In their letter to the editor, Ailawadhi and Padmanabhan raise a number of questions relating to the donor versus no-donor analysis, recently reported by the Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) cooperative group and the subsequent meta-analysis with the Medical Research Council (MRC), Bordeaux-Grenoble-Marseille-Toulouse (BGMT), and European Organisation for Research and Treatment of Cancer (EORTC) studies.1 Here, a specific reply to each question is provided.
(1) Patients were not stratified on the basis of performance status. We wish to stress that, even in older patients (> 40 years of age), treatment-related mortality (TRM) was not particularly high. It was estimated at approximately 25%. However, the latter TRM value, along with a relapse rate of 35%, did not result in a significantly superior disease free survival (DFS) in patients beyond 40 years of age with a donor compared with those without a donor.
(2) The commonly used conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) was high dose cyclophosphamide and myeloablative total body irradiation (TBI; 2 × 6 Gy). If patients had received irradiation before, a combination of busulfan and cyclophosphamide was used. The preparative regimen prior to autologous SCT contained high-dose busulfan and cyclophosphamide.
(3) Treatment-related mortality data are specifically given in Table 4 of our paper.1 Overall, TRM was estimated at 21% (± 2%, SD) in the donor group and 4% (± 1%) in the no-donor group. As most recipients of an allogeneic SCT received TBI, we cannot compare the impact of different transplant techniques.
(4) Anthracyclins used in combination with cytarabin were daunomycin at 45 mg/m2 for 3 days in the first cycle in the HOVON 4/4A studies and idarubicin at 12 mg/m2 for 3 days in the first cycle in the HOVON 29 and 42 studies. In addition, patients treated with chemotherapy as consolidation therapy were treated with mitoxantrone at 10 mg/m2 for 5 days (combined with etoposide; see “Treatment protocols” in Cornelissen et al.1 ).
The study by Wiernik et al (cited by Ailawadhi) was performed in patients with acute lymphoblastic leukemia. That same cooperative group has also performed a study in AML, comparing 30 mg/m2 and 45 mg/m2 daunomycin in remission induction. While a higher response rate was observed, no enhanced survival could be demonstrated nor was excessive toxicity noted following the higher dose level of daunomycin (45 mg/m2).2
(5) Fifty-five patients in the donor group did not proceed to allo-SCT. They were, however, analyzed within the donor group according to the “intention to treat” principle. Reasons for withdrawal from allo-SCT were as follows: refusal (n = 12), worsened condition (n = 9), early relapse or death (n = 19), good risk cytogenetics (n = 10), and unknown causes (n = 5). Thus, only a minority of these patients did not proceed to allo-SCT because of favorable risk AML.
(6) As stated in the discussion of our manuscript, data with respect to FLT3 and NMP1 mutations were not available for the majority of patients. As a result, those subsets of patients could not be studied.
We present this letter on behalf of all co-authors.
Authorship
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Jan J. Cornelissen, Erasmus University Medical Center-Daniel den Hoed, Department of Hematology, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands; e-mail:j.cornelissen@erasmusmc.nl.
