Secondary Malignancies After Autologous Stem Cell Transplantation In Patients With Relapsed / Refractory Hodgkin´s Lymphoma. A Retrospective Analysis On Behalf Of The Lymphoma Working Party Of The European Society For Blood and Marrow Transplantation (EBMT)

The occurrence of late events [i.e. secondary malignancies (SM)] after therapy is of special relevance in patients with Hodgkin«s lymphoma (HL) as the median age of this population is quite low and first line therapy is curative in a high proportion of them. Autologous stem cell transplantation (ASCT) is the standard of care for patients with HL in first relapse and chemosensitive disease and for those patients who demonstrate to be primary refractory. The administration of chemotherapy +/- radiotherapy is a risk factor for the development of SM and, high dose chemoradiotherapy given as conditioning regimen before stem cell infusion can further increase this risk. In this retrospective study we have analyzed the incidence of SM as well as of the different subtypes [acute leukemias (AL) / myelodisplastic syndromes – myeloproliferative disorders (MDS-MPD), lymphomas and solid tumors (ST)] in more than 2000 HL patients undergoing an ASCT with a very long follow up after transplantation.

2261 patients with HL being treated with an ASCT between January/1985 and December/1995 and reported to the Lymphoma Database of the EBMT have been included in this analysis. There were 871 (38.5%) females and 1390 (61.5%) males with a median age at diagnosis of 26.8 years and at transplantation of 30.2 years. Median follow up for surviving patients was 9.1 years. Median time from diagnosis to ASCT was 26.6 months and 1989 patients (88% of the series) received at least 2 lines of chemotherapy before undergoing the autologous procedure. 694 patients were autografted in complete remission (CR) and the remaining 1567 with visible disease (amongst them, 279 patients had primary refractory disease, 458 patients sensitive relapse and 216, refractory relapse). Total body irradiation (TBI)-containing regimens only represented 4.2% of all conditioning protocols. 1300 patients were conditioned with BEAM / BEAM like protocols, 670 with CBV and 197 with other combinations. As expected because of the year of transplantation, bone marrow was used as the source of stem cells in 1407 patients (62.2%).

After a median follow up of 10.5 years for all patients, 978 (45.4%) are alive and 1178 (54.6%) have died, 959 patients (43.7%) have relapsed after ASCT and 378 (17.5%) have died of non-relapse mortality (NRM). Relapse rate (RR) of the whole population of patients was 43.5%, 46.2% and 47% at 5, 10 and 15 years, respectively. NRM ranged from 14.6% to 19.8% at 5 and 15 years after ASCT, respectively. Disease free survival (DFS) was 41.9%, 36.5% and 33.2% at 5, 10 and 15%, respectively and finally, overall survival (OS) at 5, 10 and 15 years was 53.1%, 44.4% and 38.8%, respectively. 122 patients (5.4% of the series) developed a SM after ASCT. The most frequent ones were ST (49 patients – 40.2% of the series) followed by AL / MDS-MPD (26 patients – 21.3% / 23 patients – 18.8%), lymphomas (17 patients – 11.5%) and others (9 patients – 7.4%). 95 patients (78%) were in CR at the time of developing the SM and 27 patients (22%) had already relapsed after ASCT and being treated with additional chemotherapy.

30 patients with SM died of this late effect after ASCT (3% of NRM for the whole population of patients).

In conclusion, the development of a SM after an ASCT represents a significant late effect in this big population of HL patients with a very long follow up, the most frequent ones being the ST that, as expected seem to develop later after transplantation than AL / MDS – MPD and lymphomas. The impact of prior therapy as well as other well know prognostic factors in the development of SM after ASCT is still unclear and needs to be better defined.