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Chronic Leukemias

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What is the basic pathophysiology/diagnosis of CML?
Treat with Imatinib (antibody against translocation target), or progresses from chronic to accelerate to blast crisis in 4.4 years

1) Diagnosed by establishing clonal expansion of hematopoietic stem cell possessing reciprocal translocation between chromosome 9 and 22 (BCR on 22 and ABL on 9)

2) Chimeric gene product contains Nh2-terminal BCR and COOH-terminal ABL (P210 bcr/abl) causes 3 things:

- Constitutive activation of Abl as tyrosine kinase, activating downstream kinases that prevent apoptosis.

- DNA-protein-binding activity of Abl attenuated

- Binding of Abl to cytoskeletal actin microfilaments is enhanced
Patient presents with fatigue, malaise and slight weight loss over a period of 1 year.

On PE, you notice moderate splenomegaly.

Labs come back showing leukocytosis (immature and mature), with increased myelocytes, metamyelocytes and band forms, as well as thrombocytosis and a normochromic, normocytic anemia.

You decide to continue with bone marrow evaluation and chromosomal analysis.

What do you expect to see and how will you treat if you are correct?
Generaled signs of anemia with weight loss and splenomegaly make you think of a hematological malignancy.

Leukocytosis with prevalence of myelocytes/metamyelocytes/bands, along with elevated platelets and normocytic anemia suggest CML.

1) Bone marrow will show hypercullularity, with increased myeloid:erythroid ratio.

- Normal blast percentage in chronic phase, but will elevate in accelerated stages (10-20%)

2) Chromosomal findings include t(9;22)(q34;q11.2) and are required to diagnose CML

3) Targeted treatment with Imatinib (Gleevec) or allogeneic transplantation (side effects significant)
How does Imatinib work to treat CML?
For early CML, NOT blast crisis (often requires SCT ultimately)

Oral antibody that acts as competitive inhibitor of ATP-binding site of Abl kinase in the inactive conformation, preventing downstream kinase activation and resulting in decreased suppression of apoptosis.

Imatinib > IFN-a and cytarabine

**Second line option is Dasatinib, which can cause pleural effusion, OR SC transplant**
What are the essentials of diagnosis CL Leukemia?
Clonal malignancy of immuno-incompetent B lymphocytes that presents with
- immunodeficiency/suppression
- bone marrow failure
- organ infiltration with lymphocytes

1) Lymphocytosis > 5000/mcL
2) Co-expression of CD19, CD5 on lymphocytes
55 year old presents with fatigue and lymphadenopathy.

On PE, you notice hepatosplenomegaly.

Labs return and you notice Lymphocyte counts of 22,000 with CD19+, CD5+, CD23+ B cells. The cells express normal levels of Cyclin D1.

Platelet counts are normal and there is evience of hypogammaglobulinemia.

What is on your ddx and how do you treat?
Older individual with fatigue, lymphadenopathy and organomegaly suggests stage III/IV CLL. Normal platlet count is consistent with stage III.

CD19 and CD5 could be CLL or Mantle Cell lymphoma, but MCL usually does not have CD23 and has elevated Cyclin D1 levels.

Viral infections and Pertussis are also possible.

1) Early indolent CLL requires no treatment

2) Stage III disease requires combination Fludarabine/Rituximab, with or w/o cyclophosphamide.

3) If autoimmune hemolytic anemia is present, prednisone or splenectomy may be required if Rituximab is insufficient.

4) Allogeneic tranplant is last option
Diagnosis of Chronic Myelogenous Leukemias made by clonal expasion of translocation between which of the following chromosomes AND what is the resultant fusion protein?

1) Chromosome 9 & 21 and BCR-ABL protein
2) Chromosome 9 & 22 and RET protein
3) Chromosome 8 & 22 and BCR-ABL
4) Chromosome 9 & 22 and BCR-ABL protein
BCR protein binding to ABL results in which of the following functional changes

1) ABL protein becomes constitiutely active to a TK enzyme & in turn prevents apoptosis

2) DNA binding protein activity of ABL is attenuated

3) Binding protein of abl to actin is enhanced

4) All of the above

5) None of the above

The BCR-ABL fusion protein has multiple activities which may play roles in the pathogenesis of CML. It is assumed at this time that its primary effect is thought to be the constitutive activation of tyrosine kinase which result in the uncontrolled proliferation of granulocyte precursors in the bone marrow
Regarding the clinical findings of Chronic Myelogenous Leukemias, which of the following is correct?

