The evolution of hematopoietic SCT in myelodysplastic syndrome

Abstract

Allogeneic hematopoietic SCT (allo-HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Numerous myeloablative (MA), nonmyeloablative SCT (NST) and reduced conditioning transplant (RIC) studies have included MDS patients. Twenty-four MA HCT studies published from 2000 and 2008 reported OS and disease-free survival (DFS) ranging from 25 and 16% at 2 years to 52 and 50% at 4 years. In these publications, the incidence of grades II–IV acute GVHD was 18–100%, chronic GVHD 13–88%, relapse risk 24% at 1 year to 54.5% at 4 years and TRM 19% at day 100 to 61% at 5 years. From 2003 to 2008, 30 publications combining RIC and NST reported OS and DFS from 22 and 20% at 2 years to 79 and 79% at 4 years. Incidence of grades II–IV acute GVHD ranged from 9 to 63%, chronic GVHD 18 to 80%, relapse risk 6 to 61% and TRM 0% at day 100 to 34% at 5 years. The wide range in the published results leaves many unanswered questions. Although no ideal transplant conditioning has emerged, many of the MA and RIC studies used BU-based regimens and used a recipient age cutoff of 50–55 years for MA HCT. Similarly, there is no agreement on the use of induction or hypomethylating therapy before HCT, but azacitidine and decitabine are gaining increasing attention as a bridge to HCT. Until recently, the International Prognostic Scoring System (IPSS) dictated the use and timing of HCT. The WHO classification and WHO Prognostic Scoring System (WPSS) may be better suited in predicting the outcomes and should probably be incorporated in transplant algorithms. Most published MDS transplant series combine matched related donors (MRD) and matched unrelated donors (MUD). Umbilical cord blood (UCB) grafts will likely broaden the population of MDS patients eligible for allografting, but outcome data for MDS are scant. At this time, it is reasonable to consider the availability of an MRD or MUD as separate from an UCB graft in the decision of transplantation for MDS. The development of RIC, improvements in supportive therapy and alternative donor selection will provide better OS for MDS patients undergoing transplantation. Simultaneously, better understanding and medical therapy of MDS are leading us to re-examine patient selection and the timing of HCT. The results of HCT for MDS continue to improve together with the outlook of patients afflicted with myelodysplasia.

Introduction

As the population of industrialized countries continues to age, the prevalence of myelodysplastic syndrome (MDS) is increasing. According to SEER data (2001–2003), 86% of all MDS diagnoses were in individuals over 60 years of age with a 2-year OS <20% in patients with advanced MDS.1 Over the past 10 years, medical treatment for MDS has evolved from supportive measures, such as hematopoietic growth factors, transfusions and antibiotics to drug therapy, aimed at increasing survival. Although not curative, hypomethylating agents can improve marrow function, delay progression to acute leukemia and extend OS in MDS patients. Nevertheless, the only potential curative therapy remains allogeneic hematopoietic SCT (allo-HCT). Only studies published since 2000 on the use of myeloablative (MA) HCT and studies published since 2003 on the use of reduced intensity conditioning (RIC) and nonmyeloablative SCT (NST) in patients with MDS are included in this review. The review emphasizes allogeneic transplantation conditioning and graft sources, but also explores timing of transplantation, medical therapy before HCT, auto-SCT and new challenges in the treatment of these patients.

Medical therapy

Two hypomethylating agents, azacitidine and decitabine, have recently been approved by the Food and Drug Administration for the treatment of MDS. Both drugs are cytotoxic at high doses but at low doses they are thought to revert aberrant DNA methylation associated with gene silencing in the MDS clone. Presumably, this reactivation of epigenetically silenced genes explains responses ranging from the improvement of peripheral counts to resolution of chromosomal abnormalities. The first drug, azacitidine, was compared with supportive care in a randomized study.2 In that study, the overall response rate as defined by CR+PR+hematologic improvement was 60% for azacitidine compared with 5% for supportive care. Because of a cross-over design, differences in OS between the arms could have been muted. The median survival was 20 months (95% confidence interval, 16–26 months) for patients randomized to azacitidine compared with 14 months (95% confidence interval, 12–14 months) for patients undergoing supportive care (53% of whom received azacitidine after cross-over) (P=0.10). A recent study re-analyzed the data from three separate azacitidine trials using the WHO criteria and International Working Group (IWG) criteria; CR was seen in 10–17% of patients, PR were rare, and 23–36% of patients had hematologic improvement.3 The median duration of responses was 13.1 months. A new study, without a cross-over design, randomized patients to azacitidine or one of the three conventional care regimens that included supportive care, low dose cytarabine or induction chemotherapy.4 Median follow-up for OS analysis was 21.1 months. Azacitidine resulted in superior OS with a median Kaplan–Meier OS time of 24.4 vs 15 months for the conventional care regimen (P=0.0001).

Decitabine received approval based on a randomized trial vs supportive care without a cross-over design.5 Patients in the decitabine arm had an improved overall response rate (CR+PR+hematologic improvement) of 30%, decreased transfusion requirements, improved quality of life and a trend toward a longer median time to AML progression or death compared with patients who received supportive care alone (all patients, 12.1 vs 7.8 months (P=0.16)). For patients with the International Prognostic Scoring System (IPSS) intermediate-2/high risk, OS was 12.0 vs 6.8 months (P=0.03); for those with de novo disease, 12.6 vs 9.4 months (P=0.04); and for treatment-naive patients, 12.3 vs 7.3 months (P=0.08)). Published data support a stronger effect on OS for azacitidine than for decitabine. Whether this should determine the choice of either agent as a bridge to HCT in MDS remains to be determined.

