CANCER BIOTHERAPY & RADIOPHARMACEUTICALSVolume 18, Number 4, 2003© Mary Ann Liebert, Inc.

Editorial

Radioimmunotherapy with 131I-Rituximab:What We Know and What We Don’t Know

Malik E. JuweidDivision of Nuclear Medicine, Department of Radiology of the University of Iowa Hospitals andClinics, Iowa City, IA

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INTRODUCTION

Immunotherapy with rituximab (Rituxan®, IDECpharmaceuticals Corp., San Diego, CA), a chi-meric anti-CD20 monoclonal antibody (mAb),has truly revolutionized the management of pa-tients with B-cell non-Hodgkin’s lymphoma(NHL).1–8 Not only is rituximab, given as a sin-gle-agent, currently standard therapy for relapsedor refractory indolent NHL, but it has also be-come an essential component of various anthra-cycline-based chemotherapy regimens, most no-tably CHOP (cyclophosphamide, doxorubicin,vincristine, and prednisone), that are utilized inthe treatment of both indolent and aggressiveNHL.7,8 The widespread use of single-agent rit-uximab given in 4–8 weekly doses of 375 mg/m2

for treatment of relapsed or refractory indolentNHL is based on numerous clinical trials demon-strating its efficacy in this setting with an over-all response rate (ORR) of 50–60% and a com-plete response rate (CRR) of up to 15%.3–5 Itsuse in combination with CHOP chemotherapy inthe initial treatment of patients with diffuse-largecell lymphoma has been validated by the resultsof a randomized multicenter trial comparing thesafety and efficacy of CHOP with rituximab ver-sus CHOP alone, in which the former was dem-

onstrated to result in significantly higher CRR,progression-free survival (PFS), and overall sur-vival (OS) compared with the latter, without aclinically significant increase in toxicity.8 Sev-eral clinical trials on the efficacy of rituximab incombination with other chemotherapeutic regi-mens or other anti-B-cell lymphoma mAbs, bothunconjugated and radiolabeled, are currently un-der evaluation.9,10 It is therefore not surprisingthat rituximab was considered when searching foranti-B-cell lymphoma mAbs, suitable for ra-dioimmunotherapy (RIT) of B-cell NHL, such asin the study by Turner et al. in this issue of Can-cer Biotherapy and Radiopharmaceuticals.11

Presumably, factors other than the establishedclinical activity of rituximab, have facilitated thedevelopment of radiolabeled rituximab as a RITagent, albeit, to date, only in Australia and Eu-ropean countries.11–17 One of these factors maybe the delay in regulatory approval of a “desig-nated” RIT agent, such as 90Y-ibritumomab tiux-etan mAb (Zevalin™, IDEC Pharmaceuticals), insome countries. This prompted the search for RITagents that may be derived from already com-mercially approved unconjugated anti-B-cellNHL mAbs, such as rituximab. This process wasfacilitated by the apparently substantially lessstringent regulations in these countries (com-pared to the United States) with respect to thepermissibility of alterations to commercially ap-proved unconjugated mAbs. Investigators mayalso have been motivated by issues such as cost,and potential advantages of chimeric mAbs.18

Whatever the motivations for the development ofradiolabeled rituximab, it currently represents

Address reprint requests to: Malik E. Juweid; Departmentof Radiology, University of Iowa College of Medicine; 200Hawkins Drive, Iowa City, IA 52242; Tel.: (319) 356-4388;Fax: (319) 356-2220E-mail: malik-juweid@uiowa.edu

one of the viable agents for treatment of re-lapsed/refractory B-cell NHL, but requires criti-cal appraisal by the medical community. In thisEditorial, the experience with the use of radiola-beled rituximab is reviewed with special focus ongaps in our knowledge of its pharmacokinetics,dosimetry, mechanisms of action, and ultimatetherapeutic potential, particularly in comparisonwith other radiolabeled mAbs.

WHY 131I-RITUXIMAB?

