ALL



Banking, Investing, Professional Loans & Auto Finance | Ally

Fetch File Transfer Protocol Whether it's banking, investing, credit card, Commercial loans or auto finance, nothing stops us from doing right by you. Ally. Do It Right.

Acute lymphoblastic leukemia - Wikipedia

Jump to navigation Jump to search

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes.[1] Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain.[1] As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.[10]

In most cases, the cause is unknown.[2] Genetic risk factors may include Down syndrome, Li-Fraumeni syndrome, or neurofibromatosis type 1.[1] Environment risk factors may include significant radiation exposure or prior chemotherapy.[1] Evidence regarding electromagnetic fields or pesticides is unclear.[4][6] Some hypothesize that an abnormal immune response to a common infection may be a trigger.[4] The underlying mechanism involves multiple genetic mutations that results in rapid cell division.[2] The excessive immature lymphocytes in the bone marrow interfere with the production of new red blood cells, white blood cells, and platelets.[1] Diagnosis is typically based on blood tests and bone marrow examination.[3]

ALL is typically treated initially with chemotherapy aimed at bringing about remission.[2] This is then followed by further chemotherapy typically over a number of years.[2] Additional treatments may include intrathecal chemotherapy or radiation therapy if spread to the brain has occurred.[2]Stem cell transplantation may be used if the disease recurs following standard treatment.[2] Additional treatments such as immunotherapy are being studied.[2]

ALL affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths.[11][9] It occurs most commonly in children, particularly those between the ages of two and five.[12][4] In the United States it is the most common cause of cancer and death from cancer among children.[2] ALL is notable for being the first disseminated cancer to be cured.[13] Survival for children increased from under 10% in the 1960s to 90% in 2015.[2] Survival rates remain lower for babies (50%)[14] and adults (35%).[7]

Contents
  • 1 Signs and symptoms
  • 2 Cause
  • 2.1 Risk factors
  • 2.1.1 Genetic risk factors
  • 2.1.2 Environmental risk factors
  • 2.1.2.1 Delayed infection hypothesis
  • 3 Mechanism
  • 4 Diagnosis
  • 4.1 Immunophenotyping
  • 4.2 Cytogenetics
  • 4.3 Classification
  • 5 Treatment
  • 5.1 Chemotherapy
  • 5.2 Radiation therapy
  • 5.3 Biological therapy
  • 5.4 Immunotherapy
  • 5.5 Relapsed ALL
  • 6 Prognosis
  • 7 Epidemiology
  • 8 Pregnancy
  • 9 References
  • 10 External links
  • 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%).[15] 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.[16]

    The signs and symptoms of ALL are variable and include:[17]

  • Generalized weakness and feeling tired
  • Anemia
  • Dizziness
  • Headache, vomiting, lethargy, nuchal rigidity,[18] or cranial nerve palsies[19] (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.[4][20]

    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.[4]

    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.[4] These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes.[21][22] 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.[4] 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.[6][4][2] Individually, most of these mutations are low risk for ALL. Significant risk of disease occurs when a person inherits several of these mutations together.[4]

    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.[4]

    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.[13] Fewer than 5% of cases are associated with a known genetic syndrome.[7]

    Rare mutations in ETV6 and PAX5 are associated with a familial form of ALL with autosomal dominant patterns of inheritance.[2]

    Environmental risk factors

    The environmental exposures that contribute to emergence of ALL is contentious and a subject of ongoing debate.[6][4]

    High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia.[23] Evidence whether less radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive.[6] Studies that have identified an association between x-ray imaging during pregnancy and ALL found only a slightly increased risk.[4] 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.[6][4]

    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.[6]

    Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide.[6][24]

    Delayed infection hypothesis

    There is some evidence that a common infection, such as influenza, may indirectly promote emergence of ALL.[6][4] 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.[6]

    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.[2] 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.[2] 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.[4][2]

    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.[2] In T-cell ALL, LYL1, TAL1, TLX1, and TLX3 rearrangements can occur.[4]

    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.[4] 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.[2]

    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.[25] 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.[5]

    A bone marrow biopsy provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts.[26] 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.[17]

    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.[27]

  • 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.[5]

    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.[28]

    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.[28] 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.[29]

    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[30] 25.4%[31]t(1;19)(q23;p13) E2A–PBX (PBX1) fusion[32] 4.8%[31]t(9;22)(q34;q11) BCR-ABL fusion(P185)[33] 1.6%[31]t(4;11)(q21;q23) MLL–AF4 fusion[34] 1.6%[31]t(8;14)(q24;q32) IGH-MYC fusion[35] t(11;14)(p13;q11) TCR–RBTN2 fusion[36] 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).[37][38]

    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 prognosis 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.[39]:491

    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 cytogenetic and molecular diagnostics tests.[40]:1531–1535[28] This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.

    The WHO subtypes related to ALL are:[41]

  • 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.[42]

    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[43][44] Agents[43][44]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:[45]

  • 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.[46][47]

    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.[44]

    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.[48][49]

    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.[50]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.[48]

    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.[49][44]

    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.[51] 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.[52] 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.[53]

    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.[54] 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.[52] 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.[55] 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.[56]

    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.[57]

    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.[44]

    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%.[43][58]

    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)[59]
  • In children[60][61][62] 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 Positive at 3 - 6 months Negative at 1 month (children) or 3 months (adults)

    Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, is an important predictor of outcome.[63] Some cytogenetic subtypes have a worse prognosis than others. These include:[17]

  • 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.[44]
  • 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,[64] 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.[11][9] 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.[43] It is estimated to affect 1 in 1500 children.[8]

    Accounting for the broad age profiles of those affected, ALL newly occurs in about 1.7 per 100,000 people per year.[5] ALL represents approximately 20% of adult and 80% of childhood leukemias, making it the most common childhood cancer.[5] Although 80 to 90% of children will have a long term complete response with treatment,[40]:1527 it remains the leading cause of cancer-related deaths among children.[65] 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.[66]:1617[67] 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.[68]

    Pregnancy

    Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.[69] 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.[69]

