5Azacytidine: The New Treatment for MDS

1
5-Azacytidine The New Treatment for MDS

• Joshua Field, MD
• October 8, 2004

2
Case

• 72 year-old man presented to PMD with nosebleed.
  CBC obtained which demonstrated pancytopenia (wbc
  3100, hemoglobin 5.8, platelets 88,000).
• Bone marrow biopsy was performed which was
  consistent with myelodysplastic syndrome (RAEB).
  Cytogenetics demonstrated trisomy 14 and monosomy
  7.

3
Case

• Initiated on Procrit 20,000 units three times per
  week.
• Continued to remain transfusion dependent,
  requiring 2U PRBCs every 2 weeks.
• Initiated on 5-Azacytidine 75 mg/m2 for 7 days
  repeat every 4 weeks.

4
MDS

• Stem cell disorder resulting in ineffective
  erythropoiesis.
• Pre-leukemic disorders in which neoplastic clone
  or clones may or may not terminate in AML.
• Malignant transformation at myeloid stem cells
  secondary to chromosomal abnormalities.

5
MDS

• Balanced translocations result in acute leukemia
  t(1517), t(821).
• Unbalanced cytogenetic abnormalities result in
  myelodysplasia trisomy, monosomy, partial
  deletions.
• In myelodysplasia, leukemic clone initiate
  process, then further cytogenetic abnormalities
  are necessary to progress to leukemia.

Heaney, et al. NEJM199934021.
6
MDS FAB Classification

• Refractory anemia
• Cytopenia of at least one lineage in the
  peripheral blood.
• Normal or hypercellular marrow with dysplastic
  changes.
• Less than 1 blasts in the peripheral blood and
  less than 5 in the bone marrow.

7
MDS FAB Classification

• Refractory anemia with ringed sideroblasts
• Cytopenia, dysplastic changes, and the same
  percentages of blood and bone marrow blast as in
  refractory anemia.
• Ringed sideroblasts accounting for more than 15
  of all nucleated cells in the bone marrow.
• Refractory anemia with excess blasts
• Cytopenia of two or more lineages in the
  peripheral blood.
• Dysplastic changes in all three cell lines.
• Less than 5 blasts in the peripheral blood and
  between 5-20 blasts in the bone marrow.

8
MDS FAB Classification

• Chronic myelomonocytic leukemia
• Peripheral blood monocytosis.
• Less than 5 blasts in the peripheral blood and
  up to 20 blasts in the bone marrow.
• Refractory anemia with excess blasts in
  transformation
• More than 5 blasts in the peripheral blood and
  between 21-30 blasts in the bone marrow.

9
International Prognostic Scoring System for MDS
Good normal, -Y, del(5q), del(20q) Intermediate
trisomy 8, single or double abnormalities Poor
gt3 abnormalities, chromosome 7
Greenberg, et al. Blood199789.
10
IPSS survival

• Low (0) 5.7 years.
• Intermediate
• 1 (0.5-1.0) 3.5 years.
• 2 (1.5-2.0) 1.2 years.
• High (gt2.5) 0.4 years.

Greenberg, et al. Blood199789.
11
Epidemiology/Clinical Presentation

• Disorder of older adults, average age over 70.
• Men gt women.
• Symptoms of hematopoietic failure infection,
  bleeding, bruising, fatigue.
• Often detected on routine laboratory evaluation.

12
NCCN Practice Guidelines for the Treament of MDS
Supportive care
13
Treatment of MDS

• High intensity
• 73 90 relapse, high toxicity.
• Stem cell transplant
• Fewer than 5 patients are candidates.
• Low intensity
• Low dose ara-C 35 hematological response, no
  effect on survival or transformation to AML.
• G-CSF Increased death rate in RAEB and RAEB-T.
• Cis-retinoic acid no advantage over placebo.

Heaney, et al. NEJM199934021.
14
Treatment of MDS

• Topotecan response rate 65, no effect on
  survival or transformation.
• Thalidomide partial response 26.
• Interleukins small improvements in minority of
  patients, however side effects limit use.

Heaney, et al. NEJM199934021
15
Lenalidomide (Revlamid)

• Study of low risk MDS (88 IPSS low/Int-1).
• After 8 weeks, 64 erythroid response
  (transfusion independence or gt2g/dL increase in
  hemoglobin).
• Analogue of thalidomide, thus far no sedation or
  neuropathy noted.

List, et al. Blood.2003102 abstract 641.
16
Hypomethylating agents

• 5-azacytidine (Azacitidine)
• 5-aza-2-deoxycytidine (Decitabine)

17
Hypermethylation

• DNA methyltransferases add a methyl group to
  cytosine ring to form methyl cytosine.
• Occurs cytosine precedes guanine (CpG
  dinucleotide).
• Clusters of CpG islands in promoter regions.

Herman, et al. NEJM.2003349,21
18
Hypermethylation

• CpG islands typically unmethylated, whereas
  outlier CpG dinucleotides are methylated.
• Methylation in gene promoter silences
  transcription.
• Protective mechanism viral sequences,
  transposons, repeated components of genome.