A third agent approved by the Food and Drug Administration for MDS is lenalidomide, an immunomodulatory drug with marked activity in low grade MDS, particularly in the 5q- syndrome. In a study of 43 patients, response rates among those with deletion 5q31.1 were 83 vs 57% for those with normal karyotype and 12% for patients with other abnormalities (P=0.007).6 Of the 20 patients with karyotypic abnormalities, 11 had at least a 50% reduction in abnormal cells in metaphase, including 10 (50%) with a complete cytogenetic remission. Furthermore, a pivotal trial showed that lenalidomide rendered 67% of patients with 5q- transfusion independent.7

Despite the new drug development, allo-HCT is the only treatment that leads to complete and permanent eradication of the MDS clone, as evidenced by long-term donor hematopoiesis.8, 9, 10 Although selected patients over the age of 60 years may be offered MA HCT,11 fully ablative HCT results in excessive TRM for most patients with MDS, as 86% of them are over that age at diagnosis. Fortunately, RIC, NST and the wide use of unrelated donors have expanded the eligibility for HCT to a vast number of MDS patients, but with these advances new concerns have arisen. One of the most important is whether milder conditioning with high disease burden is accompanied by high relapse rates. As both, drug therapy and HCT strategies evolve, treatment decisions are certain to become more complex. Future therapeutic options are likely to combine both newer drugs and HCT.

Indication and timing of HCT in MDS

In contrast to acute leukemia, there are no large published studies comparing allo-HCT to medical therapy for MDS. A pivotal, retrospective IBMTR study compared a non-transplant cohort from the International MDS Risk Analysis Workshop and two transplant cohorts, one with patients diagnosed with MDS and the other patients with secondary AML transformed from MDS.12 The study showed that patients with IPSS intermediate-2- and high-risk MDS benefited from immediate HCT with matched related donors (MRD), whereas those in the IPSS low- and intermediate-1-risk groups gained in OS by delayed HCT. Of note, the cohort median ages were 40–50 years, only MA conditioning was included, and IPSS score was the only parameter analyzed against outcome. In spite of the shortcomings of this registry study, the recommendations to delay transplantation in low- or intermediate-1-risk MDS and offer HCT to patients with intermediate-2- and high-risk MDS have been largely adopted by most transplant centers.

Unfortunately, the IPSS does not capture all the risk elements affecting survival of patients who receive medical or HCT therapy. For example, the IPSS excludes secondary MDS, chronic myelomonocytic leukemia with leukocytosis and those patients with earlier therapy. A newly proposed risk model of MDS, validated in these patients and in de novo MDS, identified the following independent adverse factors: poor performance, older age, thrombocytopenia, anemia, increased BM blasts, leukocytosis, chromosome 7 or complex (3) abnormalities and earlier transfusions.13

A new study of 365 patients from the GITMO examined the power of the WHO classification and WPSS as predictors of post transplant outcome in MDS.14 The 5-year OS ranged from 80% in refractory anemia (RA) to 57% in RA with multilineage dysplasia, 51% in RA with excess blasts (RAEB)-1, 28% in RAEB-2 and 25% in acute leukemia arising from MDS. Increasing 5-year probability of relapse and TRM were seen for each category of increasing disease severity. Transfusion dependence was associated with a reduced OS and increased TRM. The negative effect of multilineage dysplasia and transfusion-dependence on OS and TRM extended to patients without excess blasts as well.

Because of the limitations listed above, IPSS intermediate-2- and high-risk MDS are no longer the only indications for HCT. The newer risk models identify factors that affect outcomes across medical and HCT therapies. Transfusion requirement is a particularly troublesome factor, as it appears to worsen outcomes regardless of the therapy chosen. Although chelation therapy may change this paradigm, it seems appropriate to consider HCT in patients with lower IPSS who become transfusion dependent and do not respond to medical therapy. Likewise, patients with adverse cytogenetics but preserved marrow function may be considered for HCT even with a low IPSS score. The optimal timing for HCT in patients with secondary MDS remains undetermined. Therapy-related MDS carries worse prognosis than de novo MDS. The new MDS scoring system may prove helpful in refining HCT indications in both de novo and secondary MDS.

Upfront transplantation, induction or low-intensity therapy before HCT

Relapse is an important barrier to the success of HCT in MDS. Higher IPSS disease score and earlier transfusions are known to predict for worse OS. Although never studied in a prospective manner, relapse is felt to be more likely after RIC and NST than MA HCT. Patients with high-grade MDS are often considered for cytoreductive therapy before HCT. A study by de Witte et al.15 evaluated intensive chemotherapy before allo- or auto-HCT. Remission-induction treatment included 1–2 cycles of idarubicin, cytarabine and etoposide followed by one consolidation with cytarabine and mitoxantrone. CR was attained in 54% of patients who underwent the remission-induction chemotherapy. Allografts were able to be performed in 72% of patients who had a donor with a median 4-year disease-free survival (DFS) of 31%. Whether high-intensity therapy contributes to DFS or introduces selection bias could only be answered with a carefully designed randomized trial using intent-to-treat analysis. A recent Japanese study compared induction chemotherapy before MA allo-HCT vs upfront HCT.16 Five-year OS in RAEB-transformation (RAEB-t) and secondary AML was 57% for upfront HCT and 54% for induction chemotherapy before HCT, which was not statistically significant (P=0.81). The surprisingly equal OS between the two groups brings into question whether induction chemotherapy leads to higher TRM and offsets the benefit of cytoreduction before HCT at least when considering full ablation.

