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DACOGEN

Pharmacological Classification: Cytotoxic Chemotherapy

CONTENTS: Decitabine

ACTIONS: Pharmacology: Mechanism of Action: Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

Clinical Studies: Phase 3 Trial: A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to Dacogen therapy plus supportive care (only 83 received Dacogen), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the Dacogen arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 1.

Table 1. Baseline Demographics and Other Patient Characteristics (ITT).
Demographic or Other Patient Characteristic Dacogen (N=89) Supportive Care (N=81)

Age (years)

  Mean ( SD)

  Median (IQR)

  (Range: Minimum - maximum )

69 10

70 (65-76)

(31-85)

67 10

70 (62-74)

(30-82)

Gender, n (%)

  Male

  Female

59 (66)

30 (34)

57 (70)

24 (30)

Race, n (%)

  White

  Black

  Other

83 (93)

4 (4)

2 (2)

76 (94)

2 (2)

3 (4)

Weeks Since MDS-Diagnosis

  Mean ( SD)

  Median ( IQR)

  (Range: Minimum-maximum)

86 131

19 (10-87)

(2-667)

77 119

35 (7-98)

(2-865)

Previous MDS Therapy, n (%)

  Yes

  No

27 (30)

62 (70)

19 (23)

62 (77)

RBC Transfusion Status, n (%)

  Independent

  Dependent

69 (78)

20 (22)

62 (77)

19 (23)

IPSS Classification, n (%)

  Intermediate-1

  Intermediate-2

  High Risk

28 (31)

38 (43)

23 (26)

24 (30)

36 (44)

21 (26)

FAB Classification, n (%)

  RA

  RARS

  RAEB

  RAEB+

  CMML

12 (13)

7 (8)

47 (53)

17 (19)

6 (7)

12 (15)

4 (5)

43 (53)

14 (17)

8 (10)

Patients randomized to the Dacogen arm received Dacogen IV infused at a dose of 15 mg/m2 over a 3-hr period, every 8 hrs, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patients clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics and hematopoietic growth factors. Co-primary endpoints of the study were overall response rate [complete response (CR)+ partial response (PR)] and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 2.

Table 2. Response Criteria for Phase 3 Trial*.

Complete Response (CR) ≥ 8 weeks

Bone marrow

On repeat aspirates:

<5% myeloblasts

No dysplastic changes

 

Peripheral blood

In all samples during response:

Hgb >11 g/dL (no transfusions or erythropoletin)

ANC ≥ 1500/microliter (no growth factor)

Platelets ≥ 100,000/microliter (no thrombopoietic agent)

No blasts and no dysplasia

Partial Response (PR) ≥ 8 weeks

Bone marrow

On repeat aspirates:

≥50% derease in blasts over pretreatment values OR

Improvement to a less advanced MDS FAB classification

 

Peripheral blood

In all samples during response:

Hgb >11 g/dL (no transfusions or erythropoietin)

ANC ≥ 1500/microliter (no growth factor)

Platelets ≥ 100,000/microliter (no thrombopoietic agent)

No blasts and no dysplasia

* Cheson BD, Bennett JM, et al. Report of an International WorkingGroup to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674

 

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