National PBM Drug Monograph

Decitabine (Dacogen™)

January 2008

VHA Pharmacy Benefits Management Strategic Healthcare Group and the
Medical Advisory Panel

# Executive Summary: 

**[Clinical Efficacy]{.underline}**

-   Decitabine is a deoxycitabine analog that inhibits DNA methylation
    at low doses

-   Hypermethylation of tumor suppressor genes is found in
    Myelodysplastic syndrome and is thought to be associated with a high
    risk for transformation to AML.

-   In a randomized phase III trial comparing decitabine (15mg/m^2^
    intravenously over 3 hours every 8 hours for 3 days repeated every 6
    weeks) plus supportive care versus supportive care, decitabine
    therapy produced higher overall response rates across all subgroups.

-   Improved time to AML or death trended toward the decitabine arm but
    was only statistically significant in subgroup analyses.

-   All decitabine responders achieved transfusion independence.

-   There was no difference between the group in overall survival

-   In a supportive trial comparing 3 different low-dose regimens, a
    schedule of 20mg/m^2^ intravenously over 1 hour daily for 5 days and
    repeated every 4 weeks produced higher response rates than the
    comparator arms.

**[Safety]{.underline}**

-   The most common adverse events were neutropenia, thrombocytopenia,
    anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation,
    diarrhea, and hyperglycemia.

-   The most serious adverse events were neutropenia, thrombocytopenia,
    anemia, and leucopenia.

-   Dose reductions or delays occurred in 35% of patients due to adverse
    events

-   Eight patients permanently discontinued therapy due to adverse
    events

**[Conclusion]{.underline}**

-   Decitabine is more effective than supportive care in high risk MDS
    patients

-   The optimal dose schedule and duration of therapy is evolving

-   IPSS Intermediate-2 patients and those with thrombocytopenia may
    benefit most

-   The exact role in therapy compared to azacitidine has yet to be
    determined.

The following recommendations are based on current medical evidence and
expert opinion from clinicians.  The content of the document is dynamic
and will be revised as new clinical data becomes available.  The purpose
of this document is to assist practitioners in clinical decision-making,
to standardize and improve the quality of patient care, and to promote
cost-effective drug prescribing.  The clinician should utilize this
guidance and interpret it in the clinical context of individual patient
situations

# Introduction

The purposes of this monograph are to (1) evaluate the available
evidence of safety, tolerability, efficacy, cost, and other
pharmaceutical issues that would be relevant to evaluating decitabine
for possible addition to the VA National Formulary; (2) define its role
in therapy; and (3) identify parameters for its rational use in the VA.

# Pharmacology/Pharmacokinetics

Decitabine is an analog of deoxycitabine. Intracellularly, it is
sequentially phosphorylated to the active compound 5AZA-dCTP which is
incorporated into DNA and forms an irreversible covalent adduct with DNA
methyltransferase, inhibiting its function. DNA methyltransferase
mediates the methylation of cytosine; this methylation is associated
with the silencing of tumor suppressor genes. Hypermethylation of the
*p15^INK4b^* gene is frequently found in patients with Myelodysplastic
Syndrome (MDS), may be acquired during disease progression, and may
predict the likelihood of progression to acute myelogenous leukemia
(AML). Decitabine is believed to cause hypomethylation, restoring normal
gene function important for differentiation and apoptosis. Cytotoxicity
may also play a role in its mechanism of action.

Table #1 Pharmacokinetic Parameters

  ------------------ ----------------------------------------------------
  **Parameter**      **Decitabine**

  Metabolism         The exact metabolic fate is unknown.

  Elimination        The exact route of elimination is undetermined.
                     Decitabine is eliminated by cytosine deaminase found
                     in liver, granulocytes, intestinal epithelium and
                     whole blood

  Half-life          0.51±0.31 hr

  Protein Binding    \<1%
  ------------------ ----------------------------------------------------

**Special Populations:** The pharmacokinetics of decitabine in patients
with renal or liver impairment has not been studied. The effects of
gender, race, or age on the pharmacokinetics have not been studied.

# FDA Approved Indication(s) and Off-label Uses

Treatment of patients with MDS including previously treated and
untreated, *de novo* and secondary MDS of all French-American-British
(FAB) subtypes (refractory anemia, refractory anemia with ringed
sideroblasts, refractory anemia with excess blasts, refractory anemia
with excess blasts in transformation, and chronic myelomonocytic
leukemia) and Intermediate-1, Intermediate-2, and High-Risk
International Prognostic Scoring System (IPSS) groups.

**Off-label:** Acute Myelogenous Leukemia, Chronic Myelogenous Leukemia,
solid tumors, Sickle Cell Disease

# Current VA National Formulary Alternatives

Azacitidine injection: Criteria for Use restricted to all FAB subtypes
(refractory anemia and refractory anemia with ringed sideroblasts must
be accompanied by neutropenia or thrombocytopenia or clinical hemorrhage
requiring platelet transfusions or anemia requiring blood transfusions).

# Dosage and Administration

**FDA Approved**

**First Cycle**

15 mg/m^2^ intravenous infusion over 3 hours every 8 hours for 3 days.

**Subsequent Cycles**

Repeat the same as above every 6 weeks for a minimum of 4 cycles. A
complete or partial response may require more than 4 cycles.

**Alternative Schedule**[^1]

20mg/m^2^ intravenous infusion over 1 hour daily for 5 days. Repeat
every 4 weeks. Give first three courses every 4 weeks regardless of
blood counts as long as there was no significant myelosuppression,
life-threatening complications (e.g. pneumonia, severe infection,
bleeding, or severe organ damage) and there is no evidence of
progressive disease in the bone marrow.

**Table #2 Dose Adjustment Based on Hematologic Toxicity**

+-----------------------------------+-----------------------------------+
| **Hematologic Recovery = ANC ≥    | **Adjustment**                    |
| 1,000/mcL and platelets ≥         |                                   |
| 50,000/mcL from a previous        |                                   |
| decitabine dose**                 |                                   |
+-----------------------------------+-----------------------------------+
| If Recovery requires more than 6  | 1\. Delay decitabine dose for 2   |
| weeks but less than 8 weeks       | weeks                             |
|                                   |                                   |
|                                   | 2\. Temporarily reduce dose by    |
|                                   | 25% to 11mg/m^2^ every 8 hours    |
|                                   | when restarting therapy           |
+-----------------------------------+-----------------------------------+
| If Recovery requires more than 8  | 1\. Examine bone marrow for       |
| weeks but less than 10 weeks      | disease progression               |
|                                   |                                   |
|                                   | 2\. Delay decitabine dose for up  |
|                                   | to 2 more weeks                   |
|                                   |                                   |
|                                   | 3\. Reduce dose 25% to 11mg/m^2^  |
|                                   | every 8 hours when restarting;    |
|                                   | maintain reduced dose or increase |
|                                   | in subsequent cycles as           |
|                                   | clinically indicated.             |
+-----------------------------------+-----------------------------------+
| Alternative Dose Schedule         | 1\. Reduce dose 25% to 15 mg/m^2^ |
|                                   | when restarting therapy.          |
| Hypocellular bone marrow (5% or   |                                   |
| less cellularity) without         |                                   |
| evidence of disease for more than |                                   |
| 6 weeks or severe                 |                                   |
| myelosuppressive complications    |                                   |
| like infections or bleeding       |                                   |
+-----------------------------------+-----------------------------------+

[Non-hematologic toxicities:]{.underline}

[Approved dose]{.underline}

Hold dose until recovered for the following: serum creatinine ≥ 2mg/dL,
SGPT or total bilirubin ≥2 times the ULN, and active or complicated
infection.

[Alternative dose:]{.underline}

Dose reduce by 25% for grade 3 or 4 toxicities (15 mg/m^2^ then 10
mg/m^2^, etc.)

