- Email: [email protected]
Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era
Accepted Manuscript Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era Moaath Mustafa Ali, MD, Lisa Rybicki, MS, Laila Nomani, MD, Basel Rouphail, MD, MBA, Robert M. Dean, MD, Brian T. Hill, MD, PhD, Deepa Jagadeesh, MD, MPH, Brad Pohlman, MD, Eric D. Hsi, MD, Mitchell R. Smith, MD, PhD PII:
S2152-2650(17)30745-0
DOI:
10.1016/j.clml.2017.07.002
Reference:
CLML 973
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 28 April 2017 Revised Date:
6 July 2017
Accepted Date: 6 July 2017
Please cite this article as: Ali MM, Rybicki L, Nomani L, Rouphail B, Dean RM, Hill BT, Jagadeesh D, Pohlman B, Hsi ED, Smith MR, Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era
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Moaath Mustafa Ali, MD1; Lisa Rybicki, MS2; Laila Nomani, MD3; Basel Rouphail, MD, MBA4;
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Robert M. Dean, MD4; Brian T. Hill, MD, PhD4; Deepa Jagadeesh, MD, MPH4; Brad Pohlman,
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MD4; Eric D. Hsi, MD3; Mitchell R. Smith, MD, PhD4,5
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Clinic Lerner Research Institute, Cleveland, OH; 3 Robert J. Tomsich Pathology and Laboratory
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Medicine Institute; 4Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
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Cleveland Clinic, Cleveland, OH; 5 Present address: George Washington Cancer Center,
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Internal Medicine, Cleveland Clinic, Cleveland, OH; 2Quantitative Health Sciences, Cleveland
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Washington DC.
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No funding to report
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Correspondence:
Mitchell R. Smith, MD, PhD
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George Washington University Cancer Center
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800 22nd St NW, Suite 8000
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Washington, D.C. 20052
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Phone Number: (202) 994-3517
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Email: [email protected]
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Brief running title: Grade 3 Follicular lymphoma
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Previous presentation: Study results were presented, in part, at the American Society of
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Number of words: 1583
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Abstract = 240 words
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Microabstract = 60 words
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Tables = 4
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Figures = 2
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Hematology Annual Meeting, December, 2015, Orlando, Florida.
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Conflict of interest statement:
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The authors declare there is no conflict of interest pertaining to this study.
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MicroAbstract:
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Whether to clinically approach follicular lymphoma (FL) grade 3 as an indolent
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or aggressive lymphoma, especially since the introduction of rituximab, is
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unclear. Our experience with FL grade 3A, compared with FL grade 3B or with concomitant
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diffuse large B cell lymphoma, primarily treated with R-CHOP suggests possible long-term
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remissions. This must be confirmed with longer follow-up and additional studies.
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Abstract
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Background: Follicular lymphoma (FL) is heterogeneous. While FL3B is treated as aggressive
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lymphoma, an optimal approach to FL3A remains unclear as little data exist on clinical
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outcomes based on sub-classification of FL grade 3 since introduction of rituximab. We report
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outcomes of FL grade 3 in the rituximab era.
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Methods: We identified and analyzed a retrospective cohort of 53 patients with FL grade 3A, 3B
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and FL grade 3 with areas of DLBCL. They were divided into two groups: aggressive lymphoma
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(aggFL) (n=21) included patients with FL3B (n=10) and FL3 (A or B) with concomitant DLBCL
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(n=11); indolent lymphoma (n=32) included only FL3A.
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Results: Baseline characteristics did not differ between the groups. R-CHOP was initial
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treatment in 79% of patients with aggFL and 72% of those with FL3A; rituximab was included in
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initial therapy in 95% and 83%, respectively. Comparing aggFL and FL3A, 5-year overall survival
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(OS) was 90% vs. 79% (P= 0.97) and 5-year progression-free survival (PFS) 44% vs 34% (P=0.75),
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respectively.
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Conclusion: We conclude that outcomes for FL grade 3, primarily treated with R-CHOP, do not
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differ between FL3A and aggFL (FL3B and FL3/DLBCL). The aggFL group showed a plateau in PFS
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confirming these should be treated with curative intent. FL3A patients, mainly managed with R-
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CHOP, also show an apparent plateau in PFS. While longer follow-up and confirmation in other
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datasets is required, this indicates potential under-treatment of FL3A with less aggressive
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regimens often used for indolent lymphoma.
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Keywords: Follicular Lymphoma Grade 3, Diffuse large B-Cell Lymphoma, Outcomes, Rituximab
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Introduction
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Follicular lymphoma (FL) comprises a heterogeneous group of histologic subtypes with varied
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clinical and pathologic characteristics that are derived from germinal center B-cells and
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generally retain a nodular growth pattern. Follicular lymphoma is classified into FL grade 1, 2
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and 3 based on the number of centroblasts by routine histologic assessment. Grade 3 FL has
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more than 15 centroblasts per high power field; it can be sub-classified as 3A when centrocytes
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are intermixed with centroblasts and 3B when there are solid sheets of centroblasts 1. These 2
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groups have distinct cytomorphologic, immunohistochemical and cytogenetic profiles 2-4.
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Despite consensus on the aggressive nature of FL3B 4-6, the behavior of FL3A remains an area of
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debate, with some studies suggesting an indolent non-curable disease while others suggest a
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potentially curable lymphoma 5-9. Most of these studies used anthracycline based regimens
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with variable rituximab incorporation
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Due to mixed results regarding clinical behavior of FL3A and 3B and lack of data in the
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immunochemotherapy era, we compared patient, disease, and treatment characteristics, PFS,
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and overall survival (OS) between 2 groups largely treated with rituximab based regimens: FL
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3A and an aggressive follicular lymphoma (aggFL) group in which we included FL3B as well as
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any FL3 that contained areas of diffuse large B-cell lymphoma (DLBCL).
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Methods
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Study population and Materials
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We identified 72 patients with FL3 in the lymphoma database of the Taussig Cancer institute of
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the Cleveland Clinic. We excluded patients who had unclassified FL 3 (N=13). Pathology material
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was available for review for 23 patients, of whom 6 were excluded as review demonstrated
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non-FL3 diagnosis. The remaining cohort included 53 patients diagnosed between 4/1998-
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7/2014 with FL3A (n=32), FL3B (n=10), FL3A with DLBCL (n=3), FL3B with DLBCL (n=5) and
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unclassified FL3 with DLBCL (n= 3). Patients with FL3B and FL3 with areas of DLBCL were
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analyzed as a single group termed aggFL. Transformation was defined as change of FL 3A or 3B
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at presentation to more aggressive lymphoma confirmed by histopathology at a later date.
