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Clinical Cancer Research Vol. 9, 3995S-4002S, September 1, 2003
© 2003 American Association for Cancer Research

Session V: CLINICAL STUDIES: HEMATOLOGICAL TUMORS

Final Results of a Phase I Radioimmunotherapy Trial Using 186Re-Epratuzumab for the Treatment of Patients with Non-Hodgkin’s Lymphoma1

Ernst J. Postema2, John M. M. Raemaekers, Wim J. G. Oyen, Otto C. Boerman, Caroline M. P. W. Mandigers, David M. Goldenberg, Guus A. M. S. van Dongen and Frans H. M. Corstens

Departments of Nuclear Medicine [E. J. P., W. J. G. O., O. C. B., F. H. M. C.] and Hematology [J. M. M. R., C. M. P. W. M.], University Medical Center Nijmegen, 6500 HB Nijmegen, the Netherlands; Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109 [D. M. G.]; and Department of Head and Neck Surgery, VU University Medical Center, 1007 MB Amsterdam, the Netherlands [G. A. M. S. v. D.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Purpose: Radioimmunotherapy (RIT) is an effective, new treatment modality for non-Hodgkin’s lymphoma (NHL). The aim of this study was to determine the maximum tolerated dose and a first impression of the therapeutic potential of 186Re-epratuzumab in patients with NHL.

Experimental Design: Patients with relapsed or refractory CD22-positive NHL of diverse histopathology and prior treatments received 99mTc-labeled epratuzumab (anti-CD22 IgG1), followed by RIT with 186Re-epratuzumab 1 week later. Dose escalation of RIT was started at 0.5 GBq/m2. Three patients were entered per dose level. If no dose-limiting toxicity occurred, the dose was increased by 0.5 GBq/m2; otherwise three additional patients were included on that dose level.

Results: A total of 18 patients received a diagnostic dose of 99mTc-epratuzumab. Fifteen patients were actually treated with 186Re-epratuzumab at four different dose levels, 0.5, 1.0, 1.5, and 2.0 GBq/m2. During or after infusion of 186Re-epratuzumab, no adverse reactions were seen. In all patients, a transient decrease of leukocyte and platelet levels was observed 1 month after treatment. At the 1.5-GBq/m2 dose level, one grade 4 hematological toxicity was observed. At the highest dose level of 2 GBq/m2, no grade 4 hematological toxicity was seen, but WBC and platelet counts of two of the three patients did not recover completely. One patient had a complete remission lasting 4 months. Four patients had a partial remission, lasting 3, 3, 6, and 14 months, respectively. Four patients had stable disease for 3, 3, 7, and 9 months, respectively.

Conclusions: 186Re-epratuzumab at a dose of 2.0 GBq/m2 is well tolerated without major toxicity. A single dose of 186Re-epratuzumab led to objective responses in 5 of 15 treated patients.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
In the last decade, RIT3 has become a rather successful treatment modality for patients with refractory or relapsed NHL (1 , 2) . Several Phase I/II studies with 131I- or 90Y-labeled mAbs have shown promising therapeutic results. One radiolabeled antibody, 90Y-labeled ibritumomab, has been approved recently for commercialization by the United States Food and Drug Administration after a successful randomized Phase III trial (3, 4, 5) . In this study, radiolabeled antibody treatment was shown to be significantly more effective than treatment with unlabeled antibodies alone (5) . The two currently most widely studied and used mAbs are the murine anti-CD20 antibodies, ibritumomab and tositumomab. Although study results confirm the enormous potential of these new drugs against NHL, they both have the disadvantage of being murine antibodies. The use of murine mAbs could induce the formation of HAMAs, eventually preventing repeated treatment with this radiopharmaceutical. Therefore, the use of chimeric or, preferably, humanized antibodies is desirable.

Another important issue in RIT is the choice of the radionuclide to be used. Both 90Y and 131I are widely used in RIT. 131I could be disadvantageous, however, because it emits high-energy, high-abundance {gamma}-rays, requiring hospitalization of treated patients for radiation safety reasons. It also emits low-energy ß-radiation with a limited penetration range in tissue, which could also be disadvantageous when treating patients with bulky disease. 90Y emits high-energy ß-radiation but lacks {gamma}-emissions, prohibiting scintigraphic evaluation after treatment. Rhenium-186 (186Re) has ideal physical characteristics for RIT. It has medium-energy ß-emissions and low-abundance {gamma}-photons with ideal energy (137 keV) for scintigraphic imaging.

