Gray Zone Lymphoma (GZL) with Features Intermediate Between Classical Hodgkin Lymphoma (cHL) and Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of Tumor Immunophenotype (IP) and Critical Examination of Therapy with Associated Impact on Outcome
Authors: Kritharis Athena , Kanakry Jennifer A. , Sehn Laurie H. , Feldman Tatyana , Kroll Aimee , Gascoyne Randy D. , Petrich Adam M. , Abramson Jeremy S. , Hernandez-Ilizaliturri Francisco , Al-Mansour Zeina , Adeimy Camille , Hemminger Jessica , Bartlett Nancy L. , Mato Anthony R. , Caimi Paolo , Advani Ranjana , Klein Andreas K. , Lossos Izidore S , Press Oliver W. , Smith Sonali M. , Fabregas Jesus C , Nabhan Chadi , Fenske Timothy S. , Friedberg Jonathan W. , Vose Julie M. , Blum Kristie A. , Evens Andrew M. 
Published: October 2019

Abstract
Background: The WHO recognizes a category of B-cell lymphoma unclassifiable with features intermediate between DLBCL and cHL, also known as GZL. This is a challenging disease entity to treat due to disease heterogeneity and lack of pathologic or clinical prognostic indicators as well as absence of standard management guidelines for untreated or relapsed/refractory patients (pts).
Methods: We performed a multicenter retrospective analysis of newly diagnosed GZL pts treated from 2001-2012 across 19 North American academic centers. Diagnosis was established by institutional expert pathology review. This work is an expansion and update of prior reported data (Evens AM et al, ASH 2013, #847) with 16 cases added to the original report. Additionally, new data were examined including histopathologic and IP analysis and detailed frontline and salvage therapy. Prognostic factors associated with survival on univariate and multivariate Cox regression analyses were examined.
Results: Characteristics of 112 GZL pts included: median age 39 years (19-86); M:F 1.8:1; ECOG PS 0-1 87%; B symptoms 40%; anemia 59%; hypoalbuminemia 30%; bulky disease (≥10cm) 24%; non-mediastinal presentation 57%; bone marrow pos 11%; Stage III/IV 52%; IPI 0-2 77%; and IPS 0-2 in 81%. The most prevalent tumor IPs were: 93% CD20+ (100/108), 91% CD30+ (98/108), 78% CD79+ (43/55), 97% Pax5+ (67/69), 97% Oct2+ (27/28), and 94% MUM1+ (32/32). CD15 (44%, 45/101) and CD45 (69%, 48/70) were variable. Only 13% and 24% of pts were CD10+ (4/30) and EBV+ (13/55), respectively. Notably, IP did not differ based on clinical presentation (ie, mediastinal vs non-mediastinal). The most common frontline treatments were R-CHOP n=52, ABVD +/- R n=34, and R-EPOCH n=11. 71% of CD20+ pts were treated with rituximab as part of frontline therapy. At 31-month median follow-up, 2-year PFS and OS for all pts were 40% and 88%, respectively. The only pathologic factor correlating with outcome was CD20 positivity (PFS: HR 0.34, 95% CI 0.16-0.73, P=0.006). Characteristics correlating with PFS were anemia (HR 0.51, 95% CI 0.29-0.91, P=0.022), low albumin (HR 0.57, 95% CI 0.32-1.00, P=0.05), and IPI (continuous: HR 1.48, 95% CI 1.19-1.82, P=0.0003). For therapy, 2-year PFS and OS for R-CHOP were 46% and 84%, respectively; ABVD+/-R 25% and 96%, respectively; and R-EPOCH 68% and 83%, respectively (Fig. 1). R-EPOCH predicted improved PFS (0.047), however this effect was abrogated after controlling for IPI, anemia and hypoalbuminemia (P=0.2). Pts who received rituximab with frontline therapy had improved 2-year PFS (51% vs 19%, respectively, P=0.012). Interestingly, the significance of CD20 persisted on Cox regression controlling for rituximab (rituximab HR 0.55, 95% 0.33-0.93, P=0.025; CD20 0.35, 95% CI 0.16-0.75, P=0.007). Furthermore, the effect of rituximab remained significant after controlling for IPI, anemia, and hypoalbuminemia (HR 0.35, 95% CI 0.18-0.69, P=0.002). Overall, 58% of pts relapsed with median time to relapse of 7 months (0-64); the mean number of salvage therapies was 3. Regimens at 1st relapse included: R-ICE (n=33), R-ESHAP (n=6), R-EPOCH (n=7), ABVD (n=1) and brentuximab vedotin (n=4). Beyond first relapse, the most common treatments were: brentuximab vedotin (n=7) and radiation (n=5). 61% of relapsed pts proceeded to stem cell transplantation (SCT) (38% allogeneic, 62% autologous). 20/27 (74%), 20/32 (63%), and 3/3 (100%) of pts who relapsed after frontline ABVD, R-CHOP and R-EPOCH, respectively, had SCT at relapse. 2-year OS was superior for pts who had SCT (88% vs 67%, P=0.014; Fig. 2), which persisted on multivariable regression (SCT: HR0.14, 95% CI 0.02-0.95, P=0.044; IPI continuous: HR 2.04, 95% CI 1.00-4.16, P=0.05; anemia: HR 2.40, 95% CI 0.32-18.25, P=0.4; low albumin: HR 5.54, 95% CI 1.08-28.44, P=0.04).
Conclusions: To the best of our knowledge, this represents the largest series of GZL reported to date. Presence of CD20 appeared to be an independent prognostic factor and treatment with a rituximab-based DLBCL-specific regimen for frontline therapy was associated with the most optimal PFS. In addition, pts who underwent SCT at relapse appeared to have superior OS, however caution should be given to this finding given likely selection bias. Continued examination of this unique lymphoma is warranted.
Figure 1. PFS comparison of frontline therapeutic regimens for GZL. Figure 1. PFS comparison of frontline therapeutic regimens for GZL.
Figure 2. Impact of SCT on OS for patients with relapsed/refractory GZL Figure 2. Impact of SCT on OS for patients with relapsed/refractory GZL

Disclosures
Bartlett: Seattle Genetics, Inc.: Other, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; ImaginAb: Research Funding; Genentech: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Advani:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Janssen Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding. Blum:Janssen, Pharmacyclics : Research Funding.