An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes

Figures & data

Table 1 Recent decitabine trials in the treatment of myelodysplastic syndromes (MDS)

Trial	No. pts	Phase	Design	Study focus	Results	Dosing	Median no courses	Time to AML progression	Median survival time
Kantarjian et al^Citation9	170	III	Randomized, multi-institutional	ORR and time to AML transformation or death	ORR 17%; CR 9% (P < 0.001); PR 8%; HI 13%	15 mg/m^2 IV over 3 h every 8 h for 3 d; total 135 mg/m^2 per course repeated every 6 wks	3	Compared to BSC: Overall, 12.1 mos vs 7.8 mos (P = 0.16). IPSS Int-2/ high-risk disease, 12.0 mos vs 6.8 mos (P = 0.03). De novo disease, 12.6 mos vs 9.4 mos (P = 0.04).	Compared to BSC: 14.0 mos vs 14.9 mos (P = 0.636)
Ruter et al^Citation29	22	Three Phase II trials	Pooled	Low dose DAC as retreatment at time of disease recurrence	OR 45%; CR 4.5%; PR 9.1%; HI 31.8%	15 mg/m^2 IV over 4 h given 3 times/d for 3 d Total 135 mg/m^2 per course repeated every 6 wks	3 additional courses		27.5 mos from time of initial treatment with DAC
Kantarjian et al^Citation26	115	II	Single center	Prognostic factors associated with outcome	OR 70%; CR 35%; PR 2%; bone marrow CR with or without HI 23%; other HI 10%	Either, (1) 20 mg/m^2 IV × 5 d; (2) 20 mg/m^2 subq × 5 d; (3) 10 mg/m^2 IV × 10 d Total 100 mg/m^2 per course every 4 wks	≥7	Not reached	22 mos
Kantarjian et al^Citation25	95	II	Randomized, single center	Optimal dosage of decitabine	Overall: OR 73%; CR 34%; PR 1%; marrow CR with or without HI 24%; HI 14% 5 d IV schedule, CR 39% (P < 0.05)	Either, (1) 20 mg/m^2 IV × 5 d; (2) 20 mg/m^2 subq × 5 d; (3) 10 mg/m^2 IV × 10 d	6+	27% over 18 mos	19 mos
Kantarjian et al^Citation23	Group A (115) and group B (376)	II	Historical comparison at single center Group A: subcohort of matched pts by age, IPSS, and cytogenetics Group B: entire cohort without matching	Compare long term results of lower intensity chemo (ie, DAC) with results from AML-type intensive chemo in higher risk MDS	CR 43% compared to 46% with intensive chemo in Group A, and 52% in Group B. Compared with Group A, mortality at 6 wks was 3% with DAC vs 13% with intensive chemo (P = 0.006); and at 3 mos 7% with DAC vs 23% with intensive chemo (P = 0.001)	Either, (1) 20 mg/m^2 IV over 1 h × 5 d; (2) 20 mg/m^2 subq in 2 doses daily; (3) 10 mg/m^2 IV over 1 h × 10 d Total 100 mg/m^2 per course			Compared to intensive chemo, pts in Group A had 22 mos vs 12 mos (P < 0.001)
Borthakur et al^Citation46	14	II	Early results	Efficacy of DAC after failure on AZA	ORR 28%; CR 21%; marrow CR with HI 7%	20 mg/m^2 IV over 1 h × 5 d every 4 wks	3	4 mos	6 mos
Steensma et al^Citation28	99	II	Multicenter, nonrandomized, and open-label	Efficacy and safety of an outpatient DAC regimen	ORR 32%, overall improvement rate 51%, CR 17%, HI 18%	20 mg/m^2 IV once daily over 1 h × 5 d every 4 wks	5		19.4 mos

Abbreviations: AZA, 5-azacitidine; AML, acute myeloid leukemia; BSC, best supportive care; CR, complete remission; DAC, decitabine; HI, hematologic improvement; IPSS, International Prognostic Scoring System; IV, intravenous; OR, objective response by modified IWG criteria; mos, months; ORR, overall response rate; PR, partial remission; pts, patients.

Figure 1 Structure and trapping mechanism of decitabine. A) The chemical structure of decitabine (4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2 (1H)-oneC₈H₁₂N₄O₄). B) The action of the DNMTs is inhibited by decitabine-incorporated DNA. Covalently trapped DNMTs are degraded, leading to depletion of cellular DNMTs.

Table 2 Reported adverse effects of decitabine

Adverse event	Grade 1%–2% affected	Grade 3%–4% affected	Reference
Neutropenia	1	31, 86*	^Citation9, ^Citation28
Thrombocytopenia	2	18, 85*	^Citation9, ^Citation28
Anemia	5	12*	^Citation9, ^Citation28
Bleeding	46	7	^Citation25
Febrile neutropenia, fever of unknown origin	3	6, 14, 20, 23*, 33	^Citation6, ^Citation9, ^Citation25, ^Citation28, ^Citation34, ^Citation46
Leukopenia		22*	^Citation9
Pyrexia		6*	^Citation9
Liver dysfunction	2, 10, 11	1, 1, 4, 6*	^Citation6, ^Citation9, ^Citation25, ^Citation26, ^Citation34
Pneumonia	1	2, 11, 15*, 20	^Citation6, ^Citation9, ^Citation25, ^Citation28, ^Citation34
Nausea	2, 17, 26	0, 1*, 7	^Citation6, ^Citation9, ^Citation25, ^Citation26, ^Citation28, ^Citation34
Pyrexia	17	0	^Citation28
Constipation	11	0, 2*	^Citation9, ^Citation28
Chills	10	0	^Citation28
Diarrhea	1, 2, 12	0*	^Citation9, ^Citation25, ^Citation26, ^Citation28, ^Citation34
Abdominal pain		2*	^Citation9
Bone aches	0, 4, 10	2, 5	^Citation25, ^Citation26, ^Citation34
Skin rash	0, 1	0	^Citation25, ^Citation26, ^Citation34
Fatigue	1, 6, 26	0, 5	^Citation25, ^Citation28, ^Citation34
Cardiovascular		8	^Citation6
Mucositis		4	^Citation6
Anorexia	12	0, 1	^Citation6, ^Citation28
Sleep disorder		1	^Citation6
Alopecia		1	^Citation6
Anaphylactic reaction		1	^Citation6
Deafness		1	^Citation6
Headache		1	^Citation6

* Grade 3 and 4 data from the Phase III Decitabine study⁹ were combined for the purposes of this review.

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