Introduction. Acta Medica Mediterranea, 2015, 31: 1195

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1 Acta Medica Mediterranea, 2015, 31: 1195 CLINICAL CHARACTERISTICS, POST-TREATMENT ASSESSMENT AND PROGNOSTIC FACTORS AFFECTING PATIENT SURVIVAL OF PATIENTS AT 65 YEARS OF AGE OR OLDER WITH HODGKIN LYMPHOMA: A RETROSPECTIVE MULTICENTER STUDY FROM TURKEY ILHAMI BERBER *1, MEHMET ALI ERKURT 1, MUZAFFER KEKLIK 2, MEHMET HILMI DOGU 3, HATICE TERZI 4, CIGDEM PALA 2, HAKAN ISMAIL SARI 3, MEHMET SENCAN 4, SERDAR SIVGIN 2, SIBEL HACIOGLU 3, FEVZI ALTUNTAS 5, ISMET AYDOGDU 6, OSMAN ILHAN 7 1 Hematology, Inonu University, Malatya - 2 Hematology, Erciyes University, Kayseri - 3 Hematology, Pamukkale University, Denizli - 4 Hematology, Cumhuriyet University, Sivas - 5 Hematology, Yildirim Beyazit University, Ankara Oncology Hospital, Celal Bayar University, Manisa - 6 Department of Hematology, Faculty of Medicine, Celal Bayar University, Manisa- 7 Hematology, Ankara University, Ibni Sina Hospital, Ankara, Turkey ABSTRACT Introduction: During the last three decades, major advances have been made in the therapy of Hodgkin s lymphoma. However, despite these advances, Hodgkin s lymphoma has a poor prognosis in the elderly. The proportion of Hodgkin s lymphoma patients aged > 60 ranges in the different reports between 15% and 35%. This study aimed to examine clinical characteristics, treatment outcomes and prognostic factors affecting patient survival in Hodgkin s lymphoma patients aged 65 years or older. Material methods: Hodgkin s lymphoma patients at 65 years of age and older managed within last 5 years in a total of 5 centers in Turkey were retrospectively assessed. Results: The median age of a total of 32 patients was 71 (65-83) years. Elderly patients presented more frequently with B symptoms, elevated sedimentation rate, mixed cellularity histologic subtype and comorbid disease. Less frequent were bulky disease, bone marrow involvement, and the application of autologous stem cell transplantation. The nodular lymphocyte predominant subtype and lymphocyte rich subtype were not observed at all. Eastern Cooperative Oncology Group, ferritin, total protein, and histological type were significant predictors affecting survival (p<0.05). Conclusions: Hodgkin s lymphoma is a more fatal disease in 65 years of age or older, when compared to the young population. Tumor biology, older age itself, and other factors related to comorbidity probably contribute to the worse outcome of elderly patients. Further large-scale studies are needed to better investigate the factors that were significant predictors of patient survival. Key words: Hodgkin lymphoma, elderly patients, prognostic factors. Received November 30, 2014; Accepted May 02, 2015 Introduction During the last three decades, major advances have been made in the therapy of Hodgkin s lymphoma (HL). This success is mainly based on the introduction of effective combination chemotherapy regimens and progress in radiation techniques. However, despite these advances, HL continues to carry a poor prognosis in the elderly (1-4). Populationbased epidemiological studies typically show a bimodal peak of HL incidence: the first around years old, the second beyond The proportion of HL patients aged > 60 ranges in the different reports between 15% and 35% (5,6). According to World Health Organization (WHO) 2008 classification HL is divided into 2 main groups as nodular lymphocyte predominant and classical HL; classical HL is further subdivided into 4 subtypes including the lymphocyte rich, mixed cellularity, lymphocyte depletion, and nodular sclerosis. The nodular sclerosis subtype is the most common subtype in developed countries whereas the mixed cellular subtype

2 1196 Ilhami Berber, Mehmet Ali Erkurt et Al predominates developing countries such as Turkey (7,8). Although its exact etiopathogenesis is unclear, Epstein- Barr Virus (EBV) infection as well as genetic and autoimmune factors are implicated in its development (9). The modified Ann-Arbor classification scheme is used in its staging that utilizes computed tomography and positron emission tomography. Treatment approach depends on age, stage, and tumor mass. Therapy for Hodgkin disease usually involves radiotherapy, chemotherapy combinations, and stem cell transplantation. The prognosis is determined by age, sex, tumor size, volume and number of involved nodal regions, extranodal involvement, histopathological subtype, clinical stages, and B symptoms (10). Older age at admission independently affects survival in an unfavorable manner. There are two theories attempting to explain