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A Phase II Study of DT Fusion Protein Denileukin Diftitox in Patients with Fludarabine-refractory Chronic Lymphocytic Leukemia¹

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157 [A. E. F., B. L. P., J. H. B., C. L.]; Medical Center of Vincennes, Vincennes, Indiana [D. R. F.]; Medical University of South Carolina, Charleston, South Carolina [P. D. H.]; and Northwestern University Medical School, Chicago, Illinois [R. G.]

	ABSTRACT

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Purpose: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. We tested the safety and efficacy in these patients of a diphtheria fusion protein DAB₃₈₉IL2 (denileukin diftitox) directed against the interleukin 2 receptor that is expressed by CLL cells.

Experimental Design: DAB₃₈₉IL2 was administered by 60 min i.v. infusions for 5 days every 21 days at 9 or 18 µg/kg/day for up to eight cycles.

Results: Eighteen patients were treated. The mean age of the patients was 61.8 years. There were 14 males and 4 females. Two had Rai stage I, 6 had Rai stage II, and 10 had Rai stage IV. The mean number of prior treatments was 4.5 (range, 1–11). Responses were evaluated by peripheral CLL counts, computed tomography scans of all nodes and bone marrow biopsies. Twelve patients received greater than or equal to three cycles of DAB₃₈₉IL2 and were evaluable for response. Eleven of 12 patients showed reductions of peripheral CLL cells, with 6 of 11 showing 95% reductions. Seven of 12 patients showed reductions of node diameters on exam and computed tomography scans, and 2 of 12 showed 60 and 80% shrinkage, respectively. Pre and postbone marrow biopsies showed a reduction in CLL marrow index in 11 patients. Seven of 11 patients had >50% reduction, including 98% reduction in 3 patients. DAB₃₈₉IL2 produced 2 of 12 (17%) partial remission and 7 of 12 (58%) minimal responses. Progression-free intervals in the responders were 1, 1, 3+, 4, 9, 10, 10+, 14 and 19+ months. Toxicities were mild to moderate and included asymptomatic, transient transaminasemia, fever, asthenia, hypoalbuminemia, nausea, vomiting, myalgias, rash, anorexia, vascular leak syndrome, and elevated creatinine kinase. Antidiphtheria toxin antibody levels were variable and ranged from 0 to 9 µg/ml (n = 5).

Conclusions: DAB₃₈₉IL2 produced a rapid decrease of leukemic cells in the bone marrow and peripheral blood of most chemotherapy refractory CLL patients. Most patients also tolerated DAB₃₈₉IL2 well, without significant myelosuppression and/or immunosuppression. The prolonged progression-free interval and subjectively observed quality-of-life in responders is intriguing. The results suggest DAB₃₈₉IL2 has biological activity in patients with B-cell CLL. Follow-up studies of combinations or altered schedules or doses to improve the response rate are warranted.

	INTRODUCTION

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There are 10,000 new cases of CLL³ each year in the United States (1) . Although some patients with CLL have indolent disease and may live for decades, most patients develop progressive disease within a few years of diagnosis and require treatment (2) . Although a few patients may be cured with allogeneic stem cell transplants, most patients are not eligible for stem cell transplants either because of lack of HLA-matched donors, excessive age, or poor performance status. Thus, therapy consists of chlorambucil, fludarabine, cyclophosphamide, rituximab, or alemtuzumab, either given as single agents or in combinations. The majority of patients respond to chemotherapy or antibody therapy, but relapses are almost universal within 1–2 years. Novel therapies with different mechanisms of action and different toxicities (less immunosuppression) are needed. One such class of novel agents are fusion proteins composed of ligands directed to cell surface receptors fused to peptide toxins (3) .

