Monitoring of Post-Transplant Hematopoiesis in Patients Receiving High-Dose Yttrium-90-Ibritumomab Tiuxetan (Zevalin®) with Autograft: Lack of Detection of Remarkable Abnormalities.

Introduction: High-dose (hd) Zevalin® radioimmunotherapy (RIT) followed by tandem peripheral blood stem cell (PBSC) reinfusion is a well tolerated myeloablative regimen with wide applicability for the treatment of NHL (Devizzi L et al, J Clin Oncol, in press). The risk of long-term hematopoietic damage and therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) due to high radiation doses to the bone marrow (BM) is a matter of concern. The present study aimed to investigate BM hematopoietic abnormalities after hd-Zevalin®.

Patients and Methods: From July 2004 through December 2007, 51 consecutive NHL patients (M/F=30/21; median age 64 yrs, range 26–76 yrs) who received hd-Zevalin® (1.2 mCi/kg) as myeloablative consolidation following sequential hd-chemotherapy were monitored after transplantation for BM progenitor cell frequency, telomere length (TL) and cytogenetic abnormalities. Disease histology included diffuse large B cell (n=21), follicular (n=19), mantle cell (n=8), marginal zone (n=2), and small lymphocytic (n=1) lymphomas. At study entry, 35 patients had relapsed or refractory disease, whereas 16 patients were chemotherapy-naive with high-risk prognostic index. Following hd-RIT, 33/51 patients were reinfused with PBSC collected after hd-cytarabine. BM and peripheral blood (PB) mononuclear cells (MNC), collected prior to Zevalin® and at 6-month intervals thereafter, were analyzed for (i) frequency of BM erythroid BFU-E, myeloid CFU-GM, and multilineage CFU-mix, (ii) TL, (iii) cytogenetic abnormalities.

Results: With a median follow-up of 25 months (range, 8–50) from autograft, a total of 196 samples have been analyzed: 51 at baseline, 39 at 6 months, 42 at 12 months and 27, 27 and 10 at 18, 24 and 36 months after RIT, respectively. As compared to pre-transplant values, a significant reduction in BM CFCs was detected 6 months after Zevalin® (median incidence per 5 x 10⁴ MNCs were as follows, BFU-E: 45 vs 26, P≤0.04; CFU-GM: 61 vs 34, P≤0.0005; CFU-mix: 0.8 vs 0.5, P≤0.2). CFCs recovered to pre-transplant values 12 months after Zevalin®, and showed sustained growth values at subsequent time-points. No difference in progenitor cells was observed by comparing Zevalin® patients with those conditioned with conventional chemotherapy. Telomere was steadily assessed in 27 patients. Similar values (p=NS) of TL were obtained on pre-transplant MNCs (median: 5,893 bp, range 4,107–8,353) and MNCs collected at 6–12 months post-transplant (median: 5,829 bp, range 3,133–8,037). BM cytogenetic analysis has been serially performed in 51 patients. To date, abnormalities have been detected in 2 cases, including one deletion of chromosome 7 and one inversion of chromosome 16 [inv(16)]. Interestingly, inv(16) was retrospectively detected in the leukapheresis collected before RIT, thus ruling out any causative role of Zevalin®.

Conclusion: In this cohort of elderly and heavily pretreated patients receiving hd-Zevalin®, hematopoietic function evaluated by progenitor cell growth and TL seems comparable to that of patients receiving conventional myeloablative chemotherapy. No increase in cytogenetic abnormalities was detected up to 36 months post-transplant. A careful monitoring is still ongoing in order to verify at long-term whether hd-Zevalin® might increase the risk of t-MDS/AML.