neutralizing antibodies. The development of neutralizing antibodies in HCL was not dose related; high levels of neutralizing antibodies were observed in three of seven patients at the 20 µg/Kg QOD x 3 dose level and in zero of five patients at the 50 µg/Kg QOD x 3 dose level. Immunogenicity was not related to prior splenectomy (  2 = 0.02; P > .05), or pre-existing CD4 counts (Wilcoxon, P = .48; n = 13). HCL patients received rituximab therapy less frequently than did non-HCL patients, and prior rituximab therapy in HCL was not associated with increased or decreased immunogenicity (2 = 2.6, P > .05).
Pharmacokinetics of BL22
Response Rate and Treatment Outcome in HCL As listed in Tables 1 and 2, patients with HCL had high response rates to BL22. A total of 25 of 31 patients responded with 19 CRs (61%) and six PRs (19%). Of the patients with HCLv, (patients 14, 18, and 26), all three achieved CR. Cytopenias improved in all responders and completely resolved in all CRs, in two of six PRs, and in one of patients patients with MR. Responding patients often had rapid reductions in circulating malignant counts (90% in 2 days; 99% in 1 week) and in spleen size. As listed in Table 1, only one HCL patient in CR had response associated with high-dose steroids (patient 18), which were used only in cycle 2; CR was not achieved in this patient until after cycle 4. Lack of a major response was associated with low doses (3 to 6 µg/Kg QOD x 3) in two patients, and massive (> 20 cm) abdominal lymph nodes in two patients. Five patients achieved CR and two patients achieved PR even though high levels of neutralizing antibodies arose after dosing. CRs were detected by bone marrow biopsy after one cycle in 11 patients and after two to 14 cycles in eight patients, so that re-treatment improved the best response. The CR rate was 86% (12 of 14) in patients enrolled at dose levels of at least 40 µg/Kg QOD x 3, compared with 41% (seven of 17) of HCL patients enrolled at lower dose levels ( 2 = 6.4; P = .011). CR rate after cycle 1 significantly correlated with dose level (P = .03). As listed in Table 1, CR in HCL was achieved in six (55%) of 11 patients with immunogenicity versus 13 (65%) of 20 patients without (2 = 0.33; P > .5). As listed in Table 1, all HCL patients had prior treatment with purine analogs, with one to three prior courses of cladribine or pentostatin, as well as other agents. The majority of these patients had never achieved CR with prior therapy (patients 14, 18, 20, 23, 26 to 28, 33, 37, and 45), six patients had no major response to the last course of cladribine or pentostatin (patients 25, 30, 31, 35, 39, and 40), and three patients had an inadequate CR to the last course of purine analog (patients 9 and 17, < 6 months; patient 38, < 2 years).
Response Duration
Response Time Course in HCL To determine how rapidly patients would respond to immunotoxin therapy, we assessed the numbers of circulating HCL cells at multiple time points, particularly during the first week of therapy. HCL patients varied widely with respect to disease burden at the time of protocol entry. Nevertheless, the decrease in the malignant count was often 90% after 2 days and 99% 1 week after protocol entry. In a typical patient (patient 23; Fig 4B) with classic HCL, in whom the malignant count was low and the spleen was enlarged, CR was achieved with one cycle of BL22 and one additional (consolidation) cycle was given. Also with classic HCL, patient 25 (Fig 4A) presented with a high HCL count, as is common after splenectomy. This patient required three cycles before achieving CR and then had two consolidation cycles. Patients with HCLv had very high malignant counts in the blood, whether the spleen had been removed or not. Patient 14 with HCLv (Fig 4C) required nine cycles to achieve CR (including six cycles after splenectomy performed for HCL-related hemorrhage), and then had two consolidation cycles. In contrast, patient 26 required only one cycle for CR and also had two consolidation cycles (Fig 4D). This exemplifies that disease burden does not prevent achievement of a CR to BL22, but sometimes additional cycles are required.
