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Originally published as JCO Early Release 10.1200/JCO.2008.21.0559 on January 26 2009 © 2009 American Society of Clinical Oncology.
In ReplyIstituto Nazionale Tumori, Milan, Italy Vanazzi et al raise several questions and advance alternative explanations for the mild and unprecedented hematopoietic toxicity clearly documented in our article.1 To begin, they state that the double infusion of CD34+ cells did not affect recovery, and alternatively suggest that the limited hematologic toxicity we observed was the consequence of an underestimation of the marrow dose of radioactivity and of the significantly better marrow reserve of our population, as reflected by our ability to collect a high amount of CD34+ cells. We agree that the use of the blood method for red marrow dosimetry is an open issue. However, to our knowledge, no established red marrow dosimetric method has been published for patients receiving yttrium-90 (90Y) –ibritumomab tiuxetan. Our own experience (unpublished data) has suggested that if a red marrow tropism is present, it is confined to the spine. This nonhomogeneous marrow involvement makes any locoregional dose evaluation method unreliable (region of interest on bone district or biopsy). Moreover, as we observed, and as reported by Ferrucci et al2 in their article, within the dose range of 0.8 to 1.5 mCi/kg, post-transplantation hematologic recovery was unaffected by the injected dose of radioactivity. Finally, the differences between our results and theirs are too great to be explained by different dosing, unless we assume major discrepancies. In our study,1 the median durations of grade 4 neutropenia and thrombocytopenia were 5 and 4 days, respectively. In the report by Ferrucci et al,2 the same figure for neutropenia was 15 days; the figure for thrombocytopenia was not reported, but on the basis of inspection of the figures, it was certainly substantial. In addition, and of greater interest, in the study by Ferrucci et al,2 the majority of the patients experienced a late drop in neutrophil and platelet counts. In conclusion, a dosing error on our part of a degree capable of accounting for these dramatic differences is quite unrealistic. As to the alleged exceptionally good marrow reserve of our patients relative to the published experience of Ferrucci et al,2 we wish to point out that the ability to collect large amounts of CD34+ cells depends mainly on the high mobilization potential of single-agent high-dose chemotherapy (cyclophosphamide or cytarabine). Our patients were part of a consecutive series of patients exclusively selected for their disease status (refractory or relapsed). After closing enrollment onto the present study,1 we were able to complete the same program in 26 additional patients, whereas one additional patient failed to provide an adequate amount of CD34+ cells. Thus, only one patient of 57 consecutive relapsed or refractory patients was unable to complete the intended program. The high 30% failure rate reported by Ferrucci et al2 clearly indicates the importance of an optimal mobilization regimen. In conclusion, the most convincing and logical explanation for the minimal hematologic toxicity observed was the tandem-infusion strategy adopted. As clearly stated in our report,1 formal proof of its role is lacking, but we believe that an unbiased look at the double wave of neutrophil recovery, which mainly resulted from early recovery after the first infusion, would yield a strong argument for the role of the first infusion in the minimal toxicity observed. Vanazzi et al also state that our patient population was not resistant or refractory. However, the terms resistant and refractory referred to response to prior therapy, not to the experimental treatment delivered. The fact that many patients achieved a complete or very good partial response clearly shows the efficacy of the high-dose sequence of chemotherapy preceding administration of 90Y-ibritumomab tiuxetan (Zevalin; Cell Therapeutics Inc, Seattle, WA) in a population of patients unable to obtain response, or progress, under a prior standard-dose salvage regimen (ie, a population correctly defined as resistant or refractory).1 A formal evaluation of the efficacy and activity of 90Y-ibritumomab tiuxetan was, as clearly stated in our report, outside the scope of the present study, and is being addressed in an ongoing randomized trial.3 The suggestion that we are probably observing the efficacy of debulking chemotherapy rather than the efficacy of consolidation with radioimmunotherapy is unsupported by the data presented. Vanazzi et al go on to suggest, on the basis of patient age, that our patient population was fit and thus fully eligible for high-dose chemotherapy regimens. We stress that the criteria for excluding patients from a myeloablative regimen are by no means limited to patient age. Any physician caring for patients would agree that the serious clinical conditions listed in Table 2 of our report1 represent a strong contraindication against a bone marrow transplantation program. As to the inpatient versus outpatient issue, we used the term outpatient to indicate that the treatment did not require hospital stays for clinical reasons, a result to our knowledge unprecedented in any high-dose myeloablative regimen. We agree that the treatment would have been better defined as a one-night inpatient regimen for Europeans instead of an outpatient regimen. However, the issue appears to us to be a semantic dispute of limited, if any, relevance. Finally, in our report,1 we explained in detail the reasons for stopping the dose escalation at 1.2 mCi/kg, and clearly acknowledged that our objective was not to define the maximum tolerated dose after individual dosimetry. Additional dose escalation would have required individual dosimetry and exposed our patients to the risk of severe toxicities for a limited dose gain. The published experience of Ferrucci et al2 clearly shows that the dose could possibly be increased by 25% (from 1.2 to 1.5 mCi/kg), but at the expenses of additional resource utilization, strict patient selection, and acceptance of the risk of toxicities of varying severity (such as liver, mucositis, and infection) in the majority of patients (four of five patients in their series). 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. 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] 3. European Union Drug Regulating Authorities Clinical Trials, Use of Zevalin at myeloablative dose for aggressive lymphoma treatment in elderly patients: A prospective randomized trial of Z-HDS1.2 v R-CHOP, EudraCT no. 2006-002524-42.
Related Correspondence
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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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