Autologous stem cell transplantation for aggressive non-Hodgkin’s lymphomas
G. San ti n i1 A. M. Con gi u1 S. Nati1 G. Mar i n o1 V. Nar di1 M. Spr i an o1 R. Vi mer cati1 A. Ru bagotti1 C. A. Sou za2
Ar ti go Especi al / Speci al Ar ti cle
Introduction
Over the last ten years, claims have been m ad e t h at seco n d an d t h i r d gen er at i o n chemotherapy (CT) regimens have improved survival in the advanced stage, intermediate or high-grade malignancy non-Hodgkin’s lymphomas (NHL) (Groups F-G-H-K/ Working Formulation, excluding lymphoblastic and Burkitt lymphoma)1. In spite of this, the percentage of achievable
1 - Depar tmen t of Haematology, Di vi si on of Haematology I, San Mar ti n o Hospi tal, Gen ova, Italy 2 - Haematology an d Blood Tr an sfu si on Cen tr e - State Un i ver si ty of Campi n as, Br azi l
Correspondence to: Gi n o San ti n i
Depar tmen t of Haematology. Di vi si on of Haematology I
Azi en da Ospedali er a San Mar ti n o e Delle Cli n i che Un i ver si tar i e Con ven zi on ate Lar go Rosan n a Ben zi 10, 16135. Gen ova, Italy
Tel: +39-010-5553078. Fax: +39-010-5556854 E-mai l: gi n o.san ti n i @Hsan mar ti n o.li gu r i a.i t
Au tologou s stem cell tr an splan tati on (ASCT) has been seen to over come r esi stan ce, allowi n g an i n cr ease i n the dose of avai lable dr u gs an d r adi other apy. In i ti ally u sed after fi r stli n e for r elapsed or r efr actor y n on -H od gki n ’s l ym ph om a s ( N-H L) , ASCT h a s si n ce been u sed i n m or e favou r able cli n i cal con di ti on s su ch as par ti al r em i ssi on ( PR) , fi r st completer emi ssi on , an d as fr on t-li n e ther apy followi n g chemother apy. Hi gh-dose chemother apy an d au tologou s stem-cell tr an splan tati on has n ow becam e the stan dar d car e for eli gi ble pati en ts w i th r ecu r r en t, chemosen si ti ve aggr essi ve NHL. Pr i mar y r efr actor y pati en ts an d r esi stan t relapse are n ot good i n di cati on s an d shou ld be con si dered a grou p eli gi ble for phase II stu di es.
There may also be a role in patients with partially responsive disease. However n ew an d larger ran domised studies are n eeded to clarify this question . A challen ge for lymphoma man agemen t i s the evalu ati on of the r ole of hi gh-dose ther apy an d ASCT as an i n i ti al tr eatmen t i n aggr essi ve NHL, i den ti fyi n g pati en ts who wi ll n ot be cu r ed wi th stan dar d ther apy. A ser i es of con cu r r en t or r etr ospecti ve an alysi s wou ld i n di cate socalled “ hi gher -r i sk pati en ts” , as defi n ed by the IPI, as poten ti al ta-r gets fo-r i n ten si fi ed ther apy. However , accor di n g to pu bli shed data, the pr oblem r emai n s open to debate. Lar ger , r an domi sed stu di es ar e n ecessar y an d welcome an d thi s shou ld be con si der ed a hi gh pr i or i ty.
Rev.br as.hematol.hemoter .,2002,24(2):77-84
Keyw or ds: Au tol ogou s stem cel l tr a n spl a n ta ti on ; n on -H od gki n ’s
lymphomas
complete remission (CR) is betw een 50% to 70%, and about 50% of these patients later relapse2-4. Consequently, the probability of long-term real cure is about 35%.
Negative prognostic factors, together w ith histologic subtypes and advanced stage, affect on the one hand, both the possibility of obtaining CR and survival, and on the other, CR maintenance and disease-free survival (DFS) (5).
had serious consequences on the course of these lymphomas, because second-line therapies offer poor possibility of salvage (6-8).