It is interesting to note that all clinical RIT orbiodistribution studies with radiolabeled ritux-imab reported to date involved the use of 131I-rit-uximab.11–17 The reason for the exclusive use of131I and not other isotopes, in particular ra-diometals, such as 90Y, is likely to be, at least inpart, related to the relatively simple methodsavailable for mAb radioiodination. Radioiodina-tion of mAb does not require chelators, such as1,4,7,10-tetra-azacyclododecane-N, N9, N0, N--tetraacetic acid (DOTA), which are essential forstable mAb labeling with radiometals.19 Some of these chelators, such as [N-[2-bis(carboyl-methyl(amino]-3-(p-isothiocyanatopheneyl)-p ropyl] - [N-[2-bis(carboxymethy)amino]2-(methyl)-ethyl]glycine (tiuxetan), used for la-beling 90Y to Zevalin, are not readily availablebecause they are protected by patents.20 Otherfactors, such as the wide availability and low costof 131I, and the ability to obtain images of thebiodistribution of 131I-labeled mAb, thereby al-lowing normal organ and tumor dosimetry priorto RIT, may also be responsible for the selectionof 131I for rituximab radiolabeling. Another lessobvious advantage associated with the use of 131I-rituximab is related to the existing abundant phar-macokinetic, dosimetric, and importantly, safetyand toxicity data for nonmyeloablative and mye-loablative doses of other 131I-anti-CD20 mAbs,albeit in the murine form (e.g., the 131I-B1 or tositumomab mAb).21–26 The dose-escalationscheme used to determine the nonmyeloablativeand myeloablative maximum tolerated doses(MTDs) of these murine 131I-anti-CD20 mAbswas dosimetry-based. The administered 131I ac-tivity was based on a prescribed radiation dose toa particular critical, dose-limiting organ ratherthan based on fixed amounts of radioactivity oramounts adjusted to body weight or surfacearea.21–26 It was therefore assumed that even ifthe pharmacokinetic and dosimetric properties of

the chimeric 131I-rituximab were different fromthose of the murine 131I-anti-CD20 mAbs (see be-low), the administration of 131I-rituximab islikely to prove safe as long as the previously es-tablished critical radiation doses to particular or-gans, determined to be the nonmyeloablative andmyeloablative MTDs in the trials using themurine 131I-CD20 mAbs (i.e., tositumomab),were not exceeded.11–17 This appears to be a rea-sonable assumption since it is quite unlikely thatthere will be significant differences in the mi-crodistribution of delivered radiation dose (i.e.,differences at the “microdosimetric” level) be-tween the radioiodinated murine (i.e., tositu-momab) and chimeric (i.e., rituximab) anti-CD20mAbs. For this reason, the nonmyeloablative andmyeloablative MTDs of 131I-tositumomab, deter-mined to be 75 cGy to the total body (as a sur-rogate for the red marrow dose) and 2700 cGy tothe lungs, respectively, were simply adopted asMTDs of 131I-rituximab in the phase II trials withnonmyeloablative and myeloablative doses ofthis agent.11–17 The use of the 75-cGy total bodydose in the study by Turner et al.11 to prescribethe nonmyeloablative regimen of 131I-rituximab,reported in this issue, represents one example ofthis approach.

PHARMACOKINETICS ANDDOSIMETRY WITH 131I-RITUXIMAB

Relatively little has been published regarding thepharmacokinetics and dosimetry with 131I-ritux-imab.11–17 Two interrelated issues are of interestin this respect: one is whether these parametersare different for chimeric 131I-rituximab and theother is whether the therapeutic indices of 131I-rituximab are different compared with the murine131I-anti-CD20 mAbs. Although ibritumomab(Zevalin) represents the “actual” murine parentof rituximab, to date, ibritumomab has only beenstudied using 111In/90Y and not with 131I.20,27–29

In contrast, tositumomab, the other extensivelystudied murine anti-CD20 mAb, has been almostexclusively labeled with 131I in the clinical RITtrials.21–26 It seems reasonable to compare the re-ported pharmacokinetics and dosimetry of thechimeric 131I-rituximab with those of the murine131I-tositumomab. Unfortunately, such compari-son is complicated by the fact that different un-labeled mAb protein doses were given in con-junction with the 131I-labeled anti-CD20 mAbsutilized in various clinical studies in order to