DAB₃₈₉IL2 (or Ontak) consists of an NH₂-terminal methionine, the first 386 amino acid residues of mature DT fused to amino acid residues 1–133 of human IL2 (4) . The IL2 moiety of the fusion molecule binds with high affinity to the IL2R, a heterotrimer composed of a M_r 55,000 -subunit (CD25), a M_r 75,000 ß-subunit (CD122), and a M_r 64,000 kDa -subunit (C132; Ref. 5 ). IL2R expression has been found on CLL cells (6) . After binding the receptor, the complex undergoes receptor-mediated endocytosis (7) . In the early endosomes, the DT portion undergoes furin cleavage at the arginine-rich loop, low pH-induced protonation of the helical hairpin carboxyl residues, insertion of the TH8 and TH9 amphipathic helices of the translocation domain in the vesicle membrane, unfolding of the catalytic domain, reduction of the disulfide bridge linking the A fragment to the remainder of DT, and transfer of the A fragment to the cytosol (7) . In the cytosol, the A fragment catalyzes ADP-ribosylation of the diphthamide residue of elongation factor 2 domain IV, leading to inactivation of protein synthesis (7) . Cells undergo lysis or programmed cell death. DAB₃₈₉IL2 is potently toxic to IL2R expressing cells in tissue culture and animal models (8 , 9) . On the basis of these laboratory findings, clinical development proceeded.

One Phase I and two Phase II clinical trials were conducted with DAB₃₈₉IL2 in patients with hematological malignancies. In the Phase I dose escalation study, five daily 5-min i.v. infusions of 3–31 µg/kg/day were given to 73 patients with refractory hematological malignancies (10) . Two different Phase II studies were conducted in patients with CTCL. In the first study, 71 CTCL patients were treated with five daily 15–60 min i.v. infusions of 9 or 18 µg/kg/day of DAB₃₈₉IL2 (11) . In the second study, 20 CTCL patients received a combination of five daily 15–60 min i.v. infusions of 18 µg/kg/day DAB₃₈₉IL2 with 8 mg/day dexamethasone (12) . Toxicities included constitutional symptoms with fever, nausea, malaise, and asthenia. A VLS was observed days to weeks after treatment and lasted up to 2 weeks, consisting of hypotension, mild uremia, hypoalbuminemia, proteinuria, edema, and dyspnea. Reversible, asymptomatic transaminasemia was seen. The DAB₃₈₉IL2 plasma half-life was 72 min, and the total exposure measured by the AUC was proportional to the dose administered. Neither the peak serum concentrations nor the AUC was affected by the soluble IL2R level. Thirty-eight percent of patients had anti-DT antibodies pretreatment and 92% of patients had anti-DT antibodies after two courses of DAB₃₈₉IL2. Anti-DT antibodies reduced the peak concentrations and AUC, but levels were still measurable in the presence of antibodies and responses were seen. Combining all three studies, DAB₃₈₉IL2 produced 3 of 17 remission in B-cell non-Hodgkin’s lymphoma (two low-grade and one intermediate grade), 1 of 21 remissions in Hodgkin’s disease, and 34 of 106 remissions in CTCL. The median duration of response in the CTCL patients was 7 months (range, 3–46+ months). The response rate in CTCL was significantly improved (from 32 to 60%) by the addition of dexamethasone to the treatment regimen. Re-treatment yielded a 47% second remission rate.

On the basis of these favorable clinical results in another hematological malignancy and the presence of IL2R on CLL cells, we undertook to test the activity of DAB₃₈₉IL2 in patients with fludarabine-refractory CLL.

