Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin s lymphoma

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1 Original article Annals of Oncology 13: , 2002 DOI: /annonc/mdf333 Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin s lymphoma R. Zanotti*, A. Trolese, A. Ambrosetti, G. Nadali, C. Visco, M. M. Ricetti, F. Benedetti & G. Pizzolo Department of Clinical and Experimental Medicine, Section of Hematology, University of Verona, Policlinico G.B. Rossi, Verona, Italy Received 4 February 2002; revised 3 June 2002; accepted 8 July 2002 Background: The International Prognostic Score (IPS) and circulating levels of the soluble form of CD30 molecule (scd30) have both been associated with poor outcome in patients with advanced Hodgkin s lymphoma (HL). The aim of this study was to assess the prognostic power of the combined evaluation of scd30 and IPS in these patients. Patients and methods: We included 101 patients with advanced HL, treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or MOPP (mechlorethamine, vincristine, procarbazine and prednisone)/abvd chemotherapy with or without radiotherapy. All were tested for pre-treatment scd30 levels. Results: Six-year estimated overall survival (OS) and failure-free survival (FFS) was 89% ± 3% and 75% ± 4%, respectively. Thirty-three patients (33%) had IPS >2; their FFS was 60% compared with 82% in the remaining patients (P = 0.027). Serum scd30 levels were 100 U/ml in 41 (41%) patients; their FFS at 6 years was 58%, compared with 87% in patients with scd30 <100 U/ml (P = 0.003). In the 18 patients with both scd U/ml and IPS >2, FFS was significantly worse (44%) than in patients with low scd30 and low IPS (89%) (P <0.001) or with only one of the two adverse prognostic factors (73%) (P = 0.03). Conclusions: In our study, the combination of IPS >2 and serum scd30 levels 100 U/ml identifies a sizeable subgroup (18%) of advanced HL patients with very poor FFS, who might take advantage of intensified up-front treatment strategies. Key words: Hodgkin s lymphoma, International Prognostic Score, prognosis, scd30 Introduction Although about two-thirds of patients with advanced Hodgkin s lymphoma (HL) can be cured with current treatment modalities, 10% of patients still do not achieve a complete response (CR) and 20 25% relapse within the first 3 years after diagnosis. It is therefore important to identify prognostic factors able to select patients with a high risk of progression or relapse for whom more intensive therapy could be proposed as firstline treatment. Numerous clinical and laboratory parameters at presentation have been recognized as prognostic variables in previous studies [1, 2], such as stage, age, gender, histology, tumor *Correspondence to: Dr R. Zanotti, Department of Clinical and Experimental Medicine, Section of Hematology, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, Verona, Italy. Tel: ; Fax: ; roberta.zanotti@univr.it burden, number of involved lymphnodal and extranodal sites, bone marrow involvement, B symptoms, erythrocyte sedimentation rate, anemia, lymphopenia, serum copper, serum lactate dehydrogenase (LDH), serum albumin and serum β2-microglobulin levels. Some of these variables have been combined in several prognostic models proposed during the last decade. Straus et al. [3] identified a group of advanced HL patients with high risk of failure after conventional treatment, based on the presence of two or more unfavorable clinical and laboratory features. Their 4-year freedom of progression of disease (FFP) was 52%. Hasenclever and Diehl [4] proposed the International Prognostic Score (IPS) for advanced HL. The IPS identified two groups with different risks of progression or relapse, on the basis of the presence of at least three of seven adverse factors. The 5-year FFP of the poor-risk group was 55%. Gobbi et al. [5] recently evaluated seven prognostic systems elaborated for patients with HL (including Straus and IPS models) in advanced HL patients treated by the Italian 2002 European Society for Medical Oncology

