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Guideline Summary
Guideline Title
The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes.
Bibliographic Source(s)
American Society for Blood and Marrow Transplantation. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes. Biol Blood Marrow Transplant. 2009 Feb;15(2):135-6. [1 reference] PubMed External Web Site Policy

Oliansky DM, Antin JH, Bennett JM, Deeg HJ, Engelhardt C, Heptinstall KV, de Lima M, Gore SD, Potts RG, Silverman LR, Jones RB, McCarthy PL Jr, Hahn T. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant. 2009 Feb;15(2):137-72. [103 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Myelodysplastic syndromes

Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Clinical Specialty
Hematology
Internal Medicine
Oncology
Pathology
Intended Users
Health Plans
Managed Care Organizations
Patients
Physicians
Guideline Objective(s)

  • To assemble and critically evaluate all the valid, peer-reviewed evidence regarding the role of cytotoxic therapy with hematopoietic stem cell transplantation related to myelodysplastic syndromes
  • To provide treatment recommendations based on the available evidence
  • To identify discrepancies in study design or methodology among published studies that may impact on the quality of the evidence
  • To identify needed areas of additional research

Target Population

Patients >15 years of age with myelodysplastic syndromes (MDS) who are candidates for hematopoietic stem cell transplantation

Interventions and Practices Considered

  1. Timing of stem cell transplantation (SCT) based on International Prognostic Scoring System (IPSS) score
  2. Pre-SCT induction chemotherapy (considered but no recommendation given)
  3. Related, unrelated, or unspecified allogeneic SCT
  4. Autologous SCT
  5. Allogeneic bone marrow transplantation (BMT)
  6. Peripheral blood stem cell transplantation (PBSCT)
  7. Conditioning regimens (reduced intensity versus high-dose regimens) (no recommendation given)

Major Outcomes Considered

  • Disease-free, relapse-free, event-free, and overall survival
  • Treatment-related mortality

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

PubMed and Medline, the Web sites developed by the National Center of Biotechnology Information at the National Library of Medicine of the National Institutes of Health, were searched on January 17, 2007, using the search terms ''myelodysplastic syndrome'' OR ''MDS'' AND ''transplant'' limited to ''human trials,'' ''English language,'' and a publication date of 1990 or later. Updated searches were conducted on October 14, 2007, and April 15, 2008. Papers that were published before 1990, included fewer than 25 MDS patients, or were not peer-reviewed were excluded. Also excluded were editorials, letters to the editor, Phase I (dose escalation or dose finding) studies, reviews, consensus conference papers, practice guidelines, and laboratory studies with no clinical correlates. Abstracts and presentations at national or international meetings were not included as evidence in this review for reasons previously described. Many of the studies evaluated for inclusion in this review presented results for de novo MDS along with acute myeloid leukemia (AML) arising from MDS (sAML) or AML following treatment for other diseases (therapy-related AML) without stratifying the results by de novo MDS versus AML. To be included in this evidence-based review, studies had to have at least 60% of the patients with de novo MDS, or results that were stratified by disease category.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Levels of Evidence
1++ High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2++

High-quality systematic reviews of case control or cohort studies; high-quality case control or cohort studies with a very low risk of confounding, bias, or chance, and a high probability that the relationship is causal

2+ Well-conducted case control or cohort studies with a low risk of confounding, bias, or chance, and a moderate probability that the relationship is causal
2- Case control or cohort studies with a high risk of confounding, bias, or chance, and a significant risk that the relationship is not causal
3 Nonanalytic studies (e.g., case reports, case series)
4 Expert opinion

Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

The "Rating Scheme for the Strength of the Evidence" and the "Rating Scheme for the Strength of the Evidence" fields of this summary define criteria used to grade the studies that were included in this review, and criteria to grade the treatment recommendations, respectively. Study design, including sample size, patient selection criteria, duration of follow-up, and treatment plan also were considered in evaluating the studies. Clinical studies are described with sufficient detail to give a concise summary of study design, sample size, eligibility criteria, and treatment schema.

All data in the text and tables of the evidence-based review were abstracted from the original manuscripts by the first author, and double checked for accuracy and clarity by 2 other authors. Some articles contained inconsistencies within the data reported; the data most consistent with the text of the article were included in this review. The authors take responsibility if errors remain.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The American Society for Blood and Marrow Transplantation (ASBMT) in 1999 began an initiative to sponsor evidence-based reviews of the scientific and medical literature for the use of hematopoietic stem cell transplantation (SCT) in the therapy of selected diseases. The steering committee convened to oversee the projects invited an independent panel of disease experts to conduct each review.

