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Continuing Education |
Division of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, Iowa
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCURRENT STANDARD MANAGEMENT OF...BASIC CONCEPTS OF RITRIT AS A SINGLE...COMBINED RIT WITH CHEMOTHERAPYANTI-ANTIBODY RESPONSEORGAN AND TUMOR DOSIMETRYRIT OF B-CELL NHL...CONCLUSIONREFERENCES |
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Key Words: B-cell non-Hodgkin’s lymphoma • radioimmunotherapy • monoclonal antibodies
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCURRENT STANDARD MANAGEMENT OF...BASIC CONCEPTS OF RITRIT AS A SINGLE...COMBINED RIT WITH CHEMOTHERAPYANTI-ANTIBODY RESPONSEORGAN AND TUMOR DOSIMETRYRIT OF B-CELL NHL...CONCLUSIONREFERENCES |
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The promise of RIT for treatment of B-cell NHL became apparent after the 1987 report of DeNardo et al. (5) of the first patient with this disease treated with RIT. These investigators used an 131I-labeled anti-B-cell lymphoma mAb, designated Lym-1, with which they demonstrated subsequently objective responses in about half of the patients treated (5–10). Since then, numerous clinical trials have been conducted using various radiolabeled anti-B-cell lymphoma mAbs, the majority of which demonstrate remarkable antitumor activity in B-cell NHL patients at various stages of the disease (3–43).
The success of RIT in B-cell NHL treatment is, at least in part, related to properties inherent in the biology and molecular biology of this disease. These include its radiosensitivity and the abundance of well-defined target antigens on its surface, making it an attractive target for important biologic and immunologic processes, such as apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) (44–50). Yet, these properties could have been effectively exploited only through the use of appropriate antibodies capable of inducing these biologic or immunologic processes and, in the case of RIT, also by the utilization of suitable therapeutic radioisotopes to deliver cytotoxic radiation to the tumor (51–53). The identification of these appropriate antibodies and isotopes suitable for their stable labeling was the ultimate fruit of extensive basic and clinical research extending over almost 2 decades and involving several disciplines, such as immunology, radiochemistry, nuclear medicine, and medical oncology.
This article reviews the basic concepts of RIT, the milestones leading to its current emergence as a treatment option for patients with B-cell NHL, and the prospects for its clinical use in the management of this disease, alone and in combination with other treatment modalities.
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CURRENT STANDARD MANAGEMENT OF B-CELL NHL |
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TOPABSTRACTINTRODUCTIONCURRENT STANDARD MANAGEMENT OF...BASIC CONCEPTS OF RITRIT AS A SINGLE...COMBINED RIT WITH CHEMOTHERAPYANTI-ANTIBODY RESPONSEORGAN AND TUMOR DOSIMETRYRIT OF B-CELL NHL...CONCLUSIONREFERENCES |
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Eighty percent of lymphomas are of B-cell origin (B-cell NHLs) and have traditionally been roughly divided into low-grade (e.g., small lymphocytic, marginal zone, follicular center cell grades I and II), intermediate-grade (e.g., diffuse large cell), and high-grade (lymphoblastic, Burkitt’s) categories, each occurring in about one third of patients (44,54). The low-grade B-cell NHLs are generally remarkable for an indolent course—therefore referred to as indolent NHLs—response to many therapies, and inevitably relapse, leading to eventual death with median survivals reported as 5–15 y, heavily dependent on the IPI score at the time of presentation. The intermediate- and high-grade B-cell NHLs have a more symptomatic presentation—therefore referred to as aggressive NHLs—and frequently respond to aggressive multiagent anthracycline-containing chemotherapy, with over half of the responses being durable (44).
Symptomatic early-stage indolent NHL (i.e., stages I and II) is an infrequent scenario, comprising <10% of patients with indolent NHL and can be treated in the short run with radiotherapy. The advanced stages (i.e., stages III and IV) are treated with a variety of chemotherapeutic or immunotherapeutic regimens, including single-agent chlorambucil, cyclophosphamide, fludarabine, or rituximab. Initial response rates are generally 50%–70% with any of these single agents, with the median duration of responses ranging from 12 to 24 mo (44). Combinations of drugs such as COP (cyclophosphamide, vincristine, and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and, more recently, CHOP and rituximab result in very high response rates (70%–100%) (43,55). Although the initial response rate with all of these regimens is excellent, virtually all patients relapse, with the median duration of the first response being 
18–50 mo, followed by progressively lower response rates and shorter response duration with additional therapy (44). Furthermore, many indolent lymphomas will eventually transform into a more aggressive histology with a difficult clinical course and the disease is, therefore, considered incurable with conventional chemotherapy (44). In the last 5 y or so, rituximab immunotherapy has found widespread use for the treatment of relapsed low-grade NHLs with almost half of relapsed or refractory patients showing an objective response (OR), defined as partial or complete remission (PR or CR, respectively), for a median duration of about 1 y. Patients who are refractory to (i.e., initially nonresponding) or who relapse after chemotherapy and immunotherapy are potential candidates for novel therapies, including RIT.
Intermediate- and high-grade (i.e., aggressive) NHLs are generally treated with combinations of cytotoxic chemotherapy, such as CHOP or other anthracycline-containing combinations and, more recently, the combination of CHOP and rituximab (44,56). With these regimens, 50%–60% of patients are cured, 20% progress during treatment or achieve only a transient PR or stable disease with subsequent progression, whereas the other 30% relapse after initial CR (44,57,58). Of those who relapse, a substantial proportion of highly selected candidates can be cured with high-dose chemotherapy and stem-cell rescue (44). Overall, about 40% of patients with aggressive B-cell NHL are not cured with standard or high-dose conventional therapy. Rituximab has been shown to induce only transient partial responses in 30% of these patients (59). All of these patients are potential candidates for novel approaches such as RIT.
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BASIC CONCEPTS OF RIT |
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TOPABSTRACTINTRODUCTIONCURRENT STANDARD MANAGEMENT OF...BASIC CONCEPTS OF RITRIT AS A SINGLE...COMBINED RIT WITH CHEMOTHERAPYANTI-ANTIBODY RESPONSEORGAN AND TUMOR DOSIMETRYRIT OF B-CELL NHL...CONCLUSIONREFERENCES |
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Antibody Production
Antibodies are immunoglobulins produced by B-lymphocytes (actually plasma cells) in response to an antigen. If a suitable animal recipient, such as a mouse, is immunized with an antigen, serum taken from the immunized host will contain a mixture of different antibodies to different epitopes of the antigen. These antibodies are produced by a heterogeneous population (i.e., different clones) of B-lymphocytes and are called polyclonal antibodies (60–62). If individual B-lymphocytes from these antibody-producing cells are isolated and cloned, each clone will produce a single species of antibody molecules, or mAbs, that bind to the same epitope. However, the production of mAbs will not be possible on a large scale because of the short survival of normal B-lymphocytes in culture. This problem was solved by the discovery of the hybridoma technique, in which the normal B-lymphocyte is immortalized by fusion with myeloma cells in culture (63). Using this technique, mice are immunized with a particular antigen that will stimulate their normal splenic B-lymphocytes to produce antibodies against this antigen, and these lymphocytes are then immortalized by fusion with myeloma cells in culture. The resulting "hybridomas" are screened subsequently using radioimmunoassay for single-cell clones capable of producing a specific antibody (i.e., an mAb) directed against the particular antigen. These selected clones can then be grown for mAb mass production either in cell culture or in the peritoneal cavity of mice (60–62). Because this mAb is produced by mouse B-lymphocytes, it is called a mouse or murine mAb. Of course, before such an mAb is used in humans, it must be tested for sterility, pyrogenicity, adventitious viruses, and general safety (64).