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Patients who transformed after diagnosis were analyzed per initial categorization.
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Transformation to DLBCL occurred in 6 patients in FL3A group and 4 patients in aggFL group.
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The diagnosis of FL 3 subtypes was established at the time of initial consultation by an expert
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hematopathologist at our institution based on WHO classification 10. As noted, 17 were
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reconfirmed for this report on available material. Response to chemotherapy was determined
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using the revised International Working Group Criteria11. The study was approved by Cleveland
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Clinic Institutional Review Board.
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Statistical analysis
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Nominal categorical variables were compared between FL3A and aggFL using Fisher’s exact
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test, ordinal categorical variables with Cochran-Mantel-Haenszel test and continuous variables
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with Wilcoxon rank sum test. The primary endpoints were OS and PFS after diagnosis. The
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event for OS was all-cause mortality and events for PFS were progression or all-cause mortality.
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Both outcomes were estimated using the Kaplan-Meier method and compared between groups
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using the log-rank test. Time to transformation, time to bone marrow transplant, and time to
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progression after diagnosis were estimated using cumulative incidence methods and compared
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between FL groups using the Gray test. Univariable prognostic factors for OS and PFS were
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assessed using Cox proportional hazards analysis; results were summarized as the hazard ratio
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(HR) and 95% confidence interval (CI). Multivariable analysis was not performed for OS due to
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insufficient events. Because of few events for PFS, only 2-variable models could be performed
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(not shown). The log-rank test was used for variables where HR could not be calculated.
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Analyses were done using SAS Software (SAS Institute, Inc., Cary, NC, USA). All tests were two-
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sided, and P<0.05 was used to indicate statistical significance.
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Results
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Patient characteristics
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Baseline characteristics in FL3A group and aggFL group were similar (Table 1). Our cohort
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included 53 patients diagnosed with FL 3A and aggFL with a median follow up of 54 (0.5-204)
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months. The median age was 60 (19-85) years, 57% (n= 30) of patients were females. Fifteen
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patients (28%) had limited stage disease (Ann Arbor Stage ≤ II).
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Outcomes
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Table 2 describes therapy and outcomes. Around 10% of patients were managed initially by
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watchful waiting. Initial therapy started at a median of 0.9 months after diagnosis and almost
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three quarters of patients received R-CHOP as first line therapy. Ten patients (19%) have died
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during follow up. There were no significant differences between FL3A and aggFL in terms of
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PFS (P=0.75; Fig 1) and OS (P=0.97; Fig 2). There was an apparent plateau in PFS after 4 years.
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Time to transformation (P=0.87) and progression (P=0.29) also did not differ between FL3A and
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aggFL (Table 2).
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Prognostic factors for overall survival and progression-free survival
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In univariable analysis (Table 3), three variables were associated with greater risk of mortality:
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older age (HR 1.76 per 10-year increase in age, P=0.05), ECOG PS 2-3 (HR 6.73, P=0.037), and
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para-aortic nodal site (HR 4.19, P=0.039). Four variables were associated with shorter PFS:
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larger nodal dimension (HR 1.24 per 1 cm increase, P=0.002), iliac nodal site (HR 2.84, P=0.011),
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spleen nodal site (HR 2.69, P=0.047), and bone marrow involvement (HR 2.43, P=0.038).
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Discussion
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There is no consensus on whether FL3A should be categorized as an indolent or aggressive form
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of NHL. Our study of FL3 subtypes largely treated with rituximab demonstrates that FL3A
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biologic behavior was similar to FL3B, with the potential to be treated with curative intent. In a
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cohort of 462 patients with FL, Wahlin et al 5 demonstrated that FL3A had a clinical course
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similar to FL 1 and 2 with frequent relapses and no plateau in OS, in contrast to FL3B with a
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plateau in OS after 5 years. Only 17 of these patients received rituximab upfront and 45% at any
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time; multivariable analysis for regimens used showed that only receiving rituximab improved
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OS (HR: 0.3, CI: 01.-0.6) compared to other regimens. Sushtik et al 6concluded that both FL3A
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and 3B were incurable with no plateau demonstrated in OS or disease specific survival (DSS)
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curves, despite an apparent plateau in DSS after ~ 7 years. Rituximab was included with initial
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therapy in 1/3 of patients. In contrast to previous findings, Koch et al 7 demonstrated no
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statistically significant difference in PFS between 47 patients diagnosed with FL3A and 14
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patients diagnosed with FL3B. They also concluded that chemotherapy may induce durable
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remission in FL3A with a plateau in PFS ~ 7 years. Rituximab was used in 59% of their FL3A and
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36% of FL3B patients. Analyzing only the 27 patients with FL3A and 5 patients with FL3B
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treated with induction R-CHOP demonstrated a plateau in survival after 4 years. In a Japanese
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study, 47 patients with FL3A and 5 patients with 3B had 10-year OS of 100%, however, no
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plateau was observed in FL 3A despite having all patients treated with rituximab-based
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regimens 12.
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Use of rituximab has revolutionized therapy for B cell lymphoma, improving both PFS and OS 13,
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14
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response to chemotherapy in patients with indolent NHL including FL improved PFS, but not OS,
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probably because patients received subsequent rituximab. That trial used the Working
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Formulation to classify indolent lymphoma, but follicular large cell was an exclusion 15.
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Published data on outcomes for FL grade 3 (Table 4) indicate the 5-year OS for FL3A and 3B is
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approximately 70%, with one quarter of patients having received rituximab with induction 5, 6.
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In contrast, our study and more recent reports in which rituximab based induction was used
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more frequently showed a 5-year OS > 80% for FL3A and 3B. Whether the apparent plateau in
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PFS for FL3A and improved 5-year OS for both FL3A and 3B are due, at least in part, to earlier
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rituximab use is not entirely clear and remains a question for future investigation. Importantly
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due to recent randomized trials, management of indolent NHL has shifted from R-CHOP to
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bendamustine with rituximab for frontline treatment 16, 17. However, in both the BRIGHT and
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StiL trials, only FL grade 1 and 2 were included. In our data set of 32 patients with FL3A, 29
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received therapy, 21 (72%) of whom received R-CHOP. As the non-R-CHOP group was only 8
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. A randomized trial showed that maintenance rituximab compared to observation after
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non-uniformly treated patients, we cannot assess whether R-CHOP is better therapy in our
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population.