    References
  • ^ a b c d e f g h "Childhood Acute Lymphoblastic Leukemia Treatment". National Cancer Institute. 8 December 2017. Retrieved 20 December 2017.
  • ^ a b c d e f g h i j k l m n o p q r s Hunger, Stephen P.; Mullighan, Charles G. (2015-10-14). "Acute Lymphoblastic Leukemia in Children". New England Journal of Medicine. 373 (16): 1541–1552. doi:10.1056/nejmra1400972. PMID 26465987.
  • ^ a b c d Ferri, Fred F. (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 743. ISBN 9780323529570.
  • ^ a b c d e f g h i j k l m n o p q r s Inaba H, Greaves M, Mullighan CG (June 2013). "Acute lymphoblastic leukaemia". Lancet. 381 (9881): 1943–55. doi:10.1016/S0140-6736(12)62187-4. PMC 3816716 Freely accessible. PMID 23523389.
  • ^ a b c d e f Baljevic, Muhamed; Jabbour, Elias; O'Brien, Susan; Kantarjian, Hagop M (2016). "Acute Lymphoblastic Leukemia". In Kantarjian, HM; Wolff, RA. The MD Anderson Manual of Medical Oncology (3 ed.). New York: McGraw-Hill Education. Retrieved 22 November 2017.
  • ^ a b c d e f g h i j Childhood acute lymphoblastic leukemia. Vora, Ajay (editor). Cham, Switzerland: Springer International Publishing. 2017. pp. 1–44, 61–86. ISBN 9783319397078. OCLC 984342596.
  • ^ a b c Paul, Shilpa; Kantarjian, Hagop; Jabbour, Elias J. (2016). "Adult Acute Lymphoblastic Leukemia". Mayo Clinic Proceedings. 91 (11): 1645–1666. doi:10.1016/j.mayocp.2016.09.010.
  • ^ a b Boer, JM; den Boer, ML (11 July 2017). "BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside". European Journal of Cancer. 82: 203–218. doi:10.1016/j.ejca.2017.06.012. PMID 28709134.
  • ^ a b c GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903 Freely accessible. PMID 27733281.
  • ^ Marino, Bradley S.; Fine, Katie S. (2013). Blueprints Pediatrics. Lippincott Williams & Wilkins. p. 205. ISBN 9781451116045.
  • ^ a b GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577 Freely accessible. PMID 27733282.
  • ^ "Acute Lymphocytic Leukemia - Cancer Stat Facts". SEER. Retrieved 20 December 2017.
  • ^ a b Tubergen, DG; Bleyer, A; Ritchey, AK (2011). "Acute Lymphoblastic Leukemia". In Kliegman, RM; Stanton, BMD; St Geme, J; Schor, NF; Behrman, RE. Nelson Textbook of Pediatrics (19th ed.). Philadelphia, PA: Elsevier/Saunders. pp. 1732–1737. ISBN 1437707556. OCLC 706780860.
  • ^ Brown, Patrick (2013-12-06). "Treatment of infant leukemias: challenge and promise". ASH Education Program Book. 2013 (1): 596–600. doi:10.1182/asheducation-2013.1.596. ISSN 1520-4391. PMC 4729208 Freely accessible. PMID 24319237.
  • ^ Clarke, Rachel T.; Bruel, Ann Van den; Bankhead, Clare; Mitchell, Christopher D.; Phillips, Bob; Thompson, Matthew J. (2016-10-01). "Clinical presentation of childhood leukaemia: a systematic review and meta-analysis". Archives of Disease in Childhood. 101 (10): 894–901. doi:10.1136/archdischild-2016-311251. ISSN 0003-9888. PMID 27647842.
  • ^ Cortes, J. (February 2001). "Central nervous system involvement in adult acute lymphocytic leukemia". Hematology/Oncology Clinics of North America. 15 (1): 145–162. doi:10.1016/s0889-8588(05)70203-3. ISSN 0889-8588. PMID 11253605.
  • ^ a b c Seiter, K (5 February 2014). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; Besa, EC, eds. "Acute Lymphoblastic Leukemia". Medscape Reference. WebMD. Archived from the original on 18 April 2014. Retrieved 17 April 2014.
  • ^ Bleyer, W. A. (August 1988). "Central nervous system leukemia". Pediatric Clinics of North America. 35 (4): 789–814. doi:10.1016/s0031-3955(16)36510-5. ISSN 0031-3955. PMID 3047654.
  • ^ Ingram, L. C.; Fairclough, D. L.; Furman, W. L.; Sandlund, J. T.; Kun, L. E.; Rivera, G. K.; Pui, C. H. (1991-05-01). "Cranial nerve palsy in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma". Cancer. 67 (9): 2262–2268. doi:10.1002/1097-0142(19910501)67:9<2262::aid-cncr2820670909>3.0.co;2-u. ISSN 0008-543X. PMID 2013032.
  • ^ Terwilliger, T; Abdul-Hay, M (June 2017). "Acute lymphoblastic leukemia: a comprehensive review and 2017 update". Blood Cancer Journal. 7 (6): e577. doi:10.1038/bcj.2017.53. ISSN 2044-5385.
  • ^ Meyer, C; Hofmann, J; Burmeister, T; Gröger, D; Park, T S; Emerenciano, M; Oliveira, M Pombo de; Renneville, A; Villarese, P (2013). "The MLL recombinome of acute leukemias in 2013". Leukemia. 27 (11): 2165–2176. doi:10.1038/leu.2013.135. ISSN 1476-5551. PMC 3826032 Freely accessible.
  • ^ Benedikt, A; Baltruschat, S; Scholz, B; Bursen, A; Arrey, T N; Meyer, B; Varagnolo, L; Müller, A M; Karas, M (2011). "The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures". Leukemia. 25 (1): 135–144. doi:10.1038/leu.2010.249. ISSN 1476-5551.
  • ^ Preston, D. L.; Kusumi, S.; Tomonaga, M.; Izumi, S.; Ron, E.; Kuramoto, A.; Kamada, N.; Dohy, H.; Matsuo, T. (1 February 1994). "Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950–1987". Radiation Research. 137 (2 Suppl): S68–97. doi:10.2307/3578893. ISSN 0033-7587. PMID 8127953.
  • ^ Smith MA, Rubinstein L, Anderson JR, et al. (Feb 1999). "Secondary Leukemia or Myelodysplastic Syndrome After Treatment With Epipodophyllotoxins" (PDF). Journal of Clinical Oncology. American Society for Clinical Oncology. 17 (2): 569–77. PMID 10080601. Archived from the original on 22 August 2009.
  • ^ Collier, J.A.B (1991). Oxford Handbook of Clinical Specialties, Third Edition. Oxford. p. 810. ISBN 0-19-262116-5.
  • ^ Longo, D (2011). "Chapter 110: Malignancies of Lymphoid Cells". Harrison's Principles of Internal Medicine (18 ed.). New York: McGraw-Hill Portable. ISBN 978-0-07-174889-6.
  • ^ Rytting, ME, ed. (November 2013). "Acute Leukemia". Merck Manual Portable. Merck Sharp & Dohme Corp. Archived from the original on 15 July 2014. Retrieved 17 April 2014.
  • ^ a b c V.,, Hoffbrand, A. Hoffbrand's essential haematology. Moss, P. A. H., (Seventh ed.). Chichester, West Sussex. ISBN 9781118408636. OCLC 910009732.
  • ^ Bhojwani, Deepa; Pei, Deqing; Sandlund, John T.; Jeha, Sima; Ribeiro, Raul C.; Rubnitz, Jeffrey E.; Raimondi, Susana C.; Shurtleff, Sheila; Onciu, Mihaela (February 2012). "ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy". Leukemia. 26 (2): 265–270. doi:10.1038/leu.2011.227. ISSN 0887-6924. PMC 3345278 Freely accessible. PMID 21869842.
  • ^ Stams WA, den Boer ML, Beverloo HB, Meijerink JP, van Wering ER, Janka-Schaub GE, Pieters R (April 2005). "Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia". Clin. Cancer Res. 11 (8): 2974–80. doi:10.1158/1078-0432.CCR-04-1829. PMID 15837750.
  • ^ a b c d Pakakasama S, Kajanachumpol S, Kanjanapongkul S, et al. (August 2008). "Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia". Int J Lab Hematol. 30 (4): 286–91. doi:10.1111/j.1751-553X.2007.00954.x. PMID 18665825.
  • ^ McWhirter JR, Neuteboom ST, Wancewicz EV, et al. (September 1999). "Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia". Proc. Natl. Acad. Sci. U.S.A. 96 (20): 11464–9. doi:10.1073/pnas.96.20.11464. PMC 18056 Freely accessible. PMID 10500199.
  • ^ Rudolph C, Hegazy AN, von Neuhoff N, et al. (August 2005). "Cytogenetic characterization of a BCR-ABL transduced mouse cell line". Cancer Genet. Cytogenet. 161 (1): 51–6. doi:10.1016/j.cancergencyto.2004.12.021. PMID 16080957.
  • ^ Caslini C, Serna A, Rossi V, et al. (June 2004). "Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein". Leukemia. 18 (6): 1064–71. doi:10.1038/sj.leu.2403321. PMID 14990976.
  • ^ Martín-Subero JI, Odero MD, Hernandez R, Cigudosa JC, Agirre X, Saez B, Sanz-García E, Ardanaz MT, Novo FJ, Gascoyne RD, Calasanz MJ, Siebert R (August 2005). "Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas". Genes Chromosomes Cancer. 43 (4): 414–23. doi:10.1002/gcc.20187. PMID 15852472.
  • ^ Zalcberg IQ, Silva ML, Abdelhay E, et al. (October 1995). "Translocation 11;14 in three children with acute lymphoblastic leukemia of T-cell origin". Cancer Genet. Cytogenet. 84 (1): 32–8. doi:10.1016/0165-4608(95)00062-3. PMID 7497440.
  • ^ Bennett, J. M.; Catovsky, D.; Daniel, M. T.; Flandrin, G.; Galton, D. A.; Gralnick, H. R.; Sultan, C. (August 1976). "Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group". British Journal of Haematology. 33 (4): 451–458. doi:10.1111/j.1365-2141.1976.tb03563.x. ISSN 0007-1048. PMID 188440.
  • ^ "ACS :: How Is Acute Lymphocytic Leukemia Classified?". Archived from the original on 23 March 2008.
  • ^ DeAngelo DJ, Pui C. Acute lymphoblastic leukemia and lymphoblastic lymphoma. Chapter 19 of American Society of Hematology Self-Assessment Program. 2013. ISBN 9780982843512
  • ^ a b Orkin, S. H.; Nathan, D. G.; Ginsburg, D.; et al. (2014). Nathan and Oski's Hematology and Oncology of Infancy and Childhood (8th ed.). Saunders. ISBN 978-1-4557-5414-4.
  • ^ Arber, Daniel A.; Orazi, Attilio; Hasserjian, Robert; Thiele, Jürgen; Borowitz, Michael J.; Beau, Michelle M. Le; Bloomfield, Clara D.; Cazzola, Mario; Vardiman, James W. (2016-05-19). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 0006-4971. PMID 27069254.
  • ^ "Acute lymphoblastic leukemia (ALL) Information – Mount Sinai – New York". Mount Sinai Health System. Archived from the original on 3 August 2016. Retrieved 18 November 2017.
  • ^ a b c d Hoffbrand, Victor; Moss, Paul; Pettit, John (31 October 2006). Essential Haematology. Wiley. pp. 192–196. ISBN 978-1-4051-3649-5. Archived from the original on 21 March 2015. Retrieved 14 September 2013.
  • ^ a b c d e f "Adult Acute Lymphoblastic Leukemia Treatment". National Cancer Institute. Retrieved 2017-12-06.