the negative impact of age on survival. One of them involves biological variations in tumor histology with accompanying aggressive behavior, variable localization of the disease-involved sites, and a shorter duration of disease symptoms (11-15). The other takes into account the increased rates of comorbidities, an increased side effect profile of the current regimens (16,17), more intense toxic symptoms associated with chemotherapy and chemotherapy-related mortality (11,12), and worse prognostic implications after relapse (18,19) in the elderly. Moreover, the analysis of elderly HL patients may be hindered by the inclusion of deaths unrelated to the disease itself (20). The prognostic scoring systems in HL are designed by stage. HL is currently examined in two stages as early (stage 1,2) and late (stage 3,4). There are more than one scoring systems used for evaluation of patients at the early stage; EORTC (European Organization For Research and Treatment of Cancer), GHSG (German Hodgkin Lymphoma Study Group), and NCIC (National Cancer Institute of Canada) assess the early-stage disease in terms of prognosis using quite similar criteria (age, histological subtype, sedimentation, mediastinal mass, number of involved lymphatic regions, extranodal involvement) (21,22,23,24). Patients with none of the risk factors defined in these scoring systems are considered to have an early stage favorable risk group while patients with at least one risk factor are considered to be in the early stage unfavorable risk group. Patients in the advanced stage are assessed by the International Prognostic Score (IPS) that takes into account age, sex, stage, hemoglobin, serum albumin level, leucocyte count, and lymphocyte count (24). According to this scoring system, patients with 4 or more poor prognostic signs are considered to have a poor prognosis. This study aimed to examine clinical characteristics and treatment outcomes of patients, prognostic factors affecting patient survival at 65 years of age or older diagnosed with HL. Material and methods HL patients at 65 years of age or older managed within last 5 years in a total of 5 centers (Hematology Department of Inonu University, Erciyes University, Pamukkale University, Cumhuriyet University and Ankara Oncology Hospital) in Turkey. To diagnose the disease, appropriate biopsies were sampled from the local disease and examined by the pathologists who had adequate experience in lymphoma classification. Histological classification was based on the WHO criteria. Sex, age, comorbid disorders, tumor stage, number of involved nodal regions, presence of B symptoms, splenic involvement, splenomegaly (> 13 mm), bone marrow involvement, and extranodal involvement and its site were recorded. Patients with a mass larger than 7 cm were considered to have bulky disease. Fever >38C, night sweats, and weight loss > 10% compared to baseline were considered as B symptoms. Pretreatment hemoglobin level, leukocyte count, lymphocyte count, hemoglobin, thrombocyte count, sedimentation rate, Blood Urea Nitrogen (BUN), creatinine, total protein, albumin, lactate dehydrogenase (LDH), B2 microglobulin, and ferritin levels of the patients were recorded. Eastern Cooperative Oncology Group (ECOG) performance status was determined in each patient. Ann Arbor staging Cotswolds Modification was used for staging. Stage I or II disease was considered as earlystage disease and stage III and IV disease as latestage disease. Each patient gave written informed consent, which was based on the institutional review board guidelines. The administered therapies (chemotherapy, radiotherapy and autologous bone marrow transplantation), the rates of response to therapy, and the final clinical state of the patients were recorded. Chemotherapies administered at the first and second steps were shown on Table 1. Radiotherapy was initiated 4 to 6 weeks after the end of chemotherapy. The total dose was between 30 and 40 Gray (Gy). The single-fraction dose was 1.8 to 2.0 Gy daily. Leukopenia, anemia, thrombocytopenia, infection, nausea, vomiting, car-

