Clinical Outcome Determinants for Sequentially Transformed Indolent Lymphomas Treated with or without Autologous Stem Cell Transplantation
Authors: Madsen Charlotte , Pedersen Martin Bjerregaard , Vase Maja Ølholm , Segel Erik , Bendix Knud , Jensen Bo Amdi , Jensen Paw , Moeller Michael Boe , Johansen Preben , Munksgaard Lars , Brown Peter de Nully , d'Amore Francesco 
Published: October 2019

Abstract
Introduction: When lymphomas originally diagnosed as indolent (IL) transform to a more aggressive histology (TIL) the result is often an accelerated clinical course and a shortened survival. The purpose of this study was (i) to investigate whether autologous stem-cell transplantation (ASCT) performed at the time of transformation improved the outcome compared to rituximab-containing chemotherapy alone, (ii) to identify clinical pre-transformation factors influencing post-transformation outcome.
Methods: Patients aged 18-68 yrs with histologically verified sequential TIL diagnosed between 1999 and 2012 at 3 Danish tertiary lymphoma referral centers were identified using the National Danish Pathology Registry. Pre-therapeutic clinico-pathological features as well as treatment- and outcome data at baseline and follow-up were collected through the Danish lymphoma registry (LYFO) and patient records. The patient cohort was subdivided into 2 major subsets according to treatment strategy at transformation i.e. ASCT or no ASCT. Selected characteristics of potential clinical relevance, treatment background and response rates were compared using χ2 test, Fisher's exact test or t test and tested in a multivariate analysis using a Cox proportional Hazards model. Treatment outcomes were estimated as 5-year overall (OS) and progression-free survival (PFS) and compared using the log-rank test.
Results: Fifty-seven patients with sequential TIL were included of which 39 patients received ASCT after initial immunochemotherapy and 18 did not. The two treatment cohorts (non-ASCT vs. ASCT) were comparable in all features including time to transformation (3.4 yrs vs. 6.5 yrs; p=0.10) and treatment with rituximab at IL-stage (n=5, 28% vs. n=7, 18%; p=0.49). Outcome determinants were tested at a median follow-up of 3.1 yrs (0.1-13.4 yrs) from the time of TIL diagnosis. The 5-yr OS was 57% if ASCT was performed and 36% if it was not (p=0.10). In terms of 5-yr PFS, ASCT treated patients had significantly higher values as compared to not transplanted ones (47% vs. 6%; p=0.003). This associated superior outcome was irrespective of prior rituximab treatment (Prior rituximab: 21% vs. 0%; p=0.02. No prior Rituximab 52% vs. 9%; p=0.03). However, the favorable impact of ASCT was greatest in patients who were rituximab-naïve at transformation (5-yr OS: 21% vs. 64%; 5-yr PFS: 21% vs. 52%). When comparing the outcome of sequential TIL patients based on the number of prior chemotherapy regimens, a higher number of prior regimens (>2) correlated with an inferior outcome (5-yr OS: 70% vs. 22%, p=0.05; 5-yr PFS: 64% vs. 23%, p=0.04) as did a high FLIPI-score. No influence on outcome was observed with regard to type of treatment at IL-stage, induction at TIL-stage (CHOP-like vs. platinum based), age or WHO-performance score at TIL diagnosis.
Conclusions: ASCT improved the outcome in sequential TIL. The beneficial impact of ASCT was greater in patients, who were rituximab-naïve at transformation. Factors with negative influence on outcome were a high FLIPI-score and the number of treatment regimens prior to transformation.

Disclosures
No relevant conflicts of interest to declare.