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In our study, mortality was higher in patients who were elderly, had poor performance status
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and who had para-aortic LN involvement. Advanced age has been associated with poor
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outcomes in several studies 5. Bone marrow involvement may predict higher mortality 5, but
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this was not shown in our study. LN size and disease location were important prognostic
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indicators in our dataset, with iliac LN, spleen and BM involvement negatively impacting PFS.
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Finally, there are several limitations of our study, as it is a single-institution experience with a
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relatively small number of patients and, being retrospective, it is missing data on some
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important factors, specifically ability to re-review all pathology material. Median follow-up is
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only 54 months. A multi-institutional collaboration with pathology-confirmed cases and
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adequate follow-up is necessary to understand the natural history of this disease.
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Conclusion
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With the caveats of having a relatively small sample size from a single institution, this study
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demonstrates that FL3A may have better 5-year OS than previously reported. Moreover, an
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apparent plateau in the PFS curve after 4 years suggests FL3A might be potentially curable,
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resembling FL3B. Prospective studies of histologically confirmed FL3A in the rituximab, and
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now targeted therapy, era are warranted, particularly regarding the use of BR or R-CHOP. These
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will require multi-institutional cooperation.
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Clinical practice points: •
While follicular lymphoma (FL) grade 3B is treated as aggressive lymphoma, an optimal approach to FL grade 3A remains unclear as little data exist on clinical outcomes based
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on sub-classification of FL grade 3 since introduction of rituximab. •
plateau in progression free survival similar to follicular lymphoma 3B.
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Patients in our cohort with FL 3A, mainly managed with R-CHOP, showed an apparent
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These data suggest that FL 3A may be best approached as an aggressive lymphoma with R-CHOP to attain durable remissions. Whether less intense regimens such as
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bendamustine-rituximab as used for indolent FL might result in similar results is
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unknown.
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Acknowledgement
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The authors declare there is no conflict of interest pertaining to this study.
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This research did not receive any specific grant from funding agencies in the public, commercial,
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or not-for-profit sectors.
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Swerdllow S, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues: France: IARC Press, 2008; 2008. Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood. 2002;99:3806-3812. Piccaluga PP, Califano A, Klein U, et al. Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas. Haematologica. 2008;93:1033-1038. Horn H, Schmelter C, Leich E, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96:1327-1334. Wahlin BE, Yri OE, Kimby E, et al. Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times. British journal of haematology. 2012;156:225-233. Shustik J, Quinn M, Connors JM, Gascoyne RD, Skinnider B, Sehn LH. Follicular nonHodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2011;22:1164-1169. Koch K, Hoster E, Ziepert M, et al. Clinical, pathological and genetic features of follicular lymphoma grade 3A: a joint analysis of the German low-grade and high-grade lymphoma study groups GLSG and DSHNHL. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2016;27:1323-1329. Ganti AK, Weisenburger DD, Smith LM, et al. Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2006;17:920-927. Hsi ED, Mirza I, Lozanski G, et al. A clinicopathologic evaluation of follicular lymphoma grade 3A versus grade 3B reveals no survival differences. Archives of pathology & laboratory medicine. 2004;128:863-868. Swerdlow SH, Cancer IAfRo, Organization WH. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues: International Agency for Research on Cancer; 2008. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244. Maeshima AM, Taniguchi H, Nomoto J, et al. Prognostic implications of histologic grade and intensity of Bcl-2 expression in follicular lymphomas undergoing rituximabcontaining therapy. Human pathology. 2013;44:2529-2535. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously
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untreated advanced follicular lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26:4579-4586. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725-3732. Barta SK, Li H, Hochster HS, et al. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer. 2016. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet (London, England). 2013;381:1203-1210. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-2952.
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Variable
Aggressive FL (n= 21) N (%)
Grade 3A FL (n= 32) N (%)
P value
57 (39-83)
61 (19-85)
0.72
8 (38)
15 (47)
0.58
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Table 1 Baseline characteristics of grade 3A and Aggressive Follicular lymphoma
26 (96)
1.0
8 (44)
16 (62)
0.29
8 (44)
8 (30)
2 (11)
1 (4)
0
1 (4)
median (range) Gender Male Race (n=16, 27)
15 (94)
ECOG performance status (n=18, 26) 0 1 2
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3
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Caucasian
Stage at diagnosis I
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Age at diagnosis, years
3 (14)
2 (6)
4 (19)
6 (19)
6 (29)
13 (41)
8 (38)
11 (34)
4 (19)
10 (31)
0.36
Low (0-1)
4 (31)
6 (23)
0.82
Intermediate (2)
3 (23)
8 (31)
High (3+)
6 (46)
12 (46)
II
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III IV
0.79
B symptoms at diagnosis Yes
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FLIPI category (n=13, 26)
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FLIPI2 category (n=7, 12) 1 (14)
2 (16)
Intermediate (1-2)
5 (71)
5 (42)
High (3+)
1 (14)
5 (42)
median (range)
3.5 (1.6-18.0)
Nodal sites at diagnosis (>1 possible)α 8 (38)
Para-aortic
10 (48)
Mediastinal Axillary Mesenteric Inguinal Cervical
Pre-auricular Hilar Spleen
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Supraclavicular
0.26
13 (41)
0.78
7 (33)
15 (47)
0.40
4 (19)
15 (47)
0.046
8 (38)
11 (34)
1.0
7 (33)
11 (34)
1.0
6 (29)
9 (28)
1.0
4 (19)
11 (34)
0.35
2 (10)
6 (19)
0.46
3 (14)
3 (9)
0.67
3 (14)
3 (9)
0.67
3 (14)
3 (9)
0.67
4 (19)
8 (25)
0.74
4 (19)
2 (6)
0.20
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Iliac
0.38
18 (56)
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Retroperitoneal
4.1 (1.3-12.6)
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Largest node dimension at diagnosis, cm (n=15, 25)
0.40
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Low (0)
Extranodal sites at diagnosis (>1 possible)β
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FL: Follicular lymphoma, ECOG: Eastern Cooperative Oncology Group, FLIPI: Follicular Lymphoma International Prognostic Index. α Lymph node sites with ≤ 10% occurrence are not included in table (pectoral, femoral, infraclavicular, Waldeyer’s ring and epitrochlear). β Extranodal sites with ≤ 10% involvement are not included in table (pleura, kidney, liver, colon, lung and skin).