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achieve more favorable tumor targeting.21–31

Several investigators have shown that the amountof administered unlabeled mAb can substantiallyinfluence the pharmacokinetics and normal organand tumor dosimetry with radiolabeled anti-B-cellNHL mAbs, including those against CD20.12,21–31

In the study by Knox et al.,30 preadministration ofunlabeled B1 or ibritumomab (both agents wereused in that study) resulted in improved biodis-tribution of the radiolabeled mAb with increasedvisualization of known disease sites and de-creased radiation doses to the spleen and lumbarspine. In the absence of unlabeled mAb, only18% of known tumor sites were imaged. Pread-ministration of 1 mg/kg unlabeled mAb resultedin imaging of 56% of known sites of disease,whereas 92% of these disease sites were imagedfollowing the preadministration of 2.5 mg/kg ofunlabeled mAb. Moreover, the estimated meantumor radiation dose was about 2.4-fold higherwith the preadministration of 1 mg/kg of unla-beled mAb. Kaminski et al.21 have also shownthat that the preadministration of 135 or 685 mgof unlabeled tositumomab consistently resulted inprolonged blood and whole body clearance of131I-tositumomab as compared with 131I-tositu-momab infusion without preadministration of un-labeled mAb. On the other hand, the preadmin-istration of unlabeled tositumomab had a variableeffect on 131I-tositumomab targeting of tumor rel-ative to normal tissues (i.e., the therapeutic in-dex). The tumor-to-whole body radiation dose ra-tios increased in some patients while theyremained the same in other patients. Thus, anycomparison of the pharmacokinetics and normalorgan and tumor dosimetry between 131I-ritux-imab and 131I-tositumomab must take differencesin the administered unlabeled Ab protein doseinto consideration.

Lacking an “intrapatient” comparison of thepharmacokinetics and normal organ dosimetrybetween 131I-rituximab and 131I-tositumomab,perhaps the closest comparison between thesetwo agents might be based on two reports, oneby Rajendran et al.,31 using the murine 131I-tosi-tumomab and the other by Behr et al.,13 using131I-rituximab. Interestingly, both studies in-volved RIT for patients with mantle cell lym-phoma given identical unlabeled mAb proteindoses of 2.5 mg/kg. A comparison of the reporteddosimetric estimates in these two studies showedthat the whole body and kidney dose were about2.5- and 2.1-fold higher with 131I-rituximab com-pared with 131I-tositumomab (1.9 vs. 0.8 and 6.5

vs. 3.1 cGy/mCi, respectively), while the liverand lung doses were similar with both agents (5.4vs. 3.9 and 5.2 vs. 4.6 cGy/mCi, for 131I-ritux-imab and 131I-tositumomab, respectively). Un-fortunately, the tumor radiation dose estimateswere not reported by Rajendran et al.,31 makingit impossible to compare the tumor-to-normal or-gan radiation dose ratios. However, the findingsof Behr et al.13 might also be compared with thoseof Kaminski et al.21 who reported the normal or-gan and tumor radiation doses with 131I-tositu-momab in a total of seven patients with follicu-lar NHL, of which four received an unlabeledtositumomab dose of 135 mg (,1.9 mg/kg)whereas the other three patients did not requireunlabeled tositumomab to achieve favorable tu-mor targeting. A comparison of the dosimetric es-timates reported in these two studies againshowed that the whole body dose was about 2.7-fold higher with 131I-rituximab compared with131I-tositumomab. However, in this comparison,the liver and lung doses were almost 2.0-foldhigher with 131I-rituximab compared with 131I-tositumomab, whereas the kidney dose was sim-ilar with both agents (6.5 vs 5.2 Gy/mCi for 131I-rituximab and 131I-tositumomab, respectively).The estimated tumor doses were also quite sim-ilar with both agents (14.3 vs. 10.6 Gy/mCi for131I-rituximab and 131I-tositumomab, respec-tively), but, most importantly, the tumor-to-wholebody, -lung and -liver radiation dose ratios wereabout 2.0-, 1.5-, and 1.6-fold higher with 131I-tosi-tumomab compared with 131I-rituximab, with sim-ilar tumor-to-kidney radiation dose ratios for bothagents.