# Efficacy 

## Efficacy Measures

1\. Overall Response Rate: as measured by the International Working
Group Response Criteria for Myelodysplastic Syndrome.

Complete Response

-   \<5% blasts in bone marrow

-   Hemoglobin \>11 g/dL

-   ANC ≥1500/mcL

-   Platelet count \> 100,000/mcL

-   No blasts

-   No dysplasia

-   No transfusions or growth factors

-   Minimum duration of response 8 weeks

Partial Response

-   50% decrease in bone marrow blasts

-   other response criteria the same as for CR

OR

-   a downgrade in FAB classification

2\. Time to transformation to AML or death

3\. Cytogenetic Response

4\. Clinical benefit -- transfusion rate

## Summary of efficacy findings 

**Phase III Decitabine plus Supportive Care versus Supportive Care in
MDS**[^2]

Design: open label, randomized controlled phase III trial comparing
efficacy and safety of intravenous low-dose decitabine to supportive
care.

Dose: 15 mg/m^2^ intravenously over 3 hours every 8 hours for 3
consecutive days. Repeat cycles every 6 weeks.

Results:

**Table #3 Decitabine Pivotal Phase III trial**

+-----------------------+-----------------------+-----------------------+
| **Response**          | **Decitabine (n=89)** | **Supportive Care     |
|                       |                       | (n=81)**              |
+-----------------------+-----------------------+-----------------------+
| Overall Response      | 17%                   | 0%                    |
| (CR+PR)               |                       |                       |
|                       | 9                     | 0                     |
| Complete Response     |                       |                       |
|                       | 8                     | 0                     |
| Partial Response      |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Hematologic           | 13%                   | 7%                    |
| Improvement           |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Median Time to CR+PR  | 3.3 mos (2.0-9.7)     | NA                    |
| Response              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Median Duration of    | 10.3 mos (4.1-13.9)   | NA                    |
| CR+PR Response        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Subgroup Overall      | 14%                   | 0                     |
| Response              |                       |                       |
|                       | 18                    | 0                     |
| IPSS                  |                       |                       |
|                       | 17                    | 0                     |
| Int-1                 |                       |                       |
|                       | 13                    | 0                     |
| Int-2                 |                       |                       |
|                       | 16                    | 0                     |
| High-risk             |                       |                       |
|                       | 21                    | 0                     |
| Cytogenetics          |                       |                       |
|                       | 14                    | 0                     |
| 5q abnormal           |                       |                       |
|                       | 17                    | 0                     |
| 5q normal             |                       |                       |
|                       | 16                    | 0                     |
| 7q abnormal           |                       |                       |
|                       | 15                    | 0                     |
| 7q normal             |                       |                       |
|                       | 17                    | 0                     |
| MDS                   |                       |                       |
|                       |                       |                       |
| *De novo*             |                       |                       |
|                       |                       |                       |
| Secondary             |                       |                       |
|                       |                       |                       |
| Prior Therapy         |                       |                       |
|                       |                       |                       |
| Yes                   |                       |                       |
|                       |                       |                       |
| No                    |                       |                       |
+-----------------------+-----------------------+-----------------------+

**Table#4 Time to AML or Death**

  ----------------- ----------------- ----------------- -----------------
  **MDS Group**     **Decitabine**    **Supportive      **P value**
                                      Care**            

  All patients      12.1 mos          7.8 mos           0.16

  Treatment naïve   12.3 mos          7.3 mos           0.08

  Int-2 or          12 mos            6.8 mos           0.028
  High-risk IPSS                                        

  High-risk         9.3 mos           2.8 mos           0.01
  ----------------- ----------------- ----------------- -----------------

Cytogenetic Response

-   Complete Response was seen in 35% of patients on the decitabine arm
    and 21% of patients on the supportive care arm in those patients
    with baseline clonal abnormalities.

Number of Courses

The median number of courses was 3 (range 0-9).

Transfusion Requirements

100% of decitabine responders were RBC transfusion-independent and
platelet transfusion-independent during the time of response.

Survival

Median survival was not different between the groups (14 mos vs 14.9
mos, P=0.636) Decitabine responders had extended survival versus
non-responders (23.5mos vs 13.7 mos; p=0.007)

Quality of Life\
Improved global health status (p\<0.05), fatigue (p\<0.05) and dyspnea
scores (p\<0.05) in decitabine group.

**Supportive Trials**

**Phase II study of low-dose decitabine in high-risk MDS**[^3]

Uncontrolled, open-label, single arm, multicenter study evaluating
decitabine efficacy and safety in elderly patients with primary or
secondary high-risk MDS.

Dose: 15mg/m^2^ intravenously over 4 hours every 8 hours for 3
consecutive days repeated every 6 weeks if hematologic parameters
returned to normal or baseline.

**Table #5 Phase II Response Rates**

+-----------------------------------+-----------------------------------+
| **Response**                      | **ITT Population**                |
|                                   |                                   |
|                                   | **N=66**                          |
+-----------------------------------+-----------------------------------+
| Complete Response                 | 20%                               |
|                                   |                                   |
| Partial Response                  | 4                                 |
|                                   |                                   |
| Overall Response (CR+PR)          | 24                                |
+-----------------------------------+-----------------------------------+
| Response (CR+PR+HI) by IPSS Group | 25%                               |
|                                   |                                   |
| Intermediate-1                    | 48%                               |
|                                   |                                   |
| Intermediate -2                   | 64%                               |
|                                   |                                   |
| High Risk                         |                                   |
+-----------------------------------+-----------------------------------+

HI=hematologic improvement

**3-arm alternative dosing trial**^1^

Single-center, phase II, randomized trial evaluating efficacy and safety
of three different low-dose schedules of decitabine in MDS and Chronic
Myelomonocytic Leukemia (CMML). After the 45^th^ patient an adaptive
Bayesian model was used that randomized patients to the arm with the
highest complete response rate.

Dose Schedules:

(1). Decitabine 20mg/m^2^ intravenously over 1 hour daily for 5 days
repeat every 4 weeks

\(2\) Decitabine 20mg/m^2^ daily in 2 divided subcutaneous doses (i.e.
10mg/^2^ twice a day) for 5 days repeat every 4 weeks

\(3\) Decitabine 10mg/m^2^ intravenously over 1 hour daily for 10 days
repeat every 4 weeks

**Table#6 Response Rate by Treatment Arm**

+-----------------------------------+-----------------------------------+
| **Decitabine Schedule**           | **Complete Response**             |
|                                   |                                   |
|                                   | **ITT=95**                        |
|                                   |                                   |
|                                   | **%**                             |
+-----------------------------------+-----------------------------------+
| 20mg/m^2^ Intravenously daily for | 39                                |
| 5 days                            |                                   |
|                                   | (n=64)                            |
|                                   |                                   |
|                                   | P\<0.05                           |
+-----------------------------------+-----------------------------------+
| 20mg/m^2^ subcutaneously daily    | 21                                |
| for 5 days (10mg/m^2^ twice a     |                                   |
| day)                              | (n=14                             |
+-----------------------------------+-----------------------------------+
| 10mg/m^2^ intravenously daily for | 24                                |
| 10 days                           |                                   |
|                                   | (n=17)                            |
+-----------------------------------+-----------------------------------+

-   In a subgroup analysis of patients with baseline thrombocytopenia,
    49% achieved platelet counts ≥100,000/mcgL

-   At a median follow-up of 10 months, 17% have progressed to AML

-   The median number of courses given was 6

-   The incidence of myelosuppression-associated complications,
    prolonged myelosuppression, and hospitalization rates were worse
    with the 10 day intravenous schedule

For further details on the efficacy results of the clinical trials,
refer to Appendix: Clinical Trials

