High-dose therapy and autologous stem cell rescue for patients with Hodgkin s disease in first relapse after chemotherapy: results from the EBMT

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1 Bone Mrrow Trnsplnttion, (1997), Stockton Press All rights reserved /97 $12.00 High-dose therpy nd utologous stem cell rescue for ptients with Hodgkin s disese in first relpse fter chemotherpy: results from the EBMT JW Sweetenhm 1, G Tghipour 2, D Millign 3, AK Blystd 4, D Cbllero 5, A Fsss 6 nd AH Goldstone 2 on behlf of the Lymphom Working Prty of the Europen Group for Blood nd Mrrow Trnsplnttion 1 CRC Wessex Medicl Oncology Unit, University of Southmpton, UK; 2 Deprtment of Hemtology, University College London, UK; 3 Hertlnds Hospitl, Birminghm, UK; 4 Norwegin Rdium Hospitl, Oslo, Norwy; 5 Hospitl Clinico, Slmnc, Spin; nd 6 George Ppnicolo Generl Hospitl, Thessloniki, Greece Summry: The purpose of this study ws to investigte the results The use of conventionl-dose slvge chemotherpy in of high-dose therpy nd utologous stem cell trnscombintion ptients with Hodgkin s disese who relpse fter initil plnttion in dult ptients with Hodgkin s disese in chemotherpy is ssocited with high first relpse fter chemotherpy, to determine the overlonger remission rtes, especilly if the initil CR durtion is ll nd progression-free survivl, identify prognostic thn 1 yer. 1 5 However, long-term follow-up stud- fctors for outcome, nd to define the role of conventionl ies hve shown tht less thn % of these ptients chieve dose slvge therpy given prior to the high dose long-term disese-free survivl. 6 regimen. A retrospective nlysis of 139 dult ptients High-dose therpy, with utologous stem cell trnsplnreported to the lymphom registry of the Europen ttion (ASCT), hs been used extensively in ptients with Group for Blood nd Mrrow Trnsplnttion (EBMT) relpsed Hodgkin s disese In erly studies, its use ws between Februry 1984 nd July 1995 is considered. confined to ptients who hd filed multiple combintion Dt on ll ptients were reviewed nd prognostic fc- chemotherpy regimens. Anlysis of prognostic fctors in tors determined in univrite nlysis. The cturil 5- these studies demonstrted tht extensive prior therpy, yer overll survivl (OS) nd progression-free survivl short remission durtion, resistnce of disese to conven- (PFS) for the entire group of 139 ptients were 49.4 nd tionl-dose chemotherpy nd bulk disese t the time of 44.7%, respectively. In univrite nlysis for OS, dis- ASCT were commonly identified dverse fetures. ese bulk t the time of high-dose therpy, second-line As result of these findings, nd of decision nlyses regimen, initil remission durtion nd sttus t trns- regrding the use of high-dose therpy, 15 severl groups plnt hd no predictive vlue. Sttus t trnsplnt ws hve recently reported the use of high-dose therpy in predictive for OS when ptients in second complete ptients with Hodgkin s disese t the time of the first remission (CR) were nlysed seprtely from those in relpse fter chemotherpy. 10,13,14,16 These single institution chemosensitive relpse. Similr trends were observed studies hve shown fvourble outcome for these ptients for PFS. We concluded tht high-dose therpy nd utocompred with historicl series of conventionlly treted logous stem cell trnsplnttion is n effective strtegy ptients, nd hve gin identified prognostic fctors for for ptients with Hodgkin s disese in first relpse fter long-term disese-free survivl, including durtion of initil chemotherpy. These results suggest tht it should be remission, disese bulk t the time of ASCT, nd sensitivity used regrdless of initil remission durtion. The role to conventionl-dose therpy given prior to the high-dose of conventionl-dose slvge given prior to high-dose therpy is uncler, since disese sttus, disese bulk t regimen. However, the prognostic vlue of some of these the time of trnsplnttion, nd the second-line regimen fctors hs been questioned in recent reports. hd no significnt effect on outcome. However, in