leukemia higher risk myelodysplastic syndrome and ...

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Prepublished online August 1, 2006; doi:10.1182/blood-2006-05-021162

Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia Hagop Kantarjian, Yasuhiro Oki, Guillermo Garcia-Manero, Xuelin Huang, Susan O'Brien, Jorge Cortes, Stefan Faderl, Carlos Bueso-Ramos, Farhad Ravandi, Zeev Estrov, Alessandra Ferrajoli, William Wierda, Jianqin Shan, Jan Davis, Francis Giles, Hussain I Saba and Jean-Pierre J Issa

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Blood First Edition Paper, prepublished online August 1, 2006; DOI 10.1182/blood-2006-05-021162

Results of a Randomized Study of Three Schedules of Low-Dose Decitabine in Higher Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia

Hagop Kantarjian, M.D. Yasuhiro Oki, M.D. Guillermo Garcia-Manero, M.D., Xuelin Huang, Ph.D.,2 Susan O’Brien, M.D., Jorge Cortes, M.D., Stefan Faderl, M.D., Carlos Bueso-Ramos, M.D.,3 Farhad Ravandi, M.D., Zeev Estrov, M.D., Alessandra Ferrajoli, M.D., William Wierda, M.D., Ph.D., Jianqin Shan, Ph.D., Jan Davis, R.N., B.S., Francis Giles, M.D., Hussain I. Saba, M.D., Ph.D.,4 Jean-Pierre J. Issa, M.D.

From the Departments of Leukemia, Biostatistics2, and Hematopathology3 The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and The H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Short Title: Decitabine and hypomethylation in Higher Risk MDS and CMML

Address correspondence to: Hagop Kantarjian, M.D. Department of Leukemia M.D. Anderson Cancer Center 1515 Holcombe Blvd. Box 428 Houston, TX 77030 Phone: 713-792-7026 Fax: 713-794-4297 E-mail: [email protected]

Total Word Count: Abstract Word Count: # Tables # Figures:

4173 200 4 2

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Copyright © 2006 American Society of Hematology


ABSTRACT Epigenetic therapy with hypomethylating drugs is now standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose-schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to one of 3 decitabine schedules: 1) 20 mg/m2 IV daily x 5; 2) 20 mg/m2 SQ daily x 5; and 3) 10 mg/m2 IV daily x 10. Randomization followed a Bayesian adaptive design. Ninetyfive patients were treated (77 with MDS, all with IPSS score >1.0, 18 with CMML). Overall 32 patients (34%) achieved CR, and 69 (72%) had an objective response by the new modified International Working Group criteria. The 5-day IV schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared to 21% in the 5-day SQ arm and 24% in the 10 day IV arm (p 12 109/L) being intermediate-2 or high risk. After the 45th

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patient was enrolled, more patients were increasingly treated with the decitabine schedule of 20 mg/m2 daily x 5 since it showed a higher CR rate than the other 2 arms. At the 65th patient, this schedule was chosen according to the statistical design of the trial as the one most likely to be associated with the highest CR rate. Therefore, the remaining 30 patients were all treated on this selected dose schedule.

Response and Outcome Overall, 32 patients (34%) achieved CR, 1 (1%) had PR, 23 (24%) had marrow CR without (n = 10, 11%) or with other HI responses (n = 13, 14%), and 13 (14%) had HIs including two or more HIs in 5 (5%). Overall, 69 of 95 patients (73%) demonstrated objective responses (Table 2). The CR rate was higher with the 5 day IV schedule (39%) compared with the other two schedules (21% for the 5-day SQ and 24% for the 10-day IV, p 60 [median]

67 [65]

•

Age (years)

•

Gender

Female

29 (31)

•

Hemoglobin (g/dl)

< 11.0

81 (85)

•

Granulocytes (x 109/L)

< 1.0

42 (44)

•

Platelets (x 109/L)

< 100

68 (72)

•

Chromosomal abnormalities

Yes

53 (56)

•

Bone marrow blasts (%)

6

36 (38)

[median]

[3.2]

Yes

58 (61)

Growth factors

35 (37)

Others

23 (24)

Yes

30 (32)

Chemotherapy

7

Irradiation

5

Both / other

0

Surgery only

8

MDS

77 (81)

CMML

18 (19)

Intermediate 1

19 (33)

Intermediate 2

26 (46)

