PRACTICE GUIDELINE SERIES

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1 PRACTICE GUIDELINE SERIES 131 I Tositumom in lymphom M.C. Cheung MD,* J.A. McEchern MD,* A.E. Hynes,* R.M. Meyer MD,* K. Imrie md* nd the Memers of the Hemtology Disese Site Group # of Cncer Cre Ontrio s Progrm in Evidence-Bsed Cre ABSTRACT Rdioimmunoconjugtes re rdioisotope-ound monoclonl ntiodies tht trget rdition specificlly to sites of lymphom involvement. Initil studies of 131 I tositumom in non-hodgkin lymphom (nhl) hve suggested enefit in ptients with relpsed or refrctory indolent disese. However, the routine doption of this gent is tempered y concerns out ssocited toxicities nd uncler long-term enefit. Bsed on comprehensive serch for studies on 131 I tositumom use in lymphom, this systemtic review summrizes nd evlutes the evidence on the enefits nd risks of this novel therpy, the predictors for response nd toxicity, nd the role of dosimetry nd imging studies efore tretment. We identified 18 trils investigting the use of 131 I tositumom for the tretment of dult ptients with nhl. In trils of ptients with relpsed or refrctory indolent nhl, overll response rtes rnged from The Progrm in Evidence-Bsed Cre is supported y the Ontrio Ministry of Helth nd Long-Term Cre through Cncer Cre Ontrio. The Progrm in Evidence-Bsed Cre is editorilly independent of Cncer Cre Ontrio nd the Ontrio Ministry of Helth nd Long-Term Cre. 67% to 83%. In ptients with folliculr nhl refrctory to the monoclonl ntiody rituxim, response rtes remined high (65% 72%). However, in rituximnïve ptients with relpsed or refrctory indolent or trnsformed nhl, improvements in time to progression or survivl hve not een clerly estlished. 131 I Tositumom is n ctive gent in relpsed nd refrctory non-hodgkin lymphom tht should e considered in selected ptients. KEY WORDS 131 I Tositumom, Bexxr, indolent lymphom, systemtic review 1. INTRODUCTION Non-Hodgkin lymphoms (nhls) constitute heterogeneous group of mlignncies with vrile presenttions tht rnge from indolent to ggressive 1. Ptients with folliculr nd other indolent lymphoms cn sustin prolonged remission periods, ut they eventully relpse nd require susequent courses of therpy tht led to fewer nd shorter remissions 2. Novel tretment options re necessry to improve the nturl history of this condition. Rituxim is chimeric monoclonl ntiody directed ginst the CD20 surfce ntigen found on most B-cell lymphoms 3. Although rituxim represents n importnt dvnce in indolent disese ecuse of its efficcy, short durtion of therpy, nd cceptle toxicity profile 4, relpse remins inevitle. Therpies tht re more effective re thus needed for ptients who re refrctory to or who relpse fter currently ville tretments, including rituxim. Rdioimmunoconjugtes re monoclonl ntiodies ound to rdioisotopes, nd this emerging clss of 32 Copyright 2009 Multimed Inc.

2 CHEUNG et l. gents hs ctivity in lymphom. These gents llow for the delivery of trgeted rdition therpy with the inding of the monoclonl ntiody to ntigens on the surfce of mlignnt cells. 131 I Tositumom (Bexxr: Corix Corportion, South Sn Frncisco, CA, nd GlxoSmithKline, Phildelphi, PA, U.S.A.) is rdioimmunoconjugte consisting of n nti- CD20 murine monoclonl ntiody (tositumom) covlently ound to the gmm-emitting rdioctive isotope 131 I 5,6. Initil studies hve reported on the use of 131 I tositumom in ptients with refrctory or relpsed low-grde, folliculr, or trnsformed lymphom. Further reserch is exploring the role of this compound in other settings, including in ptients with ggressivehistology lymphoms nd in the setting of stem-cell trnsplnttion. However, the routine doption of this gent is tempered y concerns out incresed costs, complex dosimetry requirements, nd possile toxicities. With the recent vilility of rdioimmunoconjugtes, creful review of the risks nd enefits of such therpy is wrrnted. The im of the present systemtic review is to ddress the following questions in ptients with lymphom of ny type or stge: Wht re the enefits ssocited with tretment with 131 I tositumom? Wht re the toxicities ssocited with the use of 131 I tositumom? Which ptients re more or less likely to enefit from tretment with 131 I tositumom? Is imging or dosimetry required for therpy to e sfe nd effective? 2. MATERIALS AND METHODS The methodology guiding this systemtic review ws developed y the Cncer Cre Ontrio (cco) Progrm in Evidence-Bsed Cre (pec) ccording to the prctice guidelines development cycle 7. Memers of the pec Hemtology Disese Site Group (dsg) selected, reviewed, nd interpreted the evidence. The Hemtology dsg hs 25 memers, including hemtologists, medicl nd rdition oncologists, n epidemiologist, nd two ly representtives. 2.1 Literture Serch We serched the medline (1966 to July 2005), emse (1980 to July 2005), nd Cochrne Lirry (2005, Issue 3) dtses using the serch strtegy shown in Tle i. In ddition, we serched the conference proceedings of the Americn Society of Hemtology (sh) for 2000 to 2004 nd those of the Americn Society of Clinicl Oncology (sco) for 2000 to Reference lists of relevnt trils nd reviews were serched for dditionl pulictions. In ddition, the uthors serched their personl files. The Cndin Medicl Assocition Infose (mdm.c/cpgsnew/cpgs/index.sp), the Ntionl Guidelines Cleringhouse ( tle i Step Literture serch strtegy nd the U.K. Ntionl Institute for Helth nd Clinicl Excellence ( were lso serched for existing evidence-sed prctice guidelines. 