Summary: Patients and methods

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1 (2002) 30, Nature Publishing Group All rights reserved /02 $ Hodgkin s disease High-dose chemotherapy with autologous stem cell transplantation is an effective treatment of primary refractory Hodgkin s disease. Retrospective study of the Polish Lymphoma Research Group JCzyż 1, A Hellmann 1, R Dziadziuszko 1,JHansz 2,JGoździk 2, J Hołowiecki 3, B Stella-Hołowiecka 3, Ł Kachel 3, W Knopińska-Posłuszny 1, A Nagler 4, J Meder 5, J Walewski 5, E Lampka 5, K Sułek 6, W Sawicki 6, A Lange 7, K Forgacz 7, K Suchnicki 7, T Pacuszko 7, A Skotnicki 8, P Mensah 8, W Jurczak 8, K Kuliczkowski 9,TWróbel 9, G Mazur 9, A Dmoszyńska 10, M Wach 10, T Robak 11 and K Warzocha 11 1 Medical University, Gdańsk, Poland; 2 University of Medical Sciences, Poznań, Poland; 3 Silesian Medical University, Katowice, Poland; 4 The Chaim Sheba Medical Centre, Tel-Hashomer, Israel; 5 Maria Skłodowska-Curie Memorial Cancer Centre-Institute of Oncology, Warsaw, Poland; 6 Central Military Hospital, Warsaw, Poland; 7 K Dłuski Hospital-Institute of Immunology and Experimental Therapy, Wrocław, Poland; 8 Collegium Medicum Jagiellonian University, Cracow, Poland; 9 Medical University, Wrocław, Poland; 10 Medical University, Lublin, Poland; and 11 Copernicus Memorial Hospital-Medical University, Łódź, Poland Summary: We analysed the treatment outcome of primary refractory HD patients managed with high-dose chemotherapy and haematopoietic cell transplantation. Data of 65 adult patients who underwent HDC/ASCT in nine Polish centres for primary resistant Hodgkin s disease between June 1991 and July 2000 were collected retrospectively. Response rate to HDC/ASC: CR, 54%; PR, 20%; less than PR, 15%; early deaths, 11%. Actuarial 3-year OS and PFS were 55% and 36%, respectively. In multivariate analysis, lack of bulky lymph nodes and use of immunotherapy were favourable factors for both OS and PFS. IPF 3 at the time of transplantation was predictive for PFS. However, the prognostic impact of immunotherapy should be interpreted with caution since this group included more patients who achieved CR after HDC/ASCT. The results of HDC/ASCT are encouraging and confirm earlier findings. The role of immunotherapy should be further investigated in prospective trials. (2002) 30, doi: /sj.bmt Keywords: high-dose chemotherapy; primary refractory Hodgkin s disease Modern chemotherapy results in a more than 80% complete remission rate in advanced Hodgkin s disease. 1,2 However, prognosis in patients with an incomplete response after induction treatment is poor. Salvage chemotherapy is generally ineffective and prolonged survival is observed only Correspondence: Dr J Czyż, Department of Haematology, Medical University of Gdansk, Gdansk, ul. Debinki 9, Poland Received 31 October 2001; accepted 21 March 2002 occasionally. 3,4 For selected patients, salvage radiation therapy may be considered as an alternative option if the patient has not been previously irradiated. 5 Recently, encouraging reports on high-dose chemotherapy with autologous stem cell transplantation (HDC/ASCT) in this group of patients have been published by European and American institutions, but randomised trials comparing this treatment with standard therapy are still lacking At present, autologous bone marrow transplantation procedures are performed in adult patients in 11 centres in Poland. Data from nine of them, which were active before 1999, were collected retrospectively and analysed in the current study. The aim of the study was to evaluate treatment results and prognostic factors in univariate and multivariate models for overall and progression-free survival. Patients and methods Data of 65 adult patients who underwent HDC/ASCT for primary resistant Hodgkin s disease between June 1991 and July 2000 were collected retrospectively. Eligibility criteria for this study included: disease progression during first-line chemotherapy, or partial remission after induction treatment with progression within 3 months of completion of treatment. Patients with persistent scan abnormalities without local progression or residual disease in other sites were not considered to be primary resistant. Clinical data were collected until September Out of the initial 100 records received, we identified 65 which strictly fulfilled the above criteria. Data of the remaining 35 patients were excluded due to lack of evidence of disease progression within the specified period of 3 months after first-line treatment. In January 2001, records of all these patients were reviewed and reporting centres were contacted to provide additional information and follow-up. The median follow-