  • ^ Jabbour E, Thomas D, Cortes J, et al. (15 May 2010). "Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies". Cancer. 116 (10): 2290–300. doi:10.1002/cncr.25008. PMID 20209620.
  • ^ M. Yanada (2015). "Time to tune the treatment of Ph+ ALL". Blood. 125 (24): 3674–5. doi:10.1182/blood-2015-04-641704. PMID 26069331.
  • ^ Seiter K, Harris JE. Acute Lymphoblastic Leukemia Treatment Protocols. emedicine; Medscape. "Archived copy". Archived from the original on 1 September 2015. Retrieved 16 August 2015.
  • ^ a b V.,, Hoffbrand, A. Hoffbrand's essential haematology. Moss, P. A. H., (Seventh ed.). Chichester, West Sussex. ISBN 9781118408674. OCLC 909538759.
  • ^ a b Paul, Shilpa; Kantarjian, Hagop; Jabbour, Elias J. (2016). "Adult Acute Lymphoblastic Leukemia". Mayo Clinic Proceedings. 91 (11): 1645–1666. doi:10.1016/j.mayocp.2016.09.010.
  • ^ Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA (January 2012). "Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators". Mol Cell Endocrinol. 351 (2): 142–51. doi:10.1016/j.mce.2012.01.003. PMID 22273806.
  • ^ Grupp SA, Kalos M, Barrett D, et al. (2013). "Chimeric antigen receptor-modified T cells for acute lymphoid leukemia". N. Engl. J. Med. 368 (16): 1509–18. doi:10.1056/NEJMoa1215134. PMC 4058440 Freely accessible. PMID 23527958.
  • ^ a b Barrett DM, Singh N, Porter DL, et al. (2014). "Chimeric antigen receptor therapy for cancer". Annu. Rev. Med. 65: 333–47. doi:10.1146/annurev-med-060512-150254. PMC 4120077 Freely accessible. PMID 24274181.
  • ^ Alonso-Camino V, Sánchez-Martín D, Compte M, et al. (2013). "CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors". Mol Ther Nucleic Acids. 2: e93. doi:10.1038/mtna.2013.19. PMC 4817937 Freely accessible. PMID 23695536.
  • ^ Zufferey R, Dull T, Mandel RJ, et al. (1998). "Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery". J. Virol. 72 (12): 9873–80. PMC 110499 Freely accessible. PMID 9811723.
  • ^ Commissioner, Office of the. "Press Announcements—FDA approval brings first gene therapy to the United States". www.fda.gov. Archived from the original on 3 September 2017. Retrieved 12 September 2017.
  • ^ Ledford, Heidi (12 July 2017). "Engineered cell therapy for cancer gets thumbs up from FDA advisers". Nature. doi:10.1038/nature.2017.22304.
  • ^ Kantarjian, Hagop; Stein, Anthony; Gökbuget, Nicola; Fielding, Adele K.; Schuh, Andre C.; Ribera, Josep-Maria; Wei, Andrew; Dombret, Hervé; Foà, Robin (2017-03-01). "Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia". New England Journal of Medicine. 376 (9): 836–847. doi:10.1056/nejmoa1609783.
  • ^ Hutter, John J. (2010-06-01). "Childhood Leukemia". Pediatrics in Review. 31 (6): 234–241. doi:10.1542/pir.31-6-234. ISSN 0191-9601. PMID 20516235.
  • ^ "Prognosis and survival for acute lymphocytic leukemia - Canadian Cance". www.cancer.ca. Retrieved 2017-12-06.
  • ^ Nelson Essentials of Pediatrics By Karen Marcdante, Robert M. Kliegman, Richard E. Behrman, Hal B. Jenson p597
  • ^ The Guide Paediatrics. ISBN 978-978-917-9909. p51
  • ^ V.,, Hoffbrand, A. Hoffbrand's essential haematology. Moss, P. A. H., (Seventh ed.). Chichester, West Sussex. p. 194. ISBN 9781118408674. OCLC 909538759.
  • ^ Moorman AV, Harrison CJ, Buck GA, et al. (15 April 2007). "Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial". Blood. 109 (8): 3189–3197. doi:10.1182/blood-2006-10-051912. PMID 17170120.
  • ^ Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. (January 2009). "A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study". Lancet Oncol. 10 (2): 125–34. doi:10.1016/S1470-2045(08)70339-5. PMC 2707020 Freely accessible. PMID 19138562.
  • ^ Guo LM, Xi JS, Ma Y, et al. (2014). "ARID5B gene rs10821936 polymorphism is associated with childhood acute lymphoblastic leukemia: a meta-analysis based on 39,116 subjects". Tumour Biol. 35 (1): 709–13. doi:10.1007/s13277-013-1097-0. PMID 23975371.
  • ^ Greer, J. P.; Arber, D. A.; Glader, B.; et al. (2013). Wintrobe's Clinical Hematology (13th ed.). Lippincott Williams & Wilkins. ISBN 978-1-4511-7268-3.
  • ^ K. Y. Urayama; A. Manabe (2014). "Genomic evaluations of childhood acute lymphoblastic leukemia susceptibility across race/ethnicities". Rinsho Ketsueki. 55 (10): 2242–8. PMID 25297793.
  • ^ Ries, LAG; Smith, MA; Gurney, JG; Linet, M; Tamra, T; Young, JL; Bunin, GR (1999). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD: National Cancer Institute, SEER Program.
  • ^ a b Shapira T, Pereg D, Lishner M (September 2008). "How I treat acute and chronic leukemia in pregnancy". Blood Rev. 22 (5): 247–59. doi:10.1016/j.blre.2008.03.006. PMID 18472198.
  • External links
  • Acute Lymphocytic Leukemia at American Cancer Society
  • Childhood ALL Treatment at National Cancer Institute
  • v
  • t
  • e
  • Arthritis in childrenInflammatoryIdiopathic
  • Juvenile idiopathic arthritis
  • Inflammatory disease
  • Inflammatory bowel disease
  • Sarcoidosis
  • Cystic fibrosis
  • Autoimmune hepatitis
  • Blood cancer
  • Acute lymphoblastic leukemia
  • Lymphoma
  • Malignancy
  • Neuroblastoma
  • Reactive
  • post-streptococcal
  • Rheumatic fever
  • postenteric, post-viral
  • Infection
  • Septic arthritis
  • Osteomyelitis
  • Tuberculosis
  • Lyme arthritis
  • Mechanical
  • Osgood–Schlatter disease
  • Tumours of cartilage bone or muscleBenign
  • Osteoid osteoma
  • Pigmented villonodular synovitis
  • Hemangioma
  • Malignant
  • Synovial sarcoma
  • Rhabdomyosarcoma
  • Ewing's sarcoma
  • Central Nervous System Idiopathic pain syndromes Local Complex regional pain syndrome/Reflex sympathetic dystrophy Generalized Fibromyalgia
  • v
  • t
  • e
  • Chromosome abnormalities (Q90–Q99, 758)AutosomalTrisomies
  • Down syndrome
  • 21
  • Edwards syndrome
  • 18
  • Patau syndrome
  • 13
  • Trisomy 9
  • Warkany syndrome 2
  • 8
  • Cat eye syndrome/Trisomy 22
  • 22
  • Trisomy 16
  • Monosomies/deletions
  • 1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome
  • 1
  • Wolf–Hirschhorn syndrome
  • 4
  • Cri du chat/Chromosome 5q deletion syndrome
  • 5
  • Williams syndrome
  • 7
  • Jacobsen syndrome
  • 11
  • Miller–Dieker syndrome/Smith–Magenis syndrome
  • 17
  • DiGeorge syndrome
  • 22
  • 22q11.2 distal deletion syndrome
  • 22
  • 22q13 deletion syndrome
  • 22
  • genomic imprinting
  • Angelman syndrome/Prader–Willi syndrome (15)
  • Distal 18q-/Proximal 18q-
  • X/Y linkedMonosomy
  • Turner syndrome (45,X)
  • Trisomy/tetrasomy,other karyotypes/mosaics
  • Klinefelter syndrome (47,XXY)
  • XXYY syndrome (48,XXYY)
  • XXXY syndrome (48,XXXY)
  • 49,XXXYY
  • 49,XXXXY
  • Triple X syndrome (47,XXX)
  • Tetrasomy X (48,XXXX)
  • 49,XXXXX
  • Jacobs syndrome (47,XYY)
  • 48,XYYY
  • 49,XYYYY
  • 45,X/46,XY
  • TranslocationsLeukemia/lymphomaLymphoid
  • Burkitt's lymphoma t(8 MYC;14 IGH)
  • Follicular lymphoma t(14 IGH;18 BCL2)
  • Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH)
  • Anaplastic large-cell lymphoma t(2 ALK;5 NPM1)
  • Acute lymphoblastic leukemia
  • Myeloid
  • Philadelphia chromosome t(9 ABL; 22 BCR)
  • Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1)
  • Acute promyelocytic leukemia t(15 PML,17 RARA)
  • Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1)
  • Other
  • Ewing's sarcoma t(11 FLI1; 22 EWS)
  • Synovial sarcoma t(x SYT;18 SSX)
  • Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB)
  • Myxoid liposarcoma t(12 DDIT3; 16 FUS)
  • Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS)
  • Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1)
  • Other
  • Fragile X syndrome
  • Uniparental disomy
  • XX male syndrome/46,XX testicular disorders of sex development
  • Marker chromosome
  • Ring chromosome
  • 6; 9; 14; 15; 18; 20; 21, 22
  • v
  • t
  • e
  • Hematological malignancy/leukemia histology (ICD-O 9590–9989, C81–C96, 200–208)Lymphoid/Lymphoproliferative, Lymphomas/Lymphoid leukemias (9590–9739, 9800–9839)B cell(lymphoma,leukemia)(most CD19
  • CD20)
  • Bydevelopment/markerTdT+
  • ALL (Precursor B acute lymphoblastic leukemia/lymphoma)
  • CD5+
  • naive B cell (CLL/SLL)
  • mantle zone (Mantle cell)
  • CD22+
  • Prolymphocytic
  • CD11c+ (Hairy cell leukemia)
  • CD79a+
  • germinal center/follicular B cell (Follicular
  • Burkitt's
  • GCB DLBCL
  • Primary cutaneous follicle center lymphoma)
  • marginal zone/marginal zone B-cell (Splenic marginal zone
  • MALT
  • Nodal marginal zone
  • Primary cutaneous marginal zone lymphoma)
  • RS (CD15+, CD30+)
  • Classic Hodgkin's lymphoma (Nodular sclerosis)
  • CD20+ (Nodular lymphocyte predominant Hodgkin's lymphoma)
  • PCDs/PP(CD38+/CD138+)
  • see immunoproliferative immunoglobulin disorders
  • By infection
  • KSHV (Primary effusion)
  • EBV
  • Lymphomatoid granulomatosis
  • Post-transplant lymphoproliferative disorder
  • Classic Hodgkin's lymphoma
  • Burkitt's lymphoma
  • HCV
  • Splenic marginal zone lymphoma
  • HIV (AIDS-related lymphoma)
  • Helicobacter pylori (MALT lymphoma)
  • Cutaneous
  • Diffuse large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • Primary cutaneous marginal zone lymphoma
  • Primary cutaneous immunocytoma
  • Plasmacytoma
  • Plasmacytosis
  • Primary cutaneous follicle center lymphoma
  • T/NKT cell(lymphoma,leukemia)(most CD3
  • CD4
  • CD8)
  • Bydevelopment/marker
  • TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma)
  • prolymphocyte (Prolymphocytic)
  • CD30+ (Anaplastic large-cell lymphoma
  • Lymphomatoid papulosis type A)
  • CutaneousMF+variants
  • indolent: Mycosis fungoides
  • Pagetoid reticulosis
  • Granulomatous slack skin
  • aggressive: Sézary disease

