4 S.J. GoldsmithWorking Formulation which differentiated NHLfrom Hodgkin’s lymphoma and divided NHLinto four grades (low, intermediate, high, andmiscellaneous) related to onset and prognosis.There were further subdivision into 16 differenttumor types based on histopathologic featuressuch as size and shape of affected cells.Subsequently, in the mid-1990s, the Europeanand American hematology-oncology communitydeveloped the Revised European-AmericanLymphoma (REAL) Classiﬁcation based onimmunophenotypic and genetic features of NHL.This classiﬁcation was revised again by the WorldHealth organization (WHO) in 2001 and updatedin 2008. There are now many diagnostic catego-ries of lymphoma but approximately 85% of thelymphomas in the United States and WesternEurope are B-cell lymphomas including the twomost common NHLs: Follicular lymphoma (anindolent, low grade lymphoma) and diffuse largeB-cell lymphoma (DLBCL) (an aggressive, highgrade lymphoma) .B-cell lymphoma means that the tumor cells arederivedfromamalignanttransformationofB-cells,lymphocytes that in fetal life originate in the bonemarrow, spleen, and liver in contrast to T-cellswhich are derived from thymic tissue. B-cells andT-cells possess different properties and take on dif-ferent roles in immune system function.Both normal B-cells and tumors derived fromthem have in common the frequent expression ofsimilar surface antigens. When an antigen hasbeen characterized by two different antibodies, itis identiﬁed as a “cluster of differentiation” andare designated “CD” followed by a number.Many clusters of differentiation have beenidentiﬁed on cells from all tissues and tumors.Although the individual antigens are not charac-teristic of a speciﬁc tumor, there are patterns ofexpression of these antigens on speciﬁc cell typesand tumors arising from those cells. For example,the epitope CD 45 is widely expressed on whiteblood cells but CD 20 appears on the pro-B lym-phocyte as it evolves from the stem cell. CD 20expression increases as the lymphocyte maturesbut is no longer expressed after full maturity ofthe normal lymphocyte or its evolution to aplasma cell or the myeloma tumor cells derivedfrom plasma cells. When certain histopathologi-cal patterns are ambiguous rendering a precisehistopathological diagnosis uncertain, immuno-histopathologic CD cell typing can providedeﬁning information.As stated, the marker CD 20 is expressed in thepro-B-cell stage (as the B-cell evolves from thestem cell precursor) and throughout the life of themature B-cell but CD 20 is neither present in stemcells nor in plasma cells derived from B-cells.Other surface markers such as CD 19 and CD 22are also frequently expressed on the differentiatedB-cell and the tumors that evolve when these cellsundergo malignant transformation.The antigen CD 20 was of particular interestsince it is expressed on many of the most com-mon B cell lymphomas, follicular lymphoma,and DLBCL. DLBCL is the most common NHL,accounting for 40% of the lymphoma diagnosedin adults and it is the most common aggressive,high grade lymphoma. The median age at presen-tation is 70 years. With treatment, patients survivewith a median duration of 10 years. For manyyears, chemotherapy with cyclophosphamide,hydroxydaunorubicin, oncovin (vincristine), andprednisone (CHOP) or cytoxin, vincristine, andprednisone (CVP) for older patients was fre-quently the treatment of choice. This regimenincludes multiple treatments for several weeksper month over many months with considerablediscomfort and toxic side effects [1–3].Follicular lymphoma is the second most com-mon NHL, and the most common indolent NHLaccounting for approximately 22% of NHLs.Currently, it is expected that nearly 14, 000 peo-ple will be diagnosed with Follicular NHLannually. The median age at diagnosis of follicu-lar lymphoma is 59 years and the median survivaltime is 11 years from the time of diagnosis. Asstated, indolent lymphomas such as follicularlymphoma may be asymptomatic at the time ofdiagnosis. Given the toxicity of standard coursesof chemotherapy, treatment may be deferred atthe time of initial diagnosis. Eventually thepatient will become symptomatic or developobjective evidence of progression resulting in adecision to treat. In the past, the great majority(perhaps about 80%) of the patients responded totheir initial course of chemotherapy with CHOPor CVP [1–3].
51 Radioimmunotherapy of LymphomaA feature of the clinical course of low gradefollicular lymphoma is the so-called “low gradelymphoma paradox”; as mild as the disease maybe when initially diagnosed and even when thereis a well documented clinical response to chemo-therapy, patients will eventually relapse andrequire an additional round of therapy. A fractionof patients respond when retreated with the sameor a similar regimen. Even when relapsed patientsrespond to retreatment, the duration of responseis frequently shorter than the initial disease-freeinterval. Characteristically, after the third courseof treatment, the remission is usually only a fewmonths in duration.Despite the frequent success in treating lowgrade follicular lymphoma, this combination ofclinical features: large numbers of patientsaffected, a multifocal disease, frequent relapseswith shorter disease-free intervals rendered folli-cular lymphoma as a worthwhile target for aninnovative therapy that is capable of providingtargeted antitumor therapy.DLBCL and low grade follicular lymphoma,therefore, represent a diagnostic category ofgreatest need in terms of number of individualsaffected as well as providing adequate numbersof patients for clinical trials. This is an importantcomponent of bringing a therapeutic agent toclinical application, given the complexity andcost of verifying efﬁcacy in these disorders.ImmunotherapyThe REAL and subsequent WHO revision of theclassiﬁcation of NHL made clear that the CDexpression on tumor samples provided the bestmethodology to identify speciﬁc tumor types andcharacteristics. The CD 20 antigen is frequentlyexpressed in both follicular lymphoma andDLBCL. In addition to the relevance of thisdesignation for the precise diagnosis of an NHL,the CD classiﬁcation identiﬁed “a target ofopportunity” for the development of speciﬁcmonoclonal antibodies directed toward thespeciﬁc antigens expressed on a particular NHL.Monoclonal antibodies are immunoglobulins,usually IgG, of approximately 160 kDa com-posed of several polypeptide chains usually char-acterized as two heavy chains and two lightchains in the characteristic “Y” conﬁgurationwith disulﬁde linkages binding the stems of theheavy chains as well as the light chains to thearms of the heavy chains. (Fig. 1.1) The terminalportion of the heavy and light chain is the immu-norecognition portion.Fig. 1.1 Schematic demonstrating structural similaritiesand differences amongst human, murine, chimeric and“humanized” IgG molecules. Generic names for monoclo-nal antibodies end with “mab.” Mouse monoclonal antibod-ies are “-momabs”; chimeric are “-ximabs” and humanizedIgGs are “-zumabs.” Antibodies to tumor antigens ofteninclude “tu”; hence “…tumomab”, a murine monoclonalantibody to a tumor antigen; “…tuximab”, a chimericmonoclonal antibody to a tumor antigen and “…tuzumab”,a humanized monoclonal antibody to a tumor antigen
6 S.J. GoldsmithImmunization of an intact animal results instimulation of many plasma calls to produce avariety of immunoglobulins with varying degreesof speciﬁcity and afﬁnity to the stimulating anti-gen, summarized in the term “immunoreactivity.”In the monoclonal antibody development pro-cess, immunoglobulins from isolated hybridencoded plasma cells are evaluated and selectedfor their immunoreactivity . Following immu-norecognition and binding to an epitope, someimmunoglobulin-epitope complexes are internal-ized whereas others are not. This phenomenon(internalization) is apparently epitope speciﬁcand has an inﬂuence on the choice of thespeciﬁc radiolabel, a radiometal vs. radioiodine.Regardless of whether or not the immunoglobu-lin is internalized, there are several consequencesto the immunoglobulin-epitope binding whichmake possible the use of immunoglobulins asantitumor therapeutic agents. These include:Antibody dependant cell cytolysis, complementdependant cytolysis and antibody-induced apop-tosis. These processes represent useful antitumoreffects but are dependant upon direct binding tothe tumor cell. One of the potential limitations ofthe immunotherapy approach, therefore, is thatalthough there are usually an abundant number ofantigen binding sites on a tumor cell cluster, theimmunoglobulin principally affects the cell onwhich it is bound. Given the vagaries of tumorperfusion, the antibody may not have access toeach cell. This limitation tends to impair theeffectiveness of immunotherapy for treatment ofsoft tissue tumors.RituximabAfter the development of a variety of anti-CD 20monoclonal antibodies, it was observed that theseimmunoglobulins had antitumor effects in cellsuspensions and other laboratory models. One ofthese immunoglobulins, ibritumomab, was devel-oped as a chimeric antibody in which