leukemias - philadelphia university · leukemias leukemias are a group of cancers of the blood or...
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LEUKEMIAS
By
Dr. Qutaiba Al- Khames Aga Ms. Noor Batarseh
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Leukemias
Leukemias are a group of cancers of the blood or bone marrow and are characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes).
Leukemia is a broad term covering a spectrum of diseases. Any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs and which is usually accompanied by anemia and thrombocytopenia
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Classification of leukemias Two major types (4 subtypes) of leukemias Acute leukemias Acute lymphoblastic leukemia (ALL) Acute myelogenous leukemia (AML) (also "myeloid" or "nonlymphocytic") Chronic leukemias Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML) The adjectives ‘myeloid’ and ‘lymphoid’ refer to
the predominant cell involved, and the suffix-cytic and -blastic to mature and immature cells, respectively.
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Epidemiology Acute leukemia Chronic leukemia
ALL AML CLL CML • Predominantly a
childhood disease • Peak incidence in the
3–5 year age group • Most common
childhood cancer.
• Rises steadily with age
• Occurring only rarely in young children
• Mainly affects an older age group > 50 years
• It rarely occurs in young people
• Is twice as common in men as in women.
• Is primarily a disease of middle age
• Median onset in the 40–50 year old age group
• It can occur in younger people
Myeloid vs Lymphoid Myeloid Lymphoid
• Any disease that arises from the myeloid elements (white cell, red cell, platelets) is a myeloid disease (AML, CML)
• Any disease that arises from the lymphoid elements is a lymphoid disease (ALL, CLL)
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Myeloid vs Lymphoid
Myeloid Lymphoid
• Any disease that arises from the myeloid elements (white cell, red cell, platelets) is a myeloid disease (AML, CML)
• Any disease that arises from the lymphoid elements is a lymphoid disease (ALL, CLL)
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Acute vs. chronic leukemia
Acute leukemias Chronic leukemias
• Young, immature, blast cells in the bone marrow (and often blood)• More fulminant presentation• More aggressive course
• Accumulation of mature, differentiated cells• Often subclinical or incidental presentation• In general, more indolent (slow) course• Frequently splenomegaly • Mature appearing cells in the B. marrow and blood
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On a CBC, if you see
• Predominance of blasts in blood consider an acute leukemia
• Leukocytosis with mature lymphocytosis consider CLL
• Leukocytosis with mature neutrophilia consider CML
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Etiology • The etiology of leukemia is not fully
understood. Leukemia is thought to result from a combination of factors that induce genetic mutations, which allow mutated cells to proliferate faster than normal cells and/or to fail to die in response to normal apoptotic signals.
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Risk factors for the development of leukemia:
• 1. Radiation (Nagasaki and Hiroshima , patients who received radiotherapy for the treatment of malignant and non-malignant conditions)
• 2. Exposure to chemicals and cytotoxic drugs (cyclophosphamide and radiotherapy, exposures to paint, insecticides and solvents, in particular, the aromatic solvent benzene
• 3. Viruses (Human T-cell lymphotrophic virus, an RNA retrovirus endemic in Japan and the West Indies
• 4. Genetic factors (Down's syndrome ,Fanconi's anaemia )
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Risk factors for the development of leukemia:
5. Haematological disorders (non-leukaemic myeloproliferative disorders, aplastic anemia and paroxysmal nocturnal haemoglobinuria
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Pathophysiology: In leukemia, the normal process of haemopoiesis is altered. Transformation to malignancy appears to occur in a single cell, usually at the pluripotential stem cell level
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Pathophysiology: Acute leukaemias
Ø In acute leukaemia, the normal bone marrow is replaced by a malignant clone of immature blast cells derived from the myeloid (in AML) or lymphoid (in ALL) series.
Ø More than 20% of the cellular elements of the bone marrow are replaced with blasts.
Ø This is usually associated with the appearance of blasts in the peripheral circulation accompanied by worsening pancytopenia as a result of the marrow's reduced ability to produce normal blood cells as the proportion of malignant cells increases.
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Pathophysiology: Acute leukaemias
Ø In ALL, the blasts may infiltrate lymph nodes and other tissues such as liver, spleen, testis and the meninges, in particular.
Ø In AML, blasts tend to infiltrate skin, gums, liver and spleen.
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Pathophysiology: Chronic leukaemias
Ø In chronic leukaemia, the normal bone marrow is replaced by a malignant clone of maturing haemopoietic cells.
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Clinical manifestations: Acute leukaemia
Most of the clinical manifestations of acute leukemia are related to bone marrow failure. v Symptoms of infection, v Anemia v Bleeding are common and life-threatening
presenting problems. v Disseminated intravascular coagulation
(DIC)
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Clinical manifestations: Acute leukaemia
v The involvement of other tissues such as spleen, liver, lymph nodes and meninges is more common in ALL than AML.
v Involvement of the central nervous system (CNS) may give rise to headaches, vomiting and irritable behaviour.
v hypermetabolism, hyperuricaemia or generalised aches and pains.
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Clinical manifestations: Chronic leukaemia/Chronic myelocytic
leukaemia ü Patients with CML commonly present with
non-specific symptoms, such as malaise, weight loss and night sweats.
ü Splenomegaly and Hepatomegaly ü Neutropenia and thrombocytopenia are
uncommon ü Thus, unlike the acute leukaemias, patients
with CML rarely present with symptoms of infection or haemorrhage.