Relapse is a frequent outcome of RIC and NST for advanced MDS. For example, an NST series in RAEB and RAEB-t using TBI 2 Gy and fludarabine (Flu), showed a relapse rate of more than 0.52 per patient/year.17 As induction chemotherapy is not suitable for many patients with MDS, hypomethylating agents are gaining attention as prelude to RIC and NST.

A study of patients with advanced MDS treated with decitabine showed a better OS rate compared with historic controls receiving intensive chemotherapy owing to lower early mortality, not to response rate.18 Recently, a pilot study analyzed the outcomes of 12 patients with MDS with a median age of 58 years who received decitabine before undergoing an allo-HCT with MRD, matched unrelated donors (MUD) or umbilical cord blood (UCB) grafts. After a median follow-up of 11 months, 8 patients are in CR.19 A larger study analyzed the outcomes for 34 MDS patients who had a MA HCT from either a MRD or MUD, 14 patients had received 1–7 cycles of azacitidine before transplantation.20 The 1-year Kaplan–Meier estimates for OS and PFS were 64 and 64% for the azacitidine group vs 70 and 51% for the non-azacitidine group. At this time there is no clear evidence that intensive chemotherapy or hypomethylating agents impact the outcome of HCT for MDS, and selection bias may play a large role in the studies conducted thus far. Upfront transplantation and HCT preceded by induction chemotherapy or hypomethylating agents are all valid approaches in advanced MDS and deserving of further studies.

Age and conditioning

As the US population ages, MDS will be diagnosed in more patients. Individuals over age 70 years have a 61.8% age-adjusted incidence of MDS.21 The vast majority of MDS diagnoses occur in individuals over the age of 55–60 years, often considered the cusp for the use of full myeloablation. A study of outcomes in 215 patients aged 50–67 (median 57) years who underwent allogeneic MA HCT for early or advanced hematologic malignancies showed a day +100 and day +365 TRM of 13 and 30% for early disease and 21 and 49% for late stage disease.22 Advanced disease and grades II–IV GVHD were determining factors for TRM in this older patient population. A second study compared MA HCT for 436 patients, age >50 years (n=59), 40–50 years (n=124) and <40 years (n=253).23 TRM at day +100 ranged from 24 to 18% and from 36 to 33% at 1 year. OS at 2 years were 48, 48 and 58% for each group, respectively. With the exception of higher TRM at day 30 for the older cohort, there were no significant differences in TRM or OS for the groups. A study from Seattle on 52 patients with a median age 63 (60–68) years showed that MA HCT from MRD resulted in non-relapse mortality (NRM) at 100 days and 3 years of 27 and 43%.11 Although MA HCT may be a viable option for selected patients over age 50 years, the relatively high TRM/NRM has provided impetus for the use of NST and RIC in patients over 55–60 years of age and in those with comorbid conditions. For example, the use of 2 Gy TBI combined with Flu resulted in a cumulative 3-year NRM of 21% for standard-risk patients with a median age of 55 years.17 No randomized prospective studies have compared NST or RIC vs MA HCT, but a retrospective review comparing NST and MA for patients >50 years with various hematological malignancies showed a trend toward improved OS at 2 years in the NST arm with no difference in PFS.24 The relapse risk was greater with the NST conditioning, but the NRM was lower.

Although the existing data for NRM do not provide a strong bias favoring RIC for patients in the 50–60 years age bracket, there are also no compelling MDS studies that favor MA over RIC/NST in terms of OS and DFS. GVHD is more common in older individuals undergoing HCT. RIC and NST result in lower incidence of acute GVHD compared with MA conditioning. This element may favor the use of RIC in individuals over age 50 years with MDS. Improvements in RIC and NST regimens, GVHD prophylaxis, supportive care and medical therapy of MDS will afford HCT to increasingly older patient populations.

Stem cell source

Two meta-analyses have compared PBSCs to BM grafts in MA allo-HCT.25, 26 Compared with BM grafts, PBSC grafts had faster neutrophil and platelet recovery, with decreased relapse rates at 3 years (21 vs 27%) in both early and late stage disease.25 No difference was seen in NRM between the two stem cell sources. Unfortunately MDS only constituted 5–13% of diagnoses; therefore, no conclusions can be drawn about the best stem cell source for MDS patients. Both trials showed an increased relative risk of acute and chronic GVHD with PBSC grafts.25, 26 In NST, faster neutrophil recovery, decreased transfusion requirements and increased risk of chronic GVHD (86 vs 42%) was seen with PBSCs.27 An EBMT study on 234 MDS patients who underwent MRD HCT analyzed outcomes according to BM (n=132) or G-CSF-mobilized PBSC (n=102) grafts.28 The use of PBSC was associated with a decrease in treatment failure, despite a higher proportion of patients with low-risk MDS in the BM group resulting in 2-year EFS of 50% in the PBSC group and 39% in the BM group. Neutrophil recovery failed in only seven patients in each group (P=0.60), but neutrophil recovery occurred significantly earlier in the PBSC cohort. In summary, PBSC allografts appear superior to BM for patients with advanced MDS. They convey a possible decreased relapsed risk accompanied by an increased risk of acute and chronic GVHD.