# Adverse Events (Safety Data)[^4]

**Table#7 Adverse Events in ≥5% in decitabine group in phase III trial**

+---------------------------------+------------------+-----------------+
| **Event**                       | **Decitabine     | **Best          |
|                                 | N=83**           | supportive Care |
|                                 |                  | N=81**          |
|                                 | **%**            |                 |
|                                 |                  | **%**           |
+---------------------------------+------------------+-----------------+
| **Blood and lymph systems**     | 90               | 72              |
|                                 |                  |                 |
| Neutropenia                     | 89               | 79              |
|                                 |                  |                 |
| Thrombocytopenia                | 82               | 74              |
|                                 |                  |                 |
| Anemia NOS                      | 29               | 6               |
|                                 |                  |                 |
| Febrile neutropenia             | 28               | 14              |
|                                 |                  |                 |
| Leukopenia NOS                  | 12               | 7               |
|                                 |                  |                 |
| Lymphadenopathy                 | 5                | 1               |
|                                 |                  |                 |
| Thrombocythemia                 |                  |                 |
+---------------------------------+------------------+-----------------+
| **Cardiac**                     | 6                | 0               |
|                                 |                  |                 |
| Pulmonary edema NOS             |                  |                 |
+---------------------------------+------------------+-----------------+
| **Eye**                         | 6                | 0               |
|                                 |                  |                 |
| Blurred vision                  |                  |                 |
+---------------------------------+------------------+-----------------+
| **GI**                          | 42               | 16              |
|                                 |                  |                 |
| Nausea                          | 35               | 14              |
|                                 |                  |                 |
| Constipation                    | 34               | 16              |
|                                 |                  |                 |
| Diarrhea NOS                    | 25               | 9               |
|                                 |                  |                 |
| Vomiting NOS                    | 14               | 6               |
|                                 |                  |                 |
| Abdominal pain NOS              | 13               | 5               |
|                                 |                  |                 |
| Oral mucosal petechiae          | 12               | 6               |
|                                 |                  |                 |
| Stomatitis                      | 12               | 1               |
|                                 |                  |                 |
| Dyspepsia                       | 10               | 2               |
|                                 |                  |                 |
| Ascites                         | 8                | 6               |
|                                 |                  |                 |
| Gingival bleeding               | 8                | 4               |
|                                 |                  |                 |
| Hemorrhoids                     | 7                | 4               |
|                                 |                  |                 |
| Loose stools                    | 7                | 2               |
|                                 |                  |                 |
| Tongue ulceration               | 6                | 2               |
|                                 |                  |                 |
| Dysphagia                       | 6                | 1               |
|                                 |                  |                 |
| Oral soft tissue disorder NOS\  | 5                | 4               |
| Lip ulceration                  |                  |                 |
|                                 | 5                | 1               |
| Abdominal distension            |                  |                 |
|                                 | 5                | 1               |
| Abdominal pain upper            |                  |                 |
|                                 | 5                | 0               |
| GERD                            |                  |                 |
|                                 | 5                | 0               |
| Glossodynia                     |                  |                 |
+---------------------------------+------------------+-----------------+
| **General disorders**           | 53               | 28              |
|                                 |                  |                 |
| Pyrexia                         | 25               | 16              |
|                                 |                  |                 |
| Edema peripheral                | 22               | 17              |
|                                 |                  |                 |
| Rigors                          | 18               | 6               |
|                                 |                  |                 |
| Edema NOS                       | 13               | 6               |
|                                 |                  |                 |
| Pain NOS                        | 12               | 4               |
|                                 |                  |                 |
| Lethargy                        | 11               | 0               |
|                                 |                  |                 |
| Tenderness NOS                  | 8                | 4               |
|                                 |                  |                 |
| Fall                            | 7                | 4               |
|                                 |                  |                 |
| Chest discomfort                | 6                | 4               |
|                                 |                  |                 |
| Intermittent pyrexia            | 5                | 1               |
|                                 |                  |                 |
| Malaise                         | 5                | 1               |
|                                 |                  |                 |
| Crepitations NOS                | 5                | 1               |
|                                 |                  |                 |
| Catheter site edema             | 5                | 0               |
|                                 |                  |                 |
| Catheter site pain              | 5                | 0               |
|                                 |                  |                 |
| Injection site swelling         |                  |                 |
+---------------------------------+------------------+-----------------+
| **Hepatobiliary**               | 14               | 5               |
|                                 |                  |                 |
| Hyperbilirubinemia              |                  |                 |
+---------------------------------+------------------+-----------------+
| **Infections**                  | 22               | 14              |
|                                 |                  |                 |
| Pneumonia NOS                   | 12               | 7               |
|                                 |                  |                 |
| Cellulitis                      | 10               | 1               |
|                                 |                  |                 |
| Candidal infection NOS          | 8                | 0               |
|                                 |                  |                 |
| Catheter related infection      | 7                | 1               |
|                                 |                  |                 |
| UTI NOS                         | 7                | 0               |
|                                 |                  |                 |
| Staph infection                 | 6                | 2               |
|                                 |                  |                 |
| Oral candidiasis                | 5                | 2               |
|                                 |                  |                 |
| Sinusitis NOS                   | 5                | 0               |
|                                 |                  |                 |
| Bacteremia                      |                  |                 |
+---------------------------------+------------------+-----------------+
| **Metabolism and Nutrition**    | 33               | 20              |
|                                 |                  |                 |
| Hyperglycemia NOS               | 24               | 17              |
|                                 |                  |                 |
| Hypoalbuminemia                 | 24               | 7               |
|                                 |                  |                 |
| Hypomagnesemia                  | 22               | 12              |
|                                 |                  |                 |
| Hypokalemia                     | 19               | 16              |
|                                 |                  |                 |
| Hyponatremia                    | 16               | 15              |
|                                 |                  |                 |
| Decreased appetite NOS          | 16               | 10              |
|                                 |                  |                 |
| Anorexia                        | 13               | 4               |
|                                 |                  |                 |
| Hyperkalemia                    | 6                | 5               |
|                                 |                  |                 |
| Dehydration                     |                  |                 |
+---------------------------------+------------------+-----------------+
| **Musculoskeletal**             | 20               | 10              |
|                                 |                  |                 |
| Arthralgia                      | 19               | 10              |
|                                 |                  |                 |
| Pain in limb                    | 17               | 6               |
|                                 |                  |                 |
| Back pain                       | 7                | 1               |
|                                 |                  |                 |
| Chest wall pain                 | 6                | 0               |
|                                 |                  |                 |
| Musculoskeletal discomfort      | 5                | 1               |
|                                 |                  |                 |
| Myalgia                         |                  |                 |
+---------------------------------+------------------+-----------------+
| **Nervous system**              | 28               | 14              |
|                                 |                  |                 |
| Headache                        | 18               | 12              |
|                                 |                  |                 |
| Dizziness                       | 11               | 1               |
|                                 |                  |                 |
| Hypoesthesia                    |                  |                 |
+---------------------------------+------------------+-----------------+
| **Psychiatric**                 | 28               | 14              |
|                                 |                  |                 |
| Insomnia                        | 12               | 4               |
|                                 |                  |                 |
| Confused state                  | 11               | 10              |
|                                 |                  |                 |
| Anxiety                         |                  |                 |
+---------------------------------+------------------+-----------------+
| **Renal**                       | 6                | 4               |
|                                 |                  |                 |
| Dysuria                         | 5                | 1               |
|                                 |                  |                 |
| Urinary frequency               |                  |                 |
+---------------------------------+------------------+-----------------+
| **Respiratory**                 | 40               | 31              |
|                                 |                  |                 |
| Cough                           | 16               | 7               |
|                                 |                  |                 |
| Pharyngitis                     | 14               | 1               |
|                                 |                  |                 |
| Crackles lung                   | 10               | 9               |
|                                 |                  |                 |
| Decreased breath sounds         | 10               | 5               |
|                                 |                  |                 |
| Hypoxia                         | 8                | 2               |
|                                 |                  |                 |
| Rales                           | 5                | 2               |
|                                 |                  |                 |
| Postnasal drip                  |                  |                 |
+---------------------------------+------------------+-----------------+
| **Skin**                        | 22               | 15              |
|                                 |                  |                 |
| Ecchymosis                      | 19               | 9               |
|                                 |                  |                 |
| Rash NOS                        | 14               | 6               |
|                                 |                  |                 |
| Erythema                        | 11               | 4               |
|                                 |                  |                 |
| Skin lesion NOS                 | 11               | 2               |
|                                 |                  |                 |
| Pruritis                        | 8                | 1               |
|                                 |                  |                 |
| Alopecia                        | 6                | 1               |
|                                 |                  |                 |
| Urticaria NOS                   | 6                | 0               |
|                                 |                  |                 |
| Swelling face                   |                  |                 |
+---------------------------------+------------------+-----------------+
| **Vascular**                    | 39               | 16              |
|                                 |                  |                 |
| Petechiae                       | 23               | 12              |
|                                 |                  |                 |
| Pallar                          | 6                | 5               |
|                                 |                  |                 |
| Hypotension NOS                 | 5                | 4               |
|                                 |                  |                 |
| Hematoma NOS                    |                  |                 |
+---------------------------------+------------------+-----------------+
| **Other**                       | 10               | 1               |
|                                 |                  |                 |
| Blood urea increased            | 7                | 0               |
|                                 |                  |                 |
| Blood albumin decreased         | 6                | 1               |
|                                 |                  |                 |
| Blood bicarbonate increased     | 6                | 1               |
|                                 |                  |                 |
| Blood chloride decreased        |                  |                 |
+---------------------------------+------------------+-----------------+

