Bone Marrow Transplantation (2001) 27, Nature Publishing Group All rights reserved /01 $

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1 Bone Mrrow Trnsplnttion (2001) 27, Nture Publishing Group All rights reserved /01 $ Hodgkin s disese Autotrnsplnts for Hodgkin s disese in first relpse or second remission: report from the utologous blood nd mrrow trnsplnt registry (ABMTR) HM Lzrus 1, FR Loberiz Jr 2, M-J Zhng 2, JO Armitge 3, KK Bllen 4, A Bshey 5, BJ Bolwell 6, LJ Burns 7, CO Freytes 8, RP Gle 9, J Gibson 10, RH Herzig 11, CF LeMistre 12, D Mrks 13, J Mson 14, AM Miller 15, GA Milone 16, S Pvlovsky 16, DE Reece 17, JD Rizzo 2, K vn Besien 18, JM Vose 3 nd MM Horowitz 2 1 Deprtment of Medicine, Irelnd Cncer Center, University Hospitls of Clevelnd, Cse Western Reserve University, Clevelnd, Ohio; 2 Lymphom Working Committee of the Autologous Blood nd Mrrow Trnsplnt Registry, Helth Policy Institute, Medicl College of Wisconsin, Milwukee, Wisconsin; 3 Deprtment of Internl Medicine, University of Nebrsk Medicl Center, Omh, Nebrsk; 4 Bone Mrrow Trnsplnt Progrm, University of Msschusetts Medicl Center, Worcester, Msschusetts; 5 Division of Hemtology/Oncology, University of Cliforni, Sn Diego, Cliforni; 6 Bone Mrrow Trnsplnt Progrm, Clevelnd Clinic Foundtion, Clevelnd, Ohio; 7 Deprtment of Medicine, University of Minnesot, Minnepolis, Minnesot; 8 Division of Hemtology/Oncology, University of Texs Helth Science Center, Sn Antonio, Texs, USA; 9 Center for Advnced Studies in Leukemi, Los Angeles, Cliforni; 10 Hemtology Deprtment, Royl Prince Alfred Hospitl, Cmperdown, NSW, Austrli; 11 Jmes Grhm Brown Cncer Center, University of Louisville, Louisville, Kentucky, USA; 12 Texs Trnsplnt Institute, Sn Antonio, Texs; 13 Bone Mrrow Trnsplnt Unit, Bristol Royl Hospitl for Sick Children, Bristol, UK; 14 Scripps Clinic nd Reserch Foundtion, L Joll, Cliforni; 15 Bone Mrrow Trnsplnt Progrm, Tulne University Medicl Center, New Orlens, Louisin, USA; 16 Bone Mrrow Trnsplnt Progrm, Fundleu, Buenos Aires, Argentin; 17 Mrkey Cncer Center, University of Kentucky, Lexington, Kentucky; nd 18 Section of Hemtology/Oncology, University of Illinois, Chicgo, Illinois USA Summry: Although ptients with relpsed Hodgkin s disese hve poor prognosis with conventionl therpies, high-dose chemotherpy nd utologous hemtopoietic stem cell trnsplnttion (utotrnsplnttion) my provide long-term progression-free survivl. We reviewed dt from the Autologous Blood nd Mrrow Trnsplnt Registry (ABMTR) to determine relpse, disese-free survivl, overll survivl, nd prognostic fctors in this group of ptients. Detiled records from the ABMTR on 414 ptients with Hodgkin s disese in first relpse (n = 295) or second complete remission (CR) (n = 119) receiving n utotrnsplnt from 1989 to 1995 were reviewed. Medin ge ws 29 (rnge, 7 64) yers. Medin time from dignosis to relpse ws 18 (rnge, 6 219) months; medin time from relpse to trnsplnt ws 5 (rnge, 1 215) months. Most ptients received high-dose chemotherpy without totl body irrdition for conditioning (n = 370). The most frequently used high-dose regimen ws cyclophosphmide, BCNU, VP- 16 (CBV) (n = 240). The grft consisted of bone mrrow (n = 246), blood stem cells (n = 112), or both (n = 56). Correspondence: Dr HM Lzrus, Deprtment of Medicine, University Hospitls of Clevelnd, Euclid Avenue, Clevelnd, Ohio USA The contents of this rticle re solely the responsibility of the uthors nd do not necessrily represent the officil views of the Ntionl Cncer Institute Received 15 September 2000; ccepted 2 November 2000 Medin follow-up ws 46 (rnge, 5 96) months. One hundred-dy mortlity (95% confidence intervl) ws 7 (5 9)%. One hundred nd sixty-five of 295 ptients (56%) trnsplnted in relpse chieved CR fter utotrnsplnttion. Of these, 61 (37%) recurred. Twentyfour of 119 ptients (20%) trnsplnted in CR recurred. The probbility of disese-free survivl t 3 yers ws 46 (40 52)% for trnsplnts in first relpse nd 64 (53 72)% for those in second remission (P 0.001). Overll survivl t 3 yers ws 58 (52 64)% fter trnsplnttion in first relpse nd 75 (66 83)% fter trnsplnttion in second CR (P 0.001). In multivrite nlysis, Krnofsky performnce score <90% t trnsplnt, bnorml serum LDH t trnsplnt, nd chemotherpy resistnce were dverse prognostic fctors for outcome. Progression of Hodgkin s disese ccounted for 69% of ll deths. Autotrnsplnttion should be considered for ptients with Hodgkin s disese in first relpse or second remission. Future investigtions should focus on strtegies designed to decrese relpse fter utotrnsplnttion, prticulrly in ptients t high risk for relpse. Bone Mrrow Trnsplnttion (2001) 27, Keywords: Hodgkin s disese; utotrnsplnt; relpse; second complete remission The tretment of Hodgkin s disese represents one of the success stories of modern oncology. Five-yer survivl of newly dignosed ptients is 80% in recent series. 1 More

