Myeloid Blastic Transformation of Myeloproliferative Neoplasms A Review of 112 Cases

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Myeloid Blastic Transformation of
Myeloproliferative Neoplasms A Review of 112
Cases 

• Presenter Syed Jawad Noor, PGY3
• Mentor Meir Wetzler
• June 09, 2010

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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
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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

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MPN Types

• Polycythemia Vera (PV)
• Essential Thrombocythemia (ET)
• Myelofibrosis (MF)
• Primary MF (PMF)
• Secondary MF (SMF)

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Polycythemia Vera (PV)

• An expansion in red blood cell production

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Myelofibrosis (MF)

• A fibrotic bone marrow and peripheral cytopenia
• Higher risk of leukemic transformation

Primary or secondary (post-PV or post-ET)
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JAK2 mutation in MPN
Signaling
95 in PV 50-60 in ET and MF
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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
  JAK2-positive MPN continue to carry the mutation
• Pathogenesis of the blastic transformation in MPN
  remains unclear

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Known risk factors for Blastic Transformation

• Alkylating agents
• Radiation
• DNA damaging chemotherapy drugs

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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

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Methods
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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

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Contd

• Therapy
• anthracycline (daunorubicin at 60 mg/m2)
  cytosine arabinoside (100 mg/m2) chemotherapy in
  a 73 fashion

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Contd

• 3 pt had SCT in addition to chemotherapy
• All other pts received supportive care only
• Response was CR or CRi

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Statistical Analyses

• Fishers exact test.
• Wilcoxon rank sum test.
• Kaplan-Meier method.
• log-rank test.
• SAS (version 9.1)

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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

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Comparison between RPCI dataset and other three
datasets
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Diagnosis Differences
Percent
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Time from MPN diagnosis to Blast phase
Percent
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Less than 3 Therapies
Percent
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Prior Hydroxyurea Therapy
Percent
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Prior Alkylating Agents
Percent
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Prior Erythropoietin
Percent
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Normal Karyotype
Percent
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Insignificant Variables of both Cohorts

• Age _at_ MPN diagnosis
• Age _at_ AML diagnosis
• Gender
• Prior use of Interferon
• Karyotype aberrations

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Overall Survival
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Survival analysis for RPCI other three data
sets
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Survival By Diagnosis
Months
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Age at MPN Diagnosis
P0.0493
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Less than 3 Therapies
lt3 Therapies
P0.0242
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Complex Karyotype
P0.0104
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Non-significant variables

• Time from MPN diagnosis to Blast phase
• Age _at_ AML diagnosis
• Gender
• Prior Hydroxyurea
• Prior Alkylating Agents
• Prior Erythropoietin
• Prior Interferon
• Karyotype abnormalities other than Complex
  Kryotype

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Survival analysis for RPCI dataset
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P lt0.0001
P 0.0031
P 0.0119
P 0.0009
Median Survival in Months
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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

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Contd.

• Superior survival with allogeneic SCT
• SCT should be considered before the disease
  progresses to the blastic phase

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Contd.

• Selective JAK1 and JAK2 inhibitor, INCB018424,
  has demonstrated some single agent activity in
  relapsed/refractory patients with leukemic
  transformation of Myelofibrosis

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Conclusion

• Patients with lt3 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

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