3 Clinical characteristics, post-treatment assessment and prognostic factors affecting patient survival diac and respiratory problems were considered chemotherapy toxicity. WHO recommendations (25) were taken into consideration when assessing the response criteria. Complete remission (CR) was defined as disappearance of all lesions for at least 4 weeks. Partial response (PR) was defined as a reduction by 50% or greater in the product of the largest perpendicular diameters of all measurable tumor masses for at least 4 weeks. All other patients were considered non-response. Cause and time of death of the patients were recorded. that 13 (40.6%) patients were ECOG I. One (3.1%) patient was HbsAg positive and 3 (9.3%) were EBV positive. Two of the them were in the mixed cellular type. Sixteen patients (50%) had B symptoms. Only 1 (3.1%) patient had bone marrow involvement and 4 (12.5%) patients had bulky disease (>7 cm). Seven (21.8%) patients had extranodal disease and 6 (18.8%) patients had splenomegaly. Detailed clinical and laboratory data of the study population were presented on Table 2. Used Treatment Protocols Protocols used in the primary line treatment Number of Patients (%) 32 (%100) ABVD 31 (%96.8) MOPP 1 (%3.2) Protocols used in the secondary line treatment 10 (%31.2) Statistical analysis Survival analysis was performed with Kaplan- Meier method and the comparison of survival times with respect to categorical variables was carried out with the Log-Rank test. Cox regression analysis was used for the assessment of the numerical variables effect on survival rate and for multivariate regression analysis taken into consideration all factors. A p value less than 0.05 was considered statistically significant. Results DHAP 3 (%9.3) BEACOPP 3 (%9.3) ICE 2 (%6.2) ESHAP 1 (%3.1) Mini-BEAM 1 (%3.1) Table 1: Chemotherapy regimens used in the first and second line treatments. This study included 32 patients with a median age of 71 (65-83) years. Most of these patients were male. Twenty-nine (90.6%) of these patients had a comorbid disease, of which hypertension was the most prevalent (n=11; 37.9%). None of our patients had nodular lymphocyte predominant or lymphocyte rich type. The most common type was the mixed cellular type. The patients most commonly had stage 2 disease at the initial admission (n=17; 53.1%). The performance status of the patients assessed by the ECOG performance scale showed Table 2: Clinical and laboratory characteristics of the patients at initial presentation characteristics. *HR: Hazard Ratio; ** Statistics could not be made because death was not observed in this group; ***Identical with the same letter and different with different letters.

4 1198 All patients except for 1 patient were treated with 4-8 cycles of Adriamycin - Bleomycin Vinblastine - Dacarbazine (ABVD) based on disease stage at the first step. One patient received Nitrogen Mustard-Vincristine-Prednisone Prokarbaz (MOPP) treatment protocol. Nine (28.1%) patients also received radiotherapy for the involved area after the first step therapy. While 24 (75%) patients showed complete response after the first step therapy, 6 (18.75%) showed partial response and 2 (6.25%) showed no response but progression. During the first step therapy 18 (56.2%) of 32 patients developed chemotherapy toxicity. Second step therapies were commenced for 4 patients who developed recurrence after a median of 16 months following complete response in the first step therapy, 4 patients who developed recurrence after a median of 6.5 months following a partial response in the first step therapy, and 2 patients who showed progression. Chemotherapy-induced toxicity emerged in 6 (31.2%) of a total of 10 patients who were applied second step therapy. Two patients who showed disease progression were lost to disease-related causes during Dexamethasone High-dose cytarabine- Cisplatin (DHAP) and Ifosfamide - Carboplatin -Etoposid (ICE) therapies. Four patients who gave a partial response to first step therapy and had a recurrence were administered second step therapy. Three (9.3%) of these patients received autologous stem cell transplantation. They were at complete remission at the time of the writing of this report (Figure 1). Ilhami Berber, Mehmet Ali Erkurt et Al 40,6-72,1) months, median survival time was 56.0 (%95 C.I.: 26-86) months, and 5-year survival rate was 44.3%. The mean progression-free survival rate was (%95 G.A.= ) months and progression-free survival percentage was 93.8%. Overall survival and progression free survival curves of the study population were shown on Figure 2 and Figure 3. Figure 2: Overall Survival of all patients. Figure 3: Progression free survival of all patients. Figure 4: Overall survival according to early and late stage. Figure 1: Remission status of all patients. Over a median of 16.5 months of follow-up, the mean survival duration was 56.4 (%95 C.I.: An analysis of the survival rates by disease stage showed that the mean survival time was (95% C.I. = ) months for early-stage disease and 56 (95%C.I.=56-56 ) months for latestage disease (p=0,460). (Figure 4). It was 50.2% for early stage and 0% for late stage.

