Outcomes of Second-Line Chemotherapy and Autologous Stem Cell Transplantation for Primary Refractory Diffuse Large B Cell Lymphoma

Introduction: Patients (pts) with primary refractory Diffuse Large B Cell Lymphoma (REF DLBCL - defined as progession within 3 months of completion of primary therapy) sensitive to salvage chemotherapy are treated with high dose therapy and autologous stem cell transplantation (ASCT). The randomized Parma trial demonstrated survival benefit for patients with chemosensitive relapse undergoing ASCT but did not include primary refractory cases, thus current practice is based largely on retrospective series

Methods: We conducted a retrospective review of 112 consecutive cases of REF DLBCL identified from our database between 1999–2007. All pts had evidence of stable or progressive disease (SD or PD) following primary treatment. Responses were assessed retrospectively using International Workshop Criteria (JCO 1999). Logistic regression was used to predict overall response rate (ORR) to salvage therapy; Cox Proportional-Hazards regression was used to analyze overall survival (OS) and progression-free survival (PFS). Salvage chemotherapy consisted of 2–3 cycles of platinum-based therapy; responding pts proceeded to PBSC mobilization and subsequent ASCT. High dose therapy consisted of VP16 60 mg/kg day –4 and melphalan 180 mg/m2 day –3 with PBSC infusion day 0. Pts with bulk disease (³ 5 cm) at progression received involved field radiation post-ASCT.

Results: Median age was 46 (range 19–67); 77% had ECOG of 0–1 and 46% had limited stage disease at primary treatment failure. Where available (n=77), LDH was elevated in 74%. 21% had > 1 extranodal site. Primary treatment consisted of: CHOP 66%, R-CHOP 33% or ABVD 1%; radiotherapy was given in 15 pts. Response to primary therapy was: CR 9%, PR 31%, SD 20% and PD 41%. Second-line chemotherapy consisted of: DHAP 49, ESHAP 31, GDP (gemcitabine, dexamethasone, cisplatin) 24, or another platinum based-regimen 8. 5 pts received rituximab with the salvage regimen. ORR to first salvage chemotherapy was 24%. 2/35 pts receiving a second line and 0/6 pts receiving a third line of non-cross-resistant salvage therapy achieved response. 28 pts (25%) underwent ASCT. 6 pts received post-ASCT radiation as consolidation. With a median follow-up of 5.9 months (range 0.9–93.8), the median PFS and OS from primary treatment failure were 3 and 10 months respectively. OS may have been overestimated due to a high rate of loss to follow up after progression and subsequent censoring. In pts who underwent ASCT (median follow-up 18 months, range 0.3–89 months), median PFS was15 months after ASCT while median OS was not reached. ORR to salvage chemotherapy was predicted by normal LDH (OR=3.1; 95% CI=1.0–9.1; p=0.04). Proceeding to ASCT was predicted by normal LDH (OR=4.3; 95% CI=1.5–12.5; p=0.007), ECOG 0–1 (OR=5.2; 95% CI=1.1–23.6; p=0.03), and CR/PR with primary treatment (OR=3.2; 95% CI=1.5–12.3; p=0.01). Inferior PFS was found in pts with elevated LDH (HR=2.5; 95% CI=1.3–4.6; p=0.004), ECOG ≥ 2 (HR=1.8; 95% CI=1.1–2.9; p=0.01), and in pts having SD/PD with primary treatment (HR=1.7; 95% CI=1.1–2.6; p=0.02). OS was reduced in pts with elevated LDH (HR=5.3; 95% CI=1.8–15.0; p=0.002) and ECOG ≥ 2 (HR=2.7; 95% CI=1.4–5.2; p=0.004). Age, stage, number of extranodal sites and prior rituximab treatment were not significant predictors of any outcome.

Conclusions: In summary, outcomes in patients with REF DLBCL are poor with an ORR of 25% to salvage chemotherapy and a median PFS of 15 months post-ASCT. Elevated LDH and poor functional status predict for inferior overall survival. Novel treatment approaches should be pursued in REF DLBCL.