2 388 Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l thn 80% of ptients with erly stge Hodgkin s disese nd more thn hlf with dvnced stge disese re cured with chemotherpy, rdition, or combintion Once ptients relpse fter initil therpy, however, conventionldose chemotherpy regimens usully fil to provide durble complete remissions In the series with the longest follow-up, Longo nd ssocites 17 reported tht lthough 93% of relpsing ptients could be re-induced into second complete remission, only 17% of these remissions were durble. Other studies confirm tht only minority of ptients experience prolonged disese-free survivl with slvge chemotherpy. 19,20,22 24 Consequently, high-dose therpy with utologous hemtopoietic stem cell support (utotrnsplnttion) is incresingly used to tret recurrent Hodgkin s disese. We nlyzed results of utotrnsplnttions reported to the Autologous Blood nd Mrrow Trnsplnt Registry (ABMTR), performed in 414 people with Hodgkin s disese in first relpse or second complete remission. Our objectives were to determine overll nd disese-free survivl nd to identify ptient-, disese-, nd tretment-relted vribles correlted with outcome. Methods ABMTR The ABMTR is voluntry orgniztion of more thn 170 trnsplnt centers in the United Sttes, Cnd, Centrl nd South Americ nd Austrli tht report dt on consecutive utotrnsplnttions to Sttisticl Center t the Medicl College of Wisconsin. The ABMTR defines utotrnsplnttion s tretment with sufficiently high dose of chemotherpy to require utologous bone mrrow or bloodderived hemtopoietic stem cell support. The ABMTR begn dt collection in Dt were collected retrospectively for ptients who received utotrnsplnts between 1989 nd 1992 nd prospectively therefter. The ABMTR collects dt t two levels: registrtion nd reserch. Registrtion dt include disese type, ge, sex, pretrnsplnt remission sttus, dte of dignosis, grft type (bone mrrow- nd/or blood-derived stem cells), purging, high-dose conditioning regimen, post-trnsplnt sttus nd survivl. Updtes on disese nd survivl sttus for registered ptients re requested t 6 month intervls. All ABMTR tems contribute registrtion dt. Reserch dt re collected on subsets of registered ptients nd include comprehensive pre- nd post-trnsplnt clinicl informtion. Physicin review of submitted dt, computerized error checks, nd on-site udits ensure dt ccurcy. Ptients re followed longitudinlly, nd informtion on progression nd deth is requested nnully. Bsed on dt collected by the Centers for Disese Control Hospitl Surveys, 25,26 pproximtely one-hlf of utotrnsplnttions in North Americ were registered with the ABMTR during the study period. Ptients Between 1 Jnury 1989 nd 31 December 1995, 990 utotrnsplnts for Hodgkin s disese in first relpse or second complete remission were registered with the ABMTR. Reserch dt (see bove) were vilble for 425 (43%). Survivl nd demogrphics of these ptients were similr to those of ll registered ptients. Relpse is defined s recurrence of Hodgkin s disese fter documented complete remission lsting t lest 1 month. Second complete remission is defined s complete disppernce of ll known disese for t lest 4 weeks, induced fter first relpse nd before utotrnsplnt. Prtil remission is defined s hving t lest 50% reduction in gretest dimeter of ll sites of known disese nd without ny new sites. Eleven ptients did not hve sufficient dt for key vribles to be included in the multivrite nlysis. To mintin homogeneity in the smple utilized for ll multivrite models, these ptients were excluded leving comprehensive dt vilble for 414 subjects. Ptients were reported to the ABMTR by 84 centers in eight different countries. Medin follow-up ws 46 months (5 96 months) fter utotrnsplnttion. Sttisticl methods Outcomes studied were 100-dy mortlity, relpse, disesefree survivl, nd overll survivl. Probbilities of 100-dy mortlity (deth from ny cuse in the first 100 dys fter trnsplnt), disese-free survivl nd overll survivl were clculted using the Kpln Meier product limit estimte. 