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Table 2 Therapy and outcomes in grade 3A and aggressive Follicular Lymphoma (FL) Variable
Aggressive FL (n= 21) N (%)
Grade 3A FL (n= 32) N (%)
P value
3 (9)
1.0
2 (10)
Months from diagnosis to first-line treatment median (range)
0.9 (0-117)
First-line treatment included Rituximab (n=19, 29) 18 (95)
24 (83)
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Yes
0.8 (0-12)
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Yes
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Started with watchful waiting
0.53
1.0
First-line treatment was R-CHOP regimen (n=19, 29) 15 (79)a
21 (72)b
1.0
2 (0-10)
0.47
6 (19)
0.87
27.5 (0.9 - 95)
0.34
4 (19)
5 (16)
0.98
24 (6-29)
32 (25- 37)
0.18
9 (43)
16 (50)
0.29
Yes
Number of lines of treatment (n=19, 29)
Transformation* Yes
2 (0-6)
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median (range)
4 (19)
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If transformed, months after diagnosis (n=4, 6) median (range) 15.8 (0-39) Autologous stem cell transplant (ASCT) Yes
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Months from diagnosis to ASCT (n=4, 5) median (range)
Disease progression Yes
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If progressed, months after diagnosis (n=9, 16) 22 (0-39)
Patient status at follow-up (log-rank) Alive
17 (81)
If alive, months of follow-up after diagnosis (n=17, 26) 62 (14-204)
26 (81)
51 (1-133)
0.55
0.97
0.54
SC
median (range)
19 (1-87)
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median (range)
298 299 300 301
a
302 303
* Transformation was defined as change of FL 3A or 3B to more aggressive lymphoma at a later stage not present at time of diagnosis.
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Table 3 Univariable prognostic factors for Overall Survival and Progression-Free Survival Variable
Overall Survival
Progression-Free Survival
95% CI
P-value
Indolent / Aggressive
1.02
0.29-3.66
0.97
1.13
0.54-2.37
0.75
1.76
1.00-3.10
0.05
0.86
0.69-1.08
0.21
0.73
0.20-2.62
0.63
6.73
1.12-40.5
0.037
0.57
0.16-2.05
0.98
per 10-year increase Gender
ECOG (n=44) 2-3 / 0-1 Stage III-IV / I-II
Yes / No
P-value
0.59-2.56
0.58
2.42
0.69-8.51
0.17
0.39
1.48
0.63-3.50
0.37
0.20-4.71
0.98
0.97
0.39-2.42
0.95
0.90-1.23
0.53
1.24
1.08-1.41
0.002
1.99
0.72-5.47
0.18
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1.23
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95% CI
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Age at diagnosis
HR
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HR Follicular lymphoma group
Largest node dimension (n=40) per 1 cm increase
High / Int+Low
1.05
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FLIPI category (n=39)
5.35
0.62-45.8
0.13
Nodal sites (each expressed as Yes / No) Retroperitoneal
1.40
0.39-5.03
0.60
1.24
0.60-2.57
0.57
Para-aortic
4.19
1.08-16.3
0.039
1.62
0.76-3.46
0.21
Mediastinal
0.13
0.02-1.02
0.052
0.68
0.31-1.48
0.33
Axillary
0.80
0.20-3.12
0.74
1.67
0.79-3.51
0.18
Mesenteric
0.32
0.07-1.54
0.15
0.68
0.30-1.54
0.35
Inguinal
0.16
0.02-1.30
0.09
1.46
0.70-3.07
0.31
Cervical
0.34
0.04-2.74
0.31
1.07
0.47-2.45
0.86
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2.21
0.62-7.89
0.22
2.84
1.27-6.36
0.011
Supraclavicular
0.62
0.08-4.91
0.65
2.43
0.97-6.10
0.06
Pre-auricular
0.82
0.10-6.50
0.85
0.93
0.28-3.11
0.91
0.68
0.20-2.29
0.53
Hilar
[P=0.24; log-rank test]
Spleen
2.23
0.47-10.6
0.31
2.69
1.01-7.17
0.047
0.65
2.43
1.05-5.62
0.038
0.18
0.02-1.33
0.09
Extranodal sites (each expressed as Yes / No) Bone marrow
1.38
[P=0.26; log-rank test]
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Bone
0.35-5.41
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Iliac
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Table 4 Studies investigating outcomes of FL 3 subtypes
Study/ year
Regimen used
Follow up duration
Population size
Wahlin et al 5 /2011
10 years
94:23
Largely anthracycline regimens
5 and 10-Year OS= 71: 43 and 60:43
Shustik et al 6 / 2011
~ 4 years
139:22
Anthracycline regimen in 36%:82%
5-Year OS= 72:71
Maeshima et al 12/ 2013
~ 6 years
47:5
Largely R-CHOP regimen
Koch et al 7/ 2016
~ 7 years
47:14
Current study
~ 5 years
32:21*
FL3A:FL3B
Overall Survival
Study conclusion
FL 3A%: FL3B%
Upfront 17:9
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FL3A%: FL3B%
Rituximab used
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FL 3A indolent with similar behavior to FL 1 and 2.
FL 3A and 3B showed no plateau, similar outcomes
6-Year OS= 100:100
Upfront 100:100
FL 3A and 3B had good outcomes in rituximab era, no plateau observed in PFS
R-CHOP induction in 59%:36%
5-Year OS= 84:79
Upfront 59:36
Long-lasting remission in FL 3A is possible
Largely R-CHOP
5-Year OS= 80:90*
Upfront 86:86*
FL 3A showed plateau in PFS and relapse curve after ~ 4 years.