In this study, the humanized anti-CD22 mAb epratuzumab was used, which is also being investigated as an unlabeled mAb as well as a mAb labeled with the radionuclides 131I and 90Y. The aim of the study was to determine the safety and MTD of RIT using epratuzumab labeled with 186Re.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patient Population.
This dose-escalation study was performed in patients with B-cell NHL who had relapsed after or did not respond to at least one line of treatment and who were not eligible for potentially curative high-dose chemotherapy followed by stem cell support. All patients had histologically proven, CD22-positive NHL. Patients had to have a life expectancy of at least 2 months and had to be at least 18 years of age. Patients had to have a WHO performance status of 0, 1, or 2. No other antitumor therapy should be given within at least 3 weeks before study entry. WBC count had to be at least 2.5 x 109/liter, and platelet count had to be at least 75 x 109/liter. Patients were excluded in case of life-threatening infection, allergic diathesis with current complaints, organ failure, pregnancy, known seropositivity for HIV, >25% bone marrow involvement by lymphoma as determined by bone marrow histology and histochemistry, concomitant treatment with other investigational drugs, or spread of the malignancy to the central nervous system. The study was approved by the institutional review board of the University Medical Center Nijmegen. Written informed consent was obtained from all patients.

Antibody.
Epratuzumab (hLL2) is a humanized monoclonal IgG1 antibody directed against CD22 on B cells (6) . CD22 is expressed in the cytoplasm of early pre-B and progenitor cells and appears on the surface of mature B cells. The CD22 antigen is broadly expressed on both normal and malignant B cells, with a distribution comparable to that of CD20, although antigen density may be more variable (7) . Unlabeled epratuzumab is used in clinical trials in chemotherapy-refractory NHL patients (8) and in combination with rituximab (9) . Initial data of the Phase I/II dose-escalation study show that the lowest dose level at which objective responses were seen was the dose level with four weekly infusions of 240 mg/m2 epratuzumab (8) . Epratuzumab was kindly provided by Immunomedics, Inc. (Morris Plains, NJ) as a sterile pyrogen-free solution.

Labeling.
Epratuzumab was labeled with 99mTc using MAG3 as a chelator according to the method described by Visser et al. (10) . A preparation with a specific activity of 100 MBq/mg was prepared. Patients received 750 MBq of 99mTc-MAG3-epratuzumab. The protein dose of the preparation was adjusted to 0.5 mg/kg body weight with unlabeled epratuzumab.

186Re-epratuzumab was prepared according to the same method (10) . Again, the protein dose of the preparation was adjusted to 0.5 mg/kg body weight by adding unlabeled epratuzumab to the radiolabeled preparation.

Protocol.
Pretherapy evaluation consisted of history, physical examination, blood sampling for hematological and biochemical analysis, bone marrow histology and cytology, and computed tomography of the chest and abdomen. After inclusion, a diagnostic dose of 750 MBq of 99mTc-epratuzumab was administered i.v. over 45 min. One week after this diagnostic procedure, the patient was hospitalized overnight for RIT with 186Re-epratuzumab. The infusion time of 186Re-labeled epratuzumab was also 45 min. The starting dose level was 0.5 GBq/m2 body surface area. If no dose-limiting toxicity occurred (i.e., no grade 3 or 4 nonhematological toxicity and no grade 4 hematological toxicity according to the National Cancer Institute Common Toxicity Criteria 2.0) in consecutive patients, the dose level was escalated by 0.5 GBq/m2. Three patients were included at each dose level. If dose-limiting toxicity was observed in one patient at a specific dose level, three additional patients were treated at that same dose level. In case of dose-limiting toxicity in two or more patients at a particular dose level, the dose level below that level would be considered the MTD. Patients were monitored weekly for adverse reactions and toxicity. Patients were evaluated for responses 4–6 weeks after RIT, using physical examination, biochemical analysis, computed tomography scanning, and bone marrow examination, as far as involved at the start. In case of SD or responses, this procedure was repeated every 3 months thereafter.

Pharmacokinetics.
Blood samples for pharmacokinetics were taken 10 min, 30 min, and 1, 2, 3, 4, and 24 h after injection of the diagnostic dose of 99mTc-epratuzumab. After RIT, blood samples were taken at the same time points and additionally after 2, 5, 7, and 14 days. mAb blood clearance rates were determined by counting the samples in a shielded well-type counter. The plasma clearance of 99mTc-epratuzumab was fit to a monoexponential function, and the blood clearance of 186Re-epratuzumab was fit to a biexponential function. On the basis of these curves, T1/2 (the time point when 50% of the activity was cleared from the circulation), T1/2,{alpha} (representing the distribution phase) and T1/2,ß, (representing the elimination phase) were calculated.