Most hybridomas produce IgG mAbs of various isotypes, most commonly IgG1 and IgG2. An IgG mAb has a molecular weight of 150,000 and consists of 2 identical heavy chains and 2 identical light chains comprising the constant and variable regions of the mAb (Fig. 1). The constant region determines the immune effector function of the mAb, such as the ability to fix complement and to interact with effector cells, which are important for the "naked" mAb effects due to CDC and ADCC, respectively. This constant region is the same for all IgG mAbs of the same isotype. The variable region contains the 2 antigen-binding sites that are unique for each IgG mAb and is, therefore, responsible for its specificity. Each IgG molecule can be enzymatically split into an Fc (fragment crytallizable) fragment, consisting of most of the constant region of an IgG molecule, and 2 Fab (fragment antigen binding) fragments, comprising the variable region and the smaller portion of the constant region. Each Fab fragment has only 1 antigen-binding site.
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With the advent of genetic engineering, it is now possible to produce humanized mAbs that are considerably less immunogenic (i.e., capable of inducing anti-antibody responses) than murine mAbs (Fig. 1). The first-generation humanized mAbs were chimeric mAbs produced by cloning the variable region genes of a murine mAb into a human expression vector containing the appropriate human constant region, resulting in a murine/human chimera or chimeric mAb (67). Because only the variable region of the chimeric mAb is of murine origin, it is considerably less immunogenic than murine mAb. Second-generation humanized mAbs are produced using a technique known as complementarity-determining region (CDR) grafting and, therefore, often called humanized CDR-grafted mAbs (19,24). Here, antigen-binding sites, which are formed by 3 CDRs of the heavy chain and 3 CDRs of the light chain are excised from cells producing murine mAb and grafted into the DNA coding for the human antibody framework. The second-generation or hyperchimeric mAbs contain less murine protein than the first-generation chimeric mAbs because only the antigen-binding CDRs rather than the entire variable domain of the murine mAb are grafted and, hence, are less immunogenic than the first-generation chimeric mAbs (67). Nevertheless, both the first- and second-generation chimeric mAbs induce anti-antibody responses, albeit in a very small fraction of patients compared with murine mAbs (3,4,19,24,26–29). These antibodies are called human antichimeric antibodies (HACA) (3,4,25–28) or human antihuman antibodies (HAHA), a term used to describe anti-antibody responses to the second-generation CDR-grafted hyperchimeric mAbs (19,24). Anti-antibody responses to radiolabeled mAbs used in RIT of B-cell NHL will be discussed in more detail after the review of the clinical trials conducted using these mAbs. However, humanized chimeric or hyperchimeric mAbs generally possess a much more potent immune effector function (i.e., are much more capable of inducing ADCC and CDC) compared with their murine parents and, therefore, are presumably more effective antitumor agents (1,2,48,49).
Tumor-Specific or Tumor-Associated Antigens as Antibody Targets
The specificity of a particular antibody used in RIT of cancer is determined primarily by the choice of the target antigen. Ideally, this antigen should be specific for the tumor cells with no or very minimal expression on normal cells. However, in practice, most of the target antigens, including those on B-cell NHLs, are actually tumor associated rather than tumor specific. This means that they are also expressed on the surface of normal cells of certain organs or tissues (depending on the particular antigen), albeit usually on a substantially lower percentage of these cells or in a lower antigen number per cell (44,45). Consequently, the antibodies directed against these antigens are only relatively rather than absolutely tumor specific.
Table 1 shows the most important target antigens on B-cell NHLs and the names of reported unconjugated mAbs against these antigens with their known radiolabeled counterparts (1–43, 68–72). As can be seen, most of these antigens are the so-called "CD" (cluster of differentiation) antigens, such as CD19, CD20, CD21, CD22, CD37, and CD52 with the HLA-DR antigens representing another group of important target antigens for anti-B-cell lymphoma mAbs. All of these antigens are also expressed on the surface of normal B-lymphocytes in the blood, spleen, lymph nodes, and bone marrow and on some of their precursors in the marrow (44,45). The latter depends on the particular antigen. For example, the CD20 antigen, against which the unconjugated rituximab, 111In/90Y-ibritumomab tiuxetan, and 131I-tositumomab mAbs are directed, is expressed only on the pre-B-cells in the marrow but not on the stem cells or progenitor cells (pre-pre-B-cells) (44).
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The CD20 antigen is characterized by its high frequency of expression (i.e., >90%) on B-cell NHLs, fairly homogeneous expression on the cell surface of these tumors, with generally high antigen number (i.e., >100,000) per cell (44,45). Another important characteristic of this antigen is that it is slowly internalizing (i.e., transported into the tumor cell after antibody binding) compared with rapidly internalizing antigens, such as CD19 or CD22 (45). Thus, mAbs directed against CD20 are considered slowly internalizing, whereas those directed against CD19 or CD22 are rapidly internalizing. As discussed below, this has important implications with respect to the choice of the radioisotope used to radiolabel these mAbs.
Therapeutic Radioisotopes Used for RIT and Antibody Radiolabeling
Several therapeutic radioisotopes for radiolabeling the various mAbs used in RIT are available (51–53). Table 2 lists some of these isotopes with their physical properties, advantages, and disadvantages.
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-Particles are another type of radiation that has been used for RIT of cancer. In contrast to ß-particles, these have only a short range in tissues of usually <100 µm. However, their high linear-energy transfer (LET) ionization makes them severalfold more effective than ß-particles because they can deliver lethal radiation to tumor cells by a single hit (51–53). Because of their short range in tissues, -particles are more suitable for treatment of easily accessible tumors, such as leukemic cells in the blood or bone marrow. These cells have to possess a fairly homogeneous antigen expression on their surface because every, or nearly every, tumor cell needs to be targeted with the antibody carrying the -emitting isotope. One such isotope is 211As (75). 213Bi is another -emitting isotope that has been used successfully for treatment of leukemia (76). Regardless of the type of radiation emitted by the various radioisotopes used for RIT, they can be grossly divided into 2 categories on the basis of their chemical characteristics: halogens (e.g., 131I and 211As) and radiometals (90Y, 186Re, 188Re, 67Cu, and 213Bi). In general, halogens, 131I in particular, can be labeled easily and directly using the IODO-GEN (Pierce, Rockford, IL) or chloramine-T methods (77,78), whereas radiometals require chelators such as benzyl-diethylenetriaminepentaacetic acid, [N-[2-bis(carboxymethyl)amino]-3-(p-isothiocyanatophenyl)-propyl]-[N-[2-bis(carboxymethyl)amino]-2-(methyl)-ethyl]glycine (tiuxetan), or 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), which are conjugated to the antibodies to allow stable antibody labeling (79,80). The use of suboptimal, unstable chelators will invariably result in leaching of the isotope from the antibody (79–82).