2.2 Inclusion Criteri Serch term 1 zevlin.mp. 2 iritumom tiuxetn.mp. 3 nti-cd20.mp. 4 nticd20.mp. 5 nticd-20.mp. 6 idec-y28.mp. 7 idecy28.mp. 8 idec-28.mp. 9 idec28.mp. 10 idec-in28.mp. 11 idecin28.mp. 12 idec-129.mp. 13 idec129.mp. 14 or/ lymphom.mp. 16 exp lymphom/ 17 exp lymphom, lrge-cell/ 18 or/ nd limit 19 to humn 21 limit 20 to English lnguge 22 comment.pt. 23 letter.pt. 24 editoril.pt. 25 or/ not 25 c not not 25 d Included in the originl literture serch (July 2003). Included in the My 2004 literture serch. c Results for cittions in the English lnguge. Rndomized controlled trils, other comprtive trils, prospective single-rm trils, systemtic reviews (with or without met-nlyses), nd evidence-sed prctice guidelines were considered for this review of the evidence if they met the following criteri: Study of dult ptients with lymphom of ny type, t ny stge, nd for ny performnce sttus 131 I Tositumom studied s single gent or in comintion with other regimens Results reported for one or more of the following outcomes: survivl, qulity of life (qol), time to progression (ttp), response durtion, response rte, dverse effects, tumour dosimetry or imging Report pulished in English 33

3 PRACTICE GUIDELINE SERIES Letters, comments, nd editoril pulictions were excluded. Conference strcts tht preceded full-pper finl results were not included; however, strcts tht provided updted results or novel dt were included for further dt strction. 2.3 Dt Extrction nd Interprettive Summry Relevnt rticles nd strcts were selected in n unlinded mnner independently y two memers of the Hemtology dsg. Dt were extrcted nd summrized to ddress the following questions regrding dult ptients with lymphom of ny type, t ny stge, nd for ny performnce sttus: Is 131 I tositumom effective in improving survivl, qol, ttp, response durtion, or response rte? Wht re the toxicities ssocited with the use of 131 I tositumom? Which ptients re more or less likely to enefit from tretment with 131 I tositumom? Is imging or dosimetry required for therpy to e sfe nd effective? The nlysis of the dt uses descriptive sttistics. Ctegoricl vriles re reported s numers nd proportions, nd continuous dt re reported s mens nd stndrd devitions. The heterogeneity mong studies precluded ny pooling of results using forml met-nlytic techniques. 3. RESULTS We identified 255 cittions in the literture serches of medline, emse, nd the Cochrne Lirry, including twenty-one full pulictions of eleven trils. Eleven strcts of seven trils were identified from the conference proceedings of sh nd sco. One dditionl strct ws identified tht provided qol dt tht were not reported in the relevnt full puliction. Only the most recent strct or full puliction ws referenced for ech tril, except where dditionl dt were ville in previous pulictions (Tle ii ). In totl, this systemtic review includes eighteen trils investigting the use of 131 I tositumom for the tretment of dult ptients with nhl. No systemtic reviews, met-nlyses, or evidence-sed prctice guidelines were identified. We divided the trils into two ctegories sed on ptient tretment history: previously untreted 25,27,29,31,35 nd previously treted ptients with nhl. The previously treted ctegory ws further divided into rndomized 22 nd single-rm trils of 131 I tositumom. The single-rm trils included reports of ptients with disese relpsed or refrctory to chemotherpy without prior rituxim 5,8,11,12,19,28 ; disese relpsed or refrctory to rituxim lone 34,39 ; disese treted with 131 I tositumom conditioning Also see Appendix, which descries n updte to the originl serch nd the rticles locted s result. tle ii Primry nd dditionl pulictions of trils included in this systemtic review Primry puliction Pulictions with dditionl informtion Press et l., Liu et l., Gopl et l., Press et l., Liu et l., Gopl et l., Kminski et l., Kminski et l., Kminski et l., Whl et l., Bennet et l., Press et l., Gopl et l., Vose et l., Kminski et l., Sgouros et l., Bennet et l., Kminski et l., Kminski et l., Sgouros et l., Bennet et l., Dvis et l., Bennet et l., Kminski et l., Kminski et l., , Press et l., Press et l., , Zelenetz et l., Dvies et l., None None Leonrd et l., Leonrd et l., , Link et l., None Mones et l., Mones et l., , Horning et l., Bennet et l., Kminski et l., Korl et l., Nir et l., Vose et l., Korl et l., Korl et l., Korl et l., Bennet et l., None None See Appendix for detils regrding this puliction. for utologous stem-cell trnsplnttion (sct) 17,40 ; nd disese treted with 131 I tositumom in lterntive regimens or lterntive popultions of previously treted ptients 23, Ptients with Previously Treted NHL Study Qulity Only one of the thirteen trils of 131 I tositumom in ptients with previously treted nhl ws rndomized 34

4 CHEUNG et l. controlled tril 22. Tht tril hs een pulished in strct form only, nd therefore little informtion regrding study qulity ws reported. However, the uthors did report tht the tril ws multicentred nd open-lel. The 78 study ptients were rndomized either to 131 I tositumom or to unlelled tositumom nd were followed for medin of 42.6 months. No smple-size clcultion ws provided. One single-rm tril, reported s full puliction y Kminski et l. 5, compred ech ptient s durtion of response fter 131 I tositumom with the durtion of response to their lst qulifying chemotherpy regimen ( pired control ). The remining studies were single-rm noncomprtive phse i or ii trils. Eight of those trils 5,8,11,12,17,19,22,28,34,40 hve een fully pulished, with smple sizes rnging from 11 ptients to 60 ptients. The remining three trils 23,32,39 hve een pulished in strct form only, with smple sizes rnging from 11 ptients to 32 ptients. Eight of twelve single-rm trils reported medin follow-up times tht rnged from 12 months 11 to 39 