Bone Marrow Transplantation (2011) 46, 901–903 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11
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LETTER TO THE EDITOR
Radioimmunotherapy with 90Y-ibritumomab tiuxetan is a safe and efficient treatment for patients with B-cell lymphoma relapsed after auto-SCT: an analysis of the international RIT-Network Bone Marrow Transplantation (2011) 46, 901–903; doi:10.1038/bmt.2010.202; published online 27 September 2010 High-dose chemotherapy followed by Auto-SCT (ASCT) achieves prolonged disease-free survival in patients with relapsed or refractory non-Hodgkin’s lymphoma. Relapse, however, remains the most common cause of treatment failure and death. Several trials had documented significant benefit from radioimmunotherapy (RIT) with yttrium-90 (90Y)-ibritumomab tiuxetan (Zevalin) or iodine-131 (131I)tositumomab (Bexxar) for patients with relapsed follicular lymphoma (FL), leading to the approval of RIT as a treatment option for such patients.1–5 As to the marrow toxicity of RIT, patients with a history of ASCT had been excluded from most trials, resulting in only limited data on the safety and efficacy of RIT in patients with relapsed disease after ASCT.6,7 However, a phase 1 clinical trial of Vose et al.5 recently documented the feasibility of RIT with ibritumomab tiuxetan up to dose levels of 0.2 mCi/kg, providing a rationale to offer RIT also to patients after ASCT. We here summarize retrospective data collected outside clinical trials from 109 patients treated with RIT for lymphoma relapsed after ASCT, as reported to the international RIT registry (RIT-NT). The RIT-Network represents a Web-based, international registry that collects observational data from RIT-treated patients with malignant lymphoma. From December 2006 to November 2009, 1111 patients had been registered in the database. Of 105 patients who had received RIT after ASCT, the complete data sets of 70 patients were available for this analysis, predominantly treated with 90Y-ibritumomab tiuxetan (n ¼ 66). The study cohort comprised mainly patients with FL (n ¼ 48) and 22 patients with other B-cell malignancies (2 CLL, 7 diffuse large B-cell lymphoma, 6 mantle cell lymphoma, 2 marginal zone lymphoma, 1 ALL, 3 transformed follicular and 1 unspecified B-cell lymphoma). All patients had received several lines of prior chemotherapy including at least one high-dose protocol (Table 1), as well as prior radiotherapy in 40% of cases. Nine patients had undergone a previous RIT. In most patients (n ¼ 51) BM involvement had been excluded before RIT, whereas minor (o25%) and major (o25%) involvement had been documented in 12 and 2 patients, respectively. For seven patients BM status before RIT was not known. RIT was performed at a median interval of 698 days (range, 5–4435 days) after ASCT. The patients of this cohort were mainly treated with 90Yibritumomab tiuxetan (n ¼ 66; for n ¼ 4 the radioisotope
not documented) at a median total dose of 1095 MBq, equivalent to a median dose of 0.39 mCi/kg evaluable for 39 patients (range, 0.01–0.5 mCi/kg). As expected, hematotoxicity was observed as the most common side effect after RIT. Median nadir values for hemoglobin, neutrophils and platelets were 9.6 g per 100 mL (range, 5.4–15.1 g per 100 ml), 48/mL (range, 0–412 ANC/mL) and 84/mL
Table 1
Patients characteristics
No of Patients Male/female Median age (range) n460 years Stage I II III IV ND Previous treatments Chemotherapy 1–3 4–6 47 Auto-SCT 1 2 Radioimmunotherapy
70 53/17 49 (23–64) 11 (16%) No. of patients (%) 3 (4%) 6 (9%) 18 (26%) 42 (60%) 1 (1%)
37 (53%) 30 (43%) 3 (4%)
66 (94%) 4 (6%) 9 (13%)
Bone marrow infiltration prior to RIT No infiltration 51 (73%) Infiltration 12 (17%) o25% 9 (75%) 425% 3 (25%) Response CR PR SD PD ND
30 14 2 12 12
(43%) (20%) (3%) (17%) (17%)
Hematotoxicity No. of patients Hemoglobin
53
Neutrophils
46
Platelets
53
Median nadir values (range) Median time to nadir (range) 9.6 g per 100 mL (5.4–15.1) 53 days (1–400) 48/mL (14–412) 48 days (14–412) 84/mL (7–153 000) 35 days (14–404)
Letter to the Editor
902 PFS
Survival distribution function
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0.75
0.50
0.25 Median follow up: 367.5 days 0.00 0
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600
800
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1200
Days OS Survival distribution function
1.00
0.75
0.50
0.25 Median follow up: 367.5 days
0.00 0
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400
600 Days
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Figure 1
Kaplan–Meier estimates of PFS (a) and OS (b) for patients treated with radioimmunotherapy after high-dose chemotherapy and ASCT.
(range, 7–153 000 platelets per mL), respectively, observed at a median time after transplantation of 53 days for hemoglobin (range, 1–400 days), 48 days for neutrophils (range, 14–412 days) and 35 days for thrombocytes (range, 14–404). Complete recovery of blood counts was reached after a median interval of 132 days (range, 47–1323 days; compare Table 1). Thus we documented significant, particularly delayed hematotoxicities in this cohort of heavily pretreated patients, exceeding those previously reported.6–8 Comparing the quartiles of patients with lowest and those with the most severe hematotoxicity, we found no differences between such patient groups regarding age, tumor stage, previous chemotherapies, line of therapy, histologic subtype of the lymphoma, BM infiltration, days from transplantation to RIT, dose of radionuclide and indication for RIT. The overall response rate to RIT was 53%, with best responses representing CR in 30, PR in 14 and s.d. in 2 patients, respectively; for 12 patients response was not documented (Table 1). Disease progression occurred in 12 patients, a median time of 98 days (range, 81–154 days) after RIT. In total, 51 (72%) and 47 (67%) patients were alive (mean OAS, 571 days) and disease-free survival (mean Bone Marrow Transplantation
TTP, 144 days), respectively, after a median observation time of 367.5 days (Figure 1). Relapse of lymphoma disease after ASCT infers a dismal prognosis for patients with malignant lymphoma. A standard of care yet remains to be defined for this situation. An increasing number of novel agents are under evaluation, and Allo-SCT emerges as a potentially curative option for selected patients. However, for the majority of patients, current chemotherapy regimens provide only transient disease remissions, and cannot prevent death due to final disease progression. RIT exploiting targeted irradiation by 90 Y-ibritumomab tiuxetan is of substantial benefit for patients with B-cell lymphoma, both in the setting consolidation and relapse therapy trials. In addition, efficacy and safety of RIT had also been shown for limited numbers of patients, who had been treated for relapsed disease after ASCT.6–8 The data of this report, obtained in the real-life setting of an international registry, confirm the feasibility of RIT in patients after ASCT and corroborate the value of 90 Y-ibritumomab tiuxetan as particularly potent treatment modality to obtain clinically meaningful, in part long-lasting remissions in patients with relapsed B-cell lymphoma. K Hohloch1, PL Zinzani2, W Linkesch3, W Jurczak4, A Deptala5, M Lorsbach6, C Windemuth-Kiesselbach6, GG Wulf1 and LH Truemper1 1 Department of Hematology and Oncology, Georg August University, Go¨ttingen, Germany; 2 Department of Hematology/Oncology, Istituto Seragnoli, University of Bologna, Bologna, Italy; 3 Department of Hematology and Stem Cell Transplantation, Medical University of Graz, Graz, Austria; 4 Haematology/Oncology, University of Krakow, Krakow, Poland; 5 Haematology/Oncology, Central Hospital Warszawa, Warszawa, Poland and 6 Alcedis GmbH, Giessen, Germany E-mail:
[email protected]
References 1 Wiseman GA, Gordon LI, Multani PS, Witzig TE, Spies S, Bartlett NL et al. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 2002; 99: 4336–4342. 2 Witzig TE, White CA, Wiseman GA, Gordon IE, Raubitschek N, Janakiraman CEA et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin’s lymphoma. J Clin Oncol 1999; 17: 3793–3803. 3 Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN et al. White treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximabrefractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 2002; 2: 3262–3269. 4 Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M et al. Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000; 96: 1259–1266.
Letter to the Editor
903 5 Vose JM, Bierman PJ, Enke C, Hankins J, Bociek G, Lynch JC et al. Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23: 461–467. 6 Vose JM, Biermann PJ, Loberiza FR, Bociek RG, Matso D, Armitage JO. Phase I trial of 90Y-ibritumnumyb tiutexan in patients with relapsed B-cell non-Hodgkin’s lymphoma following high-dose chemotherapy and autologous stem cell transplantation. Leuk Lymphoma 2007; 48: 683–690.
7 Molina A, Krishnan A, Fung H, Flinn IW, Inwards D, Winter J et al. Use of radioimmunotherapy in stem cell transplantation and posttransplantation: focus on yttrium 90 ibritumomab tiutexan. Curr Stem Cell Res Ther 2008; 2: 239–248. 8 Jacobs SA, Vidnovic N, Joyce J, McCook B, Torok F, Avril N. Full-dose 90Y ibritumomab tiuxetan therapy is safe in patients with prior myeloablative chemotherapy. Clin Cancer Res 2005; 11: 7146s–7150s.
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