2 1909 Lymphoma Study Group. They demonstrated that none of these clinical models could identify a group of patients including >10% of the whole population and with a failure risk 50%. Some biological parameters, such as concentration of the soluble form of the CD30 molecule (scd30) and interleukin-10, have been proposed as prognostic factors in HL patients [6 9]. On the other hand, the analysis of gene profiles by microarray techniques, which have been developed recently for various hematological malignancies, can not yet be applied for the prognostic application in HL. We have shown previously that the combination of high serum scd30 levels ( 100 U/ml) and advanced stage (III IV) at presentation identifies patients with unfavorable outcome and 5-year event-free survival (EFS) of 51% [10]. Axdorph et al. [11] recently suggested that serum levels of scd30 might improve the IPS in predicting outcome of HL patients: elevated serum scd30 levels and IPS >2 predicted a 5-year cause-specific survival (CSS) of 54%. In this study we analyzed a single-institution series of patients with advanced HL, evaluating whether serum levels of scd30 in association with IPS may be helpful in identifying HL patients with a high risk of treatment failure. Patients and methods Patients Between August 1984 and June 1997, 136 untreated patients with advanced HL, defined as stage III and IV or II with B symptoms or bulky disease, received ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or MOPP (mechlorethamine, vincristine, procarbazine and prednisone)/abvd chemotherapy, with or without consolidation radiotherapy, at our department. In this study, we retrospectively analyzed 101 of 136 patients for whom serum samples collected at diagnosis were available for determination of scd30 levels. Their clinical and laboratory characteristics, detailed in Table 1, were comparable to those of the entire group, except for the absence of cases with lymphocyte depletion histology. The patient group comprised 49 males and 52 females, aged years (median 30 years). The histological subtype was: nodular sclerosis (NS) in 74 patients; mixed cellularity (MC) in 22; and lymphocyte predominance (LP) in three. In the remaining two cases, a confident classification of the histological subtype could not be ascertained. The median followup for surviving patients was 108 months (range months). Staging and treatment Staging was based on Ann Arbor criteria (modified by Cotswold meeting) [12]. Only four patients were pathologically staged by laparotomy. Fortytwo patients were classified as stage II, 32 as stage III and 27 as stage IV. Thirty-nine patients had bulky disease defined as a mediastinal mass exceeding one-third of the thoracic diameter measured at the D5 D6 level, and/or an extramediastinal mass >10 cm. B symptoms were present in 59 cases. Sixty-eight patients received MOPP/ABVD chemotherapy (67%) and 33 received ABVD (33%). The planned number of cycles was stage-dependent: six for stage IIB or bulky disease, and eight for stage III and IV disease. Combined treatment with radiotherapy (RT) (30 36 Gy) was administered to 58% of patients at the site of bulk or residual disease. Table 1. Presenting clinical and laboratory features in 101 advanced HL patients No. of patients (%) Gender Male 49 (48) Female 52 (52) Age (years) (81) (19) Ann Arbor stage IIB or bulk 42 (41) III 32 (32) IV 27 (27) Histological type Lymphocyte predominance 3 (3) Nodular sclerosis 74 (73) Mixed cellularity 22 (22) Lymphocyte depletion 0 (0) Unclassifiable 2 (2) Bulky disease 39 (39) B symptoms 59 (58) Bone marrow involvement 14 (14) Hemoglobin <10.5 g/dl 16 (16) White cell count /mm 3 17 (17) Lymphocyte count <600/mm 3 or <8% of WBC 11 (11) Serum albumin <4 g/dl 61 (60) International Prognostic Score >2 33 (33) scd U/ml 41 (41) Lactate dehydrogenase greater than 30 (32) normal value a a Available in only 94 cases. scd30, soluble form of the CD30 molecule. Response to treatment and survival All patients were considered assessable for treatment, since they received at least four cycles of chemotherapy. Response was assessed according to standard criteria [12]. In particular, patients with residual mediastinal enlargement were considered clinical complete responders (ccr) when this lesion remained stable for at least 2 months. Complete response was obtained in 96 patients (95%) after first-line treatment: three failed to reach CR and two progressed during treatment. Of the 96 complete responders, 21 (21%) relapsed, seven (33%) of these within 1 year from the end of treatment. Fifteen patients (15%) died: eight as a direct consequence of disease and seven due to complications after second-line treatment, including two myelodysplastic syndromes (MDS) transformed into acute myeloid leukemias (AML) and one breast cancer. Prognostic variables Prognostic features evaluated for their effect on OS and FFS included: IPS >2 (which requires male gender, age 45 years, stage IV, hemoglobin