months Study Chrcteristics Tle iii presents study nd ptient chrcteristics for the trils of 131 I tositumom in ptients with previously treted nhl. The rndomized tril reported y Dvis et l. 22 included ptients with CD20+ nhl tht ws relpsed or refrctory (defined s progression within 1 yer of tretment) to regimen contining either n nthrcycline, n nthrcenedione, or n lkylting gent. Ptients were rndomized to either 131 I tositumom (n = 42) or to unlelled tositumom (n = 36). Ptients who did not respond to unlelled tositumom could cross over to the 131 I tositumom rm if they did not hve humn nti-mouse ntiody (hm) response. The uthors did not report the doses given to ptients in either rm. Ptient chrcteristics were well mtched etween the two tretment rms. Six of the single-rm trils enrolled ptients with nhl tht ws relpsed or refrctory to chemotherpy without rituxim: one phse i dose-escltion tril 8, one phse i/ii dose-escltion tril 12, nd four phse ii trils 5,11,19,28. One of the phse ii trils used ech ptient s self pired control for compring the durtion of response to 131 I tositumom with the durtion of response in the ptient s lst qulifying chemotherpy regimen 5. The phse i tril reported y Press et l. 8 ws dose-escltion study tht provided seprte outcomes dt for the 12 ptients who received therpeutic doses of 131 I tositumom. Gopl et l. 10 reported study tht compred ptients in sequentil trils reported y Press et l. 22,27 (tretment group, n = 27) with historicl control group of ptients who received conventionl high-dose therpy nd sct (control group, n = 98). Two single-rm phse ii trils enrolled ptients with nhl relpsed or refrctory to rituxim, with or without chemotherpy. The first tril, reported y Horning et l. 34 included ptients who were relpsed or refrctory to rituxim. Nir et l. 39 reported tril tht enrolled ptients with CD20+ nhl refrctory to chemotherpy nd rituxim. Two single-rm phse i dose escltion trils treted ptients who hd chemotherpy-resistnt nhl with regimen including 131 I tositumom conditioning for sct 17,40. Mones et l. 32 reported the results of phse i tril tht enrolled ptients who hd relpsed or refrctory low-grde nhl nd more thn 25% one mrrow involvement. The first cohort of ptients received 131 I tositumom t totl ody dose of 45 cgy, with incrementl increses of 10 cgy for susequent cohorts. Four of the single-rm trils reported sugroup dt for ptients with trnsformed nhl 5,12,19,28. Three dditionl trils 17,23,34 reported tht 12% 23% of enrolled ptients hd trnsformed nhl, ut they did not provide outcomes dt for tht sugroup of ptients. An integrted pooled nlysis of five of these studies 5,12,19,28,34 reported outcomes unique to this sugroup of ptients 43,44,45. In this popultion of 71 evlule ptients with trnsformed nhl, the medin time from dignosis to therpy ws 74 months, nd the medin time from trnsformtion ws 21 months Response Rte In previously treted ptients, ojective response rtes rnged from 85% to 100%, with complete response (cr) rtes of 20% 84% 5,8,11,12,17,19,22,23,28,32,34,39,40 (Tle iv). In the rndomized tril 22, sttisticlly significnt difference ws oserved in ojective response etween the 131 I tositumom group nd the unlelled tositumom group (55% vs. 19%), with cr rtes of 33% versus 8% (sttisticl significnce not reported). Response rtes in rituxim-nïve ptients rnged from 57% 19 to 100% 8 with cr rtes from 20% 5 to 83% 8. Response to 131 I tositumom ppered to compre fvourly with the response to the preceding line of therpy (chemotherpy lone) 5. For ptients tht hd relpsed fter or were refrctory to rituxim (with or without chemotherpy), response rtes were 65% 34 nd 72% 39 respectively. The response rtes were 65% 40 nd 87% 17 in the trils tht treted ptients with 131 I tositumom s prt of multi-gent chemotherpy conditioning for sct, with cr rtes of 57% 40 nd 77% 17. One tril treted ptients with more thn 25% one mrrow involvement ( reltive contrindiction to the use of 131 I tositumom) nd oserved n ojective response rte of 18% in 11 ptients 32. A pooled nlysis of five trils 43,44,45 provided response dt for the sugroup of ptients with trnsformed nhl. A pooled response rte of 39% with cr rte of 25% ws reported Time to Progression In previously treted ptients, ttp dt were reported for ten trils (Tle iv). One rndomized tril 22 reported tht medin ttp ws longer in the 131 I tositumom 35

5 PRACTICE GUIDELINE SERIES tle iii Trils of 131 I tositumom ( 131 it) in ptients with previously treted non-hodgkin lymphom (nhl): study chrcteristics Reference Study type Ptient chrcteristics Intervention Pts (n) Relpsed or refrctory to chemotherpy without rituxim Press et l., Single-rm CD20+ or CD37+ B-cell nhl 131 it phse i [totl ody dose: Gy 12 unresponsive to conventionl systemic therpy (dose escltion)], utologous stem cell trnsplnttion if needed Press et l., Single-rm CD20+ nhl relpsed fter 131 it (totl ody dose: cgy), utologous stem cell 25 t lest one chemotherpy regimen trnsplnttion or peripherl stem cell trnsplnttion if needed Kminski et l., Single-rm Relpsed or refrctory CD20+ B-cell nhl 131 it phse i/ii (phse ii totl ody dose: 75 cgy) 59 Vose et l., Single-rm Low-grde or trnsformed low-grde CD20+ nhl 131 it (totl ody dose: 75 cgy, 47 relpsed or refrctory to t lest one nthrcycline- or 65 cgy if pltelets 149,000/mm 3 ) nthrcenedione-contining chemotherpy regimen Kminski, Single-rm Low-grde or trnsformed low-grde CD20+ B-cell 131 it (totl ody dose: 75 cgy, 60 nhl relpsed or refrctory fter t lest two prior 65 cgy if pltelets < 150,000/mm 3 ) chemotherpy regimens Dvis et l., Rndomized Relpsed or refrctory CD20+ nhl 