the murineIgG backbone of the anti-CD 20 antibody wasenzymatically cleaved and replaced with the cor-responding portion of a human IgG molecule forthe potential treatment of CD 20+ NHL (Fig. 1.1).This chemical manipulation maintains the immu-norecognition portion of the speciﬁc murineantibody developed to recognize CD 20but reduces the likelihood of the patient develop-ing human anti-murine antibodies (HAMA).Development of HAMA would preclude therepeated use of this antisera, primarily becausethe subsequent HAMA-anti-CD 20 complexwould be rapidly eliminated from the circulationwithout an opportunity to achieve a therapeuticeffect. To clarify the sometimes confusing nomen-clature, consider that the “ibri-” preﬁx was cleavedto “ri” and the “mo” component (indicatingmurine origin) became “xi” (indicating a chimericstructure) according to the custom developed formonoclonal antibody nomenclature. Thus “ibri tumo mab” becomes “ri tu xi mab.”In 1993, a pivotal clinical trial that comparedseveral common chemotherapeutic regimen aloneto similar regimen augmented with rituximabinfusions was completed . There were greaterresponse rates of longer duration with no addi-tional side effects in the patients who received themonoclonal antibody rituximab in conjunctionwith chemotherapy. In short order, the addition ofrituximab infusions to many different chemother-apeutic regimens became the standard of practicefor patients with CD 20+ NHL, including bothfollicular lymphoma and DLBCL. This wasreﬂected in the regimen terminology which tran-sitioned to CHOP-R or R-CHOP, R-CVP, etc. Inaddition, it was found that rituximab infusions atregular intervals following the initial chemother-apy course reduced the relapse rate in patientswith CD20+ B cell lymphomas (principally fol-licular lymphoma) and that on occasion, patientswith relapsed NHL disease responded to subse-quent rituximab infusions. Nevertheless, overtime many patients became or were found to berefractory to the chemotherapy-rituximab combi-nation and subsequent rituximab infusions.RadioimmunotherapyIt is against this background: (1) a relativelylarge number of patients with follicular, lowgrade lymphoma who had become refractory
71 Radioimmunotherapy of Lymphomato chemotherapy and rituximab; (2) a well-characterized tumor that almost always expressedCD 20 antigen; (3) demonstration that anti-CD20 monoclonal antibodies were able to target CD20+ tumor cells and (4) knowledge that lym-phoma in general is a relatively radiosensitivetumor—that groups of biomedical scientistsbegan to develop and evaluate radiolabeled anti-CD 20 antibodies. Early in the course of clinicaltrials, it was appreciated that the principal toxic-ity, the dose limiting toxicity, was bone marrowsuppression, particularly thrombocytopenia. Thiscomplication is increasingly manageable with theavailability of granulocyte colony stimulatingfactor (GCSF) and platelet transfusion (and ofcourse, either erythropoietin or packed red bloodcell transfusions if necessary). Nevertheless,most clinical trials were designed to evaluate theefﬁcacy of the so-called “nonmyeloablative” pro-tocol which subsequently led to the approval ofthe two clinical agents, Bexxar®and Zevalin®, inthe United States. These agents are currentlyavailable for clinical use and the approved proto-cols are designed to avoid bone marrow ablationor severe damage.Bexxar® and Zevalin® NomenclatureIt is customary in the scientiﬁc literature touse generic names for diagnostic andtherapeutic products rather than theirproprietary name. Since Bexxar®consists ofa combination of tositumomab and131I-tositumomab administered sequentiallyand Zevalin®consists of rituximab followedby 90Y-ibritumomab tiuxetan. In this chapter,the “commercial” names, Bexxar®orZevalin®, are used for convenience and brev-ity since both the Bexxar®and Zevalin®regi-men involve the combination two unlabeledantibody infusions followed by a labeledantibody infusion. In both instances, thissequential infusion of the “cold” antibodyfollowed by the radiolabeled antibody is pre-ceded 1 week earlier by an infusion of the“cold” antibody.Early in the evolution of radioimmunotherapy,however, there was recognition that since bonemarrow transplantation is widely used during thecourse of other treatment of a variety of tumorsincluding NHL and bone marrow transplantationinitially involves effectively destroying thepatient’s bone marrow, it would seem reasonableto administer larger doses of radioactivity inthe hope of eliminating disease even at theexpense of the bone marrow which could be sal-vaged by pretreatment bone marrow or stem cellharvest and subsequent transplantation. Thismyeloablative approach, however, has been eval-uated only in limited investigational studies (tobe discussed below).Physical and Chemical Propertiesof RadionuclidesBy the 1990s, based on the use of iodine-131[131I] for the treatment of thyroid cancer andhyperthyroidism, there was essentially 50 yearsof experience with 131I as a radionuclide with abeta particle emission that could provide effec-tive targeted radiation therapy. Accordingly, sev-eral of the initial efforts to develop a radiolabeledmonoclonal antibody chose 131I as the radionu-clide. Proteins including immunoglobulins arereadily iodinated and puriﬁed with retention ofimmunoreactivity.At about the same time, there was a growinginterest in the potential for the radiometalYttrium-90 [90Y] to serve as a radiolabel for ther-apeutic applications. 90Y had a number of theo-retical advantages over 131I: it had a more energeticbeta particle with an associated greater range intissue. It also had a shorter half life and the chem-ical properties of a metal which meant that onceinternalized into cells, it remained even if the car-rier molecule was subsequently digested.There has been considerable debate ever sincewhether or not these differences between the tworadiolabels available at that time provide an advan-tage to one or the other treatment regimen [6–8].There is evidence that there is a relationshipbetween tumor size and beta emission energy andthat low energy is more effective within the zone
8 S.J. Goldsmiththat it irradiates rendering the efﬁcacy dependantupon the distribution of the radiolabel .Moreover, if tumor foci are deposited in sensitivetissue such as bone marrow, there is less irradia-tion of these surrounding elements when a lowerenergy beta emitter is used. At one time, it wasthought that a shorter physical half-life wasadvantageous because of the radiobiologic prin-ciple “dose rate effectiveness factor” but this isunlikely to be signiﬁcant when dealing with irra-diation rates as slow as encountered with eitherof these radionuclides.Furthermore, it is argued by some that a halflife similar to the biologic half life of the labeledmolecule, in this instance an immunoglobulin,provides the optimal opportunity for tumor irra-diation. Of course, the overall product of physicaland biologic half life is the effective half lifewhich will always be shorter that the shorter ofthe two values. Thus, in the instance of 131I labeledto an immunoglobulin whose biologic half lifemight vary from 1 to 3 weeks, there would beconsiderable variation in the whole body radiationabsorbed dose for any given amount of radiola-beled antibody administered whereas for 90Y, theeffective half life of the radiolabeled antibodywill always be shorter than the 2.6 day physicalhalf life of 90Y. While there may be small differ-ence in the whole body radiation absorbed dosefrom patient to patient, these differences will beminor when the physical half life is so shortunless there is some other factor affecting thebiodistribution of the radiolabeled product (suchas preexisting HAMA or other factors that resultin hastened reticuloendothelial extraction of theradiolabeled product from the circulation) .Another difference between 131I and 90Y is that131I emits both a beta particle and a gamma pho-ton whereas 90Y is a so-called pure beta emitter(Table 1.1). Beta particles are difﬁcult to quantifyand image in the event that this is desirable orrequired to determine or conﬁrm biodistribution.Techniques utilizing Brehmsstrahlung radiationand more recently positron imaging (based on thesmall component of pair production associatedwith emission of high energy beta particles) havebeen described but these techniques have notcontributed to the design or execution of clinicalstudies or practice. More commonly, it has beenconvenient to use 111In as a substitute for 90Ywhen it is necessary to evaluate targeting orbiodistribution of a 90Y labeled monoclonal anti-bodies. The combined emissions characteristic of131Iallowforthedirectdetectionandquantiﬁcationof the radioiodine distribution.In recent years, another radiometal,Lutetium-177 [177Lu] has become available buthas not yet been used in any clinically availableradioimmunotherapy regimen for the treatmentof NHL. 177Lu has a longer physical half life than90Y and a lower energy beta emission. Thus, as ageneralization, it can be stated that 177Lu has thechemical properties of a radiometal and physicalproperties closer to 131I than 90Y (Table 1.1).Table 1.1 Radionuclides used for radioimmunotherapy of lymphomaRadionuclide Physical T1/2 (days) Decay Particle energy (MeV) Path length (mm) g Energy90Y 2.7 b 2.3 5.3 None131I 8.1 b, g 0.6 0.8 364 keVTable 1.2 Five clinical trials in the initial evaluation of Bexxar®(from Fisher et al. )Trial Patient population No. of patients Median (range)Phase 1 single center Relapsed-refractory 42 3 (1–11)Phase 2 multicenter Relapsed-refractory 47 4 (1–8)Randomized phase 2 multicenter Relapsed-refractory 61 2 (1–4)Comparative; multicenter Refractory 60 4 (2–13)Phase 2 multicenter Rituximab relapsed-refractory 40 4 (1–11)Total 250 4 (1–13)
