lymphoblastic lymphoma

リンパ芽球性リンパ腫 LL

WordNet

1. a neoplasm of lymph tissue that is usually malignant; one of the four major types of cancer
2. an immature lymphocyte

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2018/03/20 20:08:58」(JST)

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Acute lymphoblastic leukemia
Synonyms	Acute lymphocytic leukemia, acute lymphoid leukemia
Bone marrow aspirate smear from a person with precursor B-cell ALL. The large purple cells are lymphoblasts.
Specialty	Hematology, oncology
Symptoms	Feeling tired, pale color, fever, easy bleeding or bruising, bone pain, enlarged lymph nodes
Complications	Infection, tumor lysis syndrome
Usual onset	2–5 years old
Types	B-cell ALL, T-cell ALL
Causes	Usually unknown
Risk factors	Identical twin with ALL, Down syndrome, Fanconi anemia, ataxia telangiectasia, Klinefelter syndrome, high birth weight, significant radiation exposure
Diagnostic method	Blood tests and bone marrow examination
Similar conditions	Infectious mononucleosis, acute myeloid leukemia, lymphoblastic lymphoma, aplastic anemia
Treatment	Chemotherapy, stem cell transplantation, radiation therapy, targeted therapy
Prognosis	Children: 90% five-year survival rate Adults: 35% five-year survival
Frequency	1 in 1,750 children
Deaths	111,000 (2015)

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.

Most cases occur due to an unknown reason. Genetic risk factors may include Down syndrome, Li-Fraumeni syndrome, or neurofibromatosis type 1. Environment risk factors may include significant radiation exposure or prior chemotherapy. Evidence regarding electromagnetic fields or pesticides is unclear. Some hypothesize that an abnormal immune response to a common infection may be a trigger. The underlying mechanism involves multiple genetic mutations that results in rapid cell division. The excessive immature lymphocytes in the bone marrow interfere with the production of new red blood cells, white blood cells, and platelets. Diagnosis is typically based on blood tests and bone marrow examination.

ALL is typically treated initially with chemotherapy aimed at bringing about remission. This is then followed by further chemotherapy typically over a number of years. Additional treatments may include intrathecal chemotherapy or radiation therapy if spread to the brain has occurred. Stem cell transplantation may be used if the disease recurs following standard treatment. Additional treatments such as immunotherapy are being studied.

ALL affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths. It occurs most commonly in children, particularly those between the ages of two and five. In the United States it is the most common cause of cancer and death from cancer among children. ALL is notable for being the first disseminated cancer to be cured. Survival for children increased from under 10% in the 1960s to 90% in 2015. Survival rates remain lower for babies (50%) and adults (35%).

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An explanation of acute myeloid and lymphoblastic leukemia

Signs and symptoms

Initial symptoms can be nonspecific, particularly in children. Over 50% of children with leukemia had one or more of five features: a liver one can feel (64%), a spleen one can feel (61%), pale complexion (54%), fever (53%), and bruising (52%). Additionally, recurrent infections, feeling tired, arm or leg pain, and enlarged lymph nodes can be prominent features. The B symptoms, such as fever, night sweats, and weight loss, are often present as well.

Central nervous system (CNS) symptoms such cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature B-cell ALL (Burkitt leukemia) at presentation.

The signs and symptoms of ALL are variable and include:

• Generalized weakness and feeling tired
• Anemia
• Dizziness
• Headache, vomiting, lethargy, nuchal rigidity, or cranial nerve palsies (CNS involvement)
• 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
• Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
• Testicular enlargement
• Mediastinal mass

Cause

In ALL, lymphoid cell development stops at the lymphoblast (arrow), which are also overproduced

The cancerous cell in ALL is the lymphoblast. Normal lymphoblasts develop into mature, infection-fighting B-cells or T-cells, also called lymphocytes. Signals in the body control the number of lymphocytes so neither too few nor too many are made. In ALL, both the normal development of some lymphocytes and the control over the number of lymphoid cells become defective.

ALL emerges when a single lymphoblast gains many mutations to genes that affect blood cell development and proliferation. In childhood ALL, this process begins at conception with the inheritance of some of these genes. These genes, in turn, increase the risk that more mutations will occur in developing lymphoid cells. Certain genetic syndromes, like Down Syndrome, have the same effect. Environmental risk factors are also needed to help create enough genetic mutations to cause disease. Evidence for the role of the environment is seen in childhood ALL among twins, where only 10–15% of both genetically identical twins get ALL. Since they have the same genes, different environmental exposures explain why one twin gets ALL and the other does not.