131 it (totl ody dose: nr) Unlelled tositumom Dvies et l., Single-rm B-Cell nhl in first or second recurrence 131 it (totl ody dose: 75 cgy, 65 cgy if pltelets 149,000/mm 3 ) 44 Relpsed or refrctory to rituxim with or without chemotherpy Horning et l., Single-rm Indolent or trnsformed nhl 131 it (totl ody dose: 75 cgy, 43 relpsed or refrctory to rituxim 65 cgy if pltelets < 150,000/mm 3 ) Nir et l., Single-rm CD20+ nhl refrctory to chemotherpy plus rituxim 131 it (totl ody dose: 75 cgy, 65 cgy if pltelets < 150,000/mm 3 ) it conditioning for utologous stem cell trnsplnttion Press et l., Single-rm CD20+ nhl relpsed or refrctory to previous 131 it [totl ody dose: Gy (dose escltion)], 52 chemotherpy, one mrrow involvement < 25% followed y etoposide (60 mg/kg), plus cyclophosphmide (100 mg/kg), plus utologous stem cell trnsplnttion Vose et l., Single-rm Previously treted chemotherpy-resistnt 131 it [totl ody dose: cgy (dose escltion)], followed y 23 CD20+ ggressive nhl em (crmustine 300 mg/m 2 dy 1; plus etoposide 100 mg/m 2 twice dily, dys 2 5; plus cytrine 100 mg/m 2 twice dily, dys 2 5; plus melphln 140 mg/m 2 dy 6), plus utologous stem cell trnsplnttion (dy 7) 131 it in lterntive regimens Kminski et l., Single-rm Low-grde or trnsformed low-grde nhl 131 it phse i previously treted with 131 it (totl ody dose: nr) Mones et l., Single-rm Relpsed or refrctory low-grde nhl, 131 it phse i [totl ody dose: 45cGy 11 one mrrow involvement > 25% (10 cgy dose-escltion increments)] Rndomized or enrolled/eligile. Of the 43 enrolled ptients, 19 received therpeutic doses, nd only 12 of the 19 received 131 it. Pts = ptients; nr = not reported. 36

6 CHEUNG et l. tle iv Trils of 131 I tositumom ( 131 it) in ptients with previously treted non-hodgkin lymphom: response nd survivl Reference Study Intervention Pts or cr Medin results (months) for type (n) (%) (%) ttp Response durtion os Follow-up Relpsed or refrctory to chemotherpy without rituxim Press et l., Single-rm 131 it phse i nr [totl ody dose: Gy (dose escltion)] Press et l., Single-rm 131 it (totl ody dose: 27 Gy) 21 c Not yet reched nr Not yet reched 12 Kminski et l., Single-rm 131 it phse i/ii nr 41 d 37.2 (phse ii totl ody dose: 75 cgy) Vose et l., Single-rm 131 it (totl ody dose: 75 cgy, nr 65 cgy if pltelets 149,000/mm 3 ) Kminski et l., Single-rm 131 it (totl ody dose: 75 cgy, nr 65cGy if pltelets < 150,000/mm 3 ) Dvis et l., Rndomized 131 it (totl ody dose: nr) Not yet reched nr 42.6 Unlelled tositumom nr p=0.002 p=0.031 Dvies et l., Single-rm 131 it (totl ody dose: 75 cgy, 41 e Not yet reched cgy if pltelets 149,000/mm 3 ) Relpsed or refrctory to rituxim with or without chemotherpy Horning et l., Single-rm 131 it (totl ody dose: 75 cgy, 40 f nr Not yet reched cgy if pltelets < 150,000/mm 3 ) Nir et l., Single-rm 131 it (totl ody dose: 75 cgy, nr nr nr cgy if pltelets < 150,000/mm 3 ) 131 it conditioning for utologous stem cell trnsplnttion Press et l., Single-rm 131 it [totl ody dose: cgy (dose escltion)], g 77 g 40 h nr 2-Yer: nr followed y etoposide, plus cyclophosphmide, plus 83% utologous stem cell trnsplnttion Vose et l., Single-rm 131 it [totl ody dose: cgy (dose escltion)], i nr 34 d 38 followed y em (crmustine, etoposide, cytrine, melphln), plus utologous stem cell trnsplnttion 131 it in lterntive regimens Kminski et l., Single-rm 131 it phse i (totl ody dose: nr), nr 26 previous tretment with 131 it Mones et l., Single-rm 131 it phse i nr nr nr nr nr [totl ody dose: 45 cgy (dose escltion)], one mrrow involvement > 25% Only 12 of the 43 enrolled ptients received therpeutic dose of 131 it. Includes ptients with complete, prtil, or minor response. c Of 25 enrolled ptients, 4 did not receive tretment nd were not included in the response nd survivl dt nlysis. d Estimted from Kpln Meier survivl curve. e Of 44 enrolled ptients, 3 did not receive tretment nd were not included in the finl nlysis. f Of 43 enrolled ptients, 3 did not receive tretment nd were not included in the finl nlysis. g Response rtes were clculted sed on 31 ptients tht were evlule for response. h Estimted from Kpln Meier progression-free survivl curve. i Event-free survivl, estimted from Kpln Meier event-free survivl curve. 37

7 PRACTICE GUIDELINE SERIES rm s compred with the unlelled tositumom rm (6.3 months vs. 5.5 months, p = 0.031). Six single-rm trils of ptients who were previously treted with chemotherpy or rituxim, or oth 5,12,19,28,34, or with prior 131 I tositumom 23, reported medin ttp rnges from 8.4 months to 12 months. One tril reported 1-yer progression-free survivl of 66% Response Durtion Dt on response durtion in previously treted ptients were reported in eight trils (Tle iv). In the rndomized tril 22, medin response durtion ws not reched in the 131 I tositumom rm; it ws 28.1 months in the unlelled tositumom rm (p = not reported). In previously treted ptients who hd not received rituxim, medin response durtion rnged from 6.5 months 5 to 15 months 6. In the tril tht compred 131 I tositumom response with tht ttined for lst chemotherpy regimen in the sme ptients 5, 17 of 60 ptients chieved response durtion fter 131 I tositumom tht ws equivlent to their most recent lymphom tretment; 53% chieved longer response durtion fter 131 I tositumom (p < 0.001). In individuls with trnsformed nhl, the pooled nlysis of five trils documented medin response durtion of 20 months. In ddition, of the 25% of individuls who ttined cr, medin response durtion reched 36.5 months Survivl In the trils tht included ptients who hd nhl relpsed or refrctory to chemotherpy without rituxim, the medin os