Autologous stem cell transplantation (ASCT) has been seen to overcome resistance, allow ing an increase in the dose of available drugs and radiotherapy. Stem cell rescue can shorten the hypoplastic period decreasing life-threatening risks. Initially used after first-line for relapsed or refractory NHL, ASCT has since been used in more favourable clinical conditions such as partial remission (PR), first CR, and as front-line therapy follow ing CT.
ASCT as salvage treatment in relapsed or
refractory NHL
The conventional management of refractory or relapsing NHL is usually associated w ith poor results. About 30% of patients achieve CR, but median survival time is less than 1 year, 3-year probability of survival is from less than 20% to 30%, and 3-year probability of time to treatment failure is less than 10% (6-8).
The first historical 152 patients, observed after joining together small groups of relapsed or refractory patients treated w ith ASCT by various authors (unpublished data from: Appelbaum, Armitage, Philip, Phillips, Ricci, Santini, Verdonck), show ed these patients w ere able to achieve a CR rate of 59%. About 50% of patients later relapsed. In conclusion about 25% of patients maintained CR status. However, an initial stratification of these patients in tw o groups, true chemoresistant on the one hand, and chemosensitive on the other (sensitive relapse and PR), showed that probability to achieve and maintain CR w as very poor (less than 10%) in chemoresistant patients. This initial observation was well defined by Philip et al. (1987) (9), w ho pointed out three groups of patients w ith different outcomes after ASCT. Sensitive relapse patients, after CR, had a 3-year DFS probability of 36%, w hile resistant relapse and refractory patients had a DFS of 14% and of 0%, respectively. The problem of truly resistant patients (resistant relapse and refractory patients) remains unresolved. Our personal experience10 in this su b set o f p at i en t s, u si n g h i gh -d o se
cyclophosphamide (7 gr/ sm) follow ed by BEAM regimen and ASCT show s a 5-year progression-free survival probability of 11%.
The Parma randomised trial, published by Philip et al. in 1995 (11), clarifies the role of ASCT in relapsed patients. Tw o hundred and fifteen patients in relapse, w ith aggressive NHL, w ere treated with DHAP chemotherapy for two courses. One hundred and nine chemosensitive patients w ere randomly assigned to receive DHAP for 4 courses plus radiotherapy ver su s BEAC regimen and ASCT. The response rate w as 83.7% in ASCT arm and 42.5% in conventional CT arm. Five-year probability of survival w as 53% ver su s 32% in the tw o arms (p=0.03) respectively, in favour of the intensified therapy arm. Similar results w ere observed in terms of event-free survival: 46% in ASCT arm, and 12% in conventional arm (p=0.001), respectively.
Follow ing these results, ASCT has been considered the standard treatment of aggressive NHL in sensitive relapse.
ASCT as the primary treatment for
aggressive non-Hodgkin’s lymphoma
1) In partial remission
Survival of patients responding to initial chemotherapy but not in remission after induction is very poor, in spite of salvage treatment. The median survival duration ranges from betw een 5 and 14 months, w ith a 2-year survival probability of less than 30% (6-8, 12).
Follow ing the concept that ASCT can cure about 50% of chemosensitive relapsed patients, ASCT procedure was applied in a subset of patients w ho partially responded to front-line therapy. In 1988 Philip et al. (13) reported interesting results in 17 patients treated w ith high-dose therapy and ASCT w hile in PR after conventional CT. Thirteen patients (76%) are disease-free, w ith a 6-year survival probability of 75% after ASCT. In 1993 the Non-Hodgkin’s Lymphoma Co-operative Study show ed an overall probability of DFS of 36% at 5 years in 21 patients, suggesting a potential cure of about one in three patients autotransplanted in PR after front-line therapy (14).
published in this field. In 1995, Verdonck et al. (15) evaluated the impact of ASCT in patients who failed to achieved CR after 3 courses of CHOP therapy. Patients were randomised to receive high-dose therapy plus ASCT or 5 additional courses of CHOP chemotherapy. The majority of patients en ro l l ed i n th i s tri al h ad l o w an d l o w to intermediate risk disease (5). The study failed to demonstrate any benefit from ASCT in first PR patients. On the contrary, a trend in favour of conventional therapy w as reported.