Infant ALL is a rare variant that occurs in babies less than one year old. KMT2A (formerly MLL) gene rearrangements are most common and occur in the embryo or fetus before birth. These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes. In contrast to childhood ALL, environmental factors are not thought to play a significant role. Aside from the KMT2A rearrangement, only one extra mutation is typically found. Environmental exposures are not needed to help create more mutations.

Risk factors

Genetic risk factors

Common inherited risk factors include mutations in ARID5B, CDKN2A/2B, CEBPE, IKZF1, GATA3, PIP4K2A and, more rarely, TP53. These genes play important roles in cellular development, proliferation, and differentiation. Individually, most of these mutations are low risk for ALL. Significant risk of disease occurs when a person inherits several of these mutations together.

The uneven distribution of genetic risk factors may help explain differences in disease rate among ethnic groups. For instance, the ARID5B mutation is less common in ethnic African populations.

Several genetic syndrome also carry increased risk of ALL. These include: Down syndrome, Fanconi anemia, Bloom syndrome, X-linked agammaglobulinemia, severe combined immunodeficiency, Shwachman-Diamond syndrome, Kostmann syndrome, neurofibromatosis type 1, ataxia-telangiectasia, paroxysmal nocturnal hemoglobinuria, and Li-Fraumeni syndrome. Fewer than 5% of cases are associated with a known genetic syndrome.

Rare mutations in ETV6 and PAX5 are associated with a familial form of ALL with autosomal dominant patterns of inheritance.

Environmental risk factors

The environmental exposures that contribute to emergence of ALL is contentious and a subject of ongoing debate.

High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia. Evidence whether less radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive. Studies that have identified an association between x-ray imaging during pregnancy and ALL found only a slightly increased risk. Exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased risk of ALL. This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known.

High birth weight (greater than 4000g or 8.8lbs) is also associated with a small increased risk. The mechanism connecting high birth weight to ALL is also not known.

Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide.

Delayed infection hypothesis

There is some evidence that a common infection, such as influenza, may indirectly promote emergence of ALL. The delayed-infection hypothesis states that ALL results from an abnormal immune response to infection in a person with genetic risk factors. Delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness. Several studies have identified lower rates of ALL among children with greater exposure to illness early in life. Very young children who attend daycare have lower rates of ALL. Evidence from many other studies looking at disease exposure and ALL is inconclusive.

Mechanism

Several characteristic genetic changes lead to the creation of a leukemic lymphoblast. These changes include chromosomal translocations, intrachromosomal rearrangements, changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. Chromosomal translocations involve moving a large region of DNA from one chromosome to another. This move can result in placing a gene from one chromosome that promotes cell division to a more actively transcribed area on another chromosome. The result is a cell that divides more often. An example of this includes the translocation of C-MYC, a gene that encodes a transcription factor that leads to increased cell division, next to the immunoglobulin heavy- or light-chain gene enhancers, leading to increased C-MYC expression and increased cell division. Other large changes in chromosomal structure can result in placement of two genes directly next to each other. The result is the combination of two usually separate proteins into a new fusion protein. This protein can have a new function that promotes the development of cancer. Examples of this include the ETV6-RUNX1 fusion gene that combines two factors that promote blood cell development and the BCR-ABL1 fusion gene of the Philadelphia chromosome. BCR-ABL1 encodes an always-activated tyrosine kinase that causes frequent cell division. These mutations produce a cell that divides more often, even in the absence of growth factors.

Other genetic changes in B-cell ALL include changes to the number of chromosomes within the leukemic cells. Gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly. Less often, chromosomes are lost, called hypodiploidy, which is associated with a poorer prognosis. Additional common genetic changes in B-cell ALL involve non-inherited mutations to PAX5 and IKZF1. In T-cell ALL, LYL1, TAL1, TLX1, and TLX3 rearrangements can occur.

ALL results when enough of these genetic changes are present in a single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes. The initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes, the mediastinum, the spleen, the testicles, and the brain, leading to the common symptoms of disease.