91 Radioimmunotherapy of LymphomaDespite the differences in the physicalproperties of the several different radionuclidesused in clinical studies to date, there has been norandomized comparison of different beta emit-ters. Accordingly, the differences in physicalproperties remain of theoretical interest althoughthese differences do have an impact in the proto-col design. For example, if it is necessary ordesirable to obtain biodistribution data or todetermine Residence Time when using a purebeta emitting radionuclide like 90Y, it is necessaryto prepare and administer an 111In labeled versionof the antibody of interest prior to or coincidentalwith the 90Y product.Role of “Cold Antibody”When a radiolabeled or nonradiolabeled (naked)antibody is injected into the circulation, it travelsthrough the venous system to the right side of theheart, passes through the pulmonary circulationinto the left heart and then it is distributedthroughout the arterial system to the capillariesthat perfuse the various organs in the body. Evenwhen the plasma is carrying a substance like anantibody, ligand or drug capable of a high afﬁnityinteraction, the extraction efﬁciency is consider-ably less than 100%. In the instance of a mono-clonal antibody against an antigen expressed on atumor, if the target antigen is not unique to thetumor, the biodistribution of the immunoglobulinwill depend in part on the relatively blood ﬂowand tissue distribution. Since there are a largenumber of B cells in the circulation and thespleen, there is a large extratumoral sink for anantibody that recognizes CD 20. Accordingly,and perhaps somewhat counterintuitive, it is nec-essary to initially administer unlabeled (cold ornaked) antibody to saturate the large number ofCD 20 binding sites on cells other than tumorcells (Fig. 1.2). It has been demonstrated that thisFig. 1.2 Anterior whole body scan at 1 h after131I-tositumomab, without and with prior administration(predose) of unlabeled tositumomab. Without a predose of“cold” antibody, a major portion of the injected radiola-beled antibody is removed by the spleen. When the patientreceives a predose of “cold” antibody, a greater fraction ofthe radiolabeled antibody remains in the circulation.Predosing increases the percent of the administered dosein the tumor. The amount of cold antibody appropriate forthis effect depends on the speciﬁcity of both the antigentarget and the antibody as well as the amount of alterna-tive sites for antibody binding 
10 S.J. Goldsmithstrategy in fact prolongs the plasma half-life ofsubsequently infused radiolabeled antibody andincreases the amount of subsequently infusedradiolabeled antibody. Because of the large CD20 “sink,” it is necessary to administer severalhundred milligrams of unlabeled antibody priorto the administration of the labeled antibodyregardless of whether it is the 131I-labeled mate-rial or the 90Y labeled immunoglobulin. Hencefor clinical trials of radiolabeled monoclonalantibodies, the therapies are properly called aregimen consisting of an infusion of cold, unla-beled immunoglobulin followed by the labeledmaterial.Both Bexxar®and Zevalin®regimens haveemployed relatively large amounts of “cold”antibody, independent of the tumor burden, inorder to prolong plasma levels of the labeledmonoclonal antibody to allow continued tumorperfusion and access to the radiolabeled antibodyover time. The notion of “individualized” doseselection of both the total antibody dose as wellas the administered radiolabeled product wasraised early by Press et al. . While this mayindeed be an ideal approach, practical issues interms of production of a uniform radiopharma-ceutical renders this concept as an unlikely to berealized.Clinical ApplicationsEarly Clinical Studies: 131I-Lym-1Prior to the delineation of clusters of differentia-tion which provided a speciﬁc classiﬁcation sys-tem for cell surface antigens in general, and tumorcells including lymphoma in particular, twomonoclonal antibodies, Lym-1 and Lym-2, weredeveloped. These antibodies of murine originwere reactive with membrane antigens on cells ofB-cell lineage and tumors derived from thesecells. In cell suspensions and immunohistopatho-logic sections from a variety of lymphoma tissue,it was demonstrated that there were signiﬁcantnumber of binding sites on the cell surfaces ofthese tissue samples and virtually no binding toT cell lymphocytes, T-cell lymphomas or othersoft tissue tumors. These antibodies identiﬁed40% (Lym-1) to 80% (Lym-2) of the B-cell lym-phoma samples and were speciﬁc for B-cell lym-phoma with the exception that they boundHodgkin’s tissue also .The group at the University of California,Davis in Sacramento, headed by Drs. GeraldDeNardo and Sally DeNardo, radioiodinated theLym-1 antibody and determined that predosingwith unlabeled antibody prolonged blood clear-ance and increased tumor uptake of the radiola-beled antibody. Subsequently, they administeredthe antibody combination using incrementaldoses of 131I-labeled antibody to a small group ofpatients with considerable tumor burdens. Oneof these patients, a 67-year-old woman withRichter’s transformation of chronic lymphaticleukemia had massive lymphadenopathy atmultiple sites and appeared to be refractory tochemotherapy. She responded to what in retro-spect appears to have been relatively small dosesof 131I-Lym-1 and survived for 2 years beforedying from an infection. In a summary publishedin 1997, they reported their experience with thetreatment of 58 patients, 31 of whom received60 mCi or less of the 131I-labeled antibody .In 17 of these patients, a partial or completeremission was observed. In a subsequent protocolto determine a maximum tolerated dose (MTD),of 24 patients who received doses from 40 to100 mCi/m2, 13 patients had a decrease in tumorsize. Myelosuppression was observed and throm-bocytopenia was the most frequent dose-limitingtoxicity.Development and Assessmentof Current PracticeBexxar® [131I-Tositumomaband Tositumomab]Clinical indications and efﬁcacy: In reports dat-ing to the early 1990s, the group at the Universityof Michigan developed the details of an effectiveprotocol for the use of an anti-CD 20 murinemonoclonal antibody, tositumomab, that hadbeen prepared by Coulter, Inc (San Diego, CA)
111 Radioimmunotherapy of Lymphoma[11–14]. Although they were working initiallywith suboptimal doses of unlabeled antibody aswell as the radio-iodinated version, they demon-strated an antitumor response. In addition, theyrealized that response was related to the amountof activity targeted and that the response wasmore related to the whole body radiation absorbeddose than to the amount of radioactivity adminis-tered on a body weight or body surface area basis.From these early clinical trials, the present proto-col for Bexxar®administration evolved. The pro-cedure protocol to determine the patient speciﬁcdose of 131I-tositumomab is described in detail ina recent review .Limited Availability of LymphomaRadioimmunotherapyAt the present time, Bexxar®is availableonly in the United States and Canadawhereas Zevalin®is available in Europe andthe Middle East as well as the United States.Apparently, availability of production facili-ties and transportation issues as well as theneed for the manufacturer/distributor to pro-vide marketing and educational support hasinterfered up to this time with wider distri-bution of Bexxar®as well as Zevalin®.Initially, Bexxar®was approved by the FDA forthe treatment of patients who were refractory orhad relapsed following chemotherapy includingrituximab.After completion of early clinical trials usingBexxar®to determine the dose to be administeredand demonstrate safety and efﬁcacy, Phase 3 tri-als were conducted initially in patients with con-siderable tumor burdens who had relapsedfollowing chemotherapy at least twice . Someof the patients, in fact, had undergone three ormore previous courses of chemotherapy. Twohundred and twenty-six of the 250 patients (90%)had Stage III or IV disease; 46% had bone mar-row involvement and 61% of the patients hadbulky tumors (diameter greater than 5 cm). Theoverall response rate (ORR) was 56% and themedian duration of response was 12.9 monthswith a range from 10.9 to 17.3 months. A com-plete response (CR) was seen in 30% of thepatients with a minimum duration of response of28.3 months and a median duration of responseof almost 5 years (58.4 months). Many patientswere still in