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Figure 1 Progression-free survival of Grade 3A FL and aggressive follicular lymphoma (FL 3B+FL3/DLBCL)
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FL: follicular lymphoma, DLBCL: diffuse large B cell lymphoma
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321 322
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Figure 2: Overall survival of Grade 3A FL and aggressive follicular lymphoma (FL 3B+FL3/DLBCL)
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S2152-2650(17)30745-0
DOI:
10.1016/j.clml.2017.07.002
Reference:
CLML 973
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 28 April 2017 Revised Date:
6 July 2017
Accepted Date: 6 July 2017
Please cite this article as: Ali MM, Rybicki L, Nomani L, Rouphail B, Dean RM, Hill BT, Jagadeesh D, Pohlman B, Hsi ED, Smith MR, Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era
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Moaath Mustafa Ali, MD1; Lisa Rybicki, MS2; Laila Nomani, MD3; Basel Rouphail, MD, MBA4;
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Robert M. Dean, MD4; Brian T. Hill, MD, PhD4; Deepa Jagadeesh, MD, MPH4; Brad Pohlman,
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MD4; Eric D. Hsi, MD3; Mitchell R. Smith, MD, PhD4,5
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Clinic Lerner Research Institute, Cleveland, OH; 3 Robert J. Tomsich Pathology and Laboratory
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Medicine Institute; 4Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
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Cleveland Clinic, Cleveland, OH; 5 Present address: George Washington Cancer Center,
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Internal Medicine, Cleveland Clinic, Cleveland, OH; 2Quantitative Health Sciences, Cleveland
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Washington DC.
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No funding to report
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Correspondence:
Mitchell R. Smith, MD, PhD
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George Washington University Cancer Center
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800 22nd St NW, Suite 8000
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Washington, D.C. 20052
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Phone Number: (202) 994-3517
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Email: [email protected]
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Brief running title: Grade 3 Follicular lymphoma
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Previous presentation: Study results were presented, in part, at the American Society of
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Number of words: 1583
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Abstract = 240 words
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Microabstract = 60 words
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Tables = 4
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Figures = 2
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Hematology Annual Meeting, December, 2015, Orlando, Florida.
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Conflict of interest statement:
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The authors declare there is no conflict of interest pertaining to this study.
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MicroAbstract:
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Whether to clinically approach follicular lymphoma (FL) grade 3 as an indolent
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or aggressive lymphoma, especially since the introduction of rituximab, is
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unclear. Our experience with FL grade 3A, compared with FL grade 3B or with concomitant
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diffuse large B cell lymphoma, primarily treated with R-CHOP suggests possible long-term
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remissions. This must be confirmed with longer follow-up and additional studies.
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Abstract
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Background: Follicular lymphoma (FL) is heterogeneous. While FL3B is treated as aggressive
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lymphoma, an optimal approach to FL3A remains unclear as little data exist on clinical
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outcomes based on sub-classification of FL grade 3 since introduction of rituximab. We report
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outcomes of FL grade 3 in the rituximab era.
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Methods: We identified and analyzed a retrospective cohort of 53 patients with FL grade 3A, 3B
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and FL grade 3 with areas of DLBCL. They were divided into two groups: aggressive lymphoma
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(aggFL) (n=21) included patients with FL3B (n=10) and FL3 (A or B) with concomitant DLBCL
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(n=11); indolent lymphoma (n=32) included only FL3A.
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Results: Baseline characteristics did not differ between the groups. R-CHOP was initial
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treatment in 79% of patients with aggFL and 72% of those with FL3A; rituximab was included in
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initial therapy in 95% and 83%, respectively. Comparing aggFL and FL3A, 5-year overall survival
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(OS) was 90% vs. 79% (P= 0.97) and 5-year progression-free survival (PFS) 44% vs 34% (P=0.75),
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respectively.
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Conclusion: We conclude that outcomes for FL grade 3, primarily treated with R-CHOP, do not
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differ between FL3A and aggFL (FL3B and FL3/DLBCL). The aggFL group showed a plateau in PFS
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confirming these should be treated with curative intent. FL3A patients, mainly managed with R-
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CHOP, also show an apparent plateau in PFS. While longer follow-up and confirmation in other
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datasets is required, this indicates potential under-treatment of FL3A with less aggressive
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regimens often used for indolent lymphoma.
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Keywords: Follicular Lymphoma Grade 3, Diffuse large B-Cell Lymphoma, Outcomes, Rituximab
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Introduction
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Follicular lymphoma (FL) comprises a heterogeneous group of histologic subtypes with varied
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clinical and pathologic characteristics that are derived from germinal center B-cells and
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generally retain a nodular growth pattern. Follicular lymphoma is classified into FL grade 1, 2
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and 3 based on the number of centroblasts by routine histologic assessment. Grade 3 FL has
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more than 15 centroblasts per high power field; it can be sub-classified as 3A when centrocytes
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are intermixed with centroblasts and 3B when there are solid sheets of centroblasts 1. These 2
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groups have distinct cytomorphologic, immunohistochemical and cytogenetic profiles 2-4.
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Despite consensus on the aggressive nature of FL3B 4-6, the behavior of FL3A remains an area of
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debate, with some studies suggesting an indolent non-curable disease while others suggest a
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potentially curable lymphoma 5-9. Most of these studies used anthracycline based regimens
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with variable rituximab incorporation
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Due to mixed results regarding clinical behavior of FL3A and 3B and lack of data in the
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immunochemotherapy era, we compared patient, disease, and treatment characteristics, PFS,
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and overall survival (OS) between 2 groups largely treated with rituximab based regimens: FL
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3A and an aggressive follicular lymphoma (aggFL) group in which we included FL3B as well as
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any FL3 that contained areas of diffuse large B-cell lymphoma (DLBCL).
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Methods
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Study population and Materials
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We identified 72 patients with FL3 in the lymphoma database of the Taussig Cancer institute of
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the Cleveland Clinic. We excluded patients who had unclassified FL 3 (N=13). Pathology material
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was available for review for 23 patients, of whom 6 were excluded as review demonstrated
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non-FL3 diagnosis. The remaining cohort included 53 patients diagnosed between 4/1998-
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7/2014 with FL3A (n=32), FL3B (n=10), FL3A with DLBCL (n=3), FL3B with DLBCL (n=5) and
94
unclassified FL3 with DLBCL (n= 3). Patients with FL3B and FL3 with areas of DLBCL were
95
analyzed as a single group termed aggFL. Transformation was defined as change of FL 3A or 3B
96
at presentation to more aggressive lymphoma confirmed by histopathology at a later date.
97
Patients who transformed after diagnosis were analyzed per initial categorization.
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Transformation to DLBCL occurred in 6 patients in FL3A group and 4 patients in aggFL group.
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The diagnosis of FL 3 subtypes was established at the time of initial consultation by an expert
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hematopathologist at our institution based on WHO classification 10. As noted, 17 were
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reconfirmed for this report on available material. Response to chemotherapy was determined
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using the revised International Working Group Criteria11. The study was approved by Cleveland
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Clinic Institutional Review Board.