Diagnosis

Diagnosing ALL begins with a thorough medical history, physical examination, complete blood count, and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and exam are not specific to ALL, further testing is often needed. A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically points to a worse prognosis. While white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral blood smears in the majority of cases.

A bone marrow biopsy provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts. A lumbar puncture (also known as a spinal tap) can determine whether the spinal column and brain have been invaded. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests.

Pathological examination, cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether the leukemic cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes). Cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be. 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, whereas 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.

• 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

Immunophenotyping

In addition to cell morphology and cytogenetics, immunophenotyping, a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of immunophenotyping is through flow cytometry. In the malignant lymphoblasts of ALL, expression of terminal deoxynucleotidyl transferase (TdT) on the cell surface can help differentiate malignant lymphocyte cells from reactive lymphocytes, white blood cells that are reacting normally to an infection in the body. On the other hand, myeloperoxidase (MPO), a marker for the myeloid lineage, is typically not expressed. Because precursor B cell and precursor T cells look the same, immunophenotyping can help differentiate the subtype of ALL and the level of maturity of the malignant white blood cells. The subtypes of ALL as determined by immunophenotype and according to the stages of maturation.

B cell Lineage	T cell Lineage
pre-pre-B ALL (pro-B-ALL)	precursor T- ALL
common ALL	mature T-cell ALL
pre-B ALL
mature B-cell ALL (Burkitt leukemia - FAB L3)

An extensive panel of monoclonal antibodies to cell surface markers, particularly CD or cluster of differentiation markers, are used to classify cells by lineage. Below are immunological markers associated with B cell and T cell ALL.

Immunological Markers	B cell Lineage	T cell Lineage
B cell Lineage
CD19, CD22, CD79a	+	-
CD10	- or + (common ALL)
cytoplasmic Ig	- or + (pre-B ALL)
surface Ig	- or + (mature B-cell ALL)
TdT	+	+
T cell Lineage
CD2, CD3, CD4, CD5, CD7, CD8	-	+
TdT	+	+

Cytogenetics

Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information is particularly valuable for classification and can in part explain different prognosis of these groups. In regards to genetic analysis, cases can be stratified according to ploidy, number of sets of chromosomes in the cell, and specific genetic abnormalities, such as translocations. Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid is defined as cells with less than 44 choromosomes. Hyperdiploid cases tend to carry good prognosis while hypodiploid cases do not. For example, the most common specific abnormality in childhood B-ALL is the t(12;21) ETV6-RUNX1 translocation, in which the RUNX1 gene, encoding a protein involved in transcriptional control of hemopoiesis, has been translocated and repressed by the ETV6-RUNX1 fusion protein.

Below is a table with the frequencies of some cytogenetic translocations and molecular genetic abnormalities in ALL.

Cytogenetic translocation	Molecular genetic abnormality	%
cryptic t(12;21)	TEL–AML1 fusion	25.4%
t(1;19)(q23;p13)	E2A–PBX (PBX1) fusion	4.8%
t(9;22)(q34;q11)	BCR-ABL fusion(P185)	1.6%
t(4;11)(q21;q23)	MLL–AF4 fusion	1.6%
t(8;14)(q24;q32)	IGH-MYC fusion
t(11;14)(p13;q11)	TCR–RBTN2 fusion

Classification

French-American-British

Historically, prior to 2008, ALL was classified morphologically using the French-American-British (FAB) system that heavily relied on morphological assessment. The FAB system takes into account information on size, cytoplasm, nucleoli, basophilia (color of cytoplasm), and vacuolation (bubble-like properties).

FAB Subtype	Cell Type	Characteristics	Comments
ALL - L1	T cell or pre-B cell	Small and homogeneous (uniform) cells
ALL - L2	T cell or pre-B cell	Large and heterogeneous (varied) cells
ALL - L3	B cell	Large and varied cells with vacuoles	Mature B-cell ALL also named Burkitt leukemia. Typically, poor prognosi with standard therapy

While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of limited impact on treatment choice and prognostic value.

World Health Organization

In 2008, the World Health Organization classification of acute lymphoblastic leukemia was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions. This system recognized differences in genetic, immunophenotype, molecular, and morphological features found through cytogeneticand molecular diagnostics tests. This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.

