AML - Acute Myeloide Leukemie: Allogene beenmergtransplantatie geeft significant betere resultaten voor patienten met slechte en matige prognose bij AML

15 juni 2009: Bron: 1: JAMA. 2009 Jun 10;301(22):2349-61.

Allogene beenmergtransplantatie geeft significant betere resultaten voor patienten met slechte en matige prognose bij AML - Acute Myolide Leukemie echter niet voor patienten met een goede prognose. Dit blijkt uit een meta-analyse van 2 grote gerandomiseerde fase III studies. hier het abstract van de studie en daaronder een verklarend artikel uit Medscape. In fiete wordt bevestigd dat de aanpak van AML zoals die nu wordt gehanteerd de juiste is. Alleen voor aptienten met een matrige prognose zou de aanpak wel eens ander skunnen zijn. Maar is juist afhankelijk van een goede analyse van de kansen op een recidief bij elke individuele patient, aldus wetenschappers in het artikel van Medscape.

Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials.

Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, Wadleigh M, DeAngelo DJ, Stone RM, Sakamaki H, Appelbaum FR, Döhner H, Antin JH, Soiffer RJ, Cutler C.

Division of Hematologic Malignancies, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA. john_koreth@dfci.harvard.edu

CONTEXT: The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML.

OBJECTIVE: To quantify relapse-free survival (RFS) and overall survival benefit of allogeneic SCT for AML in CR1 overall and also for good-, intermediate-, and poor-risk AML.

METHODS: Systematic review and meta-analysis of prospective trials evaluating allogeneic SCT vs nonallogeneic SCT therapies for AML in CR1. The search used the combined search terms allogeneic; acut* and leukem*/leukaem*/leucem*/leucaem*/aml; myelo* or nonlympho* in the PubMed, Embase, and Cochrane Registry of Controlled Trials databases in March 2009. The search identified 1712 articles.

STUDY SELECTION: Prospective trials assigning adult patients with AML in CR1 to undergo allogeneic SCT vs nonallogeneic SCT treatment(s) based on donor availability and trials reporting RFS and/or overall survival outcomes on an intention-to-treat, donor vs no-donor basis were identified.

DATA EXTRACTION: Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were determined.

DATA SYNTHESIS: Overall, 24 trials and 6007 patients were analyzed (5951 patients in RFS analyses and 5606 patients in overall survival analyses); 3638 patients were analyzed by cytogenetic risk (547, 2499, and 592 with good-, intermediate-, and poor-risk AML, respectively). Interstudy heterogeneity was not significant. Fixed-effects meta-analysis was performed. Compared with nonallogeneic SCT, the HR of relapse or death with allogeneic SCT for AML in CR1 was 0.80 (95% CI, 0.74-0.86). Significant RFS benefit of allogeneic SCT was documented for poor-risk (HR, 0.69; 95% CI, 0.57-0.84) and intermediate-risk AML (HR, 0.76; 95% CI, 0.68-0.85) but not for good-risk AML (HR, 1.06; 95% CI, 0.80-1.42). The HR of death with allogeneic SCT for AML in CR1 was 0.90 (95% CI, 0.82-0.97). Significant overall survival benefit with allogeneic SCT was documented for poor-risk (HR, 0.73; 95% CI, 0.59-0.90) and intermediate-risk AML (HR, 0.83; 95% CI, 0.74-0.93) but not for good-risk AML (HR, 1.07; 95% CI, 0.83-1.38).

CONCLUSION: Compared with nonallogeneic SCT therapies, allogeneic SCT has significant RFS and overall survival benefit for intermediate- and poor-risk AML but not for good-risk AML in first complete remission.

PMID: 19509382 [PubMed - in process]

June 11, 2009 — The optimal treatment of acute myeloid leukemia (AML) for patients in their first complete remission remains unclear, especially patients with intermediate-risk AML. However, a new meta-analysis shows that allogeneic stem-cell transplantation (SCT) is associated with a significant overall and relapse-free survival benefit among adult patients in first complete remission with intermediate- and poor-risk but not good-risk AML.

The results of the study, published in the June 10 issue of the Journal of the American Medical Association, are consistent with current practice, which recommends myeloablative allogeneic SCT for poor-risk but not for good-risk AML, say the authors. But there has been no consensus or preferred therapy for intermediate-risk AML, which encompasses the largest portion of AML patients. Allogeneic SCT, consolidation chemotherapy, and autologous SCT have been considered to be of equivalent benefit.

But now we are able to say that, compared with other therapies, donor transplantation is better.

"This strengthens the fact that what has been done as the current standard of care for good/poor-risk patients is actually appropriate," said lead author John Koreth, MBBS, DPhil, from the Dana-Farber Cancer Institute in Boston, Massachusetts. "For good-risk patients, our data show that there is no benefit to donor transplantation up front, and for poor-risk patients, there actually is a benefit, which really wasn't very clear until now."

