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Acute B Lymphoblastic Leukemia (B-ALL)

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Definition

Acute lymphoblastic leukemia (ALL) is a clonal expansion of the lymphoid blasts in bone marrow, blood or other tissues. ALL can be either T or B lineage (see T ALL) . Pre-B ALL is the proliferation of the blasts of the B lineage.
Sample Cases
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Case Name
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ALL-1 ALL-2 ALL-3 case 22 ALL case


Epidemiology

pre-B All pre-B ALL with myeloid Antigens pre B ALL pre B ALL
This case was kindly provided by the ASCP Press. It is part of Flow Cytometry in Clinical Diagnosis by John Carey, Phil McCoy and David Keren.

5 Mb 7 Mb 2.86 Mb 7.54 MB 2.8 MB

pre B ALL case submitted by UTMC. Compare with Normal PB.

The incidence of acute leukemia is approximately 4 cases per 100,000 per year. 30% of these are ALL. ALL is generally seen in children 75% of cases are usually in children under 6 years of age. There are approximately 3200 cases of ALL in the United States per year; 80-85% of these are precursor B-ALL, the others are precursor T-ALL. The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival.
Possible causes

Similar to AML, possible factors that have been associated with ALL are viruses, radiation, cytotoxic chemotherapy and benzene exposure. Exposure to the atomic bomb of WWII increased

the incidence of all leukemias including ALL. There is also evidence that may suggest a genetic factor in some cases.
Morphology

Lymphoblasts (T or B) vary in size from similar to that of a mature lymphocyte to the size of a neutrophil. These blasts have scant to moderate basophillic cytoplasm with occassional azurophillic granules (T ALL). The nuclear chromatin can be fine to clumped, with occasionally prominant nucleoli.

Typical morphology of B lymphoblasts


WHO classification

The recent WHO International panel on ALL recommends that the FAB morphologic classification (L1, L2, L3) be abandoned, since this classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic classification. There are 2 main immunologic types: pre-B cell and pre-T cell. The mature B-cell ALL (L3) is now classified as Burkitt leukemia/lymphoma. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.
Immunophenotyping

Blasts in pre B ALL can be initially identified using a SSC vs CD45 plot. These blasts have low SSC (many times smaller than normal lymphocytes) and dim to negative CD45. This differs from blasts in AML where the SSC is generally higher.

Example peripheral blood with CD45 negative B lymphoblasts and characteristically small (low SSC)

Example bone marrow with CD45 dim B lymphoblasts.

Once the blasts are identified and gated, the following markers are useful in classification of pre B ALL. Included are marking prevalence: Marker CD10 CD13 CD19 CD20 CD22 CD33 CD34 CD45 (bright) CD45 (moderate) CD45 (dim) CD45 (negative) CD56 CD79a CD117 cytoplasmic IgM HLA Dr Prevalence 89% 5% 100% 24% 69% 31% 76% 2% 33% 36% 29% 36% 88% 0% 22% 98%

TdT
Example Dot plots in pre B ALL

91%

pre B ALL cells characteristically coexpress CD10 and CD19. In addition, CD20 and CD23 (other B cell markers) are not expressed.

Expression of CD34 and TdT indicates immaturity and is characteristic in pre B ALL. cytoplasmic expression of CD79 confirms B cell lineage.

CD38 is an expression of immaturity. The ploidy as seen by the DNA Histogram, indicates a hypodiploidy (DI=0.53) indicating poor prognosis.

The phenotype of the blasts is an idependent prognostic parameter. B-ALL is subdivided into: early pre B-ALL: TdT+, CD19+, CD10common ALL: CD19+, CD10+/CALLA+ pre B ALL: CD10+/-, CD19+, HLA Dr+, cytoplasmic IgM+

mature B ALL: CD10+, CD19+, CD20+, CD22+, surface IgM+


Other relevant tests

Genetics: Some cytogenetic subtypes have a worse prognosis than others. These include:

A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL. A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months. Not all translocations of chromosomes carry a poorer prognosis. Some translocations are relatively favorable. For example, Hyperdiploidy (>50 chromosomes) is a good prognostic factor.