The WHO subtypes related to ALL are:

• B-lymphoblastic leukemia/lymphoma
  • Not otherwise specified (NOS)
  • with recurrent genetic abnormalities
  • with t(9;22)(q34.1;q11.2);BCR-ABL1
  • with t(v;11q23.3);KMT2A rearranged
  • with t(12;21)(p13.2;q22.1); ETV6-RUNX1
  • with t(5;14)(q31.1;q32.3) IL3-IGH
  • with t(1;19)(q23;p13.3);TCF3-PBX1
  • with hyperdiploidy
  • with hypodiploidy
• T-lymphoblastic leukemia/lymphoma
• Acute leukemias of ambiguous lineage
  • Acute undifferentiated leukemia
  • Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
  • MPAL with t(v;11q23.3); KMT2A rearranged
  • MPAL, B/myeloid, NOS
  • MPAL, T/myeloid, NOS

Treatment

Two girls with ALL demonstrating intravenous access for chemotherapy

The aim of treatment is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow).

Over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. Possible treatments for acute leukemia include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and/or growth factors.

Chemotherapy

Chemotherapy is the initial treatment of choice, and most ALL patients receive a combination of medications. There are no surgical options because of the body-wide distribution of the malignant cells. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs tailored to each patient. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.

Phase	Description	Agents
Remission induction	Aim to: Rapidly kill most tumor cells Reduce leukemic blasts in the bone marrow to <5% and eliminate tumor cells from blood Induce absence of other signs and symptoms of the disease. Must monitor closely for tumor lysis syndrome after initiating therapy Monitoring initial response to treatment is important as failure to show clearance of blood or bone marrow blasts within the first 2 weeks of therapy has been associated with higher risk of relapse May need to intensify treatment if remission is not induced Start CNS prophylaxis and administer intrathecal chemotherapy via Ommaya reservoir or multiple lumbar punctures	Combination of: steroids - prednisolone or dexamethasone vincristine asparaginase (better tolerance in pediatric patients) daunorubicin (used in Adult ALL) Central nervous system prophylaxis can be achieved via: cranio-spinal irradiation cytarabine + methotrexate or liposomal cytarabine In Philadelphia chromosome-positive ALL, the intensity of initial induction treatment may be less than has been traditionally given.
Consolidation/intensification	Use high doses of chemotherapy to further reduce tumor burden	Typical protocols use the following given as blocks (varies from 1-3 blocks depending on patient's risk category) in different multi-drug combinations: vincristine cyclophosphamide cytarabine daunorubicin etoposide thioguanine mercaptopurine Central nervous system relapse is treated with intrathecal administration of hydrocortisone, methotrexate, and cytarabine.
Maintenance therapy	Kill any residual cell that was not killed by remission induction and intensification regimens Can sometimes start immediately after remission induction and be interrupted by bursts of consolidation/intensification therapy Although such residual cells are few, they will cause relapse if not eradicated Length of maintenance therapy is 3 years for boys, 2 years for girls and adults	Typical protocol would include: daily oral mercaptopurine weekly oral methotrexate monthly 5-day course of intravenous vincristine and oral corticosteroids

Due to presence of CNS involvement in 10–40% of adult patients at diagnosis, most providers start Central nervous system (CNS) prophylaxis and treatment during the induction phase, and continue it during the consolidation/intensification period.

Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. It should be known that 2 subtypes of ALL (B-cell ALL and T-cell ALL) require special considerations when it comes to selecting an appropriate treatment regimen in adult patients. B-cell ALL is often associated with cytogenetic abnormalities (specifically, t(8;14), t (2;8) and t(8;22)), which require aggressive therapy consisting of brief, high-intensity regimens. T-cell ALL responds to cyclophosphamide-containing agents the most.

As the chemotherapy regimens can be intensive and protracted, many patients have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath, usually placed near the collar bone, for lower infection risks and the long-term viability of the device.

Males usually endure a longer course of treatment than females as the testicles can act as a reservoir for the cancer.

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). In the past, physicians commonly utilized radiation in the form of whole-brain radiation for central nervous system prophylaxis, to prevent occurrence and/or recurrence of leukemia in the brain. 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 of radiation therapy for CNS prophylaxis, instead using intrathecal chemotherapy.

