CML is classified under myeloproliferative neoplasms (MPNs) with proliferation of granulocytic components in marrow.
CML refers to the following
Chronic myelogenous Leukemia, BCR-ABL1 positive
Atypical CML, BCR-ABL1 Negative
Chronic Myelomonocytic leukemia (CMML)
Other MPNs include many others, which is a different discussion.
BCR-ABL POSITIVE CML
Any signals that causes phosphorylation of tyrosine kinase will activate RAS and thereby enhances cell growth by P13K/AKT and MAPK pathways. Tyrosine can autophosphorylate itself when it is a dimer.
In a specific mutation like reciprocal translocation between chromosomes 9 and 22 denoted by t(9;22)(q34;11), a new protein is coded which is composed of BCR and ABL. BCR has a dimerisation domain, and ABL has a tyrosine kinase moiety. So, it acts as an activator of RAS which is not under the regulatory mechanisms as normal tyrosine kinases. Instead, it activates other pro-growth mediators which causes a clonal proliferation of the stem cell it was coded from. The mutated chromosome is also known as the Philadelphia chromosome.
CMML and Atypical CML
Both of these are Myelodysplastic syndromes rather than a simple myeloproliferative neoplasm. No BCR-ABL protein or corresponding mutations are identified.
Three pathologically distinct phases of the disease has been identified.
Chronic phase (CP)
Accelerated phase (AP)
Blast phase (BP)
Majority of the cases are diagnosed in chronic phase. Only 5% of the cases have an uneventful chronic phase and diagnosed at AP or BP.
AP and BP have an accentuated severity of the CP symptoms. All untreated CPs progress to AP and BP.
Patient will have all the constitutional symptoms of malignancy, like fever, myalgia, night sweats, weight loss, etc.
Half of them will have splenomegaly. Occasionally hepatomegaly and lymphadenopathy. Explained by infiltration of sinuses by the mature & immature granulocytes and extramedullary hematopoiesis.
Furthermore, AP and BP are unresponsive to classical therapy with TKI.
CBC and Peripheral Smear
Peripheral smear is more than enough for diagnosing CML. Marrow is required if the findings in CML are atypical or inadequate.
Normocytic normochromic anemia.
Leukocytosis with absolute basophilia is the most important clue.
Absolute neutrophilia, absolute eosinophilia will be there.
Peaks in myelocyte and neutrophil counts are diagnostic.
Monocytes are high but <3%.
Blasts are <2% in smear for CP
Platelet count may be increased because of megakaryocyte proliferation.
Persistant WBC counts >10000 /microL
Basophils ≥ 20% of total WBC
Blasts 10 - 19% of WBC in PS and BM
Persistant thrombocytosis >10 lakhs /microL
Or persistant thrombocytopenia <1 lakh /microL unrelated to therapy
Evidence of cells with Philadelphia chromosome
Proliferation of Myeloid series. With increased myelocytes and mature neutrophils.
All WBC findings corresponding to the peripheral smear.
Blasts account for <5% of marrow in CP
Erythroid series is suppressed.
Megakaryocytes are normal or proliferated. This is because of BCR-ABL which affects MK cells also.
MK will be "Dwarf Megakaryocytes" due to the small size and hypo-lobate nucleus.
Pseudo-Gaucher cells are common
BM Biopsy sections show a 5 - 10 cell thick layer of immature granulocytes in the paratrabecular region. (Normally just 2 - 3 cells thick)
Biopsy also reveals marrow fibrosis.
Dysplastic changes in myeloid series
Blasts 10 - 19% of WBC in PS and BM
Sheets of Megakaryocytes
Marked fibrosis - reticulin and collagen
Lymphoblastic crisis shows lymphoid blasts in aspirate
Blasts ≥ 20% of WBC in PS and BM
Blasts can be of myeloid, erythroid, monocytic, megakaryocytic or even lymphoid in lineage.
Blasts can be extra medullary also; in skin, lymph nodes, etc