view We hve therefore nlysed the outcome for ptients of the low ptient numbers, no firm conclusion is posswith Hodgkin s disese receiving high-dose therpy nd ible, nd this issue requires prospective ssessment. ASCT in first relpse fter chemotherpy who hve been Keywords: high-dose therpy; ASCT; Hodgkin s disfor Blood nd Mrrow Trnsplnttion, in n ttempt to reported to the Lymphom Registry of the Europen Group ese; first relpse identify predictive fctors for outcome fter high-dose therpy, nd to ttempt to define the role of conventionl-dose slvge therpy given immeditely prior to the high-dose Correspondence: Dr JW Sweetenhm, CRC Wessex Medicl Oncology Unit, University of Southmpton, Southmpton Generl Hospitl, regimen. Tremon Rod, Southmpton SO16 6YD, UK Received 5 April 1997; ccepted 30 June 1997

2 746 Ptients nd methods (doxorubicin, bleomycin, vinblstine, dcrbzine), 19 MOPP lternting with ABVD, or vrints of these regimens such s MVPP (mustine, vinblstine, procrbzine, Ptient chrcteristics prednisone) or ChlVPP (chlormbucil, vinblstine, pro- Between Februry 1984 nd July 1995, totl of 139 dult crbzine, prednisone). 21 A smll proportion of ptients ptients with Hodgkin s disese, treted with high-dose received hybrid regimens such s MOPP/ABV (mustine, therpy nd ASCT for first relpse fter chemotherpy were vincristine, procrbzine, prednisone, doxorubicin, bleoreported to the EBMT from 31 centres. mycin, vinblstine), 22 or intensive weekly regimens such s Ptients were included in this nlysis if they hd PACE/BOM (prednisone, doxorubicin, cyclophosphmide, chieved complete remission (CR), or complete remission etoposide, bleomycin, vincristine, methotrexte) 23 or uncertin (CR u ) ccording to the Cotswolds response cri- VAPEC-B (vinblstine, doxorubicin, prednisone, etopoteri, 17 fter initil combintion chemotherpy. side, cyclophosphmide, bleomycin). 24 Eighty one ptients Their medin ge t dignosis ws 28 yers 7 months received chemotherpy lone s induction therpy. (rnge: 16 yers 1 month 55 yers 2 months), nd t trns- Additionl rdiotherpy ws used in 57 ptients, ccording plnt ws 31 yers 7 months (rnge: 18 yers 6 months to ctive protocols t prticipting institutions. yers 8 months). The medin time from dignosis to Ptients were ssessed for response 1 month fter the ASCT ws 2 yers 4 months (rnge: 3 months 18 yers). completion of chemotherpy, nd the durtion of first Other ptient chrcteristics t presenttion re shown remission ws clculted from the dte on which CR ws in Tble 1. Sixty-three ptients hd medistinl msses t confirmed, to the dte of relpse. The medin remission presenttion, mesuring 1/3 of the trnsthorcic dimeter durtion following first-line chemotherpy ws 11.5 months in 27. (rnge, 0.5 months to 16 yers 6 months). Sixty-three ptients (45%) relpsed within 12 months of chieving CR, First-line therpy nd 57 ptients (41%) relpsed lter thn 12 months. Dt on durtion of first remission could not be obtined for the The detils of initil chemotherpy regimens re shown in remining 19 ptients. Tble 1. Most ptients received either MOPP (mustine, vincristine, procrbzine, prednisone), 18 ABVD Second-line therpy Most ptients were treted with second-line combintion Tble 1 Presenting chrcteristics nd tretment detils chemotherpy regimen t the time of relpse. A totl of 22 ptients (16%) were treted with high-dose therpy t the No. % time of relpse, with no ttempt to induce second remission with conventionl-dose chemotherpy. These Totl 139 Mle ptients did not differ significntly from those who received Femle second-line therpy in terms of their chrcteristics t Stge: relpse. In prticulr, the disese bulk t relpse ws I 5 4 eqully distributed mongst ll ptient groups, with no II III trend for higher proportion of ptients with low disese IV bulk in the untested relpse group. B symptoms For those ptients receiving second-line chemotherpy, Mximum disese bulk: the regimens used re shown in Tble 1. Ptients received 5 cm vrible number of courses of chemotherpy for reinduc cm cm 14 