	PATIENTS AND METHODS

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Eligibility criteria for patient entry in the study included a diagnosis of B-cell CLL, an intermediate to high-risk category in the modified three-stage Rai staging system (2) and be refractory or relapsed within 6 months of fludarabine. All patients had to have CD25 (IL2R) expression on 20% of the circulating CLL cells. Flow cytometry was used to determine CD25 expression. Briefly, peripheral blood (100 µl) was mixed with FITC-conjugated anti-CD25 monoclonal antibody (10 µl; Dako, Carpenteria, CA) or FITC-conjugated IgG1 isotype control (Dako) and incubated at room temperature for 15 min. Cells were washed with PBS, pelleted at 600 x g for 5 min, lysed with Whole Blood:Lysing Reagent (1 ml; Coulter, Hialeah, FL), fixed with 8% formaldehyde (250 µl), washed twice with PBS, resuspended in 1 ml of PBS, and analyzed on an Epics-XL flow cytometer gated for lymphocytes. Percent CD25-positive cells were the percentage of lymphocytes showing fluorescence intensity 99% of cells stained with fluorescein-conjugated isotype control mouse IgG1 antibody. Patients had to be 18 years old, have a serum albumin 3 g/dl, have serum AST 5 x upper limit of normal, have serum creatinine 2 mg/dl, and have no uncontrolled infections, central nervous system leukemia, pregnancy, nursing, or poor performance status (Zubrod 3 or 4). Written informed consent was obtained from each patient before entry into the study.

DAB₃₈₉IL2 (Ontak) produced under good manufacturing practice and aliquoted in single-use vials containing 300 µg in 2 ml of 20 mM citrate buffer (pH 7) with 50 mM EDTA and 0.8% polysorbate 20 (NDC 64365-503-01, six vials in a package) was obtained from Ligand Pharmaceuticals, Inc. (San Diego, California). Vials were stored at -10°C until used. Before treatment, vials were thawed to room temperature, and appropriate amounts of drug dispensed in a laminar flow hood for individual daily doses by diluting with sterile saline into empty plastic i.v. bags or plastic syringe to a final concentration of 15 µg/ml following the recommendations in the package insert. Patients received allopurinol 300 mg/day beginning 1 day before therapy and continuing for 14 days. Patients were also given dexamethasone (2 mg twice daily on the day before treatment, 2 mg daily on the days of treatment, 1 mg daily for 3 days after treatment, followed by 0.5 mg daily for 4 days). Concurrently with dexamethasone, patients received sulfamethoxazole/trimethoprim (800/160 mg) twice daily three times a week and prilosec 20 mg daily. Thirty to sixty min before each DAB₃₈₉IL2 infusion, patients received 650 mg of acetaminophen and 25 mg of diphenhydramine. Patients also received at least 1 liter/day of 5% dextrose in water supplemented with 80 of mEq sodium bicarbonate on treatment days. DAB₃₈₉IL2 was administered as 60 min i.v. infusions of 18 µg/kg/day for 5 days (9 µg/kg/day were used for patients with age >70 years or Zubrod performance status of 2). Cycles were administered every 21 days for a maximum of eight cycles of treatment. All treatments were given on an outpatient basis at oncology infusion centers. While on study, patients received only washed blood products and were not to be given i.v. immunoglobulin. This reduced exposure to allogeneic anti-DT antibodies.

Patients were monitored with weekly histories, physical exams, blood counts, urinalyses, and chemistries. Toxicity and toxicity grade were determined using the revised NCI Common Toxicity Criteria (version 2.0). The Leukemia Special Adverse Event Criteria was used to grade hemoglobin, platelets, neutrophils/granulocytes, and fibrinogen. VLS was characterized by >2 of the following three findings: hypoalbuminemia; edema; and/or hypotension. Staging with bone marrow biopsies, computerized tomography scans and flow cytometry for circulating CD5+/CD19+/CD25+ cells were done pretreatment after four and eight cycles and then every 3 months until relapse or progression. Lymph node disease was quantitated by measurements of the areas of individual nodal masses using the equation, area = shortest diameter x the longest diameter determined by computerized tomography and exam. The sum of the areas of identifiable, pathological masses was calculated pre- and posttreatment. Twelve patients had pre and posttreatment computerized tomography and exams. Responses were graded using the Cheson criteria (2) . Complete remission required the absence of constitutional symptoms, the absence of adenopathy and organomegaly, a normal hemogram, and <30% lymphocytes on bone marrow biopsy. Partial remission consists of an improvement in stage, >50% reduction in nodes, peripheral blood values, and/or organomegaly. Minimal response is an improvement in all of the parameters but not achieving partial remission. Progressive disease is defined by an increase in 25% in masses, organomegaly or lymphocytosis or worsening stage. Evaluable patients for response were defined as those patients who received at least three cycles of DAB₃₈₉IL2.