Of the isotopes listed in Table 2, 131I and 90Y are by far the most commonly used in the various RIT trials. Because 131I has traditionally been the conventional and most commonly used isotope in radionuclide therapy (i.e., for treatment of patients with hyperthyroidism and thyroid cancer), it is understandable why most of the antibodies used in the initial RIT trials, including those in B-cell NHL, were labeled with this radioisotope. 131I has some advantages, which include its low cost, the relatively simple radioiodination methods available for antibody labeling, and the ability to obtain images of the organ and tumor biodistribution with 131I-labeled mAbs, before (through the use of a tracer dose) or after RIT, because of the 
-emission (in addition to ß-emission) of this isotope. This latter advantage is offset, however, by the increased radiation exposure to the treating personnel or relatives, which requires more stringent radiation precautions or, in the case of administration of high amounts of radioactivity, patient isolation.
Another important disadvantage of 131I is related to the effect of dehalogenation, which inevitably occurs after catabolism of conventionally labeled radioiodinated mAbs in various normal organs (e.g., liver, spleen, bone marrow, and kidneys) and, albeit to a variable degree, also in tumor cells (83). The free iodine released requires protection for the thyroid and, particularly when high doses of 131I-labeled mAbs are administered, can result in hypothyroidism despite thyroid blockade (18,36,37). A more significant problem is seen when rapidly internalizing mAbs (e.g., anti-CD19 and CD22 mAbs) are labeled with 131I (24,83). In this case, the rapid internalization, and, hence, the usually associated rapid intracellular degradation of the radiolabeled mAb in the lysosomes, result in a substantial fraction of 131I being liberated from tumor cells. Consequently, there is a significant decrease in the residence time of radioiodine and, hence, the radiation absorbed dose in the tumor. Therefore, these mAbs are much better suited for radiolabeling with radiometals, such as 90Y, because these remain in the intracellular compartment (bound to the stable chelator) after mAb internalization and subsequent catabolism (24,84). Slowly internalizing mAbs are much less susceptible to the effects of intratumoral dehalogenation, although significant dehalogenation has been observed with some slowly internalizing mAbs, such as those against carcinoembryonic antigen or HLA-DR; therefore, it is possible that, even for these mAbs, radiometals may offer an advantage compared with radioiodine (85–87). However, both radioiodine and radiometals are suitable labels for slowly internalizing mAbs, explaining why both 131I and radiometals are used for radiolabeling the various anti-CD20 mAbs used in clinical RIT trials (3,4,16–18,23,26–38,40–43).
90Y is now being used increasingly to radiolabel various mAbs, including both rapidly and slowly internalizing ones, a development that has been greatly facilitated by the current availability of stable chelators. With their use, the problem of significant leaching of free 90Y from the mAb with subsequent localization in bone, and, hence, increased bone marrow toxicity, has been largely eliminated (3,4,22–24,26–29,39,40,43). The requirement for a chelator for antibody labeling with 90Y may be considered by some a disadvantage because this may not always be available at the labeling laboratory or institution and because it must first be conjugated to the "naked" mAb before the labeling procedure. However, because mAbs already conjugated with a suitable chelator can be made available, even commercially (e.g., ibritutomab tiuxetan), this requirement is only a relative disadvantage.
90Y is a pure ß-emitter, and, hence, imaging cannot be performed with this isotope when standard doses of 90Y-labeled mAbs are given. Bremsstrahlung imaging is possible when very high amounts of radioactivity are given with considerable concentration in organs and tumors, which is not the case in most clinical situations (88). It also results in low-quality images. Thus, a chemical surrogate for 90Y that emits -radiation must be used to determine the organ and tumor biodistribution and dosimetry with 90Y-mAbs. Luckily, 111In, the isotope used frequently in nuclear medicine imaging, represents such a surrogate that for all practical purposes can predict these parameters for the corresponding 90Y-mAbs. Here again, with the availability of corresponding 111In-mAbs to virtually all 90Y-mAbs used for RIT (e.g., 111In/90Y-ibritumomab tiuxetan), the need for 111In is only a minor disadvantage. On the other hand, because 90Y is a pure ß-emitter, there is negligible radiation exposure to treating personnel or relatives with this isotope and outpatient therapy can, therefore, be performed even with very high doses of 90Y (89).
Other important advantages of 90Y are related to the longer pathlength of its ß-particles compared with those of 131I, which is particularly advantageous in tumors with heterogeneous antibody distribution, as is the case in most tumors. Moreover, because 90Y is not a halogen, it can be used to label both rapidly and slowly internalizing mAbs with a clear advantage compared with 131I with the former and a potential advantage with the latter (24,82,83,85–87). Other isotopes used for RIT of B-cell NHLs are 186Re and 67Cu, but clinical trials using these isotopes have been quite limited to date (21,25). Their advantages and disadvantages for RIT are summarized in Table 2.
Nonmyeloablative and Myeloablative RIT
Two distinct approaches of RIT are used to deliver cytocidal radioactivity to tumors, including B-cell NHLs: the nonmyeloablative or low-dose RIT approach and the myeloablative or high-dose RIT approach (90,91). In the nonmyeloablative RIT approach, the radionuclide dose given does not result in bone marrow ablation. Myelosuppression is usually the only significant and dose-limiting toxicity ([DLT] i.e., the toxicity determining the maximum tolerated dose [MTD]). This toxicity usually occurs 2–3 wk after therapy with the nadir reached at about 4–8 wk and full recovery usually before 12 wk after RIT. Only minimal nonhematologic toxicity is usually observed with this approach, including patients with B-cell NHLs treated with the various radiolabeled anti-B-cell NHL mAbs (3–10,12–17,19–35,38–40). In myeloablative RIT, considerably higher amounts of radioactivity are administered, which are very likely or almost certain to result in ablation of marrow (11,18,19,36,37,39,92). This approach, therefore, requires a hematopoietic, usually autologous, stem-cell transplant (HSCT) with peripheral blood stem cells or bone marrow. With this approach, significant nonhematologic or "second-organ" toxicity is observed, occurring within 1–2 mo after therapy with recovery usually completed within a few weeks, in addition to severe hematologic toxicity rescued with HSCT. The most commonly observed nonhematologic toxicity is gastrointestinal, hepatic, and, at the highest doses, also cardiopulmonary, with the latter in addition to gastrointestinal toxicity usually representing the DLT (11,18,19,36,37,92). As described below, this is also true with myeloablative doses of radiolabeled anti-B-cell NHL mAbs (11,18,19,36,37).