  • Adult T-cell leukemia/lymphoma
  • Non-MF
  • CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma
  • Pleomorphic T-cell lymphoma
  • Lymphomatoid papulosis type B
  • CD30+: CD30+ cutaneous T-cell lymphoma
  • Secondary cutaneous CD30+ large-cell lymphoma
  • Lymphomatoid papulosis type A
  • Otherperipheral
  • Hepatosplenic
  • Angioimmunoblastic
  • Enteropathy-associated T-cell lymphoma
  • Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma)
  • Subcutaneous T-cell lymphoma
  • By infection
  • HTLV-1 (Adult T-cell leukemia/lymphoma)
  • NK cell/(most CD56)
  • Aggressive NK-cell leukemia
  • Blastic NK cell lymphoma
  • T or NK
  • EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma)
  • Large granular lymphocytic leukemia
  • Lymphoid+myeloid
  • Acute biphenotypic leukaemia
  • Lymphocytosis
  • Lymphoproliferative disorders (X-linked lymphoproliferative disease
  • Autoimmune lymphoproliferative syndrome)
  • Leukemoid reaction
  • Diffuse infiltrative lymphocytosis syndrome
  • Cutaneous lymphoid hyperplasia
  • Cutaneous lymphoid hyperplasia
  • with bandlike and perivascular patterns
  • with nodular pattern
  • Jessner lymphocytic infiltrate of the skin
  • Retrieved from "https://en.wikipedia.org/w/index.php?title=Acute_lymphoblastic_leukemia&oldid=855180397"

