The majority of patients with HL are cured using conventional chemoradiotherapy. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the standard of care for medically fit patients with relapsed HL6
. The results of HDT/ASCT depend on different prognostic factors. The most important prognostic factors are clinical stage at relapse, tumor sensitivity to salvage chemotherapy, and remission duration between first-line treatment and relapse. The outcome is generally poor for patients relapsing after ASCT. If the disease progresses during HDT, relapsed patients who cannot benefit from ASCT should be considered for allo-SCT.
Early registry data7
show that allo-SCT after MAC results in lower relapse rates (RRs) but with significantly higher toxicity than ASCT. Studies from the 1990s suggest that the application of allogeneic strategies in patients with relapsed/refractory HL is limited by high nonrelapse mortality (NRM) varying from 40% to 60%7
. The high procedure-related morbidity and mortality also prevents the widespread use of allo-SCT. The introduction of RIC regimens addresses this problem by reducing NRM while providing the GVL effect. The introduction of allo-SCT after RIC for relapsed/refractory HL patients results in a decreased cumulative incidence of NRM ranging from 11% to 13%. However, approximately 50% of all patients who undergo RIC-allo-SCT relapse8
The Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT), together with the Grupo Español de Linfomas/ Trasplante Autólogo de Médula Ósea, conducted the largest multicenter phase II prospective clinical trial that aimed to analyze NRM and other major outcome parameters after RIC-allo-SCT in relapsed HL9
. This study included 92 patients with relapsed HL, among which 14 died from progressive lymphoma before transplantation, and 78 continued with allograft (unrelated donors, n
=23). The RIC regimens consisted of fludarabine (150 mg/m2
IV from day -8 to day -4) and melphalan (140 mg/m2
IV from day -3 to day -2). In addition, anti-thymocyte globulin (ATG) (45 mg/kg IV from day -4 to day -2) was used as graft-versus-host-disease (GVHD) prophylaxis in the recipients of stem cells obtained from matched unrelated donors (MUD). The NRM at 100 days and 1 year was 8% and 15%, respectively. For the allografted population, the 1-year and 4-year progression-free survival (PFS) rate was 48% and 24%, respectively. Patients allografted in complete remission (CR) exhibited remarkably better results, and 1-year and 4-year OS was 71% and 43%, respectively. Chronic GVHD (cGVHD) was associated with lower RRs (P
=0.04). A significant improvement in PFS was also found in patients developing cGvHD (P
=0.05). Donor type and stem cell source had no significant influence on post-transplant outcomes in HL patients, and the results were similar for sibling and MUD transplants. Although the RIC regimens significantly improved the survival outcomes in HL patients compared with the myeloablative strategies, the high relapse or progression rates are major challenges. Robinson et al.8
retrospectively investigated 285 adult relapsed/refractory HL patients undergoing different RIC regimens. They found that 89% of the patients were <45 years old and had chemosensitive disease. Furthermore, 80% of the patients had previously undergone ASCT, and 25% had refractory disease at transplant. Fludarabine/melphalan (FluMel), busulfan/fludarabine (BuFlu), and fludarabine/cyclophosphamide (FluCy) alone or with thiotepa were used as conditioning regimen. The early and cumulative 3-year TRM rates were 11% and 21%, respectively, and the 5-year progression rates reached up to 59%. The 3-year OS and PFS rates were 29% and 25%, respectively10
. Researchers found that RR was lower for patients with GVHD. Relapse within 6 months of prior ASCT was associated with higher RR and lower PFS. Comparable results were observed in previous studies on the use of RIC regimens in HL patients. Despite the lower TRM rates, the OS and disease-free survival were not more than 50%4,7
. Current data suggest that the chemosensitivity and CR status at transplant are the most important factors in improving survival after allo-SCT. Moreover, RIC-allo-SCT may be an effective salvage strategy for HL patients. However, the main cause of treatment failure following RIC-allo-SCT is disease progression.