LEUKEMIAS

By

Dr. Qutaiba Al- Khames Aga Ms. Noor Batarseh

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

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.

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)

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)

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

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

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.

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 )

Risk factors for the development of leukemia:

5. Haematological disorders (non-leukaemic myeloproliferative disorders, aplastic anemia and paroxysmal nocturnal haemoglobinuria

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

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.

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.

Pathophysiology: Chronic leukaemias

Ø In chronic leukaemia, the normal bone marrow is replaced by a malignant clone of maturing haemopoietic cells.

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)

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.

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.

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.

Investigations

Findings at diagnosis in leukemia

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.

Blood Film-Normal

Normal human blood

White Cell Red Cell

Platelet

Blood with leukemia

Blasts Red Cell

Platelet

White Cell

Blood Film-Normal

Blood Film-Normal

Normal BM cells

AML

AML Auer rods

ALL

Bone Marrow-ALL

Treatment

• Acute lymphoblastic leukaemia

  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.

•  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.

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.

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.

Treatment of Acute myeloblastic leukemia

Three types of standard treatment are used: Ø  Chemotherapy Ø Radiation therapy Ø Stem cell transplantation

Treatment of Chronic

leukaemia

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.

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.

Stem cell transplantation

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.

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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