Therapeutic options for patients with primary resistant or relapsed Hodgkin Lymphoma (HL) have remained largely unchanged for the past 20 years, comprising salvage chemotherapy consolidated by autologous transplantation. Newer agents such as brentuximab vedotoxin may increase response rates, and are being evaluated in the maintenance setting after transplantation. For patients with chemosensitive disease, autologous transplantation confers 5yr progression-free-survival rates of 40–50%. Prognosis is worse in primary resistant or early relapsing disease (within 12 months of primary therapy). Functional imaging also provides prognostic information. Patients with metabolic complete response (mCR) prior to autograft have progression-free survival (PFS) rates in excess of 70% at 3–5yrs, whilst in those with chemosensitive disease (CR/PR) but residual metabolically active lesions these figures drop to 25–30%. The feasibility of performing allogeneic hematopoietic stem cell transplants in patients with HL using reduced intensity conditioning is well established. However, reduced non-relapse mortality rates have been associated with increased relapse, which is now the major cause of treatment failure. Registry data suggest the importance of dose intensity in determining relapse risk. Consideration of transplantation earlier in the disease pathway may improve the tolerability of increased dose intensity. We evaluated the feasibility of a response-adjusted transplantation strategy, based on assessment of disease status by FDG-PET-CT following salvage chemotherapy. Between November 2007 and December 2010 we treated 61 patients with primary refractory or relapsed HL at our institution. Patients were restaged following 1 line of salvage. Those in mCR were consolidated with a BEAM autograft, whilst non-progressive patients with <mCR were offered a BEAM-alemtuzumab allograft. Those with progressive or bulky residual disease were given further salvage until they demonstrated stable disease or better, at which point they were eligible for an allograft. Patients were monitored following the allograft for lineage-specific chimerism and restaged by PET-CT, and received dose-escalating donor-lymphocytes from 6 months post-transplant for mixed chimerism or residual disease/progression. 53/61 (87%) patients achieved sufficient response and were fit for high-dose therapy. 28 patients proceeded to autograft and 25 to allograft (8 related donor, 12 HLA-matched unrelated donor, and 5 HLA-mismatched unrelated donor). The majority had received ABVD as first-line therapy (n=48), and ESHAP as first-line salvage (n=48). 21 of those proceeding to allograft received mini-BEAM as additional salvage. The median number of lines of salvage was 2 (1–8) in the allograft cohort. 12/13 ‘late' relapses, 5/9 ‘early' relapses and 11/31 primary resistant cases received an autograft. The median age at transplant was 32 in both groups (range 18–66 for autograft vs 16–50 for allograft). Median follow-up is 2.5 vs 2.3 years respectively (range 0.5–3.6yrs in both). Outcomes in the autograft group were understandably good. NRM was 4%, and relapse incidence 11%. 3yr OS and PFS were 92% and 85% respectively. Outcomes following allografting in the higher risk cohort were also encouraging. All engrafted. NRM was 8% and relapse incidence only 16%, with all relapses occurring within 9 months of transplantation. 4 patients received donor-lymphocytes for relapse. All responded and 3 (all CR) are maintained. 3yr OS, PFS and ‘current' PFS are therefore 88%, 71% and 84% respectively. 4 patients developed grade II and 2 patients grade III acute graft-versus-host disease, and no patients were taking immune suppressants beyond 18 months after transplantation. The combined 3yr outcomes for all 53 transplanted patients are 90% OS, 78% PFS and 84% cPFS. In conclusion, the data demonstrate favorable survival outcomes for the entire cohort of primary resistant and relapsed patients. They illustrate that selected patients with primary resistant and early relapsed disease may do well following autografting, but more strikingly that those predicted to have poor outcomes based on functional imaging may have very favorable outcomes following alemtuzumab-based allografting with aggressive post-transplant immune modulation. The data now form the basis for 2 national UK studies.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.