In 1996, Martelli et al. (16) reported results of a randomised study designed to evaluate, by a second randomisation, the effect of DHAP ver su s
ASCT in aggressive NHL in early PR after first-line therapy. A group of 286 patients entered first randomisation and 49 second randomisation. Twenty-seven patients entered the DHAP arm and 22 the ASCT arm. CR was achieved in 59% of DHAP patients and in 96% of ASCT patients, respectively. The probability of progression-free survival (PFS) w as 73% for ASCT and 52% for DHAP, w ith a p r o b ab i l i t y o f su r v i v al o f 73% an d 59%, respectively. How ever, because of the small number of patients involved, the study was unable to determine w hether ASCT or a standard salvage therapy is better for PR patients.
We must conclude that the problem of ASCT in PR patients remains unresolved.
2) In 1st complete remission
Following the failure of 2nd and 3rd generation regimens over 1st generation in improving outcome in aggressive advanced stage NHL, a series of studies were carried out in favourable situations
on patients in CR after front-line therapy. In these CR patients w e expect a relapse rate ranging from 40 to 50%, in spite of received treatment (2-4).
In 1994, follow ing single phase II studies suggesting a potential benefit of ASCT for 1st CR aggressi ve NH L (17, 18), the French Group
published a randomised study in w hich entered 790 patients w ith aggressive NHL w ho had at least one adverse prognostic factor (19). Follow ing an initial randomisation on antracycline, 464 patients in 1st CR after induction therapy w ere randomised to receive high-dose therapy (CVB) plus ASCT or a consolidative sequential therapy including
i f o sf am i d e, et o p o si d e, asp ar i gi n ase, an d cytarabine. With a median follow -up duration of 28 months, the 3-year DFS w as similar in both arms, 52% in the sequential arm and 59% in the ASCT arm (p=0.46). Overall survival w as once again similar, at 71% and 69% respectively (p=0.60). A retrospective analysis show ed a positive trend in favour of higher-risk patients (2-3 negative factors at diagnosis), as defined by the I.P.I. adjusted for age < 60 years (5), w ho had received ASCT. Successive, intermediate and final analyses published by the same Group in 1997 and in 2000 confirm a statistical benefit of ASCT over sequential therapy in higher-risk NHL in terms of DFS (59% and 39% at 5 years, respectively, p=0.01) (20), and in terms of overall survival (64% and 49% at 8 years, respectively, p=0.04) (21).
The hypothesis that ASCT could improve outcome in higher-risk patients has also been reported by Pettengell et al. (22) in 1996 and by Santini for the NHLCSG (23) in 1998. The first author found a statistically better outcome in terms of survival and PFS in favour of patients receiving ASCT, but the study includes tw o successive, not randomised, cohorts of patients. The second study show ed a statistical improvement for patients treated w ith ASCT in terms of DFS, but this w as only a retrospective analysis, and the study does not include higher-risk patients randomised at diagnosis.
In 2001 a randomised study proposed by Vitolo et al (24) does not confirm any difference in response rate and outcome of higher-risk patients treated with high-dose sequential therapy (HDS: APO, dose/ cyclophosphamide, dose methotrexate, dose VP16) plus high-dose therapy and ASCT versu s patients treated with an i n t en si f i ed o u t p at i en t CT. A seco n d retrospective analysis of a randomised study presented in 2002 by Santini for the NHLCSG (25) does not show any difference in terms of survival and PFS for patients treated with VACOP-B + dose sequential therapy (dose/ cytoxan, high-dose VP16), BEAM regimen and ASCT ver su s
patients treated w ith VACOP-B (plus HDS and ASCT in case of persistent disease after front-line therapy).