remission beyond 5 years when theresults were reported .Despite these impressive results, by the timethese studies were complete rituximab as a com-ponent of chemotherapy regimens had becomethe new standard of practice. Accordingly, it wasnecessary to evaluate the efﬁcacy of the Bexxar®regimen in patients who had become refractory(unresponsive) to rituximab infusions. Themedian number of prior chemotherapies was 4.Thirty-ﬁve patients in this category were treatedwith Bexxar®according to the established proto-col based on whole body radiation absorbed doseadjusted for platelet count. The ORR was 65%(with a 95% conﬁdence limit of 45–79%) and theCR was 29% (15–46% CI). Even more impres-sive, the duration of response in the ORR was 25months (4+ to 36 months, CI) and it had not beenreached in the CR group with a median durationof follow-up of 26 months. Among folliculargrade 1 or 2 patients with tumors £7 cm (n=21),the OR and CR rates were 86 and 57% (Fig. 1.3).Given the excellent results that were initiallyachieved with Bexxar®in heavily pretreatedpatients, it occurred to several teams to developprotocols that offered Bexxar®therapy earlier inthe course of their disease. In patients who hadonly failed chemotherapy once, Bexxar®per-formed even better. This encouraged a number ofinvestigators to evaluate the efﬁcacy of Bexxar®as a component of so-called ﬁrst-line therapy,either as the sole therapeutic or as a componentof the initial therapy regimen in combination withchemotherapy [17, 18].When Bexxar was used as a component of theinitial regimen following Fludarabine for 3 cyclesin 76 patients with stage III or IV follicular lym-phoma, the ORR was 97 and 76%of the patientshad a complete response (CR). The minimal pro-gression-free survival (PFS) was 27 months andthe median PFS was determined to be greaterthan 48 months although it had not been reached
12 S.J. Goldsmithafter 58 months of follow-up. In contrast topatients who had received no immunosuppressivetherapy, HAMA formation was observed in only6% of the patients [17, 18].A multicenter group evaluated the efﬁcacy ofBexxar®in what is essentially a consolidationprotocol several weeks after completion of acourse of CVP. In 76 patients with CD 20+ NHL,the ORR was 96%, the CR was 76% and themedian time to progression (TTP) was notreached after 6 years of follow-up. In other words,although some relapses did occur over time, mostof the patients remained in remission .One of the frequently expressed concerns isapprehension about the utility of subsequenttherapy in the event of patient relapse. Dosiket al. evaluated the effects of subsequent chemo-therapy in 44 of 68 patients who had previouslyreceived Bexxar®therapy and either failed torespond or relapsed following a response toBexxar®RIT . The median values for theabsolute neutrophil count and hemoglobin at thetime of disease recurrence were not signiﬁcantlydifferent from preradioimmunotherapy values.The median platelet value had a modest decreasefrom 190,000 cells per microliter to 130,000.Fig. 1.3 18F-ﬂuorodeoxy glucose PET maximum intensityprojection (MIP) images of a 49-year-old man with docu-mented diffuse large cell lymphoma with a very largeabdominal lymphomatous mass as well as multiple sitesof smaller lymph node involvement in the neck, chest andabdomen. Patient was initially diagnosed 11 years earlierand underwent treatment with six cycles of CHOP.Relapsed 5 years later at which time he was treated withDICE chemotherapy and rituximab. In January 2004,patient relapsed and was referred for treatment withthe Bexxar®regimen. Patient’s symptoms subsided overseveral weeks. Repeat FDG imaging in June 2004 showclearing of tumor metabolic activity consistent with acomplete response. Because of involvement of his lefthemi-thorax pleura and recurrent effusions, he had previ-ously undergone pleurectomy. Foci of FDG activity fromgranulation tissue persist in the left pleura. Diffuse largecell lymphoma is not the usual basis for referral for anti-CD20 radioimmunotherapy but the biopsy conﬁrmedexpression of CD20 and both the patient and thereferring physician were reluctant to retreat with standardchemotherapy
131 Radioimmunotherapy of LymphomaThe relapsed patients received a variety of cyto-toxic chemotherapy regimen and many were pro-vided with stem cell transplantation. At the timeof the report, 50% of the patients completed asubsequent course of treatment and responded orwere still receiving treatment. Eighteen patientswho were severely ill prior to radioimmunother-apy and continued to have progressive diseasefailed to respond to repeat chemotherapy also.These ﬁndings demonstrate that the bone marrowdoes recover from the radiation exposure fromBexxar®radioimmunotherapy. Furthermore, thebone marrow matrix is receptive to stem celltransplantation. Many patients with progressivedisease after Bexxar®treatment are able to receivesubsequent cytotoxic chemotherapy includinganthracyclines, platinum, or ﬂudarabine, immu-notherapy alone or in combination as well asstem cell transplantation . The subsequentclinical course is similar to patients with similardisease burdens and therapeutic histories whonever received Bexxar®radioimmunotherapy.Zevalin® (90Y-Ibritumomaband Rituximab)The procedure protocol to determine the patientspeciﬁc dose of 90Y-ibritumomab tiuxetan isdescribed in detail in a recent review .Clinical Indications and efﬁcacy: In 2004, Witzigsummarized the various clinical trials involvingmajor steps in the development and subsequentFDA approval of Zevalin®. There were twophase I trials of 90Y-ibritumomab tiuxetan con-ducted to evaluate the toxicity proﬁle and themaximum tolerated single dose that could beadministered to outpatients without the use ofstem cells or prophylactic growth factors. In theﬁrst trial, cold ibritumomab was used prior toibritumomab tiuxetan; the second trial used thehuman chimeric antibody rituximab which is thecomposition of the subsequently deﬁned Zevalin®protocol. The phase I trials determined that inpatients with a platelet count ³150×103platelets/mL (150,000), intravenous rituximab 250 mg/m2on days 1 and 8, and 0.4 mCi/kg of intravenous90Y-ibritumomab tiuxetan on day 8 was safe andeffective and did not require stem cell rescue.A 0.3 mCi/kg dose was shown to be safe forpatients with a baseline platelet count of 100,000–149,000. Adverse events were primarily hemato-logic. There was no normal organ toxicity. TheZevalin®protocol includes pretreatment withrituximab 1 week prior to infusion of a repeatrituximab infusion followed by the 90Y-labeledibritumomab tiuxetan. The initial randomizedcontrolled trial of Zevalin®radioimmunotherapyvs. rituximab immunotherapy for patients withrelapsed or refractory low-grade, follicular ortransformed B-cell NHL was reported in 2002.The ORR was 80% for 73 patients treated withZevalin®vs. 56% in 70 patients who receivedrituximab weekly for 4 weeks . The CR was30% vs. 16% and there were an additional 4%unconﬁrmed CRs in each group. The Duration ofResponse for Zevalin®was 14.2 months com-pared to 12.1 months for rituximab immunother-apy alone. None of the patients had previouslyreceived rituximab. Reversible myelosuppressionwasobservedintheZevalin®group.Subsequently,there was an additional report evaluating Zevalin®treatment in 57 patients who had not respondedto rituximab or who relapsed following rituximabtherapy in less than 6 months . The ORR was74 with 15% CR. The TTP was 8.7 months forthe responders. The incidence of grade 4 neutro-penia was 35%, thrombocytopenia 9% and ane-mia 4%. These ﬁndings became the basis for theinitial approval of Zevalin®as the ﬁrst radioim-munotherapeutic agent approved in the UnitedStates by the FDA f or the treatment of CD20+follicular low grade lymphoma.Emmanouilides et al. evaluated the responseto Zevalin®therapy in 211 patients in a multi-center trial when it was used after the ﬁrst relapsecompared to patients who had had two or moreprior therapies and relapses. 63 patients receivedZevalin®after one relapse and 148 patients (70%)had relapsed at least twice. Demographics of thetwo groups were otherwise similar except thatthere was higher rate of bone marrow involve-ment in the group who had had multiple bouts oftherapy and relapse. Overall, patients whoreceived Zevalin®after a single relapse responded
