Leukemia

The term leukemia refers to a range of cancers in which any one of the types of white blood cell (leukocytes) undergoes progressive over-proliferation in the bone marrow or other haematopoietic organs and circulates throughout the blood and lymphatic systems.  This is generally accompanied by suppressed production of other types of leukocyte.  Leukocytes are the cells that make up the innate and adaptive immune system and there are five main types: neutrophils, eosinophils and basophils (collectively called granulocytes), monocytes and lymphocytes.  Granulocytes and monocytes are collectively called myeloid cells – hence any leukocyte that isn’t a lymphocyte is a myeloid cell.  There are two major classifications of leukemia based on the rate of progression of the disease (acute or chronic) and further sub-divisions depending on the type of cell involved (myeloid or lymphoid).

Acute leukemias are also usually associated with the presence of primitive immature “blast” cells (see below), whilst chronic leukemias are characterised by the presence of increased numbers of mature progeny.

Blast cells are immature precursors of either lymphocytes (lymphoblasts), or granulocytes (myeloblasts). They are not normally present in peripheral blood and the appearance of these abnormally large cells often signifies acute leukemia.

Acute lymphoblastic leukemia (ALL) is characterized by an excess of lymphoblasts and accounts for about 70% of all cases of childhood leukemia. Treatment for childhood ALL is very successful but the prognosis for adult ALL is less good.

Acute myeloid leukemia (AML) is a malignancy of myeloblasts, the precursors of myeloid white blood cells. Although this involves uncontrolled myeloblast growth, there are multiple forms of AML. AML can now be distinguished from ALL by genome-wide expression profiling which has also revealed new molecular subtypes.

Chronic lymphoid leukemia (CLL: alternatively called B-cell chronic lymphocytic leukemia), also involves excessive production of abnormal lymphocytes but progression is usually slow. CLL accounts for 25% of all leukemia.

Chronic myelogenous leukemia (CML), also called chronic myeloid leukaemia or chronic granulocytic leukaemia (i.e. granulocytes are the cancerous cells), involves increased production of granulocytes and is characterized by the chromosomal translocation known as the Philadelphia chromosome. A small proportion of patients with a similar myeloproliferative disorder do not have the Philadelphia chromosome. CML is a relatively rare disease, representing about 14% of all leukemias.

There are several sub-categories within these main groupings. In addition there are other rare forms of leukaemia: Hairy cell leukaemia (HCL) and large granular lymphocytic leukaemia and T-cell prolymphocytic leukaemia (T-PLL, also called T-cell chronic lymphocytic leukemia), a rare and aggressive adult form. Adult T-cell leukemia/lymphoma (ATL) is caused by infection of CD4+ T cells by human T-lymphotropic virus (HTLV).

The leukemias are part of a larger group of diseases called haematological malignancies that includes the four sub-types of Hodgkin’s lymphoma and the various forms of non-Hodgkin lymphoma [including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), post-transplant lymphoproliferative disorder (PTLD) and B-cell prolymphocytic leukaemia (B-PLL)]. The incidence of non-Hodgkin lymphomas is rising in the western world.

Leukemias (total):

New cases/year World 2008: 195,456 USA 2011 (est): 44,600 UK 2008: 7,659
Deaths/year World 2008: 143,555 USA 2011 (est): 21,780 UK 2008: 4,367

Hodgkin lymphoma:

New cases/year World 2008: 40,265 USA 2011 (est): 8,830 UK 2008: 1,730
Deaths/year World 2008: 18,256 USA 2011 (est): 1,300 UK 2008: 302

Non-Hodgkin lymphoma:

New cases/year World 2008: 199,736 USA 2011 (est): 66,360 UK 2008: 11,861
Deaths/year World 2008: 109,484 USA 2011 (est): 19,320 UK 2008: 4,438
ALL Acute lymphoblastic leukemia
New cases/year

USA 2011 (est): 5,730; UK 2008: 654. About 6 in 10 cases occur in children.

Deaths/year

USA 2011 (est): 1,420; UK 2008: 262

Risk factors

The most common leukemia in young children: also affects adults, particularly over the age of 65. Exposure to high levels of radiation, previous chemotherapy and chemical carcinogens (e.g., benzine) are possible risk factors.

Symptoms Vague and non-specific but may include weakness and fatigue, fever, susceptibility to infection, skin rash, bleeding from gums or nose, blood in urine or stools, rash (purpura), enlarged lymph nodes, enlarged spleen, weight loss. Infection by human T cell leukaemia virus (HTLV-1) may lead to a form of adult T cell leukemia.
Subtypes There are four main subtypes in the FAB classification:Early precursor B cell (60%-65% of cases)

Precursor B cell (20%-25%; 70% of childhood ALL)

Mature B cell (2%-3%)

T cell (13%-15%)

However, more meaningful is the WHO recommended classification into the categories Precursor B cell, Precursor T cell, Burkitt’s leukemia/lymphoma and the rare sub-type acute biphenotypic leukemia. In Precursor B cell ALL major genetic alterations are:

TEL-AML1 (25% of cases)

BCR-ABL1 (25%): the Philadelphia chromosome (present in 95% of CML cases): occurs in 5% of pediatric ALLs.

