MPN

The recent discovery of the JAK2 V617F and MPL mutations has resulted in a comprehensive reclassification of myeloproliferative disorders in 2008 by the World Health Organization¹ and has prompted a race to deliver corresponding drug therapies.

Myeloproliferative Neoplasm Differentiation

The JAK2 V617F mutation is found, in varying degrees, in:

1. Polycythemia Vera (PV) is a disease of hematopoietic stem cells
   • JAK2 V167F mutation positive in over 95% of cases
   • JAK2 exon 12 mutation positive in about 4% of cases
2. Essential Thrombocythemia (ET) is a disease that results in the overproduction of platelets
   • JAK2 V167F mutation positive in 30 - 50% of cases
3. Primary Myelofibrosis (PMF) is a disorder in which fibroblasts produce too much fibrous or scar tissue within bone marrow space
   • JAK2 V167F mutation positive in ~50% of cases
Chronic Myelomonocytic Leukemia (CMML) is a condition in which the body increases its production of monocytes
• JAK2 V167F mutation positive in about 3% of cases
4. Atypical Chronic Myelogenous Leukemia (aCML) has bone marrow and peripheral blood patterns morphologically similar to CML although it lacks the BCR/ABL fusion gene
   • JAK2 V617F mutation identified in about 20% of cases
5. Chronic Neutrophilic Leukemia (CNL) cytogenetic results are normal in approximately 77% of patients at diagnosis
   • JAK2 V167F mutation positive in about 20% of cases

MPL mutations are found in thrombocythemia (ET) and primary myelofibrosis (IMF) but not in PV or other myeloproliferative neoplasms, thereby finally providing the first step in distinguishing one BCR/ABL-negative myeloproliferative neoplasm from another.

1. Essential Thrombocythemia (ET) is a disease that results in the overproduction of platelets
   • MPL W515L mutation positive in about 1% of cases
     
2. Primary Myelofibrosis (PMF) is a disorder in which fibroblasts produce too much fibrous or scar tissue within bone marrow space
   • MPL W515L mutation positive in about 5% of cases

Response to Therapy
Yet another step in unraveling the mystery of MPNs is their selective response to imatinib (Gleevec®). While CMML, hypereosinophilic syndrome (HES), PDGFRA and PDGFRB myeloid neoplasms, as well as mast cell disease, respond well to Gleevec, FGFR1 neoplasms and chronic eosinophilic leukemia (CEL) do not respond to Gleevec therapy.

Imatinib (Gleevec) Responsive Neoplasms

1. Chronic Myelomonocytic Leukemia (CMML) is a condition in which the bodyincreases its production of monocytes
• Patients respond well to imatinib
2. Hypereosinophilic Syndrome (HES)
   • patients respond well to imatinib (Gleevec)
3. PDGFRA Neoplasms (FIP1L1-PDGFRA) is a therapeutic target for the treatment of chronic eosinophilic leukemia and is found in approximately half of the patients with HES
   • FIP1L1-PDGFRA-positive CEL patients respond very well to imatinib
4. PDGFRB, t(5;12), Neoplasms (PDGFRB) is frequently found in leukemia and is often associated with hypereosinophilia and about 1-2% of CMML
   • patients respond very well to imatinib

Imatinib (Gleevec) Resistant Neoplasms

1. Mast Cell Disease (MS) exhibits at least two relevant gene mutations (KIT and PDGFRA). The KIT mutation D816V is seen in about 80% of cases
   • Gleevec is used as first line therapy in SM associated with either PDGFRA or non-D816V KIT mutations, whereas it is unlikely to be effective in KITD816V-positive cases
2. FGFR1 Neoplasms (FGFR1) activation is associated with a syndrome known as the 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma syndrome that has a grave prognosis and can rapidly transform into acute leukemia
   • patients resistant to imatinib (Gleevec)
3. Chronic Eosinophilic Leukemia (CEL) is a subset of clonal eosinophilia that is neither molecularly defined nor classified as an alternative assigned myeloid malignance such as acute leukemia, MDS, classical MPN, SM or CMML. It exhibits genetic mutations for PDGFRA and PDGFRB
   • does not respond to imatinib

At Clarient, with our broad MPN assay menu, we have the key to position you in a leadership role as new therapies arrive. If you would like your local Clarient representative to provide more information or to assist in any way, please register today!

References

1. Tefferi A and Wardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22: 14-22, 2008.