The role of hypomethylating agent therapy (HMT) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) in patients with myelodysplastic syndrome (MDS) remains undetermined. We investigated the feasibility of HMT followed by alloHCT in patients with MDS. In all, 19 patients who received HMT followed by alloHCT were analyzed. A total of 7 patients were classified as low-risk and 12 as high-risk, based on World Health Organization (WHO) classification at the time of HMT. HMT consisted of decitabine in 9 patients and azacitidine in 10. After HMT, two patients achieved CR, six mCR, three hematologic improvement alone, and six SD in terms of best response. HMT did not alter WHO classification in 15 patients (79%), whereas 1 patient (5%) improved and 3 (16%) progressed to AML. Most patients (95%) received a non-myeloablative conditioning regimen based on fludarabine/BU/anti-thymocyte globulin, and peripheral blood-mobilized stem cells. Neutrophil and platelet engraftments were achieved in 95 and 79% of patients, respectively. The incidences of acute and chronic GVHD were 42 and 26%, respectively. In all, 2-year OS rates were 68%, and the overall outcomes of those who achieved CR/mCR with HMT tended to be superior to those without CR/mCR. HMT followed by alloHCT was a feasible and effective treatment strategy for patients with MDS.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by hyperproliferative BM, cellular dysplasia and ineffective hematopoiesis. Treatment of MDS involves improving patient survival and quality of life, while decreasing the likelihood of progression to AML. Until recently, the mainstay of treatment for patients with low-risk MDS consisted of supportive care, including transfusion of blood products, administration of growth factors and treatment of infections. Allogeneic hematopoietic cell transplantation (alloHCT) has been the only curative modality for selected patients with low-risk MDS and for most patients with high-risk MDS.
The recent development of three chemotherapeutic agents, lenalidomide, azacitidine (AZA) and decitabine (DEC), has altered the treatment paradigms for patients with MDS. Treatment with AZA has resulted in CR rates of 10–20% and hematologic improvement (HI) rates of 23–49%,1, 2 and has significantly improved survival compared with supportive care for patients with high-risk MDS.3 Although DEC did not significantly extend OS,4, 5 the overall response rate to DEC among patients with high-risk MDS was 30–49%.6, 7, 8, 9 Lenalidomide has been reported to reduce anemia and transfusion dependence among MDS patients with a chromosome 5q deletion.10
Although these agents have induced hematological and cytogenetic responses in a substantial portion of patients, these therapies are not curative.11 Because alloHCT remains the only curative therapy for MDS, new treatment modalities such as hypomethylating agents (HMA) may be used as a bridge to more definitive therapy to improve the outcome of alloHCT, although the appropriate HMA dose and schedule before alloHCT have not yet been determined.12
Several hypotheses have been advanced as rationales for bridging therapy to alloHCT. AZA and DEC inhibition of DNA methyltransferase is thought to be responsible for the hypomethylation and reactivation of tumor suppressor genes, inducing the terminal differentiation and apoptosis of neoplastic cells, which may contribute to improvements in alloHCT outcome by a reduction in tumor burden.13, 14 Alternatively, an increase in phenotypic expression during the differentiation and modification of leukemia cells may make them susceptible to immune surveillance mechanisms, and may result in their increased sensitivity to a GVL effect of alloHCT.15, 16, 17 It is unclear, however, whether treatment with hypomethylating therapy before alloHCT will increase the toxicity of the preparative regimen or otherwise affect the results of transplantation. We therefore assessed the outcomes of alloHCT in 19 patients with MDS who were treated with hypomethylating agents before transplantation.
Patients and methods
Patients who were diagnosed with MDS, treated with HMA and received alloHCT were included in this retrospective analysis. The assignment of drug (AZA or DEC) was not randomized, and was at each physician's discretion. AZA was administered s.c. at a dose of 75 mg/m2 once-daily on days 1–7 of each 28-day cycle (total dose 375 mg/m2), and DEC was administered i.v. at a dose of 20 mg/m2 once-daily on days 1–5 of each 28-day cycle (total dose 100 mg/m2). Patients were treated until the initiation of alloHCT. All patients received oral ciprofloxacin and itraconazole solution for bacterial and fungal prophylaxis, respectively. Prophylactic blood product transfusion and granulocyte-stimulating factor were allowed.