E2A-PBX1 (5%)

MLL-AF4 (2%): very common in infantile leukaemias, about 80% of which have MLL rearrangements and are very aggressive.

MLL-AF10 (mainly in pediatric not adult ALL)

IGH-MYC

TCR-RBTN2

TEL-AML1 translocations are associated with a good prognosis: BCR-ABL1, MLL-AF4 and IGH-MYC have poor prognoses.

Major gene mutations In addition to the translocations defining subtypes, mutations in more 30 other genes have been associated with ALL, including components of the RAS signalling pathway.
Treatment Over 30 drugs are approved for ALL including abitrexate (methotrexate), clofarabine and Gleevec (Imatinib).Childhood ALL: prednisolone, vincristine, asparaginase, daunorubicin.

Therapy: cytotoxic drug +/- stem cell transplantation.

Side effects

Vary depending on the drugs used and the individual patient. May include nausea, general suppression of the immune system and increased infection risk, hair loss and increased infection risk. Transplantation therapy may induce an immune response that can cause skin problems and diarrhoea. Some children may suffer delayed effects of chemotherapy months or years after treatment. These ‘late side-effects’ may affect development and fertility and give rise to learning disabilities.

Prognosis

Survival rates are ~80% in children, ~30% in adults. In some groups 20-80% of patients relapse or develop cancers resistant to treatment.

AML Acute myeloid leukemia
New cases/year USA 2010 (est): 12,330; UK 2008: 2,343
Deaths/year USA 2010 (est): 8,950; UK 2008: 2,143
Risk factors

More common in adults than children and in men rather than women. Risk group assigned on basis of karyotype.

Symptoms

Vague and non-specific but may include weakness and fatigue, fever, susceptibility to infection, skin rash, bleeding from gums or nose, blood in urine or stools, enlarged lymph nodes, enlarged spleen, weight loss.

Sub-type There are two systems for classifying AML, the World Health Organisation (WHO) system and the French American British (FAB) system.The WHO system is based on cell type and whether (1) there are specific chromosomal changes, (2) abnormalities are detected in more than one type of cell, (3) leukemia developed from myelodysplasia, and (4) previous cancer treatment has led to the leukemia (‘treatment-related AML’)

The FAB system is based on the morphology (appearance) of the leukaemia cells and is numbered from M0 to M7, depending on cell type:

AML-M0: Acute myeloblastic leukemia: minimal differentiation (very immature cells).

AML-M1: a high percentage of blasts in the bone marrow without significant evidence of myeloid maturation. Blasts constitute over 90% of the non-erythroid cells.

AML-M2: More than 20% blasts in the bone marrow or blood and evidence of maturation to more mature neutrophils. (More than 10% of neutrophils are at different stages of maturation). Monocytes comprise over 20% of bone marrow cells.

AML-M3: Acute promyelocytic leukemia (APL: promyelocytes are mature myeloblasts),

AML-M4: Acute myelomonocytic leukemia.

AML-M5: Acute monocytic leukaemia: Over 20% blasts in the marrow, 80% of which are of the monocytic lineage.

AML-M5a: Over 80% monoblasts.

AML-M5b: mixture of monoblasts (80%) and promonocytes.

AML-M6: Acute erythroleukemia (affecting precursor red cells)

AML-M7: Acute megakaryoblastic leukemia (affecting megakaryocytes).

Major gene mutations

Numerous chromosome translocations generate fusion proteins. These include RUNX1-RUNX1T1, NUP98-HOXA9 and MOZ-TIF2. The 10 most common occur in about 15% of AMLs. About 50% do not have translocations but have mutations in a large number of genes (e.g., NPM1, FLT3, KIT, RAS, MLL). Mutations in isocitrate dehydrogenases (IDH1/2) can cause widespread changes in gene expression.

Both translocation and mutation patterns can give rise to a gene-expression signature indicating whether the prognosis is poor or good.

Treatment

Over 30 drugs are approved for AML. The mainstays of therapy are anthracyclines such as daunorubicin and cytarabine. Gemtuzumab ozogmicin (Myelotarg), a monoclonal antibody that targets a cytotoxic antibiotic to leukemic blast cells via binding to the surface protein CD33, can improve survival figures in 10% of patients in specific subgroups.