Dosimetry of Radiolabeled Antibodies as RIT Agents
The dosimetric approaches used to calculate the total-body, normal organs (including the red marrow), and tumor radiation absorbed doses from radiolabeled antibodies used in RIT are similar to those for other radiopharmaceuticals. These have been discussed extensively in a previous continuing education article in this journal (93) and in numerous publications on this subject (93–107). Briefly, generally planar anterior and posterior gamma-camera images of the entire body or the chest, abdomen, pelvis, and any other tumor-containing region are obtained on at least 3 or 4 occasions after a tracer injection of radiolabeled mAb, given 1 wk before therapy. In the case of 90Y-mAb, the tracer dose is labeled with 111In (as 90Y surrogate) to allow -imaging. Regions of interest (ROIs) are then drawn around the organs and tumors, with the appropriate background ROIs, and their "actual" content of radioactivity is determined using an activity quantification technique for the gamma camera based on either the geometric mean method, a modification thereof, or the buildup factor methodology (95,96). The organ and tumor time-activity data are then fit to either an exponential function or by a trapezoidal modeling method and then integrated to obtain the cumulated activity. The cumulated activity in the red marrow is calculated either using a blood-derived method, assuming a red marrow-to-blood activity concentration ratio of 0.2–0.4, or an imaging-based method based on a well-defined ROI in the lumbar or sacral marrow (99–102,108). The cumulated activity in the total body is calculated using either whole-body scanning or -probe (i.e., thyroid or hand-held probe) counts obtained on at least 3 occasions over a 1-wk period (103). The normal organ, tumor, red marrow, and total-body residence times (
), defined as the area under the curve of cumulated activity divided by the activity injected, are then determined, and the radiation absorbed doses are calculated by multiplying by the appropriate S factors, according to one of the dosimetry programs of the MIRD Committee (104–106). The weights of normal organs needed for calculating the S factors are estimated using either CT or the standard human weights given by the MIRD Committee, whereas tumor masses are usually determined by CT.
RIT Dosing Methods
Principally, 2 RIT dosing methods can be used to determine the radioactive amount of radiolabeled mAb to be prescribed for patients treated using the nonmyeloablative or myeloablative approach (90,91). One of these methods is dosimetry-based—that is, the radioactive amount given is based on a prescribed radiation dose to the critical dose-limiting organ: the red marrow or the total body (as marrow surrogate) in the case of nonmyeloablative RIT (12,16,17,24,30–35) or the critical dose-limiting second organ (e.g., lungs, liver, or kidneys) in the case of myeloablative RIT (11,18,36,37,92). Using this approach, the radioactivity (in MBq) to be administered to an individual patient is calculated by dividing the prescribed radiation dose (in cGy) by the anticipated radiation dose to the critical organ per MBq of administered activity (i.e., in cGy/MBq) determined by a pretherapy tracer study. Using this approach, it is assumed that the radiation dose to the critical organ per MBq of administered activity will be very similar for both the tracer and the therapy doses, which has been confirmed using various 131I-labeled mAbs, with imaging both before and after therapy (16,17,24,30–35,38). Because the mAb pharmacokinetics, and, hence, red marrow, total-body, and organ radiation doses, are unique to each patient and are influenced by factors such as patient size, body mass, and tumor burden, this method is considered patient specific (11,16,17,24,30–35,38). An important example of the utilization of this method in nonmyeloablative RIT is the approach used to determine the patient-specific radioactive amount of 131I-tositumomab based on a prescribed total-body dose, which is used here as a surrogate for the red marrow dose (16,17,30–35,38). An example of the use of the dosimetry-based method for myeloablative RIT is the approach used to determine the patient-specific radioactive amount of 131I-anti-CD20 (1F5 and B1) and 131I-anti-CD37 (MB-1) mAbs based on a prescribed radiation absorbed dose to the critical second organs (11,18,36,37).
The other dosing method is based on fixed amounts of radioactivity or amounts adjusted to the body weight (i.e., MBq/kg) or body surface area (i.e., MBq/m2) (3–10,13–15,19–23,25,26–29,39). This method does not require a pretherapy tracer study to calculate the therapy dose, although a tracer study is usually still performed to determine tumor targeting or altered mAb biodistribution in normal organs. One important example of the use of this method in nonmyeloablative RIT trials is the approach used to determine the radioactive amount of 90Y-ibritumomab tiuxetan, which is based on the patient’s body weight (3,4,26–29).
Advantages of RIT Compared with Immunotherapy
The approach of conjugating the antibodies with suitable therapeutic radioisotopes distinguishes RIT from immunotherapy either with unconjugated (naked) antibodies or with those conjugated to toxins, so-called immunotoxins (60). Treatment with antibodies conjugated to radioisotopes (RIT) rather than with immunotoxins or naked antibodies results in several distinct advantages. One obvious advantage, at least compared with treatment with unconjugated anti-B-cell NHL mAbs, is that with RIT, both biologic and immunologic mechanisms of the antitumor effects of these mAbs, such as apoptosis, ADCC, and CDC, along with the effects of targeted radiation play a role in the antitumor responses observed (3–43). Another important advantage is that with RIT, there is no need to target every tumor cell with a particular antibody to cause an antitumor effect at the cellular level because even antigen-negative nontargeted cells can be irradiated and potentially killed by radiation from targeted neighboring cells. This is not the case with unconjugated antibodies or immunotoxins, where each particular tumor cell must be targeted with the antibody for the antitumor effect to occur at the cellular level. Consequently, if the antigen in not expressed on each or nearly each tumor cell, it is unlikely that a complete regression of tumor mass will occur with unconjugated antibodies or immunotoxins. This factor may, at least in part, explain the generally higher fraction of CRs among the ORs (i.e., both CRs and PRs), using even nonmyeloablative doses of radiolabeled mAbs compared with similar unconjugated mAbs (2–4,16,17,20–35,38,39). Another potential advantage of RIT is that its mode of radiation delivery at the low-dose rate of usually <20 cGy/h may make it more effective than the high-dose rate external-beam radiation (XRT) on a gray-by-gray basis, the so-called inverse-dose-rate effect. This is presumably related to the effects of apoptosis on lymphoma cells and to cell cycle redistribution with cell accumulation in the radiosensitive G2-M phase of the cell cycle (46,47).