HI was evaluated after each HMA cycle, with best response recorded for each patient. BM assays, including cytogenetic analyses, were performed after the completion of two DEC cycles and four AZA cycles. Responses were evaluated according to the International Working Group response criteria.18
AlloHCT was recommended when patients had good performance status and an acceptable donor was available. Partially mismatched unrelated donors with fewer than two low-resolution mismatches or fewer than three high-resolution mismatches were accepted as donors. The numbers of infused cells were targeted to 5 × 108 total nucleated cells/kg and 5 × 106 CD34-positive cells/kg. A haploidentical familial donor was considered when both the sibling and the acceptable unrelated donor were not available.
AlloHCT conditioning consisted of a myeloablative regimen (BU 3.2 mg/kg i.v. once-daily on days −7 to −4; total dose 12.8 mg/kg, and CY 60 mg/kg i.v. once-daily on days −3 and −2; total dose 120 mg/kg) for patients aged less than 55 years with no severe co-morbidity, or a non-myeloablative regimen (fludarabine 30 mg/m2 i.v. once-daily on days −7 to −2; total dose 180 mg/m2, BU 3.2 mg/kg i.v. once-daily on days −7 and −6; total dose 6.4 mg/kg and anti-thymocyte globulin) for patients who could not tolerate a myeloablative regimen due to age and/or comorbidity. The total dose of anti-thymocyte globulin was 3.75 mg/kg for sibling HLA-matched donors, 9 mg/kg for unrelated donors and 12 mg/kg for haploidentical familial donors. CYA, alone or combined with MTX, was used for prophylaxis of GVHD.
Continuous variables were compared between the AZA and DEC groups using the t-test. Relapse-free survival was defined as the interval (in months) from alloHCT to the confirmation of progression, as defined by International Working Group response criteria. OS was defined as the interval (in months) from the start of hypomethylating agent therapy (HMT) until death from any cause. Associations of clinical parameters with overall outcomes were evaluated using Cox proportional hazards models or Kaplan–Meier methods. All statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA).
From September 2006 to May 2009, 19 patients (12 males, 7 females) were treated with HMT and thereafter underwent alloHCT. The median age of these 19 patients was 47 years (range, 23–69 years). Patient characteristics are summarized in Table 1.
According to WHO criteria, nine patients were classified as low risk, eight as high risk and one as MDS-U. Among AZA-treated patients, seven were low risk and three were high risk; among DEC-treated patients, two were low risk and six were high risk. One patient showed no response to previous immunosuppressive therapy with anti-thymocyte globulin and CYA. Five patients had received synthetic androgen therapy for anemia and thrombocytopenia before the initiation of HMT. One patient who did not respond to previous AZA but received DEC as a second-line therapy was included.
Median time from diagnosis of MDS to the initiation of HMT was 1.5 months for all patients. Median number of cycle was 3 (range, 1–13) for all patients, and AZA-treated patients tended to receive more treatment cycles than DEC-treated patients.
Of the 19 patients, 11 (59%) showed best responses to HMT beyond hematological improvement (HI) (Table 2). Eight patients (43%) achieved CR and marrow CR (mCR), with DEC-treated patients showing higher response rates than AZA-treated patients (66 vs 20%). In all, 10 of the 11 patients (91%) who responded to HMT showed initial responses during the first two treatment cycles. Overall, 14 patients (73%) required fewer than three cycles to achieve best response.
Cytogenetic response was not evaluable among 10 patients because their BM responses were not evaluated or they had no initial cytogenetic abnormalities. Among the nine evaluable patients, three (33%), all treated with DEC, showed cytogenetic responses greater than PR.
The most common reason for terminating HMT was ‘consideration of HCT for curative intent, due to an available donor and patient good performance status, regardless of response to HMT’ (48%), followed by ‘no beneficial effect from continuation of HMT’ (26%), ‘progression of disease despite continuing HMT’ (16%) and ‘prolonged severe cytopenia after HMT’ (11%).