14 S.J. Goldsmithbetter than patients with multiple relapses. 51%of the follicular lymphoma patients and 49% ofthe entire group of patients including patientswith transformed B-cell NHL responded toZevalin®after their ﬁrst relapse with a medianTTP of 15.4 months and 12.6 months respectivelyvs. 28% CR regardless of the NHL diagnosis anda TTP of 9.2 and 7.9 months respectively if thepatients had relapsed more than once (Fig. 1.4).Data from several clinical trials involving sub-sequent treatment of patients with disease pro-gression following Zevalin®radioimmunotherapywere summarized byAnsell et al. . Subsequenttherapy varied from site to site and includedchemotherapy such as CHOP, CVP, and otheraggressive chemotherapeutic protocols, radiationtherapy, bioimmunotherapy, or autologous stemcell transplantation (ASCT). An ORR of 53% wasobtained in patients receiving chemotherapy.Ansell et al. compared the hematologic toxicity toretreatment with chemotherapy in 59 patients pre-viously treated with Zevalin®to a control group of60 age, gender, and histopathologically matchedpatients who had not received Zevalin®.There was no signiﬁcant difference between theZevalin®and control group in terms of grade 4cytopenia, neutropenic fever, number of hospital-izations for complications or requirement forGCSF or platelet transfusion. The recent course ofZevalin®with the attendant radiation exposure ofmarrow and transient depression of hematologicFig. 1.4 18F-ﬂuoro deoxy glucose PET coronal projec-tion (left) of a 54-year-old woman who was diagnosedwith Follicular non-Hodgkin’s lymphoma 5 years earlier;treated with traditional CHOP regimen with a completeresponse. Clinical relapse after 4½ years; received multi-ple infusions of rituximab with no response. 18FDG PETimaging 2 weeks prior to referral for radioimmunother-apy.Whole body planar image 48 h after 111In-ibritumomabtiuxetan infusion as initial component of Zevalin®regi-men. Patient was predosed with rituximab infusion as perprotocol and subsequently received 90Y-ibritumomab tiux-etan infusion. 111In-ibritumomab imaging is not requiredfor nonmyeloablative therapy in Europe and elsewhereandisnolongerrequiredintheUnitedStates.Nevertheless,it is a valuable tool to document the pattern of biodistribu-tion. In this instance, there is good correlation of111In-ibritumomab accumulation in the previously demon-strated FDG avid abdominal mass
151 Radioimmunotherapy of Lymphomaindices did not interfere with subsequent efforts toharvest stem cells. An adequate collection of stemcells was obtained in 7 of 8 patients who receivedgrowth factor mobilization in preparation forautotransplantation. In the eighth patient, directbone marrow sampling was necessary. In all 8patients, the subsequent transplant was successfulwith development of satisfactory blood indices. Inanother study, successful transplantation wasreported in 9 patients who had received Zevalin®,a median of 13.3 months previously.A 0.3 mCi/kg dose was shown to be safe forpatients with a baseline platelet count of 100,000–149,000. Adverse events were primarilyhematologic. There was no normal organ toxic-ity. The ORR was 67% for all NHL patients and82% in patients with low-grade NHLs. A subse-quent phase III trial randomized 143 patients toeither rituximab or ibritumomab tiuxetan. TheORR was 80% with the 90Y-ibritumomab tiuxetanprotocol vs. 56% for rituximab alone (p=0.002).Since the nonradioactive monoclonal antibodyhad become a key element in management ofpatients with NHL, another trial evaluatedZevalin®in 54 rituximab refractory patients. AnORR of 74% was found in these rituximab-refractory patients. Another trial evaluated 30patients in order to evaluate whether the reduceddose of 0.3 mCi/kg 90Y-ibritumomab tiuxetan inpatients with platelet counts <150,000 (but atleast 100,000 platelets) was as effective as the0.4 mCi/kg dose is in patients with platelets³150,000. The ORR was 83% .In summary, these data demonstrate thatZevalin®is an effective therapy with an ORR ofapproximately 80% and a CR of approximately30% in patients who are refractory to unlabeledantiCD20 immunotherapy and chemotherapy, orhave relapsed following these therapies. In the CRsubgroup, there is an impressive duration ofresponse. These results have been obtained withmanageable hematologic toxicity. The concernthat patients treated with Zevalin®will have severemarrow impairment rendering them ineligible forfurther therapy is not substantiated by the resultsof several studies comparing retreatment with che-motherapy, stem cell mobilization and successfulautotransplantation of Zevalin®treated patients tootherwise matched control groups .As stated, the basis for the initial FDAapprovalof the Zevalin®protocol in the United States andsubsequently throughout the European Union,are the studies that show a deﬁnite improvementin the ORR and CR in patients who were refrac-tory to rituximab in terms of relief from diseaseactivity or who had relapsed despite rituximabtherapy alone or in conjunction with chemother-apy. In 2009, a multicenter Phase III trial waspublished that demonstrated the efﬁcacy of theRituxin regimen as consolidation therapy afterpatients responded (CR or PR) to ﬁrst-linetherapy with a variety of chemotherapeutic agentsincluding CHOP, ﬂudarabine alone or in combi-nation with rituxin. These patients were random-ized to one of two groups: either the Controlgroup who received no additional therapy or theconsolidation group which involved the Zevalin®regimen (rituxin 250 mg/m2) on day minus 7 fol-lowed 7 days later by repeat rituxin infusion and14.8 MBq/kg of 90Y-ibritumomab tiuxetan. Thedemographic and clinical details of the twogroups were remarkably similar but the results interms of PFS were striking. The median TTP was36.5 months for the group who received Zevalin®vs. 13.3 months for the control group. Theseﬁndings had a p value of <0.0001. The resultswere even more impressive when the data wassegregated on the basis of whether the patient hadbeen categorized as a CR or PR prior to theConsolidation therapy. CR patients had a medianPFS of 53.9 months compared to the controlswith a PFS of 29.5 months. The PR patients hada PFS of 29.3 months if they received the consoli-dation protocol and only 6.2 months if they hadno further therapy (control group) . These arereally striking results and they support the con-clusion that even patients with a good response tothe initial therapeutic regimen will do better for amuch longer period if they receive radioimmuno-therapy even while in remission.Issues Relevant to Both Bexxar®and Zevalin®Despite the overall excellent results achievedwith Bexxar®and Zevalin®, hematologists andoncologists with clinical responsibilities for
16 S.J. Goldsmithpatient management have not utilized radioim-munotherapy as frequently as might be expected.In a national survey, it was conﬁrmed thathematologists and oncologists overall continue toharbor concern that the bone marrow radiationexposure associated with radioimmunotherapycompromises the bone marrow and puts thepatient at greater risk of adverse hematologicconsequences when the need arises for subse-quent chemotherapy . Nuclear medicinephysicians appear also to be somewhat reluctantto embrace radioimmunotherapy because of theperceived complexity of the procedure includingthe need to coordinate infusions and patient fol-low-up .The question frequently arises as which of thetwo therapeutic regimen is superior. There hasbeen no direct, side by side, randomized study ofthe relative efﬁcacy of these agents. The group atJohns Hopkins analyzed their experience in 38patients but reported results at only 12 weeks offollow-up. 20 received Zevalin®and 18 receivedBexxar®. Twenty-six of 38 patients receivedthe full dose of the particular regimen (plateletcount ³150,000); 12 received attenuated doses.There was no statistically signiﬁcant differencebetween the two groups but it would be difﬁcultto ascertain a difference between two relativelyeffective therapies when the groups studied wereso small. The ORR at 12 weeks was 47% and theCR 13% which are lower values than observed inother reports but the period of follow-up mayhave been too brief for this purpose also.Nevertheless, not surprisingly, the overall sur-vival was better amongst patients who respondedto either regimen (ORR vs. less than a partialresponse). Grade 3 or 4 thrombocytopenia wasobserved in 57 and 56% for Zevalin®and Bexxar®respectively. The percent decline in platelets was79% (±17%) following Zevalin®vs. 63% (±28%)for Bexxar®(p=0.04). The ANC nadir forZevalin®was 36 days±9 vs. 46±14 days(p=0.01) for Bexxar®.As summarized in this chapter, there are nowabundant reports of statistically impressive ORRsand CRs in patients with CD+NHL, both follicu-lar lymphoma and DLBCLD. These regimenswere initially used in standard of therapy-refractory patients, that is patients who had failedchemotherapy repeatedly even if in combinationwith rituximab and remain either symptomatic orhad evidence of impending clinical deterioration.In addition, both regimens have been employedas Consolidation Therapy; that is administeredfollowing an initial response to whatever chemo-therapeutic agent chosen for initial control of thesymptoms and the disease itself. Despite theexcellent results reported in the medical litera-ture, the issue of physician reluctance to utilizeeither Bexxar®or Zevalin®remains a concern tothose involved in delivering these apparentlyeffective therapeutics [27, 28].Clinical ProtocolsFor both Bexxar®and Zevalin®nonmyeloabla-tive regimens, there are several requirements foreligibility. These include histopathologicconﬁrmation of CD 20 expression on the tumorsample obtained at the time of diagnosis as wellas any subsequent tumor tissue that might havebecome available. Patients should have had arelatively recent (within 2–3 months) bone mar-row biopsy to conﬁrm that there is less than 25%bone marrow involvement. Twenty-ﬁve percentor greater percent bone marrow involvementresults in unacceptable incidence of Grade 4hematological toxicity. The approved use ofthese agents is for a so-called “nonmyeloabla-tive” regimen. Although when available, har-vested stem cells have been successfullyimplanted in patients who have had myeloabla-tive doses of radiolabeled antibodies, neitherBexxar®nor Zevalin®are currently approved forthat indication and insurance companies andgovernment will not approve reimbursement forthat indication.Both Bexxar®and Zevalin dose determinationis based upon the patients platelet count with fulldose (to be deﬁned) for patients with plateletsgreater than150,000 cells/mL and somewhatattenuated doses for patients with platelet countsbetween 100,000 and 150,000.In the Zevalin®protocol, the full90Y-ibritumomab tiuxetan dose for patients150,000 platelets/ml is 0.4 mCi/kg (30 MBq/kg)and 0.3 mCi/kg (22.5 MBq/kg) for patients with