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RIT AS A SINGLE MODALITY FOR B-CELL NHL |
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TOPABSTRACTINTRODUCTIONCURRENT STANDARD MANAGEMENT OF...BASIC CONCEPTS OF RITRIT AS A SINGLE...COMBINED RIT WITH CHEMOTHERAPYANTI-ANTIBODY RESPONSEORGAN AND TUMOR DOSIMETRYRIT OF B-CELL NHL...CONCLUSIONREFERENCES |
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Interestingly, several of the initially used mAbs were abandoned subsequently in favor of more optimal ones or second-generation humanized chimeric or hyperchimeric mAbs. For example, Press et al. (11,18) and Kaminski et al. (12) initially investigated the 131I-MB-1 anti-CD37 mAb as a candidate for RIT of B-cell NHL, but this was later abandoned, because of its considerable cross-reactivity with a wide range of B-cell precursors, in favor of 131I-labeled anti-CD20 mAbs with a more restricted cross-reactivity (16–18). The OKB7 mAb initially investigated by Sheinberg et al. (14) was not further developed for clinical use. Goldenberg et al. (15) and Vose et al. (20) used a murine 131I-labeled anti-CD22 LL2 mAb, but this was later replaced by the humanized hyperchimeric 90Y-labeled LL2 (90Y-hLL2 or epratuzumab) because of the known rapid internalization of LL2, expectedly reduced immunogenicity, and potentially greater immune effector function of the humanized compared with the murine mAbs (19,24,25). Thus, many of the conducted pilot or phase I trials have enabled the recognition of ideal candidate mAbs (labeled with either 131I or 90Y) for further drug development as RIT agents in patients with B-cell NHL. These were then the subject of formal phase I studies, with the primary goal of determining their MTD, followed by definitive phase II and III trials to formally determine their efficacy in well-defined patient populations.
It is noteworthy that both the nonmyeloablative and the myeloablative approaches of RIT were used even in the initial trials and that both the dosimetry-based method (11,12,16–18,24) and dosing based on fixed amounts of radioactivity or radioactive amounts adjusted to the body weight or surface area were used for RIT dosing (3–10,13–15,20–23,25). The specific dosing method used in the dose-escalation process to determine the MTD of a particular mAb was usually maintained in the subsequently performed phase II and III trials with the same mAb (3,4,11,16–18,26–38).
The selection criteria for B-cell NHL patients entered into the pilot or phase I/II trials were quite similar among the various trials: All required prior treatment with standard chemotherapy and most of them adhered to the standard eligibility criteria for investigational therapy trials. The latter included normal renal and hepatic function, no surgery or chemotherapy for at least 4 wk before RIT, a white blood cell count of 
3,000 per mm3, or an absolute neutrophil count (ANC) of 1,500 per mm3 and a platelet count of 100,000 per mm3. Initially, some trials did not require bone marrow biopsy to determine eligibility and, therefore, some patients with extensive marrow involvement were treated (6,14,15,21). Subsequently, however, nearly all of the trials required that the degree of lymphomatous marrow involvement does not exceed 25% of the hematopoietic marrow elements, based on unilateral or bilateral marrow biopsies (3,4,11–13,16–20,22–25). These criteria remained, with minor modifications, through the subsequently performed phase II and III trials and should apply for the clinical use of RIT in the nonmyeloablative setting using the now commercially available 90Y-ibritumomab tiuxetan mAb. Clinical trials of myeloablative RIT required additional criteria such as normal cardiac and pulmonary function and availability of an adequate number of bone marrow mononuclear cells or CD34+ peripheral blood stem cells (11,18,19,39).
Although multiple mAbs, labeled with various isotopes, have been tested in the many trials of RIT of B-cell NHL, the single-dose nonmyeloablative or myeloablative MTD has been reported for only a few mAbs (3,4,17,18,22). Most notable are 131I-tositumomab, for which both the nonmyeloablative and the myeloablative MTDs are now known (17,18), and 90Y-ibritumomab tiuxetan, for which only the nonmyeloablative MTD has been reported to date (3,4). Interestingly, whereas Press et al. (18) reported the myeloablative MTD for "131I-anti-CD20 (1F5 and B1) and anti-CD37 (MB-1) mAbs," all used in the same dose-escalation trial, all of the patients treated at the higher dose levels received 131I-B1 (tositumomab). However, because these investigators used a dose-escalation scheme based on escalating radiation doses to critical dose-limiting second organs rather than escalating amounts of radioactivity, it might be argued that the determined MTD may in fact have been quite similar for the different mAbs used. Taking this even further, one might also argue that this MTD may be quite similar for the various anti-B-cell NHL mAbs used, at least when labeled with 131I, provided that there are no major differences in the microdistribution of delivered radiation dose (i.e., differences at the "microdosimetric" level). This may be a reasonable assumption for virtually all currently used anti-B-cell lymphoma mAbs. On the other hand, the dosing methods used in the phase I dose-escalation trials designed to determine the nonmyeloablative MTDs of 131I-tositumomab and 90Y-ibritumomab tiuxetan mAbs were considerably different: A dosimetry-based approach based on total-body radiation dose, used as a surrogate for the red marrow dose, was used for the former, whereas dosing based simply on body weight was used for the latter (3,4,17). Subsequently, the same dosing approaches unique for each of these 2 mAbs were used in the phase II and III nonmyeloablative RIT trials with these mAbs, and the dosing approach used for 90Y-ibritumomab tiuxetan is now also used in the standard clinical practice (26–35,38,109). It is very important to emphasize, however, that the use of the total-body dose as a surrogate for the red marrow dose appears reasonable only in the case of 131I-labeled mAbs. This is because, with 131I-labeled mAbs, there is usually a moderate correlation between the total-body dose and the red marrow dose, at least when calculated on the basis of blood, and because the total-body dose (actually, remainder of the body dose) contributes significantly (i.e., 40%–50%) to the red marrow dose (107). The latter is related to the penetrating -radiation of 131I. In contrast, with 90Y-labeled mAbs, poor correlation is expected between the total-body dose and the imaging or blood-based red marrow dose because most of the residualizing 90Y label is retained in the body independent of the amount of cumulated activity in the red marrow. Moreover, because of the nonpenetrating radiation of 90Y, the total-body dose contributes only little (i.e., <10%) to the red marrow dose. For all of these reasons, the total-body dose of 75 cGy found to be the MTD for 131I-tositumomab could not be used as the MTD for 90Y-labeled mAbs (e.g., 90Y-ibritumomab tiuxetan).
The final results of the phase I trial with nonmyeloablative doses of 131I-tositumomab were reported by Kaminski et al. (17). Thirty-four patients were entered, 18 with low-grade NHL and 16 with intermediate-grade NHL. Twenty-one patients had chemotherapy-resistant NHL and 14 had large tumor burdens (i.e., >500 g). The administered 131I-tositumomab doses were based on escalating radiation doses to the total body predicted by a pretherapy tracer study (185 MBq [5 mCi]; 15 mg). The same amount of unlabeled antibody protein ranging from 150 to 700 mg in the majority of patients was preinfused 1 h before the labeled tracer or therapy dose to improve the 131I-tositumomab biodistribution. Dose escalation was started at a radiation dose of 25 cGy to the total body, increasing in increments of 10 cGy. The MTD was then determined to be 75 cGy to the total body in patients who had not undergone a prior marrow transplant but appeared to be lower in patients with a prior bone marrow transplant (see below). The radioactive doses given ranged from 1.26 to 5.56 GBq (34–161 mCi) 131I-tositumomab. Twenty-two of 28 evaluable patients (79%) responded, with 14 (50%) having a CR. The median CR duration was >13 mo, with 8 patients remaining disease free at the time of the published report.