This changes the recommendations for the intermediate-risk group, explained Dr. Koreth in an interview. "Until now, the guidelines did not clearly define treatment for this group. But now we are able to say that, compared with other therapies, donor transplantation is better."

Potentially Practice Changing

Peter D. Emanuel, MD, director of the University of Arkansas for Medical Sciences Winthrop P. Rockefeller Cancer Institute in Little Rock, agrees that this analysis helps clarify the role of transplantation for the largest group of AML patients. "There has pretty much been agreement across leukemia experts that good-risk patients should not receive an allogeneic transplant, and that poor-risk patients should receive one," he told Medscape Oncology.

"But what hasn't been agreed at all upon is the optimal treatment for the intermediate-risk group," said Dr. Emanuel, who was not involved with the study. "Up until now, there haven't been any reports that gave any indication or hint about how those patients should be treated. It was basically left as an open question."

The current treatment consensus is reflected in the National Comprehensive Cancer Network guidelines, explained Dr. Emmanuel, which are based on the cytogenetic stratification of good-, intermediate-, and poor-risk AML. According to the guidelines, it is recommended that patients in complete remission with good-risk AML undergo consolidation chemotherapy, and that autologous SCT is an acceptable alternative. Allogeneic SCT is recommended for poor-risk patients, but there is no specific recommendation for intermediate-risk patients.

One paper or meta-analysis doesn't change clinical practice, but it certainly sends things down that path.

"There aren't any data saying that one therapy is better or worse than another for the intermediate-risk group," Dr. Emanuel pointed out. "This meta-analysis starts to say, in a credible fashion, that these patients should receive allogeneic transplantation. One paper or meta-analysis doesn't change clinical practice, but it certainly sends things down that path."

Dr. Emanuel added that these results are potentially practice changing because it gives clinicians some direction in selecting the most suitable therapy for their intermediate-risk patients.

Benefit Seen for Poor or Intermediate Risk, None for Good Risk

In outlining the aim of the current study, the researchers note that prospective clinical trials, retrospective studies, and systematic reviews have all helped to determine the current treatment consensus for AML patients in first complete remission. However, the results of these studies have not provided definitive evidence to support treatment recommendations.

To quantify relapse-free and overall survival benefit of allogeneic SCT for AML patients in complete remission from the totality of the clinical-trial data available, Dr. Koreth and colleagues conducted a systematic literature review and meta-analysis of all prospective biological assignment clinical trials of allogeneic SCT vs consolidation chemotherapy, autologous SCT, or both for AML in complete remission, on an intention-to- treat donor vs no-donor basis.

A total of 24 trials met the inclusion criteria, which included 6007 patients. Of this group, 5951 patients were included in relapse-free survival analyses, 5606 were included in overall survival analyses, and 3638 were analyzed by cytogenetic risk (547 good, 2499 intermediate, and 592 poor).

The researchers found that, compared with nonallogeneic SCT, the hazard ratio (HR) for relapse or death with allogeneic SCT was 0.80 (95% confidence interval , 0.74 - 0.86). When broken down by cytogenetic risk, a significant relapse-free survival benefit for allogeneic SCT was documented for both poor-risk (HR, 0.69; 95% CI, 0.57 - 0.84) and intermediate-risk (HR, 0.76; 95% CI, 0.68 - 0.85) AML. However, the same benefit was not seen for good-risk AML (HR, 1.06; 95% CI, 0.80 - 1.42).

The overall HR for death with allogeneic SCT in this population was 0.90 (95% CI, 0.82 - 0.97), but significant overall survival benefit with allogeneic SCT was observed only for poor-risk (HR, 0.73; 95%CI, 0.59 - 0.90) and intermediate-risk (HR, 0.83; 95% CI, 0.74 - 0.93) patients. Again, there was no significant benefit noted for good-risk AML (HR, 1.07; 95% CI, 0.83 - 1.38).

"This analysis combined the highest-quality clinical-trial data in a comprehensive way, and therefore would qualify this as one of the highest levels of clinical evidence that one can use to define treatment," said Dr. Koreth. "The emphasis here is that there is a clear benefit in overall survival, and it is clearly based on the patient's chromosomal analysis."

Down the road, there will be newer molecular characterization, he added. "We might be able to further stratify and individualize the risk. But in this analysis, we are setting the foundation for the routine tests that are immediately applicable today."

Dr. Koreth has disclosed no relevant financial relationships. Coauthor Hisashi Sakamaki, MD, PhD, from Tokyo Metropolitan Komagome Hospital in Japan, reports serving as a member of the advisory boards of Bristol-Myers Squibb and Wyeth. Coauthor Corey Cutler, MD, from the Dana Farber Cancer Institute in Boston, Massachusetts, reports receiving partial funding from the Stem Cell Cyclists of the Pan-Massachusetts Challenge.

JAMA. 2009;301:2349-2361. Abstract

prognose, Acute Myeloide Leukemie, AML