Chronic Myeloid Leukemia Overview

Chronic Myeloid Leukemia (CML)

• Philadelphia chromosome is found in ~95% of cases
• JAK2V617F mutation is associated with polycythemia vera in most cases.
• Chromosomal abnormalities are present.

Chronic Myeloproliferative Disorders

• Chronic myeloid leukemia (CML)
• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Primary myelofibrosis (PMF)
• Chronic neutrophilic leukemia (CNL)
• Chronic myelomonocytic leukemia (CMML)
• Juvenile myelomonocytic leukemia (JMML)

Polycythemia Vera Major Criteria (WHO)

• Hemoglobin >16.5 g/dL (men), >16 g/dL (women)
• Hematocrit >49% (men), >48% (women)
• Increased red cell mass >35 mL/kg (men), >31 mL/kg (women)
• Bone marrow biopsy with hypercellularity and panmyelosis
• Presence of JAK2V617F or JAK2 Exon 12 mutations
• Subnormal serum EPO levels

Polycythemia Vera Minor Criteria (WHO)

• A single genetic translocation in a pluripotent hematopoietic stem cell leads to clonal overproduction of immature neutrophils.
• Usually diagnosed between ages 45-55.

Chronic Myeloid Leukemia (CML) Etiology

• A single genetic translocation in a pluripotent hematopoietic stem cell causes clonal overproduction of immature neutrophils.
• Usually diagnosed between ages 45-55.

Chronic Myeloid Leukemia (CML) Chromosomal Abnormality

• Philadelphia chromosome

Chronic Myeloid Leukemia (CML) Morphological Features

• Myeloblasts, promyelocytes, bands, segmented neutrophils (all stages of neutrophil development)

Polycythemia Vera (PV) Symptoms

• Triad of bone marrow fibrosis, splenomegaly, and anemia with teardrop cells (dacrocytes).

Polycythemia Vera (PV) Lab Findings

• Increased hemoglobin, hematocrit, red cell mass; low serum EPO levels.

Polycythemia Vera (PV) Peripheral Blood Findings

• Increased RBCs, total WBCs, granulocytes, and platelets; LAP stain normal to increased.

Polycythemia Vera (PV) Bone Marrow Findings

• Hypercellular bone marrow with increased normoblasts, granulocytes, megakaryocytes, and reticulin fibers.

Essential Thrombocythemia (ET) Etiology

• Clonal myeloproliferative neoplasm leading to increased megakaryopoiesis and thrombocytosis.

Essential Thrombocythemia (ET) Chromosomal Abnormality

• JAK2V617F

Essential Thrombocythemia (ET) Other Common Mutations

• CALR and MPL mutations

Essential Thrombocythemia (ET) Treatment

• Hydroxyurea, JAK2 inhibitors (Ruxolitinib, Lestaurtinib), low-dose aspirin (prevents thromboses)

Primary Myelofibrosis (PMF) Etiology and Chromosome Abnormality

• Splenomegaly and ineffective hematopoiesis caused by hypercellularity, fibrosis, and increased megakaryocytosis of the bone marrow.
• JAK2V617F

Primary Myelofibrosis (PMF) Treatment

• Hydroxyurea, JAK2 inhibitors (Ruxolitinib, Lestaurtinib), CYT387, TG101348

Chronic Neutrophilic Leukemia (CNL)

-Extreme neutrophilia; increased neutrophil precursors; Decreased monocytes. RBCs and platelets are normal. Hepatosplenomegaly, mucocutaneous bleeds, gout, pruritis (itching)

Chronic Neutrophilic Leukemia (CNL) Peripheral Blood Findings

• Extreme neutrophilia (<70% of cells), WBC count increased >25x10⁹/L, monocytes decreased <1x10⁹/L.

Chronic Neutrophilic Leukemia (CNL) Bone Marrow Findings

• Hypercellular; increased neutrophils; myeloblasts >5% of nucleated cells.

Chronic Myelomonocytic Leukemia (CMML)

• Malignant hematopoietic stem cells lead to bone marrow dysplasia and monocytosis. May transition to Acute Myeloid Leukemia (AML)
• Deletion of chromosome 7 and trisomy 8

Juvenile Myelomonocytic Leukemia (JMML)

• An aggressive hematopoietic disorder, presenting in childhood (~2 years). Some abnormalities present include PTPN-11, K-RAS, N-RAS, CBL, or NF1 mutations (seen in ~90% of cases). Philadelphia chromosome is NOT implicated..
• Dysplastic/abnormal monocytes.

Chronic Myeloid Leukemia(CML) therapy related treatments

• Immunosuppressive therapy
• Farnesyltransferase inhibitors
• Hematopoietic stem cell transplant (cure)

Additional Chromosomal Abnormalities in the Accelerated Phase of CML

-Other than Philadelphia chromosome additional clonal chromosomal abnormalities appear in the accelerated phase.