The higher whole body radiation dose with131I-rituximab compared with 131I-tositumomabis consistent with its higher mean biologic andeffective whole body T-1/2s.11,16,21 Both Turneret al.11 and Scheidhauer et al.16 have shown thatthe effective whole body T-1/2 of 131I-rituximabwas about 85 hours compared to 56 hours for 131I-tositumomab.21 This resulted in a whole body ra-diation dose that is almost 2-fold higher with 131I-rituximab compared with 131I-tositumomab. It isalso interesting to note, that very similar effec-tive whole body T-1/2’s were found in the stud-ies of Scheidhauer et al.16 and Turner et al.11 de-spite the very different unlabeled rituximabprotein dose given in the two studies: only 20–40mg of rituximab were given in the study byScheidhauer et al.,16 while a rituximab dose of375 mg/m2 or about 650 mg was administered byTurner et al.11 This may suggest that the whole

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body pharmacokinetics and, hence, radiationdose with 131I-rituximab may be relatively in-sensitive to changes in the unlabeled mAb dosebeyond 20–40 mg. It is conceivable that doseshigher than the 20–40 mg of unlabeled mAbserve, in at least a fraction of patients, to alter thebiodistribution in favor of extramedullary or ex-trasplenic tumor targeting, while decreasing be-nign or malignant B-cell targeting in the marrowand/or spleen. This would result in increasing thepercentage of injected dose (%ID), and, hence,the radiation dose to these extramedullary or ex-trasplenic tumors without substantially alteringthe whole body doses.

In summary, the currently available dataclearly indicate that the whole body radiationdose is higher with 131I-rituximab comparedwith 131I-tositumomab and also suggest that thetumor-to-whole body radiation dose ratio islower with the former compared with the latter.If this data is confirmed in a well-controlledstudy, preferably with both agents administeredin the same patients, or at least in similar pop-ulations of patients using the same unlabeledmAb protein dose, then this has important con-sequences on the use of chimeric 131I-rituximabrather than murine 131I-anti-CD20 mAb, at leastin the nonmyeloablative setting. Similar conse-quences would also apply to the myeloablativesetting, if the tumor-to-lung, -liver or -kidneyradiation doses also prove to be substantiallylower with 131I-rituximab compared with 131I-tositumomab. Further research is thereforeneeded to ascertain if there are indeed signifi-cant differences in the therapeutic indices be-tween 131I-rituximab and 131I-tositumomab.

THERAPEUTIC RESULTS WITH 131I-RITUXIMAB

While consideration of the therapeutic indices of 131I-rituximab compared with murine 131I-la-beled anti-CD20 mAbs, such as tositumomab, isimportant, it might be argued that the ultimatetest of the therapeutic potential of any radiola-beled anti-B-cell NHL mAb is its documented an-titumor activity in relationship to its toxicity pro-file. It is therefore just as critical to review thereported efficacy and toxicity data with nonmye-loablative and myeloablative doses of 131I-ritux-imab in comparison with similar regimens ofother 131I- or 90Y-labeled anti-B-cell NHL mAbsin order to determine if this agent has certain ad-