Autologous transplantation

Auto-SCT has been used as a consolidation modality in patients with AML in CR1 and beyond who lack a suitable donor. Less is known about its use in MDS (Table 1). One study on the long-term outcomes of MDS patients who underwent auto-SCT in CR after intensive chemotherapy showed that although auto-SCT was feasible in 60% of patients who achieved a CR, the relapse rate was 75% with most of the events occurring in the first 2 years.29 Of note, the use of PBSCs as an autograft provided faster hematopoietic recovery but resulted in similar outcomes to BM.30

Table 1 Autologous HCT

A multicenter study compared allo- and auto-HCT as post-consolidation therapy for patients with advanced MDS, secondary AML or chronic myelomonocytic leukemia according to the availability of a MRD. Four-year DFS and OS in patients with or without a MRD were 31 vs 27% and 36 vs 33%, respectively.15 Three EBMT studies have addressed auto-SCT for MDS and tAML. One report on 65 patients who underwent auto-SCT showed a cumulative incidence of relapse of 58% and TRM of 12%.31 An earlier study compared MUD and MRD HCT with auto-SCT and showed 3-year DFS for MUD: 25%, MRD: 36% and auto-SCT: 30%. Relapse rates of 58% for auto-SCT vs 36% for MRD and 41% for MUD were observed.32 A more recent retrospective study of 593 patients compared MUD HCT with auto-SCT and showed better 3-year OS as follows: MUD-CR1 (50%), auto-SCT-CR1 (41%) and MUD-untreated (40%) (P=0.01). A higher relapse rate for auto-SCT-CR1 (62%) was verified compared with 24 and 30% for MUD-CR1 and MUD-untreated (P<0.001).33 Although auto-SCT may be feasible and provide long-term DFS to some MDS patients, a high relapse rate has generally favored allografting.

Myeloablative transplantation

Since the year 2000, 24 trials from around the world, both prospective and retrospective, have evaluated the use of MA allo-HCT in patients with MDS (Table 2). The number of patients included on those trials ranged from 23 to 885 with an age range of 32–59 years. The largest trial was a retrospective review of all transplantations reported to the EBMT from 1983 to 1998.32 A majority of the 1378 patients reported (n=885) received MRD allo-HCT. There were a small number of MUD (n=198), mismatched related donor (n=91) and auto-SCT (n=173) included in the paper, but the mismatched related donor and auto-SCT data were not compared with the MRD allo-HCT data and therefore not included in the table. Only 13 MA studies reported time from diagnosis to transplantation. In those studies, most patients were transplanted within 1 year of diagnosis.

Table 2 Myeloablative HCT

Most of the MA HCT studies included de novo and secondary MDS, chronic myelomonocytic leukemia, myeloproliferative disorders, de novo and secondary AML/tAML. As patient numbers were small, subset analyses for each disease category were not available for most studies. None of the MA studies presented in our review included only de novo MDS. In addition, most of the studies included multiple types of donors; syngeneic, MRD, mismatched related donor, MUD, mismatched unrelated donor and UCB. An article by Chang et al.,48 included a small number of NST transplants (n=26). PBSC and BM stem cell grafts were allowed in most studies. The most commonly used conditioning regimens were BU/CY and CY/TBI in the reviewed studies. GVHD prophylaxis was largely CsA-based. Only one study, carried out at the Fred Hutchinson Cancer Research Center, formally compared different MA regimens in MDS.53 Seventy-eight patients received oral BU 16 mg/kg targeted to plasma concentrations of 800–900 ng/ml and CY 2 × 60 mg/kg, and 50 patients received BU 7 mg/kg and TBI 1200 cGy over 3 days. There was no significant difference in OS, EFS and NRM between the two regimens regardless of donor status negating the perception that targeted therapy offers improvements in these parameters.

Length of follow-up varied between the studies ranging from 5 months to 7.9 years. The risk of grades II–IV acute GVHD varied from 18 to 100%. The lowest and highest published relapse risks were 24% at 1 year to 36% at 5 years. In a study by Chang et al.,48 the relapse risk was 33% for tAML, 36% for RAEB and 12% for RA/RA with ringed sideroblasts at 5 years. OS and NRM ranged from 25% at 2 years to 52% at 4 years and from 19% at day +100 to 61% at 5 years, respectively. In many studies the incidence of primary graft failure ranged from 0 to 9%. One study with an incidence of approximately 14% primary graft failures had a majority of patients transplanted with genotypically non-identical-related donors.37

Hematopoietic SCT remains the only curative therapy for MDS. MA HCT has a high TRM and is limited to young patients with few comorbidities. Moreover, the MA studies reported here have a short follow-up. Future goals for MA HCT include deciding on the best use of pretransplant therapy, better selection of eligible patients and improvement of supportive care measures.

Non-ablative/reduced-intensity transplantation

Myelodysplastic syndrome is more prevalent in older adults. In this setting, an estimated 3-year NRM of 43% in MA HCT11 favors NST and RIC, but a concern is that less cytoreduction could yield higher relapse rates. Of note, in this review NST and RIC terms were used as defined by the authors of the publications. One study comparing NST vs RIC transplantation for patients with MDS and AML did not show any difference in actuarial survival (P=0.790).54 Since the year 2003, 30 studies addressed the use of NST or RIC HCT for MDS (Table 3). Both retrospective and prospective studies from multiple centers around the world included cohorts of 16–215 patients with a median age >40 years with the exception of a pediatric trial from Germany.69 In the 13 trials that provided such data, there was a longer time from diagnosis to transplantation in the NST trials compared with the MA trials. The range for time of diagnosis to HCT in those articles was approximately 2–18 months. Induction chemotherapy was given to a small portion of patients on the NST trials. Unfortunately, no trial specifically looked at induction therapy before HCT. The chemotherapy regimens that these patients received were not detailed in the reviewed publications.

