Clinical Outcome Determinants for Sequentially Transformed Indolent Lymphomas Treated with or without Autologous Stem Cell Transplantation

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.