The two-sample t test was used to compare outcomes in the responders versus nonresponders. A ² test was used to assess differences between groups in the number of responders (categorized above and below five cycles of treatment).

Anti-DT antibody levels in the serum were measured using a direct antibody enzyme-linked immunoassay as described previously (13) . Briefly, 96-well plates were coated with DT protein, washed with PBS, incubated with dilutions of serum or controls, rewashed with PBS and incubated with alkaline-phosphatase labeled antihuman IgG, and developed with p-nitrophenylphosphate. Absorbance of wells at 405 nm was measured. Each sample was run in duplicate. The median (range) interassay and intra-assay coefficient of variations were 9.8% (0–18%) and 9.3% (0.5–22.5%).

	RESULTS

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Patients.
Thirty patients were referred for the study and 22 of 30 (73%) had CD25 expression on at least 20% of circulating CLL cells. Of these, 19 patients registered for the study, but 1 patient changed his mind before beginning therapy. Thus, 18 patients were treated with DAB₃₈₉IL2. The mean age was 61.8 years. There were 14 males and 4 females. Two patients were Rai stage I, 6 patients were Rai stage II, and 10 patients were Rai stage IV. The patients had a mean of 4.5 (range, 1–11) prior therapies (Table 1) .

View larger version (114K): [in this window] [in a new window]   Fig. 1. H&E-stained 6-µm paraffin section of the bone marrow biopsies obtained pretreatment (A) and after four cycles (B) on patient no. 1.

View larger version (86K): [in this window] [in a new window]   Fig. 2. Image of the pelvic computerized tomography of patient no. 1 pretreatment and after four cycles. The arrows point to a CLL nodal mass.

Immune Responses.
Antibody levels to DT were determined on patient nos. 1, 2, 3, 10, and 18 and were 2.8, 0, 1.8, 9.0, and 1.4 µg/ml, respectively.

	DISCUSSION

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Patients with advanced CLL have a chronic disease with allogeneic stem cell transplant offering the only currently available curative regimen (14) . Thus, selection of palliative therapies is, in part, guided by patient tolerance. Current salvage treatments with combination chemotherapy or alemtuzumab are associated with significant immunosuppression and infections requiring frequent hospitalizations (15) . Targeted biologics such as DAB₃₈₉IL2 offer the potential of better patient acceptance and quality-of-life. The results from this pilot study are encouraging, but additional work is needed.

There is a learning curve for patients, nurses, and physicians for DAB₃₈₉IL2 administration and side effects. Only 3 of the first 9 (33%) patients completed four cycles of DAB₃₈₉IL2, whereas 6 of the last 9 (67%) patients had four or more cycles of treatment (P = 0.02). There was no significant difference in age, sex, number of prior therapies, or disease stage to account for this difference. After the first few patients, significant time was spent with patients, families, nurses, and physicians to explain the nature of DAB₃₈₉IL2 side effects. With frequent communication after each cycle and aggressive intervention for any complaints, patient acceptance improved. Aggressive management of fevers was also initiated, reducing the incidence of serious infections. Recurrent fevers exceeding 38°C were evaluated with history, examination, blood and urine cultures, chest X-ray, and viral cultures. Broad spectrum antibiotics were initiated. Thus, changes in supportive care alone may permit better tolerance and lead to an improved response rate to DAB₃₈₉IL2 in CLL. No formal measurements of quality-of-life were made. Another approach to improve tolerance may be higher doses (8 mg/day) of dexamethasone. Foss et al. (12) found fewer toxicities and improved response rate in CTCL patients treated with DAB₃₈₉IL2 and 8 mg/day dexamethasone. We used a lower dose of steroids in our pilot study (1 mg of dexamethasone for 6 days every 3 weeks) to reduce side effects without complicating analysis of response. Our low-dose steroids are much lower than doses of corticosteroids associated with remissions in chemotherapy-refractory CLL patients (16) . However, in future studies, the use of the higher dose dexamethasone should be considered.

