| | The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Therapy of Myelodysplastic Syndromes: An Evidence-Based ReviewReceived 2 December 2008; accepted 2 December 2008.
Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of myelodysplastic syndromes (MDS) in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in Table 3, and were reached unanimously by a panel of MDS experts. The identified priority areas of needed future research in MDS include: (1) the benefit of using alternative donor sources (eg, cord blood; haploidentical family donors) for patients without matched sibling or unrelated donors; (2) the role and appropriate timing of allogeneic SCT in combination with hypomethylating and immunomodulatory treatment regimens; (3) randomized trials comparing the safety and efficacy of various novel agents for treating MDS; and (4) the influence of the various MDS treatment modalities on patient-reported quality-of-life outcomes. Introduction  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. Six previous reviews have been published in Biology of Blood and Marrow Transplantation on the use of SCT in the therapy of: diffuse large B cell non-Hodgkin lymphoma [1], multiple myeloma [2], pediatric acute lymphoblastic leukemia (ALL) [3], adult ALL [4], pediatric acute myeloid leukemia (AML) [5], and adult AML [6]. The goals of the current review are to assemble and critically evaluate evidence regarding the role of SCT in the therapy of myelodysplastic syndromes (MDS), make treatment recommendations based on the available evidence, and identify areas of needed research. Literature Search Methodology 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 [3]. Many of the studies evaluated for inclusion in this review presented results for de novo MDS along with 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. Qualitative and Quantitative Grading of the Evidence The hierarchy of evidence, including a grading system for the quality and strength of the evidence and strength of each treatment recommendation, was published as an editorial policy statement in Biology of Blood and Marrow Transplantation in 2005 [7]. Table 1, Table 2, reprinted from the policy statement, 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. | | |  | Levels of Evidence | |
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| 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 (eg case reports, case series) | | | 4 | Expert opinion | | | | |
| | | | Grades of Recommendation | |
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| 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+ | | | | |
All data in the text and tables were abstracted from the original manuscripts by the first author (D.O.), and double checked for accuracy and clarity by 2 other authors (T.H. and P.L.M.). 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 D.O., T.H., and P.L.M. take responsibility if errors remain. Treatment Recommendations The strength of this review is in the grading of the strength of the evidence and quality of the study designs as described in the text and outcome summary tables included in each major section. Table 3 contains the summary of treatment recommendations made by the MDS expert panel based on the summarized evidence. | | | | Indication for SCT | Treatment Recommenddation Grade∗ | HighestLevel of Evidence† | Reference No.↕ | Treatment Recommendation Comments | |
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| Timing of Transplantation | C | 2+ | 8, 10 | Early SCT is recommended for patients with an IPSS score of INT-2 or High risk at diagnosis, who have a suitable donor, and meet the transplant center's eligibility criteria, and for selected patients with a Low or INT-1 risk IPSS score at diagnosis who have poor prognostic features not included in the IPSS (ie, older age, refractory cytopenias, etc.). | | | Pre-SCT Induction Chemotherapy | No recommendation | 2++ | 11, 12 | In the absence of randomized controlled trials, there are insufficient data 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. | | | DONOR SELECTION | | | Related versus Unrelated Allogeneic SCT | No recommendation | 2+ | 15, 16, 17, 18, 19, 20 | There is no evidence of a survival advantage based on donor relation. In clinical practice, matched related donor allogeneic SCT is recommended if available. If a matched related donor is not available, an unrelated donor allogeneic SCT may provide equivalent outcomes. The published data do not reflect the selection of donors on the basis of molecular HLA typing. | | | Related, unrelated, either, or unspecified allogeneic SCT | B | 2++ | 21, 22, 27, 32, 33 | There are sufficient data demonstrating a long-term curative outcome for related and unrelated allogeneic SCT. | | | Autologous versus Allogeneic SCT | C | 2++ | [43] | Based on data and expert opinion, an 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 CR is achieved with induction therapy, an autologous SCT can be considered in the context of a clinical trial. | | | TRANSPLANTATION TECHNIQUES | | | BMT versus PBSCT | | | Allogeneic BMT versus PBSCT | B | 1+ | [47] | For low-risk disease, allogeneic PBSCT and BMT from related donors have equivalent outcomes. Based on one study [49], patients with high-risk disease may have a survival advantage with related donor allogeneic PBSCT. | | | No recommendation | There is insufficient evidence to recommend bone marrow versus peripheral blood for unrelated donor allogeneic SCT. | | | Autologous BMT versus PBSCT | No recommendation | 2+ | [50] | There is no evidence of a survival advantage based on stem cell source. | | | Conditioning Regimen Comparisons | | | Reduced Intensity Conditioning versus High Dose Regimen | No recommendation | 2++ | [51] | There are insufficient data to make a recommendation for an optimal conditioning regimen intensity. A range of dose intensities is currently being investigated, and the optimal approach will likely depend on disease and patient characteristics, such as age and comorbidities. | | | Comparison of ≥2 High-Dose Regimens | No recommendation | 2+ | 56, 57, 58 | There are insufficient data to make a recommendation. There is no evidence of a survival advantage with any one high dose conditioning regimen. | | | | |
| ∗ Definitions: Grade of Recommendation (Table 2): (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+. †Definitions: Levels of Evidence (Table 1): 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; or 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 (eg, case reports, case series); 4 Expert opinion. ↕The references listed represent the highest level of evidence used to make the treatment recommendation and are not inclusive of all evidence described in the review. |
Format of the Review Evidence is taken from self-described studies which included MDS patients ≥15 years of age. In each section of this review, the highest quality studies are presented first; studies of equal quality are presented in descending order by cohort size. The design of each study is described in the text and, unless otherwise noted, an accompanying table in each section presents the outcomes for each study. Timing of Transplantation This section describes two studies examining the impact of timing of transplantation and three studies examining the effect of pretransplantation induction chemotherapy on patient outcomes in the treatment of MDS. Table 4 presents a summary of the patient outcomes from these studies. | | | | Reference No. | Quality and Strength of Evidence∗ | Patient Population† | Protocols | Diagnosis or Subtype (at Dx Unless Otherwise Stated) | Median Follow-up | Study Groups (n) | (Interval) % TRM | (Interval) % DFS/RFS/EFS (Significance) | (Interval) % OS (Significance) | |
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| TIMING OF TRANSPLANTATION | | | [8] | 2+ | | | | | | Not stated | Not stated | Not stated | | | | | IMRAW—No SCT n = 184 Age range: 18-60 Median age 49.8 years | IMRAW (n = 184) Not stated | IMRAW RA 51.6% RARS 16.9% RAEB 25.0% RAEBt 6.5% | | | | | See Figure 1 | | | | | | | | 1990-1999 IBMTR—SCT Multicenter n = 193 Age range: 18-59 Median age 39.4 years | IBMTR and FHCRC (n = 260) Unspecified ablative conditioning regimens | IBMTR RA 30.57% RARS 2.07% RAEB 28.5% RAEBt 34.72% Unknown 4.15% | IBMTR and FHCRC 11.4 months | | | | | | | | | | | | 1990-1999 FHCRC—SCT Single center n = 67 Age range: 20-60 Median age 45.6 years | | FHCRC RA 38.81% RARS 4.48% RAEB 37.31% RAEBt 17.91% Unknown 1.49% | | | | | | | | | | | [10] | 2+ | 1983-1994 EBMT Multicenter (44) n = 131 | No IC chemo Conditioning varied by center; most TBI-containing or chemo alone | RA/RARS 35% RAEB 27% RAEBt 21% CMML 3% sAML 14% | 27 months | | (5-year %TRM) | (5-year %DFS) | (5-year %OS) | | | | | | | | Age range: 2-55 Median age 33 years 92% >16 years 86% MDS | HLA-identical sibling allo-SCT | | | Disease duration ≤3 months (36) 4-12 months (53) >12 months (39) | 29% ± 10% 48% ± 7% 51% ± 9% (P = .05) | 38% ± 10% 25% ± 7% 42% ± 9% (P = .03) | 54% ± 9% 27% ± 7% 43% ± 9% (P = .03) | | | Pretransplantation Induction Chemotherapy | | | [11] | 2++ | 1990-1997 MDACC Chemo-only Single center n = 215 CR1 n = 135 | | | | | Not stated | (4-year %DFS) | (4-year %OS) | | | | | | | | Age range: 15-60 Median age not stated | MDACC HD Ara-C Alone + Flu + IDR + Flu + IDR + Topotecan + DNR | MDACC RAEB 17.7% RAEBt 43.4% sAML 39% | | | | 17.3% ± 3.7% | 25.5% ± 4.6% | | | | | | | | 1992-1997 EORTC Chemo + SCT Multicenter (35) n=184 CR1 n=100 67% MDS | EORTC Induction: SD Ara-C + IDR + VP-16 Consolidation: Ara-C + MITO Transplant Regimen: Cy + f-TBI Or Bu + Cy | EORTC RA 3.8% RARS .5% RAEB 29.4% RAEBt 32.6% (CMML 8.7%, not included in analysis) sAML 25% | | EORTC IC Chemo + SCT (Auto or Allo) (100) | | 28.9 ± 4.85% | 34.4% ± 5.1% | | | | | | | | | (ITT analysis) | | (P=.017) | (P=.16) | | | | | | [12] | 2++ | 1991-2001 JSHCT Multicenter n = 283 | IC Chemo not specified | IC Group RA 15.5% RAEB 15.5% RAEBt 29% CMML 10% sAML 30% | 36.5 months | | (Not stated, %TRM) | Not stated | (5-year %OS) | | | | | | | | Age range: 16-65 Median age 41 years | TBI-based or chemo-based conditioning regimens | | | RA + RAEB Total n = 119 IC Group— CR IC Group— NR No IC Group | | | | | | | | 76% MDS | HLA-identical sibling allo-SCT | No IC Group RA 34% RAEB 30.5% RAEBt 16% CMML 6% sAML 13.5% | | RAEBt + sAML Total n=139 IC Group - CR IC Group - NR No IC Group | | | | | | | | | | | | 54% 20% 57% (P signif, but not stated) | | | | | | [13] | 2+ | 1992-2002 Single center n = 125 | IC: ARA-C + anthracycline | IC Group RAEB 9% RAEBt 18% tAML 73% | Not stated | | (3-year %TRM) | (3-year %RFS) | Not stated | | | | | | | | IC Group Age range: 2-64 Median age 45 years | Conditioning Regimen: Bu+TBI or t-Bu+Cy | No IC Group RAEB 67% RAEBt 24% tAML 9% | | IC Group (33) | 34% | 13% | | | | | | | | | No IC Group Age range: 3-66 Median age 50 years | HLA-matched related or unrelated donor allo-SCT | | | No IC Group (92) | 44% | 26% | | | | | | 74% MDS | | | | | (P not signif) | (P = .26) | | | | | | | [14] | 2+ | 1980-1988 Multicenter (21) n = 78 | Conditioning Regimen: TBI+chemo or Bu+Cy | IC Group RAEB 12% RAEBt 29% CMML 3% sAML 56% | 27 months | | (Not stated, %TRM) | (2-year %DFS) | Not stated | | | | | Age range: 2-52 Median age 32 years | HLA-matched sibling, syngeneic, or mismatched sibling allo-SCT | No IC Group RA/RARS 20% RAEB 27% RAEBt 23% sAML 30% | | IC Group In CR (sAML or RAEBt) (16) | Not stated | 60% ± 13% | | | | | | 70% MDS | | | | Partial (10) | 60% | Not stated | | | | | | | | | | Resistant (8) | 100% | | | | | | | | | | | No IC Group RA/RAS (9) RAEB (12) RAEBt (10) sAML (13) | | 58%±19% 74%±14% 50%±15% 18%±11% | | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †Allo indicates allogeneic; Chemo, chemotherapy; BMT, bone marrow transplantation; SCT, stem cell transplantation; IC, induction chemotherapy; CR, complete remission; DX, diagnosis; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RAEB, refractory anemia with excess blasts; RAEBt, refractory anemia with excess blasts in transformation; CMML, chronic myelomonocytic leukemia; sAML, secondary acute myeloid leukemia; tAML, therapy-related AML; IMRAW, International MDS Risk Analysis Workshop; EORTC, European Organization of Research and Treatment of Cancer; MDACC, M.D. Anderson Cancer Center; EBMT, European Group for Blood and Marrow Transplantation; FHCRC, Fred Hutchison Cancer Research Center; JSHCT, Japan Society for Hematopoietic Cell Transplantation; TRM, treatment-related mortality; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; P, probability; OS, overall survival; CI, 95% confidence interval; HD, high dose; SD, standard dose; t-Bu, targeted busulfan; Ara-C, Cytarabine; Cy, cyclophosphamide; Bu, Busulfan; TBI, total-body irradiation; f-TBI, fractionated TBI; IDR, Idarubicin; VP-16, etopocide; MITO, Mitoxantrone; DNR, Daunorubicin. |