rnged from 21 months 8 to 41 months 12, with two trils reporting tht the medin os ws not reched t 12 months 11 nd 36 months 28 of follow-up (Tle iv). In ptients with disese tht ws relpsed or refrctory to rituxim, medin os hd not yet een reched t 39 months 34. In ptients who received 131 I tositumom conditioning for sct, one tril reported medin os of 36 months 40, nd nother tril reported 2-yer os of 83% Qulity of Life Only one of the thirteen trils of 131 I tositumom in previously treted ptients reported dt on qol 20. The Europen Orgniztion for Reserch nd Tretment of Cncer qulity of life questionnire ws dministered to the ptient cohort receiving 131 I tositumom fter previous lymphom tretment without rituxim. The uthors reported tht the scles for emotionl function, socil function, glol helth sttus, nuse/ vomiting, nd ppetite loss demonstrted sttisticlly significnt improvements t one or more time points; however, no dt or p vlues were reported Adverse Events The rndomized tril 22 compring 131 I tositumom with unlelled tositumom reported comprtive grde 4 hemtologic toxicities. Thromocytopeni (12% vs. 0%), neutropeni (17% vs. 3%), nd nemi (5% vs. 0%) occurred more frequently with rdioimmunotherpy, lthough whether these differences were sttisticlly significnt ws not reported (Tle v). The rtes of dverse events were similr in ptients who hd 34,39 nd who hd not 5,8,11,12,19,28 received prior rituxim. Myelosuppression ws common, ut tended to e delyed in onset, with cytopeni ndirs occurring 7 9 weeks fter tretment. Eight trils reported on the rte of infection, with grdes 1 4 infections occurring in 21% 55% of ptients 5,8,11,12,19,23,34. The rte of hospitliztion from infection ws reported in three trils nd rnged from 2% to 15% 5,23,28. Non-hemtologic toxicity ws common (reported in 80% of ptients), generlly mild, nd relted to drug infusion. Grdes 1 nd 2 dverse events occurred in high proportion of ptients in ll trils, with the most common events eing hedche, fever, chills, infection, nuse, nd vomiting. Tle v summrizes these dverse events. The rte of hm response ws reported in ten single-rm trils, occurring in 0% 35% of ptients 5,8,11,12,19,17,23,28,34,40. Hypothyroidism ws reported in six trils, nd for the 131 I tositumom rm of the rndomized tril, it occurred in 7% 42% of ptients 5,8,11,12,22,23,34. The rte of myelodysplstic syndrome (mds) ws reported in eight trils nd rnged from 0% to 9% 5,8,9,11,12,23,28,34,40. One study tht included ptients from six trils nd n expnded ccess progrm reported on mds nd cute myeloid leukemi (ml) in ptients treted with 131 I tositumom 16 : 35 of 1071 ptients developed mds or ml for n nnulized incidence of 1.4% per yer (95% confidence intervl: 1.0% to 2.0% per yer) Prognostic Fctors Predictors for overll response included tumour urden elow 500 g 5, grde i or ii disese nd tumour size 7 cm or less 34, lymph node dimeter less thn 5 cm 28, low-grde nhl 5,12, one mrrow involvement 5, fewer thn 4 prior chemotherpy regimens 5, nd no prior rdiotherpy 5. The prior use of 2 or more chemotherpy regimens ws ssocited with shorter durtion of remission Dosimetry nd Imging Dosimetry is method of estimting the dose of rdition dministered to specific orgns. Imging refers to the evlution of gmm imges to ensure tht drug iodistriution is pproprite 46. Dosimetry is required to determine the dose of 131 I tositumom to e dministered 21,47, nd it ws used in ll trils in ptients with previously treted nhl. No dose response reltionship ws noted etween sored dose nd tumour response 21. Also, no correltion ws oserved etween totl ody tumour urden nd ojective response or toxicity

8 CHEUNG et l. tle v Trils of 131 I tositumom ( 131 it) in ptients with previously treted non-hodgkin lymphom: dverse events Reference Study type Intervention Pts Thromo- Neutropeni Anemi Infection Ferile Humn (n) cytopeni (grdes 3 4) (grdes 3 4) (grdes 1 4) neutropeni nti-mouse (grdes 3 4) (%) (%) (%) (%) (%) ntiody (%) Relpsed or refrctory to chemotherpy without rituxim Press et l., Single-rm 131 it phse i 43 [totl ody dose: Gy (dose escltion)] Press et l., Single-rm 131 it (totl ody dose: 27 Gy) 21 nr nr nr 21 nr 7 nr nr nr 38 c nr 19 Kminski et l., Single-rm 131 it phse i/ii nr 17 (phse ii totl ody dose: 75 cgy) Vose et l., Single-rm 131 it (totl ody dose: 75 cgy, 47 nr 11 (grde 4) nr 24 nr 2 65 cgy if pltelets 149,000/mm 3 ) Kminski et l., Single-rm 131 it (totl ody dose: 75 cgy, 60 2 (grde 4) 18 (grde 4) 0 (grde 4) cgy if pltelets < 150,000/mm 3 ) Dvis et l., Rndomized 131 it (totl ody dose: nr) (grde 4) 17 (grde 4) 5 (grde 4) nr nr 27 Unlelled tositumom 36 0 (grde 4) 3 (grde 4) 0 (grde 4) nr nr 19 Dvies et l., Single-rm 131 it (totl ody dose: 75 cgy, 65 cgy if pltelets 149,000/mm 3 ) 41 d (grde 3 4) 5 10 Relpsed or refrctory to rituxim with or without chemotherpy Horning et l., Single-rm 131 it (totl ody dose: 75 cgy, 40 e nr 0 65 cgy if pltelets < 150,000/mm 3 ) Nir et l., Single-rm 131 it (totl ody dose: 75 cgy, (grde 4) nr nr nr nr nr 65 cgy if pltelets < 150,000/mm 3 ) 131 it conditioning for utologous stem cell trnsplnttion Press et l., Single-rm 131 it [totl ody dose: cgy (dose escltion)], (grde 4) nr 71 f nr 13 followed y etoposide, plus cyclophosphmide, plus utologous stem cell trnsplnttion Vose et l., Single-rm 131 it [totl ody dose: cgy (dose escltion)], (grde 4) nr 52 >90% 35 followed y em (crmustine, etoposide, cytrine, melphln), plus utologous stem cell trnsplnttion 131 it in lterntive regimens Kminski et l., Single-rm 131 it (totl ody dose: nr) nr Mones et l., Single-rm 131 it [totl ody dose: 45 cgy 11 nr nr nr nr nr nr (10 cgy dose escltion increments)] Twelve ptients received therpeutic dose of 131 it; the numer of ptients tht received dosimetric dose of 131 it ws not reported. Of 25 enrolled ptients, 4 did not receive tretment nd were not included in the finl nlysis. c Two ptients hd grde 3 or 4 infection, nd one ptient died from infection (grde 5). d Of 44 enrolled ptients, 3 did not receive tretment nd were not included in the finl nlysis. e Of 43 enrolled ptients, 3 did not receive tretment nd were not included in the finl nlysis. f Four ptients hd grde 3 or 4 infection. Pts = ptients; nr = not reported. 39