HAHA Analysis.
Serum samples for HAHA analysis were obtained before the infusion with 99mTc-epratuzumab, before the infusion with 186Re-epratuzumab, and 7, 14, 28, and 56 days after treatment. An ELISA performed by Immunomedics, Inc. was used to assess human anti-hLL2 antibodies. Results were reported as a number (in ng/ml) or as undetected (<1 ng/ml). Levels above 50 ng/ml are considered to be elevated (results from Immunomedics, Inc.).

Scintigraphy.
One h and 1 day after injection of the diagnostic dose, a whole body scan was made with a double-head gamma camera (Siemens Multispect 2; Siemens Medical Solutions USA, Inc., Hoffmann Estates, IL) equipped with low-energy, high-resolution collimators. Scintigraphy after RIT was performed 1 h, 1 day, 2 days, and 5 days postinjection at a speed of 5 cm/min.

Dosimetry.
Scans made after RIT were used for dosimetric analysis. ROIs were drawn around the whole body, heart, right lung, liver, spleen, left kidney, and testes. Background regions were drawn adjacent to these ROIs. Using the counts in the ROIs, corrected for background, residence times in the organs as listed above were estimated. These residence times were entered in MIRDOSE3, version 3.1 (Oak Ridge Associated Universities, Oak Ridge, TN) to calculate absorbed doses. For males, the adult phantom was used; for females, the adult female phantom was used. The absorbed dose in the bone marrow was calculated using the blood-derived method as described by Shen et al. (11) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Patient Characteristics.
Eighteen patients (12 men and 6 women) were included, 15 of whom were actually treated. The mean age was 57 years (range, 41–75 years). Patient characteristics are listed in Table 1Citation . The number of courses of chemotherapy and/or external beam radiation before inclusion in our study ranged from 1–7, with a median number of 4. Of these patients, three had had high-dose chemotherapy followed by autologous peripheral stem cell transplantation. Three patients were not treated with 186Re-epratuzumab because of unfavorable biodistribution (n = 2), as described in "Scintigraphy" and because of an acute allergic reaction to the first, diagnostic infusion (n = 1), as described in "Toxicity" section. Patients were treated at four different dose levels, 0.5 GBq/m2 (n = 3), 1.0 GBq/m2 (n = 3), 1.5 GBq/m2 (n = 6), and 2.0 GBq/m2 (n = 3).


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  		Table 1 Patient characteristics and therapeutic effects

 
Toxicity.
During or directly after infusion of the diagnostic dose of 750 MBq of 99mTc-epratuzumab, fever and chills were observed in 9 of 18 patients within 1 h after infusion. This reaction was self-limiting and required no specific medical intervention. Chills lasted 30–45 min, whereas the fever lasted several hours. One patient experienced an acute allergic reaction with airway obstruction within half an hour after infusion, for which administration of clemastine and prednisolone and inhalation of albuterol and ipratropium were required. One patient had slight dyspnea during infusion, which diminished after stopping the infusion. After restart of the infusion at half speed, the dyspnea did not recur. Two patients had a vasovagal episode after infusion. Finally, one patient had herpetiform lesions on the left lower arm 1 week after the diagnostic infusion. During infusion of the therapeutic dose of 186Re-epratuzumab, no clinical adverse reactions were seen in any of the patients. Within 1 h after infusion, fever was observed in only two patients. In all patients, platelet and leukocyte levels decreased 4–6 weeks after the therapeutic injection. The nadirs are listed in Table 1Citation . Figs. 1Citation and 2Citation depict the platelet and WBC count, respectively, over time. In only one patient was a grade 4 hematological toxicity observed (WBC of 0.5 x 109/liter) 6 weeks postinfusion of 1.5 GBq/m2. In patient 2 (0.5 GBq/m2 dose level), an isolated WBC count drop was observed as early as 2 weeks after therapy and was probably caused by a viral infection. Other toxicity consisted of a facial zoster reactivation (n = 1), oral candidiasis (n = 1), and loss of taste (n = 1).



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  		Fig. 1. Platelet counts after RIT.

 


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  		Fig. 2. WBC counts after RIT.

 
Pharmacokinetics.
Elimination from the circulation of both 99mTc- and 186Re-labeled epratuzumab varied widely between patients. Table 2Citation shows T1/2, T1/2,{alpha}, and T1/2,ß in all patients. The T1/2,ß varied from 30.3 to 176.1 h, indicating that the antibody is circulating for a long time, as expected when using a humanized mAb. The percentage of the injected dose that was excreted via the urine is also listed in Table 2Citation . Up to 45.9% of injected dose could be detected in the urine, indicating that after catabolization of the mAb, 186Re-MAG3 is cleared renally.


