Impact of histologic grading on survival in the SWOG S0016 follicular lymphoma cohort

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1 Published Ahead of Print on February 22, 2018, as doi: /haematol Copyright 2018 Ferrata Storti Foundation. Impact of histologic grading on survival in the SWOG S0016 follicular lymphoma cohort by Lisa M. Rimsza, Hongli Li, Rita M. Braziel, Catherine M. Spier, Daniel O. Persky, Jennifer Dunlap, Michael LeBlanc, Nancy Bartlett, John P. Leonard, Sonali M. Smith, Oliver W. Press, and Jonathan W. Friedberg Haematologica 2018 [Epub ahead of print] Citation: Lisa M. Rimsza, Hongli Li, Rita M. Braziel, Catherine M. Spier, Daniel O. Persky, Jennifer Dunlap, Michael LeBlanc, Nancy Bartlett, John P. Leonard, Sonali M. Smith, Oliver W. Press, and Jonathan W. Friedberg. Impact of histologic grading on survival in the SWOG S0016 follicular lymphoma cohort. Haematologica. 2018; 103:xxx doi: /haematol Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

2 Impact of histologic grading on survival in the SWOG S0016 follicular lymphoma cohort Authors: Lisa M. Rimsza 1, Hongli Li 2, Rita M. Braziel 3, Catherine M. Spier 4, Daniel O. Persky 5, Jennifer Dunlap 3, Michael LeBlanc 2, Nancy Bartlett 6, John P. Leonard 7, Sonali M. Smith 8, Oliver W. Press 2, Jonathan W. Friedberg 9 1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA 3 Department of Pathology, Oregon Health Sciences University, Portland, OR, USA 4 Department of Pathology, University of Arizona, Tucson, AZ, USA 5 University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA 6 Washington University-Siteman Cancer Center, St. Louis, MO, USA 7 Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA 8 Department of Medicine, University of Chicago, Chicago, IL, USA 9 James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA Corresponding Author: Lisa M. Rimsza, M.D E. Shea Blvd, CRB Scottsdale, AZ rimsza.lisa@mayo.edu Phone:

3 Summary: This study examined the impact of higher grade follicular lymphoma (FL) on early progression and survival as well as the reproducibility of grading in a large prospective, phase III randomized intergroup trial, S0016, comparing 6 cycles of CHOP-R with 6 cycles of CHOP followed by iodine I-131 tositumomab radioimmunotherapy (RIT). We show a lack of correlation between histologic grade on patient outcome in the rituximab plus doxorubicin-containing chemotherapy era; and that grade is often revised, and lowered, during expert hematopathology review. Other biomarkers of early progression should be sought for FL. Introduction: Follicular lymphoma (FL) is a complex disease with variable histologic appearance and clinical outcome. There are clinical and genetic indices with prognostic capability, including the FL International Prognostic Index (FLIPI) and the more recent M7-FLIPI, which incorporates the mutation status of 7 genes with superior power to distinguish patient risk.(solal-celigny et al, 2004) (Pastore et al, 2015) In addition to baseline prognostic tools, early progression of disease at 24 months (EFS24) following R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is a powerful predictor of overall survival. (Casulo et al, 2015) Prior to these various methods, the original histologic grading scheme was developed and is still retained in the revisions to the World Health Organization (WHO) lymphoma classification scheme.(mann & Berard, 1983;Swerdlow et al, 2016) Per current World Health Organization criteria, FL is divided into grades based on the average number of centroblasts from 10 representative high power fields (HPF) taking into account areas with both few and frequent centroblasts. Grades 1 and 2, contain an average of 0-5 and 6-15 centroblasts per HPF respectively, and are now considered together as low grade (hereafter referred to as FL1/2). Grade 3 with greater than 15 centroblasts per HPF, is further subdivided into 3A with admixed centrocytes and 3B without admixed centrocytes with the latter representing an essentially pure population of centroblasts. Using current criteria, FL3A and FL3B must demonstrate a follicular pattern (otherwise the diagnosis is moved into the diffuse large B cell lymphoma category). Although centroblast counts have been a staple of FL grading since the 1980s, the reproducibility of this method is debatable and the methods somewhat

4 complex and time-consuming.(metter et al, 1985;LaCasce et al, 2008) Furthermore, there are conflicting reports about whether there is a significant biological or survival difference between grades 3A and 3B. Some reports note that survival is similar while others find that FL3B has unique biological features.(ott et al, 2002;Wahlin et al, 2012) These conflicting data challenge the clinical utility of grading distinctions with current therapeutic options. The importance of FL grade has not been examined in a large uniformly treated cohort, particularly using progression of disease within 2 years after diagnosis, which is strongly associated with poor outcomes in patients receiving first-line R- CHOP.(Casulo et al, 2015) Previously, the SWOG Cooperative Group conducted a Phase III randomized intergroup trial S0016, which at initial publication, demonstrated no significant improvement in progression free (PFS) survival between the 2 arms (although PFS and overall survival, OS, were outstanding on both arms). (Press et al, 2013a;Press et al, 2013b) Recently, the 10 year update on the trial, demonstrated a PFS, but not OS benefit in the Bexxar arm. (Shadman et al, 2016) A subsequent S0016 paper evaluated clinical factors and found lactate dehydrogenase (LDH), beta 2 microglobulin, and FLIPI scores significantly correlated with outcome, however, did not address grade or histologic pattern. (Press et al, 2013a). S0016 is an excellent cohort for assessment of the prognostic significance of FL grading and pattern due to the use of immunochemotherapy, uniform treatment and outcome data, and centralized pathology review. We therefore sought to evaluate whether FL grading continues to be important clinical parameter in the modern treatment era. Methods: We previously confirmed the diagnosis of FL for S0016 at the time of study closure.(press et al, 2013b) This is a mature cohort with a median follow up of 10.2 years (range 50 days to 15.3 years). Briefly, the available slides and associated Pathology reports were reviewed by one of 3 SWOG Lymphoma Committee Pathologists (RMB, CMS, and LMR) for eligibility per recently revised WHO criteria.(swerdlow et al, 2016) Due to the known, high reproducibility of diagnosis of FL1/2, if the reviewing SWOG Pathologist agreed with the original diagnosis of FL1/2, no further review was conducted. If the SWOG Pathologist changed the diagnosis or changed the grade, the case was brought to consensus review, during which all 3 SWOG Pathologists reviewed the case at a multi-headed microscope, discussed the findings, and agreed on the final