Flow Diagnosis

To diagnose B ALL: CD45 downregulated, CD19+, TdT+, CD10+, surface light chains negative.
References

1. World Health Organization Classification of Tumors. Tumors of Haematopoetic and Lymphoid Tissue. Jaffe, E., Harriss, N., Stein, H., Vardiman, J. IARC Press 2001 2. Flow Cytometry in Neoplastic Hematology-Morphologic-Immunophenotypic Correlation. Gorczyca W., Informa Healthcare 2007 3. 2006 Bethesda International Consensus Recommendations on Immunophenotypic Analysis of Hematolymphoid Neoplasia by Flow Cytometry. Cytometry Part B, 2007 4. Clinical Flow Cytometric Analysis of Hematolymphoid Cells; Approved Guideline - Second Edition H43-A2 Clinical and Laboratory Standards Institute (CLSI) 2007
Contributors to this page

Teri (34 edits) David Novo (12 edits) Chris Concannon (7 edits) Tanya Tolmachoff (6 edits) Tanya (1 edits) mccoyca (1 edits)

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Acute lymphoblastic leukemia

From Wikipedia, the free encyclopedia

Acute lymphoblastic leukemia (ALL)


Classification and external resources

ICD-10 ICD-9 ICD-O: DiseasesDB eMedicine MeSH

C91.0 204.0 M9835/3 195 med/3146 ped/2587 D054198

Acute lymphoblastic leukemias (ALL), is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts. Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone marrow, and by spreading (infiltrating) to other organs. ALL is most common in childhood with a peak incidence at 25 years of age, and another peak in old age. The overall cure rate in children is about 80%, and about 45%-60% of adults have long-term disease-free survival.[1] Acute refers to the relatively short time course of the disease (being fatal in as little as a few weeks if left untreated) to differentiate it from the very different disease of Chronic Lymphocytic Leukemia which has a potential time course of many years. It is interchangeably referred to as Lymphocytic or Lymphoblastic. This refers to the cells that are involved, which if they were normal would be referred to as lymphocytes but are seen in this disease in a relatively immature (also termed 'blast') state. Symptoms The signs and symptoms of ALL are variable but follow from bone marrow replacement and/or organ infiltration.

Generalized weakness and fatigue Anemia

Frequent or unexplained [fever] and [infection] Weight loss and/or loss of appetite Excessive and unexplained bruising Bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity) Breathlessness Enlarged lymph nodes,liver and/or spleen Pitting edema (swelling) in the lower limbs and/or abdomen Petechia, which are tiny red spots or lines in the skin due to low platelet levels

The signs and symptoms of ALL result from the lack of normal and healthy blood cells because they are crowded out by malignant and immature leukocytes (white blood cells). Therefore, people with ALL experience symptoms from malfunctioning of their erythrocytes (red blood cells), leukocytes, and platelets. Laboratory tests which might show abnormalities include blood count tests, renal function tests, electrolyte tests and liver enzyme tests.

Diagnosis
Diagnosing ALL begins with a medical history, physical examination, complete blood count, and blood smears. Because the symptoms are so general, many other diseases with similar symptoms must be excluded. Typically, the higher the white blood cell count, the worse the prognosis.[2] Blast cells are seen on blood smear in majority of cases (blast cells are precursors (stem cells) to all immune cell lines). A bone marrow biopsy is conclusive proof of ALL.[3] A lumbar puncture (also known as a spinal tap) will tell if the spinal column and brain has been invaded. Pathological examination, cytogenetics (particularly the presence of Philadelphia chromosome) and immunophenotyping, establish whether the Myeloblastic (neutrophils, eosinophils or basophils) or Lymphoblastic (B lymphocytes or T lymphocytes) cells are the problem. RNA testing can establish how aggressive the disease is; different mutations have been associated with shorter or longer survival. Immunohistochemical testing may reveal TdT or CALLA antigens on the surface of leukemic cells. TdT is a protein expressed early in the development of pre-T and pre-B cells while CALLA is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML. Medical imaging (such as ultrasound or CT scanning) can find invasion of other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys and reproductive organs.[4]

[edit] Pathophysiology
In general, cancer is caused by damage to DNA that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth, or interrupting chemical signals that control growth. Damage can be caused through the formation of fusion genes, as well as the dysregulation of a proto-oncogene via juxtaposition of it to the

promoter of another gene, e.g. the T-cell receptor gene. This damage may be caused by environmental factors such as chemicals, drugs or radiation. ALL is associated with exposure to radiation and chemicals in animals and humans. The association of radiation and leukemia in humans has been clearly established in studies of victims of the Chernobyl nuclear reactor and atom bombs in Hiroshima and Nagasaki. In animals, exposure to benzene and other chemicals can cause leukemia. Epidemiological studies have associated leukemia with workplace exposure to chemicals, but these studies are not as conclusive. Some evidence suggests that secondary leukemia can develop in individuals who are treated for other cancers with radiation and chemotherapy as a result of that treatment.[5]

[edit] Cytogenetics
Cytogenetic translocations associated with specific molecular genetic abnormalities in ALL
Cytogenetic translocation cryptic t(12;21) t(1;19)(q23;p13) t(9;22)(q34;q11) t(4;11)(q21;q23) t(8;14)(q24;q32) t(11;14)(p13;q11) Molecular genetic abnormality TEL-AML1 fusion[6]
7]

% 25.4%[

E2A-PBX (PBX1) fusion[8] 4.8%[7] BCR-ABL fusion(P185)[9] MLL-AF4 fusion[10] IGH-MYC fusion[11] TCR-RBTN2 fusion
[12]

1.6%[7] 1.6%[7]

12:21 is the most common translocation and portends a good prognosis. 4:11 is the most common in children under 12 months and portends a poor prognosis.

