B-precursor acute lymphoblastic leukemia is often preceded by a period of low- or middle-grade febrility, which can evince a duration of even months. The symptoms caused by the early stages of the disease are not pathognomonic and include anorexia, fatigue, weight loss or a developmental arrest in younger children.

When the malignancy is diagnosed, the abnormal proliferation of lymphoblasts in the bone marrow has already induced an arrest in the production of the other cell lines, namely erythrocytes, platelets and other white blood cells. This state of pancytopenia leads to a multitude of symptoms and signs that are also nonspecific and may include any of the following:

• Pallor, fatigue and weakness, caused by anemia
• Recurring infections due to leukocytopenia
• Petechiae, epistaxis, hematuria or ecchymoses due to thrombocytopenia.
• Skeletal pain
• Neurological symptoms, such as headaches, seizures or vomiting; these may indicate the involvement of the central nervous system.
• Hepatosplenomegaly
• Enlarged lymph nodes

A specific sign that constitutes a warning of a potentially aggressive and refractory disease is telangiectasias on the bulbar conjunctiva in a child with B-ALL; those patients respond poorly to chemo- and radiotherapy.

• Splenomegaly

  Lymphadenopathy, hepatomegaly, splenomegaly, arthralgia and bone pain are signs and symptoms also reported (1, 3, 6). The white blood cell count varies from decreased to sharply increased (7). [jbpml.org.br]

  Minor prognostic factors, or those that have had some significance with certain treatment regimens, are the percentage of circulating blast cells; the degree of bone marrow involvement; the presence of hepatomegaly, splenomegaly, or lymphadenopathy; lactate [cancernetwork.com]

  Lymphadenopathy, splenomegaly, and hepatomegaly is seen in about 20% of patients with ALL. Abdominal masses are uncommon and if present suggest mature B-cell ALL (Burkitt’s lymphoma/leukemia). [cancertherapyadvisor.com]

  57%) 43 (43%) 0.257 Fever 144 (72.0%) 76 (76%) 68 (68%) 0.208 Infection 128 (64.0%) 66 (66%) 62 (%) 0.556 Bleeding 96 (48.0%) 45 (45%) 51 (51%) 0.396 Lymphadenopathy 112 (56.0%) 53 (53%) 59 (59%) 0.393 Hepatomegaly 84 (42.0%) 46 (46%) 38 (38%) 0.252 Splenomegaly [omicsonline.org]

  In some cases, this rapid cytokine release can even trigger hemophagocytic lymphohistiocytosis and macrophage activation syndrome, which are disorders of abnormal immune system activation characterized by high fever, splenomegaly, hyperferritinemia, hypertriglyceridemia [dovepress.com]

• Easy Bruising

  These include: being very tired, weak, or pale swollen lymph nodes infections (like bronchitis or tonsillitis) that keep coming back a fever night sweats easy bruising or petechiae (tiny red spots on the skin caused by easy bleeding) bone and joint pain [kidshealth.org]

  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]

  Symptoms of ALL include: Frequent infections Fever Easy bruising Bleeding that is hard to stop Flat, dark-red skin spots (petechiae) due to bleeding under the skin Pain in the bones or joints Lumps in the neck, underarm, stomach or groin Pain or fullness [stjude.org]

  bruising or bleeding bleeding under the skin shortness of breath weight loss or loss of appetite pain in the bones or stomach pain or a feeling of fullness below the ribs painless lumps in the neck, underarm, stomach, or groin tests that examine the [icd10data.com]

• Prolonged Bleeding

  Fatigue, Weakness, or Decrease of Energy Shortness of Breath Continuous or Prolonged Bleeding from Minor Cuts Red Spots Beneath Skin: These spots are the size of pinheads. [knowcancer.com]

• Fever

  We present the case of a 9-year-old girl from northwestern Greece admitted to our Hospital because of malaise, low-grade fever, intermittent hip joint pain, anemia, leukopenia and thrombocytopenia. [ncbi.nlm.nih.gov]

  Recurrent fevers/infections. The child with leukemia often shows non-specific symptoms of infection such as fever and fatigue. [chop.edu]