Minimal Residual Disease in HCL Patients Treated With BL22 HCL patients achieving CR to purine analogs have a 13% to 50% incidence of minimal residual disease (MRD), defined as collections of CD20+ or TRAP+ cells in the bone marrow biopsy by immunohistochemistry.38-41 The presence of MRD after cladribine or pentostatin is considered a risk factor for earlier relapse. Of the 19 patients achieving CR with BL22, only one patient (patient 27) had MRD by this definition. We found that flow cytometry of the peripheral blood is highly sensitive as an assay for MRD, and is able to detect less than 0.01% HCL cells due to strong expression of light chains, CD20, CD11c, and also expression of CD103.42 Flow cytometry was positive in two of 19 CRs (patients 18 and 38). As we previously reported,42 in patients treated with BL22 or other HCL therapies, polymerase chain reaction using consensus primers is less sensitive than flow cytometry for detecting MRD. In the patients in CR after BL22, none were positive by polymerase chain reaction. Thus BL22 was capable of inducing CRs without MRD in HCL.
Response in CLL and NHL
We treated patients with CD22+ malignancies with BL22 and observed high rates of overall response (81%) and CR (61%). This experience extends the previous report of 11 of the first 16 patients achieving CR.30 BL22 is the first agent since purine analogs reported to have a high CR rate in HCL. Unlike most trials of purine analogs, all HCL patients on our protocol had prior treatment with cladribine and most were judged unlikely to respond to an additional course. The effectiveness of BL22 in chemoresistant patients is probably due to its different mechanism of action, in that HCL cells from chemoresistant patients continue to display high levels of surface CD22; this is exemplified by its high efficacy in HCLv, which is poorly responsive to chemotherapy but yet strongly expresses CD22.36
Duration of CR in HCL
Efficacy of BL22 in HCL Versus Other Disorders
Efficacy of Rituximab for HCL
Mechanism of HUS in Patients Treated With BL22 In conclusion, BL22 is well tolerated and highly effective in HCL after one cycle at 40 µg/Kg QOD x 3. Its safety after re-treatment in HCL is currently under investigation. BL22 is also being tested in CLL and pediatric ALL. A higher affinity mutant of BL22,51 termed HA22, is currently being prepared for phase I testing, particularly for diseases like CLL with lower CD22 expression compared with HCL.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) (B) $10,000-99,999 (C)
The authors would like to recognize several research nurses involved in the care of our patients, including Karen Bergeron, Miranda Raggio, Michelle Zancan, Diana O'Hagan, Kelly Cahill, Rita Mincemoyer, and Linda Ellison. We also recognize the valuable contributions of several technicians, including Inger Margulies and Maria Gallo, and valuable data management from Barbara Debrah. We thank Seth Steinberg for statistical assistance. We recognize Elaine Jaffe for evaluating immunohistochemistry in several NHL patients. We also recognize the valuable contributions of Toby Hecht, PhD, and Steve Giardina, PhD, at the Monoclonal Antibody and Recombinant Protein Facility (MARP), Frederick, MD, Jay Greenblatt, PhD, Thomas Davis, MD, Helen Chen, MD, and Julie Rhie, PhD, at CTEP, and David Waters, PhD, at the SAIC, Frederick, MD. We recognize the important preclinical work on BL22 by Elizabeth Mansfield, PhD, the contribution of RFB4 antibody by Ellen Vitetta, MD, and the RFB4 hybridoma by Peter Amlot, MD. Lastly, we thank the many medical oncology fellows and nurses at the NIH Clinical Center who were involved in the care of our patients.
Supported by the intramural program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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51. Salvatore G, Beers R, Margulies I, et al: Improved Cytotoxic activity towards cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display. Clin Cancer Res 8:995-1002, 2002 Submitted January 11, 2005; accepted April 27, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
40 µg/Kg every other day x 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 µg/Kg IV. QOD x 3. The most common toxicities at 30 to 50 µg/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. 