vantages or disadvantages compared with theseother mAbs. The study by Turner et al.11 in thisissue provides potentially valuable information inthis respect. A total of 35 patients with low- orintermediate-grade B-cell NHL were treated with131I-rituximab based on a prescribed total bodydose of 75 cGy, an approach similar to that usedin previous phase I/II trials with 131I-tositu-momab. A dose of 375 mg/m2 (,650mg) of rituximab was administered prior to the diagnos-tic/dosimetric and therapeutic doses of 131I-rit-uximab. This unlabeled mAb dose is only some-what higher than the rituximab dose of 250 mg/m2 given prior to the administration of 111In/90Y-Zevalin or the unlabeled tositumomab dose of450 mg given prior to 131I-tositumomab in thephase II studies with this agent.20–30 An ORR of71% was found with a CRR of 54%, with a me-dian follow-up of 14 months.11 This ORR is sim-ilar to that reported by Kaminski et al.23 in theirsingle-center phase I/II study with 131I-tositu-momab where an ORR of 71% (42/59 patients)was found and also similar to the ORR of 67%obtained in a phase I/II trial with 90Y-Zevalin re-ported by Witzig et al.27 The CRR of 54% ap-pears somewhat higher than the 34% CRR re-ported by Kaminski et al.23 in the same study orthe 25% CRR found in the phase I/II study with90Y-Zevalin.27 Interestingly, the ORR and CRRwith 131I-rituximab in patients with the “classic”low-grade NHL categories (28/35 patients treated),were 71% and 53%, respectively, not substan-tially different from the overall population. Thelatter values are not substantially different thanthose reported by Kaminski et al.23 who foundORR and CRR of 86% and 46% in patients withlow-grade NHL treated in the single-center phaseI study with 131I-tositumomab. A very high ORRof 82% was also found with 90Y-Zevalin in pa-tients with low-grade NHL, albeit with a CRR ofonly 27%.27 The median PFS with 131I-rituximabwas 14 months in all patients and 20 months inthose with CR, not substantially different fromrespective values reported for 131I-tositumomabor 90Y-Zevalin.23,27 However, one pitfall of thestudy by Turner et al.11 is that an unknown frac-tion of the treated patients who were rituximab-naive received four cycles of rituximab therapy(each containing 375 mg/m2) at one week inter-vals in addition to 131I-rituximab. Depending onhow many patients received this additional ther-apy, the therapeutic results obtained in at least afraction of patients may be in part due to the ef-fects of sequential therapy with 131I-rituximab

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and the standard four cycles of unlabeled ritux-imab. This raises concern regarding the validityof using the therapeutic results obtained byTurner et al.11 for comparison with those ob-tained with 131I-tositumomab and 90Y-Zevalinusing a RIT regimen not followed by four cyclesof rituximab therapy. We do not know what theORR and CRR or PFS would be if RIT with thesemAbs were followed by rituximab immunother-apy. On the other hand, comparing the toxicitydata obtained with the chimeric 131I-rituximaband the murine 131I-tositumomab is quite rea-sonable, particularly since a similar dosimetry-based treatment regimen was used in the RITstudies with both agents. As might be expected,the data with 131I-rituximab showed similarhematologic toxicity to those observed in previ-ous studies with 131I-tositumomab.24 For exam-ple, the median ANC, platelet, and hemoglobinnadirs of 1500 cells per mm3, 87000 cells permm3, and 11.9 g/dL respectively, following 131I-rituximab, are not substantially different from therespective values of 1300, 68000, and 11.2 re-ported for 359 patients treated with 131I-tositu-momab delivering a 75 cGy dose to the totalbody.24

In summary, the data reported by Turner et al.11

using nonmyeloablative doses of 131I-rituximab,albeit given in combination with four cycles ofrituximab therapy in a fraction of patients andbased on a single center study with a relativelysmall number of patients, suggest that 131I-ritux-imab represents an effective treatment regimenwith acceptable toxicity in patients with re-lapsed/refractory low-grade NHL, and possiblyother forms of B-cell NHL. Even if all patientshad received four cycles of rituximab therapy inaddition to 131I-rituximab, the ORR and CRR re-ported with this regimen are clearly superior tothose obtained even with eight cycles of ritux-imab therapy, suggesting that the cytotoxic radi-ation from 131I contributed significantly to thetherapeutic results obtained. This nonmyeloabla-tive treatment regimen therefore represents yetanother nonmyeloablative treatment option forpatients with relapsed/refractory B-cell NHL.However, more studies are required to determinehow the efficacy of 131I-rituximab RIT alone oras part of a treatment regimen containing addi-tional cycles of rituximab immunotherapy com-pares with that of other radiolabeled anti-B-cellNHL mAbs given in a similar regimen or doseschedule.