Gisselbrecht et al (26) compared an experimental shortened treatment followed by high-dose therapy and ASCT versu s ACVBP regimen plus sequential consolidation therapy in 370 higher-risk patients younger than 60 years. Results showed a statistical better survival and event-free survival in favour of patients treated with ACVBP conventional treatment. The conclusive comment was that the received dose-intensity before high-dose therapy was too low and that ASCT was given too early.
In conclusion, the real benefit of ASCT over conventional therapy for higher-risk patients is still open to debate.
3) Af t er f u l l -co u r se st an d ar d i n d u ct i o n therapy
The results observed w ith ASCT in other clinical situations have led many investigators to extend this aggressive approach as part of the initial therapy in aggressive advanced stage NHL.
In 1997, Vitolo et al. (27) reported a phase II study in which 50 high-risk patients, presenting advanced stage disease at diagnosis w ith high tumour burden and elevated lactate dehydrogenase level or bone marrow involvement, were treated w ith an escalating sequential therapy. Patients received MACOP-B for 8 w eeks follow ed by intensified therapy (mitoxantrone, high-dose ARA-C, dexametathasone), BEAM regimen and ASCT. This study showed a progressive increased response rate according to the number of chemotherapy steps
with a final CR rate of 72%. With a median follow-up time of 32 months from the start of treatment, overall survival and failure-free survival rates are 56% and 50%, respectively. In conclusion, the sequential scheme with intensified and high-dose CT with ASCT was seen to be feasible, with an improved outcome in a poor category of patients. In 2000, the NHLCSG (28) reported similar r esu l t s i n 40 p at i en t s w i t h b o n e m ar r o w i nvol vement at di agnosi s. Pati ents recei ved VACO P-B f o r 8 w eek s, h i gh -d o se cyclophosphamide (7 gr/ m2), BEAM regimen and ASCT. CR rate improved according to the various steps and, at the completion of treatment w as
72.5%. The actuarial 3-year overall survival, DFS and failure-free survival w ere 48%, 55% and 40%, respectively.
Ran d o m i sed st u d i es ar e cu r r en t l y i n progress, and in 1997 Gianni et al (29) reported on 98 patients w ith diffuse high-risk, large B-cell NHL (Groups G and H/ WF), w ho w ere randomi sed to ei ther standard therap y w i th MACOP-B, or HDS (six chemotherapeutic agents ad m i n i stered seq u en ti al l y at a h i gh d o se) follow ed by high-dose therapy and ASCT. In this study, T-cell lymphoma and patients w ith bone marrow involvement w ere excluded. After a medi an fol l ow -up of 55 months, p ati ents treated w i th H D S had a si gni fi cantl y better outcome w hen compared w ith those receiving MACOP-B. CR rate w as 96% vs 49% (p=0.001), freedom from progression 84% vs 49% (p<0.001), freedom from relapse 88% vs 70% (p=0.055), and event-free survival 76% vs 49% (p=0.004) in the tw o arms respectively. Overall survival, in spite of a large trend in favour of HDS, show ed no statistical difference (81% vs 55%, p=0.09). The conclusion w as that HDS is superior to standard therapy for patients w ith diffuse large B-cell NHL.
to remain disease-free if they received additional ASCT (3-year DFS rate, 87% for ASCT vs 48% for standard therapy, p=0.008). In conclusion, this study show ed an ap p arent i mp rovement i n survival (65% in both arms) compared w ith the survival of about 50% to be expected w ith a conventional front-line therapy.
