Autologous Stem Cell Transplantation (AuSCT) with Total Lymphoid Irradiation (TLI) and High-Dose Chemotherapy (CT) Results in High Survival Rates for “Poor-Prognosis” Relapsed/Refractory (R/R) Hodgkin’s Disease (HD): Multivariate Analysis of Outcome Shows Marked Benefit for TLI in a Prospective Phase I/II Trial.
Authors: Evens Andrew M. , Rademaker Alfred , Mittal Bharat B. , Altman Jessica K. , Patton David , Kaminer Lynne , Singhal Seema , Variakojis Daina , Williams Stephanie , Tallman Martin S. , Mehta Jayesh N. , Winter Jane N. , Gordon Leo I. 
Published: October 2019

Background: Poor prognostic factors for patients (pts) with R/R HD include primary refractory disease and resistance to salvage CT with long-term progression- free survival (PFS) of 40–52% and 11–19%, respectively. Results of a prospective phase I/II trial incorporating TLI conditioning with AuSCT for pts with R/R HD are reported.

Methods: 47 pts received salvage CT followed by peripheral blood AuSCT from November 1993 to April 2005. Salvage consisted of ESHAP (n=29), ICE (n=9), MOPP (n=3), ABVD (n=2) and unknown (n=4). Conditioning for AuSCT consisted of accelerated fractionation TLI 150 cGy BID starting day −35, with 1500 cGy to previously uninvolved nodal sites, 3000 cGy to previously involved, and 3540–4000 cGy to sites of active disease. After 1 week rest, conditioning CT consisted of carboplatin (450 mg/m2/d CI, D -6 to D-3), etoposide (700 mg/m2/d CI, D -6 to D-3), and cyclophosphamide (60 mg/kg/d D -3 and D-2) (CCE). Pts with no prior radiation (RT) received TLI + CCE, while those with prior RT received CCE alone. The first 18 pts received escalating etoposide doses up to 700 mg/m2/d with no unexpected toxicity.

Results: Of 47 pts, primary and salvage therapy is known for 43; 14 had primary refractory HD, 20 pts had initial remission < 1 year (combined, 79% of study population). 26 pts responded to salvage (10 CR), and 17 pts < PR (40% CT-resistant). All 47 pts proceeded to AuSCT. 32 received TLI + CCE and 15 CCE alone. Median age is 36 years (range 18–66). PFS and overall survival (OS) for all pts was 47% and 57%, respectively (Figure) (median followup from AuSCT is 21 months, range 0.7 to 128 months). We also compared PFS for TLI + CCE versus CCE-alone conditioning, and a univariate analysis shows markedly increased PFS for TLI + CCE (p<.0001) (Figure).

Figure Figure

The PFS and OS for pts receiving TLI + CCE with primary refractory HD was 83% (10/12) and 92% (11/12) and for CT-resistant disease was 56% (5/9) and 78% (7/9). Using proportional hazards regression for a multivariate model including: histology, stage, initial remission < 1 year, B symptoms, CT resistance, prior RT and TLI, only TLI remained statistically significant (p=.017). Treatment related mortality (TRM) was 8.5% (4/47), including 2 secondary leukemias (100 day TRM was 4.2%).

Conclusions: TLI and CCE conditioning was well-tolerated with low TRM and high and durable survival rates for pts with R/R HD. Moreover, very high PFS and OS rates were seen in historically poor-prognosis pts if TLI was given. TLI-based regimens should be studied further in randomized clinical trials compared to CT-alone conditioning regimens.