[edit] Prognosis
The survival rate has improved from zero four decades ago, to 20-75 percent currently, largely due to clinical trials on new chemotherapeutic agents and improvements in stem cell transplantation (SCT) technology. Five-year survival rates evaluate older, not current, treatments. New drugs, and matching treatment to the genetic characteristics of the blast cells, may improve those rates. The prognosis for ALL differs between individuals depending on a variety of factors:

Sex: females tend to fare better than males.

Ethnicity: Caucasians are more likely to develop acute leukemia than AfricanAmericans, Asians and Hispanics and tend to have a better prognosis than non-Caucasians. Age at diagnosis: children between 110 years of age are most likely to develop ALL and to be cured of it. Cases in older patients are more likely to result from chromosomal abnormalities (e.g. the Philadelphia chromosome) that make treatment more difficult and prognoses poorer. White blood cell count at diagnosis of less than 50,000/l Cancer spread into the Central nervous system (brain or spinal cord) has worse outcomes. Morphological, immunological, and genetic subtypes Patient's response to initial treatment Genetic disorders such as Down's Syndrome

Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, is an important predictor of outcome.[13] Some cytogenetic subtypes have a worse prognosis than others. These include:

A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL. A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months. Not all translocations of chromosomes carry a poorer prognosis. Some translocations are relatively favorable. For example, Hyperdiploidy (>50 chromosomes) is a good prognostic factor. Genome-wide copy number changes can be assessed by conventional cytogenetics or virtual karyotyping. SNP array virtual karyotyping can detect copy number changes and LOH status, while arrayCGH can detect only copy number changes. Copy neutral LOH (acquired uniparental disomy) has been reported at key loci in ALL, such as CDKN2A gene, which have prognostic significance.[14][15][16] SNP array virtual karyotyping can readily detect copy neutral LOH. Array CGH, FISH, and conventional cytogenetics cannot detect copy neutral LOH. Cytogenetic change Risk category Poor prognosis Poor prognosis Poor prognosis

Philadelphia chromosome t(4;11)(q21;q23) t(8;14)(q24.1;q32)

Complex karyotype (more than four abnormalities) Low hypodiploidy or near triploidy

Poor prognosis Poor prognosis

High hyperdiploidy (specifically, trisomy Good 4, 10, 17) prognosis del(9p) Good prognosis

Correlation of prognosis with bone marrow cytogenetic finding in acute lymphoblastic leukemia
Prognosi s Cytogenetic findings

Favorable Hyperdiploidy > 50 ; t (12;21) Intermedia Hyperdiploidy 47 -50; Normal(diploidy); del (6q); te Rearrangements of 8q24 Unfavorabl Hypodiploidy-near haploidy; Near tetraploidy; del (17p); t e (9;22); t (11q23)

Unclassified ALL is considered to have an intermediate prognosis.[17]

[edit] Classification
As ALL is not a solid tumour, the TNM notation as used in solid cancers is of little use.

[edit] The FAB classification


Subtyping of the various forms of ALL used to be done according to the French-AmericanBritish (FAB) classification,[18] which was used for all acute leukemias (including acute myelogenous leukemia, AML).

ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features)

Each subtype is then further classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. There are 2 main immunologic types: pre-B cell and

pre-T cell. The mature B-cell ALL (L3) is now classified as Burkitt's lymphoma/leukemia. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.

[edit] WHO proposed classification of acute lymphoblastic leukemia


The recent WHO International panel on ALL recommends that the FAB classification be abandoned, since the morphological classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic classification mentioned below. 1- Acute lymphoblastic leukemia/lymphoma Synonyms:Former Fab L1/L2

i. Precursor B acute lymphoblastic leukemia/lymphoma. Cytogenetic subtypes:[19] o t(12;21)(p12,q22) TEL/AML-1 o t(1;19)(q23;p13) PBX/E2A o t(9;22)(q34;q11) ABL/BCR o T(V,11)(V;q23) V/MLL ii. Precursor T acute lymphoblastic leukemia/lymphoma

2- Burkitt's leukemia/lymphoma Synonyms:Former FAB L3 3- Biphenotypic acute leukemia

[edit] Variant Features of ALL


12345-

Acute lymphoblastic leukemia with cytoplasmic granules Aplastic presentation of ALL Acute lymphoblastic leukemia with eosinophilia Relapse of lymphoblastic leukemia Secondary ALL

