Associate professor of Internal Medicine CHRONIC LEUKEMIA Dr. Hayam Hebah Associate professor of Internal Medicine AL Maarefa College

CHRONIC MYELOID LEUKEMIA

It is a myeloproliferative stem cell disorder resulting in proliferation of all hematopoietic lineages but manifesting predominantly by the granulocyte series Age 30-80 (peak at 55 y) , in all races Rare 1.8/100000 and accounts for 20% of all leukemias Cc is the chromosome abnormality called Philadelphia chromosome.

Philadelphia chromosome is a specific abnormality of chromosome 22, which is unusually short, acquired with CML. BCR-ABL1, that juxtaposes the ABL1 gene on chromosome 9 (region q34) to a part of the BCR("breakpoint cluster region") gene on chromosome 22 (region q11)  (Ph) chromosome is not sufficiently specific to diagnose CML (inspite presence in 90%) , since it is also found in (ALL, 25–30% in adult and 2–10% in pediatric cases) and occasionally in  (AML).

The disease has 3 phases: A chronic phase: responsive to ttt, last for 3-5 y( may reach 8 y after imatinib).mostly mature leukemia cells in blood and bone marrow. An accelerated phase( not always seen): disease control is more difficult. Immature WBCs(5-30%) in blood and BM. Clinically fever, weight loss and poor appetite . Median duration 6-9 mo. Blast crisis: disease transforms into acute leukemia either myeloid(70%) or lymphoblastic( 30%) which is relatively refractory to ttt. - Immature WBCs are in blood and bone marrow. Recurrent infections and anemia are typical. This is the cause of death in the majority of cases( median survival 3-6 mo).

C/P: lethargy, weight loss, sweating , abdominal discomfort , but 25% may be asymptomatic at diagnosis Splenomegaly in 90% and may be massive>15 cm below costal margin . Splenic friction rub may be heard in cases of splenic infarction. Hepatomegaly in 50% Lymphadenopathy : unusual - Gum hyperplasia

Investigations: N N anemia WBCs:10-600*10⁹/L (Typically, in excess of 100,000/mm3.) . In 1/3 of cases, platelets> 2000*10⁹/L Blood film: full range of granulocyte precursors from myeloblasts to mature neutrophils( predominantly neutrophils and myelocytes). Absolute increase in esinophils and basophils Nucleated red cells are common. At blast phase:↑circulating blasts, platelet count drop dramatically Bone marrow: confirm diagnosis, phase of disease, Philadelphia chromosome presence, RNA analysis for demonstration of BCR ABL gene product. LDH and uric acid may be high.

Tyrosine kinase inhibitors are the first line ttt of chronic CML and they reduce proliferation of WBCs

Chronic Lymphocytic Leukemia (chronic lymphoid leukemia, CLL)

BACKGROUND: CLL is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. B cells do not respond to antigens most common form of leukemia found in adults 30%. Allogeneic stem cell transplantation is the only known curative therapy.

The cells of origin in most patients with CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells.  As in the case of most malignancies, the exact cause of CLL is uncertain. higher among whites than blacks. higher in males than in females 2:1 CLL is a disease that primarily affects the elderly, with the median age of presentation being 72 years. Prognosis: variable but most live 5-10 years.

C/P C/P: - discovered accidently in 70% -Onset is insidious, and can be discovered incidentally after a blood cell count is performed for another reason. Lymphadenopathy( painless) is the most common presenting symptom, but patients may present with a wide range of symptoms and signs. anemia, infections, weight loss, night sweats Early satiety and/or abdominal discomfort may be related to an enlarged spleen. Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia. Richter syndrome or Richter transformation refers to the transformation of CLL into an aggressive large B-cell lymphoma and is seen in approximately 3-10% of cases. Patients will often present with symptoms of weight loss, fevers, night sweats, muscle wasting, (ie, B symptoms) and increasing hepatosplenomegaly and lymphadenopathy. Treatment remains challenging and prognosis poor, with median survival in months.