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Statistical analysis
105
Nominal categorical variables were compared between FL3A and aggFL using Fisher’s exact
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test, ordinal categorical variables with Cochran-Mantel-Haenszel test and continuous variables
107
with Wilcoxon rank sum test. The primary endpoints were OS and PFS after diagnosis. The
108
event for OS was all-cause mortality and events for PFS were progression or all-cause mortality.
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Both outcomes were estimated using the Kaplan-Meier method and compared between groups
110
using the log-rank test. Time to transformation, time to bone marrow transplant, and time to
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progression after diagnosis were estimated using cumulative incidence methods and compared
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between FL groups using the Gray test. Univariable prognostic factors for OS and PFS were
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assessed using Cox proportional hazards analysis; results were summarized as the hazard ratio
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(HR) and 95% confidence interval (CI). Multivariable analysis was not performed for OS due to
115
insufficient events. Because of few events for PFS, only 2-variable models could be performed
116
(not shown). The log-rank test was used for variables where HR could not be calculated.
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Analyses were done using SAS Software (SAS Institute, Inc., Cary, NC, USA). All tests were two-
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sided, and P<0.05 was used to indicate statistical significance.
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Results
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Patient characteristics
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Baseline characteristics in FL3A group and aggFL group were similar (Table 1). Our cohort
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included 53 patients diagnosed with FL 3A and aggFL with a median follow up of 54 (0.5-204)
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months. The median age was 60 (19-85) years, 57% (n= 30) of patients were females. Fifteen
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patients (28%) had limited stage disease (Ann Arbor Stage ≤ II).
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Outcomes
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Table 2 describes therapy and outcomes. Around 10% of patients were managed initially by
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watchful waiting. Initial therapy started at a median of 0.9 months after diagnosis and almost
129
three quarters of patients received R-CHOP as first line therapy. Ten patients (19%) have died
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during follow up. There were no significant differences between FL3A and aggFL in terms of
131
PFS (P=0.75; Fig 1) and OS (P=0.97; Fig 2). There was an apparent plateau in PFS after 4 years.
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Time to transformation (P=0.87) and progression (P=0.29) also did not differ between FL3A and
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aggFL (Table 2).
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Prognostic factors for overall survival and progression-free survival
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In univariable analysis (Table 3), three variables were associated with greater risk of mortality:
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older age (HR 1.76 per 10-year increase in age, P=0.05), ECOG PS 2-3 (HR 6.73, P=0.037), and
138
para-aortic nodal site (HR 4.19, P=0.039). Four variables were associated with shorter PFS:
139
larger nodal dimension (HR 1.24 per 1 cm increase, P=0.002), iliac nodal site (HR 2.84, P=0.011),
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spleen nodal site (HR 2.69, P=0.047), and bone marrow involvement (HR 2.43, P=0.038).
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Discussion
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There is no consensus on whether FL3A should be categorized as an indolent or aggressive form
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of NHL. Our study of FL3 subtypes largely treated with rituximab demonstrates that FL3A
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biologic behavior was similar to FL3B, with the potential to be treated with curative intent. In a
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cohort of 462 patients with FL, Wahlin et al 5 demonstrated that FL3A had a clinical course
147
similar to FL 1 and 2 with frequent relapses and no plateau in OS, in contrast to FL3B with a
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plateau in OS after 5 years. Only 17 of these patients received rituximab upfront and 45% at any
149
time; multivariable analysis for regimens used showed that only receiving rituximab improved
150
OS (HR: 0.3, CI: 01.-0.6) compared to other regimens. Sushtik et al 6concluded that both FL3A
151
and 3B were incurable with no plateau demonstrated in OS or disease specific survival (DSS)
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curves, despite an apparent plateau in DSS after ~ 7 years. Rituximab was included with initial
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therapy in 1/3 of patients. In contrast to previous findings, Koch et al 7 demonstrated no
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statistically significant difference in PFS between 47 patients diagnosed with FL3A and 14
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patients diagnosed with FL3B. They also concluded that chemotherapy may induce durable
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remission in FL3A with a plateau in PFS ~ 7 years. Rituximab was used in 59% of their FL3A and
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36% of FL3B patients. Analyzing only the 27 patients with FL3A and 5 patients with FL3B
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treated with induction R-CHOP demonstrated a plateau in survival after 4 years. In a Japanese
159
study, 47 patients with FL3A and 5 patients with 3B had 10-year OS of 100%, however, no
160
plateau was observed in FL 3A despite having all patients treated with rituximab-based
161
regimens 12.
162
Use of rituximab has revolutionized therapy for B cell lymphoma, improving both PFS and OS 13,
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14
164
response to chemotherapy in patients with indolent NHL including FL improved PFS, but not OS,
165
probably because patients received subsequent rituximab. That trial used the Working
166
Formulation to classify indolent lymphoma, but follicular large cell was an exclusion 15.
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Published data on outcomes for FL grade 3 (Table 4) indicate the 5-year OS for FL3A and 3B is
168
approximately 70%, with one quarter of patients having received rituximab with induction 5, 6.
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In contrast, our study and more recent reports in which rituximab based induction was used
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more frequently showed a 5-year OS > 80% for FL3A and 3B. Whether the apparent plateau in
171
PFS for FL3A and improved 5-year OS for both FL3A and 3B are due, at least in part, to earlier
172
rituximab use is not entirely clear and remains a question for future investigation. Importantly
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due to recent randomized trials, management of indolent NHL has shifted from R-CHOP to
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bendamustine with rituximab for frontline treatment 16, 17. However, in both the BRIGHT and
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StiL trials, only FL grade 1 and 2 were included. In our data set of 32 patients with FL3A, 29
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received therapy, 21 (72%) of whom received R-CHOP. As the non-R-CHOP group was only 8
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non-uniformly treated patients, we cannot assess whether R-CHOP is better therapy in our
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population.
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In our study, mortality was higher in patients who were elderly, had poor performance status
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and who had para-aortic LN involvement. Advanced age has been associated with poor
181
outcomes in several studies 5. Bone marrow involvement may predict higher mortality 5, but
182
this was not shown in our study. LN size and disease location were important prognostic
183
indicators in our dataset, with iliac LN, spleen and BM involvement negatively impacting PFS.
184
Finally, there are several limitations of our study, as it is a single-institution experience with a
185
relatively small number of patients and, being retrospective, it is missing data on some
186
important factors, specifically ability to re-review all pathology material. Median follow-up is
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only 54 months. A multi-institutional collaboration with pathology-confirmed cases and
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adequate follow-up is necessary to understand the natural history of this disease.