tion, depending upon the ctive protocols t ech prticipt- Unknown 56 ing centre. In some institutions, ptients were treted until Bone mrrow involvement ttinment of second complete remission. In other centres, First-line regimen second-line chemotherpy ws used for debulking or to MOPP, ABVD or vrint Alternting ssess disese sensitivity prior to the high-dose regimen, Hybrid but chievement of CR ws not prerequisite for high- Intensive weekly 4 3 dose therpy. Other 6 4 Fifty-six ptients chieved CR to second-line chemo- Second-line regimen therpy nd were in second CR t the time of high-dose None (untested) MOPP or vrint therpy. The disese sttus for the whole study popultion ABVD or vrint t the time of ASCT, clssified s described by Philip et MOPP/ABVD or vrint l, 28 is shown in Tble 2. Tble 3 shows the disese bulk DHAP 9 7 t the time of high-dose therpy nd ASCT. Medistinl CEP 1 1 MiniBEAM 11 8 disese ws present in 26 ptients t the time of ASCT, Other mesuring 1/3 of the trnsthorcic dimeter in five. See text for detils. DHAP = dexmethsone, cytosine rbinoside, cispltin; 25 CEP = lomustine, etoposide, prednisolone; 26 minibeam = crmustine, etoposide, cytosine rbinoside, melphln. 27 High-dose therpy nd trnsplnttion procedures The high-dose regimens vried ccording to individul institutions nd their ctive protocols. Detils of high-dose

3 Tble 2 Disese sttus t time of high-dose therpy progression. Tretment-relted deths occurring within 90 dys of the dte of stem cell reinfusion were defined s Sttus No. % erly, those occurring lter were defined s lte tretmentrelted deths. Second CR Univrite nlysis ws performed using the log rnk Sensitive relpse test, to identify ptient chrcteristics which might be pre- Untested relpse Resistnt relpse 6 4 dictive of outcome fter ASCT. The fctors exmined in univrite nlysis were s follows: sex, Ann Arbor stge t dignosis (I vs II vs III vs IV), disese bulk t dignosis ( 5 cmvs 5 10 cm vs 10 cm), durtion of first CR ( 1 Tble 3 Disese bulk t time of high-dose therpy yer vs 1 yer, nd 1 yer vs 1 2 yers vs 2 yers), second-line chemotherpy regimen (MOPP-like vs ABVDlike vs MOPP/ABVD-like vs DHAP/CEP/miniBEAM vs Bulk No. % others), disese bulk t ASCT (in CR vs 5 cmvs 5 10 In complete remission cm vs 10 cm), high-dose regimen (chemotherpy only vs 5 cm 55 TBI-bsed), source of stem cells (bone mrrow only vs 5 10 cm PBPC or both). The effect of disese sttus t ASCT ws 10 cm 7 5 nlysed in two wys. In view of the difficulty in determin- Unknown 3 2 ing remission sttus in Hodgkin s disese with residul msses of uncertin significnce, n initil nlysis ws conducted in which ptients in second CR nd sensitive therpy re given in Tble 4. Bone mrrow ws the only relpse were nlysed together (sensitive relpse vs source of utologous stem cells in 94 (68%) of ptients, untested relpse vs resistnt relpse). A further nlysis ws peripherl blood progenitor cells were used in 35 (25%), then conducted in which the second CR nd sensitive nd 10 ptients (7%) received both. No purging of bone relpse ptients were nlysed seprtely. mrrow or peripherl blood progenitor cells ws performed. Multivrite nlysis ws performed using the Cox s pro- All of the ptients underwent high-dose therpy nd portionl hzrds model. The fctors exmined were s for ASCT in registered trnsplnt centres, nd received ntibiotics, the univrite nlysis. blood product nd other supportive cre ccording to the protocols of the individul centres. The use of hemtopoietic growth fctors following stem cell reinfusion hs Results evolved during the period of this study. In totl, ptients were treted with hemtopoietic growth fctors, most commonly Response nd survivl grnulocyte colony-stimulting fctor (G-CSF), The responses to high-dose therpy nd ASCT re summr- either lone (69 ptients), or in combintion with other ised in Tble 5. growth fctors (three ptients). The cturil overll survivl (OS) nd progression-free One ptient received involved field rdiotherpy to sites survivl (PFS) for the entire group re shown in Figure 1. of prior disese bulk fter recovery from high-dose therpy With medin follow-up of 2.75 yers (rnge, nd ASCT. yers) the 5-yer cturil OS for ll ptients is 49.4%. The 5-yer cturil PFS is 44.7%. Sttisticl nlysis Survivl nlyses were performed ccording to the method Prognostic fctors of Kpln nd Meier. 