Side effects

Commonly shivering, fever, nausea.  Can cause myelosuppression and liver damage. General suppression of the immune system and increased infection risk.

Prognosis 5-year survival rate in adults: 33% (below 65 years), 4% over 65 years.  Long-term survival rate 21%, children 55%.
CLL Chronic lymphocytic leukemia
New cases/year USA 2010 (est): 14,990; UK 2008: 2,798
Deaths/year USA 2010 (est): 4,390; UK 2008: 1,129
Risk factors

The most common type of leukemia in adults, usually occurring after the age of 55. Rare in children. Two-thirds of those affected are men. Despite a strong familial basis to CLL, with risks in first-degree relatives of cases being increased sevenfold, to date the inherited genetic basis of the disease is largely unknown.

Symptoms Usually without symptoms and discovered in a blood test. It can, however, cause swollen lymph nodes, abdominal pain, tiredness and weight loss.
Staging Stage 0: high lymphocyte levels in blood but no other symptoms: indolent (slow-growing).Stage I: high lymphocyte levels in blood: enlarged lymph nodes.

Stage II: high lymphocyte levels in blood: liver, spleen or lymph nodes may be enlarged.

Stage III: high lymphocyte levels in blood: low red cell count: liver, spleen or lymph nodes may be enlarged.

Stage IV: as stage III but with reduced platelet count.

Subtypes

B-cell pro-lymphocytic leukemia is an aggressive form of CLL.

Major gene mutations Four main types of genetic damage are associated with CLL and these reflect the probable course of the disease:1.     Loss of P53 (5–10% of CLLs): very poor prognosis.

2.     Loss of ATM (5–10%): poor prognosis.

3.     An extra copy of chromosome 12 (20-25%): intermediate prognosis.

4.     Loss of specific micro RNAs (50%): good prognosis: may not require any treatment.

Treatment

No treatment (‘watchful waiting’) may be required at first diagnosis if there are no symptoms. Otherwise, chemotherapy (e.g., fludarabine with cyclophosphamide or chlorambucil) with or without radiotherapy. Therapy with rituximab (an anti-CD20 monoclonal antibody) appears to improve outcome in CLL.

Side effects

Lowered blood cell count, fatigue. General suppression of the immune system and increased infection risk.

Prognosis

5-year survival rate 75%.

CML Chronic myelogenous leukaemia
New cases/year USA 2010 (est): 4,870; UK 2008: 613
Deaths/year USA 2010 (est): 440; UK 2008: 243
Risk factors

Occurs mainly in adults between 40 and 60 years: rare in children. Radiation (e.g., radiotherapy) and chemical carcinogens (e.g., benzine).

Symptoms

85% of patients present in the chronic phase: there may be no symptoms or patients may have shortness of breath (due to anaemia), abdominal discomfort (due to massive enlargement of the spleen), weight loss, fever, sweating, headache and (rarely) bruising or bleeding.  Symptoms may cause pallor, swollen lymph nodes and spleen and bleeding into the retina of the eye.

Course

There are three phases: chronic phase followed over several years in the untreated patient by the accelerated phase (weeks to months) and ultimately blast crisis (also called the acute phase), which is clinically similar to acute leukemia. Imatinib and other tyrosine kinase inhibitors can alter the normal natural history of the disease, giving a marked reduction in progression.

Cellular effect

In the chronic phase <10% of the cells in blood and bone marrow are immature (blast) cells and the levels of myeloid progenitor cells and mature granulocytes are increased.

Major gene mutations

The genetic signature is the Philadelphia chromosome seen in 90-95% of CML cases.  This chromosomal translocation joins part of the BCR gene (from chromosome 22) to the ABL1 gene on chromosome 9. Additional genetic defects are acquired over time and are required for the progression of the disease.

Treatment

First-line for chronic phase: imatinib: gives a complete hematologic response of 96% at one year.  Acute phase patients usually have only a brief response to imatinib. Other drugs (e.g., cyclophosphamide, cytarabine) may also be used. Blast crisis, which may progress to ALL or AML, are similarly treated. Radiotherapy may be used as part of stem cell or bone marrow transplant therapy. Resistance occurs in many patients first treated with imatinib during the accelerated phase. Novel drugs designed to solve this problem are currently in clinical trials where they have shown efficacy and are currently being compared to imatinib for the treatment of newly diagnosed patients.

Side effects

Imatinib: well tolerated but can cause nausea, headaches, rashes and cytopenia.

Prognosis

The USA 5-year survival rate for 2001-2007 was between 50 and 60%. Chronic phase patients treated with imatinib: 5-survival rate 90%.  6% of chronic phase patients relapse having developed resistance to imatinib.

For further information consult The Leukemia & Lymphoma Society (LLS).