Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome

Kantarjian, Hagop M.; O’Brien, Susan; Huang, Xuelin; Garcia‐Manero, Guillermo; Ravandi, Farhad; Cortes, Jorge; Shan, Jianqin; Davisson, Jan; Bueso‐Ramos, Carlos E.; Issa, Jean–Pierre J.

doi:10.1002/cncr.22508

Cited by 166 publications

(107 citation statements)

References 19 publications

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“…2 Overall survival of responders and non-responders survival, respectively; P=.047) as well as a favorable response duration of 64 weeks. The observed median overall survival of 74 weeks in the group of responding patients corresponds well with the survival rates from the randomized phase II/III trials published for 5-AZA as well as decitabine [8,10,13,14,19], most of which had a higher number of treatment cycles. Therefore, our results suggest that even a limited number of treatment cycles may be beneficial for patients.…”

Section: Discussionsupporting

confidence: 82%

“…For responding patients, the median time to AML progression was 45 weeks (95% CI 22-68), while the median time to AML in non-responders was 14 weeks (95% CI [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. This difference was significant (P=0.038).…”

Section: Time To Aml and Overall Survivalmentioning

confidence: 99%

“…Several randomized trials with either 5-AZA or decitabine in patients with MDS have shown an overall response rate between 40% and 60%, an improved quality of life, a reduced risk of transformation to AML, and a trend toward longer overall survival compared to best supportive care [8][9][10][11][12][13][14]. In these trials, treatment was continued indefinitely until disease progression occurred.…”

Section: Introductionmentioning

confidence: 99%

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A limited number of 5-azacitidine cycles can be effective treatment in MDS

et al. 2008

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International audienceHypomethylating agents, such as 5-azacitidine (5-AZA) and 5-aza-2'-deoxycytidine (decitabine), have recently been approved for the treatment of myelodysplastic syndromes (MDS). Several randomized trials have shown favorable results concerning response rate, survival, transformation to acute leukemia, and quality of life. In these trials, treatment was administered continuously until progression. In the retrospective study presented here, we evaluated the outcome of patients with higher risk MDS or secondary acute myeloid leukemia (sAML) treated with a limited number of 5-AZA cycles. A total of 32 patients received 5-AZA alone ( = 30) or in combination with valproic acid and all-trans retinoic acid ( = 2). 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m daily for 7 days and repeated every 28 days. 5-AZA was given for a median of four courses. Treatment was continued for two more cycles as consolidation in patients who had achieved complete remission (CR), marrow CR, or stable disease with hematologic improvement. The overall response rate was 50% according to the modified International Working Group criteria. Complete remissions were achieved in 15.6% and stable disease in 34.4% of patients. Peripheral blood counts normalized in 6.3% of patients while hematologic improvement was achieved in 25%. The median time to AML in responding patients was 45 weeks, while AML occurred after a median of 14 weeks in non-responding patients ( = .038). The median survival of all patients was 60 weeks; the median survival of responders was 74 weeks compared with 26 weeks in non-responders ( = .047). In this retrospective analysis, 5-AZA was associated with a survival advantage in responding patients with higher risk MDS or sAML. These favorable results suggest that patients may benefit even from a limited number of courses of 5-AZA. A randomized controlled clinical trial is required to prospectively validate these findings

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Section: Discussionsupporting

confidence: 82%

Section: Time To Aml and Overall Survivalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A limited number of 5-azacitidine cycles can be effective treatment in MDS

et al. 2008

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“…Sixteen of the identified trials were excluded for various reasons (Figure 1). 5,8,[14][15][16][17][18][19][20][21][22][23][24][25][26][27] Of the five publications considered relevant for the meta-analysis, two reported different outcomes on the same trial, of which only one was relevant. Thus, four trials including 952 patients and performed between the years 2002 and 2008 fulfilled the inclusion criteria (Table 1).…”

Section: Resultsmentioning

confidence: 99%

5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome - a systematic review and meta-analysis

Gurion¹,

Vidal²,

Gafter‐Gvili³

et al. 2009

Haematologica

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Hypomethylating agents have recently been shown to improve the outcome of patients with myelodysplastic syndrome. A meta-analysis and systematic review was carried out of randomized controlled trials comparing treatment with hypomethylating agents to conventional care, i.e., best supportive care or chemotherapy, in patients with myelodysplastic syndrome. The outcomes assessed were overall survival, time to transformation or death, overall response rate and toxicity. Hazard ratios with 95% confidence intervals were estimated and pooled for timeto-event data. For dichotomous data, relative risks were estimated and pooled. Four trials including 952 patients examined the effect of 5-azacitidine and decitabine. Treatment with hypomethylating agents significantly improved overall survival (hazard ratio 0.72, 95% confidence interval 0.60-0.85, three trials) and time to transformation or death (hazard ratio 0.69, 95% confidence interval 0.58-0.82, four trials). In a subgroup analysis per type of drug, these benefits could be shown for 5-azacitidine but not for decitabine. Both agents favorably influenced response rates. A higher rate of grade 3/4 adverse events was observed with their use. Since 5-azacitidine prolongs overall survival and time to transformation or death it should be highly considered in the treatment of patients with high-risk myelodysplastic syndrome. Further studies are needed to establish the exact role of decitabine compared to 5-azacitidine in these patients.Key words: myelodysplastic syndrome, hypomethylating agents, 5-azacitidine, decitabine. Raanani P, survival in patients with myelodysplastic syndrome -a systematic review and meta-analysis. Haematologica. 2010; 95:303-310.

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“…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.…”

Section: Upfront Transplantation Induction or Low-intensity Therapy mentioning

confidence: 99%

The evolution of hematopoietic SCT in myelodysplastic syndrome

Kindwall‐Keller

Isola

2009

Bone Marrow Transplant

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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.

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Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome

Cited by 166 publications

References 19 publications

A limited number of 5-azacitidine cycles can be effective treatment in MDS

A limited number of 5-azacitidine cycles can be effective treatment in MDS

5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome - a systematic review and meta-analysis

The evolution of hematopoietic SCT in myelodysplastic syndrome

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