Cutler et al. [8] presented the results of a study using a Markov decision model to determine the optimal timing of human leukocyte antigen- (HLA) identical sibling donor allogeneic transplantation to treat MDS, dependent upon the patients' International Prognostic Scoring System (IPSS) scores [9]. Included were three cohorts of adults (18-60 years) with MDS whose data were derived from prospectively collected databases. A nontransplantation cohort (n = 184) from the International MDS Risk Analysis Workshop (IMRAW) was compared with a transplantation cohort (n = 260) that combined patients from the International Bone Marrow Transplant Registry (IBMTR) and from the Fred Hutchinson Cancer Research Center (FHCRC). The transplantation cohort (IBMTR + FHCRC) was younger and more likely to have more advanced MDS than the nontransplantation (IMRAW) cohort. The treatment regimen(s) for the nontransplantation cohort (IMRAW) was supportive care only. The transplantation cohort received HLA-identical sibling donor allogeneic SCT following unspecified ablative conditioning regimens. Median follow-up was 35.4 months and 11.4 months for the nontransplantation and transplantation cohorts, respectively. Median survival times were significantly influenced by IPSS score at the time of diagnosis. Figure 1 illustrates the impact of timing of SCT on life expectancy by IPSS risk group. For low- and intermediate-1-risk MDS, maximal life expectancy was associated with delayed allogeneic SCT. For Intermediate-2- and high-risk MDS, immediate allogeneic SCT was associated with maximal life expectancy. Runde et al. [10] examined the impact of early HLA-identical sibling donor allogeneic bone marrow transplantation (BMT) in 131 adult (92% ≥16 years) patients with MDS (86%) or sAML reported to the Chronic Leukemia Working Party (CLWP) of the European Group for Blood and Marrow Transplantation (EBMT). Median disease duration was 7 months, and 14 patients had progressed from de novo MDS to AML by the time of BMT. No patients received induction chemotherapy prior to BMT. Conditioning regimens varied by center, but most patients (70%) received a total-body irradiation (TBI)-containing regimen. Twelve percent of patients received T cell-depleted bone marrow. In multivariate analysis, French-American-British (FAB) classification and disease duration significantly influenced overall survival (OS) and disease-free survival (DFS). Pretransplantation Induction Chemotherapy Oosterveld et al. [11] reported the results of a retrospective cohort study of 399 adults (15-60 years) with MDS (67%) or sAML treated either at the M.D. Anderson Cancer Center (MDACC, n = 215) or enrolled in the multicenter European Organization for Research and Treatment of Cancer (EORTC) 06921 trial (n = 184), comparing the effectiveness of chemotherapy only versus induction chemotherapy + SCT. The MDACC cohort (MDS n = 131 [61%], sAML n = 84) was older, more likely to have poor performance status, and included more sAML patients, whereas the EORTC cohort (MDS n = 138 [75%], sAML n = 46) had a higher proportion of MDS patients. Patients at MDACC received chemotherapy only, consisting of various high-dose cytarabine-containing regimens for remission induction followed by reduced doses for 6 to 12 months. Of 215 patients, 135 achieved complete remission (CR). The EORTC patients (Chemo + SCT cohort) received standard dose cytarabine + idarubicin + etoposide for remission induction (100 patients achieved CR), followed by one consolidation course of cytarabine + mitoxantrone, then an allogeneic SCT (n = 28, of 39 patients who achieved CR and had a sibling donor) or autologous SCT (n = 36, of 61 patients in CR without a sibling donor) after conditioning with cyclophosphamide + fractionated TBI or busulfan + cyclophosphamide. One patient received an HLA-matched unrelated donor allogeneic SCT. Reasons for not receiving a transplant in CR included early relapse (n = 26), toxicity or treatment refusal (n = 7), or death (n = 2). In multivariate analysis, cytogenetics, white blood cell (WBC) count at diagnosis, age, platelet count, and hemoglobin significantly influenced OS, whereas treatment protocol (EORTC versus MDACC), cytogenetics, and hemoglobin significantly influenced DFS. Nakai et al. [12] compared the outcomes of 283 adult (16-65 years) patients with MDS (76%) or sAML who received (n = 188) or did not receive (n = 95) induction chemotherapy prior to HLA-identical sibling donor allogeneic SCT and were registered with the Japan Society for Hematopoietic Cell Transplantation (JSHCT). There were significantly more patients with advanced disease and poor karyotype in the group that received induction chemotherapy (chemo group) than in the no chemo group. Of those patients in the chemo group, 81 (43%) underwent allogeneic SCT in CR. The conditioning regimen for allogeneic SCT consisted of a TBI-based (n = 173) or chemotherapy-based regimen (n = 110). Stem cell sources were bone marrow (n = 218) or peripheral blood (n = 65). Median time from diagnosis to SCT was 8 months. Survival outcomes were stratified by FAB because of the significantly higher proportion of RAEB-t and AML patients in the chemo group. In multivariate analysis, FAB, presence or absence of induction chemotherapy, and karyotype significantly influenced OS. Scott et al. [13] presented the results of 125 adult (median age, 47 years) patients with advanced MDS (74%) or therapy-related AML who underwent an HLA-identical related or unrelated donor allogeneic SCT, comparing the outcomes of patients who received induction chemotherapy 1 to 6 months (median, 2 months) before SCT (n = 33) with those who did not receive induction chemotherapy (n = 92). Median disease duration was 6 months for both groups. Most patients in the induction chemotherapy group received cytarabine-based therapy (82%). Allogeneic SCT conditioning regimens included busulfan + cyclophosphamide (n = 76) or busulfan + TBI (n = 49). Stem cell sources were bone marrow (n = 80) or peripheral blood (n = 45) from HLA-matched related (n = 65) or unrelated donors (n = 60). Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. De Witte et al. [14] reported the outcomes of 78 adult (median age, 32 years) patients with MDS (70%) or sAML who underwent an HLA-matched (n = 74), syngeneic (n = 3), or mismatched (n = 1) related allogeneic SCT, comparing the outcomes of patients who received induction chemotherapy and were in CR (n = 16), those who received induction chemotherapy but were not in CR (n = 18), and those who did not receive induction chemotherapy prior to allogeneic SCT (n = 44). Conditioning regimens varied by center, but the majority (89%) received TBI + chemotherapy (unspecified). Median time from diagnosis to allogeneic SCT was 7 months. Thirteen patients with sAML without preceding MDS were transplanted at a median of 4 months after diagnosis. Outcomes were presented according to IPSS and disease status at SCT. Donor Selection This section presents studies that compare patient outcomes using allogeneic and autologous SCT in the treatment of MDS. Table 5 presents a summary of the patient outcomes from these studies. | | | | Reference No. | Quality and Strength of Evidence∗ | Patient Population† | Protocols | Diagnosis or Subtype (at Dx Unless Otherwise Stated) | Median Follow-up | Study Groups (n) | (Interval) % TRM | (Interval) % DFS/RFS/EFS (Significance) | (Interval) % OS (Significance) | |
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| ALLOGENEIC SCT | | | Related versus Unrelated Allogeneic SCT | | | [15] | 2+ | 1993-2000 Single center n = 109 | Bu + Cy | RA/RARS 63% RAEB 22% RAEBt 9% CMML 6% | Not stated | | (3-year %TRM) | (3-year %RFS) | Not stated | | | | | | | | | Related (45) | 28% | 56% | | | | | | Age range: 6-66 Median age, 46 years | | | | Unrelated (64) | 30% | 59% | | | | | | | | | | | | (P Not Signif) | | | | | | | [16] | 2+ | Study dates not stated Single center n = 62 | Induction Chemo:Flu +Ara-C+IDR- containing regimens | RA/RARS 26% RAEB-I 15% RAEB-II 16% CMML 6% AML 37% | 473 days | | (1-year %TRM) | (1-year %DFS) | (1-year %OS) | | | Age range: 22-70 Median age, 53 years | | | | Related (24) | 5% | 61% | 73% | | | 63% MDS | | | | Unrelated (38) | 21% | 59% | 71% | | | | | | | | | (P Not Signif) | (P Not Signif) | | | | | | [17] | 2+ | 1994-1999 Single center n = 60 | | RAEB 35% RAEBt 27% CMML 13% sAML 25% | 54 months | | (3-year %TRM) | (3-year %RFS) | (3-year %OS) | | | | | | Related (20) | 35% | 30% | 26% for all patients | | | Age range: 12-62 Median age, 40 years | | | | Unrelated (40) | 55% | 25% | | | | 75% MDS | | | | | | (P Not Signif) | | | | | | | [18] | 2+ | 1995-2002 Single center n = 51 | | (At SCT) RA 23.5% RAEB 25.5% RAEBt 18% sAML 33% | 3.7 years | | (3-year %TRM) | Not stated | (3-year %OS) | | | | | | | Related (21) | 31% | | 48% | | | Age range: 19-70 Median age, 44 years 66% MDS | | | | Unrelated (30) | 51% | | 30% | | | | | | | | | | (P = .19) | | | | | | [19] | 2+ | 2000-2004 Single center n = 43 | | RA 19% RARS 2% RAEB 30% RAEBt 14% sAML 35% | 38 months | | (2-year %TRM) | (2-year %DFS) 51.2% (CI 43.3%-58.5%) (all patients) | (2-year %OS) | | | | | | Related (19) | 31.6% | | 47.4% | | | Age range: 30-71 Median age, 58 years 65% MDS | | | | Unrelated (24) | 37.5% | | 58.3% | | | | | | | | | | (P = .64) | | | [20] | 2+ | Study dates not stated Multicenter (8) n = 37 | | RA 21% RAEB 16% RAEBt 35% CMML 8% sAML 20% | 20 months | | (3-year %TRM) | (3-year % DFS) | (3-year %OS) | | | | | | Related (19) | 12% | 31% (CI 9%-53%) | 45% (CI 19%-71%) | | | Age range: 23-72 Median age, 55 years 81% MDS | | | | Unrelated (18) | 45% | 25% (CI 4%-47%) | 51% (CI 29%-73%) | | | | | | | | (P = .03) | (P not signif) | (P not signif) | | | Related Allogeneic SCT | | | [21] | 2++ | 1978-2001 EBMT Multicenter n = 1482 | TBI- or non-TBI-containing regimens | Twins RA/RARS 33% RAEB/CMML 20% RAEBt/sAML 47% Unclassified | Not stated | | (5-year %TRM) | (5-year %DFS) | (7-year %OS) | | | Twins Age range: 6-71 Mean age, 43.5 years | Syngeneic or HLA-identical sibling allo-SCT | | Twins (38) | 27% (CI 13%-55%) | 34% (CI 14%-54%) | 36% (CI 15%-57%) | | | HLA-Identical Sibs Age range: 1-69 Mean age, 37.3 years | | Sibs RA/RARS 13% RAEB/CMML 25.5% RAEBt/sAML 61.5% | | Siblings (1444) | 38% (CI 36%-41%) | 28% (CI 25%-31%) | 32% (CI 29%-35%) | | | | | | | (P = .05) | (P = .20) | (P = .09) | | | | | | [22] | 2++ | 1998-2005 Multicenter (6) n = 93 MDS only n = 34 | | MDS subtypes not stated | 43 monthss | | (4-year %TRM) | (4-year %DFS) | (4-year %OS) | | | | HLA-identical sibling allo- PBSCT (BMT in 1 patient) | | | | Overall | MDS only | MDS only | | | All patients: Age range: 21-70 Median age, 53 years | | | | | 20% (CI 14%-32%) | 49% (CI 31%-67%) | 49% (CI 31%-76%) | | | | | | [23] | 2+ | 1989-1997 IBMTR Multicenter (143) n = 452 | Bu + Cy Bu + Cy + TBI Bu + Cy + other Cy + TBI Cy + TBI + other TBI + other (not Cy) Various | RA 27% RARS 4% RAEB 30% RAEBt 30% CMML 9% | 49 months | | (3-year %TRM) | (3-year %DFS) | (3-year %OS) | | | Age range: 2-64 Median age 38 years 86% >18 years | HLA-identical sibling allo-SCT | | | | 37% (CI 32%-42%) | 40% (CI 36%-45%) | 42% (CI 37%-47%) | | | [24] | 2+ | 1982-1991 FBMTR Multicenter (24) n = 71 | TBI + Cy Bu + Cy Various other ± TBI | | 6 years | | (7-year %TRM) | (7-year %EFS) | (7-year %OS) | | | Age range: 5-55 Median age, 37 years 93% >15 years | HLA-identical sibling allo-SCT | | | | 39% ± 7% | 39% ± 7% | 32% ± 6% | | | | | | [25] | 2+ | 1979-2002 Single center n = 52 | Bu + Cy Cy + TBI Bu + Flu Cy | RA 25% RAEB 32% RAEBt 8% CMML 2% | 4.6 years | | (3-year %TRM) | Not stated | (3-year %OS) | | | Age range: 60-68 Median age, 62.8 years 67% MDS | HLA-matched sibling allo-SCT | | | | 43% Overall | | MDS 36% Overall 34% | | | | | | [26] | 2+ | | Bu + Cy | Hyploplastic MDS 13% RAEB or RAEBt 47% MDS w/ marrow fibrosis 19% sMDS or AML 21% | Not stated | | (2-year %TRM) | (2-year %DFS) | (2-years %OS) | | | Age range: 5-55 Median age, 35 years 50% > 35 years 79% MDS | HLA-identical sibling allo-BMT | | | | 50% | 38% (CI 24%-55%) | 45% (CI 30%-61%) | | | | | | Unrelated Allogeneic SCT | | | [27] | 2++ | 1999-2004 Single center n = 75 | RIC Flu + Bu + Alemtuzumab | RCMD 39% RAEB I/II 20% CMML 9% sAML 32% | 1038.5 days | | (3-year %TRM) | (3-year %DFS) | (3-year %OS) | | | Age range: 24-68 Median age, 52 years 68% MDS | HLA-matched or mismatched unrelated allo-SCT | | | | 30% (CI 24%-36%) | 41% (CI 35%-47%) | 43% (CI 37%-49%) | | | | | | [28] | 2+ | 1988-1998 NMDP Multicenter (87) n = 510 | f-TBI + Cy ± other Bu + Cy ± other TBI + Bu + Cy Other | RA 37% RARS 2% RAEB 32% RAEBt 21% CMML 4% Myelofibrotic-MDS 2% Unknown 2% | 24 months | | (2-year %TRM) | (4-year %DFS) | (4-year %OS) | | | Age range: 1-62 Median age, 38 years 72% >20 years | HLA-matched or mismatched unrelated allo- SCT | | | | 54% (CI 53%-61%) | 26% (CI 22%-30%) | 26% (CI 22%-30%) | | | [29] | 2+ | 1986-1996 EBMT Multicenter (49) n = 118 | Chemo (not specified) + TBI Chemo + serotherapy | RA/RARS 20% RAEB 22% RAEBt 29% CMML 10% sAML 19% | Not stated | | (2-year %TRM) | (2-year %DFS) | (2-year %OS) | | | Age range: <1–53 Median age, 24 years 61% >18 years 81% MDS | HLA-matched or mismatched unrelated allo- SCT | | | | 58% | 28% | 28% | | | | | | [30] | 2+ | | Bu + CyBu + Cy + TBI | (at BMT) RA 39% RAEB/CMML 19% RAEBt 17% sAML 25% | Not stated | | (2-year %TRM) | (2-year %DFS) | (2-year %OS) | | | Age range: 1-53 Median age, 32.6 years 72% >20 years | HLA-matched or mismatched unrelated allo- SCT | | | | 48% | 38% | 40% | | | 75% MDS | | | | | | | | | | [31] | 2+ | 1987-1990 NMDP Multicenter (28) Total n = 462 MDS only n = 32 (7%) | Not stated | MDS 7% | Not stated | | Not stated | (2-year %DFS) | (2-year %OS) | | | | HLA-matched or mismatched unrelated allo- SCT | | | | | MDS only | MDS only | | | MDS age range: 1.4-45.5 MDS Median age, 24.3 years | | | | | | 18% ± 14% | 29% ± 15% | | | Related or Unrelated (or Unspecified Donor Relation) Allogeneic SCT | | | [32] | 2++ | 1980-1998 FBMTR Multicenter n = 70 | Bu + Cy Cy + TBI Cy + Mel Other ± TBI Other, no TBI | | 7.9 years | | (2-year %TRM) | (2-year %EFS) | (2-year %OS) | | | Age range: 16-55 Median age, 37 years | | | | | | | | | 44% MDS | HLA-matched or mismatched related or unrelated allo-SCT | | | | | | | | | [33] | 2++ | 1998-2004 Single center n = 43 | Bu + Cy Bu + Cy + TBI Bu + f-TBI Bu + TBI + amifostine Flu +Bu Cy + TBI Bu + Cy + ATG Cy + ATG + TBI Flu + TBI TBI + iodine + antibody | | 2096 days | | (Not stated, %TRM) | (4-year %RFS) | (4-year %OS) | | | Age range: 1-66 Median age, 48 years | HLA-matched or mismatched related or unrelated allo- SCT | | | | 34% | 41% | 41% | | | | | | [35] | 2+ | 1981-1990 Single center n = 93 | | RA 43% RAEB 33% RAEBt 15% CMML 2% Other 7% | 6.1 years | | (5-year %TRM) | (5-year %DFS) | Not stated | | | Age range: 1-60 Median age, 30 years 75% >20 years | HLA-matched related or unrelated allo- SCT | | | | 40% | 41% | | | | | | | [37] | 2+ | 1986-1996 Single center n = 60 | Bu + Cy Cy + f-TBI Bu + Cy + other Cy + TBI + other | RA/RARS 23% RAEB 18% RAEBt 39% sAML 20% | 70 months | | | (7-year %EFS) | Not stated | | | Age range: 15-55 Median age, 40 years | | | | 50% (CI 37%-64%) | 29% (CI 16-43%) | | | | 80% MDS | HLA-matched or mismatched related or unrelated allo- SCT | | | | | | | | | [38] | 2+ | 1981-1988 Single center n = 59 | | RA 29% RAEB 41% RAEBt 10% AA 10% Myelofibrosis 7% Unclassified 3% | Not stated | | (3-year %TRM)43% | (3-year %DFS) | Not stated | | | Age range: 4-54 Median age, 29 years 80% >20 years | | | | | 45% (CI 32%-59%) | | | | 83% MDS | HLA-matched or mismatched related or unrelated allo- SCT | | | | | | | | | [39] | 2+ | 1989-1998 Single center n = 50 | Cy + f-TBI Cy + f-TBI w/ lung shield Bu + f-TBI Bu + Cy t-Bu + Cy | RA 26% RAEB 38% RAEBt/sAML 32% CMML 4% | 2.2 years | | (2-year %TRM) | (2-year %RFS) | (2-year %OS) | | | Age range: 55-66 Median age, 58.8 years | | | | 39% | 42% | 46% | | | 68% MDS | HLA-matched or mismatched related or unrelated allo- SCT | | | | | | | | | [40] | 2+ | 1988-2000 EBMT Multicenter (43) n = 50 | TBI-containing regimen Chemo (unspecified) | CMML 100% | 40 months | | (1-year %TRM) | (5-year %DFS) | (5-year %OS) | | | Age range: 19-61 Median age, 44 years | HLA-matched related or HLA-matched or mismatched unrelated allo- SCT | | | | 55% (CI 36%-68%) | 18% (CI 13%-23%) | 21% (CI 15%-27%) | | | [41] | 2+ | | Flu + Bu | RA 14% RAEB 26% RAEBt 9.5% CMML 12% Treated sAML 24% Untreated sAML 5% CML 9.5% | 18 months | | (Not stated, %TRM) | (Not stated, %DFS) | (Not stated, %OS) | | | Age range: 12-65 Median age, 52 years | HLA-matched or mismatched related or unrelated allo- SCT | | | | 24% | 34.9% | 42.4% | | | 62% MDS | | | | | | | | | | [42] | 2+ | 1986-1994 Single center n = 35 | Cy + TBI ± IDAOther | RA 37% RAEB 20% RAEBt 31% CMML 3% sAML 9% | 20 months | | (Not stated, %TRM) | (2-year %DFS) | Not stated | | | Age range: 23-60 Median age, 41 years | HLA-matched related or unrelated allo- BMT | | | | 40% | 39% (CI 22%-56%) | | | | 91% MDS | | | | | | | | | | Autologous versus Allogeneic SCT | | | [43] | 2++ | 1992-1997 EORTC Multicenter (35) n = 184 Eligible for analysis n = 159 HLA-Typed n = 128 Included in analysis n = 117 | Induction: SD Ara-C + IDR + VP-16 | No Donor (Auto) RA/RARS 6.2% RAEB 29.2% RAEBt 40.0% CMML 6.2% sAML 18.5% | 3.6 years | | Not stated | (4-year %EFS) | (4-year %OS) | | | Consolidation: Ara-C + MITO | | No Donor (Auto) (65) | | 21.5% ± 5.3% | 39.0% ± 6.5% | | | Age range 16-60 Median age, 47 years | Conditioning for SCT: Cy + f-TBI or Bu + Cy | Donor (Allo) RA/RARS 3.8% RAEB 30.8% RAEBt 30.8% CMML 7.7% sAML 26.95% | | Donor (Allo) (52) | | 23.1% ± 6.2% | 33.3% ± 6.7% | | | 75% (of 184) MDS | | | | | (P=.66) | (P = .18) | | | | | | [45] | 2+ | 1983-1998 EBMT Multicenter (193) n = 1347 | Not Stated | Not Stated | Not Stated | | (3-year %TRM) | (3-year %DFS) | (3-year %OS) | | | | | | | | 29% | 30% | 32% | | | | | | | Allo: MRD-Sib (885) Mismatched family donor (91) MUD (198) | 43% | 36% | 41% | | | Mismatched Family Donor 60% >20 years | | | | | 25% | 26% | | | | | | | | (P not stated) | (P not stated) | (P not stated) | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †Allo indicates allogeneic; Auto, autologous; chemo, chemotherapy; BMT, bone marrow transplantation; SCT, stem cell transplantation; PBSCT, peripheral blood SCT; DX, Diagnosis; MDS, myelodysplastic syndromes; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RAEB, refractory anemia with excess blasts; RAEBt, refractory anemia with excess blasts in transformation; CMML, chronic myelomonocytic leukemia; sMDS, secondary MDS; tMDS, treatment-related MDS; sAML, secondary acute myeloid leukemia; tAML, treatment-related AML; EBMT, European Group for Blood and Marrow Transplantation; EORTC, European Organization of Research and Treatment of Cancer; IBMTR, International Bone Marrow Transplant Registry; FBMTR, French Bone Marrow Transplantation Registry; NMDP, National Marrow Donor Program; HLA, human leukocyte antigen; TRM, treatment-related mortality; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; signif, significance (Probability); OS, overall survival; CI, 95% confidence interval; P, probability; RIC, reduced-intensity conditioning; SD, standard dose; Ara-C, Cytarabine; Flu, Fludarabine; IDR, Idarubicin; MITO, Mitoxantrone; ATG, antithymocyte globulin; Cy, Cyclophosphamide; Bu, Busulfan; t-Bu, targeted Bu; Mel, Melphalan; VP-16, etoposide; TBI, total-body irradiation; f-TBI, fractionated TBI; MRD, matched related donor; MUD, mtched unrelated donor; ‡Proliferative CMML = WBC count >13 × 109/L; Nonproliferative CMML = WBC count ≤13 × 109/L. |
Allogeneic SCT Related Versus Unrelated Deeg et al. [15] reported the outcomes of 109 adult (median age, 46 years) patients with MDS who received HLA-matched or partially mismatched related (n = 45) or unrelated (n = 64) allogeneic SCT after conditioning with busulfan + cyclophosphamide. Etiology of MDS included de novo (n = 78), therapy-related (n = 14), or antecedent hematological disorder (n = 17). The median interval from diagnosis to SCT was 10 months. Stem cell sources were bone marrow (n = 81) or peripheral blood (n = 28). In multivariate analysis, no patient or treatment variables were significantly associated with relapse-free survival (RFS). Figure 2 presents DFS by donor relation. Ho et al. [16] reported the results of 62 adult (22-70 years) patients with MDS (63%) or AML with multilineage dysplasia who received a reduced intensity conditioning regimen of fludarabine + busulfan + alemtuzumab prior to allogeneic SCT from an HLA-matched sibling (n = 24) or unrelated donor (n = 38). Forty-six patients received at least one course of induction chemotherapy. Stem cell sources were bone marrow (n = 21) or peripheral blood (n = 41). Median time from diagnosis to SCT was 15 months. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Jurado et al. [17] presented the results of 60 adult (12-62 years) patients with advanced MDS (75%) or sAML who received reduced intensity conditioning with busulfan + fractionated TBI prior to allogeneic SCT from HLA-matched or partially mismatched related (n = 20) or unrelated (n = 40) donors. Stem cell sources were bone marrow (n = 58) or peripheral blood (n = 2). The median interval from diagnosis to allogeneic SCT for all patients was 12 months; 6.6 months for related, and 14.7 months for unrelated allogeneic SCT. In multivariate analysis, cytogenetic risk and disease duration influenced RFS. Hallemeier et al. [18] reported the results of a study of 51 adult (>18 years) patients with MDS (66%) or sAML who received reduced intensity conditioning with cyclophosphamide + 550 cGy TBI prior to HLA-identical sibling (n = 21) or HLA-matched or partially mismatched unrelated (n = 30) allogeneic SCT. Stem cell sources were peripheral blood for related SCT and bone marrow for unrelated allogeneic SCT. Of the 17 patients with sAML, 15 received induction chemotherapy and two did not. Median time from diagnosis to SCT was 7 months. In multivariate analysis, survival outcome was influenced by FAB at SCT, sex, transplant type (related versus unrelated), and time from diagnosis to SCT. Nakamura et al. [19] reported the outcomes of 43 adult (30-71 years) patients with MDS (65%) or sAML who underwent an allogeneic SCT from an HLA-identical sibling (n = 19) or HLA-matched unrelated (n = 24) donor, following reduced intensity conditioning with fludarabine + melphalan. Four of 28 MDS patients and 13 of 15 sAML patients received induction chemotherapy. At the time of allogeneic SCT, 34 (79%) patients had persistent MDS or AML. Stem cell sources were bone marrow (n = 20) or peripheral blood (n = 23). Median times from diagnosis to SCT were 2.46 and 7.21 months for patients receiving a sibling or unrelated donor allogeneic SCT, respectively. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Kröger et al. [20] presented the outcomes of 37 adult (23-72 years) patients with MDS (81%) or sAML who received an HLA-matched related (n = 19) or HLA-matched unrelated (n = 18) allogeneic SCT following a reduced intensity conditioning regimen consisting of fludarabine + busulfan ± antithymocyte globulin. Two of the 37 patients were transplanted from a donor with a single antigen mismatch. Stem cell sources were bone marrow (n = 8) or peripheral blood (n = 29). Median time from diagnosis to SCT was 8 months. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Related Allogeneic SCT Kröger et al. [21] compared the outcomes of 38 adult (mean age, 43.5 years) patients with MDS or sAML who underwent syngeneic SCT to 1444 patients (mean age, 37.7 years) who underwent HLA-identical sibling allogeneic SCT and were reported to the EBMT registry. At the time of SCT, 24% and 35% of the twin and sibling groups, respectively, were in CR. An unspecified TBI-containing conditioning regimen was used in 36% of the twin group and 48% of the sibling group; the remaining patients received an unspecified non-TBI-based regimen. In the twin and sibling groups, stem cell sources were bone marrow (57% and 70%) or peripheral blood (43% and 30 %), respectively. Median time from diagnosis to SCT was 7.8 and 9.5 months in the twin and sibling groups, respectively. In multivariate analysis, disease status, stem cell source, and age significantly influenced OS, and stem cell source influenced DFS. Valcárcel et al. [22] presented the outcomes of 93 adult patients (21-70 years) with high-risk MDS (n = 34, 37%) or AML (n = 59) who underwent an HLA-identical sibling donor peripheral blood allogeneic SCT (one patient underwent BMT) following reduced intensity conditioning with busulfan + fludarabine. Outcomes were stratified by disease. Sixty-seven patients (72%) received induction chemotherapy, of whom 46 (49%) achieved CR1, and 11 patients (12%) had also undergone a prior autologous SCT. Median time from diagnosis to SCT was not reported. In multivariate analysis, incidence of chronic graft-versus-host disease (cGVHD) significantly influenced OS and DFS, and disease status influenced DFS. Sierra et al. [23] reported the results of 452 adult (median age, 38 years) patients with MDS who received HLA-identical sibling allogeneic SCT and were registered with the IBMTR. Of the 133 (29%) patients for whom information was available, 73 (55%) received induction chemotherapy. Conditioning regimens included TBI in 44% of patients. The interval between diagnosis and SCT was <1 year in 341 (75%) patients. In multivariate analysis, OS and DFS were influenced by age, percentage of marrow blasts, and platelet counts before allogeneic SCT. Sutton et al. [24] presented the outcomes of 71 adult (median age, 37 years) patients with de novo MDS who underwent HLA-identical sibling BMT and were registered with the French Bone Marrow Transplant Registry (FBMTR). Seventeen patients received induction chemotherapy consisting of cytarabine + anthracycline, and CR was achieved in 6 cases. Conditioning regimens varied by center, but the majority of patients received either TBI + cyclophosphamide (n = 26) or busulfan + cyclophosphamide (n = 17). The remaining 28 patients received other high-dose chemotherapy agents, plus TBI in 25 cases. Median time between diagnosis and BMT was 201 days. In multivariate analysis, OS was influenced by age, sex, previous induction chemotherapy, and percentage of marrow blasts before BMT. Event-free survival (EFS) was influenced by the same variables except sex. Wallen et al. [25] reported the results of 52 older adult (60-68 years) patients with MDS (n = 35, 67%), chronic myeloid leukemia (CML, n = 8), AML (n = 6), or other diagnoses (n = 3) who underwent HLA-matched or mismatched sibling allogeneic SCT. Conditioning regimens consisted of cyclophosphamide + busulfan (67%), cyclophosphamide + TBI (21%), busulfan + fludarabine (10%), or cyclophosphamide alone (2%). Stem cell sources were bone marrow (n = 26) or peripheral blood (n = 21). The median interval from diagnosis to SCT was not stated. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. O'Donnell et al. [26] presented the outcomes of 38 patients (median age, 35 years) with severe MDS (79%) or sMDS/AML who underwent HLA-identical sibling allogeneic BMT following a conditioning regimen of busulfan + cyclophosphamide. The median interval from diagnosis to BMT was 5 months. Multivariate analysis of the impact of patient and treatment variables on survival was not performed. Unrelated Allogeneic SCT Lim et al. [27] reported the results of a prospective study of 75 adults (19-68 years) who received a RIC regimen prior to allogeneic SCT using HLA-matched or mismatched unrelated donors for the treatment of MDS (68%), AML with tri-lineage dysplasia, or myelodysplastic/myeloproliferative disorders (MDS-MPDs). A total of 55 (73%) patients received induction chemotherapy prior to allogeneic SCT. Three patients had received a prior autologous SCT. Stem cell sources were bone marrow (n = 38) or peripheral blood (n = 47). Fifty-two donors were HLA- matched, 20 had a 1 HLA locus mismatch, and 3 were mismatched at 2 HLA loci. Reduced intensity conditioning consisted of fludarabine + busulfan + alemtuzumab. In multivariate analysis, presence of HLA mismatch significantly influenced OS and DFS, and disease status at allogeneic SCT and the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score significantly influenced OS. Castro-Malaspina et al. [28] reported the results of 510 adult (median age, 38 years) patients with MDS who underwent a matched or mismatched unrelated BMT facilitated by the National Marrow Donor Program (NMDP). Conditioning regimens consisted of cyclophosphamide + fractionated or single dose TBI ± other (62%), busulfan + cyclophosphamide ± other (25%), busulfan + cyclophosphamide + f-TBI (4%), or other (9%). Median time from diagnosis to allogeneic SCT was 9 months. The majority of patients received marrow from an unrelated donor who was a known HLA-match at the antigen or allele level (n = 376, 74%), 110 (22%) received marrow from a known HLA-mismatch at the antigen or allele level, and 24 (5%) received marrow with a potential antigen-match at HLA-A, -B, -DRB1 (antigen level for one, allele level for the other in the donor-recipient pair). In multivariate analysis, DFS and OS were significantly influenced by FAB, cell dose, recipient cytomegalovirus (CMV) serology, time from diagnosis to SCT, and year of SCT. OS was also significantly influenced by donor match. Arnold et al. [29] presented the outcomes of 118 patients (61% ≥18 years) with MDS (81%) or sAML who underwent allogeneic SCT from unrelated donors and were reported to the EBMT registry. Sixty-nine patients received conditioning consisting of unspecified chemotherapy + TBI, 30 received chemotherapy only, and the conditioning regimen was unknown for 19 patients. Donors were HLA-matched (n = 105) or 1-2 HLA locus mismatched (n = 13). Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Anderson et al. [30] reported the outcomes of 52 patients (median age, 32.6 years) with MDS (75%) or sAML who received unrelated donor SCT. Conditioning regimens consisted of cyclophosphamide + TBI (n = 33) or busulfan + cyclophosphamide (n = 19). Donors were HLA matched (n = 34), 1 HLA locus mismatched (n = 17), or mismatched at 2 HLA loci (n = 1). Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Kernan et al. [31] reported the outcomes of 462 patients with malignant or nonmalignant diseases who received an unrelated donor allogeneic SCT facilitated by the NMDP. Of these, 32 (7%) were patients with MDS (median age, 24.3 years). Pretransplant factors specific to the MDS patients were not reported. Median interval from diagnosis to SCT for MDS patients was 0.9 year. No multivariate analysis specific to MDS outcome was reported. Related or Unrelated Allogeneic SCT (or unspecified donor relation) Yakoub-Agha et al. [32] presented the outcomes for 70 adult (16-55 years) patients with therapy-related MDS (n = 31, 44%) or therapy-related AML who underwent HLA-matched or mismatched related (n = 62) or unrelated (n = 8) allogeneic SCT using stem cells from bone marrow (n = 66), peripheral blood (n = 3), or unrelated cord blood (n = 1) and were registered with the FBMTR. Thirty-three patients received induction chemotherapy, 24 (34%) of whom were in CR at the time of SCT. Conditioning regimens consisted of cyclophosphamide + TBI (n = 11), busulfan + cyclophosphamide (n = 26), cyclophosphamide + melphalan (n = 4), other high-dose chemotherapy ± TBI (n = 25), or other non-TBI regimens (n = 4). Median time from diagnosis to transplantation was 5.7 months. In multivariate analysis, age, sex, disease status at SCT, presence of CMV, and conditioning regimen significantly influenced OS and EFS. Kerbauy et al. 33, 34 presented the outcomes of 43 adult (median age, 48 years) patients with chronic myelomonocytic leukemia (CMML) (38 de novo, 5 secondary) who underwent HLA-identical or mismatched related (n = 21) or HLA-matched or mismatched unrelated (n = 22) allogeneic SCT following conditioning with various busulfan- or TBI-based regimens. Eleven (26%) patients had received pretransplant induction chemotherapy. Stem cell sources were bone marrow (n = 23) or peripheral blood (n = 20). The median interval from diagnosis to SCT was 8 months. In multivariate analysis, HCT-CI score significantly influenced OS. Anderson et al. 35, 36 presented the outcomes of 93 adult (median age, 30 years) patients with MDS who received a conditioning regimen of cyclophosphamide + TBI (n = 88) or busulfan + cyclophosphamide (n = 5) followed by HLA-matched related (n = 87) or unrelated (n = 6) donor allogeneic BMT. The median interval from diagnosis to BMT was 10 months. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Nevill et al. [37] presented the results of 60 adult (15-55 years) patients with MDS (80%) or sAML who underwent HLA-matched or mismatched related (n = 38) or unrelated (n = 22) donor allogeneic BMT. Nineteen (32%) patients received induction chemotherapy prior to BMT, 9 of whom attained CR. Conditioning consisted of cyclophosphamide + fractionated TBI for unrelated donor BMT and busulfan + cyclophosphamide for related donor BMT. Median time from diagnosis to BMT was 2.9 months. In multivariate analysis, cytogenetic risk group significantly influenced EFS. Appelbaum et al. [38] reported the outcomes for 59 adult (median age, 29 years) patients with MDS (83%) or other hematologic disorders, who underwent HLA-matched or mismatched related (n = 57) or unrelated (n = 2) allogeneic BMT following conditioning with cyclophosphamide + TBI or busulfan + cyclophosphamide regimens. Median time from diagnosis to BMT was 12 months. In multivariate analysis, OS and DFS were significantly influenced by age and cytogenetics. Deeg et al. [39] presented the outcomes for 50 adult (55-66 years) patients with MDS who received conditioning regimens consisting of busulfan + cyclophosphamide (n = 27), cyclophosphamide + fractionated TBI (n = 15), cyclophosphamide + fractionated TBI with lung and liver shielding (n = 4), or busulfan +fractionated TBI (n = 4), followed by HLA-matched or mismatched related (n = 44) or matched unrelated (n = 6) donor allogeneic BMT. Forty-two patients had de novo MDS, and 8 patients had therapy-related MDS. Three (6%) patients received induction chemotherapy. The median time from diagnosis to BMT was not reported. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Kröger et al. [40] reported the results of 50 adult (19-61 years) patients with de novo CMML who underwent an HLA-matched or mismatched related (n = 44) or matched unrelated (n = 6) donor allogeneic SCT. Twenty-six patients received a TBI-containing conditioning regimen, and 24 patients received a chemotherapy-based regimen. Stem cell sources were bone marrow (n = 40), peripheral blood (n = 9), or both (n = 1). Median time from diagnosis to SCT was 9 months. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Bornhäuser et al. [41] presented the outcomes of 42 adult (12-65 years) patients with MDS (62%), sAML (29%), or CML (9%) who received a myeloablative conditioning regimen of fludarabine (120 mg/m2) + busulfan (16 mg/kg) followed by an HLA-matched related (n = 16) or HLA-matched or mismatched unrelated (n = 26) donor allogeneic peripheral blood SCT (PBSCT). Five MDS patients and 10 sAML patients received induction chemotherapy. Median time from diagnosis to PBSCT was 9 months. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Mattijssen et al. [42] presented the results of 35 adult (23-60 years) patients with MDS (91%) or sAML who received HLA-matched or mismatched sibling or other related donor (n = 33) or matched unrelated donor (n = 2) allogeneic BMT after conditioning with cyclophosphamide + TBI ± idarubicin (n = 31) or other unspecified schedules (n = 4). Nineteen (54%) patients received induction chemotherapy, 15 of whom achieved CR. Stem cell source was T cell-depleted bone marrow for all patients. The median interval from diagnosis to BMT was 9 months. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Autologous Versus Allogeneic SCT Oosterveld et al. [43] reported the results of a retrospective analysis of a prospective study by De Witte et al. [44] comparing autologous SCT (no donor group) versus allogeneic SCT (donor group) in 184 adult (16-60 years) patients with MDS (75%) or sAML registered with the EORTC. In this analysis, only patients alive 8 weeks from the start of treatment were included (n = 159). HLA typing was performed for 128 of the 159 patients (81%), of whom 52 had an HLA-identical sibling (donor group) and 65 did not (no donor group). Eleven patients with no siblings were typed, but excluded. Induction treatment consisted of idarubicin + cytarabine + etoposide. Patients achieving CR received a consolidation course of cytarabine + mitoxantrone, followed by a transplantation regimen consisting of either cyclophosphamide + f-TBI or busulfan + cyclophosphamide, then either allogeneic SCT (donor group, n = 28) or autologous SCT (no donor group, n = 27). Analyses were based on intention to treat. Reasons for not receiving the assigned SCT included death, treatment failure, toxicity, protocol violation, patient refusal, or receipt of a nonsibling allogeneic SCT. In multivariate analysis, cytogenetic risk group significantly influenced OS. De Witte et al. 45, 46 reported the outcomes of 1378 adult (81% ≥20 years) patients who underwent transplantation for treatment of MDS (>60%) or sAML and were reported to the EBMT. Of the total, 1347 patients received an allogeneic SCT from an HLA-identical sibling donor (n = 885), HLA-nonidentical family donor (n = 91), or an unrelated donor (n = 198), and 173 patients underwent an autologous SCT. Conditioning regimens were not reported. Of the 885 patients who received an allogeneic SCT from an HLA-identical sibling, 665 (75%) had an interval from diagnosis to SCT of <12 months (not reported for the other groups). In multivariate analysis, age had a significant influence on survival for all but the nonidentical related allogeneic SCT group, and stage of disease had a significant impact on survival in both related allogeneic SCT groups. Transplantation Techniques This section describes studies that examine the impact of stem cell source and conditioning regimen on patient outcomes in the treatment of MDS. Table 6 presents a summary of the patient outcomes from these studies. | | | | Author/ Reference # | Quality and Strength of Evidence∗ | Patient Population† | Protocols | Diagnosis or Subtype (at Dx Unless Otherwise Stated) | Median Follow-up | Study Groups (n) | (Interval) % TRM | (Interval) % DFS/RFS/EFS/PFS (Significance) | (Interval) % OS (Significance) | |