Table 3 Nonmyeloablative and reduced-intesity HCT

Patients with MDS, secondary AML, tAML, chronic myelomonocytic leukemia, de novo AML, myeloproliferative disorder, non-Hodgkin's lymphoma and Hodgkin's lymphoma were included in these studies obscuring the results for MDS. The graft types used in those studied included MRD, mismatched related donor, MUD and mismatched unrelated donor grafts. PBSCs, BM stem cells and UCB stem cell grafts were used for the transplantations. Only three studies exclusively used PBSCs. The most common conditioning regimens used were fludarabine-based. CYA and tacrolimus were the most frequently used agents for GVHD prophylaxis.

With the exception of one trial reporting 23% primary engraftment failure,54 the remaining studies showed 15% primary engraftment failure. The reported incidence of grades II–IV GVHD was 9–63%. Relapse risk was between 6 and 61%. OS ranged between 44% at 1 year to 46.1% at 5 years. NRM was between 0% at day +100 and 33.9% at 5 years. The median follow-up of the patients on study ranged from 14 months to over 4 years.

Many of the NST trials have short patient follow-up and small sample sizes. In general, a high relapse rate, surprising low engraftment failure and low NRM were seen in these trials. RIC and NST are feasible treatment modalities for older patients with MDS. There is a large overlap in the rate of OS and DFS published for MA and RIC/NST. It is therefore fair to speculate that RIC and NST may be appropriate for younger patients with MDS that could otherwise tolerate myeloablation. This dilemma cannot be settled with the data presently available and a protocol-driven decision is probably the best way to approach it. Reserving MA HCT for young (<40–45 years) patients with MDS and offering RIC to all others, especially if they had a response to initial therapy with hypomethylating agents appears a sensible approach as prospective data accumulates.

Umbilical cord blood transplantation

A study on 450 BMT and 150 UCB recipients from 1996 to 2001 included 25 MDS patients who received MUD BM, 2 who received 1 antigen mismatched BM, and 10 with 1–2 antigen mismatched UCB.74 For the entire cohort, UCB conveyed less acute but more chronic GVHD. A subset analysis evaluating the MDS patients in the study was not performed. Overall mortality, TRM and treatment failure were similar for UCB and mismatched BM. A prospective study from Japan using MA UCB for 13 adult patients with advanced MDS showed a 2-year DFS of 76.2%.75 Three patients relapsed and one patient had engraftment failure. Ten patients are alive with no evidence of disease at days +171 to 1558.

A more recent study from Minnesota in patients aged 55 years compared MRD RIC (n=47) vs UCB (n=43).76 AML/MDS comprised 50% of the diagnoses; 23% in the UCB cohort had MDS. The 3-year PFS and OS for MRD and UCB were 30 vs 34%, (P=0.98) and 43 vs 34% (P=0.57). Cumulative incidences of grades II–IV acute GVHD and TRM at 180-days were comparable, but UCB produced less chronic GVHD at 1 year (40 vs 17%). UCB appears a viable allograft for patients with high-risk MDS without a suitable donor. At present, many centers probably give preference to an 8/8 allele-matched MUD over an UCB graft, but lower GVHD rates and potential use of double UCB grafts may change future selection of grafts for HCT. The selection algorithm for less well-matched donors is highly center-specific and beyond the scope of this review. Transplant recommendations for MDS using UCB will continue to evolve as more data on this transplant modality for MDS accumulates.

Persistent challenges

The concept that allo-HCT is the preferred therapy for patients with IPSS intermediate-2- and high-risk MDS is based on a registry study that included young patients receiving MA HCT with MRD. There are several shortcomings to this paradigm. Suggested algorithms for the use of HCT in MDS are presented in Figures 1 and 2. The IPSS does not account for transfusion requirement and multilineage dysplasia, which are known to affect the prognosis of patients with MDS. A new study of the WHO classification and WPSS has shown a strong association between MDS disease severity and transplant outcomes.14 In that study, transfusion dependence emerged as a predictive factor independent of blast count, whereas the outcomes for patients with RA appear very favorable. Thus, patients whose only manifestation of MDS is transfusion-dependence and do not respond to growth factor or other therapy may benefit from HCT in spite of their low IPSS score. Likewise, MDS with monosomy 7 or complex karyotype and preserved marrow would likely be considered an indication for immediate rather delayed HCT in many transplantation centers. Secondary MDS is another special consideration for HCT. As the population of cancer survivors increases, therapy-related MDS will be the focus of more studies, but currently those patients are managed following the same paradigm used in de novo MDS. At the very least, a diagnosis of secondary MDS should prompt a search for an allogeneic donor and possibly the early use of HCT as well. Table 4 summarizes accepted and probable indications of early HCT in MDS.

Figure 1
figure1

Algorithm for HCT in MDS.

Figure 2
figure2

Algorithm for medical therapy in MDS.

Table 4 Indicators for early HCT in MDS

Most patients with MDS who are eligible for HCT are older and are likely to receive a RIC transplant. In addition, the alternative to transplantation now includes medical therapy that can improve OS. No study has compared the outcome of RIC transplantation to current MDS medical therapy either retrospectively or prospectively. As the CIBMTR data on RIC and NST for MDS matures, a retrospective comparative analysis of these two groups of patients is certainly warranted. Any future prospective randomized study will need to address the heterogeneous nature of MDS; perhaps by using the WHO classification and WPSS, which have now been applied to an MDS transplantation cohort.