9 PRACTICE GUIDELINE SERIES 3.2 Ptients with Previously Untreted NHL Study Qulity No rndomized controlled trils of 131 I tositumom in ptients with previously untreted nhl were identified. All of the five studies locted were single-rm noncomprtive phse ii trils with smple sizes rnging from 13 ptients to 90 ptients 25,27,29,31,35. Medin follow-up rnged from 11 months to 61.2 months Study Chrcteristics Tle vi detils the study nd ptient chrcteristics of trils of 131 I tositumom in ptients with previously untreted nhl Response Rte Tle vii presents response dt for the five trils of 131 I tositumom in the previously untreted ptient popultion. In the four trils of 131 I tositumom lone 35 or fter chemotherpy 25,29,31, ojective response rtes rnged from 90% to 100%, with cr rtes from 67% to 83%. In tril of sequentil therpy with 131 I tositumom followed y chop (cyclophosphmide, doxoruicin, vincristine, prednisone) chemotherpy ( 6 cycles) in ptients with mntle-cell nhl, the response rte ws 83% fter 131 I tositumom (cr rte: 50%) nd y intention-totret nlysis, the response rte ws 75% fter chop (ll of which were crs) Time to Progression Tle vii presents dt on ttp. One tril reported medin ttp of 73.2 months 35 nd nother reported 2-yer progression-free survivl of 81% 25. Medin ttp hd not yet een reched in two other trils in which the medin follow-up periods were 28 nd 53 months 29, Response Durtion Only one tril 27 reported medin response durtion, which hd not yet een reched fter medin follow-up of 11 months (Tle vii). Among the suset of ptients who experienced cr 35, 40 of 57 hd experienced n ongoing cr for yers. A third tril 29 reported tht the medin durtion of cr ws not reched fter medin follow-up of 52.8 months, with 72% of 29 ptients with cr remining in remission Survivl Two trils reported survivl dt for previously untreted ptients (Tle vii). One reported 5-yer os of 89% 35, nd nother reported 2-yer os of 97% Qulity of Life None of the trils of ptients with previously untreted nhl reported dt on qol Adverse Events Tle viii summrizes dverse events in the previously untreted popultion. Grdes 3 nd 4 thromocytopeni rnged from 11% to 29%; neutropeni, from 13% to 34%; nd nemi, from 0% to 3% 25,29,31,35. Grde 3 infection occurred in 2% of ptients 25, nd ferile neutropeni ws reported s 0% in one tril 35 nd 42% in nother 27. One tril reported 0% rte of hospitliztion s result of infection 35 ; no other trils reported hospitliztion dt. Elevted thyroid-stimulting hormone occurred in 7% 12% of ptients 25,29,35, nd hm occurred tle vi Single-rm trils of 131 I tositumom ( 131 it) in ptients with previously untreted non-hodgkin lymphom (nhl): study chrcteristics Reference Ptient chrcteristics Intervention Pts (n) Press et l., Previously untreted CD20+ stge ii-iv folliculr nhl chop (cyclophosphmide 750 mg/m 2 dy 1, plus 90 doxoruicin 50 mg/m 2 dy 1, plus vincristine 1.4 mg/m 2 dy 1, plus prednisone 100 mg dys 1 5) every 21 dys for 6 cycles, followed y 131 it (totl ody dose: 75 cgy) Zelenetz et l., Previously untreted mntle-cell lymphom 131 it (totl ody dose: nr), 13 followed weeks lter y chop Leonrd et l., Previously untreted dvnced low-grde nhl Fludrine 25 mg/m 2 dily for 5 dys, 38 every 5 weeks for 3 cycles, followed y 131 it (totl ody dose: 75 cgy) Link et l., Previously untreted folliculr nhl cvp (cyclophosphmide 400 mg/m 2 dys 1 5, plus 30 vincristine 1.4 mg/m 2 dy 1, plus prednisone 100 mg/m 2 dys 1 5) every 21 dys for 6 cycles, followed y 131 it (totl ody dose: 75 cgy) Kminski et l., Previously untreted dvnced-stge folliculr nhl Numer enrolled nd eligile. Stndrd chop, ut with cyclophosphmide dose of 1000 mg/m 2. Pts = ptients; nr = not reported. 131 it (totl ody dose: 75 cgy) 76 40

10 CHEUNG et l. tle vii Single-rm trils of 131 I tositumom ( 131 it) in ptients with previously untreted non-hodgkin lymphom: response nd survivl Reference Intervention Pts or cr Medin results (months) for (n) (%) (%) ttp Response os Followdurtion up Press et l., chop followed y 131 it Not yet reched nr Not yet reched 27.6 (totl ody dose: 75 cgy) Zelenetz, it (totl ody dose: nr) nr Not yet reched nr 11 followed y chop Leonrd et l., Fludrine, followed y 131 it 35 c Not yet reched nr nr 52.8 (totl ody dose: 75 cgy) Link et l., cvp followed y 131 it Not yet reched nr nr 27.6 (totl ody dose: 75 cgy) Kminski et l., it (totl ody dose: 75 cgy) nr Not yet reched 61.2 Numer included in the nlysis. Of 13 enrolled ptients, 1 did not receive tretment with 131 it nd ws not included in the nlysis of the dt. c Of 38 enrolled ptients, 3 did not receive tretment with 131 it nd were not included in the nlysis of the dt. Pts = ptients; or = complete response, unconfirmed complete response, nd prtil response; cr = complete response nd unconfirmed complete response; ttp = time to progression; os = overll survivl; chop = cyclophosphmide, doxoruicin, vincristine, prednisone; nr = not reported; cvp = cyclophosphmide, vincristine, nd prednisone. tle viii Single-rm trils of 131 I