Follow ing all these considerations, in 2002 the NHLCSG (25) reported interim results of a new study in w hich patients w ith aggressive, advanced stage NHL w ere randomised to receive VACOP-B (+ HDS in case of persistent disease) vs VACOP-B + HDS ( CY, 7 gr/ m2; VP 16, 2 gr/ m2 and BEAM + PBPC rescue) in all cases. The aims of the study w ere: a) to confirm the Milan Group’s data; and b) to evaluate the possible use of HDS only w hen necessary. Two-hundred and twenty-three patients w ith mixed and large-cell NHL (Groups F/ G/ H/ K-WF) aged from 15 to 59 years, in stage II bulky > 10 cm, III and IV w ere included. All categories of patients, w ith B- and T-cell phenotype, and w ith initial bone marrow involvement w ere entered. When results were analysed, 223 patients w ere evaluable for response. A third interim analysis show s CR of 65% and 67% respectively. With a median observation time of 37 months, actuarial curves show a 6-yr probability of survival and of PFS of 51% and 47% respectively, w ith no difference betw een the tw o arms.
When only B-cell type, G and H/ WF NHL w i t h o u t B M i n v o l v em en t w er e an al y sed , p r o b ab i l i t y o f su r v i v al i m p r o v ed t o 70% (conventional arm) and 80% (intensified arm), and PFS to 50% and 64%, respectively. Patients w ith T-cell type NHL and w ith BM involvement show ed the poorest results . When patients w ith BM involvement w ere excluded, the probability of survival and PFS w ere 57% and 66%, and 48% and 54% in the tw o arms respectively. When outcome w as analysed according to age-adjusted IPI at diagnosis, low er-risk patients (0-1 negative factors at diagnosis) show ed a better statistical outcome compared w ith those at higher-risk (2-3 negative factors at diagnosis). Survival w as 74% vs 46% (p=0.0001) and PFS 57% vs 40% (p =0.0001), resp ecti vel y. When these tw o groups w ere analysed no difference w as seen betw een them.
This analysis seems to confirm that strategies including high-dose sequential therapy plus ASCT can give very good results in selected group of patients, and suggests that results achieved w ith conventional treatment plus HDS and ASCT are similar to those reported w ith the simple use of co n v en ti o n al th er ap y an d ASCT. O n f i n al observation is that there is no apparent difference in using intensified therapy after CT in all cases or only in cases of persistent disease, even in higher-risk patients.
I n concl usi on, thi s study suggests that differences betw een patient selection methods in various reported studies probably have an impact on the interpretation of the different results.
Conclusions
High-dose chemotherapy and autologous stem-cell transplantation has now became the standard care for eligible patients w ith recurrent, chemosensitive aggressive NHL. Primary refractory p ati ents and resi stant rel ap se are not good indications and should be considered group eligible for phase II studies.
There may also be a role in patients w ith partially responsive disease. How ever new and larger randomised studies are needed to clarify this question.
A challenge for lymphoma management i s the eval uati on of the rol e of hi gh-dose therapy and ASCT as an initial treatment in aggressive NHL, identifying patients w ho w ill be not cured w ith standard therapy. A series of concurrent or retrospective analysis w ould indicate so- called “ higher-risk patients” , as defi ned by the I PI , as p otenti al targets for i ntensi fi ed therap y. H ow ever, accordi ng to recent published data, the problem remains open to debate. Larger, randomised studies are necessary and w el come and thi s shoul d be considered a high priority.
Transplante autólogo de células progenitoras
para pacientes com linfomas não Hodgkin
agressivos
G. San ti n i , A. M. Con gi u , S. Nati , G. Mar i n o, V. Nar di , M. Spr i an o, R. Vi mer cati , A. Ru bagotti , C. A. Sou za
Resumo
O tran splan te au tólogo de célu la progen i tora ou medula óssea (ATMO) tem demon strado capacidade de superar resistên cia tumoral através da elevação da i n ten si dade de dose de dr ogas di spon ívei s e radioterapia. ATMO foi in icialmen te utilizado em LNH após recidiva em primeira lin ha ou refratários. ATMO tem d em on str a d o m a i or u ti l i d a d e em condições clínicas mais favoráveis como na remissão parcial (RP), primeira remissão completa (RC) e como primeira lin ha após quimioterapia.