29 Overll survivl ws clculted None of the fctors exmined in univrite nlysis were from the dte of utologous stem cell reinfusion to the dte predictive of overll survivl. Although trend ws of deth from ny cuse. Progression-free survivl ws cl- observed for poorer OS in ptients with resistnt relpse culted from the dte of utologous stem cell trnspln- compred with untested or responsive relpse, this did not ttion to the dte of deth or the dte of documented disese 747 Tble 4 High-dose regimens Regimen No. % Tble 5 Response to high-dose therpy nd ASCT Response No. (%) Totl 139 BEAM Mintined CR (ptients in CR2) 58 (42) CBV 28 CR 55 () Other chemotherpy only regimens PR 12 (9) Cyclophosphmide + TBI 9 6 NR 5 (4) Other TBI-bsed regimens 2 1 Relpse/progression 3 (2) Toxic deth 9 (6) BEAM = crmustine, etoposide, cytosine rbinoside, melphln; 27 CBV = cyclophosphmide, crmustine, etoposide; 16 TBI = totl body irrdition. Inevluble (too erly) 2 (1)

4 748 P = % EFS OS n = 139 PFS n = 139 CR2 n = 57 Sensitive relpse n = 54 Resistnt relpse n = 6 Figure 1 Overll survivl (OS) nd progression-free survivl (PFS) for entire group of 139 ptients. chieve sttisticl significnce (Figure 2). However, when ptients undergoing high-dose therpy in second CR, were nlysed seprtely from those in sensitive relpse who hd not ttined second CR t the time of ASCT, significnt difference in OS ws observed ccording to disese sttus t ASCT (Figure 3). Disese bulk t the time of high-dose therpy (Figure 4), hd no influence on OS fter ASCT. Similrly, the initil remission durtion hd no effect on OS whether nlysed ccording to remission durtion of 1 yer vs 1 yer, or 1 yer vs 1 2 yers vs 2 yers (Figure 5). % PFS b Resistnt relpse n = 6 P = 0.23 Chemosensitive n = 111 Untested relpse n = 22 Chemosensitive n = 111 Untested relpse n = 22 Resistnt relpse n = 6 P = Figure 2 Overll survivl () nd progression-free survivl (b) ccording to disese sttus t time of ASCT. % PFS b CR2 n = 57 Untested relpse n = 22 P = Untested relpse n = 22 Resistnt relpse n = 6 Sensitive relpse n = 54 Figure 3 Overll survivl () nd progression-free survivl (b) ccording to disese sttus t time of ASCT, with ptients in second complete remission (CR2) nlysed seprtely. In univrite nlysis for progression-free survivl, there ws gin trend for poorer PFS in ptients with resistnt relpse (Figure 2b), but this ws not significnt t the 95% level. Agin, this trend becme significnt when second CR nd sensitive relpse ptients were nlysed seprtely (Figure 3b). The only other predictive fctor for PFS ws disese bulk t the time of high-dose therpy, where ptients with either 10 cm or 5 cm bulk hd inferior PFS compred with ptients in second complete remission, or with 5 10 cm bulk (Figure 4b). In multivrite nlysis for OS nd PFS, sttus t ASCT ws predictive if ptients in second remission nd sensitive relpse were nlysed seprtely (P = for OS). No other significnt fctors were identified in multivrite nlysis. Toxicity There ws totl of nine (6.5%) erly toxic deths (within 90 dys of ASCT). The cuses were infection (six ptients), heptic veno-occlusive disese (two ptients), nd crdic toxicity (one ptient). A further eight deths were clssified s lte toxic deths, giving toxic deth rte of 8.5% t 4 yers by Kpln Meier nlysis. Cuses of lte toxic deth were infection