|---|
| BMT VERSUS PBSCT | | | Allogeneic BMT versus PBSCT | | | [47] | 1+ | 1996-2000 Randomized Multicenter (8) Total n = 227 MDS n = 36 | | | 32.8 months | (MDS only) | %TRM Not Stated | | (30 months, %OS) | | | | | | BMT (20) | | | No numeric data specific to MDS provided | | | Age range: 19-64 BMT Median age, 44 years PBSCT Median age, 45 years | HLA-matched sibling allo-SCT | | | PBSCT (16) | | | See Figure 3 | | | | | | (ITT analysis) | | | (P not signif) | | | | | | [48] | 2+ | 1995-1999 EBMT Multicenter (72) n = 234 | High-dose IC 56% received 53% achieved CR | RA 29% RAEB 37% RAEBt 32% Unclassified 2% | 1 year | | (2-year %TRM) | (2-year %EFS) | (2-year %OS) | | | BMT Age range: 4-59 Median age, 41 years 68% >35 years | Conditioning regimen not stated | | | BMT (132) | 36% | 39% | 49% | | | PBSCT Age range: 12-60 Median age, 47 years 84% >35 years | HLA-matched sibling allo-SCT | | | PBSCT (102) | 42% | 50% | 58% | | | | | | | | (P = .32) | (P=.20) | (P=.40) | | | | | | [49] | 2+ | 1985-2001 GETH Registry Multicenter n=81 | Conditioning Bu+Cy Cy+TBI Other | | 8.5 months | | | (5.8-year %EFS) | (5.8-year %OS) | | | Age range: 8-52 Median age, 39 years 54% ≥40 years | HLA-identical sibling allo-SCT | High-risk RAEB 38% RAEBt 26% | | | | | 48% | | | (P = .002) | | | | | | | Low-risk MDS BM (6) PBSC (10) | | 46% | (P not signif) | | | (P not signif) | | | | | | | High-risk MDS BM (33) PBSC (19) | | | | | | | | | | | | (P =.007) | (P =.01) | | | Autologous BMT versus PBSCT | | | [50] | 2+ | Post 1992 EBMT Multicenter n = 336 | Conditioning not stated | de novo MDS 19% t MDS 17% sAML 27% Unknown etiology 37% | Not stated | | Not stated | (4–year %DFS) | Not stated | | | 28% | | | Auto-SCT | BM (104) | 21% | | | PBSC (232) | (P=.66) | | | Age range 0-73 Median age, 49 years 87% >29 years | | | | | | | | | | 73% MDS | | | | | | | | | | Conditioning Regimen Comparisons | | | Reduced Intensity Conditioning Versus High-Dose Regimen | | | [51] | 2++ | 1997-2001 EBMT Multicenter (128) n = 836 | Conditioning RIC Bu + Flu Flu + Mel Flu + Low-dose TBI Flu + Other | RIC RA/RARS 9% RAEB 27% RAEBt 13% sAML 35% Unclassified 16% | | | (3-year %TRM) | (3-year %PFS) | (3-year %OS) | | | Age range: 27-72 Median age, 56 years | High-dose TBI + Cy/Other Bu + Cy Bu + Cy/Other Alemtuzumab None or not specified | High-dose RA/RARS 11.5% RAEB 20% RAEBt 21.5% sAML 32% Unclassified 15% | | RIC (215) | | | | | | High dose Age range: 18-67 Median age, 45 years | HLA-identical sibling allo-SCT | | | High dose (621) | | | | | | 67% MDS | | | | | (P = .04) | (P=10) | (P=.70) | | | | | | [52] | 2+ | 1998-2003 2 centers n = 150 | Induction Chemo RIC 22% received, 83% achieved CR | RIC RA/RARS 23.5% RAEB 23.5% RAEBt/tAML 53% | | | (3-year %TRM) | (3-year %PFS) | (3-year %OS) | | | Age range: 40-72 | High dose 63% received, 64% achieved CR | High dose RA/RARS 38% RAEB 31% RAEBt/tAML 31% | | | 39% | 27% | 28% | | | | Conditioning RIC 2 cGy TBI ± Flu | | | High dose (112) | 32% | 44% | 48% | | | High dose Median age, 53 years | High dose Oral t-Bu + Cy HLA-matched related or unrelated allo-SCT | | | | (P = .94) | (P=.10) | (P=.56) | | | [53] | 2+ | 1993-2000Multicenter (4)n = 52 | Induction Chemo RIC 48% received, 63% achieved CR High dose 55% received, 50% achieved CR | RA 34.5% RAEB 27% RAEBt 5.5% t-MDS/AML 10% sAML 23% | | | (2-year %TRM) | (2-year %DFS) | (2-year OS) | | | 67% MDS | Conditioning RIC Bu + Flu + Campath | | | RIC (23) | 31% | 39% | 48% | | | | High dose Bu + Cy + TBI + Campath | | | High dose (29) | 50% | 44% | 44% | | | | HLA-matched or mismatched related or unrelated allo- SCT | | | | (P not stated) | (P not stated) | (P not stated) | | | | | | [54] | 2+ | 1998-2002 Multicenter (55) Total n = 207 MDS n=50 (24%) | Conditioning RIC Cladribine-based Flu-based 2 Gy TBI-based | MDS only (no FAB subtypes stated) | | | (1-year %TRM) | Not Stated | (2-year %OS) | | | 31% | | | | High dose 12 Gy TBI-based Bu + Cy Bu + Cy + TBI | | | RIC (16) | | | | | | | HLA-identical sibling allo-SCT | | | High dose (34) | 23.5% | | | | | (P not stated) | | | High dose median age, 52 years | | | | | | | (P not stated) | | | | | | [55] | 2+ | 1997-2004 Single center n = 43 | Conditioning RIC Flu + Cy or Mel or i.v. Bu | | 18 months | | (3-year %TRM) | (3-year %RFS) | (3-year %OS) | | | Age range: 12-73 Median age, 49 years | HLA-identical sibling, unmanipulated allo-PBSCT | RIC RAEB 50% RAEBt 15% AML 35% | | RIC (20) | 27% ± 12% | 37%±11% | 39%±12% | | | 70% MDS | High dose Cy + f-TBI Cy + Flu + f-TBI | High dose RA/RARS 31% RAEB 17% RAEBt 26% AML 26% | | High dose (23) | 17% ± 9% | 59%±11% | 66%±11% | | | | HLA-identical sibling, T cell-depleted allo-PBSCT | | | | (P = .22) | (P=.059) | (P=.02) | | | Comparison of ≥2 High-Dose Regimens | | | [56] | 2+ | 1992-2002 Single center n = 128 | Induction Chemo 35 patients received (25 achieved CR) | Bu + TBI RAEB 44% RAEBt 34% tAML 22% | Not stated | | (3-year %TRM) | (3-year %RFS) | Not stated | | | Bu + TBI Age range: 1-56 Median age, 45 years | Conditioning Oral Bu+TBI (200 cGy) or Oral t-Bu + Cy | t-Bu + Cy RAEB 57% RAEBt 15% tAML 28% | | Bu + TBI (50) | 50 | 24 | | | | t-Bu + Cy Age range: 3-66 Median age, 52 years 74% MDS | HLA-matched related or unrelated allo- SCT | | | t-Bu + Cy (78) | 37 | 19 | | | | | | | | | (P not signif) | (P not signif) | | | | | | | [57] | 2+ | 1990-1993 Single center Total n = 75 | Conditioning Cy + TBI Oral Bu + Cy + 2 Gy TBI | Cy + TBI RAEB 68% RAEBt 32% | Not stated | | (3-year %TRM) | (3-year %DFS) | Not stated | | | Current Bu + Cy + TBI, n = 31 Age range: 16-54 Median age, 41 years | HLA-matched or mismatched related or unrelated allo- SCT | Bu + Cy + TBI RAEB 48% RAEBt 26% CMML 26% | | Cy + TBI (44) | 68% | 23% | | | | Historic Cy + TBI, n = 44 Age range: 1-55 Median age, 36 years | | | | Bu + Cy + TBI (31) | 36% | 30% | | | | | | | | | (P = .12) | (P=.60) | | | | [58] | 2+ | 1990-1993 Single center Total n = 68 | Conditioning Oral Bu + Cy Cy + TBI | | Not stated | | (3-year %TRM) | (3-year DFS) | Not stated | | | Age range: 5-53 71% >20 years | HLA-matched or mismatched related or unrelated allo- SCT | | | Bu + Cy (28) | 37 | 63 | | | | Current Bu + Cy, n = 30, Analyzed n = 28 Median age, 29 years | | | | Cy + TBI (38) | 37 | 60 | | | | Historic Cy + TBI, n = 38 Median age, 28 years | | | | | (P = .90) | (P=.90) | | | | | |
| ∗ Quality and strength of evidence definitions are listed in Table 1. †Auto indicates autologous; Chemo, chemotherapy; SCT, stem cell transplantation; BMT, bone marrow transplantation; PBSCT, peripheral blood SCT; CR, complete remission; DX, diagnosis; MDS, myelodysplastic syndromes; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RAEB, refractory anemia with excess blasts; RAEBt, refractory anemia with excess blasts in transformation; CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndromes; AML, acute myeloid leukemia; sAML, secondary AML; tAML, therapy-related AML; CML, chronic myelologenous leukemia; EBMT, European Group for Blood and Marrow Transplantation; GETH, Grupo Español de Trasplante Hematopoyético; HLA, human leukocyte antigen; ITT, intention to treat; TRM, treatment-related mortality; DFS, disease-free survival; EFS, event-free survival; RFS, relapse-free survival; PFS, progression-free survival; OS, overall survival; CI, 95% confidence interval; HD, high dose; IC, induction chemotherapy; Flu, Fludarabine; Cy, Cyclophosphamide; Bu, Busulfan; t-Bu, targeted Busulfan; Mel, Melphalan; TBI, total-body irradiation; f-TBI, fractionated TBI; RIC, reduced-intensity conditioning. ‡For simplicity, reduced-intensity and nonmyeloablative conditioning regimens are listed as RIC; myeloablative regimens are listed as high dose. |
BMT Versus PBSCT Allogeneic BMT Versus PBSCT Couban et al. [47] presented the results of 227 adult (19-64 years) patients with MDS (n = 36), CML (n = 109), or AML (n = 82) who were randomly assigned to receive either bone marrow or peripheral blood stem cells for an HLA-matched sibling donor allogeneic SCT. Of the 36 MDS patients, 20 received bone marrow and 16 received peripheral blood stem cells. The conditioning regimen consisted of busulfan + cyclophosphamide. Median time from diagnosis to SCT was not reported. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Figure 3 presents OS by stem cell source. Guardiola et al. [48] reported the results of 234 adult (75% >35 years) patients with MDS who underwent HLA-matched sibling allogeneic SCT, comparing the use of bone marrow (n = 132) versus peripheral blood (n = 102) as the stem cell source. Of the total, 131 patients received high-dose induction chemotherapy, 70 of whom achieved CR. The conditioning regimen was not reported. For 53% of patients, time from diagnosis to SCT was ≤6 months. In multivariate analysis, stem cell source influenced OS and EFS except in patients with refractory anemia (RA) or high-risk cytogenetics. del Cañizo et al. [49] presented the outcomes of 81 adult (median age, 35 years) patients with de novo MDS who underwent an HLA-identical sibling allogeneic SCT, comparing low risk (RA and RARS, n = 16) versus high-risk (RAEB and RAEBt, n = 52) MDS by stem cell source (bone marrow, n = 45 versus peripheral blood, n = 36). Conditioning regimens consisted of busulfan + cyclophosphamide (n = 42), cyclophosphamide + TBI (n = 32), or other (n = 7). Median times from diagnosis to SCT were 9.5 and 6 months for the bone marrow and peripheral blood stem cell groups, respectively. In multivariate analysis no patient or treatment variables were significantly associated with OS. Figure 4 presents EFS by stem cell source for the RAEB/RAEBt (high-risk) group. Autologous BMT Versus PBSCT De Witte et al. [50] reported the outcomes of 336 adults (87% were >29 years) with MDS (73%) or sAML who were transplanted after 1992 with autologous SCT using either bone marrow (n = 104) or peripheral blood stem cells (n = 232) and reported to the EBMT Registry. MDS patients were classified as having primary MDS (19%), therapy-related MDS (17%), or MDS of unknown cause (37%). Patients receiving peripheral blood stem cells tended to be older than patients receiving bone marrow (26% versus 8%, respectively, were >60 years). The conditioning regimen was not stated. The intervals from diagnosis to SCT were ≤5 months (32%), 5-8 months (44%), and >8 months (24%). In multivariate analysis, disease status and year of transplant significantly influenced DFS. Conditioning Regimen Comparisons Comparison of RIC Versus High-Dose Regimens Martino et al. [51] presented the results of 836 adult (18-72 years) patients with MDS (67%) or sAML who underwent HLA-identical sibling allogeneic SCT, comparing the outcomes of patients who received reduced intensity (n = 215) versus high-dose (n=621) conditioning regimens. Stem cell sources for the reduced intensity and high-dose conditioning groups were bone marrow (12.6% and 49.1%) or peripheral blood (87.4% and 50.9%), respectively. For the majority of patients, time from diagnosis to SCT was <6 months (reduced intensity, 73.5%; high dose, 77.4%), and 25% of reduced intensity and 11% of high-dose conditioning patients underwent a prior autologous SCT. In multivariate analysis, disease type, disease status, and age significantly influenced OS and progression-free survival (PFS). Scott et al. [52] reported the results of 150 adult (40-72 years) patients with MDS (63%) or RAEBt/therapy-related AML who received a high-dose (oral busulfan + cyclophosphamide, n = 112) or reduced intensity (2 Gy TBI ± fludarabine, n = 38) conditioning regimen followed by HLA-matched related or unrelated allogeneic SCT. Induction chemotherapy consisting of cytarabine-containing regimens was used in 22% and 63% of patients in the high-dose and reduced intensity conditioning groups, respectively. Of those, 16 (64%) and 20 (83%), respectively, achieved a CR pre-SCT. Stem cell sources were bone marrow (81% and 95%) or peripheral blood (19% and 5%) for the high-dose and reduced intensity conditioning groups, respectively. Median disease duration was 7 and 9 months for the high-dose and reduced intensity conditioning groups, respectively. In multivariate analysis, no patient or treatment variables were significantly associated with OS or PFS. Parker et al. [53] compared patient outcomes by conditioning regimen for 52 adult (18-63 years) patients with MDS (67%), sAML, or therapy-related MDS/AML who underwent matched or mismatched related or unrelated donor allogeneic SCT following high dose (busulfan + cyclophosphamide ± TBI and Campath-1G; n = 29) or reduced intensity (busulfan + fludarabine + Campath-1G; n = 23) conditioning regimens. Twenty-seven patients (52%) received prior induction chemotherapy, and 13 of these were in CR at time of SCT. The median time from diagnosis to SCT was 10 months for the high-dose conditioning and 16 months for the reduced intensity conditioning groups. Stem cell sources were bone marrow (72% and 78%) or peripheral blood (28% and 22%) for the high-dose and reduced intensity conditioning groups, respectively. Multivariate analysis of the impact of patient and treatment variables on survival outcomes was not performed. Kojima et al. [54] presented the results of 207 adult (50-59 years) patients with MDS (n = 50, 24%), AML (n = 89), ALL (n = 35), or CML (n = 33), comparing the outcomes of reduced intensity (purine analog-based or 2 Gy TBI-based) versus high-dose (TBI-based or busulfan + cyclophosphamide-based) conditioning regimens followed by HLA-identical sibling donor allogeneic SCT. Patient outcomes were stratified by disease (MDS; reduced intensity, n = 16; high dose, n = 34). Patient characteristics and pretransplant factors specific to the MDS patients were not reported. No multivariate analysis specific to MDS outcome was reported. Figure 5 presents OS by conditioning regimen. Solomon et al. [55] reported the outcomes of 43 adult (12-73 years) patients with MDS who received a reduced intensity (fludarabine + cyclophosphamide, melphalan, or intravenous busulfan, n = 20) or high-dose (fractionated TBI + cyclophosphamide ± fludarabine, n = 23) conditioning regimen followed by HLA-identical sibling donor allogeneic SCT. Patients receiving reduced intensity conditioning were older and had more aggressive disease than patients in the high-dose conditioning group. The high-dose group received a T cell-depleted peripheral blood SCT, and the reduced intensity group received a T cell-replete peripheral blood SCT. Median time from diagnosis to SCT was not reported. In multivariate analysis, MDS etiology (de novo versus secondary) significantly influenced DFS. Comparison of ≥2 High-Dose Regimens Scott et al. [56] presented the outcomes of 128 patients with advanced MDS (74%) or therapy-related AML who underwent HLA-matched related or unrelated allogeneic SCT after conditioning with either oral busulfan + TBI (n = 50, median age 45 years) or targeted oral busulfan + cyclophosphamide (n = 78, median age 52 years). Patients who received busulfan + TBI were more likely to have an unrelated donor and to receive bone marrow, and patients conditioned with busulfan + cyclophosphamide were more likely to have a related donor and to receive an allogeneic PBSCT. Median time from diagnosis was 6 months for both conditioning groups. In multivariate analysis, conditioning regimen did not significantly influence OS, RFS, or treatment-related mortality (TRM). Anderson et al. [57] compared the outcomes of 31 adult (median age, 41 years) patients with advanced MDS who were conditioned with oral busulfan + cyclophosphamide + TBI to the outcomes of 44 historical controls (median age, 36 years) conditioned with cyclophosphamide + TBI prior to HLA-matched or mismatched related or unrelated donor allogeneic BMT. Median times from diagnosis to SCT were 5 and 8.5 months for the treatment and historic control groups, respectively. In multivariate analysis, karyotype and WBC count significantly influenced DFS, and karyotype influenced OS. Anderson et al. [58] compared the results of 30 patients (median age, 29 years) with RA conditioned with oral busulfan + cyclophosphamide to 38 historic controls (median age, 28 years) with refractory anemia conditioned with cyclophosphamide + TBI prior to matched or mismatched related or unrelated donor allogeneic BMT. Median times from diagnosis to BMT were 10 and 11 months for the treatment and historic control groups, respectively. In multivariate analysis, age (decade), time from diagnosis to BMT, neutrophil count at BMT, and hematocrit significantly influenced OS. MDS Prognostic Scoring Systems and Factors This section provides a summary of MDS classification and scoring systems. The data in this section are provided for the reader's information and were not used to make treatment recommendations. MDS Classification—FAB Versus WHO The FAB classification system has been used since 1982 to categorize MDS patients [59]. FAB system limitations [60] led to a revised MDS classification system in 1999 by the World Health Organization (WHO) [61]. The following articles compared the classification of MDS by FAB versus WHO systems. Germing et al. [62] conducted a retrospective analysis of 1600 adult (16-96 years) patients with MDS, diagnosed between 1970 and 1999 at a single center, to compare the FAB and WHO classification systems as summarized in Table 7. According to the FAB subtypes, RARS had the best prognosis (median survival, 50 months), followed by RA (37 months), CMML (19 months), RAEB (12 months), and RAEB-t (5 months). Under the WHO system, del (5q) and a medullary blast count <5% reportedly had the best prognosis, followed by pure refractory anemia (PRA) and pure sideroblastic anemia (PSA) (both 69 months), RCMD (33 months), RSCMD (32 months), RAEB I (18 months), RAEB II (10 months), and del (5q), and a medullary blast count >5% (7 months). Figure 6, Figure 7 present OS according to the FAB and WHO classification systems, respectively. | | | | FAB Classification | WHO Classification | |
|---|
| Refractory anemia (RA) (n = 418) | Pure refractory anemia (PRA) (n = 107) Refractory cytopenia w/multilineage dysplasia (RCMD) (n = 284) Del (5q) (n = 18) Unclassified MDS (n = 14) | | | Refractory anemia with ring sideroblasts (RARS) (n = 328) | Pure sideroblastic anemia (PSA) (n = 138) Refractory sideroblastic cytopenia w/multilineage dysplasia (RSCMD) (n = 183) Del (5q) (n = 7) | | | Refractory anemia with excess of blasts (RAEB) (n = 344) | RAEB-I (n = 167) RAEB-II (n = 172) Del (5q) (n = 3) | | | Refractory anemia with excess of blasts in transformation (RAEB-t) (n = 273) | RAEB-t Excluded (blast count >20%) (n = 217) RAEB-I (n = 14) RAEB-II (n = 42) | | | Chronic myelomonocytic leukemia (CMML) (n = 237) | CMML Excluded (n = 116) RCMD (n = 22) RAEB-I (n = 78) RAEB-II (n = 21) | | | | |
| ∗ The numbers in this table are presented as originally reported in the text of the Germing et al. article. |
Nösslinger et al. [63] compared the FAB and WHO classifications of 431 adult (31-92 years) patients diagnosed with de novo MDS at a single center between 1976 and 1999, as summarized in Table 8. In the FAB system, median survival for RARS was 73 months, followed by RA (66 months), CMML (24 months), RAEB (15 months), and RAEB-t (9 months). Using the WHO system, the 150 patients with RAEB-t or CMML were excluded and survival for the RARS and del (5q) groups were not analyzed because of the small number of patients. Median survival for RCMD was 86 months, followed by unclassified MDS (67 months), RA (66 months), RAEB I (18 months), and RAEB II (12 months). | | | | FAB Classification | WHO Classification | |
|---|
| Refractory anemia/refractory anemia with ring sideroblasts (RA/RARS) (n = 189) | Refractory anemia (RA) (n = 43) Refractory anemia with ring sideroblasts (RARS) (n = 4) Refractory cytopenia w/multilineage dysplasia (RCMD) (n = 91) Del (5q) (n = 1) Unclassified MDS (n = 50) | | | Refractory anemia with excess of blasts (RAEB) (n = 92) | RAEB-I (n = 50) RAEB-II (n = 42) | | | Refractory anemia with excess of blasts in transformation (RAEB-t) (n = 51) | RAEB-t Excluded (blast count of 20% to 30%) (n = 51) | | | Chronic myelomonocytic leukemia (CMML) (n = 99) | CMML Excluded (n = 99) | | | | |
Malcovati et al. [64] compared FAB versus WHO classification in 467 adult (22-93 years) patients with de novo MDS at a single institution from 1992 to 2002, as summarized in Table 9. The analysis of prognostic value of the WHO classification found significant differences in survival between RA and RCMD (P < .001), RAEB I and RAEB II (P < .001), and RAEB I and RCMD (P = .005). MDS Prognostic Scoring Systems Prognostic Scoring Systems with Karyotype Once karyotypes were commonly available, new prognostic scoring systems were developed, as summarized in Table 11. MDS Prognostic Factors Table 12 summarizes patient- and disease-related prognostic factors and their reported impact on survival outcomes as determined by multivariate analyses. Although many of the referenced studies in Table 12 were described in the text and tables of this review, others were specifically prognostic factor studies not presented in this evidence-based review since they did not meet the inclusion criteria [reference numbers are listed in brackets]. Studies were not included in this table if they did not conduct a multivariate analysis. The data in this table are provided for the reader's information and were not used to make treatment recommendations. | | | | Prognostic Factor† | References of Studies Reporting Significant Impact of Prognostic Factor on Survival | References of Studies Reporting No Significant Impact of Prognostic Factor on Survival | |
|---|
| PATIENT CHARACTERISTICS | | | Age | 11, 21, 23, 24, 30, 32, 38, 44, 48, 51, 58, [74], [75], [76], [77], [78], [79] | 10, 12, 15, 17, 22, 27, 28, 43, 50, 55, [80], [81] | | | Gender | 17, 18, 32 | 12, 23, [74], [81] | | | DISEASE CHARACTERISTICS AT DIAGNOSIS | | | MDS etiology (de novo or secondary) | 15, 18, 50, 55 | 17, [77] | | | WBC count | 11, 57 | 23 | | | FAB subtype | 8, 10, 12, 18, 21, 24, 28, 48, 51, 54, [82] | 15, 22, 23, 30, 38, 52, 55, [79] | | | IPSS score | 8, [74], [80], [82] | 15, 23, 27, 33, 52, [81] | | | Hemoglobin | 11 | 23 | | | % BM blasts | 23, [74], [81] | 24, 32, 55 | | | Platelets | 11 | 23, 30, [74] | | | Cytogenetic risk group/karyotype | 11, 12, 17, 38, 30, 37, 38, 43, 57, [74], [75], [76], [77], [81] | 15, 22, 23, 27, 30, 48, 51, 55, [80] | | | Comorbidities | 27, 33, [76] | | | | DISEASE CHARACTERISTICS AT SCT | | | Time from diagnosis to SCT | 8, 10, 17, 18, 28, 58 | 12, 21, 23, 30, 33, 38, 50, [77], [78], [79], [81] | | | Prior treatment for MDS (eg, transfusions) | 23 | 30 | | | Induction chemotherapy | 12, 24 | 30, 32, 38, 43, [76] | | | Disease status at SCT | 27, 32, 44, 48, 51, [75], [77] | 10, 21, 22, 52 | | | Presence of cytopenia(s) | 58 | 32, [80] | | | % BM blasts | 24 | 37, [80] | | | Splenomegaly | | 23 | | | Recipient-donor CMV status | 17, 28, 30, 32 | 23, [76] | | | Performance status | 54 | | | | TREATMENT RELATED FACTORS | | | Type of SCT (eg, allo, auto) | [80] | 43 | | | Conditioning regimen | 24, 32, 54 | 12, 17, 21, 23, 28, 30, 33, 51, 55, 56, [76], [77], [78] | | | Stem cell source | 21, 48, [76] | 12, 15, 27, 47, 50, [77] | | | Donor relation | 18, [79] | 15, 17, 21, 56, [77], [81] | | | HLA match | 27, 28, [75] | 30 | | | Year of transplant | 28 | 23, 44, [77], [80], [78] | | | | |