Qu i mi oter api a de alta dose e ATMO se tor n ar am a terapêutica stan dard para pacien tes elegíveis com LNH a gr essi vo, r ecor r en te e qu i m i osen sí vel . Paci en tes pri mari amen te refratári os e com reci di va r esi sten te n ão são boas i n di cações e devem ser con si der ados como gr u po elegível par a estu dos de f a se I I . Ta l vez , h a j a u m pa pel d o ATMO em paci en tes par ci alm en te r espon si vos. En tr etan to, n ovos e gr a n d es estu d os r a n d om i z a d os sã o n ecessár i os par a esclar ecer esta qu estão.
Um desafi o par a o m an u sei o dos li n fom as é a defi n i ção da terapi a de alta dose segu i da do ATMO como ter apêu ti ca i n i ci al par a os LNH agr essi vos, i d en ti f i ca n d o pa ci en tes qu e n ã o possa m ser cu r ados com ter apêu ti ca con ven ci on al. Uma sér i e de estu dos r etr ospecti vos ou con tr olados par ece i n di car os cham ados paci en tes de “ alto-r i sco” , d efi n i d o pel a I PI com o poten ci a l a l vo d esta s ter apêu ti cas i n ten si fi cadas. En tr etan to, de acor do com dados pu bli cados, o pr oblem a per m an ece a ber t o pa r a d eba t es. Est u d os gr a n d es e r an dom i zados são n ecessár i os e bem vi n dos e devem ser con si der ados pr i or i dade n este campo da ci ên ci a médi ca.
Rev.br as.hematol.hemoter .,2002,24(2):77-84
Palavras-chave: Tr an splan te au tólogo de célu la pr ogen i tor a, li n fomas n ão Hodgki n
References
1. The non-Hodgkin’s Lymphoma Pathologic Classification Project. Nati on alCan cer In sti tu te spon sor ed stu d y of cl a ssi f i ca ti on of n on -H od gk i n ’ s l ym ph om a : Su m m a r y a n d d escr i pti on of a w or ki n g for m u l a ti on for cli n i cal u sage. Cancer 1982. 49: 2112-2135.
2. Gordon LI, Harrington D, Andersen J, et al:
Com pa r i son of a secon d - gen er a t i on combi n ati on chemother apeu ti c r egi men (m-BACOD) wi th a stan dar d r egi men (CHOP) for advan ced di ffu se n on -Hodgki n ’s lymphoma.
N Engl J Med 1992. 327: 1342-1349.
3. Fisher RI , Gaynor ER, Dahlberg S, et al:
Compari son of stan dard regi men (CHOP) wi th thr ee i n ten si ve chem other apy r egi m en s for advan ced n on -Hodgki n ’s lymphoma. N Engl
J Med. 1993. 328: 1002-1006.
4. Sertoli MR, Santini G, Chisesi T, et al: MACOP-B versu s ProMACE-MOPP i n the treatmen t of advan ced di ffu se n on -Hodgki n ’s Lymphomas: Resu lts of a prospecti ve ran domi zed tri al by the Non -Hodgki n ’s Lymphoma Cooperati ve Stu dy Grou p. J Clin Oncol 1994. 12: 1366-1374. 5. The International Non-Hodgkin’s Lymphoma
Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphomas. N
Engl J Med 1993. 329: 987-994.
6. Cabanillas F, Hagemeister FB, Mc Laughlin P et al: Resu lts of MIME salvage r egi m en for r ecu r r en t or r efr actor y l ym phom a. J Clin
Oncol 1987. 5: 407-410.
7. Velasquez WS, Cabanillas F, Salvador P et al:
Effecti ve salvage ther apy for lymphoma wi th ci splati n i n combi n ati on wi th hi gh-dose Ar
a-C an d dexamethason e (DHAP). 1988.Blood
71: 117-122.