[edit] Immunophenotyping in the diagnosis and classification of ALL


The use of a TdT assay and a panel of monoclonal antibodies (MoAbs) to T cell and B cell associated antigens will identify almost all cases of ALL. Immunophenotypic categories of acute lymphoblastic leukemia (ALL)
Types FAB Td T cell associate Class t antigen B cell associate c s antigen Ig Ig

Precursor L1,L2 B Precursor L1,L2 T B-cell L3

+ + + -

+ +

-/ + +

[edit] Treatment
The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow). Treatment for acute leukemia can include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and growth factors.[20]

[edit] Chemotherapy
Chemotherapy is the initial treatment of choice. Most ALL patients will receive a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs in various combinations. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.
Phase Remission induction Description Agents

The aim of remission induction is Combination of to rapidly kill most tumor cells Prednisolone or and get the patient into dexamethasone, remission. This is defined as the vincristine, asparaginase presence of less than 5% (better tolerance in leukemic blasts in the bone pediatric patients), and marrow, normal blood cells and daunorubicin (used in absence of tumor cells from Adult ALL) is used to blood, and absence of other signs induce remission. and symptoms of the disease. CNS prophylaxis should begin during this phase of treatment and continue during the consolidation/intensification period. The rationale is based on the presence of CNS involvement in 10%-40% of adult patients at

diagnosis. Typical intensification protocols use vincristine, cyclophosphamide, cytarabine, daunorubicin, etoposide, thioguanine or mercaptopurine given as blocks in different combinations. For CNS protection, intrathecal methotrexate or cytarabine is usually used combined with or without cranio-spinal irradiation (the use of radiation therapy to the head and spine). Central nervous system relapse is treated with intrathecal administration of hydrocortisone, methotrexate, and cytarabine.

Intensification uses high doses of intravenous multidrug chemotherapy to further reduce tumor burden. Since ALL cells sometimes penetrate the Central Nervous System (CNS), most protocols include delivery of chemotherapy into the CNS fluid (termed intrathecal Consolidation/Intensific chemotherapy). Some centers ation deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the CNS fluid and to extract CNS fluid for various tests). Other centers would perform multiple lumbar punctures as needed for testing and treatment delivery.

Maintenance therapy

For this purpose, daily oral mercaptopurine, once The aim of maintenance therapy weekly oral methotrexate, is to kill any residual cell that was once monthly 5-day not killed by remission induction, course of intravenous and intensification regimens. vincristine and oral Although such cells are few, they corticosteroids are usually will cause relapse if not used. The length of eradicated. maintenance therapy is 3 years for boys, 2 years for girls and adults.[21]

As the chemotherapy regimens can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; for ALL about 3 years, 2 months for males on COG protocols; 2 years, 2 months for females- longer for males as testicles are a potential reservoir), many patients have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath, a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath.

[edit] Radiation therapy


Radiation therapy (or radiotherapy) is used on painful bony areas, in high disease burdens, or as part of the preparations for a bone marrow transplant (total body irradiation). Radiation in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of childrens ALL. Recent studies showed that CNS chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited. Most specialists in adult leukemia have abandoned the use o

[edit] Epidemiology
In the US, the incidence of ALL is roughly 6000 new cases per year (as of 2009),[22] or approximately 1 in 50,000. ALL accounts for approximately 70 percent of all childhood leukemia cases (ages 0 to 19 years), making it the most common type of childhood cancer.[22] It has a peak incident rate of 25 years old, decreasing in incidence with increasing age before increasing again at around 50 years old. ALL is slightly more common in males than females. There is an increased incidence in people with Down Syndrome, Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, X-linked agammaglobulinemia and Severe combined immunodeficiency.

[edit] Additional images

acute lymphoblastic leukemia (ALL), peripheral blood of a child, Pappenheim stain, magnification x100

bone marrow smear (large magnification) from a patient with acute lymphoblastic leukemia

bone marrow smear from a patient with acute lymphoblastic leukemia

Leukemia
Note: This section has health/medical information. It was not written by a health care professional. The medical references are:

Childhood Leukemias, edited by Ching-Hon Pui, 1999, Cambridge University Press NCI web site sections on the different types of childhood leukemias, accessed 2007 Childhood Leukemia: A Guide for Families, Friends, and Caregivers, 4th ed., by Nancy Keene, 2010.

On this site: Warning Signs of Childhood Cancer: Leukemia

Leukemia is a cancer of the bone marrow, the spongy center of the bones that makes blood cells.
In leukemia, abnormal white blood cells divide out of control and crowd out the normal cells in the bloodstream. The abnormal white blood cells are not mature, and therefore cannot carry out their infection-fighting function in the blood. These cells crowd out healthy white blood cells, as

well as the red blood cells which carry oxygen to the body and the platelets which cause the blood to clot.