27 Relpse ws evluted in ptients surviving 28 dys post trnsplnt. Ptients were censored t lst follow-up or deth in continuous complete remission. Both persistent disese or recurrence were considered s relpse. Ptients with persistent disese were considered to relpse t dy 28. Surviving ptients without persistent or recurrent disese were censored t lst follow-up. Disese-free survivl ws defined s survivl in complete remission; persistent or recurrent disese nd non-relpse deths were events. Assessment of potentil risk fctors for outcomes of interest ws performed using multivrite Cox proportionl hzrds regression. 28 Vribles included in model building re shown in Tble 1. All computtions used the procedure PHREG in the sttisticl pckge SAS. Forwrd stepwise vrible selection t 0.05 significnce level ws used to identify covrites ssocited with outcomes. The ssumption of proportionl hzrds ws tested using time-dependent covrite for ll vribles; when this indicted differentil effects over time (non-proportionl hzrds), models were constructed breking the post-trnsplnt course into two time periods using the mximized prtil likelihood method to find the most pproprite brekpoint. First order interctions were tested for ll significnt covrites. Overll covrite effects were tested using the Wld test. All multivrite models were exmined for center effects using rndom effects or frilty model; 29 there were no significnt center effects. Results Chrcteristics of the study popultion re shown in Tble 2. Medin ge ws 29 yers (rnge, 7 64 yers) nd 60% were mle. At dignosis, 71% hd nodulr sclerosis his- Bone Mrrow Trnsplnttion

3 Tble 1 Vribles tested in multivrite nlysis Ptient-relted vribles Age t trnsplnt: 40 yers vs 40 yers Gender: mle vs femle Krnofsky performnce sttus t trnsplnt: 90% vs % Disese-relted vribles t dignosis Histologic subtype: nodulr sclerosis vs mixed cellulrity vs other Disese stge t dignosis: stge I/II vs stge III/IV Presence of B symptoms: yes vs no Bone mrrow involvement: yes vs no Initil therpy: rdition only vs chemotherpy or both Initil chemotherpy regimen: MOPP others vs ABVD others or MOPP/ABVD others or etoposide + others vs others Number of regimens to chieve first complete remission: 1 vs 1 Disese-relted vribles t trnsplnt Time intervl from dignosis to relpse: 12 months vs 12 months Sensitivity to slvge chemotherpy: second complete remission vs sensitive (prtil remission) relpse, vs resistnt relpse vs untreted relpse vs relpse with unknown sensitivity Number of disese sites (nodl nd extrnodl): 0 vs 1 vs 1 Size of lrgest tumor size: 5 cmvs 5 cm Number of slvge chemotherpy cycles: 2 vs 2 Serum LDH: bnorml vs norml Tretment-relted Time intervl from relpse to trnsplnt: 3 months vs 3 months Conditioning regimen: TBI vs non-tbi Involved-field rdiotherpy: yes vs no Hemtopoietic growth fctors in first 7 dys post trnsplnt: yes vs no Hemtopoietic grft type: bone mrrow vs blood vs both Yer of trnsplnt: vs MOPP = mechlorethmine, vincristine, procrbzine, prednisone; ABVD = doxorubicin, bleomycin, vinblstine, dcrbzine; LDH = lctte dehydrogense; TBI = totl body irrdition. tology, 60% hd stge III or IV disese, pproximtely onequrter hd performnce score 90%, nd 60% hd B symptoms. Eleven percent hd bone mrrow involvement t dignosis. Ninety-five percent of ptients initilly received chemotherpy, with or without rdition therpy, usully MOPP or similr regimen (13%), ABVD (27%), or n lternting or hybrid MOPP-ABV(D) regimen (47%). Sixty percent of ptients chieved their first complete remission with one chemotherpy regimen, rdition lone, or combintion. The medin time from dignosis to relpse ws 18 months (rnge, months); nerly 80% of ptients relpsed more thn 1 yer fter dignosis. Thirteen percent of ptients hd tumor mss 5 cm or lrger t relpse. Ninety-four percent of ptients received slvge chemotherpy prior to utotrnsplnt. Nerly hlf received two or more cycles of such therpy. Eighty-three percent of ptients hd chemotherpy-sensitive disese, defined s chievement of 50% reduction in ll sites of disese, with no new sites of disese. Thirty percent (n = 119) chieved second complete remission nd bout hlf (n = 207) hd prtil remission prior to trnsplnttion. Only 11% (n = 41) of ptients hd chemotherpy-resistnt relpse. One qurter of ptients hd Krnofsky performnce scores 90% nd one-qurter hd elevted serum lctic dehydrogense (LDH) levels t trnsplnt. The most commonly used high-dose preprtive regimen ws CBV Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l Tble 2 Ptient, disese, nd trnsplnt chrcteristics of ptients receiving utotrnsplnts for Hodgkin s disese in first relpse or second complete remission n evluble n (%) medin (rnge) b Ptient-relted vribles Age, yers (7 64) Age 40 yers (17) Mle gender (60) Histologic subtype 414 Nodulr sclerosing 296 (71) Lymphocyte predominnce 12 (3) Mixed cellulrity 87 (21) Lymphocyte depletion 8 (2) Unknown 7 (2) Not otherwise specified 4 (1) Krnofsky performnce score 90% t trnsplnt (66) Disese-relted vribles t dignosis Disese stge 413 I/II 163 (40) III/IV 250 (60) B symptoms (60) Mrrow involvement (11) Initil tretment 414 Rdition only 21 (5) Chemotherpy only 242 (58) Both 151 (37) Initil chemotherpy 393 MOPP ± others 51 (13) ABVD ± others 108 (27) MOPP/ABVD ± others 185 (47) Etoposide + others 14 (4) Others 35 (9) 1 chemotherpy regimens to 163 (42) chieve first remission 393 Disese-relted vribles t trnsplnt Nodl involvement t trnsplnt 414 None 185 (45) 1 nodl re 112 (27) 1 nodl re 117 (28) Lrgest tumor mss t trnsplnt 42 (13) 5 cm slvge chemotherpy 189 (46) cycles 413 Abnorml serum LDH level t 103 (26) trnsplnt 388 Time from dignosis to relpse 77 (22) 12 months 352 Time from relpse to trnsplnt 66 (19) 3 months 352 Sensitivity to slvge chemotherpy 414 Untreted relpse 26 (6) Resistnt relpse 42 (10) Sensitive, prtil remission 207 (50) Sensitive, complete remission 119 (29) Unknown 20 (5) Trnsplnt-relted vribles TBI for conditioning (11) Other field rdition (20) Continued 389 Bone Mrrow Trnsplnttion

4 390 Tble 2 Continued Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l n evluble n (%) medin (rnge) b Conditioning (preprtive) 414 regimen CBV 240 (58) Cy ± others 30 (8) BuCy ± others 27 (6) TBI ± others 27 (6) TBI ± Cy ± others 17 (4) BEAC 18 (4) BCNU ± others 21 (5) Others 34 (9) Use of hemtopoietic growth (67) fctors within 7 dys of trnsplnt Grft type 414 Bone mrrow 246 (59) Peripherl blood 112 (27) Both 56 (14) Yer of trnsplnt to (44) 1993 to (56) MOPP = mechlorethmine, vincristine, procrbzine, prednisone; ABVD = doxorubicin, bleomycin, vinblstine, dcrbzine; LDH = lctte dehydrogense; TBI = totl body irrdition; BM = bone mrrow; PB = peripherl blood; CBV = cyclophosphmide, BCNU (crmustine), VP-16 (etoposide); Cy = cyclophosphmide; Bu/Cy = busulfn + cyclophosphmide; BEAC = BCNU (crmustine), etoposide, Ar-C (cytrbine), cyclophosphmide. Ctegoricl vribles. b Continuous vribles. (cyclophosphmide, BCNU (crmustine), VP-16 (etoposide)). Totl body irrdition ws used in only bout 10% of ptients nd nother 20% received rdiotherpy to involved-fields either immeditely before or fter the trnsplnt. Forty-one percent of ptients received peripherl blood hemtopoietic stem cell grfts with or without bone mrrow cells. Of the 295 ptients not in remission t trnsplnt, 165 (56%) chieved complete remission post trnsplnt. Sixtyone (37%) of these subsequently recurred. Twenty-four (20%) ptients trnsplnted in complete remission recurred. With medin follow up of 46 (rnge, 5 96) months, the 3-yer probbility of survivl (95% confidence intervl) for ll ptients ws 63 (58 68)%. Probbility of survivl t 3 yers ws 58 (52 64)% for ptients trnsplnted in first relpse compred to 75 (66 83)% for ptients in second remission (P 0.001) (Figure 1). Among ptients in relpse, 3-yer survivl ws 65 (57 71)% for ptients with chemotherpy-sensitive disese, 37 (22 52)% for those with resistnt relpse nd 51 (35 65)% for those with untreted relpse or unknown sensitivity (Figure 1). Similrly, the probbility of disese-free survivl t 3 yers ws 46 (40 52)% for ptients trnsplnted in first relpse vs 64 (53 72)% for those in second remission (P 0.001). Among ptients in relpse, 3-yer disese-free survivl ws 53 (45 60)% for ptients with chemotherpy-sensitive disese, 19 (8 33)% for those with resistnt relpse nd 19 (8 33)% for those with untreted relpse or unknown sensitivity. Probbility, % Prtil remission (n = 207) CR (n = 119) Untreted relpse (n = 26) Resistnt relpse (n = 42) Unknown (n = 20) Yers Figure 1 Probbility of survivl fter utotrnsplnt for Hodgkin s disese in second complete remission or first relpse, ccording to sensitivity to slvge chemotherpy. One hundred nd twenty-two of 414 (29%) ptients died (Tble 3). The min cuse of deth ws Hodgkin s disese. Twenty-nine (7% of ll ptients