Biological therapy

Selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment. Tyrosine-kinase inhibitors (TKIs), such as imatinib, are often incorporated into the treatment plan for patients with Bcr-Abl1+ (Ph+) ALL. However, this subtype of ALL is frequently resistant to the combination of chemotherapy and TKIs and allogeneic stem cell transplantation is often recommended upon relapse.

Blinatumomab, a CD19-CD3 bi-specific monoclonal murine antibody, currently shows promise as a novel pharmacotherapy. By engaging the CD3 T-cell with the CD19 receptor on B cells, it triggers a response to induce the release of inflammatory cytokines, cytotoxic proteins and proliferation of T cells to kill CD19 B cells.

Immunotherapy

Chimeric antigen receptors (CARs) have been developed as a promising immunotherapy for ALL. This technology uses a single chain variable fragment (scFv) designed to recognize the cell surface marker CD19 as a method of treating ALL.

CD19 is a molecule found on all B-cells and can be used as a means of distinguishing the potentially malignant B-cell population. In this therapy, mice are immunized with the CD19 antigen and produce anti-CD19 antibodies. Hybridomas developed from mouse spleen cells fused to a myeloma cell line can be developed as a source for the cDNA encoding the CD19 specific antibody. The cDNA is sequenced and the sequence encoding the variable heavy and variable light chains of these antibodies are cloned together using a small peptide linker. This resulting sequence encodes the scFv. This can be cloned into a transgene, encoding what will become the endodomain of the CAR. Varying arrangements of subunits serve as the endodomain, but they generally consist of the hinge region that attaches to the scFv, a transmembrane region, the intracellular region of a costimulatory molecule such as CD28, and the intracellular domain of CD3-zeta containing ITAM repeats. Other sequences frequently included are: 4-1bb and OX40. The final transgene sequence, containing the scFv and endodomain sequences is then inserted into immune effector cells that are obtained from the patient and expanded in vitro. In trials these have been a type of T-cell capable of cytotoxicity.

Inserting the DNA into the effector cell can be accomplished by several methods. Most commonly, this is done using a lentivirus that encodes the transgene. Pseudotyped, self-inactivating lentiviruses are an effective method for the stable insertion of a desired transgene into the target cell. Other methods include electroporation and transfection, but these are limited in their efficacy as transgene expression diminishes over time.

The gene-modified effector cells are then transplanted back into the patient. Typically this process is done in conjunction with a conditioning regimen such as cyclophosphamide, which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to making an immunologic space within which the cells populate. The process as a whole results in an effector cell, typically a T-cell, that can recognize a tumor cell antigen in a manner that is independent of the major histocompatibility complex and which can initiate a cytotoxic response.

In 2017 tisagenlecleucel was approved by the FDA as a CAR-T therapy for acute B-cell lymphoblastic leukaemia patients who did not respond adequately to other treatments or have relapsed. In a 22-day process, the "drug" is customized for each patient. T cells purified from each patient are modified by a virus that inserts genes that encode a chimaeric antigen receptor into their DNA, one that recognizes leukemia cells.

Relapsed ALL

Typically, people who experience a relapse in their ALL after initial treatment have a poorer prognosis than those who remain in complete remission after induction therapy. It is unlikely that the recurrent leukemia will respond favorably to the standard chemotherapy regimen that was initially implemented, and instead these patients should be trialed on reinduction chemotherapy followed by allogeniec bone marrow transplantation. These patients in relapse may also receive blinatumomab, as it has shown to increase remission rates and overall survival rates, without increased toxic effects.

Low dose palliative radiation may also help reduce the burden of tumor inside or outside the central nervous system and alleviate some symptoms.

Recently, there has also been evidence and approval of use for dasatinib, a tyrosine kinase inhibitor. It has shown efficacy in cases of patients with Ph1-positive and imatinib-resistant ALL, but more research needs to be done on long term survival and time to relapse.

Prognosis

Prior to the development of chemotherapy regimens and hematopoietic stem cell transplant, children were surviving a median length of 3 months, largely due to either infection or bleeding. Since the advent of chemotherapy, prognosis for childhood leukemia has improved greatly and children with ALL are estimated to have a 95% probability of achieving a successful remission after 4 weeks of initiating treatment. Pediatric patients with ALL in developed countries have a greater than 80% five-year-survival rate. It is estimated that 60–80% of adults undergoing induction chemotherapy achieve complete remission after 4 weeks, and those over the age of 70 have a cure rate of 5%.

