Primary Bone Non-Hodgkin's Lymphoma: A Specific Clinical Entity with Aggressive Clinical Course and High Cure Rate - Retrospective Analysis of 102 Patients from Greece
Authors: Symeonidis Argiris , Papageorgiou Sotirios , Patrinos Antonis , Melachrinou Maria , Kourakli Alexandra , Pappa Vassiliki , Angelopoulou Maria K. , Sioni Anastasia , Kanellias Nikolaos , Chatzileontiadou Sofia , Hatzimichael Eleftheria , Zikos Panagiotis , Pouli Anastasia , Papaioannou Maria , Terpos Evangelos , Pangalis Gerasimos , Vassilakopoulos Theodoros P. 
Published: November 2019

Background - Objectives: Primary Bone non-Hodgkin's Lymphoma (PB-NHL) is a rare disease and constitutes about 3% of the total NHL patient population. We estimated the prevalence of this type of lymphoma in the local lymphoma registry of Western Greece and retrospectively analyzed 102 cases, in an effort to describe the clinical, histological and prognostic features of this tumor.
Patients and Methods: Among 1225 patients (pts) with all types of NHL, diagnosed between 1.1.1991 and 31.12.2018 in the area of Western Greece, 32 (2.6%) had PB-NHL. We analyzed the data of these 32 pts, together with those of additional 70 pts, treated in 7 large Hematology Departments in Greece. Pts were 60 males and 42 females (♂/♀ ratio 1.43) with a median age of 62 years (range 20-93 years) and 55% of them were <65 years at initial diagnosis. Systemic treatment was offered in 97 pts; one elderly patient received only radiotherapy. Anthracycline-based chemotherapy was given in 94 pts (96.9%) and 39 of them (40.2%) received also local/adjuvant radiotherapy. A total of 79 pts received rituximab with chemotherapy (78%).
Results: In 81 pts (79.4%) the disease presented with local symptoms only, in 4 (3.9%) with systemic/constitutional symptoms, and in the remaining 17 (16.7%), with both, local and constitutional symptoms. The mainly affected bones were pelvis (iliac-pubertal-sacral, 23 pts), femur (15), lumbar vertebrae (14), thoracic vertebrae (12), mandible, humerus and tibia (7 each), ribs/sternum (5), skull, clavicle and scapula (3 each), maxilla (2) and patella (1). The most common histological type was Diffuse Large B-cell Lymphoma Not Otherwise Specified (DLBCL-NOS: 92 pts), followed by Ki-1+ anaplastic (3), small lymphocytic (3), mantle cell (3) and follicular lymphoma (1). A B-cell phenotype was revealed in 99 cases and non-B/non-T cell CD30+ in 3. One bone site was affected in 68 pts (66.7%), alone in 25, with contiguous extranodal or lateral nodal involvement in 23, and with one additional non-contiguous extranodal or distal nodal involvement in 20. Two bone sites with or without additional nodal or extranodal involvement was found in 12 pts and multiple bone sites with or without additional nodal or extranodal involvement in the remaining 22 pts. Ann-Arbor stage was early (I-II) in 51 pts and advanced (III-IV) in 51, B-symptoms were present in 21 pts (20.6%) and the marrow was involved in 20/87 pts (23%). Anemia was present in 33 pts, leukocytosis in 14, neutrophilia in 22, thrombocytosis in 15 and symptomatic hypercalcemia in 1 patient. Elevated serum LDH was found in 60/101 pts (59.4%), CRP in 35/55 pts (63.6%), alkaline phosphatase in 20/69 pts (29%) and beta2-microglobulin in 24/60 pts (40%). Six out of 51 pts (11.8%) were HBsAg(+), 1/51 anti-HCV(+) and 1/55 anti-HIV(+). Active treatment was administered in 97 pts, which was chemoimmunotherapy (Ch-Im) alone in 58, combined modality [Ch-Im + Radiotherapy (Rx)] in 38 and Rx alone in 1. Anthracycline-based regimens were administered in 93 pts. Five pts were not evaluable for response (lost from follow-up N=4, still on treatment N=1). Seventy-three pts achieved a CR (79.3% or 75.3% on an intention to treat basis) and treatment failed in 20 (20.6%). The median DFS was 29.5 months. Survival analysis was restricted to DLBCL pts who received Ch-Im: After a median follow-up of 33 months (range, 1-207) 58/76 pts were still alive for a 5-year OS of 71%. The 5-year progression free survival (PFS) was 59%. No survival benefit in terms of PFS and OS was found among pts, who received adjuvant Rx compared to pts who received Ch-Im alone, p=0.40). Age >60 yrs, PS ≥2, elevated LDH and tumor burden were all predictive of PFS and OS in univariate analysis. Ann Arbor stage III/IV had only borderline significance restricted on PFS. Only LDH (p=0.04) and tumor burden (intermediate and high versus low; p=0.07) were independent predictors of PFS in backward stepwise multivariate analysis. LDH and poor PS were the only potential independent predictors of OS in multivariate analysis but both had borderline significance.
Discussion and Conclusive remarks: PB-NHL is a rare aggressive lymphoma subtype, with a main histology of DLBCL-NOS, which responds favorably to anthracycline-based Ch-Im and response rates are similar to other nodal and extranodal aggressive lymphomas. Radiotherapy appears not to add on survival and should only be used for local palliation.

Disclosures
Symeonidis: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Pappa:Gilead: Honoraria, Research Funding; Amgen: Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Angelopoulou:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hatzimichael:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zikos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Pangalis:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.