trnsplnted) died within 100 dys of trnsplnt. Seventeen of these (4% of ll ptients trnsplnted) died of cuses relted to toxicity of the trnsplnttion procedure, ie non-relpse deths. Ninety-three ptients died more thn 100 dys fter trnsplnt. Twenty-one of these (5% of ll ptients trnsplnted) died of lte non-relpse complictions such s interstitil pneumonitis, infection, or orgn filure. In the multivrite nlysis of tretment filure (eg relpse or deth) only four vribles in Tble 1 hd sttisticlly significnt correltions: disese sensitivity to chemotherpy, serum LDH t trnsplnt, Krnofsky performnce score t trnsplnt nd initil chemotherpy used (Tbles 4 6). Compred to ptients in second complete remission, ptients not in remission generlly hd higher risk of tretment filure; resistnce to slvge tretment conferred nerly 3.-fold increse in risk (Tble 4). Abnorml serum LDH ws ssocited with two-fold increse nd Krnofsky performnce sttus <90% ws ssocited with nerly 1.-fold incresed risk of tretment filure (Tble 4). Similrly, the risk of relpse correlted with pretrnsplnt disese stte nd serum LDH (Tble 5). Finlly, the risk of deth correlted with type of chemotherpy given for initil therpy in ddition to chemotherpy-sensitivity, LDH nd performnce sttus (Tble 6, Figures 1 4). Ptients relpsing fter receiving MOPP t dignosis hd worse outcome thn those receiving other regimens (Tble 6, Figure 4). Tble 3 Cuses of deth mong ptients receiving utotrnsplnts for Hodgkin s disese in first relpse or second complete remission Primry cuse of Erly deths Lte deths deth ( 100 dys ( 100 dys post trnsplnt) (%) post trnsplnt) (%) n Primry disese 12 (41) 72 (77) Interstitil pneumonitis 9 (31) 6 (6) Infection 1 (4) 3 (4) Orgn filure 2 (7) 5 (5) Other cuses 5 (17) 7 (8) Bone Mrrow Trnsplnttion

5 Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l Tble 4 Multivrite nlysis of tretment filure (relpse or deth) mong ptients with Hodgkin s disese receiving utotrnsplnts in first relpse or second complete remission 391 Vribles n Reltive risk of P vlue tretment filure Disese sttus t trnsplnt f b Complete remission c Prtil remission ( ) 0.05 d Resistnt relpse ( ) d Untreted relpse ( ) 0.01 d Relpse with unknown sensitivity ( ) d Serum LDH t trnsplnt e Norml c Abnorml ( ) d Unknown ( ) 0.65 d Krnofsky performnce score t trnsplnt 0.08 e 90% c % ( ) 0.03 d Unknown ( ) 0.43 d Three of 414 ptients were excluded from the model due to unknown disese sttus post trnsplnt. b P vlue for overll significnce of disese sttus with 4 degree of freedom test. c Reference group. d P vlues for pirwise comprison with reference group. e P vlue for overll significnce of vrible with 2 degree of freedom test. f Other pirwise comprisons: prtil remission vs resistnt relpse (reltive risk 2.41, P vlue = ). All other pirwise comprisons showed P vlue Tble 5 Multivrite nlysis of relpse mong ptients with Hodgkin s disese receiving utotrnsplnts in first relpse or second complete remission Vribles n Reltive risk of relpse P vlue Disese sttus pretrnsplnt f b Complete remission c Prtil remission ( ) d Resistnt relpse ( ) d Untreted relpse ( ) 0.08 d Relpse with unknown sensitivity ( ) d Serum LDH t trnsplnt e Norml c Abnorml ( ) d Unknown ( ) 0.60 d Three of 414 ptients were excluded from the model due to unknown relpse sttus or dtes post trnsplnt. b P vlue for overll significnce of disese sttus with 4 degree of freedom test. c Reference group. d P vlues for pirwise comprison with reference group. e P vlue for overll significnce of vrible with 2 degree of freedom test. f Pirwise comprisons: prtil remission vs resistnt relpse (reltive risk 2.17, P vlue = ). All other pirwise comprisons showed P vlue Discussion The results of this study suggest tht high-dose cytotoxic therpy nd utologous hemtopoietic stem cell trnsplnttion my produce long-term disese-free survivl in ptients relpsing fter initil chemotherpy for Hodgkin s disese. Although the results pper better thn those reported for conventionl slvge regimens, the findings must be interpreted cutiously in view of the observtionl nture of the study nd the potentil for ptient selection bis. Unfortuntely, there is only single, smll, prospective rndomized tril published tht ddresses the question of whether utotrnsplnttion is superior to non-trnsplnt therpy in ptients with relpsed or refrctory Hodgkin s disese. Tht study, by Linch nd co-workers, 30 found superior event-free survivl fter utotrnsplnttion compred to slvge regimen tht is not widely used, ie one with the sme gents utilized in the pre-trnsplnt conditioning regimen, but in non-myelobltive doses. There ws no difference in overll survivl, probbly becuse some ptients filing conventionl therpy were successfully slvged by utotrnsplnttion. The Linch study ws not designed to look specificlly t ptients in first relpse or second complete remission, but lso included ptients filing initil therpy nd those in second relpse. Bone Mrrow Trnsplnttion