5 P = P = >10 cm n = 7 in CR n = cm n = 17 <1 yer n = 63 >1 yer n = 57 <5 cm n = 55 b P = b >2 yers n = 34 P = % PFS >10 cm n = 7 in CR n = cm n = yers n = 23 >1 yers n = 64 >5 cm n = 55 Figure 4 Overll survivl () nd progression-free survivl (b) ccord- Figure 5 Overll survivl ccording to durtion of initil remission: () ing to disese bulk t time of ASCT. compring initil remission durtion of 1 yer vs 1 yer, nd (b) compring initil remission durtion of 1 yer vs 1 to 2 yers vs 2 yers. (four ptients), second mlignncy (three ptients) nd crdic toxicity (one ptient). Severl single institution studies, prticulrly the studies from Miln, hve observed superior long-term DFS for Discussion ptients receiving conventionl-dose slvge therpy. 2,3 For exmple, in the Miln series, 5-yer progression-free survivl High-dose therpy nd ASCT is now widely used in the of 51% ws reported for ptients with n initil tretment of relpsed nd refrctory Hodgkin s disese, remission durtion of over 12 months, who relpse fter lthough the pproprite timing of this therpeutic strtegy MOPP, ABVD or MOPP/ABVD therpy. 3 Similr, fvour- remins uncertin This is prtly due to the well docu- ble results hve been reported for novel slvge regimens mented observtion tht second, sometimes durble complete for ptients with long, nd short initil remissions. remission cn be induced with further conventionl- However, these fvourble results hve not been repro- dose therpy. 1 The high reported toxicity of high-dose therpy duced in multi-institutionl setting. For exmple, in nd ABMT hs lso influenced the timing of this recent rndomised study conducted by the Cncer nd Leuduced pproch. In most centres, until recently, high-dose therpy kemi Group B (CALGB), ptients who were initilly ws reserved for ptients in their second, or lter relpse treted with ABVD chemotherpy, who relpsed nd fter combintion chemotherpy. A decision nlysis received MOPP chemotherpy s second line hd 5-yer reported by Desch et l 15 suggested tht high-dose therpy filure-free survivl rte of 31%, compred with 15% for should be reserved for ptients in second relpse. those receiving MOPP first line nd ABVD t relpse. 4 However, long-term follow-up of ptients receiving con- By contrst, the results from the use of high-dose therpy ventionl-dose slvge fter first relpse hs been disppointing. nd ASCT in this sitution hve been encourging. In In the series reported from the NCI, 93% of series from London, Chopr et l 10 reported 47% 5 yers ptients with dvnced Hodgkin s disese relpsing fter freedom from progression for 52 ptients receiving high- MOPP chemotherpy could be reinduced into second CR dose therpy t first relpse. Similr results were reported with further MOPP therpy, if the initil remission durtion in series of 58 ptients receiving high-dose therpy t first ws greter thn 12 months. 6 However, only 17% of these relpse in Vncouver. 8 With medin follow-up of 2.3 ptients were live t yers. For ptients with initil yers, the cturil PFS ws 64%. Ndemnee et l 13 hve remission durtions of less thn 12 months, only 29% reported series of 85 ptients with relpsed Hodgkin s chieved second CR with MOPP reinduction. disese undergoing high-dose therpy, 33 of whom were

6 750 treted t first relpse or second CR. Long-term DFS ws outcome. This effect ws lessened, nd becme non-significnt reported in bout % of these ptients. when ptients in second CR nd sensitive relpse The group from Omh Nebrsk hve recently reported were combined. Direct comprison of OS for ptients trnsplnted 5-yer cturil OS of 51% nd filure-free survivl of in second CR or in chemosensitive relpse showed % for 85 ptients receiving ASCT for Hodgkin s disese significnt difference in fvour of those ptients in second following the first relpse fter chemotherpy. 14 CR (P = 0.033). However, since remission sttus cn be The results of ll of these series re clerly superior to difficult to determine in Hodgkin s disese when residul the outcomes reported for conventionl-dose slvge, but msses re present, this difference in outcome should be there is potentil for selection bis in these studies, which interpreted cutiously. No such difference in OS ws re mostly single institution series. Brice et l 30 hve observed between ptients in second CR compred with recently reported the results of multicentre, retrospective those in untested relpse (P = 0.) or between those with nlysis of outcome