After the completion of HMT, 15 patients (79%) showed no changes in WHO classification status compared with their status before HMT, 1 patient improved, and 3 (16%) progressed to AML. The patient who responded to HMT relapsed before alloHCT.
Three patients who had progressed to AML during HMT received induction chemotherapy consisting of cytarabine plus anthracycline (7+3), and failed to achieve remission. One of them received additional induction chemotherapy with the same drug combination (5+2), which also failed. All of the three patients finally received alloHCT in their chemo-resistant status.
AlloHCT was performed after a median 7.3 months (range, 3.5–89.7 months) from the diagnosis of MDS and 6.5 months (range, 2.1–23.9 months) from the initiation of HMT. Median time from diagnosis to alloHCT (17.2 vs 6.1 months) and median time from the initiation of HMT to alloHCT (12.6 vs 5.4 months) were longer among AZA- than among DEC-treated patients. Characteristics associated with alloHCT and treatment outcomes are summarized in Table 3.
All the patients with low risk received alloHCT due to transfusion-dependent status before HMT. Performance status of all patients at the time of alloHCT was >70% according to the Karnofsky score. In all, 18 patients (95%) received a non-myeloablative conditioning regimen and mobilized PBSCs. A total of 18 patients (95%) showed neutrophil engraftment (>1 × 103/μL), at a median time of 13 days; this was significantly longer in the AZA than in the DEC group (16.6 vs 11.9 days, P=0.005).
The overall incidence of acute GVHD was 42% (10% for grade 3/4 aGVHD), and was higher among DEC- than among AZA-treated patients (67 vs 20%, P=0.055 for all grades; 22 vs 0%, P=0.211 for grades 3/4). The incidence of chronic GVHD was 26%, with no case of severe (grade ⩾3) cGVHD according to National Institutes of Health criteria;19 there was no significant difference between the AZA- and DEC-groups (30 vs 22%, P=0.556). The overall incidence of veno-occlusive disease was 21%, with no significant difference between the AZA and DEC groups (20 vs 22%, P=0.667).
Overall treatment outcomes
Six patients died during follow-up, four due to AML progression, one due to acute intracranial hemorrhage on day 17 of alloHCT and one due to pneumonia plus GVHD involving the liver. The overall treatment-related mortality rate among our 19 patients was 11%.
The overall 1-year relapse rate was 22%; this was lower in the DEC (12%) than in the AZA (25%) group (Figure 1). The overall 1- and 2-year OS rates were 95 and 68%, respectively. The 1-year OS rates did not differ significantly between the AZA and DEC groups (90 vs 89%) (Figure 2).
Outcomes according to clinical features and treatment results
Table 4 shows univariate analysis of the relationships between clinical factors before/after HMT and clinical outcomes. None of the outcome variables correlated significantly with chromosomal abnormalities at diagnosis, WHO classification at the time of HMT initiation or type of HMT. When responses to HMT were classified as superior (CR, mCR) vs inferior (HI alone, stable disease, progressive disease or not evaluable response), HMT response tended to be associated with outcomes; the 2-year relapse-free survival rate was higher in the superior response group (100%) than in the inferior group (65%) and also was the 2-year OS rate (88 vs 48%), although the differences were not significant. Especially, the overall outcomes of patients who developed AML were significantly poorer than those who remained with MDS after HMT.
Beginning when AZA and DEC were first used to treat MDS, their role as a bridge to alloHCT has been evaluated. In a previous study, among 17 patients with MDS who underwent alloHCT after prior therapy with DEC, 13 (76%) achieved CR within 100 days of transplant, and following transplant, 11 (65%) remained alive and 8 (47%) remained in CR, suggesting that prior HMT did not increase toxicity and may improve outcomes of alloHCT in MDS patients.20 A comparison of patients who did or did not receive AZA before alloHCT showed that the 1-year OS (47 vs 60%) and relapse-free survival (41 vs 51%) rates were similar, with a trend toward decreased early relapse in patients receiving AZA, suggesting that HMA might stabilize the disease and allow time for patients to undergo alloHCT.21 Another study reported that almost all of the 10 MDS patients who were treated with DEC and underwent subsequent alloHCT after reduced-intensity conditioning, achieved successful engraftment and CR.22 A recent retrospective analysis showed that pre-alloHCT HMT induced rapid and high level of donor chimerism.23 All the results indicated that HMT as a bridge to alloHCT was feasible in patients who subsequently received alloHCT.