6 Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l 392 Tble 6 Multivrite nlysis of overll mortlity mong ptients with Hodgkin s disese receiving utotrnsplnts in first relpse or second complete remission Vribles n Reltive risk of deth P vlue Disese sttus t time of trnsplnt g b Complete remission c Prtil remission ( ) 0.17 d Resistnt relpse ( ) d Untreted, not in remission ( ) d Unknown, not in remission ( ) 0.07 d Serum LDH t trnsplnt f Norml c Abnorml ( ) d Unknown (2.79) 0.21 d Krnofsky performnce score t trnsplnt 0.04 f 90% c % ( ) d Unknown ( ) 0.41 d Initil chemotherpy used h,i MOPP ± others c e ABVD ± others ( ) 0.03 d MOPP/ABVD ± others ( ) 0.17 d Etoposide + others ( ) 0.21 d Others ( ) 0.13 d None ( ) 0.26 d 414 ptients were included in the model. b P vlue for overll significnce of disese sttus with 4 degree of freedom test. c Reference group. d P vlues for pirwise comprison with reference group. e P vlue for overll significnce of initil chemotherpy used with 5 degree of freedom test. f P vlue for overll significnce of vrible with 2 degree of freedom test. g Pirwise comprisons: prtil remission vs resistnt relpse (reltive risk 2.34, P vlue = ); prtil remission vs untreted relpse (reltive risk 1.44, P vlue = 0.04). All other pirwise comprisons showed P vlue h All other pirwise comprisons showed P vlue i Model using MOPP vs non-mopp regimen plus ll other significnt vribles (reltive risk 0.73, P vlue 0.06) Norml serum LDH (n = 285) 80 KPS >90% (n = 254) Probbility, % Unknown (n = 26) Abnorml serum LDH (n = 103) Probbility, % KPS <90% (n = 130) Unknown (n = 30) Yers Figure 2 Probbility of survivl fter utotrnsplnt for Hodgkin s disese in second complete remission or first relpse, ccording to serum LDH t trnsplnt Yers Figure 3 Probbility of survivl fter utotrnsplnt for Hodgkin s disese in second complete remission or first relpse, ccording to Krnofsky performnce score t trnsplnt. Brice nd collegues 31 performed retrospective nlysis of 187 ptients with Hodgkin s disese in first relpse treted with conventionl therpy or utotrnsplnttion. Although there were no significnt differences in overll survivl or freedom from second filure, the trnsplnt group hd more dverse fctors t relpse. A trend for better outcome ws seen with utotrnsplnttion in ptients with more widespred disese t relpse nd/or with n initil remission durtion of 12 months. The survivl nd disese-free survivl rtes reported in the current study re similr to those in most other single institution nd registry studies (Tble 7). Reported disesefree nd overll survivl rtes re s high s 61 79% Although ll of the series in Tble 7 exmined the outcome of utotrnsplnttion in first relpse, eligibility criteri differed. For exmple, the studies by Yhlom et l, 32 Chopr et l, 33 nd Ndemnee et l 35 included only ptients relpsing within 1 yer of completing therpy nd/or filing to Bone Mrrow Trnsplnttion

7 Probbility, % VP16 + other (n = 14) ABVD ± other (n = 108) None (n = 21) MOPP ± other (n = 51) MOPP/ABVD ± other (n = 185) Other (n = 25) Yers Figure 4 Probbility of survivl fter utotrnsplnt for Hodgkin s disese in second complete remission or first relpse, ccording to initil chemotherpy regimen dministered. respond to slvge chemotherpy. The series by Reece et l 39 specificlly excluded ptients nticipted to hve good prognosis with conventionl chemotherpy. Nonetheless, disese-free survivl rtes generlly exceeded 40 45% even in ptients with unfvorble chrcteristics. Erly non-relpse mortlity ws low in the current series, s in other series in which the dt re vilble. Erly toxic deth rtes re generlly less thn 5% in this setting, lower thn seen in ptients trnsplnted with more dvnced or resistnt disese. 