What are the different types of childhood leukemia?


The most common type of leukemia in children is acute lymphocytic (or lymphoblastic) leukemia or ALL, which is further characterized as pre-B, B, or T-cell ALL. Childhood acute myeloid leukemia or AML is less common. "Acute" means that the diseases progress rapidly. The chronic forms of these leukemias, CLL and CML respectively, are seen almost solely in adults. In general, acute leukemias are most prevalent in children and are therefore often referred to as "childhood leukemias".

ALL: acute lymphocytic leukemia (pre-B, B, or T-cell). ALL NCI PDQ AML: acute myeloid leukemia AML NCI PDQ

About 5% of childhood leukemias are distinct types of chronic myeloid leukemias. Juvenile myelomonocytic leukemia (JMML, NCI PDQ) occurs primarily in children aged 2 or under. Acute promyelocytic leukemia (APL, NCI PDQ) is a distinct subtype of AML. A good starting point for research into these and other less common childhood leukemias is on the cancer.gov myeloid leukemias page. A rare type of leukemia in children is Anaplastic Large Cell Lymphoblastic Leukemia, or ALCL. Follow this link for more information on pediatric ALCL.

Types of white blood cells


White blood cells - the blood cells that grow out of control in leukemia - are the cells that fight infection. Blood contains three types of cells:

red blood cells (RBCs, or erythrocytes): these cells carry oxygen to all parts of your body and give the blood its red color platelets (thrombocytes): these cells cause your blood to clot when you bleed white blood cells (WBCs, or leukocytes): these cells defend your body from infections

All blood cells originate in the bone marrow. In fact, they all develop from one special type of cell, called a stem cell. White blood cells come in several types, including:

granulocytes: fight bacteria by surrounding them and "eating" them. monocytes: fight germs, but aren't as specific as granulocytes. B-lymphocytes: these cells attach antibodies on germs (or anything they don't think belongs) with antibodies, which in turn signal other WBCs to get the tagged germ.

T-lymphocytes: these cells signal orders to other WBCs to come to a germ, and they make those other WBCs stay at the battle sight.

In acute lymphocytic leukemias, the B- or T-lymphocytes are growing out of control. In acute myelogenous leukemias, the granulocytes are growing out of control.

lymphocytic (ALL): uncontrolled growth of B- or T-lymphocytes myelogenous (AML) (granulocytic): uncontrolled growth of granulocytes

In all of the leukemias, immature white cells crowd out the good cells. Since they crowd out the red blood cells, a person with leukemia is anemic, without enough red blood cells to carry the necessary oxygen or energy to the body. That's why fatigue is a sign of leukemia. The leukemia cells also crowd out the platelets, so if a person with leukemia is cut, the bleeding does not stop as readily. They also bruise easier. Since the blasts are immature, non-functioning infection fighting cells, a person with leukemia is easily susceptible to infection. If you are interested in more information on blood cells, follow the links below for in-depth, technical information.

University of Virginia's site on blood cells - a good tutorial from the University of Virginia. University of Washington REAL classification of leukemia cells, flow cytometry panels, diagnosis of acute leukemia, tdt, descriptions of many diagnostic tests used in leukemia treatment. From the University of Washington, Department of Laboratory Medicine, Hematopathology Laboratory.

Treatment for childhood leukemias


ALL. The primary treatment for newly diagnosed ALL is combination chemotherapy. Radiation and bone marrow transplantation may be used in some cases. Treatment begins with an intense treatment called "induction" with a combination of several chemotherapy drugs, usually cytosine arabinoside, vincristine, prednisone, L-asparaginase, and daunorubicin. The goal of induction is to kill most of the leukemia cells; most patients do not have any leukemic cells in the bone marrow at the end of induction. (At least, not detectable in a light-microscopical examination of stained bone marrow smear.) The next phase is called "consolidation" in which a different combination of drugs is administered, usually methotrexate, cyclophosphamide, cytosine arabinoside, mercaptopurine, and prednisone. "Maintenance" follows, in which the chemotherapy is lessened to a few of the drugs administered less frequently. Maintenance is generally well tolerated by the patient. Often a period of maintenance is followed by another cycle of induction-consolidation, called "re-intensification". Total therapy lasts from two to three years. Detailed information on this web site:

ALL clinical trials page and ALL main page on this ped-onc site

AML. In general, newly diagnosed AML is initially treated more aggressively than is ALL. Intensive chemotherapy followed by bone marrow transplantation is becoming the first treatment chosen, especially when a suitable donor is available. After the intensive chemotherapy and/or

bone marrow transplant, children with AML do not go on maintenance; studies have shown that AML children in remission have had as much chemotherapy as their bodies can tolerate, and additional maintenance chemotherapy does not benefit them. Chronic myeloid leukemias. As in AML, intensive chemotherapy and/or BMT are generally employed. Currently (2005), imatinib mesylate (Gleevec) is being studied in clinical trials. Chronic leukemias have three clinical phases: chronic, accelerated, and blast crisis. Prognosis depends on the clinical phase of the disease. Relapsed leukemia. Relapse, or recurrence of leukemia, can occur anytime during therapy or after completion of treatment. Generally, it is more difficult to cure a child after relapse of the leukemia; relapse during or soon after the completion of treatment is considered less favorable than relapse a year or several years after treatment. Treatment depends on the site of relapse, whether it is in the bone marrow, central nervous system, testes, or other locations. Aggressive chemotherapy and radiation treatment, often followed bone marrow transplantation, are used to treat relapse of childhood leukemia.

New Treatments
What's on the horizon for leukemia treatment? The following organization talks about new treatments:

Research updates from the Leukemia and Lymphoma Society

The big news (early 2000s) for the treatment of CML (and Ph+ ALL) is STI-571. Brian Druker (Oregon Health Sciences University in Portland) is the Leukemia and Lymphoma Society doctor prominent in this research.

Gleevec web site

ALL: New ideas for treatmentbys for ALL are also listed on the Clinical Trials for ALL page. In 2004, ara G entered the treatment plans for T-cell ALL. Clofarabine (2005) shows promise for refractory (relapsed) ALL. More information in an essay on your author's private web site:

from sea to ara c

Statistics

Leukemia accounts for approximately 35% of all childhood cancers Approximately 1 in 1000 children will be diagnosed with leukemia by the age of 19 It is more common in children under the age of 10 The five year survival rate for children diagnosed with leukemia and subsequently treated is approximately 70% 2500 cases of leukemia are diagnosed per year in the US

Ped-Onc Resources for Leukemia


The following ped-onc resource lists have appropriate sections for parents of children with leukemia:

childhood cancer e-mail lists - the ACOR ALL-kids list and the general childhood cancer list, ped-onc, are both appropriate support organizations - Leukemia and Lymphoma books and printed materials - leukemias and lymphomas (and don't miss the book for children, I'm Still Me) young people with leukemia - personal home pages Kidz With Leukemia. Computer program for kids. Read my in-depth review for details.

Links to More Information


The following web sites provide good, general information on lymphomas cancers and their treatment.

General Information on Leukemia and Leukemia Research


Leukemia Education Series on the Leukemia and Lymphoma site. A variety of information. Childhood Leukemia Center. This site is the online version of Childhood Leukemia by Nancy Keene (listed above under books). Cancer.gov site. Excellent. MedLine Plus. Links to a lot of useful information. The Leukemia and Lymphoma Society. This US society web site provides good basic information on leukemias. They have booklets to download as pdf files (or to send for), disease descriptions, treatments, patient services, etc. Especially recommended: NewsLine articles Leukaemia and Lymphoma Research. Information on leukemia from this British society. There are a lot of "goodies" on this site, links to reviews as well as good basic information. Leukemia Links: Granny Barb and Art's. This classic site provides useful and informative information with great links. St. Jude's Research Hospital page on Leukemia. This page has information on leukemia and the latest research at St. Jude's. ALL-KIDS web site, the reference site for the ALL-kids mail list. JMML Foundation. Excellent resource, specific for JMML, Juvenile Myelomonocytic Leukemia. Founded by parents, covers all aspects of JMML. AML: Caylee's Hope. Good resources for AML, another parent site. Children's Cancer Web. Links and descriptions of leukemia. Excellent. Medicine Online. Information on leukemia and links to more information. Although this is a dot-com site, it has some good links, and may acquire more good links in the future. I like the atlas of acute leukemia and the leukemia links.

National Children's Leukemia Foundation. Provides a range of services, from help in finding donors to referrals to fundraising.

Technical Information

University of Virginia's site on blood cells - a good tutorial from the University of Virginia. University of Washington REAL classification of leukemia cells, flow cytometry panels, diagnosis of acute leukemia, tdt, descriptions of many diagnostic tests used in leukemia treatment. From the University of Washington, Department of Laboratory Medicine, Hematopathology Laboratory. ASCO online, links to abstracts on pediatric lymphoma and leukemia. ASH: American Society of Hematology. Links to the annual meetings and abstracts and to journals. A good way to follow the latest research in leukemia.