Despite the limitations inherent in a small, retrospective analysis, this study is unique in that 95% of our patients underwent alloHCT with the same non-myeloablative conditioning protocol and that this study included patients treated with AZA and DEC. Moreover, we analyzed the effects of characteristics associated with MDS and clinical parameters related to HMT on the outcomes of alloHCT.
The CR rates including mCR among patients treated with DEC was 66% in the current study. Although the CR rate was relatively low in a few phase III trials at a dose/schedule of 15 mg/m2 thrice a day i.v. for 3 days every 6 weeks, potentially higher CR rates may be obtained by administering DEC at dose/schedule of 20 mg/m2/day i.v. for 5 days every 28 days in other trials,6, 9 as this is the dose and schedule we employed in the current study.
Response evaluation with BM assay was performed differently between patients who received DEC (every two cycles) and AZA (every four cycles), because the number of cycles to first response has been reported to be lesser with DEC than with AZA, and this may affect the risk of documenting lower response and shorter time interval between hypomethylating therapy and Allo-SCT for DEC.
Although patients received a median three cycles of HMT, alloHCT was performed after a median 6.5 months from the initiation of HMT. This discrepancy in time to transplant after initiation of HMT and the median number of cycles of HMT administered was mainly due to loss of response and waiting for a donor to be found.
The 19 patients included in our study showed an acceptable neutrophil engraftment rate (95%) and an acceptable median time to engraftment (13 days). The rates of all-grade aGVHD (42%), grade 3/4 aGVHD (10%) and GVHD-related mortality (5%) were tolerable. Moreover, the rate of cGVHD was 26%, with no severe episodes, and the rate of VOD was 21% without any mortality. These findings indicate that the rates of transplant-related complications were similar to those of many previous reports.12
As induction therapy, HMT before alloHCT can increase the risk of death or prevent proceeding to alloHCT owing to associated toxicities. HMT can also increase the rates of GVHD and other complications such as infection, contributing to increased treatment-related mortality rate.21 We observed a treatment-related mortality rate of 11%, similar to previously reported rates,12 which was even lower than our previously reported one among patients who did not receive HMT before alloHCT.24 Our findings thus indicate that pre-transplant HMT did not adversely affect post-alloHCT outcomes.
We found that the achievement of CR or mCR with HMT tended to the improved outcome after alloHCT. The absence of statistical significance in the outcome differences between response groups may be due to the limitation of retrospective analyses with small number of patients. Despite this limitation, it is encouraging that none of the patients who achieved CR or mCR relapsed. Additional prospective studies are required to further assess the association between HMT response and alloHCT outcome.
We could not properly compare the efficacy of AZA and DEC owing to the limitations of this retrospective, non-randomized trial involving few patients. Although DEC-treated patients showed higher mCR/CR/cytogenetic response rates, this was not correlated with improvements in alloHCT outcome. Most of our patients received non-myeloablative conditioning and mobilized PBSCs, with median doses of >5 × 106 CD34+ cells/kg in both the AZA and DEC groups. DEC, however, was superior to AZA in terms of engraftment rate and time to engraftment. Due to the limitations of our study, further investigations are needed to compare the efficacy and safety of AZA and DEC as bridging therapies to alloHCT.
In conclusion, HMT followed by alloHCT may be feasible and effective as a bridging therapy strategy for patients with MDS. Although DEC showed more favorable mCR/CR and cytogenetic responses than AZA, this did not correlate with improved alloHCT outcomes. Overall outcomes of those who achieved CR/mCR with HMT tended to be superior to those without CR/mCR, especially in terms of relapse rate. Prospective trials are required to confirm the possible benefit of HMA bridging therapy followed by alloHCT in patients with MDS.
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This study was supported by a Grant (2010-489) from the Asan Institute for Life Sciences, Seoul, Korea.
The authors declare no conflicts of interest.
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