32,33,41 44 As shown in Tble 7, investigtors often report tretment-relted mortlity for ll ptients in their series, which hmpers prctitioners in scertining the risk for ptients with specific chrcteristics. However, the low risk of ftl toxicity nd consistently fvorble outcomes ll support the use of trnsplnttion s the preferred tretment of ptients in first relpse or second remission. In our study the outcome of ptients in second complete remission ws significntly better thn tht of ptients in either chemotherpy-sensitive or resistnt first relpse. The strtegy for utilizing slvge chemotherpy in Hodgkin s disese reflects, in prt, dt generted in relpsed non- Hodgkin s lymphom, where disese sttus t utotrnsplnttion predicts outcome. 45 Such n nlysis, however, is hmpered by the fct tht remission sttus cn be difficult to determine when residul msses re present. Furthermore, chievement of complete remission before trnspln- Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l ttion my simply reflect less ggressive tumor biology leding to incresed likelihood of cure regrdless of tretment. One cnnot predict nti-tumor response to slvge therpy, nd some ptients in first relpse my never chieve second complete remission. Some of these subjects my not proceed to trnsplnttion becuse of intercurrent medicl problems ssocited with multiple ttempts to induce remission. This inherent selection bis my explin, in prt, the less fvorble results in untested relpse ptients, reported by groups such s Sweetenhm nd collegues 34 nd Arrnz et l. 40 Thus, superior results for second complete remission ptients my not be the result of beneficil effect of re-induction therpy but rther from identifiction of good prognosis ptients. Of the mny vribles exmined in multivrite nlysis (Tble 1), only Krnofsky performnce score 90%, bnorml serum LDH, resistnt relpse, nd MOPP therpy t dignosis were dverse prognostic fctors for disesefree survivl. Severl investigtors hve identified poor prognostic fctors in heterogeneous ptient groups including individuls with more dvnced relpse or those who filed initil induction therpy. Fewer studies hve exmined prognostic fctors specificlly in first relpse or second remission ptients (Tble 8). In keeping with our findings, Lumley nd ssocites 50 reported elevted serum LDH t trnsplnt to be unfvorble, while Jgnnth et l, 46 Tble 8 Fctors predicting poor outcome in prior studies of utotrnsplnts for relpsed or refrctory Hodgkin s disese Intervl from end-of-therpy until relpse 12 months (34, 36, 39) 1 extr-nodl disese site t relpse (34, 35, 39, 40) Abnorml ECOG performnce sttus (38, 43, 46, 49, 51, 52) Resistnt relpse (38, 42, 47) B symptoms t relpse (39, 48, 49) Bulk disese t trnsplnt (33, 40, 41, 44, 49, 53) Femle gender (33) Exposure to mny chemotherpeutic regimens prior to trnsplnt (33, 35, 46, 47, 51, 52) Elevted serum LDH t trnsplnt (50) Relpse in previous rdition field (44) Disseminted lung or mrrow disese t relpse (49) Fctors reported specificlly in first relpse/second complete remission ptients. Numbers in prenthesis refer to study cited. 393 Tble 7 Results of published series of utotrnsplnts for Hodgkin s disese in first relpse or second complete remission Ref. n Preprtive regimens Erly TRM ( 100 dys) Disese-free survivl Overll survivl ftli/vp16/cy 8/47 (17%) 79% 3.3 yers NS BEAM NS 47% 5 yers NS BEAM, CBV, Cy/TBI, or other 9/139 (7%) 45% 5 yers 49% 5 yers BCNU/VP16/Cy or ftbi/vp16/cy 7/85 (8%) 39% 3 yers NS CBV 3/85 (4%) 40% 5 yers 51% 5 yers BEAM, or BEAC/CBV 17/280 (6%) NS 71% 4 yers CBV NS 42% 5 yers NS CBV ± cispltin 2/58 (3%) 61% 5 yers NS Number with Hodgkin s disese in first relpse or second remission; most series lso include ptients trnsplnted in other disese sttes. TRM = trnsplnt-relted mortlity (totl deths/totl number of ptients in series, which my include ptients other thn first relpse or second remission); NS = not stted; VP16 = etoposide; TBI = totl body irrdition; ftbi = frctionted totl body irrdition; ftli = frctionted totl lymphoid irrdition; Cy = cyclophosphmide; BEAM = BCNU, etoposide, cytrbine, melphln; BEM = BCNU, etoposide, melphln; CBV = cyclophosphmide, BCNU, etoposide; BEAC = BCNU, etoposide, cytrbine, cyclophosphmide; Bu = busulfn. Bone Mrrow Trnsplnttion

