27 - Chronic Myeloid Leukemia (CML) mcqs

Which of the followings are correct about chronic myeloid leukemia?

A. It is common in young adults and children.
B. It typically takes a biphasic chronic and acute course.
C. Pseudo-Gaucher cells are present in the bone marrow.
D. Immunohistochemistry for terminal deoxynucleotidyl transferase is a helpful way to confirm the diagnosis.
E. Immunohistochemistry for tryptase is a helpful way to confirm the diagnosis.

answer C is the only true statement.

Summary: Chronic myeloid (myelogenous) leukemia (CML) is a clonal (neoplastic) myeloproliferative disorder of hematopoietic stem cells with leukemia as the cardinal clinical and pathologic feature. It is essentially a disease of older people and takes a triphasic (chronic, accelerated, and blast crisis). Demonstration of translocation t(9;22) or Bcr-Abl fusion (Philadelphia chromosome) is the gold standard for diagnosis.

Behavior and Prognosis:

• Untreated cases: CML takes a triphasic course (chronic, accelerated, and blast phase). After a median of 3 to 5 years, untreated patients with chronic phase CML inevitably progress to blast phase, which is rapidly fatal. The risk of transformation to CML-BP is estimated at 3% to 4% per year.
• Treated cases: Therapeutic options before the imatinib era included cytotoxic drugs such as busulfan and hydroxyurea, interferon-α and allogeneic stem cell transplantation. Imatinib is the standard therapy for CML today because of its remarkable activity and mild toxicity profile. However, it has a history of only 5 years, and does not seem to cure this leukemia by itself, since the discontinuation of therapy is followed by recurrence in most cases.

Age:

• The incidence increases with age with the peak incidence at 65 years of age.
• CML is exceedingly rare in children.

Sex: Slight male predominance, M:F of 1.4:1.

Incidence:

• Very common: CML accounts for approximately 15 to 20 percent of cases of leukemia in adults.
• Annual incidence: 1.6 cases per 100,000 adults

Clinical features:

• Onset: The onset is slow. The initial symptoms are very non-specific and patients may be asymptomatic. The diagnosis is made incidentally after a routine CBC in nearly 50% of the patients.
• Symptomatic patients, the symptoms are generally related to the expansion of CML cells and consist typically of malaise, weight loss, and abdominal discomfort caused by splenomegaly. Tenderness over the lower sternum, due to an expanding bone marrow, is sometimes seen.
• Bleeding episodes due to platelet dysfunction can occur.
• Acute gouty arthritis may also present at this time, due to overproduction of uric acid.
• Hyperviscosity: In cases of very high WBC count signs and symptoms are related to of hyperviscosity, and include retinal hemorrhage, priapism, cerebrovascular accidents, tinnitus, confusion, and stupor.
• Spleen, liver, lymph nodes, and bone marrow: The excess of neoplastic and immature  neutrophils will lead to splenomegaly, and occasionally hepatomegaly or lymphadenopathy, and by varying degrees of myelofibrosis and extramedullary hematopoiesis.

Triphasic clinical course:

• Chronic phase: present at the time of diagnosis in approximately 85 to 90 percent of patients.
• Accelerated phase: The neutrophil differentiation becomes progressively impaired and leukocyte counts are more difficult to control with myelosuppressive medications
• Blast phase (crisis): A condition that resembles acute leukemia in which myeloid or lymphoid blasts fail to differentiate. After a median of 3 to 5 years, untreated patients with chronic phase CML inevitably progress to blast phase, which is rapidly fatal. The risk of transformation is estimated at 3% to 4% per year.