171 Radioimmunotherapy of Lymphomaplatelets between 100,000 and 149,000/mL[21–23]. One week prior to the administration ofthe 90Y-ibritumomab tiuxetan dose, the patientreceives an infusion of 450 mg of rituximab. Thisinfusion is part of the Zevalin®protocol regard-less of whether or not the patient will also receivean imaging dose of 111In-ibritumomab tiuxetan.The 450 mg infusion of rituximab is repeated onthe day of the 90Y-ibritumomab tiuxetan infusion(0.4 mCi/kg) if platelets exceed 150,00; 0.3 mCiof platelets are below 150,000 but greater than100,000/mL.Bexxar® Clinical ProtocolPrior to beginning protocolMeet patient in consultationConﬁrm diagnosis and request to treat•Review clinical history and pertinent phys-•ical ﬁndings (if any)Including age, height, and weight–Conﬁrm histopathology report docu-–menting CD 20+ lymphomaConﬁrm recent bone marrow biopsy–(interval ﬂexible; 6–12 weeks at most)Conﬁrm most recent CBC, speciﬁcally–ANC >3500; platelets >100,000Review protocol with patient•Address radiation safety issues and•concernsObtain consent for radioimmunotherapy•Prescribe SSKI; three drops three times a•day; begin at least 24 h prior to ﬁrst dose of131I-labeled tositumomab; continue for atleast 1 week post treatment doseDay protocol beginsReview above details of bone marrow•biopsy, WBC count, platelet countAdminister Tylenol• ®and Benadryl®; beginIV saline infusion (keep open drip); utilize22 micron Millipore®ﬁlter; three way stop-cock to allow access to infusion withoutinterruption of infusionPharmacist brings “cold” and labeled•monoclonal antibody preparation to roomtemperaturePhysician or nurse conﬁrm good IV access•and ﬂow“Cold” infusion begins•Vital signs (heart rate; blood pressure)–are monitoredFollowing completion of “cold” infusion,•shielded pump with 131I-labeled tositu-momab is brought to infusion area. IVaccess conﬁrmed; all valve positionsconﬁrmed (open to pump infusion); con-nect to 3-way stopcock• 131I-labeled tositumomab infusion begins atrate 90 ml/min; usually completed in20 minConﬁrm delivery of radiolabeled antibody•with survey meterObserve patient for 30–60 min•Obtain whole body scan, anterior and pos-•terior projectionsPatient Returns at 48 h after initial infusionObtain whole body scan, anterior and pos-•terior projectionsPerform preliminary dosimetry calcula-•tion; order therapy dosePatient returns at 96–120 hObtain whole body scan, anterior and pos-•terior projectionsComplete dosimetry calculations and deter-•mination of dose to be administeredDay of radioimmunotherapy infusionPrepare dose to be administered•Begin IV infusion as on Day 0•Following: “cold” tositumomab infusion,•infuse 131I-labeled tositumomabMonitor patient for 30–60 min•Obtain radiation ﬂux at surface and 1 m•with survey meterComplete calculation of Radiation Safety•GuidelinesDischarge patient with guidance re: weeklyCBC including platelet count
18 S.J. GoldsmithBexxar®dosing is based upon whole bodyradiation absorbed dose as it was demonstratedthat both efﬁcacy and toxicity correlated betterwith the whole body radiation absorbed dose thanwith dosing based upon mCi/kg (or MBq/kg) [15,17, 18, 20]. The procedure to determine the131I-tositumomab dose to be administered in theBexxar protocol is described in detail in a recentreview . It involves administration of a rela-tivelysmallamount(5–6mCi)of131I-tositumomabafter infusion of 450 mg of “cold” tositumomab.A whole body scan is performed within an houror two and the geometric mean of the anteriorand posterior projections is determined to estab-lish the 100% value. This is followed at approxi-mately 48 h and again at 96–120 h. The geometricmeans of each pair of whole body scans is calcu-lated and expressed as a percent of the initialvalue. From these values, the Residence Timecan be determined using either a computer pro-gram provided by the distributor or performing asemilog plot vs. time. By convention, the resi-dence time is the 37% intercept of the semilogplot. All of the calculations of the product ofactivity and residence time which would result ina whole body radiation absorbed dose of 75 cGyhave been predetermined. The nuclear medicinephysician is provided with a table of activity timevalues for various patient weights. The activitytime value divided by the residence time yieldsthe dose to be administered. If it is preferred tolimit the whole body radiation absorbed dose to65 cGy (because of a platelet count less than150,000), the 131I-tositumomab dose is reducedby 65/75 or approximately 87% of the dose thatwould deliver 75 cGy.When Zevalin was initially introduced in theUnitedStates,a5–6mCidoseof111In-ibritumomabwas administered after the infusion of rituximab1 week prior to the therapeutic infusion. A wholebody scan is performed at approximately 48 h toconﬁrm biodistribution. During clinical trials, thewhole body scan of the 111In-ibritumomab wasperformed in order to determine the organ radia-tion absorbed dose. An instance of abnormalbiodistribution was observed during these trials.Consequently, FDAapproval continued to requirethis procedure until recently. The EU RegulatoryAgency did not require this imaging component;thus there was no need for the 111In-ibritumomabinfusion in the EU and other regions. Currently,this is no longer obligatory in the United Statesbut as of this writing, the 111In-ibritumomab con-tinues to be available albeit optional. However,since rituximab has some antitumor effects, inboth the United States and Europe, the initialrituximab infusion 1 week prior to the repeatrituximab and 90Y-ibritumomab tiuxetan contin-ues to be a component of the Zevalin®protocol. Itis not clear that this prior infusion of “cold” tosi-tumomab in the Bexxar®protocol or of rituximabin the Zevalin®protocol has any positive impacton the overall clinical response. Moreover,whereas it has been demonstrated the predosingwith “cold” antibody increases the plasma bio-logic half life of the labeled therapeutic dose,thereby increasing the quantity available to thetumor cells, it has been speculated that a non-patient-speciﬁc dose based upon tumor burdenmay decrease the total fraction of the dose deliv-ered to the tumor. It has been suggested that theremight be advantages to predosing with an anti-body to one anti-B cell CD followed by adminis-tration of a labeled monoclonal antibody directedtoward a different CD .Zevalin® Clinical ProtocolPrior to beginning protocolMeet patient in consultationConﬁrm diagnosis and request to treat•Review clinical history and pertinent•physical ﬁndings (if any)Including age, height, and weight–Conﬁrm histopathology report docu-–menting CD 20+ lymphomaConﬁrm recent bone marrow biopsy–(interval ﬂexible; 6–12 weeks at most)Conﬁrm most recent CBC,–speciﬁcally ANC >3500; platelets>100,000Review protocol with patient•(continued)
