Natural History of Transformed Non-Hodgkin Lymphoma in the Rituximab Era: Analysis of the National Comprehensive Cancer Network (NCCN) NHL Outcomes Database.
Authors: Ban-Hoefen Makiko , Vanderplas Ann , Kelly Jennifer L. , Crosby-Thompson Allison , Abel Gregory A. , Czuczman Myron S. , Gordon Leo I. , Kaminski Mark S. , Millenson Michael , Nademanee Auayporn , Rodriguez Maria A. , Zelenetz Andrew D. , Niland Joyce , LaCasce Ann , Friedberg Jonathan W. 
Published: October 2019

Abstract
Abstract 2669

Background
The prognosis of histologic transformation (HT) of indolent non-Hodgkin's Lymphoma (NHL) in the pre-rituximab era has been dismal, with a median survival after HT of approximately one year. The natural history of HT in the rituximab era has not been previously described.

Methods
Using the National Cancer Comprehensive Network (NCCN) NHL database, a multicenter prospective registry of comprehensive clinical, treatment, and outcome data for patients (pts) with NHL, we evaluated the natural history of HT. All HT-NHL pts in participating NCCN centers between July 1, 2000-February 29, 2011, were eligible for inclusion in this cohort. Definition of transformation: (1) confirmed documentation of initial pathologic diagnosis of indolent disease, (2) biopsy proven transformation to Diffuse Large B-Cell Lymphoma (DLBCL) > 6 months from the initial diagnosis of the indolent histology.

Results
Clinical characteristics of pts at transformation (n=118): median age: 59; histology of indolent lymphoma: Follicular Lymphoma (FL) grades 1–2a: 86 (72%), FL grade 3 or 3a: 12 (10%), FL grade NOS: 4 (3%), other indolent NHL: 16 (13%). Treatment for the indolent lymphoma pre-HT: 83 (70%) treated with rituximab, 60 (51%) exposed to anthracyclines, and 23 (19%) observed without any treatment. Median number of one prior therapeutic line given prior to HT. Median time from indolent NHL to HT: 30 months (range: 6–184).
Treatment modalities for HT included autologous stem-cell transplant (auto-SCT) (n=50), allogeneic SCT (allo-SCT) (n=18), and no transplant (n=50). For the non-transplanted pts, treatment for HT included chemotherapy (94%) at HT, of which an R-CHOP-based regimen was the most commonly used (56%). A salvage regimen (cytarabine- or platinum-based) was used in 19 (38%), a lenalidomide-based regimen was used in 2 (4%), and radioimmunotherapy was administered in 3 (6%). There were three (6%) patients who neither obtained transplantation nor any treatment for HT. Pts not transplanted were older than those transplanted (64 vs 57 years, p=0.002), and pts in the auto-SCT group were older compared to the allo-SCT group (60 vs 52 years, p<0.0001). A higher percentage of the transplanted pts had a history of being treated with chemotherapy for their indolent lymphoma than were the non-transplanted pts (p=0.005).
For all 118 pts, the 2 and 5-year overall survival (OS) were 68% (95%CI: 59–76%) and 49% (95%CI: 37–59%). The 2-year OS for the non-SCT and any-SCT pts were 53% (95%CI: 39–68%) and 79% (95%CI: 69–89%). In non-SCT pts, those who were not exposed to chemotherapy prior to HT (n=16) experienced a 2-year OS of 81% (95%CI: 52–94%). The 2-year OS was 83% (95%CI: 70–91%) in the auto-SCT group, and 65% (95%CI: 39–83%) in the allo-SCT group. For HT pts age ≤60 (n=61), the 2- and 5-year OS were: 67% (95%CI: 53–77%) and 51% (95%CI: 34–65%) respectively. For auto-SCT pts age ≤60 (n=24), the 2-yr OS was 74% (95%CI: 51–87%). For non-transplanted pts age ≤60 (n=19), 2-yr OS was: 59% (95%CI: 32–78%). Amongst the non-transplanted pts age ≤60, the 2-year OS of the 6 patients naïve to chemotherapy prior to transformation was superior to that of the 13 patients who were exposed to chemotherapy prior to transformation (100% vs 35%, p=0.03).

Conclusion
Compared with historical series, the natural history of HT appears more favorable in the rituximab era. Long-term survival is seen with a variety of treatment strategies. In this largest prospective cohort of pts with strictly defined HT, pts who received auto-SCT for HT experienced a 2-year OS of 83%. Selected younger pts who are not exposed to chemotherapy prior to HT experience a prolonged survival even without transplantation. Future studies should evaluate predictive factors to determine which pts may benefit from a conservative approach to treatment of HT. Moreover, our study serves as a benchmark for future trials of novel approaches for HT.

Disclosures:
Zelenetz: Roche/Genentech: Advisor Other.