3 1910 <10.5 g/dl, serum albumin <4 g/dl, white cell count /mm 3, lymphocyte count <600/mm 3 or <8% of the white cell count), MC histology (versus NS), presence of B symptoms, more than two extranodal sites involved, bulky disease, bone marrow infiltration, inguinal nodal involvement, abnormal serum LDH levels and serum scd30 levels 100 U/ml. The cut-off level of scd30 was chosen according to our previously published results [10]. Data were available for all patients, except serum LDH levels, which were available for 94 (93%). IPS was computed according to the recommendations of Hasenclever and Diehl [4]. scd30 assay scd30 levels were determined in serum samples stored at 70 C by a sandwich enzyme-linked immunosorbent assay [CD30 (K1 antigen) ELISA; DAKO, Glostrup, Denmark], based on the use of two monoclonal antibodies reacting with two different epitopes on the 88-kDa soluble form of the CD30 molecule, as described previously [13]. Sera from 113 blood donors (79 males and 34 females, median age 30 years) served as normal controls. Statistical analysis Overall survival was calculated from the start of therapy until death from any cause. Failure-free survival (FFS) was computed from the start of treatment until one of the following events occurred: failure to reach CR, disease progression during treatment, or relapse after CR. Patients who died of a disease-unrelated cause during remission were censored. Actuarial OS and FFS curves were constructed according to Kaplan Meier method and differences were analyzed by the log-rank test. Overall survival and FFS are always reported at 6 years unless otherwise stated. Statistically significant variables obtained by univariate analysis were included in the multivariate analysis performed by Cox s proportional hazard model. Results The estimated OS for all patients was 89% ± 3% [standard error of the mean (SE)] and FFS 75% ± 4% (Figure 1). Overall survival was not significantly influenced by any clinical and laboratory feature evaluated at diagnosis by univariate analysis (Table 2). FFS was significantly affected by the presence of bone marrow involvement, IPS >2 and serum scd30 levels 100 U/ml (Table 2). FFS of 14 patients (14%) with bone marrow involvement was 50%, compared with 78% without bone marrow involvement (P = 0.024). The FFS of 33 patients (33%) with IPS >2 was 60%, which was significantly lower than in the remaining patients (82%) (P = 0.027) (Table 2). Table 3 shows FFS according to IPS. Estimated FFS ranged from 82% of patients with score 0, to 0% of patients with score 5. The estimated FFS was <50% only in patients with IPS 4. This subgroup represents 7% of the patients evaluated. In 41 cases (41%), serum scd30 levels were 100 U/ml. The difference in FFS was highly significant for patients with scd30 levels above and below 100 U/ml at diagnosis (FFS 58% compared with 87%, respectively; P = 0.003) (Table 2). Using multivariate analysis, which included IPS, bone marrow involvement and scd30, only serum scd30 levels 100 U/ml were found to be an independent prognostic factor associated with lower FFS (P = 0.015) (Table 4). We therefore divided our patients into three groups according to scd30 and IPS values: (i) 45 (45%) patients had scd30 <100 U/ml and IPS 2 (group A); (ii) 38 (37%) patients had either high serum scd30 levels or high IPS (group B); and (iii) 18 (18%) had both high serum scd30 levels and high IPS (group C). FFS of group C (44% ± 11%) was significantly worse than that of groups A (89% ± 4%) (P <0.001) and B (73% ± 7%) (P = 0.03). The FFS of group A was not significantly better than that of group B (Figure 2). Among the 59 patients with stage III IV disease, the 23 cases (39%) belonging to group A (seven classified as stage IIIA, eight as IIIB, seven as IVA and one as IVB) had a very favorable prognosis, with FFS of 96% ± 4%, significantly higher compared with that of groups B (64% ± 11%) (P = 0.01) and C (44% ± 12%) (P <0.001). The FFS of group B was not significantly better than that of group C (Figure 3). Figure 1. Overall survival (OS) and failure-free survival (FFS) in 101 advanced Hodgkin s lymphoma patients.