Physical examination: In addition to localized or generalized lymphadenopathy, patients may manifest the following: Splenomegaly (30-54% of cases) Hepatomegaly (10-20% of cases) Petechiae Pallor

LN groups

Investigations Peripheral smear: CLL: Mature lymphocytosis( >5*10⁹/L) for longer than 3 months. The absolute neutrophil count is usually normal . RBCs and platelet counts are mildly decreased. Immunophenotyping: B cells express CD19 and CD23 with either kappa or lambda Ig light chains Characteristic aberrant T cell antigen CD5 ↑LDH and direct Coombs test( autoimmune hemolytic anemia) Serum immunoglobulins( hypogammaglobulinemia due to immune deficiency)

Bone marrow: not essential for diagnosis of CLL but may be helpful for prognosis and to monitor response to therapy. BM usually has more than 30% monoclonal lymphocytes and is either normocellular or hypercellular the peripheral smear or bone marrow should show normal mature small lymphocytes with less than 55% atypical or blast forms. Prognosis: Majority of stage A have normal life expectancy. Advanced CLL die from disease or infections. Rarely , CLL transform to an aggressive high grade lymphoma called Richter‘s transformation

Patients with fewer than 5000 B-lymphocytes/µL with lymphadenopathy and without cytopenias more likely have small lymphocytic lymphoma (SLL), although this diagnosis should be confirmed by lymph node biopsy. Large atypical cells, cleaved cells, and prolymphocytes are also often seen on the peripheral smear and may account for up to 55% of peripheral lymphocytes

Management: No specific treatment for most stage A. indications of treatment: Bone marrow failure Massive or progressive lymphadenopathy or splenomegaly Systemic symptoms as weight loss or night sweats. Rapidly increasing lymphocyte count Autoimmune hemolytic anemia or thrombocytopenia.

Treatment & Management CLL patients do not need to be treated with chemotherapy until they become symptomatic or display evidence of rapid progression of disease, as characterized by the following: Weight loss of more than 10% over 6 months Extreme fatigue Fever related to leukemia for longer than 2 weeks Night sweats for longer than 1 month Progressive marrow failure (anemia or thrombocytopenia) Autoimmune anemia or thrombocytopenia not responding to glucocorticoids Progressive or symptomatic splenomegaly Massive or symptomatic lymphadenopathy Progressive lymphocytosis, as defined by an increase of > 50% in 2 months or a doubling time of less than 6 months

Stages B&C Oral chemotherapy with chlorambucil. Recently fludarabine, cyclophosphamide,rituximab In BM failure or cytopenias---steroids Supportive care: Transfusions, ttt of infections, immunoglobulin replacement. Radiotherapy splenectomy

Prolymphocytic leukemia In males >60 y 25% of cases are T cell variety Massive splenomegaly Leucocytic count exceeds( 400*10⁹/L) Cc cell is a large lymphocyte with a prominent nucleolus. Prognosis ---very poor Ttt------unsuccesful

Hairy cell leukemia Rare B cell lymphoproliferative disorder Male to female 6:1 Median age 50 y c/p: ill health ,infections, splenomegaly Cc severe neutropenia , monocytopenia, hairy cells in the blood and bone marrow Express CD25 and CD 103

MYELODYSPLASTIC SYNDROME MDS presents with consequences of BM failure in old age( median 69 y) Blood film: cytopenias and abnormal dysplastic cells(macrocytic RBCs, hypogranular neutrophils with nuclear hyper or hyposegmentation. Bone marrow: hypercellular with dysplastic changes in the 3 cell lines. ↑blast cells but <20% Chromosomes 5 or 7 abnormalities. DISEASE IS INCURABLE Supportive ttt is the mainstay ttt Progress to AML

Myelodysplasia: The myelodysplastic syndromes are all disorders of the hematopoietic stem cells in the bone marrow (only related to myeloid lineage). In MDS, hematopoiesis (i.e., blood production) is disorderly and ineffective FAB classification: Refractory anemia (RA) Refractory anemia with ring sideroblasts (RARS) Refractory anemia with excess blasts (RAEB) Refractory anemia with excess blasts in transformation (RAEB-T) Chronic myelomonocytic leukemia (CMML), not to be confused with chronic myelogenous leukemiaor CML

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