Fibrosis of Bone Marrow (PMF)

• Increased Platelet Derived Growth Factor (PDGF) leads to increased collagen and reticulin fiber synthesis.

Pre-PMF Criteria (WHO)

• Major: increased megakaryopoiesis, increased granulopoiesis, decreased erythropoiesis, NO reticulin fibrosis, hypercellular BM, JAK2, CALR, or MPL mutation.
• Minor: anemia not attributed to another condition, leukocytosis 11*10⁹/L, palpable splenomegaly, and elevated LDH.

Overt PMF Criteria (WHO)

• Major: increased megakaryopoiesis with reticulin or collagen fibrosis; presence of JAK2, CALR or MPL mutation. No other WHO diagnoses available.
• Minor: anemia, leukocytosis <11*10⁹/L, palpable splenomegaly, elevated LDH, leukoerythroblastosis (immature Granulocytes and RBCs in peripheral blood).

Essential Thrombocythemia (ET) Criteria (WHO)

• Major: platelet count ≥ 450 x 10⁹/L; BM biopsy showing mainly enlarged megakaryocytes with hyperlobulated nuclei. No significant increase in reticulin fibers; presence of JAK2, CALR, or MPL mutations. Does not meet criteria for different diagnoses.
• Minor: presence of clonal marker OR absence of reactive thrombocytosis

Different types of MDS classifications and Characteristics

• MDS-SLD (MDS with single lineage dysplasia): 1 dysplastic lineage; 1-2 cytopenias; <15% ringed sideroblasts; BM <5% blasts; PB <1% blasts; No auer rods; any cytogenetics that does not cause MDS-5q-.
• MDS-RS-SLD (MDS with ringed sideroblasts, single lineage dysplasia ): 1 dysplastic lineage ; 1-2 cytopenias; <15% ringed sideroblasts ; BM <5% blasts; PB <1% blasts; No auer rods; any cytogenetics that does not cause MDS-5q-.
• MDS-RS-MLD (MDS with ringed sideroblasts, multilineage dysplasia): 2-3 dysplastic lineages; 1-3 cytopenias; <15% ringed sideroblasts; BM <5% blasts; PB <1% blasts; no auer rods; any cytogenetics that does not cause MDS-5q-.
• MDS-MLD (MDS with multilineage dysplasia): 2-3 dysplastic lineages; 1-3 cytopenias; <15% ringed sideroblasts; BM <5% blasts; PB <1% blasts. no auer rods; any cytogenetics that does not cause MDS-5q-.

Other MDS Classifications and Characteristics

• MDS-U 1% blasts, 1-3 dysplastic lineage, 1-3 cytopenias, none or any ringed sideroblasts, BM <5% blasts, PB <1%blasts, no auer rods.
• MDS-U with SLD and pancytopenia: 1 dysplastic lineage; 3 cytopenias; none or any ringed sideroblasts; BM <5% blasts; PB <1% blasts; No auer rods
• MDS-U defining cytogenetic abnormality: 0 dysplastic lineages; 1-3 cytopenias; <15% ringed sideroblasts; BM <5% blasts; PB <1% blasts; no auer rods.
• MDS-U refractory cytopenia of childhood : 1-3 dysplastic lineages; 1-3 cytopenias; no ringed sideroblasts; BM <5% blasts; PB <2% blasts any cytogenetics

MDS treatment

• Supportive care: transfusions, pain meds
• Lealidomide, azacytidine, deitabine
• Growth factors: EPO (erythropoietin), TPO(thrombopoietin), G-CSF (granulocyte colony stimulating factors).

Additional information for MDS and other disorders

• Auer rods: formed by granules fusing together, appear like lines branching off the nucleus.
• Splenomegaly unresponsive to therapy
• Thrombocytosis or thrombocytopenia
• e20% blasts in peripheral blood -10-19% blasts in bone marrow.
• Decreased adhesion to endothelium.
• Phagocytosis is decreased.
• Chemotaxis is decreased.
• RBCs have a shortened survival.
• RBCs have decreased response to EPO.
• Increased bleeding despite high platelet counts.
• Increased Platelet Derived Growth Factor (PDGF)
• Increased collagen and reticulin fibers in the bone marrow.
• Myelodysplastic Syndrome (MDS) characteristics include: oval macrocytes; hypochromic microcytes; dimorphic RBC population; poikilocytosis; basophilic stippling; Howell-Jolly bodies; siderocytes; and Pappenheimer bodies. Key features of RBC precursors in the bone marrow include multi-nucleated RBC precursors; abnormal nuclear shapes (lobes, buds, fragments, nuclear bridging).
• Ringed sideroblasts and megablastic cellular development
• Acquired clonal hematologic disorders causing progressive cytopenia; defects in erythroid, myeloid and/or megakaryocytic maturation.
• MDS affects older individuals (typically around 76 years old). .
• Pathological changes/mutations in hematopoietic stem cells lead to mutations and cloning of stem cells, resulting in Dyspoiesis.
• Decreased adhesion to endothelium