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Conclusion
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With the caveats of having a relatively small sample size from a single institution, this study
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demonstrates that FL3A may have better 5-year OS than previously reported. Moreover, an
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apparent plateau in the PFS curve after 4 years suggests FL3A might be potentially curable,
194
resembling FL3B. Prospective studies of histologically confirmed FL3A in the rituximab, and
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now targeted therapy, era are warranted, particularly regarding the use of BR or R-CHOP. These
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will require multi-institutional cooperation.
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Clinical practice points: •
While follicular lymphoma (FL) grade 3B is treated as aggressive lymphoma, an optimal approach to FL grade 3A remains unclear as little data exist on clinical outcomes based
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on sub-classification of FL grade 3 since introduction of rituximab. •
plateau in progression free survival similar to follicular lymphoma 3B.
204 205
Patients in our cohort with FL 3A, mainly managed with R-CHOP, showed an apparent
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These data suggest that FL 3A may be best approached as an aggressive lymphoma with R-CHOP to attain durable remissions. Whether less intense regimens such as
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bendamustine-rituximab as used for indolent FL might result in similar results is
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unknown.
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Acknowledgement
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The authors declare there is no conflict of interest pertaining to this study.
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This research did not receive any specific grant from funding agencies in the public, commercial,
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or not-for-profit sectors.
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Swerdllow S, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues: France: IARC Press, 2008; 2008. Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood. 2002;99:3806-3812. Piccaluga PP, Califano A, Klein U, et al. Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas. Haematologica. 2008;93:1033-1038. Horn H, Schmelter C, Leich E, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96:1327-1334. Wahlin BE, Yri OE, Kimby E, et al. Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times. British journal of haematology. 2012;156:225-233. Shustik J, Quinn M, Connors JM, Gascoyne RD, Skinnider B, Sehn LH. Follicular nonHodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2011;22:1164-1169. Koch K, Hoster E, Ziepert M, et al. Clinical, pathological and genetic features of follicular lymphoma grade 3A: a joint analysis of the German low-grade and high-grade lymphoma study groups GLSG and DSHNHL. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2016;27:1323-1329. Ganti AK, Weisenburger DD, Smith LM, et al. Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2006;17:920-927. Hsi ED, Mirza I, Lozanski G, et al. A clinicopathologic evaluation of follicular lymphoma grade 3A versus grade 3B reveals no survival differences. Archives of pathology & laboratory medicine. 2004;128:863-868. Swerdlow SH, Cancer IAfRo, Organization WH. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues: International Agency for Research on Cancer; 2008. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244. Maeshima AM, Taniguchi H, Nomoto J, et al. Prognostic implications of histologic grade and intensity of Bcl-2 expression in follicular lymphomas undergoing rituximabcontaining therapy. Human pathology. 2013;44:2529-2535. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously
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untreated advanced follicular lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26:4579-4586. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725-3732. Barta SK, Li H, Hochster HS, et al. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer. 2016. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet (London, England). 2013;381:1203-1210. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-2952.
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Variable
Aggressive FL (n= 21) N (%)
Grade 3A FL (n= 32) N (%)
P value
57 (39-83)
61 (19-85)
0.72
8 (38)
15 (47)
0.58
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Table 1 Baseline characteristics of grade 3A and Aggressive Follicular lymphoma
26 (96)
1.0
8 (44)
16 (62)
0.29
8 (44)
8 (30)
2 (11)
1 (4)
0
1 (4)
median (range) Gender Male Race (n=16, 27)
15 (94)
ECOG performance status (n=18, 26) 0 1 2
TE D
3
M AN U
Caucasian
Stage at diagnosis I
RI PT
Age at diagnosis, years
3 (14)
2 (6)
4 (19)
6 (19)
6 (29)
13 (41)
8 (38)
11 (34)
4 (19)
10 (31)
0.36
Low (0-1)
4 (31)
6 (23)
0.82
Intermediate (2)
3 (23)
8 (31)
High (3+)
6 (46)
12 (46)
II
EP
III IV
0.79
B symptoms at diagnosis Yes
AC C
295
FLIPI category (n=13, 26)
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FLIPI2 category (n=7, 12) 1 (14)
2 (16)
Intermediate (1-2)
5 (71)
5 (42)
High (3+)
1 (14)
5 (42)
median (range)
3.5 (1.6-18.0)
Nodal sites at diagnosis (>1 possible)α 8 (38)
Para-aortic
10 (48)
Mediastinal Axillary Mesenteric Inguinal Cervical
Pre-auricular Hilar Spleen
EP
Supraclavicular
0.26
13 (41)
0.78
7 (33)
15 (47)
0.40
4 (19)
15 (47)
0.046
8 (38)
11 (34)
1.0
7 (33)
11 (34)
1.0
6 (29)
9 (28)
1.0
4 (19)
11 (34)
0.35
2 (10)
6 (19)
0.46
3 (14)
3 (9)
0.67
3 (14)
3 (9)
0.67
3 (14)
3 (9)
0.67
4 (19)
8 (25)
0.74
4 (19)
2 (6)
0.20
TE D
Iliac
0.38
18 (56)
M AN U
Retroperitoneal
4.1 (1.3-12.6)
SC
Largest node dimension at diagnosis, cm (n=15, 25)
0.40
RI PT
Low (0)
Extranodal sites at diagnosis (>1 possible)β
AC C
Bone marrow Bone
FL: Follicular lymphoma, ECOG: Eastern Cooperative Oncology Group, FLIPI: Follicular Lymphoma International Prognostic Index. α Lymph node sites with ≤ 10% occurrence are not included in table (pectoral, femoral, infraclavicular, Waldeyer’s ring and epitrochlear). β Extranodal sites with ≤ 10% involvement are not included in table (pleura, kidney, liver, colon, lung and skin).