for ptients with Hodgkin s disese in sensitive relpse nd untested relpse (P = 0.48). first relpse. In this study, no difference ws observed in As with overll survivl, sttus t ASCT ws predictive overll survivl for ptients receiving high-dose compred for PFS if second CR nd chemosensitive ptients were with conventionl-dose slvge therpy. Prospective rn- nlysed seprtely, but the effect ws lessened if these two domised comprisons of conventionl-dose therpy with groups were combined, nd becme non-significnt. high-dose therpy nd ASCT re required. To dte, one Disese bulk t ASCT ws predictive of DFS, with smll rndomised tril with ptients hs been reported poorer DFS in the group with 5 cm disese t the time by the British Ntionl Lymphom Investigtion. 27 This of ASCT. This observtion is difficult to explin, since study included ptients in first or subsequent relpse, who ptients with 10 cm disese bulk hd significntly better were rndomised to receive high-dose therpy nd ASCT, DFS. A similr trend ws seen for this group with respect using BEAM, or conventionl dose therpy, mini- to overll survivl, lthough this ws not significnt t the BEAM, including the sme drugs t non-myelobltive 95% level. We hve explored the possibility tht the group doses. A significnt difference in event-free survivl ws with 5 cm disese bulk hs higher proportion of ptients observed for ptients receiving BEAM compred with with chemoresistnt disese t relpse, but this ws not the mini-beam, lthough no difference in OS ws observed. cse only two ptients in this group underwent ASCT in However, since some ptients who relpsed fter mini- resistnt relpse. BEAM were treted t relpse with BEAM nd ASCT, the In most centres, ptients undergoing high-dose therpy impct of high-dose therpy on OS is difficult to interpret. for relpsed Hodgkin s disese re initilly treted with The results reported in our series must clerly be interpreted conventionl-dose slvge therpy. This pproch is bsed cutiously in view of the registry-bsed nture of on erly experience in relpsed non-hodgkin s lymphom, the study, nd the potentil for selection bis. However, the demonstrting the prognostic significnce of disese sensi- 5-yer cturil OS of 49.4% nd DFS of 44.7% re very tivity t the time of ASCT. Reduction of tumour bulk prior similr to the single institution series reported bove, nd to high-dose therpy is nother potentil dvntge of suggest tht this pproch is superior to conventionl-dose this pproch. slvge therpy. However, bsed on the results of the present nlysis, The selection of pproprite ptients for high-dose sl- the role of initil conventionl-dose therpy is uncler. No vge t first relpse remins uncertin. Anlysis of prognostic survivl dvntge ws observed for ptients with chemo- fctors in these ptients hs yielded conflicting results sensitive disese when compred with those in untreted in previous series. For exmple, in the series from Vncouver relpse or resistnt relpse, lthough it is importnt to note 8 nd London, 10 nd in report from Miln, 3 n tht only six ptients were treted in resistnt relpse, nd initil remission durtion of greter thn 1 yer ws ssocited there ws non-significnt trend for poorer outcome in this with superior long-term DFS nd OS. In contrst, group, which might hve chieved significnce with higher no such effect ws seen in the series from Ndemnee et numbers. Similrly, disese bulk t the time of ASCT hd l. 13 Similrly, the Nebrsk group reported tht the no impct on overll survivl. These findings re consistent durtion of initil remission hd no significnt effect on with some previous reports. In the study reported by Bier- outcome. 