## Deaths and Other Serious Adverse Events (optional)

Deaths: Six deaths associated with the underlying disease and
myelosuppression were considered at least possibly due to drug
treatment.

Highest incidence of Grade 3 or 4 adverse events:

-   Neutropenia 87%

-   Thrombocytopenia 85%

-   Febrile neutropenia 23%

-   Leucopenia 22%

Most frequent cause of dose reduction, delay, and discontinuation: bone
marrow suppression

## Common Adverse Events

Neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough,
petechiae, constipation, diarrhea, and hyperglycemia.

## Tolerability

Eight patients permanently discontinued therapy due to adverse events.

[Most frequent adverse events requiring clinical
intervention]{.underline}

Discontinuation: thrombocytopenia, neutropenia, pneumonia, MAC
infection, cardio-respiratory arrest, increased blood bilirubin,
intracranial hemorrhage, abnormal liver function tests

Dose delay: neutropenia, pulmonary edema, atrial fibrillation, central
line infections, febrile neutropenia

Dose reduction: neutropenia, thrombocytopenia, anemia, lethargy, edema,
tachycardia, depression, Pharyngitis

# Precautions/Contraindications

## Precautions

[General:]{.underline}

Complete blood counts should be measured to monitor response and
toxicity since decitabine therapy is associated with neutropenia and
thrombocytopenia. At a minimum, complete blood counts should be
performed prior to each dosing cycle. Early institution of growth
factors and antibiotics should be considered for the prevention and
treatment of infections. Myelosuppression and worsening neutropenia
occur more frequently during the first 2 cycles of treatment.

Dosing has not been investigated in patients with renal or hepatic
dysfunction. In clinical trials, decitabine was not administered to
patients with serum creatinine \> 2.0mg/dL, transaminases greater than 2
times the ULN, or serum bilirubin \> 1.5mg/dL.

[Carcinogenicity, Mutagenicity, and Infertility:]{.underline}

No formal carcinogenicity studies have been performed.

Mutagenetic potential has been evaluated in *in vitro* and *in vivo*
animal models. There was increase mutation frequency in both systems.
Chromosomal rearrangements were seen in fruit fly larvae.

Mouse models were used to test the effects of decitabine on fertility.
No consistent effects were seen in female mice exposed to decitabine *in
utero*. Males had reduced testicular weight, abnormal histology, and
significant decreased sperm counts. Untreated females mated to treated
males pregnancy rates were decreased and preimplantation loss was
increased.

[Pregnancy]{.underline}:

Teratogenic effects: Category D

[Nursing Mothers:]{.underline}

It is not known if decitabine is excreted into breast milk and could
potentially cause adverse events in nursing babies. A decision on
whether or not to continue using decitabine in a nursing mother should
take into account the importance of the drug for the mother.

[Pediatric Use:]{.underline}

Safety and efficacy has not been evaluated in this population

[Geriatric Use:]{.underline}

In the phase 3 clinical trial 61 of 83 patients on decitabine were
greater than 65 years old and 21 patients were 75 years old or older. No
overall difference in efficacy and safety was observed in this trial and
other trials for older patients. Increased sensitivity of some patients
cannot be ruled out.

## Contraindications

In patients with a known hypersensitivity to decitabine.

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

LA/SA for generic name decitabine: cytarabine (high-alert drug),
capecitabine, azacitidine, zalcitabine, dacarbazine, desirudin,
dobutamine, gemcitabine,

LA/SA for trade name Dacogen: Desogen Dulcogen, Adagen, Depacon,
Drotrecogin

# 

# Drug Interactions

## Drug-Drug Interactions

No formal investigation into drug-drug interactions has been performed
with decitabine. While it is extensively metabolized by deamination, the
cytochrome P450 system does not appear to be involved.

# Acquisition Costs

\$960.61 per 50mg vial

Table #8 Comparative Acquisition Pricing

+---------------+------------------+-----------------+-----------------+
| **Drug**      | **Dose**         | **Cos           | **Cost/6        |
|               |                  | t/Cycle/patient | cycles/patient  |
|               |                  | (\$)**          | (\$)**          |
+---------------+------------------+-----------------+-----------------+
| Decitabine    | 15mg/m^2^every 8 | \$8,645.49      | \$51,872.94     |
|               | hours for 3 days |                 |                 |
|               |                  | \$4,803.05      | \$28,818.30     |
|               | 20mg/m^2^ daily  |                 |                 |
|               | for 5 days       |                 |                 |
+---------------+------------------+-----------------+-----------------+
| Azacitidine   | 75 mg/m^2^ daily | \$4,267.34      | \$25,604.04     |
|               | for 7 days       |                 |                 |
+---------------+------------------+-----------------+-----------------+
| Lenalidomide  | 10mg orally      | \$5,008.56      | \$30,051.34     |
|               | daily            |                 |                 |
+---------------+------------------+-----------------+-----------------+

# Pharmacoeconomic Analysis

# There are no published pharmacoeconomic models.

# 

# Conclusions

[Clinical Efficacy]{.underline}

In a phase III trial comparing decitabine therapy plus supportive care
to supportive care alone, decitabine produced a better overall response
rate compared to supportive care. The responses were seen across all FAB
classifications, all IPSS prognostic groups, in patient who had and had
not been previously treated, and in both *de novo* and secondary MDS.
There was a trend toward a longer time to AML or death but this was only
statistically significant in subgroup analyses. One third of patients
who had baseline cytogenetic abnormalities had complete cytogenetic
responses. All decitabine responders became transfusion independent. The
median number of courses delivered was 3 due to study design. Other
hypomethylating agents allowed a longer duration of treatment.
Maintenance courses may, in fact, become a necessary part of MDS
treatment in the future.

