Leukemia Flashcards
What is acute leukaemia
Acute leukemias are malignant neoplastic diseases that arise from either lymphoid (acute lymphocytic ALL) or myeloid (acutenmyelocytic leukemia, or AML) cell lines.
Acute leukemias are characterized by the proliferation of immature, non-functional cells in the bone marrow that are released into the bloodstream.
ALL is the most common childhood malignancy, whereas
AML mostly affects adults.
What is chronic myeloid leukaemia
It is a malignancy of the hematopoietic stem cells with excessive proliferation of the myeloid lineage (especially granulocytes).
It is caused by the Philadelphia chromosome 22 that results in the formation of a BCR-ABL fusion gene. The increased activity of this gene’s product – a tyrosine kinase – promotes unregulated proliferation of myeloid progenitor cells, which eventually differentiate into mature cells.
CML has three distinct clinical phases.
1)The chronic phase is characterized by nonspecific symptoms (fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years.
2)The accelerated phase is characterized by complications secondary to the suppression of the other cell lines (thrombocytopenia, anemia, recurrent infections)
3) Blast crisis
The blast crisis is the terminal stage of CML.
Symptoms resemble those of acute leukemia.
Rapid progression of bone marrow failure → pancytopenia, bone pain
Severe malaise
Subtypes :
Myeloid blast crisis → AML (⅔ of cases)
Lymphoid blast crisis → ALL (⅓ of cases)
What is chronic lymphoid leukaemia
Chronic lymphocytic leukemia (CLL) belongs to the group of low-grade non-Hodgkin lymphomas (NHL) and is a B-cell lymphoma that presents with lymphocytic leukocytosis.
CLL is the most common form of leukemia in adults and is typically considered a disease of the elderly.
Clinical features:
painless lymphadenopathy!!!
fatigue, chronic pruritus, and an increased susceptibility to infections.
Important diagnostic markers are smudge cells (Gumprecht shadows) in a blood smear, a high percentage of small, mature lymphocytes in the bone marrow, detection of B-CLL antigens in flow cytometry.
The Rai staging system is primarily based on lymphocyte count, sites of lymphatic tissue involvement, anemia, and platelet count.
The medical treatment of CLL consists of chemotherapy and monoclonal antibodies, but does not necessarily increase survival time. Allogeneic stem cell transplantation, which is the only curative treatment option, is often not viable because of the advanced age of most patients.
How does the two hit hypothesis explain the pathophysiology of acute lymphoid Leukemia
The two-hit hypothesis assumes that leukemia is the result of two separate genetic mutations.
The first mutation causes clonal proliferation of a lymphoid or myeloid stem cell, while the second impairs its normal hematopoietic differentiation.
As a result, the bone marrow is filled with numerous immature, non-functional cells that impairs normal hematopoiesis and cause the following abnormalities:
Leukopenia (↑ risk of infections)
Thrombocytopenia (↑ bleeding)
Anemia: pallor etc
Following further proliferation, the leukemic cells eventually enter the bloodstream and infiltrate other organs (e.g., the liver or the spleen), leading to organ-specific symptoms.
RF for leukemia
1)Genetic factors Immune deficiencies ALL 2)Chromosome abnormalities Down syndrome, Klinefelter syndrome, Recklinghausen disease. NEUROFIBROMATOSIS Fanconi anemia -AML
3)Viral infections
Epstein-Barr virus
HTLV-1= ALL In adults
4)Environmental factors
Ionizing radiation exposure
Toxic substances: benzene derivates
Drugs: alkylating agents, epipodophyllotoxins
5) myeloproliferative disorders for AML
Osteomyelofibrosis
Chronic myelogenous leukemia
Sx of acute leukemia in both AML& ALL
Fatigue, pallor, and weakness (caused by anemia)
Excess Bleeding :petechiae, epistaxis, or hematoma, caused by thrombocytopenia)
Hepatomegaly and/or splenomegaly (caused by leukemic infiltration)
Headache, visual field changes, or other CNS symptoms (caused by CNS infiltration ) more common in B-ALL
Fever (due to increased risk of infection) however veterans w/o infection is ALL
Syndrome of extramedullary blast syndrome Sx of ALL (most common)
Painless lymphadenopathy!!! 1st sign
Fever, night sweats, unexplained weight loss!! Second sign
Bone pain
Hepatomegaly(70%) splenomegaly(60%)
Testicular enlargement (rare finding)
Airway obstruction (stridor, difficulty breathing) caused by mediastinal infiltration in T-cell ALL with thymic infiltration or mediastinal adenopathy !!!