| ∗ Survival = any one or more of the following: OS, DFS, RFS, LFS, EFS, PFS. †Factors were not included if the study did not conduct a multivariate analysis. |
Novel Agents Versus Supportive Care This section describes the impact of various novel chemotherapy agents versus supportive care in the treatment of MDS. These studies are restricted to meta-analyses and randomized controlled trials (RCT) except for the Immunomodulatory Agents section, which includes phase II studies. The data in this section are provided for the reader's information and were not used to make treatment recommendations. Cytokine Therapy Ross et al. [83] presented the results of a meta-analysis of 59 studies conducted between 1990 and 2005 to determine the efficacy and safety of erythropoiesis-stimulating proteins in the treatment of MDS. The majority were single-arm studies, and five (n = 354) were controlled studies of epoetin versus control (4 RCT, 1 non-RCT). In the controlled studies, patients who received epoetin had a significantly better hemoglobin response (odds ratio, 5.2; 95% confidence interval [CI], 2.5%-10.8%); the overall hemoglobin response was 27.3%. Three of the RCT studies in this meta-analysis are described below in more detail. The Italian Cooperative Study Group [84] reported the outcomes of 87 adult (18-80 years) patients enrolled in a multicenter, randomized, double-blind, placebo-controlled study analyzing the effect of recombinant human erythropoietin (rHuEpo) on hemoglobin level and transfusion requirement in low-risk MDS. In the double-blind phase, patients were randomized to receive 150 U/kg per day of epoetin (n = 44) or placebo (n = 43) for 8 weeks. Thirty-eight and 37 patients in the epoetin and placebo arms, respectively, completed the double-blind phase. Analysis was on an intention-to-treat basis. A full response was defined as an increase in hemoglobin by ≥2 g/dL or no transfusion for at least 2 months; partial response was defined as an increase in hemoglobin by 1-2 g/dL or 50% decrease in need for transfusion for at least 2 months. For analysis, full and partial responses were pooled because of the low number of full responses (epoetin, n = 5; placebo, n = 0). There was a significantly better response in the epoetin arm (36.8% versus 10.8%, P = .007). Incidence of adverse effects was not significantly different between the two groups. Thompson et al. [85] assessed the safety and efficacy of epoetin + granulocyte-macrophage colony-stimulating factor (GM-CSF) for treating anemic, neutropenic adult (21-95 years) patients with MDS in a multicenter, randomized, double-blind, placebo-controlled study. Patients were stratified by their level of endogenous serum erythropoietin (≤500 mU/mL, n = 37; >500 mU/mL, n = 29), then randomized in a 2:1 ratio to receive either epoetin + GM-CSF (n = 45) or placebo + GM-CSF (n = 21) three times per week for 12 weeks. Hemoglobin response occurred in 9% and 5% of patients in the epoetin and placebo groups, respectively (P not significant). For patients with >500 mU/mL endogenous erythropoietin levels, the adjusted mean change in baseline hemoglobin was greater for the epoetin than for the placebo group (+0.07 g/dL versus −0.96 g/dL, P = .048). Transfusions were required for 90% of placebo and 76% of epoetin groups (P not significant). In the epoetin group, a significantly lower percentage of patients in the ≤500 mU/mL endogenous erythropoietin group were transfused compared to the >500 mU/mL endogenous erythropoietin group (60% versus 95%, P = .0069). Casadevall et al. [86] reported the results of 60 adult (43-89 years) patients with MDS and serum erythropoietin levels <500 mU/mL in a multicenter, randomized trial comparing recombinant human (rHu)-Epo + rHuG-CSF (arm A, n = 24) and supportive care (arm B, n = 26). Patients in arm A received treatment three times per week for 12 weeks, after which responders were given rHuEpo for another 40 weeks. Patients in arm B received supportive care, including transfusion of red blood cells as needed and iron chelation treatment for 52 weeks. Twenty-one and 24 patients from arms A and B, respectively, completed the 12 week trial. Analyses were on an intention-to-treat basis. At the 12 week evaluation, 42% of patients in arm A had erythroid responses compared to 0% of arm B patients (P = .01). In arm B there were no significant changes in transfusion requirements or mean hemoglobin level from baseline to 12 weeks. Chemotherapy ± Cytokine Therapy Zwierzina et al. [87] reported the results of 180 adult (28-83 years) patients with MDS in a multicenter, randomized controlled study comparing low-dose cytosine arabinoside (AraC) alone (arm A, n = 59) or in combination with GM-CSF (arm B, n = 59) or Interleukin-3 (IL-3) (arm C, n = 62). Complete, partial, or minor response was achieved in 44.1%, 33.9%, and 40.3% of arms A, B, and C, respectively (P = .52). At a median follow-up of 3.7 years, OS was 18.7%, 14.7%, and 20.2% (P = .60) and PFS was 8.9%, 7.8%, and 13.0% (P = .27) in arms A, B, and C, respectively. Treatment related mortality was 8.2%, 10.0%, and 7.9% in arms A, B, and C, respectively (P not stated). Verbeek et al. [88] presented the outcomes of 29 adult (20-73 years) patients with high-risk MDS in a prospective, multicenter, randomized, double-blind, placebo-controlled study comparing the efficacy of high-dose AraC and mitoxantrone chemotherapy plus GM-CSF (n = 16) or placebo (n = 13). Complete remission was achieved in 34.5% and 38% (P = .49) and treatment-related mortality was 44% and 23% (P = .22) in the GM-CSF and placebo arms, respectively. Hypomethylating Agents Decitabine Kantarjian et al. [89] presented the results of a multicenter, randomized controlled trial investigating the efficacy of decitabine + supportive care (n = 89) versus supportive care (n = 81) alone in 170 adult (62-76 years) patients with MDS. Supportive care included red blood cell and platelet transfusion as needed. In an intention-to-treat analysis, overall response rate was higher in the decitabine group compared to the supportive care only group (17% versus 0%, P < .001). Median survival was not significantly different between the decitabine and supportive care groups (14.0 versus 14.9 months, P =.636). Azacitidine Silverman et al. [90] reported the results of 191 adult (31-92 years) patients with MDS in a multicenter, randomized controlled study comparing the efficacy of subcutaneous azacitidine-C (Aza C, n = 99) to supportive care alone (n = 92). Both groups received transfusions and antibiotics as needed. In an intention-to-treat analysis, 23% of Aza C and 0% of supportive care patients achieved complete or partial remission (P < .0001). Of the Aza C patients, 37% met the criteria for hematologic improvement compared to 5% of the supportive care patients (P < .0001). The median time to AML or death was 12 months for supportive care compared to 21 months for the azacitidine group (P = .007). For high-risk FAB subtypes (RAEB, RAEB-t, CMML), the median time to AML or death was 8 months for supportive care versus 19 months for the azacitidine group (P = .004). AML transformation as the first event occurred in 38% of the supportive care group compared to 15% of the azacitidine group (P = .001). Crossover from supportive care to azacitidine was allowed, and a subgroup analysis suggested that early azacitidine treatment may improve survival. Immunomodulating Agents This section includes Phase II studies, because Phase III studies and meta-analyses are lacking. Thalidomide Raza et al. [91] reported the outcomes of 83 adult (median age, 67 years) patients with MDS enrolled in a single center, nonrandomized pilot study of the efficacy of thalidomide. Patients were given a daily dose of 100-400 mg orally, as tolerated. Fifty-one patients completed the minimum period for response evaluation of 12 weeks, whereas 32 went off study prior to 12 weeks because of disease progression (n = 6), other medical problems (n = 11), or drug side effects (n = 14). Analysis was on an intention-to-treat basis, with all off-study patients being classified as nonresponders. Sixteen patients (31%) showed hematologic improvement; no complete remissions were achieved. Strupp et al. [92] presented the results of 34 adult (54-83 years) patients with MDS in a single center, nonrandomized pilot study of thalidomide. Patients received a 100 mg dose, which was increased every week by 100 mg until hematologic improvement was achieved or adverse events occurred. The dose was continued until no further improvement was noted, then gradually decreased as long as peripheral blood counts were maintained. At a median follow-up of 13 months, 4 patients discontinued treatment because of side effects, 1 died, 6 showed progressive disease (including 5 with AML transformation), 4 had stable disease, and 19 (56%) showed hematologic improvement; none achieved complete response. Lenalidomide List et al. [93] reported the outcomes of 43 adult (28-85 years) patients with MDS treated in a single center, nonrandomized study of the safety and efficacy of lenalidomide. Patients received 25 mg daily (n = 13, arm A), 10 mg daily (n = 13, arm B), or 10 mg daily for 21 days of every 28-day cycle (arm C, n = 17). Adverse effects resulted in decreased dosing or interruption of treatment in 25 (58%) patients. Response to treatment was assessed at 16 weeks. Twenty-four (56%) patients had a hematologic response, including 20 with sustained transfusion independence. List et al. [94] presented the results of a multicenter study to determine the efficacy of lenalidomide in reducing transfusion dependence in 148 adult (37-95 years) MDS patients with chromosome 5q deletion. Forty-six patients received 10 mg of lenalidomide daily for 21 of a 28-day cycle, and 102 received continuous daily dosing. Patients were assessed for response after 24 weeks of treatment by an intention-to-treat analysis. Of 148 patients, 112 (76%) responded to treatment, with 99 achieving transfusion independence and 13 patients achieving a >50% reduction in transfusion need. There was no significant difference in response rate between the two treatment schedules (P = .26). At a median follow-up of 104 weeks, 53 patients remained transfusion independent. Of 85 patients for whom baseline and week 24 cytogenetic data were available, 38 (45%) had a complete cytogenetic remission and 24 (28%) had a partial cytogenetic response. Raza et al. [95] reported the results of 214 adult (27-94 years) patients enrolled in a multicenter trial of the efficacy of lenalidomide in the treatment of transfusion-dependent, low- or intermediate-1-risk MDS with karyotypes other than chromosome 5q deletion. Patients received 10 mg lenalidomide daily (n = 100) or for 21 days of a 28-day cycle (n = 114). In an intention-to-treat analysis, 56 (26%) patients achieved transfusion independence after a median 4.8 weeks of treatment, which was maintained at a median of 41 weeks. An additional 37 patients achieved a ≥50% reduction in transfusions, yielding a 43% overall rate of hematologic improvement. Infliximab (monoclonal antibody) Raza et al. [96] presented the outcomes of 37 adult (median age, 68 years) patients in a single-center trial evaluating the efficacy of treatment with infliximab, a chimeric monoclonal antibody, in low-risk MDS. Patients received either 5 (n = 18) or 10 (n = 19) mg/kg of infliximab intravenously every 4 weeks for 4 cycles. Of 37 patients, 27 were able to complete all 4 cycles, whereas 10 discontinued therapy because of disease progression or adverse effects. In an intention-to-treat analysis, there were 8 (21.6%) responders, 3 from the 5 mg/kg cohort and 5 from the 10 mg/kg cohort. Two patients achieved transfusion independence and two patients had a >50% reduction in transfusions. Quality of Life This section provides information on common symptoms of MDS that influence patient quality of life, as well as several studies of treatment effectiveness in improving the quality of life for MDS patients. The data in this table are provided for the reader's information and were not used to make treatment recommendations. MDS Symptoms and Quality of Life Steensma et al. [97] reported the results of 359 adult (20-90 years) patients with MDS in a