Myeloid Blastic Transformation of
Myeloproliferative Neoplasms
A Review of 112 Cases
Presenter: Syed Jawad Noor, PGY3
Mentor: Meir Wetzler
June 09, 2010
Our Team
Syed J. Noor
Wei Tan
Gregory E. Wilding
Laurie A. Ford
Maurice Barcos
Sheila N.J. Sait
Annemarie W. Block
James E. Thompson
Eunice S. Wang
Meir Wetzler
Myeloproliferative Neoplasms (MPNs)
• Clonal hematologic diseases
• Excess production of ≥1 lineages of mature
blood cells
• Predisposition to bleeding and thrombotic
complications
• Extramedullary hemotopoiesis
• A variable progression to leukemia
MPN Types
• Polycythemia Vera (PV)
• Essential Thrombocythemia (ET)
• Myelofibrosis (MF)
Primary MF (PMF)
Secondary MF (SMF)
Polycythemia Vera (PV)
An expansion in red blood cell production
Essential Thrombocytosis (ET)
An isolated elevation in platelet count
Myelofibrosis (MF)
• A fibrotic bone marrow and peripheral
cytopenia
• Higher risk of leukemic transformation
Primary or secondary (post-PV or post-ET)
JAK2 mutation in MPN
L
P JAK2
JAK2 P
Signaling
JAK2
JAK2
Signaling
95% in PV;
50-60% in ET and MF
Myeloid Blastic Transformation of
Myeloproliferative Neoplasms
• MPNs are known to transform into acute
leukemia in approximately 4-6% of the
patients
• ~50% of acute leukemia cases following JAK2positive MPN continue to carry the mutation
• Pathogenesis of the blastic transformation in
MPN remains unclear
Known risk factors for Blastic
Transformation
• Alkylating agents
• Radiation
• DNA damaging chemotherapy drugs
Research Study Objectives
• To gain more insight into the evolution & risk
factors playing role in blastic transformation
• Treatment outcome of patients developing
blastic transformation from classic MPN
Methods
Patients
• 89 cases from literature
• 23 cases from RPCI
• PV, ET, MF, SMF or MPN-U
• Blast phase defined as persistent ≥20%
marrow or peripheral blood blasts
Contd…
• Therapy
• anthracycline (daunorubicin at 60
mg/m2) + cytosine arabinoside (100
mg/m2) chemotherapy in a “7+3”
fashion
Contd…
• 3 pt had SCT in addition to
chemotherapy
• All other pts received supportive care
only
• Response was CR or CRi
Statistical Analyses
• Fisher’s exact test.
• Wilcoxon rank sum test.
• Kaplan-Meier method.
• log-rank test.
• SAS (version 9.1)
Results
• Both RPCI and literature pt. populations
•
•
•
•
•
did not differ in
Age at diagnosis of MPN or blastic
transformation,
Gender
Prior use of interferon
Karyotype aberrations
Overall survival of the two cohorts was
similar and poor
Comparison between RPCI dataset and
other three datasets
Diagnosis Differences
60
53.3
Percent
50
40
30
20
24.4
26.1
22.2
26.1
21.7
17.4
8.7
10
0
ET
PMF
PV
0
0
SMF
UN
Other
RPCI
Time from MPN diagnosis to Blast
phase
80
68.2
70
60
Percent
P 0.0173
60.9
50
40
39.1
31.8
30
20
10
0
<5Years
≥ 5 Years
Other
RPCI
Less than 3 Therapies
120
P <0.0001
100
100
84
Percent
80
Other
RPCI
60
40
20
16
0
0
Yes
No
Prior Hydroxyurea Therapy
80
73.2
70
P .0057
63.2
Percent
60
50
36.8
40
30
26.8
20
10
0
Yes
No
Other
RPCI
Prior Alkylating Agents
100
94.7
90
P <0.0001
80
Percent
70
60
54.9
45.1
50
40
30
20
5.3
10
0
Yes
No
Other
RPCI
Prior Erythropoietin
120
P 0.0339
100
100
89.5
Percent
80
Other
RPCI
60
40
20
0
10.5
0
Yes
No
Normal Karyotype
100
92.7
90
P 0.0033
80
65
Percent
70
60
Other
RPCI
50
35
40
30
20
10
7.3
0
Yes
No
Insignificant Variables of both Cohorts
• Age @ MPN diagnosis
• Age @ AML diagnosis
• Gender
• Prior use of Interferon
• Karyotype aberrations
Overall Survival
Survival analysis for RPCI + other three
data sets
Survival By Diagnosis
35
30
Months
25
20
Median
Survival
15
10
5
0
ET
PMF
PV
SMF
UN
Age at MPN Diagnosis
Age @ MPN
<60
≥60
P=0.0493
Less than 3 Therapies
<3 Therapies
N
Y
P=0.0242
Complex Karyotype
Complex Karyotype
N
Y
P=0.0104
Non-significant variables
• Time from MPN diagnosis to Blast phase
• Age @ AML diagnosis
• Gender
• Prior Hydroxyurea
• Prior Alkylating Agents
• Prior Erythropoietin
• Prior Interferon
• Karyotype abnormalities other than
Complex Kryotype
Survival analysis for RPCI dataset
14
P <0.0001
P 0.0009
8
P 0.0119
10
P 0.0031
Median Survival in Months
12
Yes
6
No
4
2
0
Induction
Allogenic
Supportive care
Chemotherapy Transplantation
Response
Discussion
 Reasons for the heterogeneity
-- Differing criteria for MPN diagnosis
--Variety in the yield of karyotype analysis
 Whether blastic transformation is a sequel
of therapy, natural progression or a
combination of the two continues
Contd….
• Superior survival with allogeneic SCT
• SCT should be considered before the
disease progresses to the blastic phase
Contd….
• Selective JAK1 and JAK2 inhibitor,
INCB018424, has demonstrated some
single agent activity in relapsed/refractory
patients with leukemic transformation of
Myelofibrosis
Conclusion
• Patients with <3 prior therapies &
• Lack of complex karyotype have longer
survival
• Attempts for early identification of
patients at risk for disease progression
• Allogeneic SCT for the eligible patient
• Searching for novel therapeutic agents,
alone or in combination