2 30 up period was 26 months (range: months). Patient characteristics at presentation, initial therapy, transplantation, and details of high-dose therapy are presented in Tables 1 3. Prognosis was assessed using the International Prognostic Factors score on advanced Hodgkin disease (IPF), proposed by Hasenclever and Diehl. 11 Thirty-five patients received involved or extended field radiotherapy before HDC/ASCT, and four were irradiated as consolidation of HDC/ASCT. No grafts were manipulated in vitro. Thirty-eight percent of patients received haematopoietic growth factors. Table 1 Characteristics of patient s initial presentation and therapy No. of No. (%) evaluable patients Histology 65 Nodular sclerosis 38 (58) Mixed cellularity 21 (32) Lymphocyte depletion 6 (9) Sex 65 Female 29 (45) Male 36 (55) Disease stage at diagnosis 65 II 18 (28) III 28 (43) IV 19 (29) B symptoms at diagnosis 65 No 11 (17) Yes 54 (83) Extranodal localisation 65 No (57) Yes 28 (43) Mediastinal involvement 65 No 9 (14) Yes 56 (86) Elevated LDH 52 No 32 (62) Yes 20 (38) International Prognostic 43 Factors score 3 No 24 (56) Yes 19 (44) Age at diagnosis (years) 65 Median (range) 23 (12 51) First-line regimen 65 ABVD 24 (37) MOPP/ABV D 24 (37) MOPP 15 (23) Other 2 (3) Second-line regimen 65 ABVD 13 (20) DHAP 13 (20) MiniBEAM-like 8 (12) EVA 5 (8) None 7 (11) Other 19 (29) No. of induction 65 chemotherapy regimens Median (range) 2 (1 5) Radiotherapy before transplantation 65 No 30 (46) Yes 35 (54) The response was usually assessed 1 month after completion of chemotherapy. Physical examination, plain X-ray and computed tomography scanning were routinely used for response evaluation. Gallium scintigraphy and magnetic resonance imaging were used in selected cases. Partial remission was defined according to WHO criteria. A complete remission group also included patients with persistent scan abnormalities without biopsy confirmation (complete remission uncertain). Four patients received involved field radiotherapy after Table 2 Patients characteristics at the time of transplantation Variable No. of No. (%) evaluable patients B symptoms 64 No 20 (31) Yes 44 (69) Extranodal localisation 65 No 37 (57) Yes 28 (43) Elevated LDH 56 No 33 (59) Yes 23 (41) Internal Prognostic Factors 62 score 3 No 43 (69) Yes 19 (31) Bulky lymph nodes ( 5cm) 62 No 55 (89) Yes 7 (11) Age (years) 65 Median (range) 25 (16 52) Table 3 Characteristics of HDC/ASCT Management No. (%) Conditioning regimen BEAM 43 (66) CBV 18 (28) Other regimens 4 (6) Stem cell source Bone marrow 29 (45) Peripheral blood 33 (51) Both 3 (5) Haematopoietic growth factors after transplantation No 40 (62) Yes 25 (38) Response to high-dose chemotherapy CR 35 (54) PR 13 (20) PR 9 (14) Toxic death 8 (12) Radiotherapy after transplantation No 61 (94) Yes 4 (6) Immunotherapy after transplantation No 47 (72) Interferon 14 (22) Interferon interleukin-2 4 (6)

3 Table 4 Significant prognostic factors for PFS after HDC/ASCT 31 Variable n Univariate analysis Multivariate analysis, final model Hazard 95% Confidence P Hazard ratio 95% Confidence P ratio (HR) interval (95%CI) (HR) interval (95%CI) IPF score at diagnosis NA IPF score at HDC/ASCT Immunotherapy after HDC/ASCT No 47 Yes Lymph node diameter at HDC/ASCT 5 cm 43 5 cm NS, not significant (dropped from the final model); NA, not able to calculate (too few patients). HCD/ASCT. Eighteen patients in two centres received immunotherapy as part of running protocols: 14 patients received recombinant interferon U/day s.c. every other day for 1 month. The dose was then escalated to U/m 2 s.c. every other day for 5 months. Four patients were treated with recombinant interleukin-2, U/m 2 daily for 1 week. After a 2-week interval, interleukin-2 was given at the same dose concomitantly with recombinant interferon U/day for 4 weeks (20 doses). Finally, after a 4-week interval, interferon was administered three times a week for 6 months at a dose of U. The remaining patients received no consolidation treatment after transplantation. Statistical methods Median follow-up time was calculated as proposed by Schemper et al. 12 Analysis of overall (OS) and progressionfree survival (PFS) was performed with the Kaplan Meier method. For PFS analysis, the survival time was calculated from the date of ASCT to the date of disease progression or treatment-related death, whichever occurred first. The following variables were included in univariate and multivariate Cox regression models of prognostic factors for OS and PFS: (1) At the time of diagnosis: age, sex, presence of B symptoms, pathology, extranodal disease, mediastinal involvement, International Prognostic Factors score, serum LDH. (2) At the time of transplantation: age, presence of B symptoms, conditioning regimen, haematopoietic cell source, International Prognostic Factors score, serum LDH, lymph node diameter, radiotherapy before and after transplantation, immunotherapy after HDC/ASCT. Wald s test was used to evaluate the impact of each variable in univariate and multivariate Cox models. All variables with complete data were included in the preliminary backward regression model for OS and PFS. Hazard ratios and their 95% confidence intervals were reported in univariate and final multivariate analyses. Table 5 Significant prognostic factors for OS after HDC/ASCT Variable n Univariate analysis Multivariate analysis, final model Hazard ratio 95% Confidence P Hazard 95% Confidence P (HR) interval (95%CI) ratio (HR) interval (95%CI) IPF score at diagnosis NA IPF score at HDC/ASCT NS Immunotherapy after HDC/ASCT No 47 Yes Lymph node diameter at HDC/ASCT 5 cm 43 5 cm NS, not significant (dropped from the final model); NA, not able to calculate (too few patients).