8 394 Autotrnsplnts in relpsed Hodgkin s disese HM Lzrus et l Wheeler et l, 38 Reece et l, 43 Horning et l, 49 Biermn et l, 51 nd Anderson et l 52 identified bnorml performnce sttus s predictor for poor outcome. We lso corroborted the observtions of severl noting tht resistnt relpse herlded n inferior result fter trnsplnt. 38,42,47 It is uncler why MOPP therpy t dignosis provided inferior outcome, nd no single cuse of deth ccounted for this finding. Persistent or recurrent Hodgkin s disese ws the mjor cuse for filure; 69% of deths resulted from progressive tumor. This suggests tht strtegies designed to ddress miniml residul disese should be explored to improve upon current results. One pproch involves the complementry role of involved-field rdition therpy in conjunction with high-dose chemotherpy. The inclusion of such rdiotherpy recently ws shown to be of benefit when used in the peri-trnsplnt setting in non-hodgkin s lymphom (JM Vose, unpublished observtions). Dt from three series 33,41,46 suggest benefit for this modlity in utotrnsplnts for recurrent Hodgkin s disese. Ptient selection clerly plys role, s such tretment my be fesible in only minority of ptients due to prior rdition exposure, disese involving multiple sites, or low blood cell counts. We did not observe benefit in this study but the number of ptients receiving involved-field rdiotherpy ws reltively smll. Post-trnsplnt immunotherpy for miniml residul disese is nother intriguing pproch. Immunotoxins directed ginst Reed Sternberg cell ntigens CD15, CD25, CD30, CD40, nd CD80 54 hve been employed in clinicl trils with vrying degrees of success Another novel pproch includes the IL-2/diphtheri fusion toxin, which ws ssocited with some success when given s sole slvge modlity. 58 Allogeneic trnsplnttion my provide potent grft-versus-lymphom effect. However, despite lower relpse rtes, the high tretment-relted mortlity currently ssocited with llogeneic trnsplnttion mke it unlikely to improve survivl compred with utogrfts. 59 It is possible tht llotrnsplnttion done with non-myelobltive conditioning regimens my give better result if erly indictions of lower regimen-relted toxicity prove true. Another potentilly promising pproch is tndem trnsplnttions. Ahmed et l 60 demonstrted tht chemotherpy-refrctory ptients hd n outcome similr to chemotherpy-sensitive ptients if two courses of high-dose therpy, ech with utotrnsplnttion, were given. One recent pproch is to perform utotrnsplnttion followed by non-myelobltive llotrnsplnttion, thus combining dose-intensive nd immune-medited nti-tumor pproches. These nd other pproches to improving tumor erdiction with cceptble toxicity should be the object of future investigtions. Acknowledgements This study ws supported, in prt, by Public Helth Service Grnt No. P30-CA43703 from the Ntionl Cncer Institute nd by Public Helth Service Grnts Nos P01-CA40053 nd U24-CA76518 from the Ntionl Cncer Institute, the Ntionl Institute of Allergy nd Infectious Diseses, nd the Ntionl Hert, Lung nd Blood Institute of the US Deprtment of Helth nd Humn Services; nd by grnts from Amgen, Inc.; Anonymous; Bxter Fenwl; Berlex Lbortories; Blue Cross nd Blue Shield Assocition; Lynde nd Hrry Brdley Foundtion; Bristol-Myers Squibb Oncology; Cell Therpeutics; Center for Advnced Studies in Leukemi; Chimeric Therpies; Chiron Therpeutics; COBE BCT Inc.; Elenor Nylor Dn Chritble Trust; Deborh J Derholt Memoril Fund; Empire Blue Cross Blue Shield; Eppley Foundtion for Reserch; Fromstein Foundtion; Fujisw Helthcre, Inc.; Genentech, Inc.; Hoechst Mrion Roussel; Horizon Medicl Products; Humn Genome Sciences; IDEC Phrmceuticls; Immunex Corportion; IMPATH/BIS; IntrBiotics Phrmceuticls; Kiser Permnente; Kettering Fmily Foundtion; Kirin Brewery Compny; Robert J Kleberg, Jr nd Helen C Kleberg Foundtion; Herbert H Kohl Chrities; LifeTrc/ Allinz; The Liposome Compny; Nd nd Herbert P Mhler Chrities; Mrket Certitude; Myer Ventures; MDS Nordin; MedImmune, Inc.; Millimn & Robertson, Inc.; Milstein Fmily Foundtion; Miltenyi Biotech; Milwukee Foundtion/Els Schoeneich Reserch Fund; Mutul of Omh; Nexell Therpeutics; NeXstr Phrmceuticls, Inc; Smuel Roberts Noble Foundtion; Novrtis Phrmceuticls; Orphn Medicl; Ortho Biotech, Inc.; John Oster Fmily Foundtion; Jne nd Lloyd Pettit Foundtion; Pfizer, Inc.; Phrmci nd Upjohn; Principl Life Insurnce Compny; Protide Phrmceuticls; RGK Foundtion; Rhône- Poulenc Rorer Phrmceuticls, Inc.; Roche Lbortories; SngStt Medicl Corportion; Schering AG; Schering-Plough Oncology; Serle; SmithKline Beechm Phrmceuticl; Stckner Fmily Foundtion; The Strr Foundtion; StemCell Technologies; SyStemix; Therkos; TherTechnologies; United Resource Networks; US Oncology; nd Wyeth-Ayerst Lbortories. 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