tositumom ( 131 it) in ptients with previously Untreted non-hodgkin lymphom: dverse events Reference Intervention Pts Thromo- Neutro- Anemi Infection Ferile Humn (n) cytopeni peni (grdes (grdes neutron- nti-mouse (grdes 3 4) (grdes 3 4) 3 4) (%) 1 4) (%) peni (%) ntiody (%) (%) (%) Press et l., chop followed y 131 it (grde 3) nr nr (totl ody dose: 75 cgy) Zelenetz et l., it (totl ody dose: nr) 12 c nr nr nr nr followed y chop Leonrd et l., Fludrine followed y 131 it 35 d 29 (grde 4) 34 (grde 4) 3 (grde 4) nr nr 6 (totl ody dose: 75 cgy) Link et l., cvp followed y 131 it (grde 4) 33 (grde 4) nr nr nr 0 (totl ody dose: 75 cgy) Kminski et l., it (totl ody dose: 75 cgy) nr 0 63 Numer included in nlysis. Of 90 enrolled ptients, 9 were not evlule for toxicity. c Of 13 enrolled ptients, 1 did not receive tretment with 131 it nd ws not included in the nlysis of the dt. d Of 38 enrolled ptients, 3 did not receive tretment with 131 it nd were not included in the nlysis of the dt. Pts = ptients; chop = cyclophosphmide, doxoruicin, vincristine, prednisone; nr = not reported; cvp = cyclophosphmide, vincristine, nd prednisone. in 0% 63% 27,29,31,35, with mds or ml occurring in 0% 3% of ptients 25,31, Prognostic Fctors One tril reported on predictive fctors 35. Nodl dimeters of 5 cm or more were ssocited with lower response rtes, nd one mrrow involvement ws lso ssocited with lower response rtes. Only one mrrow involvement hd significnt effect on progression-free survivl, predicting for worse outcome Dosimetry nd Imging All of the trils tht enrolled ptients with previously untreted nhl used dosimetry nd imging in the tril protocol. Dosimetry is prt of the 131 I tositumom regimen. One puliction 38 provided updted dt on ptients in three other pulictions 36,37,47 nd on n dditionl 19 ptients. The uthors reported tht, for ptients with previously untreted folliculr nhl who received 131 I tositumom, those with tumours receiving the highest rdition doses were more likely to chieve cr; however, tht ssocition ws not sttisticlly significnt. 41

11 PRACTICE GUIDELINE SERIES 4. DISCUSSION The development of the monoclonl ntiody rituxim hs significntly dvnced the tretment of lymphoms tht express the trget CD20 ntigen. The nti-lymphom enefit of rituxim is likely multifctoril, including ntiody- nd complementdependent cellulr cytotoxicity mechnisms 4. In ddition to these immunoiologic effects, rdioimmunoconjugtes hve the potentil to direct rdition exclusively to the site of disese involvement, minimizing exposure to uninvolved orgns. The doption of these gents will depend on whether the incrementl nti-lymphom ctivity cn trnslte into improved long-term outcomes without undue toxicity. Ptients with indolent lymphom re treted episodiclly with chemotherpy, immunotherpy, or rdition often over period of mny yers, sometimes decdes. Therpy is initilly highly effective in plliting symptoms nd relieving potentilly life-thretening complictions, ut it is not curtive. Over time, response rtes diminish nd ecome less durle. The outcome for ptients who re refrctory to rituxim is prticulrly poor, nd few lterntive tretment options remin. In this context of hevily pretreted disese, the evidence supports the use of 131 I tositumom. 131 I Tositumom demonstrted significnt nti-lymphom ctivity in six single-rm trils in ptients with nhl relpsed or refrctory to chemotherpy without rituxim nd in two single-rm phse ii trils in ptients with nhl relpsed or refrctory to rituxim with or without chemotherpy. For most of this hevily pretreted ptient popultion, therpeutic options hve een exhusted. A stndrd comprison therefore does not exist. However, one tril used ech ptient s pired self control for compring durtion of response with the ptient s lst qulifying chemotherpy regimen 5. Tht tril reported significnt difference in ojective response (65% with 131 I tositumom vs. 28% with lst chemotherpy), nd 53% of ptients hd longer response durtion fter 131 I tositumom thn fter their most recent chemotherpy. This longer response my represent eneficil effect on the nturl history of the disese ecuse, typiclly, lower response rte nd shorter durtion of response re oserved with ech successive tretment. In ddition, proportion of responders hd very long durle remissions. For ptients with cr, medin durtion of response ws 47.2 months s compred with only 4.8 months for their lst qulifying chemotherpy. Given the limited ville tretment options for pretreted ptients, the use of 131 I tositumom my offer enefit when other tretments (including rituxim) hve filed. The role of 131 I tositumom in individuls with trnsformed low-grde nhl is lso of interest, given the poor prognosis ssocited with currently ville therpies. An integrted nlysis of ptients with trnsformtion cross five trils documented moderte response rtes nd medin response durtion of 20 months, results tht were commensurte with the hevily pretreted low-grde popultion 43. However, this smll nd selected popultion of ptients with n extended time from trnsformtion until tretment with 131 I tositumom my not e reflective of ll ptients with trnsformed nhl 45, nd further prospective dt for this unique presenttion re wrrnted. The dt do not currently identify whether there is differentil enefit etween the vrious indolent histologies (folliculr vs. non-folliculr) enrolled in these pivotl trils. The dt supporting the use of 131 I tositumom in previously untreted ptients with nhl re limited. No rndomized controlled trils hve compred 131 I tositumom with stndrd therpy, nd therefore the use of 131 I tositumom in this ptient popultion should e reserved