191 Radioimmunotherapy of LymphomaRadiation SafetyThe radionuclide component of Bexxar®is 131I,which emits both a beta particle and a gammaphoton. Gamma photons have greater penetrabil-ity in tissue and hence are more readily detectedexternally. The gamma emission makes possibleimaging and quantitation but the penetratingradiation also results in exposure of medicalpersonnel and family members of the patient fol-lowing release from the medical facility.During the infusion of the therapeutic dose,portable shielding should be available and inter-posed between the patient and medical personnel.During dose escalation trials in whichpatients received 25–129 mCi [1–5 GBq] of131I-tositumomab to deliver 30–75 cGy total bodydose, 26 family members from 22 differentpatients were provided monitoring devices thatwere worn for up to 17 days. The measuredradiation absorbed dose values were from 17 to409 mrem, well below the 500 mrem limit appli-cable to members of the general public . Inanother study with administered quantities of131I-tositumomab in a similar range, the medianradiation absorbed dose was 150 mrem. Prior torelease, patients are given a detailed printout pro-viding guidance on the duration and proximity toothers that would minimize exposure (Fig. 1.4).This guidance is based upon patient speciﬁc vari-ables such as the administered dose, the measuredemission from the patient at the body surface andat 1 m as well as the biologic turnover rateobtained from the dosimetry calculations.Harwood et al. monitored the whole bodyradiation exposure of 20 healthcare workers,radiopharmacists, nuclear medicine technolo-gists, nurses and physicians at four institutionsfor 2–4.5 years involving 300 administrations of131I-tositumomab . The additional mean radi-ation exposure/month per healthcare workerinvolved in administering Bexxar®therapy was5.8 mrem.The therapeutic radionuclide in the Zevalin®regimen is 90Y, a pure beta emitter without agamma emission. Brehmsstrahlung radiation isproduced as the beta particle looses energy as itreacts with its environment. It is readily detect-able externally and consequently also presentspotential radiation exposure of nearby personnel.TheexposureasaconsequenceofBrehmsstrahlungemission is far below the allowable exposure andnot hazardous to medical personnel or familymembers. Patients, nevertheless, should be reas-sured and provided with instruction about inti-macy and contact with family and friends . Ingeneral, patients are advised to avoid transmis-sion of body ﬂuids (saliva, blood, urine, seminalﬂuid and stool).(continued)Address radiation safety issues and•concernsObtain consent for radioimmunotherapy•Coordinate with referring physician•and/or infusion service as to whether“cold” infusion of rituximab is to beadminister in ofﬁce, infusion area ornuclear medicineDay protocol beginsReview above details of bone marrow•biopsy, WBC count, platelet countBased on whether “cold” infusion is to be•administered in Nuclear medicine orelsewhere, Tylenol®and Benadryl®areadministered; begin IV saline infusion(keep open drip); utilize 22 micronMillipore®ﬁlter; three way stopcock toallow access to infusion without interrup-tion of infusion“Cold” monoclonal antibody prepara-•tion at room temperature is infusedVital signs (heart rate; blood pressure)•are monitoredFollowing completion of “cold” infu-•sion, patient is moved to NuclearMedicine Infusion area; IV access isconﬁrmed or restartedIf• 111In is to be infused, connect appropri-atelyshieldedsyringetoIVaccess;admin-ister 111In labeled Ibritumomab tiuxetanby slow infusion (mechanical or manual)
20 S.J. GoldsmithEvolution of Radioimmunotherapyand Alternatives to Current Practice131I-RituximabBexxar®and Zevalin®were approved by the FDAin the United States in 2002. Shortly thereafter,Zevalin became available®in Western Europeand more recently in Israel and Eastern Europeannations. In many other areas, it remains unavail-able. In Perth, Australia, the inability to obtaineither Bexxar®or Zevalin®led a group led byProfessor Harvey Turner to develop an initiativeof their own. As stated earlier, rituximab, themurine–human chimeric anti-CD 20 monoclonalantibody, is widely available and is used as aimmunotherapeutic alone or in conjunction witha variety of chemotherapeutic regimen and is alsothe unlabeled component of the Zevalin®regi-men. Accordingly, Turner et al. undertook tolabel the readily available rituximab with 131I .Since immunoglobulins, like other proteins, aremore conveniently radio-iodinated (as opposed tocovalently linking a chelating moiety and subse-quently radiolabeling with a radiometal like 90Yor 177Lu), they performed in-house labeling with131I using the Chloramine-T®method and subse-quently purifying the labeled product. This prac-tice under the auspices of qualiﬁed physiciansand pharmacy personnel is authorized by thelocal regulatory authorities.To their credit, the Perth group recognized thatthe comparatively long physical half-life of 131Icould result in signiﬁcant variation in the wholebody radiation absorbed doses in patients receiv-ing therapeutic doses of the 131I-labeled rituximabbecause of the variable biologic half-life of thelabeled antibody. To control the total body radia-tion absorbed dose, they designed a protocol forthis “hybrid radio-immunotherapeutic” whichuses the unlabeled antibody in the Zevalin®pro-tocol as the “cold” antibody component andlabeling this “cold” antibody with 131I, the radio-nuclide used in the Bexxar®regimen, similar tothe protocol used in determining Bexxar®doses. With this hybrid regimen, the safety andefﬁcacy of the 131I-rituximab and rituximab wasdemonstrated in 91 patients. 86% of the patientshad follicular NHL, 7% had mucosal-associatedlymphoid tissue (MALT) and 8% had small lym-phocytic lymphoma. The ORR was 76% and theCR was 53%. Median PFS for all patients was 23months. Median overall survival exceeded4 years. Grade 4 thrombocytopenia was observedin 4% and neutropenia in 16% at 6–7 weeks. Thisprotocol and careful observation of the clinicalresponse is on-going.Anti-CD 22 (90Y-Epratuzumab)Although CD 20 is frequently expressed on thetwo most common B-cell NHLs (follicular low-grade lymphoma and DLBCL), other CDs arecommonly expressed also. Goldenberg et al.elected to evaluate the potential utility of an anti-CD 22 antibody. This domain had previouslybeen characterized as LL2. Initially, the murineanti-CD 22 was iodinated. In contrast to the anti-CD 20 monoclonal antibody, the antibody-CD 22complex is internalized after binding resulting inintracellular metabolism of the complex withreleaseofsolubleiodinatedproducts.Accordingly,the group pursued development of a reliablelinker moiety which would allow the use of aradiometal such as 90Y for therapeutic purposesand 111In for imaging, biodistribution and dosim-etry calculations. They demonstrated that amodiﬁed DTPA moiety, DOTA (1, 4, 7, 10-tetraaza cyclododecane-N,N,N",N"-tetra acetic acid)chelated radiometals effectively and provided astable molecule with minimal release of theradiometal resulting in an excellent safety proﬁlein terms of intratumoral retention of radioactivityand virtually no free radiometal with subsequentreticulo-endothelial bone marrow localization. Inaddition, since it was speculated that fractionateddose administration would allow for a greatertotal dose of radioactivity to be administered andsubsequently delivered to tumor cells, it wasdecided to alter the immunoglobulin to produce ahumanized version (named Epratuzumab) inorder to reduce the likelihood of developing anti-antibody antibodies (HAMA) which would beexpected with repeated administrations of murine
211 Radioimmunotherapy of Lymphomaantibody . Epratuzumab was shown to beeffective as a “cold” antibody in patients withindolent NHL .In a study of fractionated 90Y-epratuzumab asa radiotherapeutic agent, patients were dividedinto two groups: patients who had previouslyreceived high dose chemotherapy requiringASCT and patients who had not had prior ASCT. All patients received a pretherapy imagingdose of 111In-epratuzumab. Plasma kinetics of the111In- and 90Y-labeled version of the antibodywere similar; 70% of the conﬁrmed lesionswere identiﬁed on 111In scintigraphy. Heavilypretreated patients received 5 mCi/kg (185 MBq/kg) of 90Y-Epratuzumab and patients who had notundergone ASCT received 10 mCi/kg (370 MBq/kg). Six weeks later if the hematologicdepression had recovered, patients received addi-tional 5 mCi/kg 90Y-epratuzumab infusions.Hematologic toxicity was manageable with theusual supportive measures. Tumor radiationabsorbed doses were calculated. Many tumors inpatients with indolent and patients with aggres-sive disease responded .Subsequently, a single center study was per-formed using once weekly infusions of 5 mCi(or185 MBq)/kg of 90Y-Epratuzumab . Onlyminor toxicity was observed after three infusionsbut a fourth was not tolerated with 2 of 3 patientsexperiencing dose-limiting toxicity. In 16patients, the ORR was 62%. Amongst patientswith indolent NHL, the ORR was 75% and inpatients with aggressive disease, the ORR was50%. CR was achieved in 25% of the patients. Inthis group, the event-free survival was from 14 to41 months. Half of the patients experienced along duration of response than they had follow-ing their previous therapy.In 2010, a multicenter fractionated dose esca-lation (Phase I/II) study of 90Y-Epratuzumab wasreported. Sixty-four patients with relapsed orrefractory NHL were evaluated including 17patients who had undergone prior ASCT. At totalcumulative doses up to 45 mCi (1,665 MBq)/m2,grade 3 or 4 hematologic toxicity was observedbut was manageable in patients with less than25% bone marrow involvement. Hence, goingforward, unless ASCT were available, patientswith >25% bone marrow involvement would notbe eligible for radioimmunotherapy with thisagent—not dissimilar to eligibility criteria forBexxar®and Zevalin®. The ORR for 61 patientswas 62% with a median PFS of 9.5 months.Forty-eight percent of the patients achieved CRs.Patients who had not progressed prior to the pro-tocol to the point where they had required therapynecessitating ASCT had an ORR of 71 with 55%CR even if they had been refractory to their previ-ous anti-CD 20 containing therapy.For patients with indolent follicular lym-phoma, the ORR was 100% with CR of 92% anda PFS of 18.3 months. The authors proposeadditional trials identifying 20 mCi/m2×2,1 week apart as a tolerable dose level with impres-sive results. Since patients who were refractory toanti-CD 20 protocols responded to this anti-CD22 radiolabeled monoclonal antibody, they sug-gest that it might be possible and efﬁcacious toutilize combinations of anti-CD 20 and anti-CD22 antibodies [37, 38].Myeloablative Clinical TrialsSince it is not uncommon for many patients witha variety of malignant tumors including NHL,multiple myeloma and the leukemias to undergostem cell harvesting followed by intensive che-motherapy and ASCT, it is somewhat surprisingthat, in general, the notion of ASCT as a compo-nent of high-dose radioimmunotherapy has notbeen pursued more vigorously or by more medi-calcentersinvolvedinthemanagementofpatientswith life threatening malignancies. Nevertheless,a few studies deserve review.131I-Tositumomab and TositumomabOliver Press and his colleagues at the Universityof Washington and the Fred Hutchinson CancerResearch Center in Seattle noted that althoughnonmyeloablative radioimmunotherapy achievedobjective responses in a variety of hematologicmalignancies, there was a steep dose–responsecurve and concluded that higher, myeloablative