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Clinical manifestations: Chronic lymphocytic leukaemia
o Symptomatic patients often suffer B symptoms: night sweats, unexplained fever and weight loss.
o Generalized lymphadenopathy and some enlargement of the liver and spleen.
o Patients are immunocompromised with a reduction in serum gammaglobulin and are at increased risk of bacterial and viral infections.
o Increased susceptibility to autoimmune disease, particularly immune haemolytic anaemias and thrombocytopenia.
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Investigations
Findings at diagnosis in leukemia
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Investigations AML ALL CML CLL
WBC ↑ in 60%, may be N or ↓
↑ in 50%, may be N or ↓↓
↑↑ commonly Commonly ↑
Differential WBC
Mainly myeloblasts
Mainly lymphoblasts
G r a n u l o c y t e s ↑↑, especiallyn e u t r o p h i l s , myelocytes,basophils and eosinophils<10% blasts present
monoclonallymphocytes
RBC
Severe anaemia Severe anaemia A n a e m i a common
Anaemia in 50% of patients, generally mild
Platelets ↓↓ ↓↓ Usually ↑, may be N or ↓
↓ in 20–30%
Lymphadenopathy Rare Common Rare Common
Splenomegaly 50% 60% Usual and severe
Usual and moderate
N, normal; ↓, reduced; ↑, increased; WBC, white blood cells;; RBC, red blood cells.
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Blood Film-Normal
Normal human blood
White Cell Red Cell
Platelet
Blood with leukemia
Blasts Red Cell
Platelet
White Cell
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Blood Film-Normal
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Blood Film-Normal
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Normal BM cells
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AML
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AML Auer rods
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ALL
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Bone Marrow-ALL
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Treatment
• Acute lymphoblastic leukaemia
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Dose Route RegimenInduction (4 weeks)• Vincristine • Prednisolone • l-Asparaginase• Daunorubicin
• 1.5 mg/m2• 40 mg/m2• 6000 u/m2 • 45 mg/m2
• i.v. • oral • i.m. • i.v.
• Weekly for 4 weeks• Daily for 4 weeks• 3 × weekly for 3
weeks• Daily for 2 days
Intensification(1 week) • Vincristine• Daunorubicin • Prednisolone • Etoposide • Cytarabine • Thioguanine
• 1.5 mg/m2• 45 mg/m2• 40 mg/m2• 100 mg/m2• 100 mg/m2• 80 mg/m2
• i.v.• i.v. • oral • i.v. • i.v. • oral
• 1 dose• Daily for 2 days • Daily for 5 days • Daily for 5 days• 2 × daily for 5 days Daily for 5 days
CNS prophylaxis (3 weeks) Cranial irradiation
24 GyMethotrexate i.t. weekly for 3 weeks also given during induction and intensification
Maintenance therapy (2 years)• Methotrexate • 6-Mercaptopurine • Prednisolone • Vincristine.
• 20 mg/m2• 75 mg/m2• 40 mg/m2• 1.5 mg/m2
• oral • oral • oral • i.v
• Weekly • Daily• 5 days/month • Monthly
i.m., intramuscular; i.v., intravenous; i.t., intrathecal; MRC, Medical Research Council; ALL, acute lymphoblastic leukaemia.
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• Patients with ALL are at a high risk of developing CNS infiltration. Cytotoxic drugs penetrate poorly into the CNS which thus acts as a sanctuary site for leukaemic cells. For this reason, all patients with ALL receive CNS prophylaxis. Cranial irradiation plus intrathecal methotrexate or high dose systemic methotrexate can be used.
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Treatment of Acute myeloblastic leukemia
• The treatment of adult AML usually has 2 phases.
Ø Remission induction therapy: This is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission.
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Treatment of Acute myeloblastic leukemia
Ø Post-remission therapy: This is the second phase of treatment. It begins after the leukemia is in remission. The goal of post-remission therapy is to kill any remaining leukemia cells that may not be active but could begin to regrow and cause a relapse. This phase is also called remission continuation therapy.
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Treatment of Acute myeloblastic leukemia
Three types of standard treatment are used: Ø Chemotherapy Ø Radiation therapy Ø Stem cell transplantation
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Treatment of Chronic
leukaemia
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Chronic myelocytic leukaemia 1. Hydroxycarbamide is initiated at a dose of 1.5–2 g/
day and usually brings the WBC under control within 1–2 weeks.
2. The dose can then be reduced to a maintenance dose of 0.5–2 g/day.
3. Interferon -∝ can control symptoms of CML but was also the first agent shown to modify the disease process.
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Chronic lymphocytic leukaemia 1. The combination of
has been adopted, in the UK, as the regimen of choice for first-line treatment of CLL as long as patients are considered fit enough. remains an excellent choice for patients with significant co- morbidities as the treatment is less immunosuppressive.
2. Corticosteroids can reduce the lymphocyte count without contributing to myelosuppression
3. Radiotherapy can also be used to control localized painful lymphadenopathy.
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Stem cell transplantation
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The basic principle
Following administration of conditioning therapy (high-dose cyclophosphamide and total body irradiation.), 2–3 days elapse to allow its elimination from the body, and then previously harvested stem cells are reinfused peripherally. The stem cells will return to and repopulate the marrow, restoring normal haemopoiesis.
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Peripheral blood stem cell transplantation
Peripheral stem cell transplantation offers some advantages over conventional bone marrow transplant techniques; • Collection of peripheral stem cells negates the need for general anesthesia it has been found that the haemopoietic recovery period following transplantation is shortened by 5–10 days. • This technique can also be used to harvest stem cells from allogeneic donors.
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