1) Patients present always with vaso-occlusive disease symptoms inc. MI, venous thrombosis, priapism, pulmonary insufficiency

2) Presence of splenomegaly despite continued treatment is a sign of disease acceleration

3) The total WBC is usually low and patients present with circulating blasts > 20%

4) Bone marrow cellularity is increased with an increased erythroid to myeloid ratio
2) The thrombotic risk in patients with CML is relatively low when compared to that seen in patients with other myeloproliferative processes (eg. essential thrombocythemia, polycythemia vera, myelofibrosis) and when it occurs is often after entry into the accelerated phase or after certain kinds of treatment. Most patients with CML present with an elevated WBC, hypercellular bone marrowm(and markedly increased M:E ratio) due to the uncontrolled proliferation of the granulocyte precursors. The majority of patients with CML have splenomegaly which almost always reduces in size with an appropriate response to therapy.
The following are all treatment options in CML Except:

1) Imatinib
2) Dasatinib
3) Sunitinib
4) Nilotinib
Chronic Lymphocytic Leukemia is a clonal malignancy involving:

1) B lymphocytes
2) T lymphocytes
3) B and T lymphocytes
The following regarding staging of Chronic Lymphocytic Leukemia are all correct EXCEPT:

1) Stage I - Lymphocytosis and lymphadenopathy
2) Stage 0 - Lymphadenopathy
3) Stage 2 – organomegaly
4) Stage III – anemia
5) Stage IV – thrombocytopenia
2- Stage 0 has only lymphocytosis
Autoimmune thrombocytopenia can occur with Chronic Lymphocytic Leukemia.

True or false

Concurrent autoimmune disorders are not uncommon among patients with lymphoproliferative neoplasms including CLL. The presence of either warm autoimmune hemolysis or immune thrombocytopenia can fool the clinician into thinking the patient has more advanced disease than is really present. Never the less, the occurrence of these complications may require more aggressive intervention than normally required according to the stage category.
Richters transformation is characterized by

1) Isolated lymph node transforming to aggressive lymphoma
2) When all lymph nodes regress and disease is quiescent
3) Disease systemically flares up with no change in lymph nodes
4) None of the above
Which of the following statements about Chronic Lymphocytic Leukemia (CLL) is INCORRECT

1) Hypogammaglobinemia is a feature of CLL in up to 50% of patients in advanced disease

2) Characteristic markers for CLL is CD 19 and CD 9

3) Patients with mutated forms of Immunoglobulin gene have a more indolent course

4) Deletion of 17p is consistent with poor prognosis.
2) CD20 and CD19

A characteristic of B cell CLL is that the malignant lymphocyte surfaces express B cell markers (CD 20, CD 19, CD 23) and CD 5 (an aberrant T cell marker). CD 9 is a surface marker frequently seen in acute nonlymphocytic leukemia or acute lymphoblastic leukemia, but not in CLL.
The following are all indications of treatment EXCEPT:

1) Progressive Fatigue
2) Asymptomatic lymphadenopathy
3) Rai stage II
4) Rai Stage III or IV disease
2- These are in relation to CLL
Treatment options for Chronic Lymphocytic Leukemia include Fludarabine, Cyclophosphamide and Rituximab. If a patient has autoimmune hemolytic anemia, fludarabine is the preferred agent of choice in these patients.

True or false

When administered as a single agent fludarabine can cause a severe, life-threatening hemolysis that is difficult to treat. When administered in conjunction with either cyclophosphamide and/or rituximab the frequency of this complication is reduced significantly. Clinical trials indicate that the response rate and duration of response is improved by the administration of this three drug combination as compared when of these three drugs are administered alone.
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