High

11 (19)

Not applicable *

39

20 IV x 5

64 (67)

•

•

•

Duration of MDS (months)

Prior therapy

Secondary MDS Prior therapy for primary malignancy

•

•

•

Morphology

IPSS Risk (56 patients)

Decitabine schedule (mg/m2 x days)

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20 SQ x 5

14 (15)

10 IV x 10

17 (18)

* Not applicable because either secondary MDS, or CMML with WBC > 12 x 109/L

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Table 2

Response data (95 patients) by the Modified IWG Criteria

Response

No. (%)

•

Complete response

32 (34)

•

Partial response

•

Marrow CR

10 (11)

•

Marrow CR + other HI

13 (14)

•

HI

1 (1)

Single lineage

9 (9)

2 or 3 lineage

4 (4)

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Table 3

Side effects No. (%)

A. Extramedullary toxicities (95 patients)

Grade 1-2

Grade 3-4

•

Fatigue

6 (6)

--

•

Bone aches

4 (4)

5 (5)

•

Liver dysfunction

10 (11)

4 (4)

•

Skin rashes

1 (1)

--

•

Nausea, vomiting

17 (17)

--

•

Diarrhea

2 (2)

--

•

Other

9 (9)

--

--

23 (4)

B. Myelosuppression-related toxicities (622 courses) •

Fever of unknown origin

•

Documented bacterial infections o

Sepsis alone

7 (1)

o

Minor infections

24 (4)

•

Pneumonias + other infections

•

Fungal infections

20 (3.5)

o

Confirmed

5 (0.8)

o

Suspected

1 (0.2)

o

With other infections

1 (0.2)

•

Bleeding

•

Hospitalization

46 (7)

7 (1) 110 (18)

Patients never hospitalized 32/95 = 34%

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Table 4

Comparison of outcome and side effects by dose schedule

Parameter

5 Day IV

5 Day SQ

10 Day IV

•

No. Patients

64

14

17

•

No. CR (%)

25 (39)

3 (21)

4 (24)

•

Median number of courses (range)

5+ (1-18)

8 (1.17)

9 (1-15)

•

Median duration of therapy in mos (range)

5.4+ (1.0 – 20.4+)

9.7 (0.5 – 22.9+)

10.8 (1.9 – 17.7+)

6.5

15

15

39 (61)

3 (21)

6 (35)

Median follow-up time (mos) No. (%) still on therapy •

Median days to granulocytes recovery to 9 10 /L or above

24

14

27

•

Median days to platelet recovery to 50 x 9 10 /L or above

20

31

27

•

Median days to delivery of subsequent courses (range)

35

35

40

•

No. courses requiring hospitalization (%)

50 (12)

14 (14)

23 (23)

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Figure Legends

Figure 1

A: Survival (A); event-free survival (event = AML or death) (B); and duration of freedom from AML (C). B: Survival in IPSS risk groups and in CMML

Figure 2

A: Relative LINE hypomethylation percentage by schedule; B: p15 expression levels by response

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FIGURE 1A

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FIGURE 1B

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Relative change (%)

0 -5 -10 -15

10mg IV (n=17) 20mg SQ (n=14) 20mg IV (n=44)

-20 -25 0

10

20

Days

FIGURE 2A

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30


-16

CR non-CR

Delta CT

-17 -18 -19 -20 -21 -22 0

10

20

Days FIGURE 2B

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30


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(12) Cheson BD, Bennett JM, Kantarjian H et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671-3674. (13) Cheson BD, Greenberg PL, Bennett JM et al. Clinical Application and Proposal for Modification of the International Working Group (IWG) Response Criteria in Myelodysplasia. Blood. Prepublished ahead of print, April 2006. (14) Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5:27-36. (15) Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103-107. (16) Yang AS, Estecio MR, Doshi K et al. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 2004;32:e38. (17) van den Bosch J, Lubbert M, Verhoef G, Wijermans PW. The effects of 5-aza-2'deoxycytidine (Decitabine) on the platelet count in patients with intermediate and high-risk myelodysplastic syndromes . Leuk Res. 2004;28:785-790. (18) Aoki E, Uchida T, Ohashi H et al. Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes. Leuk. 2000;14:589-593. (19) van Dijk JP, De Witte T. Monitoring treatment efficiency in MDS at the molecular level; possibilities now and in the future. Leuk Res. 2004;28:101-108.

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