The results of the completed phase I/II trial with nonmyeloablative doses of 90Y-ibritumomab tiuxetan mAb were reported by Witzig et al. (3) and Wiseman et al. (4). Eligible patients had relapsed or refractory CD20+ B-cell low-grade, intermediate-grade, or mantle-cell NHL. There was no limit on bulky disease, and 59% had at least 1 mass of 5 cm. Dose escalation was started at a dose of 7.4 MBq/kg (0.2 mCi/kg) of 90Y-ibritumomab tiuxetan, increasing in increments of 3.7 MBq/kg (0.1 mCi/kg) until the MTD was determined. The treatment scheme used in this trial is shown in Figure 2. As can be seen, the chimeric rituximab (250 mg/m2) was chosen as the unlabeled mAb preinfused within 4 h before the murine radiolabeled ibritumomab tiuxetan mAb to improve its biodistribution. mAb pharmacokinetics, dosimetry, and tumor targeting were determined on the basis of a pretherapy 111In-ibritumomab tiuxetan (111In-Zevalin) study (185 MBq [5 mCi]; 1.6 mg) preceded by a rituximab dose of 250 mg/m2, the same dose used before administering therapy with 90Y-ibritumomab (90Y-Zevalin). Figure 3 shows an example of imaging with 111In-ibritumomab tiuxetan demonstrating the expected whole-body and normal organ biodistribution in addition to tumor targeting in a patient with B-cell NHL.
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150,000 per mm3 and 11.1 MBq/kg (0.3 mCi/kg) for patients with a baseline platelet count of 100,000–149,000 per mm3. Fifteen patients were treated in the phase I portion and 35 patients were treated in the phase II portion of the trial, of whom 10 were treated at the 11.1-MBq/kg (0.3 mCi/kg) dose level and 25 were treated at the 14.8-MBq/kg (0.4 mCi/kg) dose level. Because similar responses were seen in the phase I and II portions of the trials (PR and CR were seen apparently independent of the dose given), the 15 patients treated in the phase I portion of the trial were combined with those enrolled in the phase II portion for an intent-to-treat analysis. The overall response rate (ORR) for all of the 51 patients entered into the trial (1 patient was not treated) was 67% (25% CR; 41% PR). The ORR for low-grade disease (n = 34) was 82% (27% CR; 56% PR; 95% confidence interval, 54–80), whereas that for intermediate-grade disease (n = 14) was 43% (29% CR; 14% PR). None of the 3 patients with mantle-cell NHL responded. Responses occurred in patients with bulky disease (7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimates of the time to disease progression (TTP) in responders and the duration of response (DR) were 12.7 mo (95% confidence interval, 10.2–17.8) and 11.6 mo (95% confidence interval, 10.2–17.8), respectively. Adverse events were primarily hematologic and correlated with the baseline extent of marrow NHL and the baseline platelet count, and only 1 patient (2%) developed an anti-antibody response (HACA/HAMA).
The results of the phase I trial with myeloablative doses of 131I-anti-CD20 (1F5 and B1) and 131I-anti-CD37 (MB-1) mAbs combined with autologous HSCT were reported by Press et al. (18). As stated earlier, these investigators used a dosimetry-based approach to determine the MTD of these mAbs. The administered radioactive amount of 131I-labeled mAb was based on escalating radiation doses to critical second organs (i.e., lungs, liver, and kidneys). More specifically, the radioactivity given to an individual patient was calculated by dividing the prescribed radiation dose (in cGy) by the anticipated radiation dose to the critical organ per MBq of administered activity (i.e., cGy/MBq) determined by a pretherapy tracer study with 185–370 MBq (5–10 mCi) 131I. The same amount of unlabeled mAb protein (2.5 mg/kg for B1 or 1F5 and 10 mg/kg for MB-1) was preinfused 1 h before the labeled tracer or therapy infusion to improve the mAb biodistribution. Dose escalation was started at a radiation dose of 1,000 cGy to the critical organ (found to be the lungs in most patients), increasing to 1,500, 1,675, 2,075, 2,375, 2,725, and 3,075 cGy. A unique feature of this trial was that only patients with favorable biodistribution, defined as those with a tumor-to-critical organ radiation absorbed dose ratio of >1.0 for all tumors, as determined by a pretherapy tracer study, were treated subsequently. Favorable distribution was achieved in 24 of the 43 patients initially considered, of whom 19 were treated subsequently, primarily with 131I-B1. The investigators found that the MTD was 2,725 cGy to the lungs (an average of 11.48 GBq/m2 [310 mCi/m2] 131I-B1). Cardiopulmonary or gastrointestinal toxicity was the principal second-organ and DLT. Other nonhematologic toxicities (e.g., hepatic) were also observed, but these were not dose limiting. Of the 19 patients treated, 18 (95%) had an OR (PR or CR) with 16 (84%) achieving a CR. Two patients had a PR and 1 had a minor response (25%–50% regression of tumor). Nine patients remained in continuous CR for 3–53 mo at the time of the report.