Future considerations

Older age limits the availability of HLA-matched sibling donors for MDS patients. The use of MUD and UCB for transplantation has been extensively validated in adults with leukemia. Less is known about the outcomes in patients with MDS. Increased risks for GVHD, NRM and infections may offset some of the benefits of allogeneic transplantation over medical therapy. Only carefully designed prospective studies will help to elucidate which therapy is superior. One could envision a large study whereby MRD and MUD allografts would be assigned on the basis of availability. However, such study could only be undertaken by a large consortium such as BMT/CTN.

Optimizing RIC regimens beyond the small number currently under use may yield improvements of OS and EFS. One study exploring the boundary between MA and RIC showed that once daily i.v. BU and Flu+/− antithymocyte globulin appeared higher to i.v. BU and CY+/− antithymocyte globulin as pretransplant conditioning therapy in AML/MDS.77 The case mix precludes making definitive statements about MDS in particular, but patients in CR1 transplanted with the BU–Flu combination had a 3-year OS and EFS of 78 and 74%, respectively.

It is widely recognized that transplantation in the setting of MDS with excess number of BM blasts (>5 to 10%) leads to high rates of relapse. This trend seems especially troublesome when combined with RIC. Therefore, an important question in MDS is whether cytoreductive and/or hypomethylating therapy before allogeneic transplantation, especially with RIC, can improve OS and DFS. The benefit of AML-type induction chemotherapy before RIC is not well established. Microbial colonization, deconditioning and substantial pretransplant mortality may result in inferior survival for the overall approach. Hypomethylating agents are well tolerated on an ambulatory basis, can decrease marrow cellularity and number of blasts. However, this therapy is not curative and most responses are eventually lost. The usefulness and ideal duration of hypomethylating therapy before HCT is currently being tested in single institutions as well as in a multicenter trial under development by CIBMTR.

In the United States of America, the Federal Program that covers individuals over the age of 65 years does not provide allogeneic transplantation benefits for patients with MDS outside of an approved study. Definitive trials to establish the role of allo-HCT in this patient population are urgently needed. Registry studies, especially in collaboration with European investigators may help to pave the way.

References

  1. 1

    Ma X, Does M, Raza A, Mayne ST . Myelodysplastic syndromes: incidence and survival in the United States. Cancer 2007; 109: 1536–1542.

  2. 2

    Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol 2002; 20: 2429–2440.

  3. 3

    Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006; 24: 3895–3903.

  4. 4

    Fenaux P, Mufti GJ, Santini V, Finelli C, Giagounidis A, Schoch R et al. Azacitidine treatment prolongs overall survival in higher-risk MDS patients compared with conventional care regimens: results of AZA-001 phase III study. Blood 2007; 110: abstract 817.

  5. 5

    Kantarjian H, Issa J-P, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106: 1794–1803.

  6. 6

    List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352: 549–557.

  7. 7

    List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355: 1456–1465.

  8. 8

    Witherspoon RP, Deeg HJ, Storer B, Anasetti C, Storb R, Appelbaum FR . Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 2001; 19: 2134–2141.

  9. 9

    Castro-Malaspina H, Harris RE, Gajewski J, Ramsay N, Collins R, Dharan B et al. Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 2002; 99: 1943–1951.

  10. 10

    Deeg HJ, Storer B, Slattery JT, Anasetti C, Doney KC, Hansen JA et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 2002; 100: 1201–1207.

  11. 11

    Wallen H, Gooley TA, Deeg HJ, Pagel JM, Press OW, Appelbaum FR et al. Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 2005; 23: 3439–3446.

  12. 12

    Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104: 579–585.

  13. 13

    Kantarjian H, O'Brien S, Ravandi F, Cortes J, Shan J, Bennett JM et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original international prognostic scoring system. Cancer 2008; 113: 1351–1361.

  14. 14

    Alessandrino EP, Della Porta MG, Bacigalupo A, Van Lint MT, Falda M, Onida F et al. WHO classification and WPSS predict post transplant outcome in patients with myelodysplastic syndrome: a study from the GITMO (gruppo italiano trapianto di midollo osseo). Blood 2008; 112: 895–902.

  15. 15

    de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 2001; 98: 2326–2331.

  16. 16

    Nakai K, Kanda Y, Fukuhara S, Sakamaki H, Okamoto S, Kodera Y et al. Value of chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome. Leukemia 2005; 19: 396–401.

  17. 17

    Kahl C, Storer BE, Sandmaier BM, Mielcarek M, Maris MB, Blume KG et al. Relapse risk in patients with malignant disease given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2007; 110: 2744–2748.

  18. 18

    Kantarjian HM, O'Brien S, Huang X, Garcia-Manero G, Ravandi F, Cortes J et al. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer 2007; 109: 1133–1137.

  19. 19

    De Padua Silva L, de Lima M, Kantarjian H, Champlin R, Faderl S, Giralt S et al. Outcome of allogeneic stem cell transplantation after hypomethylating therapy with 2′-deoxy-5 azacytidine for patients with myelodysplastic syndrome. Blood 2007; 110: abstract 1468.

  20. 20

    Field T, Perkins J, Alsina M, Ayala E, Fernandez HF, Janssen W et al. Pre-transplant 5-Azacitidine may improve outcome of allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS). Blood 2006; 108: abstract 3664.