  Frequently reported adverse events included thrombocytopenia, neutropenia, leukopenia, infection, anemia, hemorrhage, fatigue, fever, nausea, headache, liver damage, hyperbilirubinemia, and abdominal pain. [cancertherapyadvisor.com]

  nausea, headache, low levels of white blood cells with fever (febrile neutropenia), liver damage (transaminases and/or gamma-glutamyltransferase increased), abdominal pain and high levels of bilirubin in the blood (hyperbilirubinemia). [fda.gov]

• Pain

  Bone and joint pain. Pain in bones and joints is usually a result of the bone marrow being crowded with leukemic blasts. This is often mistaken for "growing pains." Recurrent fevers/infections. [chop.edu]

  We present the case of a 9-year-old girl from northwestern Greece admitted to our Hospital because of malaise, low-grade fever, intermittent hip joint pain, anemia, leukopenia and thrombocytopenia. [ncbi.nlm.nih.gov]

  The symptoms of relapsed ALL are the same as those for newly diagnosed ALL, including: Anemia Bone and joint pain Bruising or petechiae (small red spots on the skin) Fever Recurrent infections Abdominal pain Swollen lymph nodes Dyspnea or difficulty breathing [danafarberbostonchildrens.org]

  Bone pain is relatively common and described in approximately 50% of patients (1, 7). Pain may also occur in the course of the disease or during treatment. [jbpml.org.br]

• Anemia

  The most common signs and symptoms of acute lymphoblastic leukemia in children are: Anemia. Anemia occurs when normal red blood cells can't be produced because the bone marrow is overcrowded by leukemia cells. [chop.edu]

  We present the case of a 9-year-old girl from northwestern Greece admitted to our Hospital because of malaise, low-grade fever, intermittent hip joint pain, anemia, leukopenia and thrombocytopenia. [ncbi.nlm.nih.gov]

  The most common presenting symptoms are due to disrupted hematopoiesis with ensuing Anemia Thrombocytopenia Granulocytopenia Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain. [msdmanuals.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]

  Frequently reported adverse events included thrombocytopenia, neutropenia, leukopenia, infection, anemia, hemorrhage, fatigue, fever, nausea, headache, liver damage, hyperbilirubinemia, and abdominal pain. [cancertherapyadvisor.com]

• Fatigue

  The symptoms caused by the early stages of the disease are not pathognomonic and include anorexia, fatigue, weight loss or a developmental arrest in younger children. [symptoma.com]

  Frequently reported adverse events included thrombocytopenia, neutropenia, leukopenia, infection, anemia, hemorrhage, fatigue, fever, nausea, headache, liver damage, hyperbilirubinemia, and abdominal pain. [cancertherapyadvisor.com]

  They include: Fatigue Fever Loss of appetite or weight loss Night sweats Tiny red spots just under your skin (petechiae) Stomach pain Many of the symptoms happen because your body is reacting to a lack of healthy blood cells. [webmd.com]

  Important Safety Information for BESPONSA® (Inotuzumab Ozogamicin) in the EU The most common (≥ 20%) adverse reactions associated with BESPONSA were thrombocytopenia (51%), neutropenia (49%), infection (48%), anaemia (36%), leukopenia (35%), fatigue [pfizer.com]

• Weakness

  Results presented here suggest that although expression of TCR genes was weak in B-precursor ALL cells compared with T-lineage cells, these genes experience both transcriptional and recombinational crossover in B-precursor ALL. [ncbi.nlm.nih.gov]

  Her weakness and vision have improved. FIGURE 2 The fundi of (A) the right eye and (B) the left eye by funduscopic examination. [current-oncology.com]

  This state of pancytopenia leads to a multitude of symptoms and signs that are also nonspecific and may include any of the following: Pallor, fatigue and weakness, caused by anemia Recurring infections due to leukocytopenia Petechiae, epistaxis, hematuria [symptoma.com]

• Dyspnea

  The symptoms of relapsed ALL are the same as those for newly diagnosed ALL, including: Anemia Bone and joint pain Bruising or petechiae (small red spots on the skin) Fever Recurrent infections Abdominal pain Swollen lymph nodes Dyspnea or difficulty breathing [danafarberbostonchildrens.org]