14 mn et l, 9 ptients treted with ASCT in untreted relpse Disese sttus t ASCT ws not found to be predictive hd superior FFS compred with those receiving initil of outcome in the Vncouver series or in the series from conventionl-dose slvge. These uthors concluded tht City of Hope. 13 However, in the study by Chopr et l, 10 trnsplnttion should be considered for some ptients in nd the Nebrsk series, superior PFS ws reported for erly relpse, especilly with low volume disese, without ptients undergoing high-dose therpy in untreted relpse, the use of pretrnsplnt conventionl-dose slvge chemo- compred with chemosensitive or chemoresistnt ptients. therpy. Similr observtions were mde in the London Other fctors shown to be predictive for OS or PFS in other study. series hve included the number of prior chemotherpy It is lso noteworthy tht the type of second-line slvge regimens, prior rdition therpy, nd the presence of B therpy hd no influence on outcome fter ASCT, nd it symptoms t relpse. ws therefore not possible to identify n effective conventionl In the present study, we hve been unble to identify dose, pre-trnsplnt slvge therpy. prognostic fctors for overll survivl in these ptients. A Although ptients undergoing ASCT in second CR hd significnt trend ws seen for OS ccording to disese superior outcome to those in chemosensitive relpse, this sttus, with ptients treted in second CR hving superior observtion cnnot be explined on the bsis of the debulk-

7 ing effect of second-line therpy, since low disese bulk 4 Cnellos GP, Anderson JR, Propert KJ et l. Chemotherpy t the time of ASCT ws not shown to be fvourble of dvnced Hodgkin s disese treted with MOPP, ABVD, predictive fctor. This observtion my therefore simply or MOPP lternting with ABVD. New Engl J Med 1992; 327: reflect the intrinsic responsiveness of the disese to Firey AF, Med GM, Jones HW et l. CAPE/PALE slvge chemotherpy, nd does not suggest tht the second-line chemotherpy for Hodgkin s disese ptients relpsing within therpy contributes to the long-term outcome in these 1 yer of ChlVPP chemotherpy. Ann Oncol 1993; 4: 857 ptients. 8. In summry, the results of this study suggest tht high- 6 Longo DL, Duffey PL, Young RC et l. Conventionl dose dose therpy nd ASCT my produce superior long-term slvge combintion chemotherpy in ptients relpsing with disese-free nd overll survivl for ptients with Hodgprobbility Hodgkin s disese fter combintion chemotherpy: the low kin s disese in first relpse fter chemotherpy, compred for cure. J Clin Oncol 1992; 10: with conventionl-dose slvge, lthough this requires 7 Phillips GL, Wolff SN, Herzig RH et l. Tretment of pro- further evlution in prospective, rndomised trils. In gressive Hodgkin s disese with intensive chemordiotherpy ddition, they suggest tht ll ptients in first relpse should nd utologous bone mrrow trnsplnttion. Blood 1989; 73: receive high-dose therpy irrespective of the durtion of 8 Reece DE, Brnett MJ, Connors JM et l. Intensive chemotheir initil remission. The role of conventionl-dose sltherpy with cyclophosphmide, crmustine, nd etoposide vge therpy given prior to high-dose therpy remins followed by utologous bone mrrow trnsplnttion for uncler, nd prospective studies re lso required to ddress relpsed Hodgkin s disese. J Clin Oncol 1991; 9: this issue. 9 Biermn PJ, Bgin RG, Jgnnth S et l. High dose chemotherpy followed by utologous hemtopoietic rescue in Hodgkin s disese: long term follow-up in 128 ptients. Ann Acknowledgements Oncol 1993; 4: Chopr R, McMilln AK, Linch DC et l. The plce of high dose BEAM therpy nd utologous bone mrrow trnspln- The following members of the EBMT contributed ptients to this ttion in poor-risk Hodgkin s disese. A single center 8-yer study: MA Boogerts, University Hospitl Gstthuisberg, Leuven, study of 155 ptients. Blood 1993; 81: Belgium; B Bjorkstrnd, Huddinge University Hospitl, Sweden; 11 Crump M, Smith AM, Brndwein J et l. High-dose etoposide HG Prentice, Royl Free Hospitl, London, UK; D Cunninghm, nd melphln, nd utologous bone mrrow trnsplnttion Royl Mrsden Hospitl, London, UK; A Tobler, University Hosfor ptients with dvnced Hodgkin s disese: importnce of pitl, Bern, Switzerlnd; G Enhiger, University Hospitl, Tubdisese sttus t trnsplnt. J Clin Oncol 1993; 11: ingen, Germny; A Ferrnt, Cliniques Universitire St Luc, Brux- 12 Rpoport AP, Rowe JM, Kouides PA et l. One hundred