Molecular Pathology:

• Translocation t(9;22) (Philadelphia Chromosome): The "gold standard" for the diagnosis of CML is either the demonstration of the Philadelphia chromosome by conventional cytogenetic techniques, or the demonstration of the products of the underlying t(9;22) translocation, namely the BCR-ABL fusion mRNA or the Bcr-Abl protein.
• Alternate breakpoint: The occasional patients with CML who have an alternate breakpoint in chromosome 22, producing a p190 Bcr-Abl fusion protein rather than the classic p210 Bcr-Abl fusion protein, tend to have monocytosis and a low neutrophil/monocyte ratio in the peripheral blood.
• FISH and RT-PCR: In 5 – 10 % of patients with clinical features of CML Ph chromosome can not be detected by cytogenetic analysis. However, in majority of those patients the evidence of BCR-ABL gene fusion can be identified by metaphase or interphase FISH analysis or RT-PCR.
• CML without Philadelphia chromosome: However, about one-third of the group lacked molecular evidence of BCR-ABL fusion. In general, these patients have distinct clinical features, including short survival, poor response to therapy, absence of basophilia, frequent thrombocytopenia, and may progress with increasing leukocytosis, organomegaly, extramedullary infiltrates, and marrow failure, some without a terminal acute leukemia phase.
• Accelerated phase and blast phase: Additional cytogenetic abnormalities develop in patients in the accelerated phase and blast phase: trisomy 8, trisomy 19, duplication of the Ph chromosome, and isochromosome 17q.

Peripheral Blood:

• Chronic phase: CBC shows leukocytosis with a prominent left shift in the differential count, basophilia and often thrombocytosis. Occasionaly platelet count can be low. In rare instances the white blood cell (WBC) count can be as high as 1000 X 10⁹/L.  The leukocyte alkaline phosphatase (LAP) score is abnormally low, with essentially normal phagocytic function.

·         Differential count: Virtually all cells of the neutrophilic series at different stage of maturation, from mature neutrophils to myeloblasts, are present in the blood. Number of blasts in peripheral blood does not exceed 2 percents. Absolute basophilia and eosinophilia are almost universal findings.

·         “Leukemic hiatus”: The presence of a greater percent of myelocytes than the more mature metamyelocytes ("leukemic hiatus") is one of the classic findings in CML.

• Accelerated phase- presence of at least 1 of the followings :

·         10 – 19 % of blasts in the peripheral blood or bone marrow.

·         20% or more peripheral blood basophils.

·         Platelet counts lower than 100 X 10⁹/L unrelated to therapy.

·         Platelet counts higher than 1000 X 10⁹/l, despite of treatment.

• Blast phase (crisis)- presence of 1 or more of the followings:

·         >20 % of peripheral blood or bone marrow blasts.

·         Large foci or clusters of blasts on the bone marrow biopsy.

·         Presence of extramedullary blastic infiltrates (eg, myeloid sarcoma or "chloroma").

• Myeloid markers in blast cells: Blastic cells in myeloid CML blast phase closely resemble acute myeloid leukemia (AML), and blast cells express myeloid markers such as CD13, CD33, and CD117. Myeloperoxidase staining may be strongly or weakly positive or negative.
• Lymphoid markers in blast cells: Blasts may also express lymphoid markers, such as terminal deoxynucleotidyl transferase (TdT), commonly found in poorly differentiated B and T cells tumors. In most cases of lymphoid CML blast phase, blasts exhibit a B-cell immunophenotype, expressing CD10, CD19, and CD22. Frequently, myeloid markers such as CD13 and CD33 may be expressed in patients with lymphoid CML blast phase.

Bone Marrow:   

• Hypercellular and pseudo-Gaucher cells: Bone marrow aspiration and biopsy in patients with CML in chronic phase shows hypercellularity and absence of fat. All stages of myeloid maturation are present, with predominance of myelocytes. The sum of myeloblasts and promyelocytes usually accounts for less than 10% of the marrow cellularity. Megakaryocytes may be increased, and pseudo-Gaucher cells can be observed in 10 to 30 % of cases.

·         Pseudo-Gaucher cells or sea-blue histiocytes, are derived from the neoplastic clone, secondary to increased cell turnover. The electron microscopy distinguishes them from true Gaucher cells. They arise as a result of overloading of 1- glucosidase by excessive cell turnover; hence there is a relative rather than an absolute deficiency of the enzyme.

• Fibrosis: As CML progresses, varying degrees of reticulin fibrosis and vascularity may be seen, which can be related to effect of platelet-derived growth factor, transforming growth factor β, and basic fibroblastic growth factor, whose plasma levels are significantly increased in CML.

Differential Diagnosis:

Juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, and other Ph positive leukemias (acute precursor B-cell lymphoblastic leukemia, adult AML.