4 32 Comparison of proportions was performed with Fisher s exact test. Results A total of 48 patients (74%) responded to high-dose chemotherapy, including 35 (54%) in CR and 13 (20%) in PR. With a median follow-up of 26 months, probabilities of OS and PFS at 3 years are 55% (95% CI: 41 69%) and 36% (95% CI: 23 50%), respectively (Figure 1). On univariate analysis, four factors were found to influence OS and PFS: IPF 3 at the time of diagnosis (P 0.02 and P 0.05) and transplantation (P 0.01 and P 0.05), immunotherapy as a part of HDC/ASCT (P 0.04 and P 0.01) and lymph node diameter of 5 cm at the time of transplantation (P 0.01 and P 0.04) (Tables 4 and 5). The assessment of IPF at the time of diagnosis was possible for only a subgroup of patients and therefore this variable was not included in the multivariate analysis. Immunotherapy (P 0.01), lymph node diameter 5 cm(p 0.01) and IPF 3 at the time of transplantation (P 0.01) remained significant for PFS on multivariate analysis for PFS. OS was influenced only by immunotherapy (P 0.01) and lymph node diameter at transplantation (P 0.01). The group of patients treated with immunotherapy included significantly more patients who achieved CR after HDC/ASCT (P 0.04, Fisher s exact test). In the group of patients receiving immunotherapy, an analysis of the subgroup treated with recombinant interferon alone vs recombinant interleukin-2 and recombinant interferon was not possible due to the small number of patients treated. There were eight (11%) transplant-related deaths (seven early and one late, 6 months after transplantation). Infection was the most common cause of treatment-related death. Additionally, one fatal interstitial pneumonitis was observed. No cases of secondary malignancy were reported. Discussion The outcome of patients who presented with early treatment failure and were managed with standard-dose salvage Survival probability Figure 1 OS PFS Months Overall (OS) and progression-free survival (PFS). chemotherapy is poor. In the report of Longo et al, 13 the median survival of 51 patients was 16 months and no patient was alive at 8 years. Consistent results were presented by Bonfante et al 4 in a group of patients refractory to alternating MOPP/ABVD. In contrast, results of HDCT/ASCT seem to be more promising. In our group of 65 patients, the 3-year OS and PFS were 55% and 36%, respectively. In a group of 122 HD patients, Lazarus et al 8 reported 50% and 38% patients remaining alive and without progression 3 years from the salvage HDC/ASCT. Moreover, other published results of HDC/ASCT on larger series of patients demonstrated a potential benefit from HDC in primary resistant Hodgkin s disease (Table 6). However, the actual benefit of the treatment can be overestimated due to selection bias. Recently, Jostings et al 5 showed that the majority of primary resistant patients receiving salvage therapy were excluded from high-dose programmes due to progressive disease, life-threatening severe toxicity of conventional treatment or age above 60 years. According to this study, only 33% of patients reported in the database of the German Hodgkin s Lymphoma Study Group received HDC/ASCT. There are no randomised clinical trials confirming the value of high-dose chemotherapy in this highly selected group of patients. Thus, the benefit of HDC/ASCT may be estimated only through case-matching with historical controls. 7,14 In the group from the Stanford study there was no difference in OS at 4 years, but the advantage of the high-dose group was evident in freedom from progression probability (FFP, 52% vs 19%, P 0.01) and event-free survival (EFS, 52% vs 19%, P 0.01). 14 In the French study, the 6-year overall survival from diagnosis was 38% for grafted patients and 29% for patients treated conventionally (P 0.058). At present it is clear that a considerable proportion of patients with primary resistant Hodgkin s disease can be successfully treated with high-dose treatment, but the outcome in individual series is highly influenced by the distribution of risk factors. There are several variables considered to be of prognostic relevance in previous autotransplantation studies: performance status at transplantation, resistant disease at transplantation, number of unsuccessful conventional chemotherapy regimens, B symptoms at relapse, stage, age, bone marrow involvement, relapse in previous radiation therapy fields, extranodal disease at relapse, extensive pulmonary involvement, elevated serum lactate dehydrogenase and male sex. 5,6,8 10,15 22 In primary progressive Hodgkin s disease, failure to attain even temporary remission was also identified as an adverse prognostic factor for OS. 5,10 Of the variables analysed in the present study, bulky lymph nodes at transplantation and immunotherapy following HDC/ASCT were predictive for both OS and PFS, and the IPF score at transplant was predictive for PFS. The importance of bulky disease at the time of transplantation has been reported by numerous authors. 