Between November 1981 and May 2005, we treated 167 patients with HL using HDT and ASCT at our Center with 64 (38%) of these patients meeting the definition of chemoresistant disease. Baseline characteristics for this group are summarized in . In addition, front-line chemotherapy consisted of ABVD in 25 patients, an ABVD/MOPP hybrid in 22 patients, MOPP in 5 patients, Stanford V in 3 patients, other ABVD hybrids in 2 patients, and a combination of other therapies in 7 patients. Twenty-nine patients (45%) were refractory to their initial chemotherapy regimen. The median number of prior regimens was 2 (range 1–5). Thirty-two patients (50%) had received prior RT and all patients had a Southwest Oncology Group (SWOG) performance status of 0 or 1 prior to transplant. Eight patients had PET imaging prior to conditioning, of these 7 had FDG-avid foci of active disease.
Baseline Characteristics of the 64 patients with chemoresistant Hodgkin’s lymphoma who underwent autologous stem cell transplantation.
Regimens immediately prior to transplant to which the HL was deemed resistant included ICE in 14 patients, DHAP in 9 patients, MOPP/ABVD in 7 patients, CED in 7 patients, ABVD in 4 patients, MOPP in 3 patients, and COPP in 2 patients with the remaining 18 patients receiving 17 various other regimens. When all prior regimens were assessed for responses in each patient, 40 (63%) patients were found to be resistant to anthracyclines, 33 (52%) to high-dose alkylating agents (cyclophosphamide [CY] and ifosfamide), 33 (52%) to platinum (cisplatin and carboplatin), and 19 (30%) to high-dose cytarabine.
Conditioning regimens and stem cell sources
Twenty-six patients (41%) were treated with TBI-based preparatory regimens, including 23 receiving TBI/CY/etoposide (VP16) and three patients treated with CY/TBI. The remaining 38 patients (59%) were treated with chemotherapy-only regimens including: busulfan (Bu)/melphalan (Mel)/thiotepa (TT) (n=18), carmustine/CY/VP-16 (n=12), Bu/CY (n=3), carmustine/VP-16/cytararbine/Mel (n=3), Bu/TT (n=1), and Bu/CY/Lithium (n=1). Twenty-four patients received autologous bone marrow, 39 received autologous mobilized peripheral blood stem cells (PBSC), and 1 received both.
Overall and progression-free survival
The 5-year OS and PFS were estimated to be 31% (95% confidence intervals [CI] 18–44%) and 17% (95% CI 6–27%) respectively, with median follow-up of 4.2 years (range 1–16.2 years) among surviving patients (). At the last follow up, 21 patients (33%) were alive and 13 (20%) were alive and progression-free. Thirty of the 43 deaths during this study period followed relapse. Non-relapse causes of death included: respiratory failure (5 patients), infections (2 patients), AML/MDS (2 patients), hepatic toxicity (1 patient), renal failure (1 patient), and unknown causes (2 patients). Therapy for the 8 patients surviving following relapse included non-myeloablative allogeneic transplantation (3 patients), chemotherapy alone (2 patients), chemotherapy and radiation (1 patient), radiation alone (1 patient) and surgical resection (1 patient). Of the 7 patients with positive PET imaging pre-transplant, 4 are alive and progression-free from 5 months-2.1 years after transplant, 1 died of AML without relapse of HL at 4 yrs, and 2 suffered progression at 5 and 9 months, respectively. The one patient with a negative PET is alive and progression-free at 2.6 years.
Overall and progression-free survival of 64 patients with chemoresistant Hodgkin’s lymphoma following high-dose therapy and autologous stem cell transplantation.
Univariate and multivariable analyses
Hazard ratios (HR) for mortality from univariate analyses included: mixed cellularity (MC) histology, 0.42 (95% CI 0.16–1.07, p=.07 vs. all other); prior radiation, 2.05 (95% CI 1.11–3.79, p=.02); male gender, 1.05 (95% CI 0.57–1.92, p=.88); use of TBI, 0.65 (95% CI 0.34–1.21, p=.17); use of bone marrow-derived stem cells, 1.85 (95% CI 1.01–3.38, p=.05); ≥ 2 extranodal sites (ENS) of disease, 2.10 (95% CI 1.03–4.29, p=.04); and tumor bulk ≥ 5 cm, 1.39 (95% CI 0.75–2.56, p=.30). The HR for death for stage III disease was 0.94 (95% CI 0.39–2.27, p=.89) and for stage IV was 1.13 (95% CI 0.54–2.38, p=.75) when compared to patients with stage I/II disease. Age at transplant (p=.30) and number of cycles of previous chemotherapy (p=.79) were not statistically significantly associated with mortality in univariate models when evaluated as a continuous linear variable. In contrast, the year of transplant was correlated with mortality, with improved survival occurring following more recent transplants (p=.008). After adjusting for year of transplant, none of the other factors were statistically significantly associated with OS, while year of transplant remained associated with survival even after adjusting for the other factors (). Similar results were observed when PFS was evaluated, with no other factors statistically significantly associated with outcome after adjusting for year of transplant with later transplants being associated with improved PFS (p=.04). The presence of >1 ENS of disease approached statistical significance for PFS when adjusted for transplant year (HR=1.89 (95% CI 0.92–3.88), p=.08).
Multivariable analysis of associations of baseline factors with mortality adjusted for year of transplant in chemoresistant Hodgkin’s lymphoma patients undergoing high-dose therapy and autologous transplantation.
Because of the strong correlation between era of transplant and source of stem cells (all recent transplants were done with PBSC) we evaluated the impact of year of transplant within and between the PBSC (August 1993–2005) and bone marrow (1986-July 1993) periods (). Overall survival appeared to improve over time within both the bone marrow and peripheral blood stem cell source eras as did PFS though the only statistically significant differences were between the most recent and most distant time periods (OS p=.003, PFS p=.02). The absolute risk of relapse in general decreased over time, though demonstrating statistically significant differences were likely limited by the small number of events. The estimated probabilities of 3-year survival for patients transplanted between 1986–1989, 1990-July 1993, August 1993–1999, and 1999–2005 were 9%, 36%, 33%, and 49%, respectively (). Likewise, the estimated 3-year PFS for patients transplanted between 1986–1989, 1990-July 1993, August 1993–1999, and 1999–2005 were 9%, 21%, 33%, and 31%, respectively ().
Hazard ratios from a multivariable analysis of outcomes stratified by year of transplant and stem cell source.
Overall survival (left) and progression-free survival (right) of 64 chemoresistant Hodgkin’s lymphoma patients treated with high-dose therapy and autologous transplantation stratified by year of transplant.