A detailed review of the particular results of the numerous pilot or phase I/II trials of nonmyeloablative and myeloablative RIT in B-cell NHL, which were considerably different in design and in the type of the radiolabeled mAb used, is beyond the scope of this article. Nevertheless, the most important findings of these trials may be summarized in a few points: First, transient myelosuppression was found to be the only significant and DLT in the nonmyeloablative RIT trials regardless of the radiolabeled mAb used (3–10,12–17,19–25), whereas cardiopulmonary or gastrointestinal toxicity was most significant and DLT in the myeloablative trials using 131I-anti-CD20 and CD37 mAbs (11,18). Second, to date, the nonmyeloablative single-dose MTD has been reported for 2 mAbs that either are in an advanced stage of development (i.e., 131I-tositumomab or Bexxar) or are already commercially approved (i.e., 90Y-ibritumomab tiuxetan or Zevalin) (3,4,17). The MTD of the former was found to be 75 cGy to the total body, whereas that of the latter was 14.8 MBq/kg (0.4 mCi/kg) in patients with a platelet count of 150,000 per mm3 (11.1 MBq/kg [0.3 mCi/kg] in patients with a platelet count of 100,000–149,000 per mm3) (3,4,17). The single-dose MTD determined for 90Y-Lym-1 mAb was found to be 370 MBq/m2 (10 mCi/m2) (22). Although, to date, no single-dose MTD has been reported for the other 131I- or 90Y-labeled anti-B-cell NHL mAbs, doses of up to 1.66–3.7 GBq/m2 (45–100 mCi/m2) of 131I-mAbs (depending on the mAb used) or 555–740 MBq/m2 (15–20 mCi/m2) of 90Y-mAbs have been safely administered (5–10,21,24). With myeloablative RIT, the MTD was found to be 2,725 cGy to the lungs with 131I-anti-CD20 and 131I-anti-CD37 mAbs (18). Third, excellent antitumor responses were demonstrated even with nonmyeloablative RIT, with an ORR and complete remission rate (CRR) of 30%–80% and 10%–50%, respectively, in the various trials using different mAbs labeled with 131I, 90Y, 67Cu, and 186Re (3–10,12–17,19–25). These responses were often observed with tumor doses of <500 cGy regardless of the isotope used, underscoring the exquisite sensitivity of NHL (3–10,12–17,19–25). However, an even higher ORR of 95% was seen with myeloablative RIT, with a CRR of 84% using 131I-anti-CD20 and anti-CD37 mAbs, although the patients treated in the trial with myeloablative RIT were presumably highly selected; only patients with a favorable biodistribution were treated (18). Fourth, with nonmyeloablative RIT, the ORR appeared to be higher in low-grade (indolent) compared with intermediate-grade B-cell NHL (virtually the only form of aggressive NHL treated with RIT). For example, using 131I-B1 mAb, ORR and CRR of 100% and 77%, respectively, were shown in low-grade NHL compared with 43% and 14%, respectively, in intermediate-grade NHL (17). In contrast, similarly high ORRs and CRRs were seen with myeloablative RIT in low-grade and intermediate-grade NHL (18) (Dr. Oliver Press, oral communication, 2000). Fifth, the ORR, and especially the CRR, was higher with even a single nonmyeloablative dose of radiolabeled anti–B-cell lymphoma mAb compared with multiple cycles of a similar unconjugated mAb. For example, in patients with low-grade NHL, the ORR with rituximab, the unconjugated chimeric anti-CD20 mAb, was reported to be about 50%, with a CRR of only 6% despite 4 weekly infusions of 375 mg/m2 per infusion (a total of 1,500 mg/m2) (2). In contrast, the ORR for 90Y-ibritumomab tiuxetan (the murine parent mAb of rituximab) in these patients shown in the initial phase I/II trial was 82%, with a CRR of 27%. Similar ORRs and CRRs were observed using 131I-tositumomab, another similar anti-CD20 mAb (17). This observation, already apparent in these initial studies, was confirmed subsequently in a randomized trial comparing ibritumomab tiuxetan with rituximab (27) (see below).
Phase II and III Trials with Radiolabeled Anti-B-Cell NHL mAbs
The last 3 y or so in the development of RIT of B-cell NHL are characterized primarily by the conduct of definitive phase II or III trials to formally determine the efficacy of radiolabeled mAbs identified as "ideal" candidates for RIT (26–37). To date, these phase II and III trials are available only for 131I-tositumomab, given in nonmyeloablative and myeloablative doses, and for 90Y-ibritumomab tiuxetan, given in nonmyeloablative doses (26–37). A brief summary of the results of these trials follows.
Phase II and III Studies with Nonmyeloablative Doses of 131I-Tositumomab.
Vose et al. (30) have reported the final results of a multicenter phase II study evaluating the efficacy, dosimetry methodology, and safety of 131I-tositumomab in patients with chemotherapy-relapsed/refractory low-grade or transformed NHL. Patients received a dosimetric dose consisting of 450 mg of unlabeled tositumomab followed by 35 mg (185 MBq [5 mCi]) 131I-tositumomab. Serial total-body -counts were then obtained to calculate the patient-specific activity (MBq) required to deliver the therapeutic dose. A therapeutic dose of 75-cGy total-body dose (attenuated to 65 cGy in patients with platelet counts of 100,000–149,000 cells per mm3) was given 7–14 d after the dosimetric dose. Forty-five of 47 patients were treated with a single dosimetric and therapeutic dose. Twenty-seven patients (57%) had a response. The ORR was similar in patients with low-grade (57%) or transformed (60%) NHL. The median DR was 9.9 mo. Fifteen patients (32%) achieved a CR, including 5 patients (50%) with transformed NHL. The median duration of CR was 19.9 mo, and 6 patients had an ongoing CR at the time of the report. Treatment was well tolerated, with the principal toxicity being hematologic. The most common nonhematologic toxicities considered to be possibly related to the treatment were mild-to-moderate fatigue (32%), nausea (30%), fever (26%), vomiting (15%), infection (13%), pruritus (13%), and rash (13%). Additionally, 1 patient developed HAMA.
The results of the pivotal trial of 131I-tositumomab in chemotherapy-refractory low-grade or transformed low-grade NHL were reported recently by Kaminski et al. (32). The objective of this trial was to evaluate the efficacy and safety of 131I-tositumomab in these patients and to compare its efficacy to the patients’ last qualifying chemotherapy (LQC) regimens. A total of 60 patients who had been treated with at least 2 protocol-specified qualifying chemotherapy regimens and had not responded or progressed within 6 mo after their LQC were treated with a single course of 131I-tositumomab at the MTD of 75 cGy to the total body. The patients had received a median of 4 prior chemotherapy regimens. Thirty-nine patients (65%) had a CR or PR after 131I-tositumomab compared with only 17 (28%) after their LQC (P < 0.001). Two patients (3%) had a CR after their LQC compared with 12 (20%) after 131I-tositumomab (P < 0.001). The median DR for CR was 6.1 mo after the LQC and had not been reached with follow-up of >47 mo after 131I-tositumomab at the time of the report. An independent review panel verified that 32 of the 43 patients (74%) with nonequivalent DR (>30-d difference) had a longer DR after 131I-tositumomab (P < 0.001). Only 1 patient was hospitalized for neutropenic fever. Five patients (8%) developed HAMA and 1 (2%) developed an elevated thyroid-stimulating hormone (TSH) level after treatment. Myelodysplasia was diagnosed in 4 patients (6.6%) at follow-up.
