and also in the "blast crisis" of cml. medical imaging (such as ultrasound or ct scanning) can find invasion of other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys, and reproductive organs. acute lymphoblastic leukemia (all), peripheral blood of a child, pappenheim stain, magnification x100 bone marrow smear (large magnification) from a person with acute lymphoblastic leukemia bone marrow smear from a person with acute lymphoblastic leukemia immunophenotyping in addition to cell morphology and cytogenetics, immunophenotyping, a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of all. the preferred method of immunophenotyping is through flow cytometry. in the malignant lymphoblasts of all, expression of terminal deoxynucleotidyl transferase (tdt) on the cell surface can help differentiate malignant lymphocyte cells from reactive lymphocytes, white blood cells that are reacting normally to an infection in the body. on the other hand, myeloperoxidase (mpo), a marker for the myeloid lineage, is typically not expressed. because precursor b cell and precursor t cells look the same, immunophenotyping can help differentiate the subtype of all and the level of maturity of the malignant white blood cells. the subtypes of all as determined by immunophenotype and according to the stages of maturation. b cell lineage t cell lineage pre-pre-b all (pro-b-all) precursor t- all common all mature t-cell all pre-b all mature b-cell all (burkitt leukemia – fab l3) an extensive panel of monoclonal antibodies to cell surface markers, particularly cd or cluster of differentiation markers, are used to classify cells by lineage. below are immunological markers associated with b cell and t cell all. immunological markers b cell lineage t cell lineage b cell lineage cd19, cd22, cd79a + − cd10 − or + (common all) cytoplasmic ig − or + (pre-b all) surface ig − or + (mature b-cell all) tdt + + t cell lineage cd2, cd3, cd4, cd5, cd7, cd8 − + tdt + + cytogenetics cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of all from different age groups. this information is particularly valuable for classification and can in part explain the different prognoses of these groups. in regards to genetic analysis, cases can be stratified according to ploidy, a 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 are defined as cells with less than 44 chromosomes. hyperdiploid cases tend to carry a good prognosis while hypodiploid cases do not. for example, the most common specific abnormality in childhood b-all is the t(12;21) etv6–runx1 translocation, in which the runx1 gene, encoding a protein involved in transcriptional control of hemopoiesis, has been translocated and repressed by the etv6–runx1 fusion protein. below is a table with the frequencies of some cytogenetic translocations and molecular genetic abnormalities in all. cytogenetic translocation molecular genetic abnormality % cryptic t(12;21) tel–aml1 fusion 25.4% t(1;19)(q23;p13) e2a–pbx (pbx1) fusion 4.8% t(9;22)(q34;q11) bcr-abl fusion(p185) 1.6% t(4;11)(q21;q23) mll–af4 fusion 1.6% t(8;14)(q24;q32) igh–myc fusion t(11;14)(p13;q11) tcr–rbtn2 fusion classification french-american-british historically, prior to 2008, all was classified morphologically using the french-american-british (fab) system that heavily relied on morphological assessment. the fab system takes into account information on size, cytoplasm, nucleoli, basophilia (color of cytoplasm), and vacuolation (bubble-like properties). fab subtype cell type characteristics comments all - l1 t cell or pre-b cell small and homogeneous (uniform) cells all - l2 t cell or pre-b cell large and heterogeneous (varied) cells all - l3 b cell large and varied cells with vacuoles mature b-cell all also named burkitt leukemia. typically, poor 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 its limited impact on treatment choice and prognostic value.: 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.: 1531–1535 this subtyping helps determine the prognosis and the most appropriate treatment for each specific case of all. the who subtypes related to all are: b-lymphoblastic leukemia/lymphoma not otherwise specified (nos) with recurrent genetic abnormalities with t(9;22)(q34.1;q11.2);bcr-abl1 with t(v;11q23.3);kmt2a rearranged with t(12;21)(p13.2;q22.1); etv6-runx1 with t(5;14)(q31.1;q32.3) il3-igh with t(1;19)(q23;p13.3);tcf3-pbx1 with hyperdiploidy with hypodiploidy t-lymphoblastic leukemia/lymphoma acute leukemias of ambiguous lineage acute undifferentiated leukemia mixed phenotype acute leukemia (mpal) with t(9;22)(q34.1;q11.2); bcr–abl1 mpal with t(v;11q23.3); kmt2a rearranged mpal, b/myeloid, nos mpal, t/myeloid, nos treatment two girls with all demonstrating intravenous access for chemotherapy the aim of treatment is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow). over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. possible treatments for acute leukemia include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), targeted therapy, and/or growth factors. chemotherapy chemotherapy is the initial treatment of choice, and most people with all 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 person. chemotherapy for all consists of three phases: remission induction, intensification, and maintenance therapy. phase description agents remission induction aim to: rapidly kill most tumor cells reduce leukemic blasts in the bone marrow to <5% and eliminate tumor cells from blood induce absence of other signs and symptoms of the