    All | Define All at Dictionary.com

    [awl]

    SynonymsWord Origin

    See more synonyms for all on Thesaurus.comadjective
  • the whole of (used in referring to quantity, extent, or duration): all the cake; all the way; all year.
  • the whole number of (used in referring to individuals or particulars, taken collectively): all students.
  • the greatest possible (used in referring to quality or degree): with all due respect; with all speed.
  • every: all kinds; all sorts.
  • any; any whatever: beyond all doubt.
  • nothing but; only: The coat is all wool.
  • dominated by or as if by the conspicuous possession or use of a particular feature: The colt was all legs. They were all ears, listening attentively to everything she said.
  • Chiefly Pennsylvania German. all gone; consumed; finished: The pie is all.
  • pronoun
  • the whole quantity or amount: He ate all of the peanuts. All are gone.
  • the whole number; every one: all of us.
  • everything: Is that all you want to say? All is lost.
  • noun
  • one's whole interest, energy, or property: to give one's all; to lose one's all.
  • (often initial capital letter) the entire universe.
  • adverb
  • wholly; entirely; completely: all alone.
  • only; exclusively: He spent his income all on pleasure.
  • each; apiece: The score was one all.
  • Archaic. even; just.
  • Idioms
  • above all, before everything else; chiefly: Above all, the little girl wanted a piano.
  • after all, in spite of the circumstances; notwithstanding: He came in time after all.
  • all at once. once(def 9).
  • all but, almost; very nearly: These batteries are all but dead.
  • all in, Northern and Western U.S. very tired; exhausted: We were all in at the end of the day.
  • all in all,
  • everything considered; in general: All in all, her health is greatly improved.
  • altogether: There were twelve absentees all in all.
  • everything; everything regarded as important: Painting became his all in all.
  • all in hand, Printing, Journalism. (of the copy for typesetting a particular article, book, issue, etc.) in the possession of the compositor.
  • all in the wind, Nautical. too close to the wind.
  • all out, with all available means or effort: We went all out to win the war.
  • all over,
  • finished; done; ended.
  • everywhere; in every part.
  • in every respect; typically.
  • all standing, Nautical.
  • in such a way and so suddenly that sails or engines are still set to propel a vessel forward: The ship ran aground all standing.
  • fully clothed: The crew turned in all standing.
  • fully equipped, as a vessel.
  • all that, remarkably; entirely; decidedly (used in negative constructions): It's not all that different from your other house.
  • all the better, more advantageous; so much the better: If the sun shines it will be all the better for our trip.
  • all there, Informal. mentally competent; not insane or feeble-minded: Some of his farfetched ideas made us suspect that he wasn't all there.
  • all the same. same(def 9).
  • all told. told(def 2).
  • all up,
  • Printing, Journalism.(of copy) completely set in type.
  • Informal.with no vestige of hope remaining: It's all up with George—they've caught him.
  • and all, together with every other associated or connected attribute, object, or circumstance: What with the snow and all, we may be a little late.
  • at all,
  • in the slightest degree: I wasn't surprised at all.
  • for any reason: Why bother at all?
  • in any way: no offense at all.
  • for all (that), in spite of; notwithstanding: For all that, it was a good year.
  • in all, all included; all together: a hundred guests in all.
  • once and for all, for the last time; finally: The case was settled once and for all when the appeal was denied.
  • Origin of allbefore 900; Middle English al, plural alle; Old English eal(l); cognate with Gothic alls, Old Norse allr, Old Frisian, Dutch, Middle Low German al, Old Saxon, Old High German al(l) (German all); if *ol-no-, equivalent to Welsh oll and akin to Old Irish uile *ol-io-; cf. almightyCan be confusedall awl (see usage note at the current entry)SynonymsSee more synonyms for all on Thesaurus.com

    2. every one of, each of. 14. totally, utterly, fully.