until evidence ecomes ville supporting improved clinicl outcomes with 131 I tositumom s compred with current stndrd therpies. The evidence for 131 I tositumom s prt of conditioning regimen efore sct is limited to two single-rm trils 17,40. Although encourging, the limited dt preclude ny cler conclusions of enefit in tht setting. The toxicities of 131 I tositumom re predictle. The min toxicity is hemtologic, with delyed-onset cytopenis whose ndirs occur t 7 9 weeks from tretment. Prticulr ttention to severe myelosuppression is wrrnted for ptients with known one mrrow involvement nd thromocytopeni preceding therpy. Dose reductions re required if pltelets rech /L, nd the drug should not e dministered if pltelets re less thn /L, solute neutrophil count is less thn /L, or one mrrow involvement is greter thn 25%. The nnulized incidence of mds nd ml in ptients with previously treted nhl is 1.4% per yer nd would e considered cceptle in this group of ptients who hve often received prior leukemogenic nti-lymphom therpies such s lkylting gents. The incidence of hm vried from 0% to 35% nd is of questionle clinicl significnce. The evidence hs highlighted numer of predictors for response to rdioimmunotherpy. Common predictors for response include indolent-histology disese (compred with trnsformed histology), nonulky disese, nd fewer prior therpies. However, these results should e considered hypothesis-generting t this time, given the limited smple sizes on which the sugroup nlyses were sed. The finl question tht guided this review ws the role of dosimetry in estlishing the sfety nd efficcy of 131 I tositumom. Although dosimetric findings did not correlte with tumour response, dosimetry ws performed in ll clinicl studies involving this gent nd is currently mndted in North Americn nd Europen jurisdictions to determine the ptient-specific therpeutic dose. Although there my 42

12 CHEUNG et l. e logistic rriers to the performnce of dosimetry, especilly in smller centres of prctice, these limittions re out of the scope of the present review. Currently, no comprtive dt ddressing the use of one rdioimmunoconjugte over nother re ville. Another rdiolelled nti-cd20 ntiody, 90 Y-iritumom tiuxetn (Zevlin: idec Phrmceuticls, Sn Diego, CA, U.S.A.), is eing studied predominntly in indolent nd trnsformed lymphom. Importnt differences in rdition chrcteristics nd dosimetry requirements my limit the clss generlizility of these ntiodies. The strengths of the present review include the use of vlidted methods for the performnce of systemtic reviews, extension of the literture serch to include preliminry strct dt to minimize puliction is, nd ojective dt strction ccording to predefined outcome questions. However, the review does hve limittions. For most of the trils, we did not formlly pprise study qulity ecuse they were phse ii studies nd severl were reported only in strct form. This lck of pprisl limited the discrimintion nd utility of ny methodologic grding scores. Also, the vriility of the dt precluded ny pooling of results or use of met-nlytic summry techniques. We pprecite tht the dt come lrgely from single-rm studies nd tht the results re suject to selection is; however, we hve tempered our conclusions regrding this gent to reflect the currently ville evidence. Finlly, we cknowledge tht the evidence regrding the role of 131 I tositumom will continue to mture nd evolve eyond this originl systemtic review nd summry document. A current listing of phse iii trils is provided in Tle ix, nd we invite prctitioners nd ptients to review the We site of the pec ( to remin rest of the updte process mndted for these guidelines. Despite limittions, the dt suggest role for 131 I tositumom in selected ptients with nhl. The current evidence supports role in the mngement of indolent lymphom refrctory to prior therpy tht includes rituxim with or without chemotherpy. The precise role of 131 I tositumom within the lymphom rmmentrium will undoutedly continue to evolve. 5. ACKNOWLEDGMENTS Funding for this review process ws provided y Cncer Cre Ontrio nd the Ontrio Ministry of Helth tle ix Ongoing comprtive or phse iii trils Protocol ID swog S0016 NCT clg mt CTN0401 NCT CCBX NCT NCT CCBX NCT NCT Title nd detils of tril Phse iii Rndomized Study of Cyclophosphmide, Doxoruicin, Vincristine, nd Prednisone (chop) with Either Rituxim or Iodine 131 I Tositumom (Monoclonl Antiody Anti-B1) in Ptients with Newly Dignosed Folliculr Non-Hodgkin s Lymphom Outcomes: Progression-free survivl, overll survivl, response, toxicity Projected ccrul: 500 ptients Sttus: Study is ongoing, ut not recruiting prticipnts Notes: A chop-only rm closed to recruitment on Decemer 15, 2002 Summry lst modified: April 14, 2009 Accessed: My 10, 2009 Aville t: Phse iii Rituxn/em vs. Bexxr/em with Autologous Hemtopoietic Stem Cell Trnsplnttion (sct) for Persistent or Relpsed Chemotherpy Sensitive Diffuse Lrge B-Cell Non-Hodgkin s Lymphom Outcomes: Progression-free survivl, overll survivl, response, toxicity Projected ccrul: 224 ptients Sttus: Currently recruiting Summry lst modified: April 8, 2009 Accessed: My 10, 2009 Aville t: A Comprtive Study of Iodine I-131 Tositumom Therpeutic Regimen Versus Iritumom Tiuxetn Therpeutic Regimen Sttus: Withdrwn Summry lst modified: Jnury 24, Accessed: My 10, 2009 Aville t: A Study of Rituxim Versus Iodine I-131 Tositumom Therpy for Ptients with Non-Hodgkin s Lymphom Outcomes: Response nd sfety Projected ccrul: 506 ptients Sttus: Terminted Summry lst modified: Novemer 8, 2005 Accessed: My 10, 2009 Aville t: 43

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