CLL patients have low pretreatment antitoxin antibodies and do not respond normally to foreign proteins such as immunotoxins (17) . Consequently, CLL should be an excellent target for protein therapeutics such as DAB₃₈₉IL2 as antibodies capable of neutralizing the drug or inducing rapid clearance from the bloodstream should not occur. We observed variable anti-DT antibody levels in a subset of our patients. Only 1 patient showed high-level antibody (9 µg/ml). Future schedules may consider more cycles of therapy. An amnestic immune response should be low or absent. On the basis of our preliminary findings, anti-DT antibody titers should be monitored.

Most responses in the current study were minimal. There were only two partial remissions and no complete remissions. How could the response rate be improved? Analysis of predictors of response revealed CD25 expression was important. The usefulness of CD25 level determined by flow cytometry was surprising. Only 35 high-affinity IL2R are needed/cell in tissue culture for DAB₃₈₉IL2 killing (8) . Because flow cytometry can only detect thousands of receptors/cell and the assay only measured one of the receptor subunits of a heterotrimeric receptor, we did not expect a correlation of CD25 positivity with response. Nevertheless, a similar weak but present correlation was seen with the response of CTCL to DAB₃₈₉IL2 using CD25 immunohistochemistry (11) . Thus, cell surface CD25 may provide a surrogate marker for the level of high-affinity IL2R. Patients could be selected for higher CD25 levels to improve remission rates. Alternatively, combining DAB₃₈₉IL2 with agents, which may up-regulate IL2R on the surface of CLL cells, may improve response rate. Several clinically available agents should be considered, including bexarotene (Targretin; Ligand Pharmaceuticals, Inc.), IL2, IL7, and the DSP30 phosphorothioate CpG-oligodeoxynucleotide (18, 19, 20, 21, 22) .

Other factors may influence response. The pretreatment performance status may influence the likelihood of receiving adequate drug and responding to DAB₃₈₉IL2. The systemic symptoms, including asthenia, anorexia, fever, and myalgias, would be expected to be particularly morbid in patients with poor performance status. Thus, selection of better performance status patients might improve the response rate. The lower platelet count in responders is difficult to explain but may reflect the greater activity of DAB₃₈₉IL2 in marrow and blood disease compared with nodal disease.

Additional approaches may improve responses in chemoresistant CLL. As described in the results, DAB₃₈₉IL2 had greater anti-CLL activity in blood and marrow than in nodes. The reduced efficacy in nodes may be attributable to antiapoptotic effects of nurse-like or dendritic cells present in nodes (23, 24, 25) or poor penetration by large fusion proteins (17) . Combining DAB₃₈₉IL2 with rituximab may be useful because the latter has significant activity in nodal disease (26) . With additional clinical research, DAB₃₈₉IL2 may become part of the armamentarium for therapy of CLL and improve the prognosis of this debilitating, fatal disease.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Ligand Pharmaceuticals, Inc., and the Wake Forest University School of Medicine.

² To whom requests for reprints should be addressed, at Hanes 4046, Wake Forest University School of Medicine, Medical Center Drive, Winston-Salem, NC 27157. Phone: (336) 716-3313; Fax: (336) 716-0255; E-mail: afrankel{at}wfubmc.edu

³ The abbreviations used are: CLL, chronic lymphocytic leukemia; IL, interleukin; IL2R, IL2 receptor; DT, diphtheria toxin; DAB₃₈₉IL2, DT fusion protein denileukin diftitox; CTCL, cutaneous T-cell lymphoma; CMV, cytomegalovirus; AUC, area under the curve; VLS, vascular leak syndrome; AST, aspartate transferase.

Received 2/12/03; revised 3/20/03; accepted 3/21/03.

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