utoelles, Belgium; S Brunet, Hospitl Snt Creu i Snt Pu, trnsplnts for relpsed or refrctory Hodgkin s disese nd Brcelon, Spin; D Hollrd, Hopitl A Michllon, Grenoble, lymphom: vlue of pretrnsplnt disese sttus for predicting Frnce; P Colombt, Hopitl Bretonneu, Tours, Frnce; SJ Procoutcome. J Clin Oncol 1993; 11: tor, Royl Victori Hospitl, Newcstle, UK; D Millign, Hert- 13 Ndemnee A, O Donell MR, Snyder DS et l. High-dose lnds Hospitl, Birminghm, UK; A de Lurenzi, Ospedle Sn chemotherpy with or without totl body irrdition followed Cmillo, Rom, Itly; MC Bess Rodrigues Azevdo, Inst Portuby utologous bone mrrow nd/or peripherl blood stem cell gues Oncologi, Porto, Portugl; H Link, Medicl School of trnsplnttion for ptients with relpsed nd refrctory Hodg- Hnnover, Germny; P Coser, Hospitl Sn Murizio, Bolzno, kin s disese: results in 85 ptients with nlysis of prognostic Itly; G Rosti, Ospedle Civili, Rvenn, Itly; JJ Orteg, Hospitl fctors. Blood 1995; 85: Infntil Vll d Hebron, Brcelon, Spin; A Fsss, The George 14 Biermn PJ, Anderson JR, Freemn MB et l. High-dose Ppnicolo Generl Hospitl, Thessloniki, Greece; H Wndt, chemotherpy followed by utologous hemtopoietic rescue Klinik Nurnberg, Germny; D Crrer-Fernndez, Hospitl Covfor Hodgkin s disese ptients following first relpse fter dong, Oviedo, Spin; JW Sweetenhm, Southmpton University chemotherpy. Ann Oncol 1996; 7: Hospitls, UK; M Bccrni, Udine University Hospitl, Itly; PJ 15 Desch CE, Lsl MR, Smith TJ et l. The optiml timing of Crey, The Royl Infirmry, Sunderlnd, UK; J Beslduch, Hospiutologous bone mrrow trnsplnttion in Hodgkin s disese tl Sn Duret, Plm de Mllorc, Spin; V Milovic, Anrtid ptients fter chemotherpy relpse. J Clin Oncol 1992; 10: ICTEM, Hospitl Provdo, Buenos Aires, Argentin; D cbllero, 0 9. Hospitl Clinico, Slmnc, Spin; I Ben-Bsst, Tel-Aviv 16 Reece DE, Connors JM, Spinelli JJ et l. Intensive therpy University, Tel-Hshomer, Isrel; AK Blystd, The Norwegin with cyclophosphmide, crmustine etoposide ± cispltin, nd Rdium Hospitl, Oslo, Norwy; M Grmtzki, University of utologous bone mrrow trnsplnttion for Hodgkin s disese Erlngen-Nur, Erlngen, Germny. in first relpse fter combintion chemotherpy. Blood 1994; 83: References 17 Lister TA, Crowther D, Sutcliffe SB et l. 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8 752 for survivl in stge IIIB nd IV Hodkin s disese: multivri- 26 Sntoro A, Vivini S, Vlguss P et l. CCNU, etoposide te nlysis compring two specilist tretment centres. Br J nd prednisolone (CEP) in refrctory Hodgkin s disese. Cncer 1988; 46: Semin Hemtol 1986; 13 (Suppl. 1): McKendrick JJ, Med GM, Sweetenhm JW et l. ChlVPP 27 Linch DC, Winfield D, Goldstone AH et l. Dose intensifichemotherpy in dvnced Hodgkin s disese. Eur J Cncer ction with utologous bone mrrow trnsplnttion in Clin Oncol 1989; 25: relpsed nd resistnt Hodgkin s disese: results of BNLI 22 Klimo P, Connors JM. An updte on the Vncouver experi- rndomised tril. Lncet 1993; 341: ence in the mngement of dvnced Hodgkin s disese 28 Philip T, Armitge JO, Spitzer G et l. High-dose therpy nd treted with the MOPP/ABV hybrid progrm. Semin Hemtol utologous bone mrrow trnsplnttion fter filure of con- 1988; 25 (Suppl. 2): 34. ventionl chemotherpy in dults with intermedite grde or 23 Sweetenhm JW, Med GM, Jeffrey GM et l. Twelve weeks high grde non-hodgkin s lymphom. New Engl J Med 1987; lternting chemotherpy for dvnced Hodgkin s disese 316: results of pilot study. Exp Hemtol 1992; : Kpln EL, Meier P. Non-prmetric estimtion from incom- 24 Rdford JA, Crowther D. Tretment of relpsed Hodgkin s plete observtions. Am Stt Assoc 1979; 53: disese using weekly chemotherpy of short durtion: results 30 Brice P, Bstion Y, Divine M et l. Anlysis of prognostic of pilot study in ptients. Ann Oncol 1991; 2: fctors fter the first relpse of Hodgkin s disese in Velsquez WS, Cbnills F, Slvdor P et l. Effective slptients. Cncer 1996; 78: vge therpy for lymphom with cispltin in combintion with high dose Ar-C nd dexmethsone (DHAP). Blood 1988; 71: