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T-Cell Acute Lymphoblastic Leukemia

T ALL

T-cell acute lymphoblastic leukemia is a rare, but aggressive hematologic malignancy that develops due to numerous genetic mutations, eventually leading to impaired proliferation of thymocytes and bone marrow failure, characterized by anemia, thrombocytopenia and neutropenia. CNS symptoms may be observed in advanced stages of the disease. Histology and immunophenotyping through flow cytometry are necessary for diagnosis, whereas high-dose methotrexate is the mainstay of therapy.

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Presentation

Patients most often present with signs of bone marrow failure, such as anemia, neutropenia and thrombocytopenia, manifesting as recurrent and possibly life-threatening infections, fatigue, fever, pallor and frequent bleeding. In the setting of CNS involvement, which is restricted to advanced stages of the disease, symptoms including headaches, lethargy and cranial nerve palsies may be seen. Clinical examination may reveal splenomegaly and lymphadenopathy [14].

Easy Bruising
  • Additionally, the effects of reduced red blood cell count (anemia) and thrombocytes (thrombocytopenia) present with fatigue, easy bruising and bleeding.[symptoma.com]
  • Thrombocytopenia is a condition when there is a low number of platelets which can cause bleeding and easy bruising with no apparent cause. Low numbers of all three blood cell counts is called pancytopenia.[lls.org]
  • Easy bruising or bleeding. Petechiae (flat, pinpoint, dark-red spots under the skin caused by bleeding). Bone or joint pain. Painless lumps in the neck, underarm, stomach, or groin. Pain or feeling of fullness below the ribs.[cancer.gov]
Splenomegaly
  • Clinical examination may reveal splenomegaly and lymphadenopathy. The initial diagnosis can be made based on laboratory findings that reveal anemia and thrombocytopenia, with either a low or high leukocyte count, but very low neutrophil levels.[symptoma.com]
  • […] lymphadenopathy Symptoms related to a large mediastinal mass (eg, shortness of breath), particularly with T-cell lymphoblastic leukemia/lymphoma (T-ALL) Bone pain (can be severe and often atypical) Left upper quadrant fullness and early satiety due to splenomegaly[emedicine.medscape.com]
Fever
  • A 27-year-old male presented with breathlessness, ascites, bilateral pedal edema and fever. He had mild hepatomegaly. On detailed clinical examination, a diagnosis of anemia with cardiac tamponade was made.[ncbi.nlm.nih.gov]
  • As a result, the function of the bone marrow and production of white blood cells is altered, manifesting as the presence of recurrent infections that may be life-threatening, as well as fever.[symptoma.com]
  • If your child develops a fever we will use standard fever management and they will be admitted to our oncology unit in the Main Hospital. Some children develop more serious side effects requiring transfer to our Pediatric Intensive Care Unit (PICU).[chop.edu]
  • Area, New Delhi 110016, India, Tel: 918826836670; E-mail: anirban.nrs@gmail.com Received: November 14, 2016; Accepted: February 15, 2017; Published: February 23, 2017 A 12 year old premorbidly asymptomatic boy presented with complaints of on and off fever[henrypublishinggroups.com]
  • We will see the hypotension and the fevers, and we’re very likely to see neurologic sequalae, as well. Not necessarily severe, but we are very likely to see some confusion, very likely to see some aphasia that develops.[onclive.com]
Anemia
  • Additionally, the effects of reduced red blood cell count (anemia) and thrombocytes (thrombocytopenia) present with fatigue, easy bruising and bleeding.[symptoma.com]
  • We describe a 2-year-old female who presented with macrocephaly and anemia. Magnetic resonance imaging revealed a diffusely enhancing epidural lesion over the sagittal frontoparietal region.[ncbi.nlm.nih.gov]
  • His investigations revealed anemia (hemoglobin 7.1 gm/dl), leucocytosis (total leucocyte count 65800/mm 3 ), thrombocytopenia (platelet 89000/mm 3 ) and a peripheral smear having 81% blasts, phenotypically lymphoid.[henrypublishinggroups.com]
Lymphadenopathy
  • In comparison, patients 16 to 60 years old (n 21) more commonly had an anterior mediastinal mass (8 [38%]), hepatosplenomegaly (10 [48%]), and lymphadenopathy (16 [76%]).[academic.oup.com]
  • LBL frequently presents with mass in anterior mediastinum, rapid growth, respiratory emergency, pleural effusion Younger (age 16 - 60 years) patients compared to older (61 years) patients have more hepatosplenomegaly, present with mediastinal mass and lymphadenopathy[pathologyoutlines.com]
  • Clinical examination may reveal splenomegaly and lymphadenopathy. The initial diagnosis can be made based on laboratory findings that reveal anemia and thrombocytopenia, with either a low or high leukocyte count, but very low neutrophil levels.[symptoma.com]
  • Signs and symptoms Signs and symptoms of ALL include the following: Fever Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding Blood clots Palpable lymphadenopathy[emedicine.medscape.com]
Fatigue
  • Additionally, the effects of reduced red blood cell count (anemia) and thrombocytes (thrombocytopenia) present with fatigue, easy bruising and bleeding.[symptoma.com]
  • They include: Fatigue Fever Loss of appetite or weight Night sweats Many symptoms of acute lymphoblastic leukemia are the result of a shortage of normal blood cells. That's because leukemia cells crowd out these normal cells in the bone marrow.[webmd.com]
  • Anemia is a condition when there is a low number of red cells in the blood which can cause fatigue and shortness of breath.[lls.org]
  • Signs and symptoms Signs and symptoms of ALL include the following: Fever Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding Blood clots Palpable lymphadenopathy[emedicine.medscape.com]
Pallor
  • There was moderate pallor, bilateral, multiple, discrete, soft cervical lymph nodes with largest measuring up to 2 cm. There was bilateral enlargement of breast (left right); it was soft, granular in feel with no redness or discharge (Figure 1).[henrypublishinggroups.com]
  • Patients most often present with signs of bone marrow failure, such as anemia, neutropenia and thrombocytopenia, manifesting as recurrent and possibly life-threatening infections, fatigue, fever, pallor and frequent bleeding.[symptoma.com]
  • Signs and symptoms Signs and symptoms of ALL include the following: Fever Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding Blood clots Palpable lymphadenopathy[emedicine.medscape.com]
Respiratory Distress
  • distress, altered mental status) Renal failure in patients with a high tumor burden Infections, including pneumonia Petechiae (particularly on lower extremities) and ecchymoses Rashes from skin infiltration with leukemic cells See Presentation for more[emedicine.medscape.com]
Dyspnea
  • Signs and symptoms Signs and symptoms of ALL include the following: Fever Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding Blood clots Palpable lymphadenopathy[emedicine.medscape.com]
Abdominal Pain
  • We report a case of a 5-year-old boy who presented to the emergency department with gross hematuria, abdominal pain, and vomiting and was ultimately diagnosed with uric acid nephrolithiasis and acute renal failure secondary to spontaneous tumor lysis[ncbi.nlm.nih.gov]
  • Our patient presented with lower abdominal pain and clinical signs and symptoms, as well as biochemical evidence of thyrotoxicosis.[hindawi.com]
  • An 11-year-old developmentally delayed boy with a 3-week history of abdominal pain, emesis, and constipation was transferred to our tertiary care center for treatment of acute pancreatitis.[journals.lww.com]
  • The first patient, a 57-year-old woman, complained of fever and abdominal pain and distension. A computed tomography (CT) showed a solid-cystic mass in the left ovary.[elsevier.es]
Early Satiety
  • satiety due to splenomegaly (about 10% of cases) Symptoms of leukostasis (eg, respiratory distress, altered mental status) Renal failure in patients with a high tumor burden Infections, including pneumonia Petechiae (particularly on lower extremities[emedicine.medscape.com]
Hepatosplenomegaly
  • A 6-year-old male presented with a testicular mass, hepatosplenomegaly, and a pleural effusion while undergoing maintenance chemotherapy for treatment of T-cell acute lymphoblastic leukemia (T-ALL).[ncbi.nlm.nih.gov]
