Uticaj anti-CD20 monoklonskog antitela na koštane biohemijske markere i RANKL/OPG sistem kod novodijagnostikovanih bolesnika sa B-ćelijskim nehočkinskim limfomima

Abstract

UVOD: Nehočkinski limfomi predstavljaju heterogenu grupu malignih bolesti porekla limfocita različitog razvojnog stadijuma. Iako je poslednjih decenija napravljen veliki napredak u preživljavanju bolesnika sa NHL-om, postterapijske komplikacije mogu u velikoj meri da naruše kvalitet života ovih bolesnika. Dobro je poznato da hemioterapija utiče na gubitak koštane gustine i razvoj osteoporoze. Uticaj anti-CD20 monoklonskog antitela, koje je postalo standardni deo terapijskih protkola za lečenje B-ćelijskih limfoma, na koštane biohemijske markere i razvoj osteoporoze kod ovih bolesnika nije dovoljno ispitan. CILJEVI: Utvrditi stepen promena koštane gustine (BMD-g/cm2) kod bolesnika sa novodijagnostikovanim B-ćelijskim nehočkinskim limfomima šest meseci nakon početka lečenja u odnosu na koštanu gustinu izmerenu pre uvođenja terapije. Utvrditi razliku u stepenu promena koštane gustine (BMD-g/cm2) šest meseci nakon početka primene monoklonskog anti-CD20 antitela u odnosu na kontrolnu grupu bolesnika lečenih standardnim hemioterapijskim protkolima. Utvrditi razliku u stepenu promena koštanih biohemijskih markera i RANKL/OPG sistema šest meseci nakon uvođenja terapije monoklonskim anti-CD20 antitelom u poređenju sa kontrolnom grupom bolesnika lečenih standardnim hemioterapijskim protokolima. MATERIJAL I METODE: Prospektivno istraživanje je uključilo 60 novodijagnostikovanih ispitanika sa B-ćelijskim nehočkinskim lifmomima koji su podeljeni u dve grupe. Ispitivanu grupu činilo je 30 ispitanika lečenih monoklonskim anti-CD20 antitelom uz polihemioterapiju, dok su kontrolnu grupu činili ispitanici lečeni standardnim hemioterapijskim protokolima bez primene monoklonskog anti-CD20 antitela. Ispitanicima su načinjene predviđene laboratorijske analize i osteodenzitometrijski pregledi pre i šest meseci nakon započinjanja lečenja. REZULTATI: Uključeno je 60 ispitanika, 37 muškaraca i 23 žene. Medijana starosti pri postavljanju dijagnoze je bila 63,5 (raspon: 34- 82) godina. Uključeno je najviše ispitanika sa difuznim B- krupnoćelijskim limfomom (25%), odnosno folikularnim limfomom (25%). Ukupno je 66,6% ispitanika dijagnostikovano u četvrtom kliničkom stadijumu. Nakon 6 meseci lečenja, kod obe grupe ispitanika, na lumbalnoj kičmi, kuku i vratu butne kosti, je verifikovan značajan gubitak koštane gustine (r = 0,00). Osteoporozu je razvilo 12 ispitanika (20%). Nakon šest mesci, došlo je do statistički značajnog povećanja samo jednog markera koštane sinteze - P1NP-a, u obe grupe ispitanika. P1NP je značajno manje rastao kod kontrolne grupe ispitanika (r = 0,01). Veću koštanu gustinu su imali ispitanici koji su primili 6 ciklusa hemioterapije i koji su lečeni prema R-ČHOP protokolu. ZAKLJUČAK: Naši rezultati pokazuju da postoji promenjen koštani metabolizam u obe grupe ispitanika sa nehočkinskim limfomima pre i nakon primenjene terapije. Postoji razlika u promeni vrednosti P1NP- a između ispitivanih grupa, odnosno značajno veći porast vrednosti je zabeležen nakon lečenja u grupi ispitanika lečenih kombinacijom anti-CD20 monoklonskog antitela uz polihemioterapiju. Neophodno je da se bolesnici sa nehočkinskim limfomima testiraju i prate u odnosu na koštani metabolizam pre, i u dužem vremenskom periodu nakon primenjene terapije kako bi se pravovremenim uključivanjem antiresorptivne terapije smanjile negativne posledice polihemioterapije na koštano tkivo.

INTRODUCTION: Non-Hodgkin lympfomas are a heterogeneus group of malignant diseases which originate from lymphocytes in different stage of development. Despite the improvment achieved in NHL patients survival during the last decades, post-treatment complications can reduce the quality of life in these patients. It is well known that cancer therapy can cause bone mineral density loss and osteoporosis. The impact of monoclonal anti CD20 antibodies, which become a standard of care in B cell lymphomas treatment, on bone biochemical markers and osteoporosis development, is still yet to be defined. GOALS: To determine the changes in bone mineral density (BMD-g/cm2) in treatment naive B-cell non Hodgkin lymphoma patients before and six months after chemotherapy. To determinate the difference in bone mineral density (BMD-g/cm2) six months after starting treatment between the examined and control group. To determinate the difference in bone biochemical markers and RANKL/OPG ratio six months after starting treatment between the examined and control group. MATERIAL AND METHODS: The research was conducted as a prospective study which included 60 patients, devided into two groups: the wxamined group and the control group 30 patients were threated with anti-CD20 monoclonal antibody in combination with standard chemotherapy regimens, they represented the examined group, while the control group was treated only with standard chemotherapy regimens. Clinical and laboratory analysis, as well as osteodensitometry were done before and six months after chemotherapy. RESULTS: Of the 60 patients, 37 were men and 23 women. The median age at diagnosis was 63.5 (range: 34-82) years. The predominant patohistological subtypes were diffuse large B-cell lymphoma (25%) and follicular lymphoma (25%). 66.6% patients were diagnosed in the IV clinical stage. After 6 months of treatment, a significant bone density loss (p=0.00) was verified in both groups of patinets, on the lumbar spine, hip and neck of the femur. Osteoporosis developed in 12 patients (20%). After six months, there was a statistically significant increase in only one marker of bone synthesis - P1NP, in both groups of patients. P1NP grew significantly less in the control group of patients (p=0.01). Subjects who received 6 cycles of chemotherapy and who were treated according to the R-CHOP protocol had higher bone density. CONCLUSION: Our results show that there is an altered bone metabolism in both groups of patients with non-Hodgkin's lymphoma before and after therapy. There is a difference in P1NP value's changes between the examined groups. A significantly higher increase in P1NP value was recorded after treatment in the group of subjects treated with a combination of anti-CD20 monoclonal antibody and polychemotherapy. It is necessary for patients with non-Hodgkin's lymphomas to be tested and monitored in relation to bone metabolism before and after treatment in order to reduce the negative consequences of polychemotherapy on bone tissue by timely inclusion of antiresorptive therapy.