    Usage noteExpressions like all the farther and all the higher occur chiefly in informal speech: This is all the farther the bus goes. That's all the higher she can jump. Elsewhere as far as and as high as are generally used: This is as far as the bus goes. That's as high as she can jump. Although some object to the inclusion of of in such phrases as all of the students and all of the contracts and prefer to omit it, the construction is entirely standard. See also already, alright, altogether.allo-
  • a combining form meaning “other,” used in the formation of compound words (allotrope) and in chemistry to denote the more stable of two geometric isomers.
  • Also (except in chemistry) especially before a vowel, all-.

    Origin of allo-Greek, combining form of állos other; cognate with Latin alius, elseall-
  • variant of allo- before a vowel: allonym.
  • Dictionary.com Unabridged Based on the Random House Unabridged Dictionary, © Random House, Inc. 2018

    British Dictionary definitions for allalldeterminer
  • the whole quantity or amount of; totality of; every one of a classall the rice; all men are mortal
  • (as pronoun; functioning as sing or plural)all of it is nice; all are welcome
  • (in combination with a noun used as a modifier)an all-ticket match; an all-amateur tournament; an all-night sitting
  • the greatest possiblein all earnestness
  • any whateverto lose all hope of recovery; beyond all doubt
  • above all most of all; especially
  • after all See after (def. 11)
  • all along all the time
  • all but almost; nearlyall but dead
  • all of no less or smaller thanshe's all of thirteen years
  • all over
  • finished; at an endthe affair is all over between us
  • over the whole area (of something); everywhere (in, on, etc)all over England
  • typically; representatively (in the phrase that's me (you, him, us, them, etc) all over)Also (Irish): all out
  • unduly effusive towards
  • sportin a dominant position over
  • See all in
  • all in all
  • everything consideredall in all, it was a great success
  • the object of one's attention or interestyou are my all in all
  • all that or that (usually used with a negative) informal (intensifier)she's not all that intelligent
  • all the (foll by a comparative adjective or adverb) so much (more or less) than otherwisewe must work all the faster now
  • all too definitely but regrettablyit's all too true
  • and all
  • British informalas well; tooand you can take that smile off your face and all
  • Southern Africana parenthetical filler phrase used at the end of a statement to make a sl ight pause in speaking
  • and all that informal
  • and similar or associated things; et ceteracoffee, tea, and all that will be served in the garden
  • used as a filler or to make what precedes more vague: in this sense, it often occurs with concessive forceshe was sweet and pretty and all that, but I still didn't like her
  • See that (def. 4)
  • as all that as one might expect or hopeshe's not as pretty as all that, but she has personality
  • at all
  • (used with a negative or in a question)in any way whatsoever or to any extent or degreeI didn't know that at all
  • even so; anywayI'm surprised you came at all
  • be all for informal to be strongly in favour of
  • be all that informal, mainly US to be exceptionally good, talented, or attractive
  • for all
  • in so far as; to the extent thatfor all anyone knows, he was a baron
  • notwithstandingfor all my pushing, I still couldn't move it
  • for all that in spite of thathe was a nice man for all that
  • in all altogetherthere were five of them in all
  • adverb
  • (in scores of games) apiece; eachthe score at half time was three all
  • completelyall alone
  • be all … informal used for emphasis when introducing direct speech or nonverbal communicationhe was all, 'I'm not doing that'
  • noun
  • (preceded by my, your, his, etc) (one's) complete effort or interestto give your all; you are my all
  • totality or whole
  • Related formsRelated prefixes: pan-, panto-Word Origin

    Old English eall; related to Old High German al, Old Norse allr, Gothic alls all

    all-combining form
  • a variant of allo-
  • allo-before a vowel all-combining form
  • indicating difference, variation, or oppositionallopathy; allomorph; allophone; allonym
  • Word Origin

    from Greek allos other, different

    Collins English Dictionary - Complete & Unabridged 2012 Digital Edition © William Collins Sons & Co. Ltd. 1979, 1986 © HarperCollins Publishers 1998, 2000, 2003, 2005, 2006, 2007, 2009, 2012

    Word Origin and History for all

    Old English eall "all, every, entire," from Proto-Germanic *alnaz (cf. Old Frisian, Old High German al, Old Norse allr, Gothic alls), with no certain connection outside Germanic.

    Combinations with all meaning "wholly, without limit" were common in Old English (e.g. eall-halig "all-holy," eall-mihtig "all-mighty") and the method continued to form new compound words throughout the history of English. First record of all out "to one's full powers" is 1880. All-terrain vehicle first recorded 1968. All clear as a signal of "no danger" is recorded from 1902. All right, indicative of approval, is attested from 1953.

    allo-

    word-forming element meaning "other," from Greek allo-, comb. form of allos "other, different" (see alias (adv.)).

    Online Etymology Dictionary, © 2010 Douglas Harper

    all in Medicineall-allo-pref.
  • Other; different:allotransplantation.
  • Isomeric:allomorphism.
  • The American Heritage® Stedman's Medical Dictionary Copyright © 2002, 2001, 1995 by Houghton Mifflin Company. Published by Houghton Mifflin Company.

    Idioms and Phrases with allall

    The American Heritage® Idioms Dictionary Copyright © 2002, 2001, 1995 by Houghton Mifflin Harcourt Publishing Company. Published by Houghton Mifflin Harcourt Publishing Company.


    CuteFTP Pro 9.0.5 Crack Patch Serial


    http://exambrain.net/CuteFTP.Professional.v9.0.5.incl.Patch-REVENGE.zip   https://drive.google.com/open?id=1JWKF_Q5YQQMas9Dzq3pTGdj75EeXzpFJ   https://drive.google.com/file/d/1JWKF_Q5YQQMas9Dzq3pTGdj75EeXzpFJ/view?usp=sharing   https://drop.me/aq35AJ   http://www110.zippyshare.com/v/DJgWDrML/file.html   https://files.fm/u/saer6vfr   https://ufile.io/mtxhp   https://we.tl/wCFggSQYeC   http://s000.tinyupload.com/index.php?file_id=08253588975460415519   https://www.megaupload.us/Tga/CuteFTP.Professional.v9.0.5.incl.Patch-REVENGE.zip   https://www.sendspace.com/file/vxabca   https://spaces.hightail.com/receive/WDXcPYt5cI   http://www.filedropper.com/cuteftpprofessionalv905inclpatch-revenge   https://file.io/6NsQLU   https://expirebox.com/download/b0acdc8950db6700e4f78784cd772e22.html   http://www.filetolink.com/eca645a03e   https://upload.cat/dd00bae3e1888794   https://dropfile.nl/get/3U7CQV   http://fileze.net/1Mkr   http://ge.tt/6Yfu1nn2   https://www.sharebase.net/4951a01dfdc95743   http://dropmefiles.com/NGT70   https://downace.com/4Ow6l   https://quickfileshare.org/5S5/CuteFTP.Professional.v9.0.5.incl.Patch-REVENGE.zip   https://filesup.me/8vx/CuteFTP.Professional.v9.0.5.incl.Patch-REVENGE.zip  