Rating Scheme for the Strength of the Recommendations

Grades of Recommendation
A At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results
B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+
C A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++
D Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
External Peer Review
Description of Method of Guideline Validation

Not stated

Recommendations

Major Recommendations

The levels of evidence (1++ to 4) and the grades of recommendation (A-D) are defined at the end of the "Major Recommendations" field.

The following guidelines are offered for the role of stem cell transplantation (SCT) as therapy for myelodysplastic syndromes (MDS), and are based on consensus reached by an expert panel following an evidence-based review of the literature.

Timing of Transplantation

Early SCT is recommended for patients with an International Prognostic Scoring System (IPSS) score of intermediate (INT)-2 (considered high risk) at diagnosis who have a suitable donor and meet the transplant center’s eligibility criteria, and for selected patients at low risk (IPSS score of INT-1) at diagnosis who have poor prognostic features not included in the IPSS (e.g., older age, refractory cytopenias). (Grade of Recommendation C, Highest Level of Evidence 2+)

Pre-SCT Induction Chemotherapy

In the absence of randomized controlled trials, insufficient data are available to make a treatment recommendation for or against pre-SCT induction chemotherapy. The decision to use pre-SCT induction therapy should be made on an individual basis. (No Recommendation, Highest Level of Evidence 2++)

Donor Selection

  1. There is no evidence of a survival advantage based on donor relation in allogeneic SCT. In clinical practice, matched related donor allogeneic SCT is recommended if available. If not, unrelated donor allogeneic SCT may provide equivalent outcomes. (No Recommendation, Highest Level of Evidence 2+)
  2. There are sufficient data demonstrating a long-term curative outcome for related and unrelated allogeneic SCT. (Grade of Recommendation B, Highest Level of Evidence 2++)
  3. Based on data and expert opinion, a human leukocyte antigen (HLA)-matched allogeneic donor (sibling, other family member, unrelated individual, or cord blood) SCT is recommended if an appropriate donor is available. If an allogeneic donor is not available, and complete remission is achieved with induction therapy, then an autologous SCT can be considered in the context of a clinical trial. (Grade of Recommendation C, Highest Level of Evidence 2++)

Transplantation Techniques

  1. Bone marrow transplant (BMT) versus peripheral blood stem cell transplant (PBSCT):
    • For low-risk disease, allogeneic BMT and PBSCT from related donors have equivalent outcomes. (Grade of Recommendation B, Highest Level of Evidence 1+)
    • Patients with high-risk disease may have a survival advantage with related donor allogeneic PBSCT. (Grade of Recommendation B, Highest Level of Evidence 1+)
    • There is insufficient evidence to recommend BMT versus PBSCT for unrelated donor allogeneic SCT. (No Recommendation)
    • There is no evidence of a survival advantage based on stem cell source for autologous BMT versus PBSCT. (No Recommendation, Highest Level of Evidence 2+)
  2. Conditioning regimen comparisons:
    • There are insufficient data to make a recommendation for an optimal conditioning regimen intensity.  A range of dose intensities is currently under investigation, and the optimal approach likely will depend on disease and patient characteristics, such as age and comorbidities. (No Recommendation, Highest Level of Evidence 2++)
    • There are insufficient data to make a recommendation for any one high-dose conditioning regimen over another. (No Recommendation, Highest Level of Evidence 2+)

Definitions:

Levels of Evidence
1++ High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2++

High-quality systematic reviews of case control or cohort studies; high-quality case control or cohort studies with a very low risk of confounding, bias, or chance, and a high probability that the relationship is causal

2+ Well-conducted case control or cohort studies with a low risk of confounding, bias, or chance, and a moderate probability that the relationship is causal
2- Case control or cohort studies with a high risk of confounding, bias, or chance, and a significant risk that the relationship is not causal
3 Nonanalytic studies (e.g., case reports, case series)
4 Expert opinion

 

Grades of Recommendation
A At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results
B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+
C A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++
D Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate use of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of myelodysplastic syndromes

Potential Harms

  • Side effects of chemotherapy therapy
  • Treatment-related toxicity and mortality