5,9,16,20 22 The role of maintenance immunotherapy after first-line treatment is controversial and no welldesigned phase III trials addressing this issue have been conducted in HD patients. Aviles et al 23 suggested the benefit of maintenance therapy with interferon in complete responders after induction treatment. In this study, a substantial improvement in favour of immunotherapy was observed both for overall and disease-free survival (OS,

5 Table 6 Results of larger autotransplantation series in patients refractory to induction treatment 33 Author (year) No. of patients Early death PFS OS (%) Reece 6 (1995) % at 3.6 years 60% at 5 years Andre 7 (1999) % at 5 years(efs) 35% at 5 years Sweetenham 9 (1999) % at 5 years 36% at 5 years Lazarus 8 (1999) % at 3 years 50% at 3 years Josting 5 (2000) 70 Not reported 31% at 5 years(ff2p) 43% at 5 years Present series % at 3 years 55% at 3 years EFS event-free survival; FF2F freedom from second failure. 92% vs 67%; DFS, 91% vs 58%). A possible role of recombinant human interleukin-2 given concomitantly with interferon to control minimal residual disease after HDC/ASCT was reported by Nagler et al. 24 The survival probability at 48 months for HD patients receiving immunotherapy was 100% as compared to 57% in historical controls who did not receive immunotherapy (P 0.02). In an interim analysis of a prospective study, the authors observed that OS and DFS rates at 48 months were higher for HD patients who had received interleukin-2 and interferon than for the controls (88% and 84% vs 78% and 54%). 25 In our study, the benefit of immunotherapy may have been influenced by a selection bias a much higher rate of complete responders to primary chemotherapy was noted in this group. The factor that has not been analysed in previous HDC/ASCT studies, was the International Prognostic Factors Project score (IPF) on Advanced Hodgkin s Disease. 11 This system includes some parameters demonstrated to be of significance in previous autotransplantation studies: age, sex and stage. Unfortunately, in our series complete data at diagnosis were available in only 43 out of 65 patients and could not be included in multivariate analysis. Surprisingly, among 43 patients resistant to induction treatment with complete data at diagnosis, only 19 (44%) had three or more risk factors and could be included in a high-risk group. We confirm the suggestion of other authors that only a proportion of high-risk patients can be identified based on this scoring system. 26 The present data and studies of others indicate that HDC/ASCT may be of therapeutic value in HD refractory to induction treatment. Similar to other observations, we found bulky disease to be an adverse prognostic factor for HDC/ASCT outcome. We also observed that the IPF scores at the time of transplantation can help predict the results of high-dose treatment. The addition of immunotherapy with interferon, with or without interleukin 2, to HDC/ASCT may improve these results in refractory HD patients. Acknowledgements We thank Prof Jacek Jassem and Dr Jan Maciej Zaucha (Medical University of Gdańsk) for an in depth discussion of the manuscript, Dr Richard Szydlo (Hammersmith Hospital, London) for valuable comments on statistical analysis and Mrs Agnieszka Pliszka (Medical University of Gdańsk) for data management. References 1 Diehl V, Franklin J, Hasenclever D et al. BEACOPP a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin s lymphoma: interim report from a trial of the German Hodgkin s Lymphoma Study Group. J Clin Oncol 1998; 16: Horning SJ, Williams J, Bartlett N et al. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin s disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 2000; 18: DeVita VT Jr, Simon RM, Hubbard SM et al. Curability of advanced Hodgkin s disease with chemotherapy. 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