This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Balduzzi, A. Articles by Valsecchi, M. G. Search for Related Content PubMed PubMed Citation Articles by Balduzzi, A. Articles by Valsecchi, M. G. Social Bookmarking                            What's this?

Transplantation in Childhood Very High Risk Acute Lymphoblastic Leukemia in First Complete Remission: Where Are We Now?

Clinica Pediatrica Università degli Studi di Milano Bicocca, Monza, Italy

Maria Grazia Valsecchi

Dipartimento di Medicina Clinica, Prevenzione e Biotecnologia Sanitaria, Università degli Studi di Milano Bicocca, Monza, Italy

To the Editor:

In the January 1, 2007, issue of the Journal of Clinical Oncology, Ribera and colleagues¹ reported no advantage of allogeneic transplantation versus chemotherapy in children with very high-risk (VHR) acute lymphoblastic leukemia (ALL) enrolled in the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) ALL-93 trial. Of the 100 patients who achieved complete remission (CR), 24 had a compatible related donor and were genetically assigned to the allogeneic transplantation arm, and 76, lacking a related compatible donor, were randomly assigned to chemotherapy (n = 38) or autologous transplantation (n = 38). Disease-free survival (DFS) was 45%, superimposable for the donor and no donor arm, as defined by intention to treat.

The finding within this cohort is not consistent with previous reports, in particular with our prospective international trial conducted within the International Berlin-Frankfurt-Munster Study Group (I-BFM-SG), reporting 357 patients whose outcome was significantly affected by donor availability (DFS, 56.7% v 40.6%; hazard ratio, 1.49; P = .02).² We comment on some issues an attempt to explain this difference.

Patient selection, which is crucial for the outcome, was not directly comparable between the two studies. The incidence of VHR features defined by the PETHEMA and the I-BFM-SG trial was 13% and 8% of the overall ALL childhood population, respectively. This may indicate that the PETHEMA trial included a slightly broader subset of children, whose features might be less dismal and for whom the expected gap between chemotherapy and transplantation might be smaller.

Moreover, in the Discussion section, in order to support the lack of advantage of transplantation toward chemotherapy, the authors reported the same findings in older retrospective studies enrolling about one fourth of the whole childhood ALL population, also failing to show differences.^3,4 Those older studies clearly showed that not all high-risk patients are eligible for transplantation, as known for more than a decade. As the outcome yielded by chemotherapy progressively improved, eligibility for transplantation was restricted to "very high risk" ALL, carrying more and more severe prognostic features than in the past because less severe ones rated good enough with chemotherapy only, then could be spared early and late morbidity of transplantation.^4a

Ongoing first-line protocols, accounting for minimal residual disease in assessing eligibility for transplantation, might identify with better sensitivity for patients with dismal prognosis and possibly further reduce the proportion of VHR ALL patients in first CR for whom transplantation is indicated with even stronger evidence.⁵

The outcome of chemotherapy for PETHEMA ALL-93 overall was approximately as one would expect, based on its schedule, which was similar to ALL 90 BFM and 91 Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) protocols.^6,7 Only with subsequent ALL 95 BFM and AIEOP protocols, representing the chemotherapy arm of the I-BFM-SG study, better results were achieved, mostly for patients at high risk and with T-immunophenotype.^8-10

Few patients (n = 17) actually only underwent allogeneic transplantation. As noted by the authors in their Discussion, the median interval of 22 weeks (range, 12 to 67) between CR attainment and allogeneic transplantation was longer than recommended and compared with our study (16 weeks; range, 12 to 22). This delay allowed a high proportion of patients (17%) to relapse before they could undergo transplantation and could have contributed in decreasing the potential rate of success of allogeneic transplantation, as assigned by intention to treat.

In contrast, failures after allogeneic transplantation were higher than expected, compared with recent reports in the same setting, mostly due to relapse.² Reasons for higher relapse rates, other than the delay mentioned earlier, are likely to be the lack of total body irradiation (TBI) in the conditioning regimen in an unspecified number of children who received allogeneic transplantation.¹¹ The lack of TBI might have jeopardized the antileukemic effect of transplantation, as shown by the probability of relapse of 55% and 25% for patients receiving busulfan and TBI-based conditioning regimens, respectively, as presented jointly for patients who received allogeneic and autologous transplants.

Moreover, a less effective induction and consolidation chemotherapy could have left patients with a high level of minimal residual disease at the time of transplantation, limiting its curative effect.¹²

The role of autologous transplantation in VHR ALL in first CR was not previously assessed and is therefore of some interest; although, the trial was not designed and powered on the comparison between chemotherapy and autologous transplantation. The fact that its outcome seemed equivalent to chemotherapy could indicate that the latter could be preferable in order to avoid late effects related with the conditioning regimen.

A sample size of 198 patients was planned, based on parameters which were not fully specified in the statistical section (ie, which baseline, which target difference, and whether the test was one or two sided). Based on a futility analysis, which makes final results unlikely to show differences per se, the enrollment was interrupted after 106 patients, 100 of whom reached CR. With a sample size of 100 patients, allocated in a 1:3 ratio (more realistic than the 1:2 mentioned by the authors) to the two arms, no donor versus donor, and with a 5-year DFS of 45% in the no donor arm, the log-rank test would yield the stated 90% power only if the outcome of the donor arm was as high as 85%. Only a 40% difference between the two arms could have been detected, and not 10% as reported in the Results section. Numbers would be small and inadequate for reliable overall and subgroups analyses. The proportion of deviations from the donor arm was 29%, which was high but consistent with previous reports.

The enrollment between January 1993 and October 2002, and the observation time up to July 2005, would allow a maximum potential follow-up of 12 years. Curves were actually depicted up to 12 years, but numbers of patients at risk were not specified and curves depicting DFS reached a plateau early, while relapses would be expected also later on, in the third and fourth years, mostly in patients who did not receive transplants, as occurred in the previous I-BM-SG study. Did the recording process fail in recording late relapses and updating patients' status?

In conclusion, the PETHEMA report presented a similar outcome for allogeneic or autologous transplantation and chemotherapy in VHR ALL patients in first CR, which is in contrast with the previously published larger multicenter I-BFM-SG study. Slightly different VHR definition criteria, the limited sample size, and mostly the poor transplantation outcome, possibly due to the delay in performing it, and particularly the lack of TBI, may explain why this trial failed in detecting the advantage of transplantation, which has been already demonstrated.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Ribera JM, Ortega JJ, Oriol A, et al: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial. J Clin Oncol 25:16-23, 2007[Abstract/Free Full Text]

2. Balduzzi A, Valsecchi MG, Uderzo C, et al: Chemotherapy versus allogeneic transplantation in childhood very high risk acute lymphoblastic leukaemia in first complete remission: A comparison by genetic randomization in an international prospective study. Lancet 366:635-642, 2005[CrossRef][Medline]

3. Wheeler KA, Richards SM, Bailey CC, et al: Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukaemia in first remission: Results from Medical Research Council UKALL X and XI. Blood 96:2412-2418, 2000[Abstract/Free Full Text]

4. Uderzo C, Valsecchi MG, Balduzzi A, et al: Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission. Br J Haematol 96:387-394, 1997[CrossRef][Medline]

4. Blume KG, Forman SJ, Appelbaum FR: Thomas’ Hematopoietic cell Transplantation (ed 3). Boston, MA, Blackwell Publishing, 2003

5. Arico' M, Baruchel A, Bertrand Y, et al: The seventh international childhood acute lymphoblastic leukaemia workshop report: Palermo, Italy, January 29-30, 2005. Leukemia 19:1145-1152, 2005[CrossRef][Medline]

6. Shrappe M, Reiter A, Ludwig WD, et al: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: Results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95:3310-3322, 2000[Abstract/Free Full Text]

7. Conter V, Arico' M, Valsecchi MG, et al: Intensive BFM chemotherapy for childhood ALL: Interim analysis of the AIEOP-ALL 91 study: Associazione Italiana Ematologia Oncologia Pediatrica. Haematologica 83:791-799, 1998[Abstract/Free Full Text]

8. Schrappe M, Reiter A, Zimmermann, et al: Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM Study Group from 1981 to 1995: Berlin-Frankfurt-Munster. Leukemia 14:2205-2222, 2000[CrossRef][Medline]

9. Arico' M, Valsecchi MG, Conter V, et al: Improved outcome in high-risk childhood acute lymphoblastic leukaemia defined by prednisone-poor resposnse treated with double Berlin-Frankfurt-Muenster protocol II. Blood 100:420-426, 2002[Abstract/Free Full Text]

10. Schrauder A, Reiter A, Gadner H, et al: Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: Results from ALL_BFM 90 and 95. J Clin Oncol 24:5742-5749

11. Bunin N, Aplenc R, Kamani N, et al: Randomized trial of busulfan versus total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: A Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 32:543-548, 2003[CrossRef][Medline]

12. Krejci O, van der Velden VH, Bader P, et al: Level of minimal residual disease prior to haematopoietic stem cell transplantation predicts prognosis in pediatric patients with acute lymphoblastic leukaemia: A report of the Pre-BMT MRD Study Group. Bone Marrow Transplant 32:849-851, 2003[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Balduzzi, A. Articles by Valsecchi, M. G. Search for Related Content PubMed PubMed Citation Articles by Balduzzi, A. Articles by Valsecchi, M. G. Social Bookmarking                            What's this?