Graphs of overall survival rates at 5 years and 10 years in pediatric and adult ALL patients

However, there are differing prognoses for ALL among individuals depending on a variety of factors:

• Gender: Females tend to fare better than males.
• Ethnicity: Caucasians are more likely to develop acute leukemia than African-Americans, Asians, or Hispanics. However, they also tend to have a better prognosis than non-Caucasians.
• Age at diagnosis: children 1–10 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. Older patients are also likely to have co-morbid medical conditions that make it even more difficult to tolerate ALL treatment.
• White blood cell count at diagnosis of greater than 30,000 (B-ALL) or 100,000 (T-ALL) is associated with worse outcomes
• Cancer spreading into the Central nervous system (brain or spinal cord) has worse outcomes.
• Morphological, immunological, and genetic subtypes
• Patient's response to initial treatment and longer length of time required (greater than 4 weeks) to reach complete remission
• Early relapse of ALL
• Minimal residual disease
• Genetic disorders, such as Down syndrome, and other chromosomal abnormalities (aneuoploidy and translocations)

In children

Factor	Unfavorable	Favorable
Age	<2 or >10 years	3–5 years
Sex	Male	Female
Race	Black	Caucasian
Organomegaly	Present	Absent
Mediastinal mass	Present	Absent
CVS involvement	Present	Absent
Leukocyte count	B-ALL >30,000mm3 T-ALL >100,000mm3	Low
Hemogblobin concentration	>10g/dl	<10g/dl
Cell type	Non Lymphoid	Lymphoid
Cell lineage	Pre B cell + T-ALL (children)	Early Pre B cell
Karyotype	Translocation	Hyperdiploidy
Response to treatment	Slow >1 week to clear blasts from blood	Rapid <1 week to clear blasts from blood
Time to remission	>4 weeks	<4 weeks
Minimal residual disease	Negative at 1 month (children) or 3 months (adults)	Positive at 3–6 months

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

• Patients with t(9,22) positive-ALL (30% of adult ALL cases) and other Bcr-abl-rearranged leukemias are more likely to have a poor prognosis, but survival rates may rise with treatment consisting of chemotherapy and Bcr-abl tyrosine kinase inhibitors.
• A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.

Cytogenetic change	Risk category
Philadelphia chromosome	Poor prognosis
t(4;11)(q21;q23)	Poor prognosis
t(8;14)(q24.1;q32)	Poor prognosis
Complex karyotype (more than four abnormalities)	Poor prognosis
Low hypodiploidy or near triploidy	Poor prognosis
Deletion of chromosome 7	Poor prognosis
Trisomy 8	Poor prognosis
High hyperdiploidy (trisomy 4, 10, 17)	Good prognosis
del(9p)	Good prognosis

• Hyperdiploidy (>50 chromosomes) and t(12;21) are good prognostic factors and also make up 50% of pediatric ALL cases.

Based on bone marrow cytogenetics

Prognosis	Cytogenetic findings
Favorable	Hyperdiploidy > 50 ; t (12;21)
Intermediate	Hyperdiploidy 47–50; Normal(diploidy); del (6q); Rearrangements of 8q24
Unfavorable	Hypodiploidy-near haploidy; Near tetraploidy; del (17p); t (9;22); t (11q23)

Unclassified ALL is considered to have an intermediate prognosis risk, somewhere in-between the good and poor risk categories.

Epidemiology

Acute lymphoblastic leukemia affected about 876,000 people and resulted in 111,000 deaths globally in 2015. It occurs in both children and adults with highest rates seen between the ages three and seven years. Around 75% of cases occur before the age of 6 with a secondary rise after the age of 40. It is estimated to affect 1 in 1500 children.

Accounting for the broad age profiles of those affected, ALL newly occurs in about 1.7 per 100,000 people per year. ALL represents approximately 20% of adult and 80% of childhood leukemias, making it the most common childhood cancer. Although 80 to 90% of children will have a long term complete response with treatment, it remains the leading cause of cancer-related deaths among children. 85% of cases are of B-cell lineage and have equal incidences in both males and females. The remaining 15% of T-cell lineage have a male predominance.