    Castrapraetoria
    cuteftp   cuteftp free   cuteftp lite   cuteftp portable   cuteftp free download   cuteftp 8 professional   cuteftp 9 serial number   cuteftp mac   cuteftp crack   cuteftp pro download   cuteftp sftp   cuteftp software   cuteftp 8   cuteftp download   cuteftp pro   cuteftp vs filezilla   cuteftp 9   cuteftp serial number   cuteftp free download full version   cuteftp download free full version   cuteftp pro free download   cuteftp download freeware   cuteftp free download software   cuteftp pro 9   cuteftp pro 8 download   cuteftp client   cuteftp freeware version   globalscape cuteftp free download   cuteftp download free   cuteftp pro 8   cuteftp download for windows xp   cuteftp free download for windows 7   cuteftp pro 7   cuteftp linux download   cuteftp program   cuteftp for windows 7   cuteftp free full version   cuteftp full version free download   ftp software cuteftp   ftp cute   cuteftp 5 download   cuteftp full version   cuteftp version 9   cuteftp windows 7   cuteftp client windows   cuteftp 9 ftp client   cuteftp freeware download   cuteftp free version   cute fpt   cuteftp free trial download   cuteftp client free download   cuteftp 2   cuteftp version   cuteftp version 8   cuteftp iphone   cuteftp 8 home download   cuteftp 8 pro   cuteftp professional download free   cuteftp 8 professional free download   cuteftp 7 professional free download   download cuteftp 8 pro   cuteftp pro full download   cuteftp pro download full   cuteftp 8 lite full version   cuteftp 6.0 professional download   cuteftp 6.0 pro download   cuteftp pro 8.0 free download   globalscape cuteftp professional 8   globalscape cuteftp pro 8   filehippo cuteftp download   cuteftp 32   cute ft   cuteftp lite freeware   what is cuteftp   cute ftp   globalscape cuteftp 8   globalscape cuteftp 8.3 professional free download   is cuteftp free   cute_ftp   cuteftp trial   cuteftp pro review   cuteftp pro portable   cuteftp lite free   cute ftp free   cuteftp free download full version for windows 7   cuteftp latest version free download   free cuteftp   cuteftp free download for windows   cute ftp download   ftp cute download   cuteftp professional   cuteftp.com   cuteftp 3   cuteftp 6 home   cuteftp 8 home   cuteftp version 6   cuteftp home edition   cuteftp 7 pro   download cuteftp 7 professional   download cuteftp 8 professional free   download cuteftp pro 20   cuteftp pro 8 free download   cuteftp pro mac download   cuteftp 64 bit free download   cuteftp pro8   cuteftp 7.0 download   cuteftp 8.3 1 pro   cuteftp pro 8.3 2   cuteftp ftps   globalscape cuteftp software   globalscape cuteftp 8.3 professional download   cuteftp pro 7 download   cuteftp pro windows 7   globalscape cuteftp 8 pro   globalscape ftp free download   cuteftp le   cuteftp 9 download   cuteftp server download   ftp client cuteftp free download   download cuteftp 4   free ftp client cuteftp   download cuteftp 8 home   download ftp cute   free cute ftp   download ftpcute   cute free ftp   cuteftp professional free download   cuteftp free download for windows 8   download cuteftp   download cuteftp for free   free download cuteftp   free cuteftp download   cuteftp software download   cuteftp latest version   download cuteftp client   cuteftp server download free   cuteftp server free download   ftp cuteftp   ftp client cute   cuteftp version 5   download cuteftp professional free   cute ftp com   cuteftp pro 3   ftp client cuteftp   cuteftp ftp   download cuteftp for windows 7   cute download ftp   cuteftp full version download   download globalscape cuteftp   www.cuteftp.com download   free cuteftp software   cuteftp download full   free download cuteftp 8 home   free cuteftp download full version   free download cuteftp full version   free cuteftp pro download   free download cuteftp for windows 7   free download cuteftp latest version   cuteftp professional full version free download   portable cuteftp free download   ftp program cuteftp   www cuteftp com   cuteftp gratis   cuteftp 9.0   download cuteftp 8.3   cuteftp 6.0 professional   cuteftp 3.0 free download   cuteftp free download old version   cuteftp ftp server   cuteftp 4   cuteftp 8 lite download   global cuteftp   cuteftp 8.0 pro   download cute ftp professional   ftps cuteftp   download cuteftp 5   download cuteftp 8   cuteftp 7   cuteftp 8.3 professional download   cuteftp 5   globalscape cuteftp 8 professional   cuteftp 5 xp   download cuteftp pro 8   cuteftp server   cuteftp features   download cuteftp home   cuteftp home free download   download cuteftp professional   cuteftp home iphone   cuteftp version 8 download   download free cuteftp professional   free download cuteftp professional   download cuteftp 8 professional   cuteftp 8 professional download   cuteftp home windows mobile   cuteftp pro download free   download cuteftp pro free   cuteftp 8 professional download free   cuteftp 8 pro download   cuteftp trial version download   cuteftp icon   download cuteftp portable   cuteftp windows 7 compatibility   freeware cuteftp   cuteftp pro 9.0   free download cuteftp 8.0 professional   cuteftp 8.3 professional free download   globalscape cuteftp pro   cuteftp filehippo   globalscape cuteftp 8.0   download globalscape cuteftp 8.0   how to use cuteftp mac   globalscape-cuteftp 8.3 professional free download   cuteftp 64   globalscape sftp download   cuteftp linux   cuteftp writer   cute ftp software   ftp cute free   cuteftp client download   cute ftp server   cuteftp version history   free download cuteftp 8 professional   cuteftp pro 6   cuteftp 6 free download   download cuteftp 7   cuteftp login   cuteftp pro rapidshare   cuteftp pro old version   pro ftp   cuteftp 7 home   cuteftp 8.3.2 pro   ftp pro   global scape cute ftp   ftp cut   download cute ftp   cuteftp downloads   free ftp cute   cuteftp 9 free download   cuteftp xp   download cuteftp server   free ftp client cute   cuteftp client download free   download ftp cute free   cute ftp freeware   cute ftp client   cute ftp client download   cuteftp 6   features of cuteftp   cuteftp language   cuteftp reviews   download cuteftp 50   cuteftp 7 professional   cuteftp home 8 download   cuteftp 7 free download   cuteftp home reviews   cuteftp key free download   cuteftp license   cuteftp writer free download   portable cuteftp   cuteftp windows 7 64 bit   cuteftp vista   cuteftp windows vista   cuteftp sync   cuteftp 8.0   cuteftp 6.0   cuteftp 3.0   cuteftp utf-8   cuteftp 8.3 2   cuteftp professional 8.0   cuteftp 8.0 professional   cuteftp 8.3 professional   cuteftp 7.0 professional   cuteftp 8.3.2 professional   cuteftp professional 8.3.2   cuteftp professional vs filezilla   globalscape cuteftp professional   globalscape cuteftp 8.3   globalscape cuteftp 8.3 professional   globalscape cuteftp 8.0 professional download   cuteftp pro crack   download cuteftp free   cuteftp client free   download cuteftp 9   cuteftp software free download   ftp cute free download   download cuteftp free for windows 7   cute ftp download free   cuteftp for windows   free download cuteftp pro   download free cuteftp software   cuteftp free download for windows xp   download free cuteftp   download cuteftp free version   cute ftp server software download   cuteftp portable free download   cute ftp xp   download cute ftp client   free cuteftp software download   cuteftp download free version   free download cuteftp software   download cute ftp software   cute ftp freeware download   download free cute ftp   free download cute ftp software   cute ftp program download   free download cute-ftp program   cute ftp software free download   cute ftp software download   free cute ftp download   cute ftp server indir   free download cute ftp   cuteftp pro synchronize   cuteftp professional free   download cuteftp full version   cuteftp windows   cuteftp 9 professional free download   cuteftp 8 download   ftp cute professional   cuteftp full download   download cuteftp pro   free cuteftp download 8.0   download cuteftp full   cuteftp 9 professional   cuteftp full   ftp cute pro   cuteftp 8.3   cuteftp 8 home free download   cuteftp professional 8   cute ftp software for windows 7   free cute ftp download software   cuteftp freeware   ftp cute full   cuteftp 8 free download   free download cute ftp professional software   cute ftp lite   free cute ftp client   ftp cute portable   quit ftp download   cute ftp program   ftp cute server   cuteftppro   www.cuteftp.com   global cute ftp   cute ftp client windows 7   cute ftp pro   filezilla vs cuteftp   cuteftp download with crack   cuteftp pro 9 serial number   cuteftp lite 8 download   cuteftp lite crack   cuteftp pro command line   cuteftp 9 serial   cuteftp upload   cuteftp 8.2 professional   cuteftp 9.0.5 keygen   cuteftp pro free   cuteftp lite 8.3 full   download cuteftp 8.0   cuteftp pro 8.3   cuteftp 8.3 download   cuteftp home 8.3.4   globalscape ftp download   download portable cuteftp   cuteftp home software   globalscape cuteftp download   cute ftp server software   cuteftp home 8   cuteftp home   cute pro ftp   globalscape cuteftp 8.0 professional   cute ftp le   ftp server download filehippo   cuteftp com   cuteftp pro free download full version   cute ftp full   cuteftp home pc   cuteftp portable download   globalscape cuteftp   ftp 8 professional   cuteftp professional 8 free download   cuteftp 8.0 professional free download   what is cuteftp pro   cuteftp portable windows 7   cuteftp home download   cuteftp 8.3.4   cuteftp professional download   global ftp download   ftp cute pro full   filehippo ftp   cuteftp serial   cuteftp crack version   cuteftp pro v8   cuteftp pro 8.3.4 serial number   cuteftp torrent   cuteftp for mac   cuteftp pro mac   cuteftp free download with crack   cuteftp free download serial number   cuteftp pro serial key   cuteftp free download for windows 7 64 bit   cuteftp free download full version with serial number   cuteftp free download for windows 7 32bit   cuteftp professional 8.3 serial number   cuteftp pro 8.3 serial   cuteftp how to use   cuteftp 8 key   purchase cuteftp   cuteftp free mac   torrent cuteftp pro   cuteftp mac free download   cuteftp mac download free   cuteftp download mac free   download cuteftp mac free   cuteftp password recovery free   cuteftp pro 33 download   cuteftp 8 patch   cuteftp 7 crack   cuteftp full crack   crack cuteftp 9   serial number cuteftp   cuteftp 9 serial no   free cuteftp download with crack   cuteftp pro patch   patch cuteftp pro   cuteftp tutorial video   cuteftp 7 professional crack   tutorial cuteftp 8   download cuteftp mac os x   cuteftp pro free download crack   tutorial cuteftp pro 8   cuteftp serial crack   cuteftp mac serial number crack   cuteftp v8   cuteftp 8 lite free download   how to configure cuteftp   keygen cuteftp   keygen cuteftp 8   cuteftp keygen download   keygen cuteftp 8 home   cuteftp 7 professional keygen   cuteftp exe   cuteftp download cnet   cuteftp scheduler   cuteftp 8 lite keygen   cuteftp connecting ftp data socket   cuteftp uploading   godaddy cuteftp   cuteftp pro 8.1 download   cuteftp 9.0 serial no   cuteftp 8.3 serial number   cuteftp 8.3 2 serial number   cuteftp 9.0 serial key   cuteftp 8.3 professional serial no   cuteftp 8.0 professional serial   cuteftp pro 8.3 2 serial   cuteftp pro 8.3 serial key   cuteftp 8.3 home serial number crack   cuteftp pro 8.3 crack serial   cuteftp 8.0 keygen   cuteftp 8.3 professional keygen   cuteftp pro 8.3 keygen   globalscape cuteftp serial   cuteftp key exchange failed   filezilla   free ftp   best free ftp software   fireftp how to   smartftp mac download   free leapftp   best ftp client windows   fastest ftp client   professional ftp client   leapware ftp   leapftp free   www coreftp com   leapftp exe   coreftp com   free leapftp download   fireftp com   ftp programs   winftp   best windows ftp client   leapftp 3.0 free download   free download leapftp   seedbox ftp   powerful ftp server   fxp sftp   seedbox ip   evo seedbox   turbo ftp download   ws_ftp server 7 torrent   multithreaded ftp   firefox file transfer   usb ftp   ftp for windows   leech software download   download turbo ftp   turbo ftp free download   secureftp download   filezilla server anonymous   filezilla smartftp   ftp failed to establish data socket   web uploading programs   ftp application   queue ftp   upload download program   zile zilla   leechftp exe   ftp leecher   using smartftp   ftp crc check   filezilla or smartftp   ws ftp vs filezilla   the supplied message is incomplete.the signature was not verified   bftp exe   leech ftp.exe download   qftp software   ipswitch ws_ftp proxy   u3 ftp client   enterprise ftp server software   proftpd control connection closed   best leech software   mac finder ftp passive   sourceforge.net ftp   download turboftp   smartftp manual   best way to download files from seedbox   fastest ftp seedbox   ftp failed error 552   file transfer gui   jan debis   download leech ftp free   leech ftp mac os x   ftp tools   better than filezilla   multipart ftp upload   turboftp sdk   core ftp chmod   cute ftp control connection closed   al ftp server download   pgp ftp filezilla   smartftp mac alternative   upnp ftp server   ftp file compression   robo ftp pgp encryption   fxp transfer mac   upload files software   aborting code 10054   probe filezilla project org   550 the supplied message is incomplete   powweb ftp address   filezilla concurrent   ftprush   filezilla vs flashfxp   smartftp tutorials   qftp professional   seedbox download manager   winscp   secureftp cognizant com   cuteftp 7 professional