Qualifying Statements

Qualifying Statements

  • The strengths of this systematic evidence-based review are the details conveyed in the text about each study’s design, the presentation of outcomes in summary tables for each major section, and the treatment recommendations made by the myelodysplastic syndrome (MDS) expert panel. A limitation is the exclusion of nonpeer-reviewed data. Unpublished data can represent "‘negative"’ findings, which could lead to publication bias; however, the inclusion of high-quality, peer-reviewed publicly available data was of paramount importance. Data published in abstract form were not included because of the inadequate details of study design or patient characteristics, making a true assessment of the widespread applicability or impact of the treatment outside the scope of the trial difficult.
  • A limitation of the studies included in this review is the lack of comparative trials of stem cell transplantation (SCT) versus non-SCT options. Because allogeneic SCT is the only curative option, patients with an available donor receive an allogeneic SCT, making randomized trials uncommon. However, the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) provides a framework for conducting multicenter BMT trials that can address some of the areas of needed research in MDS.
  • The quality of this systematic evidence-based review is affected by treatment modalities that vary over time. Chemotherapy regimens, human leukocyte antigen (HLA) typing techniques, pre-SCT treatment regimens, stem cell sources, and post-SCT supportive care have changed and progressed considerably over the 18 years of studies included in this review. The clinical research process is lengthy, making data from many of these studies outmoded by the time of publication.
  • Many studies included in this evidence-based review combined patients with de novo MDS, therapy-related MDS, and secondary acute myeloid leukemia (AML) (AML arising from MDS) in their study population. Because these three conditions have prognostic value on treatment outcomes, results should be stratified by disease and disease etiology (de novo versus secondary).

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Timeliness

Identifying Information and Availability

Bibliographic Source(s)
American Society for Blood and Marrow Transplantation. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes. Biol Blood Marrow Transplant. 2009 Feb;15(2):135-6. [1 reference] PubMed External Web Site Policy

Oliansky DM, Antin JH, Bennett JM, Deeg HJ, Engelhardt C, Heptinstall KV, de Lima M, Gore SD, Potts RG, Silverman LR, Jones RB, McCarthy PL Jr, Hahn T. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant. 2009 Feb;15(2):137-72. [103 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2009 Feb
Guideline Developer(s)
American Society for Blood and Marrow Transplantation - Professional Association
Source(s) of Funding

National Marrow Donor Program

Guideline Committee

Myelodysplastic Syndromes Expert Panel

Composition of Group That Authored the Guideline

Primary Authors: Denise M. Oliansky, Roswell Park Cancer Institute, Buffalo, New York; Joseph H. Antin, Dana Farber Cancer Institute, Boston, Massachusetts; John M. Bennett, University of Rochester, James P. Wilmot Cancer Center, Rochester, New York; H. Joachim Deeg, Fred Hutchinson Cancer Research Center, Seattle, Washington; Christin Engelhardt, Aplastic Anemia and MDS International Foundation, Inc., Churchton, Maryland; Kathleen V. Heptinstall, The Myelodysplastic Syndromes Foundation, Inc., Crosswicks, New Jersey; Marcos de Lima, M.D. Anderson Cancer Center, Houston, Texas; Steven D. Gore, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; Ronald G. Potts, INTERLINK Health Services, Hillsboro, Oregon; Lewis R. Silverman, Mt. Sinai School of Medicine, New York, New York; Roy B. Jones, M.D. Anderson Cancer Center, Houston, Texas; Philip L. McCarthy, Jr., Roswell Park Cancer Institute, Buffalo, New York; Theresa Hahn, Roswell Park Cancer Institute, Buffalo, New York

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: A list of American Society for Blood and Marrow Transplantation (ASBMT) documents, along with links to individual position statements and evidence-based reviews are available in Portable Document Format (PDF) from the ASBMT Web site External Web Site Policy.

Print copies: Available from Theresa Hahn, PhD, Roswell Park Cancer Institute, Medicine, Elm and Carlton Sts, Buffalo, NY 14263 (e-mail: theresa.hahn@roswellpark.org).

Availability of Companion Documents

None available

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on November 13, 2009. The information was verified by the developer on December 16, 2009.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

Requests regarding copyright should be addressed to Thomas Joseph, American Society for Blood and Marrow Transplantation, 85 W. Algonquin Road, Suite 550, Arlington Heights, IL 60005, Phone: (847) 427-0224, Email: thomasjoseph@asbmt.org.

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