Globally ALL, typically occurs more often in Caucasians, Hispanics, and Latin Americans than in Africans. In the US, ALL is more common in children from Caucasian (36 cases/million) and Hispanic (41 cases/million) descent when compared to those from African (15 cases/million) descent.

Pregnancy

Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. The management of leukemia in a pregnant patient depends primarily on the type of leukemia. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester.

External links

Classification	V · T · D ICD-10: C91.0 ICD-9-CM: 204.0 MeSH: D054198 DiseasesDB: 195
External resources	eMedicine: med/3146 ped/2587

• Acute Lymphocytic Leukemia at American Cancer Society
• Childhood ALL Treatment at National Cancer Institute

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• 1. 前駆T細胞性急性リンパ芽球性白血病／リンパ腫の臨床症状、病理学的特徴、および診断 clinical manifestations pathologic features and diagnosis of precursor t cell acute lymphoblastic leukemia lymphoma
• 2. 前駆B細胞性急性リンパ芽球性白血病／リンパ腫の臨床症状、病理学的特徴、および診断 clinical manifestations pathologic features and diagnosis of precursor b cell acute lymphoblastic leukemia lymphoma
• 3. 小児および思春期の非ホジキンリンパ腫の概要 overview of non hodgkin lymphoma in children and adolescents
• 4. 非ホジキンリンパ腫の病理の概要 overview of the pathobiology of the non hodgkin lymphomas
• 5. マントル細胞リンパ腫の臨床症状、病理学的特徴、および診断 clinical manifestations pathologic features and diagnosis of mantle cell lymphoma

English Journal

• Indolent T-lymphoblastic Proliferation With Disseminated Multinodal Involvement and Partial CD33 Expression.

• Ohgami RS1, Sendamarai AK, Atwater SK, Liedtke M, Fleming MD, Natkunam Y, Warnke RA.
• The American journal of surgical pathology.Am J Surg Pathol.2014 Sep;38(9):1298-304. doi: 10.1097/PAS.0000000000000197.
• Although indolent T-lymphoblastic proliferations (iT-LBP) are rare, this diagnosis should be excluded in any patient with an extrathymic proliferation of immature TdT+T cells. Unlike T-lymphoblastic leukemia/lymphoma, patients with iT-LBP do not require chemotherapy. We report a case of iT-LBP with
• PMID 24618611

• High sensitivity of flow cytometry improves detection of occult leptomeningeal disease in acute lymphoblastic leukemia and lymphoblastic lymphoma.

• Del Principe MI1, Buccisano F, Cefalo M, Maurillo L, Di Caprio L, Di Piazza F, Sarlo C, De Angelis G, Irno Consalvo M, Fraboni D, De Santis G, Ditto C, Postorino M, Sconocchia G, Del Poeta G, Amadori S, Venditti A.
• Annals of hematology.Ann Hematol.2014 Sep;93(9):1509-13. doi: 10.1007/s00277-014-2080-6. Epub 2014 Apr 22.
• Conventional cytology (CC) of cerebrospinal fluid (CSF) fails to demonstrate malignant cells in up to 45 % of patients with acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL/LL) in whom occult leptomeningeal disease is present. Flow cytometry (FCM) is considered more sensitive than CC, bu
• PMID 24752416

• Influence of pulsed electromagnetic and pulsed vector magnetic potential field on the growth of tumor cells.

• Loja T1, Stehlikova O, Palko L, Vrba K, Rampl I, Klabusay M.
• Electromagnetic biology and medicine.Electromagn Biol Med.2014 Sep;33(3):190-7. doi: 10.3109/15368378.2013.800104. Epub 2013 Jun 19.
• Abstract Aims and Background: Tumor diseases cause 20% of deaths in Europe and they are the second most common cause of death and morbidity after cardiovascular diseases. Thus, tumor cells are target of many therapeutic strategies and tumor research is focused on searching more efficient and specifi
• PMID 23781986