5 Clinical characteristics, post-treatment assessment and prognostic factors affecting patient survival Average survival times by histological types were as follows: (95% C.I. = ) months in the nodular sclerosing type, (95% C.I. = ) months in the mixed type, and 42 (95% C.I. = ) months in lymphocyte depletion type. Ten (25%) of 32 patients were lost. The causes of death were non-disease related causes in 5 (15.6%) patients and disease-related causes in 3 (9.3%) patients. Of those who died because of nondisease related causes, 3 (9.3%) died of myocardial infarction and 2 (6.2%) died of pneumonia. The causes of disease-related death were progression in 2 patients and partial response in 1 (Figure 1). A univariate analysis showed that total protein, ferritin, ECOG performance scale, and tumor s histological type affected survival time (Table 3). Multivariate analysis indicated that no factor independently affected survival time. Discussion This retrospective study aimed to determine the clinical and epidemiological characteristics of HL patients aged 65 years or older treated at 5 institutions in our country. It also investigated the rate of treatment success and the prognostic factors affecting survival. This study is the largest one ever performed to date in HL patients aged 65 years or older in our country. HL is more common in males across all age groups (7). Engert et al., on the other hand, reported that 52% of a total of 376 affected patients aged 60 years or older and there were more female patients in the elderly group (26). Gail et al. reported that males formed 50.9% of the study population aged 60 years or older (27). Similar to the literature data, male patients constituted 59.4% of our study population. Evens et al. reported that 73% of their patients had an ECOG performance status of 0 or 1 (28). Engert et al. demonstrated that 90% of their patients had an 80 or higher performance status according to Karnofsky performance scale (26). Twenty-one (65.6%) of our patients had an ECOG status of 0 or 1, as reported by the previous studies. Evens et al., in a study in 95 patients with HL aged 60 years or older, reported that disease histology was nodular sclerosis in 47%, mixed cellularity in 31%, not otherwise specified 16%, lymphocyte predominant 5%, and lymphocyte depleted 1% (28). In 2011 Björkholm M et al. reported that the mixed cellularity was the most common type in 21 HL patients (29). Similarly, Engert et al. reported the mixed cellularity as the most common type (26). Stark et al. found that the nodular sclerosing subtype was the commonest in this older age group at 44%, followed by mixed cellularity at 32% in 102 patients with HL aged 60 years or older (23). We determined that the mixed cellularity type was the most common type, while the good prognostic histological types of nodular lymphocyte predominant and lymphocyte rich types were not observed. The most common type after mixed cellularity type was the nodular sclerosing type. B symptoms are important for determining therapy, stage, and prognosis (9-11). They are more common in elderly patients and in advanced disease. In general, 25-40% of HL cases have B symptoms (10,11). Evens et al. reported that 54% of the patients had B symptoms (28). Engert et al. detected B symptoms in 50% of their study population (26). We also showed that 50% of the patients had B symptoms that were more prevalent in older patients, as reported in the literature. One of the reasons for worse prognosis of HL among elderly patients compared to younger populations is the higher prevalence of comorbid disorders in the former (15,16). According to the results of Evens et al., 21% of the affected patients had a history of coronary artery disease, and 16% had diabetes at baseline (28). Also in our study the majority of our patients suffered a comorbid disease, of which hypertension was the most common one followed by two or more comorbid disorders (Table 2). Evens et al. demonstrated that 64% of the study population had a stage 3 or 4 disease (28). Engert et al. reported that the majority of the study population was at stage II (37%) (26). In the study by Stark et al. the disease stage could not be determined in 2 patients due to technical failure. Among others, 36% had early-stage HL (Stage 1, 2) and 54% had late-stage HL (Stage 3,4) (27). Stage II patients constitute 53.1% and early-stage (Stage 1,2) patients constitute 75% of our population. This difference between the previous studies and our study may have stemmed from staging errors, a different age group distribution, or disease diagnosis at an early stage. The study by Evens et al. reported that only 4% of the patients had bulky disease (28). The relatively low rate of bulky disease is consistent with prior elderly HL series (30,31). Engert et al. found a bulky disease rate of 49%, however, they consid-