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  		Table 2 Pharmacokinetic data of 99mTc- and 186Re-labeled epratuzumab

 
HAHAs.
A total of 90 samples of 18 patients were analyzed quantitatively for HAHAs. In seven patients, HAHA levels could be detected, ranging from 0.5 to 50 ng/ml. Six of these seven patients with detectable HAHAs had detectable HAHA levels before RIT. No positive HAHA results were obtained. Special attention was paid to serum samples of the patient experiencing an adverse reaction shortly after infusion of 99mTc-hLL2. Neither HAHA nor HAMA levels could be detected in serum samples obtained before infusion; 1, 3, and 4 h after infusion; and 1 and 9 days after infusion. There was no relation between the presence of low levels of HAHAs before treatment and the occurrence of chills and fever after the infusion of radiolabeled epratuzumab.

Scintigraphy.
On scintigrams made 1 h and 1 day after injection of 99mTc-epratuzumab, mainly activity in the blood pool was observed. In some patients, lymphoma targeting was observed, as illustrated in Fig. 3Citation . Two patients appeared to have major bone marrow uptake after the diagnostic injection, as shown in Fig. 4Citation . Both patients were known to have bone marrow involvement (but <25% involvement). Both patients were excluded from further RIT because treatment with 186Re-epratuzumab could have resulted in serious and potentially irreversible myelotoxicity.



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  		Fig. 3. Scintigraphy after infusion of 99mTc-epratuzumab, showing a normal biodistribution and targeting of an abdominal lymphoma.

 


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  		Fig. 4. Scintigraphy after infusion of 99mTc-epratuzumab, showing unfavorable biodistribution with targeting of bone marrow and an enlarged spleen.

 
During the first days after RIT, visualization of lymphoma improved. Fig. 5Citation shows scintigrams of a patient who had lymphoma localization in the inguinal regions.



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  		Fig. 5. Scintigraphy after infusion of 186Re-epratuzumab, showing targeting of inguinal lymphoma.

 
Dosimetry.
Doses absorbed in normal organs are listed in Table 3Citation . The organ with the highest absorbed dose is the spleen because the spleen is a lymphoid organ housing CD22-positive cells and involved in NHL. All absorbed doses were far below critical values. Therefore, RIT with 186Re-labeled epratuzumab is thought to be safe. Tumor dosimetry is not available yet. The dosimetric analysis will be discussed in more detail in a separate publication.4


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  		Table 3 Mean absorbed organ doses after treatment with 186Re-labeled epratuzumab

 
Therapeutic Effects.
A summary of the therapeutic effects is listed in Table 1Citation . One patient responded completely; for 4 months no lymphoma could be demonstrated. Four patients showed a PR lasting 14, 6, 3, and 3 months, respectively. Four patients had SD for 9, 7, 3, and 3 months, respectively, after RIT. Six patients progressed after RIT.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The present study shows that RIT with 186Re-labeled epratuzumab is safe, despite the fact that most patients were heavily pretreated before RIT. As expected, a transient decrease in blood counts was dose-limiting. Although grade 4 hematological toxicity was observed in only one patient treated at the third dose level of 1.5 GBq/m2, the slow recovery of platelet counts in two of the three patients at the highest dose level suggests that further dose escalation was clinically unacceptable and would probably result in prolonged low blood cell counts, increasing the risk of side effects. Platelet counts of one of the two patients recovered slowly, returning to normal within 5 months. The time to full recovery of the platelet counts of the other patient is unknown because he was treated in another hospital 12 weeks after RIT with other myelotoxic therapy. The Common Toxicity Criteria used to define toxicity did not classify prolonged cytopenia as a separate entity, although this aspect should be taken into consideration. Strictly speaking, no grade 4 toxicity was observed in the group treated at the dose level of 2.0 GBq/m2. Therefore, a dose of 2.0 GBq/m2 is considered to be the MTD.

The use of 186Re has several advantages. First of all, being a group-VII element, 99mTc and 186Re have similar chemical properties. 99mTc-labeled mAbs can therefore be used for an imaging procedure before RIT, representing 186Re-labeled mAbs. The need for a diagnostic procedure was demonstrated in this study: two patients were considered to have <25% bone marrow involvement based on classical histological examination, but scintigraphy showed that uptake in the bone marrow was so extensive that RIT was contraindicated in these patients. Although taking bone marrow samples at more than one site can be advised to prevent sampling errors, a diagnostic procedure before RIT should be advocated.