Acute Lymphoblastic Leukemia (ALL)


Acute lymphoblastic leukemia (ALL) is a fast-growing cancer of the white blood cells. Lymphocytes are a type of white blood cell that the body uses to fight infections. In ALL, the bone marrow makes lots of unformed cells called blasts that normally would develop into lymphocytes. However, the blasts are abnormal. They do not develop and cannot fight infections.

The number of abnormal cells (or leukemia cells) grows quickly. They crowd out the normal red blood cells, white blood cells and platelets the body needs.

Acute lymphoblastic leukemia symptoms and diagnosis


There are about 4,000 new cases of ALL in the United States each year. It appears most often in children younger than age 10. ALL is the most common leukemia in children. However, it can appear in people of any age about one-third of cases are adults. Acute lymphoblastic leukemia may also be called acute lymphocytic leukemia or acute lymphoid leukemia.

Signs and symptoms


The symptoms a person with ALL has depend on how many normal blood cells he or she has. Symptoms also depend on how many leukemia cells there are and where they collect in the body.

Red blood cells carry oxygen throughout the body. Low numbers of red blood cells can lead to anemia -- feeling tired or weak, being short of breath and looking pale. White blood cells fight infections. Low numbers of white blood cells can lead to fever and frequent infections that are hard to treat. Platelets control bleeding. Low numbers of platelets can lead to cuts that heal slowly, easy bruising or bleeding and tiny red spots under the skin (petechiae). High numbers of leukemia cells can cause pain in the bones or joints, lack of appetite, headache or vomiting. These symptoms are less common.

Diagnosis
ALL is diagnosed when blood and bone marrow samples show a large number of abnormal lymphocyte blasts. To find out the type of ALL and how well it might respond to treatment, doctors test samples taken from the blood and bone marrow to learn:

The size and number of leukemia cells. The type of lymphocyte affected the leukemia cells can begin from one of two types of lymphocytes, B cells or T cells. What changes appear in the chromosomes of the leukemia cells. This is called cytogenetics.

Doctors also use a test called a lumbar puncture (or spinal tap) to find out whether there are leukemia cells in the fluid around the brain and spinal cord.
Based on these tests, doctors may categorize ALL into one of the following types:

Early pre-B ALL Common ALL Pre-B-cell ALL Mature B-cell ALL (Burkitt leukemia) Pre-T-cell ALL Mature T-cell ALL

The type of ALL is one of several factors doctors use to plan treatment.

reatment options for acute lymphoblastic leukemia


ALL can get worse quickly, so doctors usually begin treatment right away. To plan the treatment, doctors look at a patient's risk factors (also called prognostic factors). Risk factors are patient and disease traits that clinical research studies have linked to better or poorer outcomes from treatment. Examples of risk factors are a patient's age and the type of ALL he or she has. For more details, see Risk Factors for Planning ALL Treatment. For a patient with ALL, the treatment plan may include:

Chemotherapy drugs that destroy cancer cells or stop them from growing (discussed further below). Some form of chemotherapy will be part of the treatment plan for all patients with ALL. Radiation therapy most patients do not receive radiation therapy. However, children who have signs of disease in the central nervous system (brain and spinal cord) or have a high risk of the disease spreading to this area may receive radiation therapy to the brain. Bone marrow or cord blood transplant (also called a BMT) a transplant (discussed further below) offers some patients the best chance for a longterm remission of their disease. Because transplants can have serious risks, this treatment is used for patients who are less likely to reach a long-term remission with chemotherapy alone.

Chemotherapy for acute lymphoblastic leukemia


There are three phases of chemotherapy treatment for ALL: induction, consolidation and maintenance. Many patients also receive treatment called intrathecal chemotherapy to prevent leukemia from spreading to the central nervous system.

Induction chemotherapy
Most patients with ALL are given induction chemotherapy. The goal of induction therapy is to bring the disease into remission. Remission is when the patient's blood counts return to normal and bone marrow samples show no sign of disease. Induction therapy achieves a remission in more than 95% of children and in about 75% to 89% of adults. [1, 2] Induction therapy is usually very intense and lasts about one month. After induction chemotherapy, the next step may be a transplant or consolidation chemotherapy, depending on the treatment plan.

When a patient is diagnosed with ALL, he or she may have 100 billion leukemia cells. If induction therapy destroys at least 99% of these cells, the patient is in remission. However, that could still leave 100 million leukemia cells in the body. If these cells are not destroyed, they can grow and multiply and cause a relapse of the disease.

Consolidation therapy
Consolidation therapy, the second phase of chemotherapy, is also intense. It lasts about four to eight months. The goal of consolidation therapy is to reduce the number of disease cells left in the body. The drugs and doses used during consolidation therapy depend on the patient's risk factors.

Maintenance therapy
If a patient stays in remission after induction and consolidation therapy, maintenance therapy begins. The goal is to destroy any disease cells that remain so that the leukemia is completely gone. Maintenance therapy is less intense than the other two phases. It may last two to three years.

