Decitabine in the treatment of myelodysplastic syndromes

Figures & data

Table 1 International prognostic scoring system (IPSS) score and prognosis

	Scorea
Prognostic variable	0	0.5	1	1.5	2.0
Marrow blasts (%)	<5	5–10	—	11–20	21–30
Karyotypeb	Good	Intermediate	Poor	NA	NA
Cytopeniasc	0/1	2/3	NA	NA	NA
Combined prognosis score	IPSS subgroup		Median time to AML transformation, 25% of patients (yrs)		Medial survival (yrs)
0	Low		9.4		5.7
0.5–1.0	Intermediate-1		3.3		3.5
1.5–2.0	Intermediate-2		1.1		1.2
>2.5	High		0.2		0.4

a Based on the combined score, four risk groups have been identified: low (combined score: 0), intermediate-1 (combined score: 0.5–1), intermediate-2 (combined score: 1.5–2), and high (combined score: >2).

b Good: diploid, -Y (loss of the Y chromosome); del(5q), del(20q), deletion of 5q and 20q chromosomes; poor: complex, chromosome 7 abnormalities; intermediate: others.

c Hemoglobin <10g/dL, neutrophils <1.5 × 10⁹/L, platelets <100 × 10⁹/L.

NA, not applicable; AML, acute myeloid leukemia.

Source: Adapted, with permission, from “International scoring system for evaluating prognosis in myelodysplastic syndromes” (Greenberg et al 1997) p2085. Copyright 1997 by the American Society of Hematology.

Figure 1 Decitabine structure.

Figure 2 Time to acute myeloid leukemia (AML) or death: (A) all patients; (B) treatment-naïve patients; (C) International Prognostic Scoring System subgroups intermediate-2 to high-risk patients. (Reprinted, with permission, from Kantarjian et al 2006).

Table 2 Response to decitabine (ITT) using the FDA approved dose of 15 mg/m² over 3 hours every 8 hours ×3 days every 6 weeks (Adapted, with permission, from Kantarjian et al (2006))

International working group response rate, onset, and duration	Decitabine (n = 89)	Supportive care (n = 81)
Overall response rate (CR + PR)	15(17%)*	0(0%)
CR	8(9%)	0(0%)
PR	7(8%)	0(0%)
HI	12(13%)	6(7%)
*p-value < 0.001 from two-sided Fisher’s exact test
Onset and duration of response (months)
Median time to (CR + PR) response	3.3(2.0 – 9.7)
Median duration of (CR + PR) response	10.3(4.1 – 13.9)	N/A

Abbreviations: ITT, intention to treat; CR, complete response; PR, partial response; HI, hematologic improvement.

Figure 3 Percentage of patients red blood cell (RBC) transfusion free per cycle (Reprinted, with permission, from Kantarjian et al 2006).

Table 3 Most common adverse events of decitabine

	Decitabine % (n = 83)*	Supportive care % (n = 81)
Neutropenia	90	72
Thrombocytopenia	89	79
Anemia NOS	82	74
Pyrexia	53	28
Nausea	42	16
Cough	40	31
Petechiae	39	16
Constipation	35	14
Diarrhea NOS	34	16
Hyperglycemia NOS	33	20
Febrile neutropenia	29	6
Leukopenia NOS	28	14
Headache	28	14
Insomnia	28	14
Edema, peripheral	25	16
Vomiting NOS	25	9
Hypoalbuminemia	24	17
Hypomagnesemia	24	7
Pallor	23	12
Pneumonia NOS	22	14
Rigors	22	17
Ecchymosis	22	15
Hypokalemia	22	12
Arthralgia	20	10

* Adverse events reported in ≥20% of patients in the decitabine group and at a rate greater than supportive care in the phase 3 myelodysplastic syndromes trial. NOS, not otherwise specified.

Table 4 Efficacy and side effects of three alternative decitabine dosing schedules (Adapted, with permission, from Kantarjian et al(2007))

Parameter	Arm A (5-Day IV)	Arm B (10-Day IV)	Arm C (5-Day SQ)
No. patients	64	17	14
No. CR/treated (%)	25(39)	4(24)	3(21)
Median number of courses (range)	5(1–18)	9(1–15)	8(1–17)
Median duration of therapy in mos (range)	5.4(1.0–20.4+)	10.8(1.9–17.7+)	9.7(0.5–22.9+)
Median follow-up time (mos)	6.5	15	15
No. (%) still on therapy	39(61)	6(35)	3(21)
Median days to granulocytes recovery to 10^9/L or above	24	27	14
Median days to platelet recovery to 50 × 10^9/L or above	20	27	31
Median days to delivery of subsequent courses (range)	35	40	35
No. courses requiring hospitalization (%)	50(12)	23(23)	14(14)

Abbreviations: IV, intravenous; SQ, subcutaneous; CR, complete response.

Table 5 Decitabine dosing schedules

Dacogen regimen	IV Dose and schedule	Total dose/course
FDA approved*	15 mg/m^2 over 3 hours every 8 hours × 3 days every 6 weeks	135 mg/m^2
Active alternative†	20 mg/m^2 over 1 hour daily × 5 days every 4 weeks	100 mg/m^2

* Kantarjian et al (2006)

† Kantarjian et al (2007)

GreenbergPCoxCLeBeauMMInternational scoring system for evaluating prognosis in myelodysplastic syndromesBlood1997892079889058730

 PubMed Web of Science ®Google Scholar

KantarjianHIssaJPRosenfeldCSDecitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized studyCancer2006106179480316532500

 PubMed Web of Science ®Google Scholar

KantarjianHOkiYGarcia-ManeroGResults of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemiaBlood200710952716882708

 PubMed Web of Science ®Google Scholar