Japanese Journal

• 嚢胞状陰影を呈した中縦隔悪性リンパ腫の1例

• 丸井 努,後藤 英子,長谷川 貴昭,二村 洋平,堀場 あかね,石黒 崇,吉田 勉,澤 祥幸
• 気管支学 : 日本気管支研究会雑誌 34(6), 594-598, 2012-11-25
• 背景.嚢胞状陰影を呈する縦隔悪性リンパ腫は稀である.今回,嚢胞状陰影を呈し中縦隔に発生した悪性リンパ腫の1例を経験したので報告する.症例. 37歳男性.前胸部痛,発熱を主訴に受診した.胸部造影CT検査にて甲状腺左葉に嚢胞性病変,及び中縦隔に腫瘍を認めた.中縦隔の腫瘍は5.3×3.8×5.1cm大の比較的均一に造影効果のある軟部組織で,内部に境界明瞭な分葉状の嚢胞成分を含んでいた.また, ^< …
• NAID 110009562567

• リンパ系腫瘍 : 造血器腫瘍の新展開 : WHO分類第4版

• 東田 修二
• 臨床病理 60(6), 560-564, 2012-06-25
• NAID 10030990548

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★リンクテーブル★

リンク元	「adult acute lymphoblastic leukemia」「childhood ALL」「L1 acute lymphocytic leukemia」「L2 acute lymphocytic leukemia」「L2 acute lymphoblastic leukemia」
拡張検索	「large-cell lymphoblastic lymphoma」「precursor B-lymphoblastic lymphoma」
関連記事	「lymphoblastic」「lymphoblast」

「adult acute lymphoblastic leukemia」

　　[★]

成人急性リンパ性白血病、成人急性リンパ芽球性白血病

関

acute lymphoblastic leukemia、acute lymphocytic leukemia、acute lymphoid leukemia、adult acute lymphocytic leukemia、childhood acute lymphoblastic leukemia、childhood ALL、L1 acute lymphocytic leukemia、L2 acute lymphoblastic leukemia、L2 acute lymphocytic leukemia、lymphoblastic leukemia、lymphoblastic lymphoma、precursor cell lymphoblastic leukemia-lymphoma

「childhood ALL」

　　[★]

小児急性リンパ性白血病

関

acute lymphoblastic leukemia、acute lymphocytic leukemia、acute lymphoid leukemia、adult acute lymphoblastic leukemia、childhood acute lymphoblastic leukemia、L1 acute lymphocytic leukemia、L2 acute lymphoblastic leukemia、L2 acute lymphocytic leukemia、lymphoblastic leukemia、lymphoblastic lymphoma、precursor cell lymphoblastic leukemia-lymphoma

「L1 acute lymphocytic leukemia」

　　[★]

L1型急性リンパ性白血病

関

acute lymphoblastic leukemia、acute lymphocytic leukemia、acute lymphoid leukemia、adult acute lymphoblastic leukemia、childhood acute lymphoblastic leukemia、childhood ALL、L2 acute lymphoblastic leukemia、L2 acute lymphocytic leukemia、lymphoblastic leukemia、lymphoblastic lymphoma、precursor cell lymphoblastic leukemia-lymphoma

「L2 acute lymphocytic leukemia」

　　[★]

L2型急性リンパ性白血病

関

acute lymphoblastic leukemia、acute lymphocytic leukemia、acute lymphoid leukemia、adult acute lymphoblastic leukemia、childhood acute lymphoblastic leukemia、childhood ALL、L1 acute lymphocytic leukemia、L2 acute lymphoblastic leukemia、lymphoblastic leukemia、lymphoblastic lymphoma、precursor cell lymphoblastic leukemia-lymphoma

「L2 acute lymphoblastic leukemia」

　　[★]

• L2型急性リンパ性白血病

関

acute lymphoblastic leukemia、acute lymphocytic leukemia、acute lymphoid leukemia、adult acute lymphoblastic leukemia、childhood acute lymphoblastic leukemia、childhood ALL、L1 acute lymphocytic leukemia、L2 acute lymphocytic leukemia、lymphoblastic leukemia、lymphoblastic lymphoma、precursor cell lymphoblastic leukemia-lymphoma

「large-cell lymphoblastic lymphoma」

　　[★]

大細胞型リンパ芽球性リンパ腫

「precursor B-lymphoblastic lymphoma」

　　[★]

前駆Bリンパ芽球性リンパ腫

「lymphoblastic」

　　[★]

• adj.

• リンパ芽球性の、リンパ芽球の

関

lymphoblast

「lymphoblast」

　　[★]

• リンパ芽球、リンパ芽球細胞

関

lymphoblastic