multicenter study examining MDS-associated symptom burden and the correlation of these symptoms with specific disease variables, such as hemoglobin level. A 120-item Internet-based survey incorporated several validated quality of life measurement instruments, including the Charlson Co-Morbidity Index, the Brief Fatigue Inventory (BFI), the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale, and the Godin Leisure Time Activity Score, as well as patient-reported demographic and disease-specific information and most recent blood counts. Fatigue was the most commonly reported symptom (89%), followed by bruising/bleeding (55%), night sweats (43%), bone pain (39%), fevers (28%), skin rash (25%), undesired weight loss (25%), and recurrent infections (20%). Fatigue was associated with impairment of health-related quality of life and ability to work or engage in desired activities. Patient mean scores on quality of life measures were significantly worse than the published norms (controls) obtained by administering the BFI to 290 healthy persons and the FACT-An to 1400 members of the general population. Means of 50.5 and 77.1 (P < .0001) on the FACT-An (where “100” is the best result) and 5.8 and 2.2 (P < .0001) on the BFI (where “0” is the best result) were obtained for patients and controls, respectively. There was no correlation between BFI or FACT-An scores and patient-reported hemoglobin level or transfusion requirement. Jansen et al. [98] presented a multicenter study investigating the association between severity of chronic anemia and health-related quality of life in 50 adult (49-93 years) patients with MDS. Hemoglobin level was measured during an outpatient visit, and patients completed a questionnaire consisting of the Short Form 36, the Multidimensional Fatigue Inventory, and the EuroQOL-5D Visual Analog Scale within 24 hours. Median scores on the three scales were worse for MDS patients than for controls of similar age and sex from the general population, specifically on physical functioning, role physical, and physical sum score on the Short Form-36 and the physical fatigue score on the Multidimensional Fatigue Inventory. There were significant correlations between hemoglobin level and the Visual Analog Scale score (P = .05), the dimensions of physical functioning (P < .001), role physical (P = .02), vitality (P = .02), and physical sum score (P = .01) on the Short Form-36, and the physical fatigue (P = .03) and reduced activity (P = .02) scores on the Multidimensional Fatigue Inventory. Effect of Treatment for MDS on Quality of Life Epoetin ± G-CSF The Casadevall et al. [86] study described previously in this review examined the impact of treatment with rHuEpo + rHuG-CSF on the quality of life of MDS patients. A validated French version of the FACT-An questionnaire was administered to the treatment and control (supportive care only) groups at baseline and weeks 12, 28, and 52 to measure four general domains of quality of life: physical, social/family, emotional, and functional well-being. The baseline questionnaire was completed by 96.7% and 93.3% of patients in the treatment and control groups, respectively, with a completion rate of 50.0% and 66.7% by week 52. Total FACT-An, anemia, and fatigue scores were similar for the two groups at baseline and throughout the study, indicating no significant effect of treatment with rHuEpo + rHuG-CSF on quality of life. Spiriti et al. [99] examined the impact of patient response to treatment with epoetin alpha on quality of life and fatigue in 133 adult (37-92 years) low-risk MDS patients enrolled in a prospective, noncontrolled, multicenter study. The FACT-An questionnaire was administered at baseline (n = 103, 77%), week 4 (n = 97, 73%), and week 8 (n = 86, 65%) after start of epoetin alpha treatment. FACT-An score changes from baseline were positively associated with hemoglobin changes at week 4 (P = .07) and week 8 (P = .01). The mean FACT-An scores increased from baseline to week 8 by +10.2 and +5.6 points in responders and nonresponders, respectively. Darbepoetin Stasi et al. [100] reported the results of a multicenter, noncontrolled study of the impact of response to darbepoetin alfa on the quality of life of 53 adult (59-82 years) patients with low- and intermediate-1-risk MDS. Patients received a 150-μg fixed dose of darbepoetin alfa administered subcutaneously once a week for 24 weeks. Quality of life was assessed using the Linear Analog Scale Assessment and FACT-An. Forty-eight patients (90%) completed 24 weeks of treatment, with an erythroid response of 45% (95% CI 31%-59%). There was a mean increase in Linear Analog Scale Assessment and FACT-An scores for hemoglobin responders, whereas nonresponders had a mean decrease in quality of life scores. Hemoglobin level was significantly related to improved quality of life scores on FACT-An (P = .025) and to energy level (P = .036), daily activities (P = .001), and overall well-being (P = .024) on the Linear Analog Scale Assessment. Azacitidine Kornblith et al. [101] and Silverman et al. [90] reported the results of 191 adult (30-80+ years) MDS patients in a randomized, multicenter Cancer and Leukemia Group B (CALGB) trial assessing the impact of treatment with Aza C (75 mg/m2 subcutaneous for 7 days every 4 weeks) versus supportive care on quality of life. A questionnaire consisting of the EORTC QOL and the Mental Health Inventory was administered to patients by standard telephone interview before randomization and on days 50, 106, and 182 after start of Aza C. Patients treated with Aza C showed significant improvements in fatigue (EORTC, P = .001), physical functioning (EORTC, P = .002), dyspnea (EORTC, P = .0014), psychosocial distress (Mental Health Inventory, P = .0015), and positive affect (Mental Health Inventory, P = .0077) compared to the supportive care group. Future Directions Areas of Needed Research After reviewing the evidence, the expert panel identified the following important areas of needed research in MDS: 1.The benefit of using alternative donor sources (eg, cord blood; haploidentical family donors) for patients without matched sibling or unrelated donors. 2.The role and appropriate timing of allogeneic SCT in combination with hypomethylating and immunomodulatory treatment regimens. 3.Randomized trials comparing the safety and efficacy of various novel agents for treating MDS. 4.The influence of the various MDS treatment modalities on patient-reported quality of life outcomes. Ongoing Studies Several studies are summarized below that address areas of needed research or other issues that may affect the treatment recommendations made in Table 3. These studies are currently accruing patients, are ongoing, or have been published in abstract form. Alternative Donor Sources Takahashi et al. [102] evaluated the safety and efficacy of unrelated bone marrow transplantation (n = 532) versus unrelated cord blood transplantation (n = 433) in a single-center study of 965 patients with MDS or secondary AML treated between 1993 and 2006. Compared with bone marrow recipients, cord blood recipients were older (median age, 52 versus 39 years), included more secondary AML patients (58% versus 38%), and were more likely to have received a reduced intensity regimen (55% versus 18%). Median follow-up was 21 and 12 months for bone marrow and cord blood transplantation, respectively. TRM (25% versus 38% at 1 year, P < .01), relapse (15% versus 26% at 3 years, P < .01), and DFS (57% versus 29% at 3 years, P < .01) were better for bone marrow compared with cord blood transplantation, respectively. The National Heart, Lung, and Blood Institute (NHLBI) has sponsored a Phase III, randomized, multicenter, prospective study (BMT CTN-0501) of single versus double cord blood transplantation in pediatric (2-21 years) patients with hematologic malignancies, including MDS at any stage. Overall survival will be measured one year after study entry, and patients will be followed for at least 24 months posttransplantation. The NHLBI and the National Cancer Institute have sponsored a Phase III, randomized, multicenter, prospective study (BMT-CTN 0201) of G-CSF-mobilized peripheral blood stem cells versus bone marrow from unrelated donors for allogeneic transplantation in patients up to 66 years of age with hematologic diseases, including MDS. Patients will be randomized to either the peripheral blood or bone marrow group in a 1:1 ratio, and will be stratified by transplantation center and disease risk. Two-year OS is the primary outcome measure. Transplantation Techniques The FHCRC has sponsored a Phase III, randomized, multicenter, prospective study comparing myeloablative (fludarabine + busulfan or cyclophosphamide + busulfan) versus nonmyeloablative (fludarabine + low-dose TBI) conditioning regimens for 270 patients (≤65 years) with MDS or AML undergoing allogeneic peripheral blood stem cell transplantation. Two-year OS is the primary outcome measure, and patients are followed for 5 years. The Southwest Oncology Group (SWOG) has sponsored a Phase III, randomized, multicenter, prospective study (SWOG-S9920) comparing busulfan + TBI versus cyclophosphamide + TBI conditioning regimens for 240 patients (16-55 years) with MDS or secondary AML undergoing HLA-identical sibling peripheral blood stem cell transplantation. Patients are stratified by disease, age, and IPSS risk group. EFS is the primary outcome measure. Transplantation in Older Patients The Center for International Blood and Marrow Transplant Research (CIBMTR) has sponsored a multicenter study evaluating patient, disease, and treatment factors in relation to transplantation outcomes in older (40-65+ years) patients. A total of 6632 patients with MDS (n = 1491), AML (n = 1613), CML (n = 2590), or diffuse or follicular non-Hodgkin lymphoma (NHL) (n = 938), who received allogeneic stem cell transplantation from an HLA-identical sibling or unrelated donor and were reported to the CIBMTR between 1995 and 2005, are included in the analysis. Patients are stratified by disease and age. DFS and OS are primary outcome measures. Novel Agent Versus Supportive Care Passweg et al. [103] reported the results of a Phase III, randomized, multicenter, prospective study (SWS-SAKK-33/99) comparing the outcomes for 88 patients (23-75 years) with MDS treated with antithymocyte globulin + cyclosporine (ATG + CSA, n = 45) versus best supportive care (BSC, n = 43) between 2001 and 2006. Patients with CMML, RAEB-t, or treatment-related MDS were excluded from the trial. Patients were stratified by treatment center and IPSS risk score. At 6 months, 13 versus 5 patients had a hematologic response in the ATG + CSA and BSC groups, respectively (P = .04). Two-year OS was 49% in the ATG + CSA group versus 61% in the BSC group (P = .90). Strengths/Limitations and Discussion 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 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 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 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, 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 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). Acknowledgments The American Society for Blood and Marrow Transplantation and Drs. Hahn and McCarthy are indebted to the members of the MDS Review Expert Panel and the ASBMT Evidence-Based Review Steering Committee, who voluntarily and enthusiastically participated in this endeavor. The authors of this review and the American Society for Blood and Marrow Transplantation thank the National Marrow Donor Program, and especially Jeffrey Chell, MD, and Michael Boo, for their support of this project. The authors acknowledge Dr. C. Fred LeMaistre for pioneering and supporting this effort, and Alan Leahigh and Dianne O'Rourke for their invaluable administrative assistance. The authors are grateful to all the patients who participated in the clinical trials, which led to the evidence upon which this review is based. Financial disclosure: Major funding for this study was provided by the National Marrow Donor Program. References 1. 1Hahn T, Wolff SN, Czuczman M, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol Blood Marrow Transplant. 2001;7:308–331.
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Financial disclosure: See Acknowledgments on page 169. PII: S1083-8791(08)00590-9 doi:10.1016/j.bbmt.2008.12.003 © 2009 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. | |
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