4 1911 Table 2. Estimated 6-year overall survival (OS) and failure-free survival (FFS) in advanced Hodgkin s lymphoma patients: Kaplan Meier analysis of clinical and laboratory parameters at diagnosis No. of patients % OS rates (% ± SE) P value SE, standard error of the mean; NS, not significant; scd30, soluble form of the CD30 molecule. FFS rates (% ± SE) International Prognostic Score ± 3 NS 82 ± > ± 7 60 ± 9 Histologic type Nodular sclerosis ± 4 NS 74 ± 5 NS Mixed cellularity ± 6 82 ± 8 Bulky disease No ± 4 NS 75 ± 6 NS Yes ± 5 74 ± 7 B symptoms No ± 3 NS 76 ± 7 NS Yes ± 5 74 ± 6 No. of extranodal sites involved < ± 3 NS 76 ± 4 NS ± ± 15 Inguinal involvement No ± 3 NS 77 ± 4 NS Yes ± ± 20 Bone marrow involvement No ± 3 NS 78 ± Yes ± ± 13 Lactate dehydrogenase Normal value ± 3 NS 72 ± 6 NS >Normal value ± 5 83 ± 7 scd30 <100 U/ml ± 3 NS 87 ± U/ml ± 6 58 ± 8 P value Discussion Current therapies for HL fail to cure about one-third of patients with advanced stage disease. Consequently, we need to identify a sizeable group of patients with FFS <50% who could be considered at high risk of failure with conventional treatment. In this group of patients, the probability of relapse or progression is so high as to justify the potential elevated short- and long-term morbidity of first-line aggressive approaches, such as autologous hematopoietic stem cell transplantation [14] or intensified chemotherapy [15]. In particular, the escalated BEACOPP regimen, proposed by the German Hodgkin Lymphoma Study Group, appeared to obtain significantly superior FFS and OS at 5 years (87% and 91%, respectively) as compared with standard BEACOPP or COPP/ ABVD [15]. Intensified chemotherapy could probably overcome the adverse prognostic variables; on the other hand, the higher toxicity of this therapy should be applied only to very high-risk patients. Unfortunately, the search for adverse prognostic features at presentation, capable of identifying this group of patients, has so far been unsatisfactory [5]. Also, the IPS proposed by Hasenclever and Diehl failed in this purpose [4]. Only Gobbi et al. [5] recently achieved this target through a complex Integrated Index, based on 15 clinical and laboratory parameters, and requiring a computed program for calculation. We evaluated the prognostic impact of IPS and serum scd30 levels in 101 patients with advanced HL, homogeneously treated with chemotherapy, combined or not with radiotherapy. Our data confirmed the significant unfavorable influence of IPS >2 on FFS (P = 0.027). In the poor prognosis group, the 6-year FFS was 60%.

5 1912 Table 3. Estimated 6-year failure-free survival (FFS) according to the International Prognostic Score (IPS) in advanced Hodgkin s lymphoma patients IPS No. of patients (%) Rate of FFS (% ± SE) P value 0 11 (11) 82 ± (27) 89 ± (29) 76 ± (26) 69 ± (4) 37 ± (3) 0 SE, standard error of mean. Table 4. Cox multivariate regression analysis with respect to failure-free survival (FFS) of advanced Hodgkin s lymphoma patients Variable Hazard ratio 95% confidence P value interval Bone marrow NS involvement IPS > NS scd U/ml IPS, International Prognostic Score. In our series, the percentage of patients with IPS >2 was lower compared with that of the original IPS report (33% compared with 42%, respectively) [4]. This finding was probably due to the higher percentage of patients (42% compared with 13%, respectively) with stage IIB or bulky disease in our study, partly related to the very small number of patients pathologically staged by laparotomy. In agreement with Hasenclever and Diehl [4], FFS was <50% only in patients with an IPS score 4. In our study, this group of patients represent only 7% of the entire population, as opposed to 19% reported in the original IPS report [4]; conversely, our percentage is similar to that (10%) reported by the Italian Lymphoma Study Group [5]. In our study, patients with serum scd30 levels 100 U/ml were associated with an FFS that was significantly worse (58%) than in patients with lower scd30 levels (87%) (P = 0.003). This finding confirms the results of previous studies [6, 7, 10]. On the other hand, also in our study, IPS >2 and serum scd30 levels 100 U/ml, when evaluated separately, failed to identify a group of patients with FFS <50%. Multivariate analysis using Cox s proportional hazards model confirmed that only scd30 was an independent variable associated with inferior FFS (P = 0.015). Although the IPS was not an independent prognostic variable in our group of patients, we evaluated its effect when combined with serum scd30 level. The FFS of the patients with scd U/ml and IPS >2 was 44%, significantly lower than in patients with low scd30 and low IPS (89%) (P <0.001), or with only one of the two adverse prognostic factors (73%) (P = 0.03) (Figure 2). This group represents 18% of the entire population of advanced HL patients. Therefore, in our series the combination of serum scd30 levels 100 U/ml and IPS >2 can identify a sizeable population of patients with a high risk of failure. Our data are in agreement with those reported by Axdorph et al. [11], although the two studies are not easily comparable. Axdorph analyzed HL patients of all stages and all ages, Figure 2. Failure-free survival according to the combination of International Prognostic Score (IPS) and serum scd30 level at diagnosis in advanced Hodgkin s lymphoma patients. (A) IPS 2 and scd30 <100 U/ml; (B) IPS >2 or scd U/ml; (C) IPS >2 and scd U/ml. (A) compared with (B), P = not significant; (A) compared with (C), P <0.001; (B) compared with (C), P = 0.03.