5 diagnosis and grade. In addition, due to the known low reproducibility of FL3, all FL3A and FL3B cases were confirmed by the panel. (LaCasce et al, 2008) For the survival analyses according to grade the SWOG Pathologist review diagnoses were used. Cases with grade 1/2 were considered together as low grade; cases of pure grade 3A were considered 3A; cases with mixed low and high grades (combinations of grade 1/2 with grade 3A) were included in the 3A category. A single case of pure FL3B was excluded due to low number. Cases with mixed FL and DLBCL were considered DLBCL and not part of this FL survival analysis. Survival was assessed using the methods of Kaplan and Meier. (Kaplan EL & Meier P, 1958) We estimated 10 year PFS and OS and compared the results with a log-rank test. Results: For survival analyses, the SWOG Lymphoma Pathology reviewers consensus diagnoses were used. A total of 491 patients were assessed for histologic grade, of which 452 (92.0%) patients had grade 1/2, and 39 (7.9%) patients had grade 3A. No cases were considered pediatric-type FL, since this trial was limited to adult patients with advanced stage disease. The distribution of FL1/2 or 3A cases was similar between treatment arms (91.8% and 8.1% for CHOP-immunochemotherapy and 92.2% and 7.7% for CHOP-R respectively). These results are summarized in Table 1. The estimated 10-year OS was 79% for FL 1/2 (95% CI: 74.6 to 82.6%); and 68% for FL3A (95% CI: 50.3 to 80.5%) (log-rank p-value ). In addition, the estimated 10-year PFS was 49% for FL 1/2 (95% CI: 44.5 to 54.1%); and 47% for FL3A (95% CI:30.1 to 61.7%) (log-rank p-value ). Survival curves are illustrated in Figure 1. A total of 521 cases were submitted with a diagnosis of FL. Of these, 497 (95.4%) had a definitive grade in the diagnostic line or description from the submitted outside pathology report. Of the 497 graded FL cases, changes to that grade occurred in 54/497 (10.8%). Interestingly, 45 of these 54 (83.3%) changes were down grades from grade FL3A to FL1/2, while in contrast, only 9/54 (16.7%) were upgraded from an original diagnosis of FL1/2 to FL3A. Altogether, these data indicate that most FL grading changes by the SWOG review panel were decreases in the FL grade and highlighted a bias towards higher grades in community practice. Microscopic review revealed that the down-graded FL cases often had either large centrocytes, sclerosis that may distort cell cytology, or many follicular dendritic cells, which may have made them particularly challenging. Discussion: This study examined both the impact of higher grade FL on early progression and survival as well as the reproducibility of grading in a large prospectively treated cohort. We show that (1) the impact of histologic grading on patient outcome in the rituximab plus doxorubicin- containing chemotherapy era is

6 negligible and that (2) there is a tendency to over-grade FL. In the United States, bendamustine has largely replaced CHOP as the preferred chemotherapy platform newly diagnosed advanced stage FL, based upon randomized data suggesting similar to improved PFS and a better toxicity profile.(flinn et al, 2014;Rummel et al, 2013) These two randomized trials excluded patients with grade 3 FL. In agreement with Koch et. al, 2016, our results suggest that, at least when doxorubicin-containing chemotherapy with an anti-cd20 monoclonal antibody are utilized, grade 3A has similar outcome to grade 1/2 disease. These observations should be validated in a cohort of patients treated with R-bendamustine. Similar to an earlier study, there were no cases showing combinations of both FL3A and FL3B stressing that these two diseases likely have different pathogenesis. (Koch et al, 2016) Challenges to the reproducibility in grading as previously reported in the literature were again found in this study. The most frequent change was downgrading of originally denoted FL3A or 3B cases to FL1/2. Our findings highlight a tendency to over-grade FL in routine practice most likely due to the difficulty in cytologically separating the various cell types within the germinal center environment. Various centroblast mimics such as large centrocytes (large cleaved cells but without nucleoli) or follicular dendritic cells (single or binucleated cells with clear nuclei and centrally placed eosinophilic nucleoli) can be difficult to identify and exclude. In agreement with our findings, Grade 3 FL was one of the least reproducible of the lymphoma diagnostic categories in the National Cancer Care Network database study.(lacasce et al, 2008) As the FL field moves forward, integrated biomarkers such as clinical features with genomics and/or expression markers are likely to be more important than grade in prognosis, and may also provide predictive information for specific therapies. Acknowledgements: LMR, RMB, CMS, JD, and HL performed the research. LMR, OP, JF, HL designed the study. HL and ML analyzed the data. LMR and HL wrote the paper. DOP, SMS, JF critically revised the manuscript. All authors approved of the submitted final version.

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