[Safety]{.underline}

The adverse event profile in the clinical trial is consistent with the
underlying disease and with other hypomtheylating agents. The most
common adverse events are hematologic. The most serious events were
primary hematologic. Whether this is due to drug therapy or disease is
unknown. In patients who responded to therapy, neutropenia,
thrombocytopenia, anemia, and leucopenia diminished over time, but were
still frequent. Gastrointestinal toxicities were mild; the package
insert states that standard antiemetic therapy may be considered.
Febrile neutropenia and pneumonia are among the most common adverse
events. Hospitalization for infection was not reported.

# Recommendations and Place in Therapy[^5]^,^[^6]^,^[^7]

# 

Myelodysplastic Syndromes is actually a group of clonal hematologic that
manifest as ineffective hematopoeisis with the potential to transform to
AML. The incidence increases with age. Although there are several
classification systems for MDS, the International Prognostic Scoring
System appears to offer a good tool for choosing therapy, and allows for
comparison across clinical trials due to its standard use in such
trials. Until recently, intensive chemotherapy regimens did not offer
much hope of response outside of the stem cell transplant arena.
Recently, the addition of hypomethylating agents and lenalidomide
offered the first real chance for any kind of significant therapeutic
outcome to be realized in advanced or higher risk MDS.

Decitabine is best reserved at this time to patients with unfavorable or
higher risk MDS. The data from the 3 arm trial looking at lower dosage
schedules is interesting as response rates appeared to improve with the
low dose given daily. The number of treatment arms to use is also still
evolving as longer durations of treatment in some phase II trials hint
at longer durations of response with decitabine. There is also some
information that patients with thrombocytopenia may respond better to
decitabine. A recent analysis update from the 3 arm trial also showed a
higher number of patients with an IPSS score of Intermediate-2 enrolled
in the trial with high response rates.

Comparison with azacitidine is difficult due to the differences in study
methodology, populations, and response criteria used. The length of
treatment in the azacitidine trials was longer than in the present
decitabine trial with a longer duration of response, suggesting a role
for maintenance therapy following a response. The differences between
these agents and their exact roles are difficulty to assess with the
available data. A comparative trial with high risk patients is needed to
best determine which populations will benefit most from each drug.

**Prepared January 2008. Contact : Mark C. Geraci, Pharm.D. BCOP,
Clinical Specialist**

# Appendix: Clinical Trials

Include a brief description of the methods used to perform the
literature search (database, period, search strategy), inclusion
criteria for studies, and sources of any other pertinent information on
clinical trials (e.g., review of reference lists, manufacturer's
formulary and AMCP dossier, medical reviews and transcripts on FDA Web
site; conference abstracts---last resort if information is lacking or
abstract is of major importance, etc.) This paragraph is optional. For
example:

A literature search was performed on PubMed/Medline (1966 to August
2004) using the search terms \<generic name\> and \<trade name\>. The
search was limited to studies performed in humans and published in
English language. Reference lists of review articles and the
manufacturer's AMCP dossier were searched for relevant clinical trials.
All randomized controlled trials published in peer-reviewed journals
were included.

Insert text here.

A [summary]{.underline} of relevant clinical trials is presented in this
section utilizing the example chart formats below. Randomized,
placebo-controlled, blinded trials (Grade A evidence) should be reviewed
in detail. If available, head-to-head trials against formulary or
standard treatments are desired. [Trials of low evidence]{.underline}
(i.e. open-label, non-comparative, abstract form) should be mentioned
with brief synopsis without going into great detail. For reviews
including multiple trials a table or chart outlining level of evidence,
results of primary efficacy measures and safety data is recommended for
easier visual comparison.

Table title (optional). This table format may be useful when many
articles are summarized.