  • In comparison, patients 16 to 60 years old (n 21) more commonly had an anterior mediastinal mass (8 [38%]), hepatosplenomegaly (10 [48%]), and lymphadenopathy (16 [76%]).[academic.oup.com]
  • […] minimal marrow involvement CNS involvement if untreated T LBL frequently presents with mass in anterior mediastinum, rapid growth, respiratory emergency, pleural effusion Younger (age 16 - 60 years) patients compared to older (61 years) patients have more hepatosplenomegaly[pathologyoutlines.com]
Jaundice
  • Obstructive jaundice: an unusual initial manifestation of intra-abdominal non-Hodgkin lymphoma in a child.[journals.lww.com]
Palpitations
  • She denied fever, chills, genitourinary symptoms, or any changes in her bowel habits but mentioned palpitations, heat intolerance, a 7-Kg unintentional weight loss, insomnia, and tremor over the preceding 6 months.[hindawi.com]
  • Signs and symptoms Signs and symptoms of ALL include the following: Fever Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding Blood clots Palpable lymphadenopathy[emedicine.medscape.com]
Hypotension
  • We will see the hypotension and the fevers, and we’re very likely to see neurologic sequalae, as well. Not necessarily severe, but we are very likely to see some confusion, very likely to see some aphasia that develops.[onclive.com]
Bone Pain
  • There was no history of cough, swelling anywhere else in the body, bone pain, abdominal distention, bleeding, blood transfusion, contact with tuberculosis, redness, trauma or discharge from breasts.[henrypublishinggroups.com]
  • pain (can be severe and often atypical) Left upper quadrant fullness and early satiety due to splenomegaly (about 10% of cases) Symptoms of leukostasis (eg, respiratory distress, altered mental status) Renal failure in patients with a high tumor burden[emedicine.medscape.com]
Long Arm
  • Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal.[ncbi.nlm.nih.gov]
Petechiae
  • Petechiae (flat, pinpoint, dark-red spots under the skin caused by bleeding). Bone or joint pain. Painless lumps in the neck, underarm, stomach, or groin. Pain or feeling of fullness below the ribs. Weakness, feeling tired, or looking pale.[cancer.gov]
  • […] atypical) Left upper quadrant fullness and early satiety due to splenomegaly (about 10% of cases) Symptoms of leukostasis (eg, respiratory distress, altered mental status) Renal failure in patients with a high tumor burden Infections, including pneumonia Petechiae[emedicine.medscape.com]
Eruptions
  • The addition of basiliximab promoted gradual improvement of the skin, allowing for chemotherapy intensification and subsequent bone marrow transplantation, after which the eruption resolved completely.[ncbi.nlm.nih.gov]
Dizziness
  • A shortage of red blood cells may cause symptoms of anemia, including: Fatigue or weakness Dizziness Feeling cold Light-headedness Shortness of breath A shortage of normal white blood cells may result in: Fevers Recurring infections A shortage of blood[webmd.com]
  • Signs and symptoms Signs and symptoms of ALL include the following: Fever Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding Blood clots Palpable lymphadenopathy[emedicine.medscape.com]
Headache
  • If the tumor has spread to the central nervous system, which is characteristic for more advanced stages of the disease, headaches, lethargy, vomiting and neck stiffness may be observed.[symptoma.com]
  • Depending upon where leukemia cells are present, other symptoms may include: A full or swollen belly from leukemia cells in the liver or spleen Enlarged lymph nodes such as in the neck or groin, under arms, or above the collarbone Bone or joint pain Headache[webmd.com]
Lethargy
  • If the tumor has spread to the central nervous system, which is characteristic for more advanced stages of the disease, headaches, lethargy, vomiting and neck stiffness may be observed.[symptoma.com]
Neck Stiffness
  • If the tumor has spread to the central nervous system, which is characteristic for more advanced stages of the disease, headaches, lethargy, vomiting and neck stiffness may be observed.[symptoma.com]

Workup

The initial diagnosis can be made based on laboratory findings that reveal anemia and thrombocytopenia, with either a low or high leukocyte count, but very low neutrophil levels. If pleural effusions are suspected during physical examination, either radiography or CT may be performed to exclude the presence of a mass in the mediastinum. Because bone marrow is the primary site of involvement, a biopsy with subsequent immunophenotyping through flow cytometry is the mainstay of diagnosis. Diffuse infiltration of the marrow by lymphoblasts is a typical feature of T-ALL, while markers of T-cell are CD1a, CD2, CD3, CD4, CD5, CD7 and CD8.

Mediastinal Mass
  • Computed tomography scan of the chest showed a large left mediastinal mass (9 7.2 7 cm) and left pleural effusion.[ncbi.nlm.nih.gov]
  • ) patients have more hepatosplenomegaly, present with mediastinal mass and lymphadenopathy; myeloid antigens and lineage inappropriate gene rearrangements are less common ( Am J Clin Pathol 2002;117:252 ) Diagnosis: T ALL if lymphoblasts are 25% or more[pathologyoutlines.com]
  • In comparison, patients 16 to 60 years old (n 21) more commonly had an anterior mediastinal mass (8 [38%]), hepatosplenomegaly (10 [48%]), and lymphadenopathy (16 [76%]).[academic.oup.com]
Pseudomonas
  • To pursue the possibility of translating those immunotoxins into clinics, we humanized the nanobody sequences (designated as dhuVHH6) as well as further truncated the Pseudomonas exotoxin A (PE)-derived PE38 toxin to produce a more protease-resistant[ncbi.nlm.nih.gov]

Treatment

High-dose aggressive chemotherapy with methotrexate, a folate analog that inhibits enzymes requiring folic acid, is the mainstay of T-ALL therapy [7]. This drug is given in doses of 20 mg/m2 per os every week or by 24-hour intravenous infusion in doses of 33.6 g/m2 [7]. Although the optimal dose of the drug has yet to be agreed upon [7].

Because NOTCH1 mutations have been identified in a large number of patients, directed therapy against receptor activity in the form of γ-secretase inhibitors (GSIs) showed promising results in initial studies [4].

Unfortunately, mutations that make the tumor resistant to GSIs have been discovered and the exact circumstances under which these mutations occur remain to be disclosed [13]. Nelarabine, a T-cell cytotoxic drug, was added to the regimen in patients with a poor prognosis and did not prolong survival rates in a significant manner, but it did reduce the rate of neutropenic infections [8].

Prognosis

Various factors have been proposed as prognostic markers, including high T-cell count (> 100x10^9/L), older age (> 35 years) and female gender [12]. Recent introduction of aggressive chemotherapy has shown to be curative in over 75% of children and in 5% of adults [4], but despite all therapeutic measures, approximately 15% of pediatric and 40% of adult patients suffer a relapse of the disease, primarily due to acquired therapy resistance [9]. More devastating is the fact that 5-year overall survival rates for adult patients are only 45% despite reaching remission, which points to a highly malignant and invasive nature of this disease [10]. On the other hand, the prognosis is somewhat better in the pediatric population, in whom long-term mortality rates are 20% [11].

Etiology

Malignant T-lymphocytes in T-ALL arise from hematopoietic progenitor cells that further develop into partially proliferated thymocytes as a result of numerous genetic mutations and alterations [4] [6]. Some of the most important mutations that have been identified include [4] [5] [6].:

  • T cell oncogenes such as HOX11, TAL1, LYL1, LMO1, and LMO2.
  • Inactivation of the CDKN2A/INK4A/ARF and p14/16 Tumor suppressor gene.
  • LIM-only domain (LMO) genes, LMO1 and LMO2.
  • Upregulation of NOTCH1 transmembrane receptors.

In approximately 40% of patients suffering from this malignant disease, chromosomal aberrations that are responsible T-ALL development remain unknown [3].

Epidemiology

ALL is considered to be the most frequently diagnosed malignant disease in children and T-ALL is responsible for approximately 15% of pediatric and 25% of adult cases, respectively [1] [12]. Numerous reports show a significant predilection toward male patients [4], while additional risk factors are currently not established.

Sex distribution
Age distribution

Pathophysiology

Dysregulated production of thymocytes is influenced by numerous genes. In up to 60% of cases, mutations in NOTCH1 are observed. The NOTCH family of protein transmembrane receptors are crucial for regulation of apoptosis, cell proliferation and their fate during development. Aberrant signalling mediated by these receptors has been established in many other tumors, not only T-ALL [13]. Mutations in LCK, tumor suppressor genes (CDKN2A/INK4A/ARF) and transcription factors have been identified in many patients as well [6]. Several T-cell oncogenes, including HOX11, TAL1, LYL1, LMO1, and LMO2 have shown abnormal expression in the setting of T-ALL and their roles in influencing proper thymocyte development have been well-established [5].

Prevention

Although the pathogenesis of T-ALL is partly understood, prevention of genetic events that lead to its development remains impossible. Certain risk factors for leukemias, in general, such as environmental exposure to benzene, ionizing radiation and lifestyle habits including smoking and obesity [15]., could be acted upon, but current preventive strategies for this type of malignancy do not exist.

Summary

T-cell acute lymphoblastic leukemia (T-ALL) is a variant of acute lymphoblastic leukemia, which is considered as the most common malignancy of childhood, comprising almost 10-15% of all cancers seen in the pediatric population [1]. It is estimated that 15% of all ALLs in the pediatric population are T-ALL, whereas the ratio in adults rises up to 25% [2]. T-ALL stems from hematopoietic progenitor cells that are set for T-cell development and it is thought that partially developed thymocytes are, in fact, the source of this malignancy [3] [4]. The pathogenesis model is complex, involving various mutations of T-cell oncogenes, tumor suppressor genes, transcription factors and proteins involved in signal transduction, the end-result being disruption of normal thymocyte proliferation [5] [6]. Mutations of NOTCH1, a family of transmembrane protein receptors involved in transcription and regulation of cellular signalling, are present in about 60% of cases [4]. In 40% of patients, however, the exact cause remains unknown [3]. This tumor is seen more commonly in males and the diagnosis mandates a high index of clinical suspicion based on findings obtained during physical examination and laboratory studies. Bone marrow failure is observed in virtually all patients, manifesting as fatigue, recurrent infections, anemia, thrombocytopenia and neutropenia, whereas the central nervous system (CNS) may be affected in more advanced stages of the disease with headaches, vomiting and lethargy. Pleural effusions produced by a mediastinal mass is not uncommon, which is why imaging studies such as computed tomography (CT) may be useful. The mainstay of diagnosis, however, is biopsy and flow cytometry to determine the immunophenotype of the tumor. The role of aggressive high-dose chemotherapy in modern treatment has substantially increased the rate of cure among patients, reaching 75% in children and 50% in adults [4]. Methotrexate is the single most important chemotherapeutic agent used in patients with T-ALL, either orally or intravenously [7]., while recent studies have suggested novel drugs for A-TLL patients. γ-secretase inhibitors (GSIs) that act against NOTCH receptor antagonists and nelarabine, a T-cell cytotoxic drug have been developed in recent years [4] [8]. Despite these measures, however, many patients relapse and have a poor prognosis under such circumstances [9]. Overall survival rates are much better if the tumor is diagnosed in children (up to 80%) compared to adults, in whom 5-year survival is only 45% [10] [11]. These findings indicate a detrimental need for an early diagnosis for timely initiation of therapy, so that maximal survival is achieved.

Patient Information

T-cell acute lymphoblastic leukemia (T-ALL) is one of the subtypes of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. T-ALL comprises about 15% of all ALL cases, but it may be seen in adults as well and the cause stems from numerous genetic mutations. Namely, genes that are responsible for regulation of cell cycle, programmed cell death (known as apoptosis) and proliferation of blood cells, specifically T lymphocytes (which carry out numerous important functions in the immune system) undergo various mutations. As a result, the function of the bone marrow and production of white blood cells is altered, manifesting as the presence of recurrent infections that may be life-threatening, as well as fever. Additionally, the effects of reduced red blood cell count (anemia) and thrombocytes (thrombocytopenia) present with fatigue, easy bruising and bleeding. If the tumor has spread to the central nervous system, which is characteristic for more advanced stages of the disease, headaches, lethargy, vomiting and neck stiffness may be observed. To make the diagnosis, it is essential to obtain basic laboratory values - a complete blood count (CBC), perform a detailed physical examination and obtain a detailed patient history regarding the onset of symptoms. Imaging studies such as computed tomography (CT scan) and magnetic resonance imaging (MRI) may be useful in assessing the state of thoracic and abdominal organs, but to make a definite diagnosis, biopsy of the bone marrow and subsequent examination of the obtained sample is necessary. The focus of treatment is administration of high-dose chemotherapy consisting primarily of methotrexate and early treatment may have curative effects in the vast majority of patients. However, T-ALL is an aggressive form of malignancy and relapses are quite frequent, despite adequate therapy. It is important to point out that the prognosis is much better in children than in adults and in males compared to females, for still unknown reasons. It is estimated that almost 20% of children will die from this disease in long-term follow-up, whereas 5-year survival rates are below 50% for adults. New therapeutic strategies are being developed that target the tumor on a molecular basis, but until their use becomes solidified in general practice, this tumor poses a significant and life-threatening risk for patients.

References

Article

  1. Vicente C, Schwab C, Broux M, et al. Targeted sequencing identifies association between IL7R/JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica. 2015;100(11):1373–1375.
  2. La Starza R, Borga C, Barba G, et al. Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocation. Blood. 2014;124(24):3577–3582.
  3. Homminga I, Pieters R, Langerak AW, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19(4):484–497.
  4. Van Vlieberghe P, Ferrando A. The molecular basis of T cell acute lymphoblastic leukemia. J Clin Invest. 2012;122(10):3398–3406.
  5. Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75–87.
  6. Soulier J, Clappier E, Cayuela JM, et al. HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood. 2005;106(1):274–286.
  7. Asselin BL, Devidas M, Wang C, et al. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children’s Oncology Group (POG 9404). Blood. 2011;118(4):874-883.
  8. Dunsmore KP, Devidas M, Linda SB, et al. Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(22):2753-2759.
  9. Durinck K, Goossens S, Peirs S, et al. Novel biological insights in T-cell acute lymphoblastic leukemia. Exp Hematol. 2015;43(8):625–639.
  10. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol. 2013;31(34):4333-4342.
  11. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147–156.
  12. Marks DI, Paietta EM, Moorman AV, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114(25):5136-5145.
  13. O'Neil J, Grim J, Strack P, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007; 204:1813–1824.
  14. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Whitehouse Station, N.J: Merck Sharp & Dohme Corp;2011.
  15. Ilhan G, Karakus S, Andic N. Risk factors and primary prevention of acute leukemia. Asian Pac J Cancer Prev. 2006;7(4):515-517.

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Last updated: 2019-07-11 20:01