  21. 21

    SEER Cancer Statistics Review 1975–2004. National Cancer Institute.

  22. 22

    Ditschkowski M, Elmaagacli AH, Trenschel R, Steckel NK, Koldehoff M, Beelen DW . Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients. Clin Transplant 2006; 20: 127–131.

  23. 23

    Du W, Dansey R, Abella EM, Baynes R, Peters WP, Klein J et al. Successful allogeneic bone marrow transplantation in selected patients over 50 years of age—a single institution's experience. Bone Marrow Transplant 1998; 21: 1043–1047.

  24. 24

    Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005; 105: 1810–1814.

  25. 25

    Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005; 23: 5074–5087.

  26. 26

    Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH . Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol 2001; 19: 3685–3691.

  27. 27

    Dey BR, Shaffer J, Yee AJ, McAfee S, Caron M, Power K et al. Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen. Bone Marrow Transplant 2007; 40: 19–27.

  28. 28

    Guardiola P, Runde V, Bacigalupo A, Ruutu T, Locatelli F, Boogaerts MA et al. Retrospective comparison of bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes. Blood 2002; 99: 4370–4378.

  29. 29

    Ducastelle S, Adès L, Gardin C, Dombret H, Prébet T, Deconinck E et al. Long-term follow-up of autologous stem cell transplantation after intensive chemotherapy in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Haematologica 2006; 91: 373–376.

  30. 30

    de Witte T, Brand R, van Biezen A, Delforge M, Biersack H, Or R et al. The role of stem cell source in autologous hematopoietic stem cell transplantation for patients with myelodysplastic syndromes. Haematologica 2006; 91: 750–756.

  31. 31

    Kroger N, Brand R, van Biezen A, Cahn J-Y, Slavin S, Blaise D et al. Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant 2006; 37: 183–189.

  32. 32

    de Witte T, Hermans J, Vossen J, Bacigalupo A, Meloni G, Jacobsen N et al. Haematopoietic stem cell transplantation for patients with myelodysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the chronic leukaemia working party of the European Group for Blood and Marrow Transplantation. Br J Haematol 2000; 110: 620–630.

  33. 33

    Al-Ali HK, Brand R, van Biezen A, Finke J, Boogaerts M, Fauser AA et al. A retrospective comparison of autologous and unrelated donor hematopoietic cell transplantation in myelodysplastic syndrome and secondary acute myeloid leukemia: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Leukemia 2007; 21: 1945–1951.

  34. 34

    Deeg HJ, Shulman HM, Anderson JE, Bryant EM, Gooley TA, Slattery JT et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 2000; 95: 1188–1194.

  35. 35

    Yakoub-Agha I, de La Salmoniere P, Ribaud P, Sutton L, Wattel E, Kuentz M et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients—Report of the French Society of Bone Marrow Transplantation. J Clin Oncol 2000; 18: 963–971.

  36. 36

    Bibawi S, Abi-Said D, Fayad L, Anderlini P, Ueno NT, Mehra R et al. Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced myelodysplastic syndrome and acute myelogenous leukemia. Am J Hematol 2001; 67: 227–233.

  37. 37

    de Witte T, Pikkemaat F, Hermans J, van Biezen A, Mackinnan S, Cornelissen J et al. Genotypically nonidentical related donors for transplantation of patients with myelodysplastic syndromes: comparison with unrelated donor transplantation and autologous stem cell transplantation. Leukemia 2001; 15: 1878–1884.

  38. 38

    Jurado M, Deeg HJ, Storer B, Anasetti C, Anderson JE, Bryant E et al. Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality. Biol Blood Marrow Transplant 2002; 8: 161–169.

  39. 39

    Sierra J, Perez WS, Rozman C, Carreras E, Klein JP, Rizzo JD et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 2002; 100: 1997–2004.

  40. 40

    Kojima R, Kami M, Kanda Y, Kusumi E, Kishi Y, Tanaka Y et al. Comparison between reduced intensity and conventional myeloablative allogeneic stem-cell transplantation in patients with hematologic malignancies aged between 50 and 59 years. Bone Marrow Transplant 2005; 36: 667–674.

  41. 41

    Solomon SR, Savani BN, Childs R, Montero A, Boss C, Read EJ et al. Improved outcome for peripheral blood stem cell transplantation for advanced primary myelodysplastic syndrome. Biol Blood Marrow Transplant 2005; 11: 619–626.

  42. 42

    Wong R, Shahjahan M, Wang X, Thall PF, de Lima M, Khouri I et al. Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant 2005; 11: 108–114.

  43. 43

    Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2006; 12: 1047–1055.

  44. 44

    Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; 108: 836–846.

  45. 45

    Scott BL, Sandmaier BM, Storer B, Maris MB, Sorror ML, Maloney DG et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia 2006; 20: 128–135.

  46. 46

    Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia 2006; 20: 322–328.

  47. 47

    Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol 2006; 24: 5695–5702.

  48. 48

    Chang CK, Storer BE, Scott BL, Bryant EM, Shulman HM, Flowers ME et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: Similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood 2007; 110: 1379–1387.

  49. 49

    Flynn CM, Hirsch B, DeFor T, Barker JN, Miller JS, Wagner JE et al. Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis. Am J Hematol 2007; 82: 867–872.