Meningeal leukemia (or leukemic meningitis) → headache, neck stiffness more likely in T-cell
Mickulicz syndrome: chronic condition characterized by the abnormal enlargement of glands in the head and neck, including the parotids, lacrimal and salivary.
Sx of AML
Leukemia cutis (or myeloid sarcoma): nodular skin lesions with a purple or gray-blue color
Gingival hyperplasia (AML subtype M4 and M5) from mucosal infiltration
Fever in AML patients is usually a sign of infection and requires immediate investigation!
Dg of acute leukemia
CBC (abnormal in most but not all children) WBC normal/high/low = unreliable ↓haemoglobin & RBC Thrombocytopenia Circulating leukaemic blast cells
Increased cell lysis: ↑ LDH and ↑ uric acid
Peripheral blood smear
presence of blasts
AML: Some subtypes (especially M3) Auer rods, which are pinkish-red, rod-shaped granular components within the cytoplasm. Show impaired granulocyte development
Bone marrow biopsy (essential to confirm diagnosis)
The marrow is replaced with lymphoblasts of various sizes :ALL >25% blasts AML > 20% myeloblasts
No myeloid or erythroid precursors are seen
megakaryocytes are absent
Chest x-ray (to identify mediastinal mass characteristic of T-cell disease)
Immunophenotyping (to classify the type of leukaemia)
B-ALL is usually positive for CD10, 19, and 20
T-ALL is usually positive for CD2-5 and CD7 and 8
AML: most are positive for CD13, 33, 34 and HLA-DR.
Flowcytometry (to differentiate T-cell and B-cell CD surface markers)
Cytogenetics/molecular genetics for Phil chromosom
Histochemistry (ALL is PAS+, AML is sudan black+ and myeloperoxidase+)
Rx of acute leukmia ( Luke,s ACS
-Aggressive chemo
ALL
Induction: vincristine, glucocorticoids
*Cases of Philadelphia chromosome mutation: BCR-ABL Tyrosine Kinase Inhibitor (imatinib)
AML
Induction: cytarabine and anthracyclines (daunorubicin)
Exception: AML M3 (promyelocytic leukemia) treated with vitamin A derivatives, such as ATRA (all-trans-retinoic acid).
-CNS prophylaxis
Intrathecal chemotherapy is indicated for all acute leukemia patients to prevent meningeal leukaemia d-2:poor CNS penetration of cytoxic drugs
-Supportive therapy: very important d/immunocompromised pts
1) prevent infec
Mucositis prophylaxis w/ local antimycotic (amphotericin B)
Broad spec Abiotics I’m suspcted infec
2)antiemetics
3)Uris acid stone prophylaxis from tumor lysis w/ allopurinol, hydration, possible diuretics
-Allogenic stem, cell transplant (genetic sim but not identical)
Chemo therapy regime IRCM
Induction therapy (goal: massive reduction of tumor cell count)
Duration: 4–6 weeks
Effective, but can cause severe side effects
Re-induction therapy (goal: similar to induction therapy)
Only indicated in case of relapse or failure of primary induction therapy
Duration: 4–6 weeks
Consolidation therapy (goal: destruction of remaining tumor cells) Duration: several months Medium doses
Maintenance therapy (goal: maintaining remission) Duration: up to 24 months Low doses
Prognostic factos
Worse Older Boys Genetic abnormality High count Myeloid is worse the lymphoid High cell count Response to treatment is major prognostic factor
Cure rate is 90%
