Prognostički faktori rane smrti i relapsa bolesti u akutnoj promijelocitnoj leukemiji

Abstract

Uvodjenjem all-trans retinoične kisleine (ATRA) u terapiju akutne promijelocitne leukemije (APL) i njenim kombinovanjem sa antraciklinima, bolest je od najagresivnijeg postala najizlečiviji podtip akutne mijeloidne leukemije, sa stopom izlečenja od oko 80%. Osnovi uzroci neuspeha lečenja su rana smrt (RS) i relapsa bolesti (RB). Iako je u okviru studija velikih kooperativnih grupa učestalost RS procenjena na 5-10%, nedavno publikovani rezultati populacionih studija ukazuju da je učestalost mnogo veća i iznosi 17-29%. Naječešći uzroci RS su: krvarenje (40-66% bolesnika), diferencijacioni sindrom (6-30%) i infekcije (1- 10 %). Sa druge strane RB se dijagnostikuje kod 5-30% bolesnika. Do sada su identifikovani brojni prediktivni faktori za razvoj RS i RB. Međutim, značaj većine je i dalje kontraverzan. Ciljevi: 1) Utvrđivanje prediktivne vrednosti parametara krvne slike, rutinskih testova hemostaze i skora za diseminovanu intravaskularnu koaguaciju Internacionalnog Udruženja za Hemostazu i Trombozu (International Society of Thrombosis and Haemostasis Scoring System for diseminated intravascular coagulation, ISTH DIK skor), citološkog tipa bolesti, imunofenotipskih i molekularno-genetskih obeležja za nastanak RS. 2) Utvrđivanje prediktivne vrednosti navedenih parametara za pojavu krvarenja kao i nastanak RS uzrokovane hemoragijom (HRS). 3) Dizajniranje prediktivnog skora za nastanak HRS. 4) Utvrđivanje prediktivne vrednosti navedenih parametara za pojavu RB. 5) Utvrđivanje značaja monitoringa ekspresije WT1 gena kao markera minimalne rezidualne bolesti (MRB). Materijal i metodologija istraživanja: U ovu prospektivno-retrospektivnu studiju uključeno je 75 bolesnika sa APL (prosečna starost 45 godina (opseg: 19 -78), žene/muškarci 40/35) koji su dijagnostikovani i lečni na ATRA + hemoterapija baziranim protokolima (PETHEMA LPA 99 i 2005), u Klinici za hematologiju Kliničkog centra Srbije u periodu od juna 2004. do juna 2014. godine. RS je definisana kao smrt iz bilo kog razloga u periodu od prvog dana hospitalizacije do završetka indukcionog lečenja. Molekularni relaps je definisan kao PMLRARα pozitivnost u dva nezavisna uzorka, kod bolesnika sa prethodno dokazanom molekularnom KR. Hematološki relaps je dijagnostikovan u slučaju > 5% blasta u koštanoj srži ili ekstramedularne boleste uz potvrdu relapsa citogenetskim analizama...

Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) from highly fatal has become the most curable of all subtypes of acute myeloid leukemias, with cure rate of 80%. Main reasons for treatment failure are early death (ED) and disease relapse. According to large cooperative groups, ED occurs in approximately 5–10 % of newly diagnosed cases. However, recently population-based studies reported considerably higher ED rates, from 17 to 29%. Hemorrhage is the major cause of mortality in 41–66 % of ED patients, followed with differential syndrome (6-30%) and infection (1-10 %). On the other hend disease realpse occured in 5-30% of patients. Previous studies identified several prognostic factors for ER and relapse. However, predictive value is controversial in majority of these factors. Aim: 1) To identify predictive value of complete blood count, routine hemostasis test and International Society of Thrombosis and Haemostasis Scoring System for diseminated intravascular coagulation (ISTH DIC score), morphologic disease type, immunophenotype and molecular-genetic markers expression for ED 2) To identify predictive value of these factors for bleeding and hemorrhagic ED (HED) development 3) To develop prognostic scoring system for HED development 4) To identify predictive value of these factors for disease relapse development 5) To quantify value of WR1 gene expression as minimal residual disease (MRD) marker. Material and methodes: This prospective-retrospective study was included 75 de-novo APL patients (median age 45 years (range: 19 -78), female/male 40/35) who were diagnosed and treated with ATRA+ hemotherapy protocols (PETHEMA LPA 99 i 2005), at the Clinic of Hematology from Jun 2004 to Jun 2014. ED was defined as death from any cause, from the first day of hospitalization up to the end of the induction treatment. Molecular relapse was defined as two successive PCR PML-RARα positive assays in patients with confirmed complete remission (CR). Hematologic relapse was defined as > 5% of blast in bone marrow or extramedullary disease with genetic confirmation...