The interim safety and efficacy results of 131I-tositumomab given in a large multicenter expanded-access trial have been reported recently (33,34). Three hundred fifty-nine patients with low-grade or transformed NHL were enrolled in this trial at 53 community and academic sites between July 1998 and March 2000. The median age of these patients was 58 y (range, 39–87 y). Ninety percent had stage III or IV at entry, 44% had bulky disease (5 cm), 60% had an elevated LDH level, and 45% had lymphomatous bone marrow involvement (
25%). The median number of prior chemotherapeutic regimens was 2 (range, 1–9). Forty-three percent failed rituximab therapy and 21% had prior radiotherapy. Again, an individualized dosing scheme that was similar to that in the phase II studies was used to deliver a total-body dose of 75 cGy. A saturated solution of potassium iodide was used to block the uptake of free 131I by the normal thyroid. As expected, the most common toxicity was reversible myelosuppression. The median ANC nadir was 1,300 cells per mm3, whereas the platelet and hemoglobin nadirs were 68,000 cells per mm3 and 11.2 g/dL, respectively. Fourteen percent of patients developed an ANC nadir of <500 cells per mm3 and 2% developed a platelet nadir of <10,000 cells per mm3 (grade 4 National Cancer Institute toxicity). The most common nonhematologic adverse experiences were grade 1 or grade 2 asthenia (23%), nausea (17%), fever (11%), and pain (10%). Eight percent of patients developed HAMA, 2% exhibited an elevated TSH level after therapy, and 4% percent developed a serious infection requiring hospitalization. Adverse experiences were not more frequent or severe in patients >60 y old compared with patients 60 y old. Two hundred seventy-three of the 359 patients could be evaluated for antitumor response at the time of the report. The ORR and CRR were 58% and 27%, respectively. Patients with poor prognostic features achieved significant ORR and CRR rates. The median DR and duration of CR have not been reached with follow-up to 17 mo at the time of the report. The TTP for all patients was about 6.7 mo and has not been reached for responders. Even in patients who failed >4 prior chemotherapeutic regimens, the ORR and CRR were 44% and 17%, respectively. The ORR and CRR were 51% and 17% for patients >60 y of age, 47% and 19% for rituximab failures, 61% and 27% for those with prior radiotherapy, and 40% and 16% for patients with transformed low-grade NHL. The ORR and CRR in patients with bulky tumors (i.e., 5 cm) were somewhat lower than those in patients with lower tumor bulk: 47% and 17% versus 66% and 35%, respectively. In contrast, the ORR and CRR in patients with bone marrow involvement were quite similar to those without such involvement: 56% and 25% versus 59% and 28%, respectively.
Whereas all of the trials with 131I-tositumomab summarized above have been conducted in patients who were treated previously with chemo- or immunotherapy, Wahl et al. (35) have conducted a phase II trial with this mAb in previously untreated (i.e., chemotherapy-naive) patients with advanced-stage low-grade or transformed NHL. This trial was in fact the first to evaluate the toxicity and therapeutic efficacy of RIT in previously untreated NHL patients of any histologic type. Seventy-six patients were studied, of whom 54 (71%) had follicular small-cleaved and 22 (29%) had follicular mixed cell histology. All had stage III or IV disease, 65% had lymphomatous bone marrow involvement of 25%, and 29% had high tumor burdens (>500 g). These patients were also treated using the dosimetry-based approach at an MTD of 75 cGy to the total body. Seventy-four of 76 patients (97%) showed a PR or CR, with 63% achieving a CR. The median DR has not been reached with follow-up of up to 38 mo and a median follow-up of 16.2 mo at the time of the report. Molecular CRs by polymerase chain reaction were common. Grade 4 neutropenia occurred in only 5% of patients, with no grade 4 thrombocytopenia noted. No patient required hematologic supportive care. However, HAMA was seen in 49 of 76 patients (64%) to this murine mAb, and about two thirds of these patients had flu-like symptoms lasting <1 wk within the first 2 wk after therapy.
In summary, the reported phase II and III trials with 131I-tositumomab show that this mAb, when given at the MTD of 75 cGy to the total body, is quite safe and effective in patients with low-grade and transformed NHL at the various stages of their disease. Moreover, the results of the phase II study conducted in patients with previously untreated low-grade or transformed NHL may provide, in principle, strong justification for considering this relatively new modality as front-line therapy for such patients either alone or in combination with chemotherapy. Unfortunately, a potential drawback related to the use of the murine tositumomab in this setting is the quite high incidence of HAMA response. This could potentially jeopardize the possibility of front-line multicycle therapy (in hopes of obtaining more frequent molecular CRs or sustained responses) or retreatment at the time of relapse. The use of humanized chimeric or hyperchimeric mAbs, mAb regimens containing smaller amounts of murine mAb (e.g., murine ibritumomab tiuxetan in combination with rituximab), and combining RIT with immunosuppressive cytotoxic chemotherapy may, at least in part, circumvent this problem (3,4,19,24–29,39–41).
Phase II and III Studies with Nonmyeloablative Doses of 90Y-Ibritumomab Tiuxetan.
The results of the formal phase II trial with 90Y-ibritumomab tiuxetan were reported by Witzig et al. (3) and Wiseman et al. (4) in conjunction with the findings of the phase I study and were described above.
Wiseman et al. (26) have reported subsequently the results of another phase II trial, in which the investigators focused exclusively on mildly thrombocytopenic patients (100,000–149,000 platelets per mm3) with relapsed/refractory low-grade or transformed B-cell NHL to evaluate the safety and efficacy of 90Y-Zevalin at the determined MTD dose of 11.1 MBq/kg (0.3 mCi/kg) in this group (a reduced dose compared with the 14.8-MBq/kg [0.4 mCi/kg] dose in patients with 150,000 platelets per mm3). Thirty patients were treated at this dose using the same treatment schedule as that used in the initial phase I/II study with this mAb (Fig. 2), except that, in this case, patients received the determined MTD rather than escalating doses of 90Y-ibritumomab tiuxetan. Patients (median age, 61 y; 90% stage III/IV at study entry; 83% follicular lymphoma; 67% with bone marrow involvement) had a median of 2 prior regimens (range, 1–9). An ORR of 83% (37% CR, 6.7% unconfirmed CR, and 40% PR) was found, with an estimated TTP of 9.4 mo (range, 1.7–24.6 mo). Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively.
Witzig et al. (27) have reported the final results of a prospective randomized phase III trial of 90Y-ibritumomab tiuxetan and rituximab immunotherapy in relapsed/refractory low-grade, follicular, or transformed NHL. This was the first prospective randomized trial comparing the efficacy of nonmyeloablative RIT with unconjugated mAb in the same patient population. As stated earlier, 90Y-ibritumomab tiuxetan is simply the murine parent mAb of the chimeric unconjugated rituximab. Patients randomized into the 90Y-ibritumomab tiuxetan arm were given a tracer dose of 185 MBq (5 mCi) 111In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then administered a therapeutic dose of 14.8 MBq/kg (0.4 mCi/kg) 90Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan doses were preceded by an infusion of 250 mg/m2 of rituximab. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m2 weekly x 4). The final efficacy analysis performed on 143 patients enrolled into this prospective phase III trial showed an ORR of 80% for 90Y-ibritumomab tiuxetan (n = 73) versus 56% for rituximab (n = 70) (P = 0.002). The CRR was 30% for 90Y-ibritumomab tiuxetan versus only 16% for rituximab (P = 0.04). The Kaplan-Meier estimated median DR was 14.2 mo for 90Y-ibritumomab tiuxetan versus 12.1 mo for rituximab (P = not significant), and the TTP was 11.2 versus 10.1 mo (P = not significant). The response to 90Y-ibritumomab tiuxetan was statistically superior to that of rituximab within prognostic subsets, including age, sex, bone marrow involvement, extranodal disease, bulk of disease, number of prior regimens, splenomegaly, and IPI risk groups. A secondary objective of this trial was to determine if radiation dosimetry before 90Y-ibritumomab tiuxetan administration is required for safe treatment in this patient population. It was found that 90Y-ibritumomab tiuxetan administered to NHL patients at its nonmyeloablative MTD deli