+-------+--------+--------+------------+---------------+-------------+
| **    | *      | **Int  | **Patient  | **Efficacy    | **Safety    |
| Citat | *Eligi | ervent | Population | Results**     | Results**   |
| ion** | bility | ions** | Profile**  |               |             |
|       | Crit   |        |            |               |             |
| **Des | eria** |        |            |               |             |
| ign** |        |        |            |               |             |
+=======+========+========+============+===============+=============+
| K     | Incl   | Decit  | <table>    | N=170         | Temporary   |
| antar | usion: | abine: | <colgroup> |               | dose        |
| jian, |        | 15m    | <col       | ITT analysis  | reductions  |
| et    | -      | g/m^2^ | s          |               | in 35% of   |
| al.   |    MDS | IV     | tyle="widt | <table>       | patients on |
|       |        | over 3 | h: 51%" /> | <colgroup>    | decitabine  |
| RCT   |    *de | hours  | <col       | <col          | due to      |
|       |        | every  | s          | style="w      | adverse     |
| Phase |  novo* | 8      | tyle="widt | idth: 40%" /> | effects.    |
| III   |     or | hours, | h: 24%" /> | <col          |             |
|       |        | repeat | <col       | style="w      | Deaths:     |
| 1º    |    sec | every  | s          | idth: 30%" /> | decitabine  |
| ORR,  | ondary | 6      | tyle="widt | <col          | 14%         |
| time  |        | weeks  | h: 24%" /> | style="w      |             |
| to    | -      | (+BSC) | <          | idth: 28%" /> | Deaths: BSC |
| AML   |   IPSS |        | /colgroup> | </colgroup>   | 22%         |
| or    |        | vs     | <tbody>    | <tbody>       |             |
| death |  score |        | <tr        | <tr           | Serious     |
|       |        | BSC:   | cl         | class="odd">  | Adverse     |
| 2º    |  \>0.5 | RBC    | ass="odd"> | <td></td>     | events:     |
| QoL   |        | t      | <td></td>  | <td><p>D</p>  |             |
|       | Excl   | ransfu | <td>D</td> | <p>           | Decitabine  |
|       | usion: | sions, | <t         | n=89</p></td> | 69\^        |
|       |        | pl     | d>BSC</td> | <             |             |
|       | -      | atelet | </tr>      | td><p>BSC</p> | BSC 56%     |
|       |   AML( | t      | <tr        | <p>           |             |
|       | blasts | ransfu | cla        | n=81</p></td> | N           |
|       | \>30%) | sions, | ss="even"> | </tr>         | eutropenia, |
|       |        | growth | <t         | <tr           | thromb      |
|       | -      | f      | d>Age</td> | class="even"> | ocytopenia, |
|       |  other | actors | <          | <             | anemia, and |
|       |        |        | td>70</td> | td><p>ORR</p> | leucopenia  |
|       |  progr | Withd  | <          | <             | diminished  |
|       | essive | rawal: | td>70</td> | p>(CR+PR)</p> | in          |
|       |        | progre | </tr>      | <p>CR</p>     | incidence   |
|       |    mal | ssion, | <tr        | <             | over the    |
|       | ignant | tr     | cl         | p>PR</p></td> | first 4     |
|       |     d  | ansfor | ass="odd"> | <             | cycles but  |
|       | isease | mation | <td        | td><p>17%</p> | remained    |
|       |        | to     | >Male</td> | <p>p          | frequent    |
|       |        | AML,   | <t         | &lt;0.001</p> | due to      |
|       |        | f      | d>66%</td> | <p>9</p>      | disease.    |
|       |        | ailure | <t         | <p>8</p></td> |             |
|       |        | to     | d>70%</td> | <td><p>0</p>  |             |
|       |        | a      | </tr>      | <p>0</p>      |             |
|       |        | chieve | <tr        | <p>0</p></td> |             |
|       |        | PR     | cla        | </tr>         |             |
|       |        | after  | ss="even"> | <tr           |             |
|       |        | 6      | <td>       | class="odd">  |             |
|       |        | c      | White</td> | <t            |             |
|       |        | ycles, | <t         | d><p>Clinical |             |
|       |        | f      | d>93%</td> | Im            |             |
|       |        | ailure | <t         | provement</p> |             |
|       |        | to     | d>94%</td> | <p>CR+PR      |             |
|       |        | a      | </tr>      | +HI)</p></td> |             |
|       |        | chieve | <tr        | <             |             |
|       |        | CR     | cl         | td><p>30%</p> |             |
|       |        | after  | ass="odd"> | <p>p&lt;0     |             |
|       |        | 8      | <          | .001</p></td> |             |
|       |        | cycles | td><p>Time | <td>7%</td>   |             |
|       |        |        | since      | </tr>         |             |
|       |        | S      | dia        | <tr           |             |
|       |        | topped | gnosis</p> | class="even"> |             |
|       |        | t      | <p>(weeks  | <t            |             |
|       |        | herapy | )</p></td> | d><p>Subgroup |             |
|       |        | after  | <          | response</p>  |             |
|       |        | 2      | td>29</td> | <p>Int-1</p>  |             |
|       |        | cycles | <          | <p>Int-2</p>  |             |
|       |        | of     | td>35</td> | <p>High-      |             |
|       |        | main   | </tr>      | risk</p></td> |             |
|       |        | tained | <tr        | <             |             |
|       |        | CR     | cla        | td><p>14%</p> |             |
|       |        |        | ss="even"> | <p>18</p>     |             |
|       |        |        | <td>MDS    | <             |             |
|       |        |        | seco       | p>17</p></td> |             |
|       |        |        | ndary</td> | <td><p>0</p>  |             |
|       |        |        | <t         | <p>0          |             |
|       |        |        | d>13%</td> | p0.011</p>    |             |
|       |        |        | <t         | <p>0</p></td> |             |
|       |        |        | d>14%</td> | </tr>         |             |
|       |        |        | </tr>      | <tr           |             |
|       |        |        | <tr        | class="odd">  |             |
|       |        |        | cl         | <t            |             |
|       |        |        | ass="odd"> | d><p>Response |             |
|       |        |        | <td>Prev.  | by            |             |
|       |        |        | trea       | cyt           |             |
|       |        |        | tment</td> | ogenetics</p> |             |
|       |        |        | <t         | <p>5q         |             |
|       |        |        | d>22%</td> | abnormal</p>  |             |
|       |        |        | <t         | <p>5q         |             |
|       |        |        | d>20%</td> | normal</p>    |             |
|       |        |        | </tr>      | <p>7q         |             |
|       |        |        | <tr        | abnormal</p>  |             |
|       |        |        | cla        | <p>7q         |             |
|       |        |        | ss="even"> | no            |             |
|       |        |        | <td><      | rmal</p></td> |             |
|       |        |        | p>IPSS</p> | <             |             |
|       |        |        | <p         | td><p>13%</p> |             |
|       |        |        | >Int-1</p> | <p>16</p>     |             |
|       |        |        | <p         | <p>p          |             |
|       |        |        | >Int-2</p> | &lt;0.001</p> |             |
|       |        |        | <          | <p>21</p>     |             |
|       |        |        | p>High-ris | <p>14</p>     |             |
|       |        |        | k</p></td> | <p>p0         |             |
|       |        |        | <t         | .003</p></td> |             |
|       |        |        | d><p>%</p> | <td><p>0</p>  |             |
|       |        |        | <p>31</p>  | <p>0</p>      |             |
|       |        |        | <p>43</p>  | <p>0</p>      |             |
|       |        |        | <p>2       | <p>0</p></td> |             |
|       |        |        | 6</p></td> | </tr>         |             |
|       |        |        | <t         | <tr           |             |
|       |        |        | d><p>%</p> | class="even"> |             |
|       |        |        | <p>30</p>  | <t            |             |
|       |        |        | <p>44</p>  | d><p>Response |             |
|       |        |        | <p>2       | by prior      |             |
|       |        |        | 6</p></td> | therapy</p>   |             |
|       |        |        | </tr>      | <p>yes</p>    |             |
|       |        |        | <tr        | <             |             |
|       |        |        | cl         | p>no</p></td> |             |
|       |        |        | ass="odd"> | <             |             |
|       |        |        | <td>       | td><p>15%</p> |             |
|       |        |        | <p>WHO</p> | <p>17</p>     |             |
|       |        |        | <p>0</p>   | <p>&lt;0      |             |
|       |        |        | <p>1</p>   | .001</p></td> |             |
|       |        |        | <p>        | <td><p>0</p>  |             |
|       |        |        | 2</p></td> | <p>0</p></td> |             |
|       |        |        | <t         | </tr>         |             |
|       |        |        | d><p>%</p> | <tr           |             |
|       |        |        | <p>27</p>  | class="odd">  |             |
|       |        |        | <p>69</p>  | <t            |             |
|       |        |        | <p>        | d><p>Response |             |
|       |        |        | 4</p></td> | by MDS        |             |
|       |        |        | <t         | status</p>    |             |
|       |        |        | d><p>%</p> | <p><em>de     |             |
|       |        |        | <p>35</p>  | novo</em></p> |             |
|       |        |        | <p>59</p>  | <p>secon      |             |
|       |        |        | <p>        | dary</p></td> |             |
|       |        |        | 5</p></td> | <             |             |
|       |        |        | </tr>      | td><p>17%</p> |             |
|       |        |        | <tr        | <p>           |             |
|       |        |        | cla        | &lt;0.001</p> |             |
|       |        |        | ss="even"> | <             |             |
|       |        |        | <td>T      | p>17</p></td> |             |
|       |        |        | ransfusion | <td><p>0</p>  |             |
|       |        |        | depen      | <p>0</p></td> |             |
|       |        |        | dence</td> | </tr>         |             |
|       |        |        | <t         | <tr           |             |
|       |        |        | d>74%</td> | class="even"> |             |
|       |        |        | <t         | <td>Time to   |             |