8. Velasquez WS, Mc Laughlin P, Tucker S et al:
ESHAP - an effecti ve chem other apy r egi m en i n r efr actor y an d r elapsi n g lym phom a: a 4-year follow-u p stu dy. J Clin Oncol 1994. 12: 1169-1176.
or hi gh-gr ade n on -Hodgki n ’s lym phom a. N
Engl J Med 1987. 316: 1493-1498.
10. Santini G, De Souza C, Congiu Am et al: Hi gh-d ose cycl oph osph a m i gh-d e f ol l ow egh-d by a u togr a fti n g ca n i m pr ove th e ou tcom e of r el a psed or r esi st a n t n on - H od gk i n ’ s lymphomas wi th i n volved or hypoplasti c bon e
marrow. Leuk Lymphoma 1999. 33: 321-330.
11. Philip T, Guglielmi C, Hagenbeek A et al:
Au tologou s bon e mar r ow tr an splan tati on as com pa r ed w i th sa l va ge ch em oth er a py i n r el a pses of ch em ot h er a pysen si t i ve n on -Hodgki n ’s lymphoma. N Engl J Med 1995. 333: 1540-1545.
12. Haq R, Sawka CA, Franssen E et al: Sign ifican ce of a par ti al or sl ow r espon se to fr on t-l i n e ch em ot h er a py i n t h e m a n a gem en t of i n t er m ed i a t e gr a d e or h i gh gr a d e n on -Hodgki n ’s lymphoma: A li ter atu r e r evi ew. J
Clin Oncol 1994. 12: 1074-1084.
13. Philip T, Hartmann O, Biron P et al: High-dose th er a py a n d a u tol ogou s bon e m a r r ow tran splan tation in partial remission after first-line induction therapy for diffuse non-Hodgkin’s lymphoma. J Clin Oncol 1988. 6:1118-1124.
14. Santini G, Congiu AM, Coser P et al: Au tologou s bon e mar r ow tr an splan tati on i n 100 cases of poor -pr ogn osi s n on -Hodgki n ’s lymphoma. A r epor t of the Non -Hodgki n ’s Lymphoma Co-oper ati ve Stu dy Gr ou p. In : Autologous Bone Marrow Transplantation, Proc of the Sixth International Symposium, Eds. Dicke KA and Keating A, Arlington (Texas) 1993. 75-82. 15. Verdonck LF, Van Putten WLJ, Hagenbeek A
et al : Compari son of CHOP chemotherapy wi th au tologou s bon e mar r ow tr an splan tati on for slowly respon di n g pati en ts wi th aggressi ve n on -Hodgki n ’s lym phom a. N Engl J Med 1995. 332:1045-1051
16. Martelli M, Vignetti M, Zinzani PL et al: Hi gh-dose chem other apy followed by au tologou s bon e m a r r ow t r a n spl a n t a t i on ver su s dexamethason e, ci splati n , an d cytar abi n e i n a ggr essi ve n on -H od gki n ’s l ym ph om a w i th par ti al r espon se to fr on t-li n e chemother apy: A pr ospecti ve r an dom i zed Itali an Mu lti cen ter Stu dy. J Clin Oncol 1996. 14: 534-542.
17. Gulati SC, Shank B, Black P et al: Au tologou s bon e marrow tran splan tati on for pati en ts wi th poor progn osi s lymphoma. J Clin Oncol 1988.
6: 1303-1313.
18. Nademanee A, Schmidt G, O’ Donnell MR et al: Hi gh dose chemor adi other apy followed by au tologou s bon e mar r ow tr an splan tati on as con soli dati on ther apy du r i n g fi r st com plete r em i ssi on i n ad u l t pati en ts w i th poor -r i sk aggr essi ve lym phom a: A pi lot stu dy. Blood
1992. 80: 1130-1134.
19. Haioun C, Lepage E, Gisselbrecht C et al:
Com pa r i son of a u tol ogou s bon e m a r r ow tran splan tati on wi th sequ en ti al chemotherapy for i n ter medi ategr ade an d hi ghgr ade n on -H od gk i n ’ s l ym ph om a i n f i r st com pl et e r em i ssi on : A stu dy of 464 pati en ts. J Clin
Oncol 1994. 12: 2543-2551.
