Myeloablative doses of Yttrium-90 (90Y)-Ibritumomab Tiuxetan combined with tandem autologous peripheral blood stem cell (PBSC) support can be safely administered to patients aged up to 76 years (Devizzi L et al, J Clin Oncol 2008). Whether marrow exposure to myeloablative doses of radiolabelled antibodies (hd-radio-immunotherapy) could increase the risk of secondary myelodysplastic syndrome and acute leukemia (sMDS/AL) remains a matter of concern. Therefore, we prospectively investigated by means of a longitudinal study the incidence of sMDS/AL in a cohort of high-risk non-Hodgkin lymphoma (NHL) patients receiving hd-radio-immunotherapy. The cumulative incidence of sMDS/AL in the study group was compared with that observed in a historical group of patients autografted following chemotherapy-based myeloablative conditioning. Additionally, to further investigate marrow damage induced by hd-radio-immunotherapy, hematopoietic and stromal progenitors, as well as telomere length (TL) were assessed.
From July 2004 through December 2007, 53 relapsed/refractory (n= 36) or de novo high-risk (n= 17) NHL patients (median age, 64 years; range, 26 – 76 years) received a high-dose sequential (HDS) chemotherapy program, including a myeloablative phase with 90Y-Ibritumomab Tiuxetan (1.2 mCi/kg body weight). Patients were monitored for frequency of colony-forming cells (CFCs), cytogenetic and TL analysis. Bone marrow (BM) samples were collected prior to hd-radio-immunotherapy, every six months for two years and annually thereafter. The study was approved by the Institutional Ethical Committee and written informed consent was obtained from each patient. The study group included 29 patients with aggressive lymphoma (diffuse large B-cell lymphoma, n = 19; mantle cell lymphoma, n = 8; Richter syndrome, n = 2) and 24 with indolent NHL subtypes (follicular lymphoma, n = 20; marginal zone lymphoma, n = 3; lymphocytic lymphoma, n = 1). Thirty patients were relapsed after one (n=15) or more (n=15) previous chemotherapy regimens, 6 patients were refractory and 17 patients were previously untreated with high-risk prognostic index. Pre-exposure to alkylating agent involved 68% of the patients. A historical group of 55 NHL patients who received an analogous HDS program with final chemotherapy-based autografting was used as control group. Study and control groups were pair-matched for age, gender, histological subtype, disease status at transplant and type of grafted PBSC.
At a median follow-up of 49 months (range, 32 – 74), 4 out of 53 patients of the study group developed sMDS/AL at 6, 12, 27 and 36 months from transplant. According to WHO criteria, refractory anemia with excess of blasts 1 (RAEB-1) was diagnosed in one patient, whereas refractory cytopenia with unilineage dysplasia (RCUD) was diagnosed in the other three cases, with acute leukemia transformation being observed in two patients at 12 and 18 months after initial detection of abnormal cytogenetics, respectively. The cumulative incidence of sMDS/AL resulted of 8.29% at 5-years. An analogous 5-year cumulative incidence of 8.05% was observed in the historical control group autografted following a chemotherapy-based conditioning. Radioimmunotherapy-treated patients showed a significant but transient decrease in granulocyte-macrophage colony forming unit (CFU-GM) at 6 months after transplant, with recovery to baseline values at 12 months. Multilineage colony-forming units (CFU-Mix), erythroid burst-forming units (BFU-E) and fibroblast CFU (CFU-F) were not show significantly affected over time. In contrast, a progressive and significant decrease in BM TL was evident from 12 months after transplant.
In our series of elderly NHL patients receiving hd-radio-immunotherapy, the incidence of sMDS/AL was found increased compared to recently reported series of younger lymphoma patients receiving chemotherapy-based conditioning. However, the increased risk of sMDS/AL was not associated with the type of myeloablative conditioning, i.e. chemotherapy vs radio-immunotherapy. Other factors may have favored the development of sMDS/AL, including advanced age at transplant, extensive pre-transplant therapy and type of reinfused PBSC. The observed progressive TL loss gives support to the concept that TL loss might be involved in sMDS/AL development.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.