  In addition, patients can present with symptoms resulting from anemia, such as dyspnea or lightheadedness, infections due to neutropenia, or easy bruisability or bleeding resulting from thrombocytopenia. [cancertherapyadvisor.com]

  Keywords: ALL, acute renal failure, initial presentation, t(1;19) Introduction Symptoms of acute lymphoblast leukemia (ALL) usually present as fatigue, lack of energy, dyspnea, dizziness, bleeding, easy bruising, and infections arising from the expansion [ncbi.nlm.nih.gov]

  The most common presenting symptoms are due to disrupted hematopoiesis with ensuing Anemia Thrombocytopenia Granulocytopenia Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain. [msdmanuals.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]

• Cough

  Any wheezing, coughing and/or labored or painful breathing requires immediate medical attention. [chop.edu]

  For the most common adverse events (greater than or equal to 10 percent incidence rate) in the BLINCYTO arm, only three events (cough, pyrexia, cytokine release syndrome) occurred at an incidence rate that was at least 5 percent higher for BLINCYTO compared [prnewswire.com]

  For the most common adverse events (greater than or equal to 10 percent incidence rate) in the BLINCYTO arm, six events (pyrexia, infusion-related reaction, cough, cytokine release syndrome, tremor, decreased immunoglobulins) occurred at an incidence [amgen.com]

• Hepatosplenomegaly

  […] lymphoma with recurrent genetic abnormalities See also related topic to be merged Usually children B acute lymphoblastic leukemia presents with pancytopenia due to extensive marrow involvement, stormy onset of symptoms, bone pain due to marrow expansion, hepatosplenomegaly [pathologyoutlines.com]

  Hepatosplenomegaly Enlarged lymph nodes A specific sign that constitutes a warning of a potentially aggressive and refractory disease is telangiectasias on the bulbar conjunctiva in a child with B-ALL; those patients respond poorly to chemo- and radiotherapy [symptoma.com]

  She displayed hepatosplenomegaly and pleural and abdominal effusions without lymphadenopathy. Lactate dehydrogenase (10,554 U/L; normal range 106–211 U/L) was elevated. [journals.lww.com]

  CT of the chest and abdomen should be done to detect mediastinal masses and lymphadenopathy and may also detect hepatosplenomegaly. [msdmanuals.com]

• Hepatomegaly

  Lymphadenopathy, hepatomegaly, splenomegaly, arthralgia and bone pain are signs and symptoms also reported (1, 3, 6). The white blood cell count varies from decreased to sharply increased (7). [jbpml.org.br]

  Minor prognostic factors, or those that have had some significance with certain treatment regimens, are the percentage of circulating blast cells; the degree of bone marrow involvement; the presence of hepatomegaly, splenomegaly, or lymphadenopathy; lactate [cancernetwork.com]

  Lymphadenopathy, splenomegaly, and hepatomegaly is seen in about 20% of patients with ALL. Abdominal masses are uncommon and if present suggest mature B-cell ALL (Burkitt’s lymphoma/leukemia). [cancertherapyadvisor.com]

  Females 106 (53%) 94 (47%) 49 (49%) 51 (51%) 57 (57%) 43 (43%) 0.257 Fever 144 (72.0%) 76 (76%) 68 (68%) 0.208 Infection 128 (64.0%) 66 (66%) 62 (%) 0.556 Bleeding 96 (48.0%) 45 (45%) 51 (51%) 0.396 Lymphadenopathy 112 (56.0%) 53 (53%) 59 (59%) 0.393 Hepatomegaly [omicsonline.org]

  Veno-occlusive disease[edit] Severe liver injury can result from hepatic veno-occlusive disease (VOD), newly termed sinusoidal obstruction syndrome (SOS).[36] Elevated levels of bilirubin, hepatomegaly, and fluid retention are clinical hallmarks of this [en.wikipedia.org]

• Hematuria

  Case report A 52-year-old woman was admitted with a 2-month history of lumbago and a 2-week history of gross hematuria. Recently, she complained that her hypertension was difficult to control in spite of antihypertensive drug treatment (Norvasc). [ncbi.nlm.nih.gov]

  This state of pancytopenia leads to a multitude of symptoms and signs that are also nonspecific and may include any of the following: Pallor, fatigue and weakness, caused by anemia Recurring infections due to leukocytopenia Petechiae, epistaxis, hematuria [symptoma.com]

  Hematuria and GI bleeding are uncommon. Patients can present with spontaneous hemorrhage, including intracranial or intra-abdominal hematomas. [msdmanuals.com]

  This causes hematuria (blood in urine), frequent urination, abdominal pain, and thrombocytopenia.[37] Graft-versus-host disease[edit] Graft-versus-host disease (GVHD) is an inflammatory disease that is unique to allogeneic transplantation. [en.wikipedia.org]

• Testicular Disease

  The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature. [cancer.gov]

• Headache

  Frequently reported adverse events included thrombocytopenia, neutropenia, leukopenia, infection, anemia, hemorrhage, fatigue, fever, nausea, headache, liver damage, hyperbilirubinemia, and abdominal pain. [cancertherapyadvisor.com]

  The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). [ncbi.nlm.nih.gov]

  The most common adverse events were pyrexia (58%), febrile neutropenia (40%), and headache (31%). [ascopost.com]

  The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness. [prnewswire.com]

  Skeletal pain Neurological symptoms, such as headaches, seizures or vomiting; these may indicate the involvement of the central nervous system. [symptoma.com]

• Seizure

  Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. [ncbi.nlm.nih.gov]

  […] cells are, you might also have: A full or swollen belly from cancer cells in your liver or spleen Enlarged lymph nodes such as in your neck or groin, under your arms, or above your collarbone Bone or joint pain Headache, trouble with balance, vomiting, seizures [webmd.com]

  This can cause neurological symptoms (related to the brain and nervous system), including: headaches seizures or fits being sick blurred vision dizziness When to get medical advice If you or your child has some or all the symptoms listed on this page, [nhs.uk]

  Skeletal pain Neurological symptoms, such as headaches, seizures or vomiting; these may indicate the involvement of the central nervous system. [symptoma.com]

• Vertigo

  /L 14.1 g/dL 12..1 mmol/L 274 µmol/L Na Diffuse infiltration VP CR 4 Zhou et al. [5] (2010) F 53 Nausea, vomiting, fever 7.9×109/L 7.8 g/dL Na 255 µmol/L 5,63 IU/L Diffuse infiltration VDLP CR 5 Gupta et al. [6] (2010) M 22 Abdominal pain, vomiting, vertigo [ncbi.nlm.nih.gov]

• Vomiting

  Skeletal pain Neurological symptoms, such as headaches, seizures or vomiting; these may indicate the involvement of the central nervous system. [symptoma.com]

  Signs and symptoms can include: Unexplained Fever Weight Loss Loss of Appetite Pale Skin Gum Bleeding Vomiting Unexplained Black-and-Blue Marks on Body Lumps Around Neck, Stomach, Underarm, or Groin: These lumps may be caused by swollen lymph nodes. [knowcancer.com]

  CASE REPORT An 8-year-old girl was admitted to the pediatric emergency with bone and abdominal pain associated with vomiting, fever, and headache. [jbpml.org.br]

  […] leukemia cells are, you might also have: A full or swollen belly from cancer cells in your liver or spleen Enlarged lymph nodes such as in your neck or groin, under your arms, or above your collarbone Bone or joint pain Headache, trouble with balance, vomiting [webmd.com]

• Abdominal Pain

  Frequently reported adverse events included thrombocytopenia, neutropenia, leukopenia, infection, anemia, hemorrhage, fatigue, fever, nausea, headache, liver damage, hyperbilirubinemia, and abdominal pain. [cancertherapyadvisor.com]

  The most common (≥ 2%) serious adverse reactions associated with BESPONSA were infection (23%), febrile neutropenia (11%), haemorrhage (5%), abdominal pain (3%), pyrexia (3%), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) (2%), and [pfizer.com]

  The symptoms of relapsed ALL are the same as those for newly diagnosed ALL, including: Anemia Bone and joint pain Bruising or petechiae (small red spots on the skin) Fever Recurrent infections Abdominal pain Swollen lymph nodes Dyspnea or difficulty breathing [danafarberbostonchildrens.org]

  pain, gamma-glutamyltransferase increased, and hyperbilirubinemia. [adcreview.com]

  pain and high levels of bilirubin in the blood (hyperbilirubinemia). [fda.gov]

• Loss of Appetite

  Signs and symptoms can include: Unexplained Fever Weight Loss Loss of Appetite Pale Skin Gum Bleeding Vomiting Unexplained Black-and-Blue Marks on Body Lumps Around Neck, Stomach, Underarm, or Groin: These lumps may be caused by swollen lymph nodes. [knowcancer.com]

  This pain may lead to loss of appetite and weight loss. Swollen lymph nodes. Lymph nodes filter the blood. Leukemia cells often collect in the nodes, causing swelling. [chop.edu]

  […] or loss of appetite pain in the bones or stomach pain or a feeling of fullness below the ribs painless lumps in the neck, underarm, stomach, or groin tests that examine the blood and bone marrow diagnose all. [icd10data.com]

  They include: Fatigue Fever Loss of appetite or weight loss Night sweats Tiny red spots just under your skin (petechiae) Stomach pain Many of the symptoms happen because your body is reacting to a lack of healthy blood cells. [webmd.com]

• Bleeding Gums

  gums, or other unusual bleeding, such as from minor cuts Depending on where the leukemia cells are, you might also have: A full or swollen belly from cancer cells in your liver or spleen Enlarged lymph nodes such as in your neck or groin, under your [webmd.com]

  Symptoms include: pale skin feeling tired and breathless repeated infections over a short time unusual and frequent bleeding, such as bleeding gums or nosebleeds high temperature night sweats bone and joint pain easily bruised skin swollen lymph nodes [nhs.uk]

  Thrombocytopenia can cause mucosal bleeding, easy bruising, petechiae/purpura, epistaxis, bleeding gums, and heavy menstrual bleeding. Hematuria and GI bleeding are uncommon. [msdmanuals.com]

• Chest Pain

  Other symptoms may include swollen lymph nodes (glands), chest pain and abdominal discomfort due to a swollen spleen or liver. Occasionally people have no symptoms and ALL is diagnosed during a routine blood test. [leukaemia.org.au]

  The most common presenting symptoms are due to disrupted hematopoiesis with ensuing Anemia Thrombocytopenia Granulocytopenia Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain. [msdmanuals.com]

• Tachycardia

  The most common presenting symptoms are due to disrupted hematopoiesis with ensuing Anemia Thrombocytopenia Granulocytopenia Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain. [msdmanuals.com]

• Petechiae

  The symptoms of relapsed ALL are the same as those for newly diagnosed ALL, including: Anemia Bone and joint pain Bruising or petechiae (small red spots on the skin) Fever Recurrent infections Abdominal pain Swollen lymph nodes Dyspnea or difficulty breathing [danafarberbostonchildrens.org]

  These include: being very tired, weak, or pale swollen lymph nodes infections (like bronchitis or tonsillitis) that keep coming back a fever night sweats easy bruising or petechiae (tiny red spots on the skin caused by easy bleeding) bone and joint pain [kidshealth.org]

  Symptoms of ALL include: Frequent infections Fever Easy bruising Bleeding that is hard to stop Flat, dark-red skin spots (petechiae) due to bleeding under the skin Pain in the bones or joints Lumps in the neck, underarm, stomach or groin Pain or fullness [stjude.org]

  They include: Fatigue Fever Loss of appetite or weight loss Night sweats Tiny red spots just under your skin (petechiae) Stomach pain Many of the symptoms happen because your body is reacting to a lack of healthy blood cells. [webmd.com]

• Night Sweats

  These include: being very tired, weak, or pale swollen lymph nodes infections (like bronchitis or tonsillitis) that keep coming back a fever night sweats easy bruising or petechiae (tiny red spots on the skin caused by easy bleeding) bone and joint pain [kidshealth.org]

  Accelerated phase of CML Children whose CML is in accelerated phase may have symptoms such as fever, night sweats, poor appetite, and weight loss. CML in the accelerated phase might not respond as well to treatment as CML in the chronic phase. [cancer.org]

  They include: Fatigue Fever Loss of appetite or weight loss Night sweats Tiny red spots just under your skin (petechiae) Stomach pain Many of the symptoms happen because your body is reacting to a lack of healthy blood cells. [webmd.com]