20. Haioun C, Lepage E, Gisselbrecht C et al: Ben efit of au tologou s bon e mar r ow tr an splan tati on over sequ en ti al chem other apy i n poor -r i sk aggressi ve n on -Hodgki n ’s lymphoma: Updated resu lts of the prospecti ve stu dy LNH87-2. J Clin
Oncol 1997. 15: 1131-1137.
21. Haioun C, Lepage E, Gisselbrecht C et al:
Su r vi val ben efi t of hi ghdose ther apy i n poor -r i sk a gg-r essi ve n on -H od gki n ’s l ym ph om a : Fi n a l a n a l y si s of t h e pr ospect i ve st u d y LNH 87-2 pr otocol – A Gr ou pe d’Etu de des Lym phom es de l’Adu lt Stu dy. J Clin Oncol
2000. 18: 3025-3030.
22. Pettengell R, Radford GR, Morgenstern JH et al: Su r vi val ben efi t fr om hi gh-dose ther apy w i t h a u t ol ogou s b l ood p r ogen i t or - c el l t r a n spl a n t a t i on i n poor pr ogn osi s n on
-H odgki n ’s lym phom a. J Clin Oncol 1996.
14: 586-592.
23. Santini G, Salvano L, Leoni P et al: VACOP-B versu s VACOP-B plu s au tologou s bon e marrow tr an splan tati on for advan ced di ffu se n on -H od gk i n ’ s l ym ph om a : Resu l t s of a r a n d om i z ed t r i a l by t h e Non -H od gk i n ’ s Lymphoma Cooper ati ve Stu dy Gr ou p. J Clin
Oncol 1998. 16: 2796-2802.
h i gh d ose ch em ot h er a py ( H D S) w i t h au tologou s stem cell tr an splan tati on (ASCT) vs i n ten si fi ed chemotherapy MegaCEOP i n hi gh r i sk di ffu se lar ge cell lymphoma (DLCL): n o di ffer en ce i n ou tcom e an d tox i ci ty. Blood
2001. 98 (11): abstr. 3028.
25. Santini G, Congiu A, Olivieri A et al: Vacop-B vs Vacop-B + hi gh-dose sequ en ti al ther apy (HD) for aggressi ve n on -Hodgki n ’s Lymphoma. Bon e Mar r ow Tr an splan t 29 2002 (suppl 2): abstr. 110.
26. Gisselbrecht C, Lepage E, Molina T et al:
Shor ten ed fi r st-li n e hi gh-dose chemother apy for pati en ts w i th poor -pr ogn osi s aggr essi ve lymphomas. J Clin Oncol 2002. 20: 2472-2479. 27. Vitolo U, Cortellazzo S, Liberati AM et al:
I n ten si f i ed a n d h i gh -d ose ch em oth er a py w i th gr an u locyte colon y-sti m u lati n g factor s a n d a u tol ogou s stem -cel l tr a n spl a n ta ti on
su ppor t a s f i r st-l i n e th er a py i n h i gh -r i sk d i ffu se l a r ge-cel l l ym phom a. J Clin Oncol
1997. 15: 491-498.
28. Santini G, Coser P, Congiu AM et al: VACOP-B, hi dose cycl ophospham i de an d hi gh-dose ther apy wi th per i pher al blood pr ogen i tor cel l r escu e f or a ggr essi ve n on -H od gki n ’ s lym phom a wi th bon e m ar r ow i n volvem en t: a stu dy by the n on -Hodgki n ’s Lym phom a Co-operati ve Stu dy Grou p. Haematologica 2000. 85: 160-166.
29. Gianni AM, Bregni M, Siena S et al: Hi gh-dose chemother apy an d au tologou s bon e mar r ow tr an splan tati on compar ed wi th MACOP-B i n aggr essi ve B-cell lym phom a. N Engl J Med
1997. 336: 1290-1297.