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AC C
EP
TE D
M AN U
SC
RI PT
296
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Table 2 Therapy and outcomes in grade 3A and aggressive Follicular Lymphoma (FL) Variable
Aggressive FL (n= 21) N (%)
Grade 3A FL (n= 32) N (%)
P value
3 (9)
1.0
2 (10)
Months from diagnosis to first-line treatment median (range)
0.9 (0-117)
First-line treatment included Rituximab (n=19, 29) 18 (95)
24 (83)
M AN U
Yes
0.8 (0-12)
SC
Yes
RI PT
Started with watchful waiting
0.53
1.0
First-line treatment was R-CHOP regimen (n=19, 29) 15 (79)a
21 (72)b
1.0
2 (0-10)
0.47
6 (19)
0.87
27.5 (0.9 - 95)
0.34
4 (19)
5 (16)
0.98
24 (6-29)
32 (25- 37)
0.18
9 (43)
16 (50)
0.29
Yes
Number of lines of treatment (n=19, 29)
Transformation* Yes
2 (0-6)
TE D
median (range)
4 (19)
EP
If transformed, months after diagnosis (n=4, 6) median (range) 15.8 (0-39) Autologous stem cell transplant (ASCT) Yes
AC C
297
Months from diagnosis to ASCT (n=4, 5) median (range)
Disease progression Yes
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If progressed, months after diagnosis (n=9, 16) 22 (0-39)
Patient status at follow-up (log-rank) Alive
17 (81)
If alive, months of follow-up after diagnosis (n=17, 26) 62 (14-204)
26 (81)
51 (1-133)
0.55
0.97
0.54
SC
median (range)
19 (1-87)
RI PT
median (range)
298 299 300 301
a
302 303
* Transformation was defined as change of FL 3A or 3B to more aggressive lymphoma at a later stage not present at time of diagnosis.
M AN U
Other first line therapies included: bendamustine – rituximab (1), rituximab (1), rituximab, cyclophosphamide and dexamethasone (1), 1 ABVD for 1 cycle then R-CHOP (1). b Other first line therapies included: bendamustine – rituximab (2), CHOP (1), DHAP-R (1), 4 not known.
AC C
EP
TE D
304
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Table 3 Univariable prognostic factors for Overall Survival and Progression-Free Survival Variable
Overall Survival
Progression-Free Survival
95% CI
P-value
Indolent / Aggressive
1.02
0.29-3.66
0.97
1.13
0.54-2.37
0.75
1.76
1.00-3.10
0.05
0.86
0.69-1.08
0.21
0.73
0.20-2.62
0.63
6.73
1.12-40.5
0.037
0.57
0.16-2.05
0.98
per 10-year increase Gender
ECOG (n=44) 2-3 / 0-1 Stage III-IV / I-II
Yes / No
P-value
0.59-2.56
0.58
2.42
0.69-8.51
0.17
0.39
1.48
0.63-3.50
0.37
0.20-4.71
0.98
0.97
0.39-2.42
0.95
0.90-1.23
0.53
1.24
1.08-1.41
0.002
1.99
0.72-5.47
0.18
TE D
B symptoms
1.23
M AN U
Male / Female
95% CI
SC
Age at diagnosis
HR
RI PT
HR Follicular lymphoma group
Largest node dimension (n=40) per 1 cm increase
High / Int+Low
1.05
EP
FLIPI category (n=39)
5.35
0.62-45.8
0.13
Nodal sites (each expressed as Yes / No) Retroperitoneal
1.40
0.39-5.03
0.60
1.24
0.60-2.57
0.57
Para-aortic
4.19
1.08-16.3
0.039
1.62
0.76-3.46
0.21
Mediastinal
0.13
0.02-1.02
0.052
0.68
0.31-1.48
0.33
Axillary
0.80
0.20-3.12
0.74
1.67
0.79-3.51
0.18
Mesenteric
0.32
0.07-1.54
0.15
0.68
0.30-1.54
0.35
Inguinal
0.16
0.02-1.30
0.09
1.46
0.70-3.07
0.31
Cervical
0.34
0.04-2.74
0.31
1.07
0.47-2.45
0.86
AC C
305
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2.21
0.62-7.89
0.22
2.84
1.27-6.36
0.011
Supraclavicular
0.62
0.08-4.91
0.65
2.43
0.97-6.10
0.06
Pre-auricular
0.82
0.10-6.50
0.85
0.93
0.28-3.11
0.91
0.68
0.20-2.29
0.53
Hilar
[P=0.24; log-rank test]
Spleen
2.23
0.47-10.6
0.31
2.69
1.01-7.17
0.047
0.65
2.43
1.05-5.62
0.038
0.18
0.02-1.33
0.09
Extranodal sites (each expressed as Yes / No) Bone marrow
1.38
[P=0.26; log-rank test]
SC
Bone
0.35-5.41
RI PT
Iliac
306
AC C
EP
TE D
M AN U
307
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308
Table 4 Studies investigating outcomes of FL 3 subtypes
Study/ year
Regimen used
Follow up duration
Population size
Wahlin et al 5 /2011
10 years
94:23
Largely anthracycline regimens
5 and 10-Year OS= 71: 43 and 60:43
Shustik et al 6 / 2011
~ 4 years
139:22
Anthracycline regimen in 36%:82%
5-Year OS= 72:71
Maeshima et al 12/ 2013
~ 6 years
47:5
Largely R-CHOP regimen
Koch et al 7/ 2016
~ 7 years
47:14
Current study
~ 5 years
32:21*
FL3A:FL3B
Overall Survival
Study conclusion
FL 3A%: FL3B%
Upfront 17:9
SC
FL3A%: FL3B%
Rituximab used
RI PT
309
FL 3A indolent with similar behavior to FL 1 and 2.
FL 3A and 3B showed no plateau, similar outcomes
6-Year OS= 100:100
Upfront 100:100
FL 3A and 3B had good outcomes in rituximab era, no plateau observed in PFS
R-CHOP induction in 59%:36%
5-Year OS= 84:79
Upfront 59:36
Long-lasting remission in FL 3A is possible
Largely R-CHOP
5-Year OS= 80:90*
Upfront 86:86*
FL 3A showed plateau in PFS and relapse curve after ~ 4 years.
EP
TE D
M AN U
Upfront 26:45
AC C
FL: follicular lymphoma; OS: overall survival, PFS: progression-free survival. * In current study, FL 3B included those with mixed FL3A and 3B as well as FL 3 with areas of DLBCL 310 311 312 313
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314 315
Figure 1 Progression-free survival of Grade 3A FL and aggressive follicular lymphoma (FL 3B+FL3/DLBCL)
316
FL: follicular lymphoma, DLBCL: diffuse large B cell lymphoma
RI PT
317 318 319 320
SC
321 322
324 325
M AN U
323
Figure 2: Overall survival of Grade 3A FL and aggressive follicular lymphoma (FL 3B+FL3/DLBCL)
326
EP
TE D
FL: follicular lymphoma, DLBCL: diffuse large B cell lymphoma
AC C
327
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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