Herman, et al. NEJM.2003349,21
19
Hypermethylation
Herman, et al. NEJM.2003349,21.
20
Azacitidine Time Line
Role in MDS
Hypomethylation noted
Clinical studies
Development
2004
2002
1964
1967
1982
May 5, 2004 FDA approved for treatment MDS
Birth of 1st year fellows
21
History of Azacitidine

• Pyrimidine nucleoside analogue, first synthesized
  in 1964 by Piskala and Sorm.
• In 1967, first clinical trials in Europe followed
  by trials in the United States.
• Mechanism of action thought to be anti-metabolite
  effect interfering with nucleic acid metabolism.

Von Hoff, et al. Annals of Internal
Medicine.197685.
22
Azacitdine and hypomethylation

• JBC, 1982 Creusot, et al, reported that
  5-azacytidine and 5-aza-2-deoxycytidine
  decreased the activity of DNA methyltransferase.
• The end result was hypomethylated DNA.
• Reported drugs resulted in the differentiation of
  erythroleukemia cells.

Creusot, et al. JBC.1982257,4.
23
B-thalassemia and Azacitidine
NEJM, 1982. Idea B-thal due to an excess of
alpha-globin. Increasing gamma-globin
synthesis corrects the imbalance. Hypomethylated
gamma-globin genes were expressed. Hypomethylatio
n would increase fetal hemoglobin. Azacitidine
increased gamma- globin gene production 7 fold.
Ley, et al. NEJM.1982307.
24
Hypermethylation and MDS

• Hypermethylation occurs in promoter region of
  tumor suppressor genes.
• p16INK4a and p15INK4b two genes inactivated in
  wide variety of neoplasms.
• Both cell cycle regulators and associate with
  cyclin-dependent kinases and inhibit activity.
• In MDS, p15INK4b is hypermethylated.

Quesnel, et al. Leukemia and Lymphoma.1999vol 35.
25
Phase II data CALGB 84218921

• 111 patients.
• Average age was 66.
• MDS RAEB 46, RAEB-t 47, CMML 7.
• Azacitidine 75 mg/m2 times 7 days.
• RR 49
• CR 12

Silverman, et al. Leukemia. 1993 7, supp 1.
26
Phase III data JCO, 2002

• Randomized study of Azacitidine versus best
  supportive care.
• 191 patients, 99 randomized to Aza C and 92 to
  supportive care.
• Eligibility criteria fulfilled FAB
  classification for MDS.
• RA and RARS met criteria for significant bone
  marrow dysfunction.

Silverman, et al. JCO. 2002 vol 20, no 10.
27
Additional criteria RA and RARS

• RBC Symptomatic anemia requiring RBC
  transfusions for at least 3 months prior to
  study.
• Platelets Thrombocytopenia with two or more
  platelet counts less than 50,000 or hemorrhage
  requiring transfusion.
• WBC Neutropenia with ANClt1000 and an infection
  requiring IV antibiotics.

28
Eligibility criteria

• Bone marrow biopsy within two weeks confirming
  diagnosis.
• Therapy related MDS cancer-free for at least 3
  years and no chemotherapy or radiation for 6
  months.

29
Treatment

• Azacitidine (75 mg/m2/day) subcutaneously for
  days 1-7 of 28 day cycle.
• Assessed after fourth cycle
• CR received 3 more cycles.
• PR continued until CR or relapse.
• Cross-over after 4 months, supportive care arm
  could cross-over if worsening. AML exited study,
  lt40 blasts crossed over to Aza C.

30
Response criteria
31
Demographics
32
Demographics
33
Results
34
Transformation to AML
P.001
35
Overall Survival
53 of supportive care crossed over to Aza C
36
Overall Survival

• Subgroup analysis
• Initially treated with Aza C survival 20 months.
• Supportive care who never crossed over or crossed
  over after 6 months survival 11 months.
• P.03

37
Aza C toxicity

• Myelosuppresion
• Leukopenia 59
• Granulocytopenia 81
• Thrombocytopenia 52
• Nausea/vomiting 4

38
Quality of Life

• Conducted telephone interviews days 50, 106, and
  182.
• European Organization for Research and Treatment
  of Cancer Quality of Life Questionnaire and
  Mental Health Inventory.
• Improvement in fatigue(P.001), dyspnea(P.0014),
  physical functioning(P.0002), positive
  affect(P.0077), psychological distress(P.015).

39
Conclusions

• Response rate 60.
• Diminished transformation to AML.
• Improved quality of life.
• Prolonged survival in subgroup analysis.

40
Case

• 10 days after receiving cycle 1 presented with
  pre-syncope.
• Noted to be pancytopenic WBC 1.3 (ANC450),
  hemoglobin 8, platelets 13,000.
• Patient decided to discontinue therapy with
  5-Azacitadine and instead opted for supportive
  care.