6 1913 Figure 3. Failure-free survival according to the combination of serum scd30 level and International Prognostic Score (IPS) in 59 patients with stage III IV Hodgkin s lymphoma. (A) IPS 2 and scd30 <100 U/ml; (B) IPS >2 or scd U/ml; (C) IPS >2 and scd U/ml. (A) versus (B), P = 0.01; (A) versus (C), P <0.001; (B) versus (C), P = not significant. including cases treated only with radiotherapy or only with MOPP chemotherapy, and the cut-off for serum scd30 levels was different. Moreover, they analyzed the cause-specific survival (CSS) as end point instead of FFS. The 5-year CSS of their prognostic group characterized by high IPS and scd30 levels was 54%, similar to the 6-year OS of our comparable group (61%) (data not shown). In our opinion, OS and CSS should not be considered the end point for prognostic studies in HL, since many patients can be rescued by salvage therapy after relapse, particularly when it occurs late. The main targets of the therapeutic strategy for HL patients with unfavorable prognosis should be both to prevent relapses, even late ones, sparing the toxicity of a second-line treatment, and to avoid the risk of overtreating patients who may be cured with conventional therapy. The advantage of using FFS for these studies is that it pools all types of failures that can be related to unsuccessful therapy and for which early-intensified treatment may be justified. In our study, the group of advanced HL patients with IPS <3 and serum scd30 levels <100 U/ml had a very good prognosis: in particular, patients with these prognostic characteristics and advanced stage III IV disease had 6-year FFS of 96%. Our results, although concerning a relatively small number of patients, can identify cases with advanced disease who could be treated less aggressively, without compromising the final anti-tumor effect. In conclusion, the IPS is easy to use and requires only routine tests. Nevertheless, an IPS >2 is not adequate for selecting patients who really need a first-line intensive treatment, which implies an elevated acute and, above all, long-term toxicity (myocardial failures, secondary cancers, AML/MDS) [16]. A biological parameter such as serum scd30 level, which is easy to obtain through the use of commercial kits, could be helpful, when combined with IPS, in obtaining a more precise selection of patients suitable for more intensive treatment. Acknowledgements We acknowledge the valuable help of Dr Christian Pattaro (Department of Medical Statistics, University of Verona, Italy). This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milano. References 1. Tubiana M. Hodgkin s disease: historical perspective and clinical presentation. Baillieres Clin Haematol 1996; 9: Specht L. Prognostic factors in Hodgkin s disease. Semin Radiat Oncol 1996; 6: Straus DJ, Gaynor JJ, Myers J et al. Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin s disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy. J Clin Oncol 1990; 8: Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin s disease. International Prognostic Factors Project on Advanced Hodgkin s Disease. N Engl J Med 1998; 339: Gobbi PG, Zinzani PL, Broglia C et al. Comparison of prognostic models in patients with advanced Hodgkin disease. Promising results from integration of the best three systems. Cancer 2001; 91: Nadali G, Vinante F, Ambrosetti A et al. Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin s disease and correlate with clinical features and prognosis. J Clin Oncol 1994; 12: Gause A, Pohl C, Tschiersch A et al. Clinical significance of soluble CD30 antigen in the sera of patients with untreated Hodgkin s disease. Blood 1991; 77:

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