22 S.J. Goldsmithradioimmunotherapy followed by ASCT mightbe beneﬁcial to patients who appeared to berefractory to more conservative therapy [39–41].In 1998, they provided a long term follow-upreport on a group of 29 patients who has receivedhigh doses of 131I-tositumomab accompanied byunlabeled tositumomab to provide optimal biodis-tribution. Organ radiation absorbed doses werecalculated since there was concern that althoughASCT and other measures would provide supportfor the hematologic toxicity, it was necessary toidentify and avoid if possible secondary organtoxicity.Doses of the 131I-tositumomab range from 280to 785 mCi (10.4–29 GBq). Major responseswere observed in 25 patients (86%); CR in 23(79%) complete responses (CRs; 79%). At amedian follow-up of 42 months, the overall sur-vival was 68% and the PFS was 42%. Fourteen ofthe initial group of 29 patients remain asymptom-atic without interval therapy and the duration ofthis apparently disease-free interval was from 27to 87 months. Two patients experienced cardio-pulmonary insufﬁciency but responded to sup-portive measures. The radiation absorbed dose totheir lungs was calculated to be ³27 Gy. The onlylate toxicity was elevated TSH which is readilymanageable. There were no instances of myelo-dysplasia .Several conclusions can be drawn from thisdata. First, myeloablative therapy is effective,and it is likely more effective with a longerdisease-free interval than nonmyeloablative ther-apy. Second, with the availability of ASCT, thehematologic consequences of this approach aremanageable. Third, it is likely that relativelydetailed organ dosimtery would be a necessarycomponent of myeloablative therapy so as toavoid secondary organ life-threatening toxicity[40, 41].90Y-Ibritumomab and RituximabA dose escalation and preliminary efﬁcacy studyusing essentially the Zevalin®protocol exceptthat organ dosimetry was determined from theinitial 111In-ibritumomab tiuxetan whole bodyimages in order to determine a subsequent doseof 90Y-ibritumomab tiuxetan that would notexceed 1,000 cGy to the highest normal organ.90Y-ibritumomab tiuxetan doses in the order of37–105 mCi were subsequently administered to31 patients; 12 with the diagnosis of follicularlymphoma, 14 with DLBCL, and 5 with Mantlecell lymphoma. The median number of prior che-motherapy treatments was two. Ten days follow-ing the 90Y-ibritumomab tiuxetan, the patientsreceived high dose eptoposide followed by cyclo-phosphomide. ASCT was performed 2 days fol-lowing completion of the chemotherapycomponent and approximately 14 days after the90Y-ibritumomab tiuxetan infusion . With amedian follow-up of 22 months, there was anestimated 2 year overall survival rate of 92% andrelapse-free survival of 78%. There were 2 deathsand 5 relapses.More recently, another clinical trial was initi-ated in the European Institute of Oncology inMilan, Italy. Although the results of the trial havenot yet been reported, as with the above study,individual organ dosimetry was performed inorder to avoid delivering excessive potentiallytoxic or lethal radiation absorbed doses to organsthat cannot be replaced as conveniently as bonemarrow. In 2 patients, the investigators observedabnormal biodistribution with increased hepaticextraction that would have resulted in a radiationabsorbed dose to the liver far in excess of the20 Gy limit that had been set as an upper safelimit. The presence of HAMA was subsequentlyidentiﬁed in one of the patients and is probablythe basis for the rapid and increased hepaticextraction. In the other patient, no basis for theabnormal localization could be identiﬁed .This report conﬁrms the important role of organdosimetry in the event the ﬁeld of radioimmuno-therapy moves on to myeloablative protocols. Italso calls into question the decision by the EUregulators and more recently by the FDA that it isnot necessary to administer the 111In-componentof the Zevalin®protocol or to perform wholebody scans of the 111In-ibritumomab tiuxetanbiodistribution. In nonmyeloablative protocolsusing 90Y doses of 0.3–0.4 mCi/kg, abnormalbiodistribution is likely not going to result in
231 Radioimmunotherapy of Lymphomaorgan toxicity, neither is it going to allow tumorirradiation at the levels prescribed or expected inZevalin®therapy.SummaryBexxar®and Zevalin®are approved by regulatoryagencies, government and private health insur-ance companies in the United States and Canadafor the treatment of patients with follicular, lowgrade NHL. They produce signiﬁcant improve-ment and at times eliminate evidence of lym-phoma completely (complete response) for manymonths to several years. Patients with partialresponses may also remain symptom-free forlong periods of time and depending upon the cri-teria used to evaluate the response may actuallyhave had complete elimination of lymphoma butinadequate CT resolution. In this regard, therecent availability of 18F-FluorodeoxygluconePET/CT is apt to make evaluation of responsesmore reliable.Radioimmunotherapy regimens were initiallyapproved for the treatment of low grade, CD 20+NHL patients who had relapsed or were refrac-tory to previous treatment. Excellent results havebeen obtained also when these agents have beenused earlier in the course of disease managementfor example as part of initial treatment. ORRs ofover 80% to almost 100% have been observed invarious studies. In addition, high grade DLBCLswhich are CD 20+ have shown excellent responseto the anti-CD 20 radiolabeled monoclonalantibodies.In recent years, other innovative solutionssuch as 131I-rituximab therapy and novel immu-noglobulins directed to CDs other than CD 20have had impressive results and deserve moreattention.The role of other immunoglobulins, the pos-sible role of combinations of immunoglobulinsas well as combinations of radionuclides is still tobe explored.Despite the considerable successes to date,many patients have been denied access to theseregimen as well as the newer experimental modal-ities because of lack of enthusiasm which is aresult of the lack of understanding of the features,safety and merits of radioimmunotherapy—evenfor the treatment of NHL, an application that hashad the most success when given an opportunityto treat disease and relieve suffering.Future DirectionsSeveral potential future directions are possible,some of which have been alluded to throughoutthe text. These include:Greater utilization of Bexxar• ®and Zevalin®.Development and utilization of immunoglob-•ulins to CDs other than CD 20.Investigation of combinations of•immunoglobulins.Evaluation of other potential radionuclides,•viz., 177Lu, alpha particle emitters.Investigation of combination of radionuclides.•Myeloablative protocols.•Alternative antibody constructs:•Bispeciﬁc antibodies.–Antibody fragments, diabodies, etc.–Hopefully, future volumes integrating theexperience and practice of radioimmunotherapywill see some of these potential “future direc-tions” realized.Acknowledgments The author expresses gratitude andappreciation to the staff of the Division of NuclearMedicine & Molecular Imaging in the Department ofRadiology at the New York Presbyterian Hospital/WeillCornell Medical Center for their support and assistance inthe clinical investigations and clinical practice of radioim-munotherapy of non-Hodgkin’s Lymphoma. In particular,I am grateful to Morton Coleman, MD, ShankarVallabhajosula, PhD, John Leonard, MD, and VasiliosAvlonitis, RPh, for their support during the period inwhich we worked together to understand and improve theprinciples and practice of radioimmunotherapy and tomake this therapy available to patients with non-Hodgkin’slymphoma.References1. Cancer statistics, NHL SEER Fact Sheets. NationalCancer Institute, 2012, USNIH. www.cancer.gov.2. Shipp MA, Mauch PM, Harris NL. Non-Hodgkin’slymphomas. In: DeVita VT, Hellman S, Rosenberg
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