|       |        |        | d>67%</td> | first         |             |
|       |        |        | </tr>      | response</td> |             |
|       |        |        | <tr        | <td><p>3.3    |             |
|       |        |        | cl         | mos</p>       |             |
|       |        |        | ass="odd"> | <p>(2-        |             |
|       |        |        | <td        | 9.7)</p></td> |             |
|       |        |        | ><p>Cytoge | <td></td>     |             |
|       |        |        | netics</p> | </tr>         |             |
|       |        |        | <p>D       | <tr           |             |
|       |        |        | el(5q)</p> | class="odd">  |             |
|       |        |        | <p>        | <td><p>Time   |             |
|       |        |        | Del(7)</p> | to AML or     |             |
|       |        |        | <p>Del(20  | death</p>     |             |
|       |        |        | )</p></td> | <p>Naïve</p>  |             |
|       |        |        | <td>       | <p>Int-2 or   |             |
|       |        |        | <p>18%</p> | HR</p>        |             |
|       |        |        | <p>21</p>  | <p>HR</p>     |             |
|       |        |        | <p>        | <p><em>de     |             |
|       |        |        | 9</p></td> | novo<         |             |
|       |        |        | <td>       | /em></p></td> |             |
|       |        |        | <p>17%</p> | <td><p>12.1   |             |
|       |        |        | <p>19</p>  | mos</p>       |             |
|       |        |        | <p>        | <p>12.3</p>   |             |
|       |        |        | 4</p></td> | <p>p0.08</p>  |             |
|       |        |        | </tr>      | <p>12</p>     |             |
|       |        |        | </tbody>   | <p>p0.03</p>  |             |
|       |        |        | </table>   | <p>9.3</p>    |             |
|       |        |        |            | <p>p0.01</p>  |             |
|       |        |        |            | <p>12.6</p>   |             |
|       |        |        |            | <p>p          |             |
|       |        |        |            | 0.04</p></td> |             |
|       |        |        |            | <td><p>7.8    |             |
|       |        |        |            | mos</p>       |             |
|       |        |        |            | <p>7.3</p>    |             |
|       |        |        |            | <p>6.8</p>    |             |
|       |        |        |            | <p>2.8</p>    |             |
|       |        |        |            | <p            |             |
|       |        |        |            | >9.4</p></td> |             |
|       |        |        |            | </tr>         |             |
|       |        |        |            | </tbody>      |             |
|       |        |        |            | </table>      |             |
|       |        |        |            |               |             |
|       |        |        |            | Quality of    |             |
|       |        |        |            | Life: in      |             |
|       |        |        |            | decitabine    |             |
|       |        |        |            | arm           |             |
|       |        |        |            |               |             |
|       |        |        |            | Improved      |             |
|       |        |        |            | global health |             |
|       |        |        |            | status at end |             |
|       |        |        |            | of cycles 2   |             |
|       |        |        |            | and 4         |             |
|       |        |        |            | (p\<0.05)     |             |
|       |        |        |            |               |             |
|       |        |        |            | Improved      |             |
|       |        |        |            | fatigue       |             |
|       |        |        |            | scores at end |             |
|       |        |        |            | of cycles     |             |
|       |        |        |            | 2,4,5,6       |             |
|       |        |        |            | (p\<0.05)     |             |
|       |        |        |            |               |             |
|       |        |        |            | Improved      |             |
|       |        |        |            | dyspnea       |             |
|       |        |        |            | scores at end |             |
|       |        |        |            | of cycle 6    |             |
|       |        |        |            | (p\<0.05)     |             |
+-------+--------+--------+------------+---------------+-------------+
| W     | Incl   | Deci   | <table>    | <table>       | Consistent  |
| ijjer | usion: | tabine | <colgroup> | <colgroup>    | with those  |
| mans, |        | 15m    | <col       | <col          | in the      |
| et.   | MDS    | g/m^2^ | s          | style="w      | phase III   |
| al.   |        | IV     | tyle="widt | idth: 50%" /> | trial       |
|       | -      | over 4 | h: 50%" /> | <col          |             |
| Phase |   refr | hours  | <col       | style="w      |             |
| II    | actory | every  | s          | idth: 50%" /> |             |
|       |        | 8      | tyle="widt | </colgroup>   |             |
| 1º    | anemia | hours  | h: 50%" /> | <tbody>       |             |
| Res   |        | for 3  | <          | <tr           |             |
| ponse |   with | conse  | /colgroup> | class="odd">  |             |
| rate  |        | cutive | <tbody>    | <td>          |             |
|       | excess | days;  | <tr        | Response</td> |             |
|       |        | repeat | cl         | <td><p>ITT    |             |
|       | blasts | every  | ass="odd"> | p             |             |
|       |        | 6      | <t         | opulation</p> |             |
|       | -      | weeks  | d>Age</td> | <p>           |             |
|       |   refr |        | <          | N=66</p></td> |             |
|       | actory |        | td>68</td> | </tr>         |             |
|       |        |        | </tr>      | <tr           |             |
|       | anemia |        | <tr        | class="even"> |             |
|       |        |        | cla        | <             |             |
|       |   with |        | ss="even"> | td><p>Overall |             |
|       |        |        | <td>       | RR            |             |
|       | excess |        | Males</td> | (CR+PR)</p>   |             |
|       |        |        | <t         | <p>CR</p>     |             |
|       | blasts |        | d>70%</td> | <             |             |
|       |     in |        | </tr>      | p>PR</p></td> |             |
|       |     tr |        | <tr        | <             |             |
|       | ansfor |        | cl         | td><p>26%</p> |             |
|       | mation |        | ass="odd"> | <p>21</p>     |             |
|       |        |        | <td><p>R   | <p>5</p></td> |             |
|       | -   c  |        | A/RARS</p> | </tr>         |             |
|       | hronic |        | <          | <tr           |             |
|       |     my |        | p>RAEB</p> | class="odd">  |             |
|       | elomon |        | <p>        | <td>Duration  |             |
|       | ocytic |        | RAEB-T</p> | of response   |             |
|       |     le |        | <p>CMM     | median</td>   |             |
|       | ukemia |        | L</p></td> | <td>9         |             |
|       |        |        | <t         | mos</td>      |             |
|       | -      |        | d><p>8</p> | </tr>         |             |
|       |   refr |        | <p>29</p>  | <tr           |             |
|       | actory |        | <p>20</p>  | class="even"> |             |
|       |        |        | <p>        | <td><p>IPSS   |             |
|       | anemia |        | 9</p></td> | ORR</p>       |             |
|       |     or |        | </tr>      | <p>Int-1</p>  |             |
|       |        |        | <tr        | <p>Int-2</p>  |             |
|       |   refr |        | cla        | <p>High-      |             |
|       | actory |        | ss="even"> | risk</p></td> |             |
|       |        |        | <td><      | <             |             |
|       | anemia |        | p>IPSS</p> | td><p>21%</p> |             |
|       |        |        | <p         | <p>24</p>     |             |
|       |   with |        | >Int-1</p> | <             |             |
|       |        |        | <p         | p>33</p></td> |             |
|       | ringed |        | >Int-2</p> | </tr>         |             |
|       |        |        | <          | </tbody>      |             |
|       | sidero |        | p>High-ris | </table>      |             |
|       | blasts |        | k</p></td> |               |             |
|       |        |        | <td        |               |             |
|       |   with |        | ><p>16</p> |               |             |
|       |     \> |        | <p>25</p>  |               |             |
|       |     3  |        | <p>2       |               |             |
|       |        |        | 5</p></td> |               |             |
|       |  units |        | </tr>      |               |             |
|       |     of |        | </tbody>   |               |             |
|       |        |        | </table>   |               |             |
|       |  RBC's |        |            |               |             |
|       |     or |        |            |               |             |
|       |        |        |            |               |             |
|       |    \>6 |        |            |               |             |
|       |        |        |            |               |             |
|       |  units |        |            |               |             |
|       |     of |        |            |               |             |
|       |        |        |            |               |             |
|       |    pla |        |            |               |             |
|       | telets |        |            |               |             |
|       |        |        |            |               |             |
|       |    per |        |            |               |             |
|       |        |        |            |               |             |
|       |   week |        |            |               |             |
|       |        |        |            |               |             |
|       | -      |        |            |               |             |
|       |   ECOG |        |            |               |             |
|       |        |        |            |               |             |
|       |  0,1,2 |        |            |               |             |
|       |        |        |            |               |             |
|       | -      |        |            |               |             |
|       | normal |        |            |               |             |