A second advantage of the use of 186Re is the fact that it emits low-energy, low-abundance {gamma} radiation. The {gamma}-emissions are ideal for imaging, making it unnecessary to label mAbs with a second radiolabel to perform dosimetry. The quality of the images is high, comparable with the quality of images made using 99mTc. Because only 10% of disintegrations are accompanied by {gamma}-emissions, the exposure rate after treatment is low, at least lower than 5 µSv·m2/h. In most countries, it is therefore possible to treat patients on an outpatient basis. Initial dosimetric analysis, as mentioned earlier, reveals that absorbed doses in normal organs are far below critical values. Further dosimetric analysis of the data of this study is currently in progress.

A disadvantage of the use of 186Re-labeled mAbs is the laborious labeling procedure, especially when compared with the labeling of mAbs with radiometals such as 90Y, 111In, and 177Lu. Another labeling procedure, using antibody sulfhydryl groups as effective carriers of reduced rhenium, as described by Griffiths et al. (12) , is less laborious, but the low specific activity of this radioimmunoconjugate requires large amounts of antibodies. Moreover, the method requires extensive reduction of disulfide bridges in the antibody molecule, leading to a loss of immunoreactivity. This labeling procedure is not thought useful for preparing doses needed for RIT (12) .

Another disadvantage may be the lower retention of the radiolabel 186Re in the tumor when compared with 90Y. Radiolabeled epratuzumab is rapidly internalized upon binding to a CD22-expressing target cell. Using radiometals such as 90Y would result in retention of the radiolabel (13) . Preclinical data suggest that although 186Re is retained better than 131I in a mouse lymphoma model, tumor uptake of 90Y-labeled is significantly higher (14) . After processing of the radiolabeled mAb, 186Re-MAG3 is excreted from the target cell and excreted renally, as shown in Table 2Citation .

The ultimate goal of this study was to define a MTD for further analysis in a Phase II study. In such a study, patients would receive repeated RIT cycles. For this approach, a nonimmunogenic mAb is required, such as the humanized epratuzumab. The formation of HAMAs is observed in a minority of heavily pretreated patients with NHL treated with murine anti-CD20 mAbs (2 , 15) . Nevertheless, HAMA formation can be observed in over 60% of patients when treating patients more upfront with murine mAbs (16) , prohibiting further treatment. When using epratuzumab, HAMA formation is not to be expected. The presence of HAHAs was determined before and after RIT with 186Re-epratuzumab, showing that in six of seven patients HAHAs were already present before RIT. The levels were low, with a maximum of 50 ng/ml, in concordance with earlier observations (17) , and below the threshold value for HAHA elevation in the test used. Other studies also reported that HAHA induction was hardly ever observed in patients who received epratuzumab (18 , 19) . Therefore, it should be feasible to repeatedly treat patients using radiolabeled epratuzumab.

In conclusion, RIT with 186Re-epratuzumab is feasible and safe, with a MTD of 2.0 GBq/m2. Even in this Phase I study of refractive/relapsed patients who were heavily pretreated, objective responses were observed. A Phase II study treating patients with repeated doses of radiolabeled epratuzumab is planned. Additional studies should reveal whether this approach leads to improved overall response rates, duration of responses, and survival of patients with NHL.


   ACKNOWLEDGMENTS
 
We thank Emile B. Koenders for assistance in administering the radiolabeled preparations and preparation of the calibration standards and pharmacokinetics samples. We also thank the referring physicians, Drs. Sinnige, Schuitemaker, Wittebol, De Vries, and Pruijt, for their close cooperation with our center in the treatment and follow-up of patients.


   FOOTNOTES
 
1 Presented at the "Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates," October 24–26, 2002, Princeton, NJ. This study was conducted with support of the Netherlands Organization for Scientific Research (ZonMw), Project 920-03-073. Back

2 To whom requests for reprints should be addressed, at Department of Nuclear Medicine (565), University Medical Center Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, the Netherlands. Phone: 31-24-361-45-10; Fax: 31-24-361-89-42; E-mail: e.postema{at}nucmed.umcn.nl Back

3 The abbreviations used are: RIT, radioimmunotherapy; NHL, non-Hodgkin’s lymphoma; mAb, monoclonal antibody; HAMA, human antimouse antibody; MTD, maximum tolerated dose; MAG3, mercaptoacetyltriglycine; ROI, region of interest; HAHA, human antihuman antibody; SD, stable disease; PR, partial response. Back

4 Postema, E. J., Buijs, W. C. A. M., de Groot, M., Raemaekers, J. M. M., Boerman, O. C., Goldenberg, D. M., Corstens, F. H. M., and Oyen, W. J. G. Dosimetric analysis of radioimmunotherapy with 186Re-epratuzumab. Manuscript in preparation. Back


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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