Outcomes of Patients with Relapsed/Refractory Double Expressor B Cell Lymphoma As Defined By Multicenter Pathology Review Treated with Ibrutinib Monotherapy
Authors: Landsburg Daniel J. , Hughes Mitchell E. , Koike Alexa , Bond David A. , Maddocks Kami J. , Guo Ling , Winter Allison M. , Hill Brian T. , Ondrejka Sarah L. , Hsi Eric D. , Dwivedy Nasta Sunita , Svoboda Jakub , Schuster Stephen J. , Bogusz Agata M. 
Published: October 2019

Abstract

Introduction: Preclinical data have suggested that B-cell receptor-associated genes are upregulated in diffuse large B cell lymphoma (DLBCL) with increased expression of MYC protein, as well as MYC and BCL2 protein, also known as "double expressor" lymphoma (DEL) (Am J Surg Pathol. 2017 Apr;41(4):541-549 and PLoS One. 2017 Feb 17;12(2):e0172364). Patients (pts) with DEL respond poorly to cytotoxic chemotherapy; thus novel treatment approaches are needed for this disease. Here, we report outcomes of pts with relapsed/refractory (R/R) DLBCL and high grade B cell lymphoma (HGBL) treated with ibrutinib (ibr) monotherapy.
Methods: Pts analyzed were those with R/R DLBCL or HGBL treated with ibr monotherapy at University of Pennsylvania, Ohio State University or Cleveland Clinic with immunohistochemical (IHC) stains for MYC and BCL2 from the tissue specimen obtained most recently prior to initiation of ibr available for hematopatholoigst (HP) review, and determined to have IHC scores of ≥40% for MYC and ≥50% for BCL2, meeting criteria for definition of DEL. Exclusion criteria were HIV positivity, post-transplant lymphoproliferative disorder, prior chronic lymphocytic leukemia and inadequate data. All available IHC stains for MYC and BCL2 were scored as positive or negative as per the aforementioned cutoffs by a HP at the treating center (HP1) as well as a second HP at one of the other centers (HP2) through review of digital slide images. In cases of disagreement, the score assigned in the clinical pathology report (CPR) was used as a tiebreaker. Progression free survival (PFS) was defined as the interval between time of initiation of ibr and documented disease progression, change in therapy (tx) if no disease response or last follow-up in remission, and overall survival (OS) between time of initiation of ibr and death or last follow-up while alive. Data were censored on 7/1/18.
Results: Twenty-five cases with IHC stains for MYC and BCL2 were reviewed, with 19 meeting criteria for DEL which were included in the analysis. Clinicopathologic characteristics at time of ibr initiation were median age 69 years, 32% female, 63% stage III-IV, 74% elevated LDH, 11% bone marrow (BM) involvement, 11% B symptoms present, 21% extranodal (EN) disease at >1 site, 32% ECOG performance status (PS) >1, 58% with International Prognostic Index score (IPI)≥3, 26% HGBL, median Ki67 80% and 21% germinal center (GCB) cell of origin (COO) by Hans algorithm. Of pts with available fluorescence in situ hybridization (FISH) data, 50% (7/14), 25% (3/12) and 14% (1/7) demonstrated MYC, BCL2 and BCL6 rearrangements, respectively, and 3 pts were known to be double hit lymphoma. First-line tx was R-EPOCH in 26% and R-CHOP in 74%. Autologous stem cell transplantation was received by 42% prior to treatment with ibr. The proportion of pts receiving ibr as 2nd, 3rd, 4th and ≥5th line of tx was 21%, 37%, 21% and 21%, respectively. The time from initiation of the prior line of tx to initiation of ibr was <6 months (mo), 6-12 mo and >12 mo in 79%, 16% and 5%, respectively. Overall response to ibr was 47% (37% complete response and 10% partial response) and 5% with stable disease. All responses were seen in pts with non-GCB COO. The median PFS was 4.7 mo, median OS 5.5 mo and median duration of response 4.2 mo. For all cases reviewed (n=25), MYC IHC was scored by HP1 and HP2 and available in the CPR in 100%, 84% and 88%, respectively, and BCL2 IHC in 100%, 84% and 100%, respectively. Rates of concordance and kappa (κ) coefficient were as follows: HP1 and HP2 for MYC 85.7% (κ=0.49), BCL2 95.2% (κ=0.64) and DEL 84.0% (κ=0.61); HP1 and CPR for MYC 86.3% (κ=0.70), BCL2 96.0% (κ=0.78) and DEL 81.8% (κ=0.62); HP2 and CPR for MYC 66.7% (κ=0.18), BCL2 90.5% (κ=0.45) and DEL 68.2% (κ=0.34). In 4 cases with disagreement between HP1 and HP2 regarding DEL status, the CPR agreed with HP1, and 4 cases were identified as DEL by both HP1 and HP2 but not by CPR.
Conclusion: An objective response to ibr was experienced by nearly half of pts with R/R DEL as defined by multicenter HP review in this series. Our data suggest a potential benefit to the use of ibr monotherapy as bridging tx to curative-intent cellular tx, as well as support the incorporation of ibr into clinical trials for the R/R DEL pt population. A relatively high rate of concordance between HP1 and CPR in identifying cases of DEL suggests that local review of MYC and BCL2 IHC may be a reasonable alternative for determining DEL status when central review is infeasible.

Disclosures
Landsburg: Curis, INC: Consultancy, Research Funding; Takeda: Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Honoraria; Teva: Honoraria. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Incyte: Research Funding; Merck: Other: DSMC; Pharmacyclics: Research Funding; Aileron: Research Funding; Roche: Research Funding; Takeda/Millenium: Research Funding; Rafael/WF: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Debiopharm: Research Funding. Svoboda:Regeneron: Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; Kyowa: Consultancy. Schuster:Physician's Education Source, LLC: Honoraria; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.