Relatively limited experience is currently

available with myeloablative doses of 131I-ritux-imab. Behr et al. were the first to report on theuse of this approach to treat five patients with re-lapsed/refractory B-cell NHL.12 The radionuclidedose given in these five patients was determinedbased on a diagnostic radiation dosimetry aimingat lung and kidney doses of ,2000 cGy. To op-timize tumor targeting, a mAb protein dose of 2.5mg/kg was given. All four patients assessable forresponse at the time of the report had a CR (n 53) or PR (n 5 1) for periods ranging from31–71 months. No significant nonhematologictoxicity was observed despite the administrationof radioactive doses ranging from 225–495 mCi(median; 439 mCi). Subsequently, the same in-vestigators initiated a study with myeloablativedoses of 131I-rituximab in patients with mantle-cell NHL, this time aiming at a lung dose of,2700 cGy,13,14 a design more similar to that ofthe phase II trial with myeloablative doses of 131I-tositumomab.26 The mAb protein dose adminis-tered was 2.5 mg/kg in all but one patient, whoreceived 10 mg/kg of mAb protein. The most re-cent update on this study showed that seven ofeight treated patients had a CR with one patientexperiencing a PR.14 Six of the eight patients re-mained in CR for periods up to 421 months post-therapy. Nonhematologic toxicity was restrictedto mild to moderate nausea, fever, and transientbilirubin or liver enzyme elevations. Six of theeight patients developed hypothyroidism despitethyroid blockage. Interestingly, the same grouptreated four other mantle-cell NHL patients withnonmyeloablative doses of 131I-rituximab, aim-ing at delivering a whole body dose of ,80cGy.14 The same mAb protein dose of 2.5 mg/Kgwas also used as in these patients. Only one ofthe four patients had a PR while the remainderdid not respond. Thus, the current experiencewith myeloablative doses of 131I-rituximab, albeitfrom a single center, suggests that this is a highlyeffective approach, even in difficult to treat formsof NHL. This approach also appears to be quitesafe with only mild to moderate nonhematologictoxicity, as long the radiation dose to the lung of2700 cGy is not exceeded. Despite the relativelysmall number of patients treated to date, the find-ing of very high ORR, including CRs, is consis-tent with what has been observed with myeloab-lative doses of 131I-tositumomab, also designedto deliver 2700 cGy to the critical organs (foundto be the lung in most patients).26 Interestingly,however, Behr et al.13 have shown that the aver-age kidney dose was somewhat higher than the

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lung dose in their patients (6.5 vs. 5.2 cGy/mCi),suggesting that at least some of their patients re-ceived kidney doses that were higher than the2700 cGy dose limit. The fact that this was ap-parently safe with no renal toxicity reported mayindicate that renal doses even higher than 2700cGy delivered with RIT are tolerated. However,longer follow-up with close monitoring of po-tential chronic renal toxicity is needed to confirmthis supposition.

In conclusion, the current data with nonmye-loablative and myeloablative RIT using 131I-rit-uximab clearly suggest that both the hematologic(relevant to the former) and nonhematologic (rel-evant to the latter) toxicity are similar to whatwas observed with murine 131I-anti-CD20 mAbs,131I-tositumomab in particular, as long as “criti-cal” radiation doses of 75–80 cGy to the totalbody (for nonmyeloablative RIT) or 2700 cGy tolung (for myeloablative RIT) are not exceeded.The remarkable antitumor responses seen withboth approaches, apparently without any demon-strable increase in toxicity when using a dosime-try-based dosing method, justify their utilizationfor treatment of relapsed/refractory B-cell NHL.While this appears to be possible both in the in-vestigational and clinical setting outside theUnited States, studies with 131I-rituximab in thiscountry can only be of investigational nature, al-most certainly requiring an investigational newdrug application (IND). Such studies may, nev-ertheless, be useful if one wishes to further in-vestigate the pharmacokinetic and dosimetricproperties of this mAb and more clearly defineits potential role in the treatment of patients withB-cell NHL.

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