Mutations associated with progression in follicular lymphoma predict inferior outcomes at diagnosis: Alliance A151303

Author:

Russler-Germain David A.1ORCID,Krysiak Kilannin234ORCID,Ramirez Cody13ORCID,Mosior Matthew13,Watkins Marcus P.1ORCID,Gomez Felicia134ORCID,Skidmore Zachary L.13,Trani Lee13,Gao Feng5,Geyer Susan6,Cashen Amanda F.14,Mehta-Shah Neha14ORCID,Kahl Brad S.14ORCID,Bartlett Nancy L.14ORCID,Alderuccio Juan P.7ORCID,Lossos Izidore S.7ORCID,Ondrejka Sarah L.8ORCID,Hsi Eric D.9ORCID,Martin Peter10,Leonard John P.10,Griffith Malachi13411,Griffith Obi L.13411ORCID,Fehniger Todd A.14ORCID

Affiliation:

1. 1Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO

2. 2Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO

3. 3McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO

4. 4Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO

5. 5Public Health Sciences Division, Department of Surgery, Washington University School of Medicine, St. Louis, MO

6. 6Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN

7. 7Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL

8. 8Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH

9. 9Department of Pathology, Wake Forest Baptist Medical Center, Winston Salem, NC

10. 10Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY

11. 11Department of Genetics, Washington University School of Medicine, St. Louis, MO

Abstract

Abstract Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, whereas others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from Cancer and Leukemia Group B/Alliance trials 50402/50701/50803, or real-world cohorts from Washington University School of Medicine, Cleveland Clinic, or University of Miami). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than in newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than in t-FL yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than in dx FL, including 6 significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a mutations associated with progression (MAP) signature as ≥2 mutations in these 7 genes (6 rel/ref FL or t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a 7-gene set offering insight into FL progression risk potentially more generalizable than the m7–Follicular Lymphoma International Prognostic Index (m7-FLIPI), which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in this high-risk subset of patients.

Publisher

American Society of Hematology

Subject

Hematology

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