Intrathecal chemotherapy
During all three phases of chemotherapy treatment, many patients receive extra chemotherapy to destroy leukemia cells that may have spread to the central nervous system (the brain and spinal cord). This chemotherapy is injected right into the spinal fluid using a lumbar puncture (spinal tap) or an Omaya reservoir (a device placed under the scalp). It is called intrathecal chemotherapy. Children with ALL who have a high risk of the disease spreading to the central nervous system may receive higher or more frequent doses of intrathecal chemotherapy. Some of these children may also be given radiation therapy to the brain. However, radiation to the brain can cause problems with growth and mental development in children, so doctors try to avoid this treatment.

Chemotherapy success rates for ALL


One way to measure the success of a treatment is tracking how many patients survive five years or more after treatment.

For children, the overall survival rate after chemotherapy is nearly 80%. [3] This includes children with all levels of risk factors. Survival rates are much lower for children with high-risk disease, while children with low-risk disease have even higher rates of survival. For adults, the overall survival rate after chemotherapy is about 40%. [3] This includes adults with all levels of risk factors. For adults with high-risk disease, survival rates are much lower, while survival rates are higher for some adults with low-risk disease.

Relapse
Induction therapy brings about a remission in most patients, but over time some patients relapse. A relapse is when the disease returns after a remission. Patients who relapse after chemotherapy may be treated with different chemotherapy drugs and/or more intense doses. Patients who relapse soon after remission or while they are receiving chemotherapy have high-risk disease. For these patients, chemotherapy is less likely to achieve a long-term remission, but a bone marrow or cord blood transplant may be effective.

Bone marrow or cord blood transplant for acute lymphoblastic leukemia


For some patients, a bone marrow or cord blood transplant may offer the best chance for a long-term remission. A transplant is a strong treatment with risks of serious side effects, so it is not used for all patients with ALL. Transplants are used when chemotherapy alone is unlikely to provide a long-term remission.

Allogeneic transplants for ALL


Most transplants for ALL are allogeneic. An allogeneic transplant replaces the abnormal cells in the patient's bone marrow with healthy blood-forming cells from a family member, unrelated donor or cord blood unit. Patients may receive an allogeneic transplant at a first remission, in second or third remission after a relapse, or while the disease is active if they do not reach remission. The state of the patient's disease at the time of the transplant can affect the likelihood of a good outcome. In addition, the closeness of the donor match can affect transplant outcomes. In general, transplants in first remission have a better chance of a good outcome than transplants received later or when the disease is not in remission. A large study of more than 1,900 ALL patients showed that allogeneic transplantation with a sibling donor is the best treatment for adults with standard-risk ALL in remission. [4]

Autologous transplants for ALL


Another option for some patients may be an autologous transplant, which uses the patient's own blood-forming cells. Autologous transplants have risks of serious side effects, but these risks are lower than for allogeneic transplants. However, patients have a higher risk of relapse of their leukemia after autologous transplants. This is because leukemia cells may be returned to the patient along with his or her bloodforming cells.

Transplant success rates


Transplants have risks of serious complications, but a transplant offers some patients the best chance for a cure of their disease. If transplant is an option for you, your doctor can talk with you about your risks and your chances of a cure with transplant. For statistics showing patients' results after transplant, see ALL transplant outcomes data.

Making treatment decisions


ALL is an acute disease that can get worse quickly. If transplant may be a treatment option for you, talk with your doctor about a consultation with a transplant doctor soon after diagnosis. Getting a transplant at the right time in the course of your disease may offer the best chance of a cure. In general, getting a transplant at first remission gives better outcomes than transplants after one or more relapses. However, the possible benefits need to be weighed against the risks of transplant and the possible risks and benefits of chemotherapy. For patients with high-risk ALL, an allogeneic transplant may be an option as soon as the patient reaches remission. (For factors considered high-risk, see Risk Factors for Planning ALL Treatment.) For patients with standard-risk ALL in first remission, the choice between allogeneic transplant, autologous transplant and continued chemotherapy is less clear. It is important to talk about your treatment options with a doctor who is experienced in treating ALL. Your doctor can discuss your specific risk factors and options with you. If you want more information to help you talk to your doctor about whether and when a transplant may be an option for you, you can share the referral guidelines (PDF) from the Physician Resources section of this Web site with your doctor.

cute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL may be distinguished from other malignant lymphoid disorders by the immunophenotype of the cells, which is similar to B- or T-precursor cells. Immunochemistry, cytochemistry, and cytogenetic markers may also aid in categorizing the malignant lymphoid clone. The image below shows preB-cell ALL.

Diagnostic workup of a patient with preB-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology.