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Originally published as JCO Early Release 10.1200/JCO.2008.20.8769 on January 26 2009 © 2009 American Society of Clinical Oncology.
Hematologic Toxicity and Double Autografting of Stem Cells After Myeloablative Activities of Yttrium-90–Ibritumomab TiuxetanDivision of Haemato-Oncology, European Institute of Oncology, Milan, Italy
Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy
Division of Haemato-Oncology, European Institute of Oncology, Milan, Italy To the Editor: In response to the original report by Devizzi et al1 and the editorial by Press2 published in Journal of Clinical Oncology, we would like to suggest a few points of discussion to promote a better understanding of the toxicity profile and efficacy of yttrium-90 (90Y) –ibritumomab tiuxetan in the myeloablative setting. As reported by Devizzi et al, the prominent characteristics of their study were the double autografting of stem cells, the use of 90Y-ibritumomab tiuxetan as consolidation, and the implementation of the same eligibility criteria currently used for standard-dose chemotherapy (CT) trials. To support the role of tandem reinfusion of stem cells, they compared their experience with our previously reported results.3 However, the hematologic toxicity described by Devizzi et al1 should only have been compared with what we reported at the same activity levels they investigated; therefore, the different populations of patients enrolled cannot be compared.3,4 The double stem-cell reinfusion did not seem to influence the extent or duration of cytopenia; 47% of patients developed grade 4 toxicity; 50% of patients required platelet transfusions, with a median number of two patients and a range of one to six patients; 47% of patients required RBC transfusions.
Where a better profile of hematologic toxicity was observed, it may have been related to a more favorable selection of patients rather than to tandem stem-cell reinfusion. All patients enrolled by Devizzi et al1 showed normal platelet and absolute neutrophil counts at time of treatment (Fig 2 in the article), and all collected In our experience, 39 patients were considered for the trial, but 11 failed stem-cell mobilization.3 Previous treatments received and older age at mobilization could explain this phenomenon.
We should also consider that even if double reinfusion plays a role, it may not always do so in patients evaluated as ineligible for high-dose (HD) CT. If one patient can collect Finally, we have investigated image analysis and marrow aspirate as alternative dosimetric approaches to compare red marrow doses and evaluate the best timing for autologous stem-cell transplantation.5 Although the alternative methods investigated are affected by uncertain factors, both have indicated comparable results—about 2.5-fold higher than those observed with the blood method—which suggests that the blood method provides an underestimate of red marrow dose. A double reinfusion does not seem to be useful at activities less than 1.5 mCi/kg.5 With regard to the use of 90Y-ibritumomab tiuxetan as consolidation, we agree with Press.2 The majority of patients had indolent histology and could not be considered resistant or refractory—because a majority of patients were in complete remission at the time of RIT—and the median follow-up was too short. We are probably now observing the efficacy of the debulking CT, rather than the efficacy of consolidation with RIT. With regard to the implementation of the same eligibility criteria currently used for standard-dose CT trials, the aim to expand the restricted criteria for HD CT does not seem to have been reached, because only 13 patients were older than 65 years of age, and all were able to receive HD cyclophosphamide and HD cytarabine, as were most younger patients. Finally, we cannot consider their regimen to have been an outpatient regimen. The preparative CT regimen required hospitalization, and even if we take into account the avoidance or simplification of dosimetry, high activities of 90Y-Ibritumomab tiuxetan cannot be performed as outpatient regimens because of European regulations on radiation protection. In their experience, dosimetry was not necessary and did not predict toxicity probably because the true maximum tolerated dose was not reached. The role of dosimetry should be confirmed, because—as Press2 correctly observed—we cannot consider 1.2 mCi/kg to have been the maximum tolerated dose. Performing dosimetry is expensive and requires specialized personnel. However, it offers important information for better understanding the toxicity profile of this procedure.6 In conclusion, we must stress the expense of RIT, especially in the myeloablative setting. The main limitation is the cost-benefit ratio, rather than the logistic issues or the collaboration between hemato-oncologists and nuclear medicine physicians. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Devizzi L, Guidetti A, Tarella C, et al: High-dose yttrium-90–ibritumomab tiuxetan with tandem stem-cell reinfusion: An outpatient preparative regimen for autologous hematopoietic cell transplantation. J Clin Oncol 26:5175–5182, 2008. 2. Press OW: Evidence mounts for the efficacy of radioimmunotherapy for B-cell lymphomas. J Clin Oncol 26:5147–5150, 2008. 3. Ferrucci PF, Vanazzi A, Grana CM, et al: High activity 90Y-ibritumomab tiuxetan (Zevalin) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomas. Br J Haematol 139:590–599, 2007.[CrossRef][Medline] 4. Vanazzi A, Ferrucci PF, Grana C, et al: High dose 90yttrium ibritumomab tiuxetan with PBSC support in refractory-resistant NHL patients. Blood 110:405a; 2007 abstr 1890. 5. Vanazzi A, Laszlo D, Cremonesi M, et al: Red marrow dosimetry and stem cell reinfusion in high dose 90Y-ibritumomab tiuxetan. Blood 112:763; 2008 abstr 2187. 6. Cremonesi M, Ferrari M, Grana CM, et al: High-dose radioimmunotherapy with 90Y-ibritumomab tiuxetan: Comparative dosimetric study for tailored treatment. J Nucl Med 48:1871–1879, 2007.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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9 x 106 CD34+ cells/kg. They were not significantly older in age, and had not undergone significant amounts of previous treatment; only 13 of 30 patients were age 65 years or older, and only 10 of 30 had a disease status defined as "more than first relapse" at enrollment. 