download   professional ftp   client ftp windows 98   cuteftp pro 3.0   cuteftp 5.0 download   cuteftp professional 8.3   rapidshare cuteftp   cute ftp for mac   sftp globalscape   cuteftp.pro.8.3.2   cuteftp 8.3.2   cute ftp iphone   cuteftp review   buy cuteftp   cuteftp .pro.8.3.2   cuteftp globalscape   ftppro   cuteftp rapidshare   ftppro software   cuteftp pro v9.0   how to use cuteftp pro   ftp global   cuteftp wiki   free download cuteftp professional with crack   cuteftp v9   cuteftp 9 full   cuteftp company   cuteftp 7 download   cuteftp trial version free download   cuteftp pro 8.3.2   cute hippo download   cuteftp screenshots   cuteftp 8 professional portable   download cuteftp 40   cutie ftp   snap 9 professional free download   global ftp   cuteftp 8.3 1 download   windows 98 ftp client   cuteftp professional torrent   cuteftp 8.3 crack free download   free ftp client windows 98   cute ftps   cuteftp installer   cuteftp lite download   cuteftp professional free download with crack   cuteftp pro 8.0   ftp cute 8   cuteftp 8.0 download   ftp client windows 98   cute client   cute ftb   cute pro   cute server   ftp server cute   ftp professional   win98 ftp client   ftp 8 download   cute ftp secure   ftp full version   global space ftp   globalscape cute   ftp globalscape   ftp client windows 98 free   cute ftp mac   globalscape free download   filezilla windows 98   globalscape ftp   ftp 9   use cute ftp   global communication .torrent   globalscape products   secure ftp clients   hippo ftp   free ftp client   free ftp server   filezilla server   filezilla server setup   putty   cuteftp pro full   filezilla download   ftp client   cyberduck   qftp download   globalscape download site   cuteftp automation   free ftp storage   cuteftp lite serial   filezilla portable   free ftp service   filezilla for mac   free ftp hosting   cuteftp pro scripting   ftp download cnet   free online ftp   smartftp free download   free ftp mac   core ftp   cuteftp free download full version crack   fireftp   sftp client   flashfxp   leech ftp windows 8   leech ftp download   smartftp   smart ftp   best ftp for windows   best free ftp program   free ftp client for mac   core ftp download   freeftpd   coreftp download   free ftp server hosting   portable apps ftp client   ftps client download   easy ftp program   cuteftp filezilla   globalscape torrent   ftp globe   cuteftp 6 professional   cuteftp 8 professional torrent   cuteftp pro 8 torrent   fire ftp   ftp services   ftp software reviews   cuteftp 7.1 professional download   cuteftp settings   box ftp   ftp software pc   file manager ftp   eft software download   global ftp server   ftp service   what is an ftp account   cuteftp command line   cuteftp show hidden files   cuteftp ssh   filezilla free download   filehippo   free file storage   cuteftp pro serial   smartftp pro   how to use filezilla   free ftp space   free ftp download   how to use ftp client   filezilla 32 bit   free music ftp   cutepdf free download   premium link generator   forklift mac   filezilla alternative   filezilla server sftp   core ftp server   ipswitch ws_ftp professional   sftp server   btsync   free ftp server windows   proftpd connection timeout   transmit   filezilla mac   cuteftp pro 9 serial   coreftp lite   fxp client   filezilla tutorial   filezilla client   421 service not available remote server has closed connection   coreftp server   free seedbox   cuteftp lite serial number   filezilla fxp   free ftp os x   turbosoft water softener   socket error 10054 ftp   an existing connection was forcibly closed by the remote host   cuteftp pro 8 serial   filezilla sftp   free ftp client for windows xp   top ftp clients   cuteftp lite 8   qftp example   socket error 10053   usenet   control channel transfer error   qnetworkaccessmanager   free ftp client windows 8   cuteftp lite 8.3 serial   tcp keepalive   proftpd connection refused by server   ftp port   qftp qt5   btguard   leech download sites   ws_ftp pro   filezilla pgp   socket error 10054 connection reset by peer   filezilla review   qt ftp   lftp   best seedbox   war ftp daemon   pgp encryption   ftp 553   ftp client pgp   coreftp   crushftp server   core ftp le   leapftp 3.0 serial   free ftp client review   whatbox   free ftp server mac   free ftp client for windows 7   proftpd connection refused   feral seedbox   openpgp   ftp for mac   winscp download   fireftp vs filezilla   filezilla command line   free ftp account   leapftp serial   wsftp   ftp ftp ftp   windows explorer sftp   sftp client for windows   foxzilla   download cuteftp full crack   best mac ftp client   free fxp   cs filezilla   setup ftp server free   serial number for cuteftp   ftp coffeecup   best ftp download   alternative to winscp   ftp client wiki   download files from ftp server   cuteftp 4.0 free download   la ftp   cuteftp ubuntu   serial cuteftp 8.3 2   sftp client linux   file sharing website template   how to setup a home ftp server   gta5 mod menu   ftp manager mac   what does ftp stand for   corel ftp   how to make ftp server   how to install wordpress on a server   upload files to server   free putty   wsftp com   ftp software mac   free ftp program download   ftp clients for mac   best windows ftp   secure ftp server   filezilla ftp setup   ftp ftp com   visualwget   google apps ftp   for file   fireftp chrome   fast ftp downloader   wise ftp 3   download ftp mozilla   cuteftp serial number crack   cyberduck connection refused   free ftp server software   filzfelt   fast ftp transfer   what is a ftp client program   ftp f   free file upload download   filezilla automated file transfer   000webhost wordpress installation   smart ftp com   simple ftp   clear apple tv cache   setup an ftp server   leapftp   triangle minecraft   freeftp download   free transmit   download qftp   how to connect to ftp server filezilla   ftp ee   easy ftp   free ftp clients download   cuteftp cnet   set-up ftp   filezip   ftp software wiki   ftp upload chrome   black box ftp   a ftp   ftp uploading   my volusion   cuteftp mavericks   cubed host   transmit ftp windows   what is an ftp site   get an ftp site   setting up ftp server filezilla   how to use cuteftp 8   ftp programs download   free ftp clients   fast ftp upload   how to download files from ftp server in windows   the ftp   setup ftp filezilla   ftp wise   how to download from an ftp server   ftpdroid   zilla ftp   simple windows ftp client   ftp site downloader   bplaced   ftp online   faster ftp download   configuring filezilla ftp server   ftp for linux   wordpress fatal error   best ftp manager   free file transfers   apex minecraft   servidor ftp   ftp program for windows 7   free upload and download file   free fireftp   ssh file transfer mac   personal ftp server   ftp from mac   ftp automatic upload   fetch for mac   web ftp client   cuteftp synchronize   cuteftp for mac download   free windows ftp client   free stp   cuteftp 8 torrent   backup wordpress website   upload file for free download   cuteftp zip   ftp upload tool   ftp web interface   econnaborted   best sftp client   how to install cuteftp   full effect hosting   winftp download   vijeo designer download   ftp download   file upload to server   gta 5 online mod menu ps3   ftp between two computers   how to ftp in windows 7   simplest ftp   how to install wordpress on cpanel   ftp os x   cyberduck alternatives   access ftp site   ps3 ftp client   webfaction ftp   ftp from internet   ftp commander   best ftp software   use filezilla as ftp server   what is ws_ftp pro   windows command line ftp   la file   transmit for windows   sourceforge download manager   godaddy ftp setup   access ftp server   port command successful consider using pasv   upload ftp chrome   windows scp client   ftp duck   ftp commands windows   kompozer download   how to use multicraft   ftp logs   transfer file free   port forwarding for ftp   ws_ftp32   free send large files   new ftp   000webhost login   filz   best free ftp client for windows   lifehacker filezilla   easy to use ftp client   ftp tool download free   ftp servers   wtp ftp   tiny ftp server   yahoo small business ftp   net 2 ftp   web ftp server   how to install plugins in wordpress   host ftp server   ftp wordpress   free ftps client   what is a com file   open source ftp client   how to go to ftp   how to download data from ftp server   ftp server on windows 7   at file   gozilla com   cyber duck   cuteftp mac rapidshare   wsftp download   how to set up cuteftp   ftp ipage   gmad extractor   smart ftp features   free file exchange   ftp file   mac winscp   how to setup a ftp server with filezilla   ftp on a mac   ftp applications   klient ftp   z ftp   ubuntu scp client   ftp on godaddy   are you sure you want to do this wordpress theme upload   ftp upload free   cuteftp multipart   free ftp setup   cuteftp manual   nfoservers   can you create your own server address for filezilla   setup ftp server windows 7   windows sftp server free   good free ftp client   fast upload ftp client      download cuteftp professional free   cute ftp com   cuteftp pro 3   ftp client cuteftp   cuteftp ftp   download cuteftp for windows 7   cute download ftp   cuteftp full version download   download globalscape cuteftp   www.cuteftp.com download   free cuteftp software   cuteftp download full   free download cuteftp 8 home   free cuteftp download full version   free download cuteftp full version   free cuteftp pro download   free download cuteftp for windows 7   free download cuteftp latest version   cuteftp professional full version free download   portable cuteftp free download   ftp program cuteftp   www cuteftp com   cuteftp gratis   cuteftp 9.0   download cuteftp 8.3   cuteftp 6.0 professional   cuteftp 3.0 free download   cuteftp free download old version   cuteftp ftp server   cuteftp 4   cuteftp 8 lite download   global cuteftp   cuteftp 8.0 pro   download cute ftp professional   ftps cuteftp   download cuteftp 5   download cuteftp 8   cuteftp 7   cuteftp 8.3 professional download   cuteftp 5   globalscape cuteftp 8 professional   cuteftp 5 xp   download cuteftp pro 8   cuteftp server   cuteftp features   download cuteftp home   cuteftp home free download   download cuteftp professional   cuteftp home iphone   cuteftp version 8 download   download free cuteftp professional   free download cuteftp professional   download cuteftp 8 professional   cuteftp 8 professional download   cuteftp home windows mobile   cuteftp pro download free   download cuteftp pro free   cuteftp 8 professional download free   cuteftp 8 pro download   cuteftp trial version download   cuteftp icon   download cuteftp portable   cuteftp windows 7 compatibility   freeware cuteftp   cuteftp pro 9.0   free download cuteftp 8.0 professional   cuteftp 8.3 professional free download   globalscape cuteftp pro   cuteftp filehippo   globalscape cuteftp 8.0   download globalscape cuteftp 8.0   how to use cuteftp mac   globalscape-cuteftp 8.3 professional free download   cuteftp 64   globalscape sftp download   cuteftp linux   cuteftp writer   cute ftp software   ftp cute free   cuteftp client download   cute ftp server   cuteftp version history   free download cuteftp 8 professional   cuteftp pro 6   cuteftp 6 free download   download cuteftp 7   cuteftp login   cuteftp pro rapidshare   cuteftp pro old version   pro ftp   cuteftp 7 home   cuteftp 8.3.2 pro   ftp pro   global scape cute ftp   ftp cut   download cute ftp   cuteftp downloads   free ftp cute   cuteftp 9 free download   cuteftp xp   download cuteftp server   free ftp client cute   cuteftp client download free   download ftp cute free   cute ftp freeware   cute ftp client   cute ftp client download   cuteftp 6   features of cuteftp   cuteftp language   cuteftp reviews   download cuteftp 50   cuteftp 7 professional   cuteftp home 8 download   cuteftp 7 free download   cuteftp home reviews   cuteftp key free download   cuteftp license   cuteftp writer free download   portable cuteftp   cuteftp windows 7 64 bit   cuteftp vista   cuteftp windows vista   cuteftp sync   cuteftp 8.0   cuteftp 6.0   cuteftp 3.0   cuteftp utf-8   cuteftp 8.3 2   cuteftp professional 8.0   cuteftp 8.0 professional   cuteftp 8.3 professional   cuteftp 7.0 professional   cuteftp 8.3.2 professional   cuteftp professional 8.3.2   cuteftp professional vs filezilla   globalscape cuteftp professional   globalscape cuteftp 8.3   [phpBB Debug] PHP Warning: in file [ROOT]/includes/functions.php on line 4517: Cannot modify header information - headers already sent by (output started at [ROOT]/index.php:29)
    [phpBB Debug] PHP Warning: in file [ROOT]/includes/functions.php on line 4517: Cannot modify header information - headers already sent by (output started at [ROOT]/index.php:29)
    [phpBB Debug] PHP Warning: in file [ROOT]/includes/functions.php on line 4517: Cannot modify header information - headers already sent by (output started at [ROOT]/index.php:29)
    Praetorian Guards - Index page

    It is currently Mon Aug 20, 2018 7:08 pm

    • Topics
      Posts
      Last post

    Login  •  Register

    Who is online

    In total there are 4 users online :: 1 registered, 0 hidden and 3 guests (based on users active over the past 5 minutes)
    Most users ever online was 92 on Thu May 17, 2018 10:04 pm

    Registered users: metapseudo
    Legend: Death Knights, Demon Hunters, Druids, Hunters, Mages, Monks, Paladins, Priests, Rogues, Shamans, Warlocks, Warriors

    Statistics

    Total posts 77983 • Total topics 11402 • Total members 955 • Our newest member tffwakka

    cron