disease. must monitor closely for tumor lysis syndrome after initiating therapy monitoring initial response to treatment is important as failure to show clearance of blood or bone marrow blasts within the first two weeks of therapy has been associated with a 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 people in pediatric care) daunorubicin (used in adult all) central nervous system prophylaxis can be achieved via: cranio-spinal irradiation cytarabine + methotrexate or liposomal cytarabine in philadelphia chromosome-positive all, the intensity of initial induction treatment may be less than has been traditionally given. consolidation/intensification use high doses of chemotherapy to further reduce tumor burden typical protocols use the following given as blocks (varies from 1–3 blocks depending on person'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 three years for boys, two 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 adult chemotherapy regimens mimic those of childhood all; however, are linked with a higher risk of disease relapse with chemotherapy alone. two subtypes of all (b-cell all and t-cell all) require special considerations when it comes to selecting an appropriate treatment regimen in adults with all. 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. 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 the occurrence and/or recurrence of leukemia in the brain. recent studies showed that cns chemotherapy provided results as favorable but with fewer developmental side effects. as a result, the use of whole-brain radiation has been more limited. most specialists in adult leukemia have abandoned the use of radiation therapy for cns prophylaxis, instead using intrathecal chemotherapy. biological therapy selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of all treatment. tyrosine-kinase inhibitors (tkis), such as imatinib, are often incorporated into the treatment plan for people 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. immunotherapy chimeric antigen receptors (cars) have been developed as a promising immunotherapy for all. this technology uses a single chain variable fragment (scfv) designed to recognize the cell surface marker cd19 as a method of treating all. cd19 is a molecule found on all b-cells and can be used as a means of distinguishing the potentially malignant b-cell population. in this therapy, mice are immunized with the cd19 antigen and produce anti-cd19 antibodies. hybridomas developed from mouse spleen cells fused to a myeloma cell line can be developed as a source for the cdna encoding the cd19 specific antibody. the cdna is sequenced and the sequence encoding the variable heavy and variable light chains of these antibodies are cloned together using a small peptide linker. this resulting sequence encodes the scfv. this can be cloned into a transgene, encoding what will become the endodomain of the car. varying arrangements of subunits serve as the endodomain, but they generally consist of the hinge region that attaches to the scfv, a transmembrane region, the intracellular region of a costimulatory molecule such as cd28, and the intracellular domain of cd3-zeta containing itam repeats. other sequences frequently included are: 4-1bb and ox40. the final transgene sequence, containing the scfv and endodomain sequences is then inserted into immune effector cells that are obtained from the person and expanded in vitro. in trials these have been a type of t-cell capable of cytotoxicity. inserting the dna into the effector cell can be accomplished by several methods. most commonly, this is done using a lentivirus that encodes the transgene. pseudotyped, self-inactivating lentiviruses are an effective method for the stable insertion of a desired transgene into the target cell. other methods include electroporation and transfection, but these are limited in their efficacy as transgene expression diminishes over time. the gene-modified effector cells are then transplanted back into the person. typically this process is done in conjunction with a conditioning regimen such as cyclophosphamide, which has been shown to potentiate the effects of infused t-cells. this effect has been attributed to making an immunologic space within which the cells populate. the process as a whole result 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 people with acute b-cell lymphoblastic leukaemia who did not respond adequately to other treatments or have relapsed. in a 22-day process, the "drug" is customized for each person. t cells purified from each person are modified by a virus that inserts genes that encode a chimaeric antigen receptor into their dna, one that recognizes leukemia cells. relapsed all typically, people who experience a relapse in their all after initial treatment have a poorer prognosis than those who remain in complete remission after induction therapy. it is unlikely that recurrent leukemia will respond favorably to the standard chemotherapy regimen that was initially implemented, and instead, these people should be trialed on reinduction chemotherapy followed by allogeneic bone marrow transplantation. these people in relapse may also receive blinatumomab, as it has shown to increase remission rates and overall survival rates, without increased toxic effects. low dose palliative radiation may also help reduce the burden of tumor inside or outside the central nervous system and alleviate some symptoms. recently, there has also been evidence and approval of use