PB1891 CLINICO-BIOLOGICAL FEATURES AND OUTCOMES OF ACCELERATED PHASE CHRONIC LYMPHOCYTIC LEUKEMIA (AP-CLL) IN THE ERA OF TARGETED AGENTS.

Abstract

Background: Patients (pts) with “accelerated” phase chronic lymphocytic leukemia (AP-CLL) associated with more aggressive clinical behavior are primarily identified by pathologic diagnosis (dx) of expanded and/or highly active proliferation centers (PCs). Aims: To characterize the molecular findings, immunohistochemistry (IHC), clinical presentation, and outcomes of AP-CLL in the era of novel agents. Methods: Retrospective pathologic assessment (2013-2018) per WHO 2016 based on expanded/confluent PCs or Ki-67 >40% in PCs and clinico-pathological characteristics were collected in a single center. Given ongoing trials of immune checkpoint inhibitors in B cell malignancies, IHC testing for programmed cell death protein (PD-1) receptor and its ligands (PD-L1) was included (anti PD-1 clone NAT105, anti PD-L1 clone SP142). Results: 15 AP-CLL cases were identified. Median age was 71yrs (range 61-81). While 6/15(40%) pts had no prior therapy (tx) before AP-CLL dx, the remaining 9 pts had prior tx exposure at some point to the following novel agents including ibrutinib 8/9(88%), idelalisib 3/9 (33%), venetoclax 1/9 (11%), and umbralisib 1/9 (11%). Median time from CLL dx to AP dx was 73 mo (range 19-160). Median Ki-67 was 50% (range 30-70%). FISH at time of AP dx: del(17p) 4/15 (27%), del(11q) 2/14 (14%), trisomy 12 7/14 (50%). Complex karyotype (CKT) was present in 6/14 (42.8%). IGHV unmutated (UM) noted in 11/14 (79%). Focused NGS revealed 5/12(41%) presence of a mutation in NOTCH1, 2/9(22%) in SF3B1, and 5/15 (33%) in TP53. Treatment post AP dx includes ibrutinib, obinutuzumab, acalabrutinib, idelalisib, and localized radiation. 4 patients have died since the AP diagnosis including two Richter's (13% transformed), one to Hodgkin Lymphoma (HL) and one to diffuse large B cell lymphoma. PCs of lymph nodes showed PD-1(+) staining of CLL cells in 13/15(87%) cases. PD-1 staining in one bone marrow was suboptimal. All cases had PD-L1(+) only in background histiocytes, but were (-) in CLL cells. AP cases showing PD-1(+) correlated with IGHV-UM, the 3 cases with IGHV-M had either a confirmed del(17p) or CKT. All AP cases were Epstein-Barr virus (EBV)(-) except for the one that transformed into Hodgkin Lymphoma (HL) with PD-L1(+) in Reed-Sternberg(RS)/EBV(+) cells. Interestingly, this AP case with PD-1(-) and known TP53/CKT was refractory to FCR and BR in 2012, responded to ibrutinib for 40mo but progressed with a BTK mutation at C481S(+). Pt was salvaged with idelalisib/rituximab and 18mo later transformed to HL. At the time of HL dx, he was EBV(+) and PDL-1(+)in RS cells and HL tissue NGS showed BTK C481(+) despite no rechallenge with ibrutinib in 19mo. Summary/Conclusion: Herein we report the clinico-biological features and outcomes of AP-CLL in the era of available targeted agents. Remarkably, 40% of pts had no prior therapy. The vast majority of pts with AP-CLL had high risk prognostic markers in some cases evolving to Richter's. Most pts in this series were treated with novel targeted agents. Though PDL-1 was negative, given the PD-1 staining in PCs (except for one HL transformed case), the outcomes of AP-CLL pts treated with checkpoint inhibitors in ongoing trials should be evaluated.