|       |        |        |            |               |             |
|       |  renal |        |            |               |             |
|       |        |        |            |               |             |
|       |    and |        |            |               |             |
|       |        |        |            |               |             |
|       |  liver |        |            |               |             |
|       |     fu |        |            |               |             |
|       | nction |        |            |               |             |
+-------+--------+--------+------------+---------------+-------------+
| K     | Inc    | Deci   | <table>    | ITT N=95      | 10mg/m^2^   |
| antar | lusion | tabine | <colgroup> |               | IV daily    |
| jian, |        | Sche   | <col       | <table>       | for 10      |
| et    | MDS    | dules: | s          | <colgroup>    | days-       |
| al.   |        |        | tyle="widt | <col          |             |
|       | -      | \(1\)  | h: 54%" /> | style="w      | Higher      |
| RCT   |   IPSS | 20m    | <col       | idth: 50%" /> | incidence   |
|       |     i  | g/m^2^ | s          | <col          | of          |
| Phase | nterme | IV     | tyle="widt | style="w      | myelo       |
| II    | diate, | over 1 | h: 45%" /> | idth: 50%" /> | suppression |
|       |        | hour   | <          | </colgroup>   | com         |
| 1º    |    hig | daily  | /colgroup> | <tbody>       | plications, |
| dete  | h-risk | for 5  | <tbody>    | <tr           | more        |
| rmine |        | days   | <tr        | class="odd">  | prolonged   |
| which | -      |        | cl         | <td></td>     | myelos      |
| dose  | normal | \(2\)  | ass="odd"> | <td></td>     | uppression, |
| sch   |        | 20m    | <td>Age    | </tr>         | more        |
| edule |  organ | g/m^2^ | ≥60</td>   | <tr           | courses     |
| was   |        | daily  | <t         | class="even"> | requiring   |
| op    |    fun | for 5  | d>71%</td> | <td>P         | hospi       |
| timal | ctions | days   | </tr>      | arameter</td> | talizations |
| in    |        | given  | <tr        | <             |             |
| res   | -      | in 2   | cla        | td>Value</td> |             |
| ponse |   CMML | subcut | ss="even"> | </tr>         |             |
| rate  |        | aneous | <td>Age    | <tr           |             |
| and   | Exc    | does   | med</td>   | class="odd">  |             |
| s     | lusion | daily  | <          | <td><p>CR     |             |
| afety |        |        | td>65</td> | by            |             |
|       | -      | \(3\)  | </tr>      | schedule</p>  |             |
| Ada   |  Prior | 10m    | <tr        | <p>20mg/      |             |
| ptive |     t  | g/m^2^ | cl         | m<sup>2</sup> |             |
| Bay   | herapy | IV     | ass="odd"> | IV</p>        |             |
| esian |        | over 1 | <td>Male   | <             |             |
| model |   with | hour   | %</td>     | p>20mg/m<sup> |             |
| after |        | daily  | <          | 2</sup>SC</p> |             |
| 45    |   cyta | for 10 | td>69</td> | <p>10mg/      |             |
| ^tth^ | rabine | days   | </tr>      | m<sup>2</sup> |             |
| pa    |     1  |        | <tr        | IV</p>        |             |
| tient |        |        | cla        | <p>Ove        |             |
|       | g/m^2^ |        | ss="even"> | rall</p></td> |             |
|       |     or |        | <t         | <td><p>39%    |             |
|       |        |        | d>Abnormal | p&lt;0.05</p> |             |
|       |   more |        | chromo     | <p>21</p>     |             |
|       |        |        | somes</td> | <p>24</p>     |             |
|       |        |        | <t         | <             |             |
|       |        |        | d>56%</td> | p>34</p></td> |             |
|       |        |        | </tr>      | </tr>         |             |
|       |        |        | <tr        | <tr           |             |
|       |        |        | cl         | class="even"> |             |
|       |        |        | ass="odd"> | <td>Platelet  |             |
|       |        |        | <td><      | response      |             |
|       |        |        | p>Duration | (&            |             |
|       |        |        | of         | gt;100K)</td> |             |
|       |        |        | MDS</p>    | <td>49%</td>  |             |
|       |        |        | <p>3-6     | </tr>         |             |
|       |        |        | mos</p>    | <tr           |             |
|       |        |        | <p>&gt;6   | class="odd">  |             |
|       |        |        | mo         | <t            |             |
|       |        |        | s</p></td> | d>Hematologic |             |
|       |        |        | <td>       | Imp           |             |
|       |        |        | <p>14%</p> | rovement</td> |             |
|       |        |        | <p>3       | <td>14%</td>  |             |
|       |        |        | 9</p></td> | </tr>         |             |
|       |        |        | </tr>      | <tr           |             |
|       |        |        | <tr        | class="even"> |             |
|       |        |        | cla        | <t            |             |
|       |        |        | ss="even"> | d>Progression |             |
|       |        |        | <t         | to AML (med   |             |
|       |        |        | d><p>Prior | follow-up     |             |
|       |        |        | t          | 10            |             |
|       |        |        | herapy</p> | months)</td>  |             |
|       |        |        | <p>Growth  | <td>17%</td>  |             |
|       |        |        | f          | </tr>         |             |
|       |        |        | actors</p> | <tr           |             |
|       |        |        | <p>Othe    | class="odd">  |             |
|       |        |        | r</p></td> | <td>18-month  |             |
|       |        |        | <td>       | survival      |             |
|       |        |        | <p>37%</p> | rate</td>     |             |
|       |        |        | <p>2       | <td>56%</td>  |             |
|       |        |        | 4</p></td> | </tr>         |             |
|       |        |        | </tr>      | <tr           |             |
|       |        |        | <tr        | class="even"> |             |
|       |        |        | cl         | <t            |             |
|       |        |        | ass="odd"> | d>Cytogenetic |             |
|       |        |        | <td        | response</td> |             |
|       |        |        | >Secondary | <td>57%</td>  |             |
|       |        |        | MDS</td>   | </tr>         |             |
|       |        |        | <t         | <tr           |             |
|       |        |        | d>32%</td> | class="odd">  |             |
|       |        |        | </tr>      | <td>Median    |             |
|       |        |        | <tr        | Number of     |             |
|       |        |        | cla        | courses</td>  |             |
|       |        |        | ss="even"> | <td><p>6</p>  |             |
|       |        |        | <td>       | <p>(1         |             |
|       |        |        | <p>MDS</p> | -18)</p></td> |             |
|       |        |        | <p>CMM     | </tr>         |             |
|       |        |        | L</p></td> | </tbody>      |             |
|       |        |        | <td>       | </table>      |             |
|       |        |        | <p>81%</p> |               |             |
|       |        |        | <p>1       | Epigenetic    |             |
|       |        |        | 9</p></td> | hy            |             |
|       |        |        | </tr>      | pomethylation |             |
|       |        |        | <tr        | more          |             |
|       |        |        | cl         | prominent on  |             |
|       |        |        | ass="odd"> | day 5 with    |             |
|       |        |        | <td><      | the 5-day arm |             |
|       |        |        | p>IPSS</p> | IV than the   |             |
|       |        |        | <p         | SC(p=0.09) or |             |
|       |        |        | >Int-1</p> | 10-day arm    |             |
|       |        |        | <p         | (p=0.02)      |             |
|       |        |        | >Int-2</p> |               |             |
|       |        |        | <          |               |             |
|       |        |        | p>High-ris |               |             |
|       |        |        | k</p></td> |               |             |
|       |        |        | <td>       |               |             |
|       |        |        | <p>34%</p> |               |             |
|       |        |        | <p>46</p>  |               |             |
|       |        |        | <p>2       |               |             |
|       |        |        | 0</p></td> |               |             |
|       |        |        | </tr>      |               |             |
|       |        |        | <tr        |               |             |
|       |        |        | cla        |               |             |
|       |        |        | ss="even"> |               |             |
|       |        |        | <td><p>    |               |             |
|       |        |        | Decitabine |               |             |
|       |        |        | sc         |               |             |
|       |        |        | hedule</p> |               |             |
|       |        |        | <p>(1)</p> |               |             |
|       |        |        | <p>(2)</p> |               |             |
|       |        |        | <p>(3      |               |             |
|       |        |        | )</p></td> |               |             |
|       |        |        | <td        |               |             |
|       |        |        | ><p>67</p> |               |             |
|       |        |        | <p>15</p>  |               |             |
|       |        |        | <p>1       |               |             |
|       |        |        | 8</p></td> |               |             |
|       |        |        | </tr>      |               |             |
|       |        |        | </tbody>   |               |             |
|       |        |        | </table>   |               |             |
+-------+--------+--------+------------+---------------+-------------+
|       |        |        |            |               |             |
+-------+--------+--------+------------+---------------+-------------+

RCT=randomized controlled trial; ORR=overall response rate; QoL=quality
of life; MDS=myelodysplastic syndrome; IPSS=International Prognostic
Scoring System; AML=acute myeloid leukemia; BS=best supportive care;
RBC=red blood cell; CR=complete reponse; PR=partial response;WHO=World
Health Organization;HI=hematologic improvement;
HR=high-risk;SC=subcutaneously

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