  50. 50

    Maruyama D, Fukuda T, Kato R, Yamasaki S, Usui E, Morita-Hoshi Y et al. Comparable antileukemia/lymphoma effects in nonremission patients undergoing allogeneic hematopoietic cell transplantation with conventional cytoreductive or reduced-intensity regimen. Biol Blood Marrow Transplant 2007; 13: 932–941.

  51. 51

    Martino R, Valcarcel D, Brunet S, Sureda A, Sierra J . Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission. Bone Marrow Transplant 2008; 41: 33–38.

  52. 52

    Nevill TJ, Hogge DE, Toze CL, Nantel SH, Power MM, Abou Mourad YR et al. Predictors of outcome following myeloablative allo-SCT for therapy-related myelodysplastic syndrome and AML. Bone Marrow Transplant 2008; 42: 659–666.

  53. 53

    Scott B, Deeg HJ, Storer B, Chauncey T, Petersdorf S, Slattery J et al. Targeted busulfan and cyclophosphamide as compared to busulfan and TBI as preparative regimens for transplantation in patients with advanced MDS or transformation to AML. Leuk Lymphoma 2004; 45: 2409–2417.

  54. 54

    de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104: 865–872.

  55. 55

    Chan GW, Foss FM, Klein AK, Sprague K, Miller KB . Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease. Biol Blood Marrow Transplant 2003; 9: 753–759.

  56. 56

    Kroger N, Bornhauser M, Ehninger G, Schwerdtfeger R, Biersack H, Sayer HG et al. Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol 2003; 82: 336–342.

  57. 57

    Taussig DC, Davies AJ, Cavenagh JD, Oakervee H, Syndercombe-Court D, Kelsey S et al. Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol 2003; 21: 3060–3065.

  58. 58

    Wong R, Giralt SA, Martin T, Couriel DR, Anagnostopoulos A, Hosing C et al. Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 2003; 102: 3052–3059.

  59. 59

    Ho AYL, Pagliuca A, Kenyon M, Parker JE, Mijovic A, Devereux S et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 2004; 104: 1616–1623.

  60. 60

    Malladi RK, Peniket AJ, Norton AE, Campbell AJ, Collins GP, Samol J et al. Favourable outcome for patients with myeloid disorders treated with fludarabine-melphalan reduced-intensity conditioning and allogeneic bone marrow stem cell transplantation without the use of T-lymphocyte-depleting antibodies. Eur J Haematol 2004; 73: 85–92.

  61. 61

    Gupta V, Daly A, Lipton JH, Hasegawa W, Chun K, Kamel-Reid S et al. Nonmyeloablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older. Biol Blood Marrow Transplant 2005; 11: 764–772.

  62. 62

    Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb H-J . Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675–5687.

  63. 63

    Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease free survival in patient with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 9387–9393.

  64. 64

    Hallemeier CL, Girgis MD, Blum WG, Brown RA, Khoury HJ, Devine SM et al. Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cGy total body irradiation and cyclophosphamide. Biol Blood Marrow Transplant 2006; 12: 749–757.

  65. 65

    Lim ZY, Ho AYL, Ingram W, Kenyon M, Pearce L, Czepulkowski B et al. Outcomes of alemtuzumab-based reduced intensity conditioning stem cell transplantation using unrelated donors for myelodysplastic syndromes. Br J Haematol 2006; 135: 201–209.

  66. 66

    Lim ZY, Pearce L, Ho AYL, Barber L, Ingram W, Usai M et al. Delayed attainment of full donor chimaerism following alemtuzumab-based reduced-intensity conditioning haematopoietic stem cell transplantation for acute myeloid leukaemia and myelodysplastic syndromes is associated with improved outcomes. Br J Haematol 2007; 138: 517–526.

  67. 67

    Nakamura R, Rodriguez R, Palmer J, Stein A, Naing A, Tsai N et al. Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and melphalan is associated with durable disease control in myelodysplastic syndrome. Bone Marrow Transplant 2007; 40: 843–850.

  68. 68

    Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant 2007; 13: 454–462.

  69. 69

    Strahm B, Locatelli F, Bader P, Ehlert K, Kremens B, Zintl F et al. Reduced intensity conditioning in unrelated donor transplantation for refractory cytopenia in childhood. Bone Marrow Transplant 2007; 40: 329–333.

  70. 70

    Huisman C, Meijer E, Petersen EJ, Lokhorst HM, Verdonck LF . Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biol Blood Marrow Transplant 2008; 14: 181–186.

  71. 71

    Laport GG, Sandmaier BM, Storer BE, Scott BL, Stuart MJ, Lange T et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant 2008; 14: 246–255.

  72. 72

    Valcarcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: Chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577–584.

  73. 73

    Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A et al. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood 2008; 112: 415–425.

  74. 74

    Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang M-J, Champlin RE et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351: 2265–2275.

  75. 75

    Ooi J, Iseki T, Takahashi S, Tomonari A, Ishii K, Takasugi K et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 2003; 101: 4711–4713.

  76. 76

    Majhail NS, Brunstein CG, Tomblyn M, Thomas AJ, Miller JS, Arora M . Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Transplant 2008; 14: 282–289.

  77. 77

    Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M et al. Once daily IV busulfan and fludarabine (IV Bu-Flu) compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant 2008; 14: 672–684.

Download references

Author information

Correspondence to L M Isola.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kindwall-Keller, T., Isola, L. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant 43, 597–609 (2009). https://doi.org/10.1038/bmt.2009.28

Download citation

Keywords

  • myelodysplastic syndrome
  • HCT
  • hypomethylating agents
  • myeloablative
  • nonmyeloablative

Further reading