6 1200 Ilhami Berber, Mehmet Ali Erkurt et Al ered a diameter threshold of 5 cm for bulky disease (26). Consistent with the literature data, we observed a rate of 12.5% for bulky disease. Evens et al. reported that 20% of the patients had extranodal involvement while bone marrow involvement was 25% (28). Engert et al., on the other hand, reported a rate of 20% for extranodal disease (26). We reported a rate of 21.8% for extranodal involvement and 3.1% for bone marrow involvement. The lower rate of bone marrow involvement may have resulted from diagnosis at an early period of the disease. Currently, Adriamycin - Bleomycin - Vinblastine - Dacarbazine (ABVD) is the standard chemotherapy regimen for early-stage cases and Bleomycin-Etoposide-Adriamycin- Cyclophosphamide-Vincristine-Prednisone- Procarbazine- Prednisolone (BEACOPP) or increased-dose BEACOPP for late-stage disease in some centers. Engert et al. used ABVD, Cyclophosphamide, Oncovin, Procarbazine and Prednisone (COPP), and BEACOPP regimens of varying doses (26). In the study by Evens et al. ABVD (70.5%) was the most commonly used treatment regimen (28). In agreement with the literature, 96.8% of our patients received ABVD regimen as the first step therapy. Nine (28.1%) of our patients received ABVD chemotherapy followed by radiotherapy of the involved field as the first step therapy. Intensive regimens, such as BEACOPP (escalated or baseline), are too toxic for elderly HL (32). Thus, BEA- COPP regimen was not preferred as the first step therapy. Enbland G et al. reported a 5-year survival rate of 45% between 1985 and 1988 and 48% between 1989 and 1992 (30). Evens et al. documented an overall 5-year Overall survival (OS) and Progressionfree survival (PFS) of 58% and 44%, respectively (28). Björkholm M et al. demonstrated a 5-year relative survival of 58% in Swedish patients aged 66 to 80 years (29). In the study conducted by Engert et al. the 5- year overall survival was 65% and the 5-year freedom from treatment failure was 80% (26). In our study, probability of 5-year survival was 44.3% and progression free survival was 93.8%. In general, the survival and progression free survival rates were similar to those reported in the literature. Engert et al. reported that 38% of the elderly patients died. Ten percent of them died of Hodgkin disease-related causes. Acute toxicity was the cause of death 6% of cases, cardiorespiratory causes in 7%, secondary malignancies in 6%, other conditions in 5%, and unknown causes in 4% (26). In the Stark et al. s study 65.6% of the patients died. Of those who died, 21.5% died of causes unrelated to HL (27). Twentyfive percent of our study population died, and majority of them did so due to causes unrelated to HL. We found a lower death rate compared to other studies conducted in the elderly HL patients and this possibly resulted from a different age distribution, a diagnosis at an early stage, different chemotherapy regimens and doses, and the number and type of accompanying comorbidities. Evens et al. reported that Stage 1 and 2 patients fared better compared with stage 3 or 4 patients (5-year PFS and OS: 61% and 79% for stage 1 or 2 vs 36% and 46% for stage 3 or 4; P =.009 and P =.001,respectively) (24). Stark et al. similarly reported a higher overall survival rate in early-stage disease (27). Our study also detected a higher overall survival in early stage, albeit statistically non-significant. Stark et al. s histological subtype did not correlate significantly with outcome in their cohort, although there was a trend for mixed cellularity / nodular sclerosing subtypes to have an inferior outcome compared with patients with lymphocyte predominant /lymphocyte-rich classical HL (27). Histological type was effective on survival and the nodular sclerosing type portended the worst prognosis. Evens et al. determined in univariate analysis that loss of daily living activities and a performance status of 3-4 were the factors affecting prognosis. However, they could not detect any relation with IPS score. The multivariate analysis showed that only 2 factors here were associated with inferior outcomes: (1) age more than or equal to 70 years (2) loss of activities of daily living (28). In the Engert et al. s study there was no significant relationship between IPS scoring system and prognosis (26). Stark et al., on the other hand, reported that the worst factors affecting survival were EBV positivity and age greater than 70 years (27). We determined that ECOG performance scale, ferritin, total protein, and histological type were effective on survival. There was no death especially in the ECOG 0 group. Elevated ferritin and lowered protein level affected prognosis in an unfavorable manner. The nodular sclerosing type had an unfavorable impact on prognosis. In our analysis, we found several differences in disease-related characteristics in older HL

7 Clinical characteristics, post-treatment assessment and prognostic factors affecting patient survival patients. Elderly patients presented more frequently with B symptoms, elevated sedimentation rate, mixed cellularity histologic subtype and comorbid disease. Less frequent were bulky disease, bone marrow involvement, and the application of autologous stem cell transplantation. The nodular lymphocyte predominant subtype and lymphocyte rich subtype that have a better prognosis than other HL subtypes were not observed at all. ECOG performance scale, ferritin, total protein, and nodular sclerosing type were the factors affecting survival. Conclusion Hodgkin s lymphoma is more fatal disease in 65 years of age or older, when compared to the young population. Tumor biology, older age itself, and other factors related to comorbidity probably contribute to the worse outcome of elderly patients. 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