  Symptoms include: pale skin feeling tired and breathless repeated infections over a short time unusual and frequent bleeding, such as bleeding gums or nosebleeds high temperature night sweats bone and joint pain easily bruised skin swollen lymph nodes [nhs.uk]

  Symptoms include fatigue, lethargy, or the presence of constitutional symptoms such as fevers, night sweats, or weight loss. [cancertherapyadvisor.com]

• Bone Pain

  pain due to marrow expansion, hepatosplenomegaly due to neoplastic infiltration, CNS symptoms due to meningeal spread and testicular involvement B acute lymphoblastic lymphoma often presents with cutaneous nodules, bone or nodal involvement, < 25% lymphoblasts [pathologyoutlines.com]

  Symptoms Signs and symptoms of acute lymphocytic leukemia may include: Bleeding from the gums Bone pain Fever Frequent infections Frequent or severe nosebleeds Lumps caused by swollen lymph nodes in and around the neck, underarm, abdomen or groin Pale [mayoclinic.org]

  Bone pain is relatively common and described in approximately 50% of patients (1, 7). Pain may also occur in the course of the disease or during treatment. [jbpml.org.br]

  Bone marrow and periosteal infiltration may cause bone and joint pain, especially in children with ALL. [msdmanuals.com]

  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 [en.wikipedia.org]

• Myalgia

  […] cytokines IL-10, IL-6, and interferon-gamma after rapid lysis of tumor cells by activated T-cells, which typically happens during the first days of the first blinatumomab infusion. 12 Reactions are mostly mild flu-like symptoms, such as pyrexia, chills, and myalgia [dovepress.com]

  Treatment with CAR T cells has been associated with cytokine release syndrome, which can be life-threatening.[ 134, 135 ] Cytokine release syndrome presents as fever, headache, myalgias, hypotension, capillary leak, hypoxia, and renal dysfunction. [cancer.gov]

• Arthralgia

  Lymphadenopathy, hepatomegaly, splenomegaly, arthralgia and bone pain are signs and symptoms also reported (1, 3, 6). The white blood cell count varies from decreased to sharply increased (7). [jbpml.org.br]

• Back Pain

  (primarily back and hips) as a result of filgrastim treatment is observed in 80 percent of donors.[49] Donation is not recommended for those with a history of back pain.[49] Other symptoms observed in more than 40 percent of donors include muscle pain [en.wikipedia.org]

• Leg Pain

  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 [en.wikipedia.org]

• Epistaxis

  This state of pancytopenia leads to a multitude of symptoms and signs that are also nonspecific and may include any of the following: Pallor, fatigue and weakness, caused by anemia Recurring infections due to leukocytopenia Petechiae, epistaxis, hematuria [symptoma.com]

  Thrombocytopenia can cause mucosal bleeding, easy bruising, petechiae/purpura, epistaxis, bleeding gums, and heavy menstrual bleeding. Hematuria and GI bleeding are uncommon. [msdmanuals.com]

B-precursor acute lymphoblastic leukemia is diagnosed via a complete blood count, that reveals pancytopenia, a bone marrow biopsy and a smear of the peripheral blood.

More specifically, peripheral blood is found to contain cells with a hypoplastic cytoplasm and comparatively oversized nuclei. The nuclei themselves typically encompass chromatin arranged in large bundles and their shape ranges from round to oval. Vacuoles or granules may also be observed in a microscopic analysis and the cytoplasm is basophilic. On the other hand, a histologic examination of the bone marrow sample is expected to reveal hypercellular characteristics, even though it may by hypocellular or normocellular under some circumstances. Alterations are diffuse and consist of lymphoblasts with hypoplastic cytoplasm and restricted size. As far as normal cells are concerned, a small number of erythroblasts can be detected; normal cells are largely eliminated. Chromatin is characterized by excessive condensation and wide dispersion.

Diagnosis is completed with a cytogenetic analysis, in order to pinpoint the DNA structure, chromosome number, rearrangements and mutations that are associated with B-ALL [20].

• Enlargement of the Liver

  Organ infiltration by leukemic cells results in enlargement of the liver, spleen, and lymph nodes. Bone marrow and periosteal infiltration may cause bone and joint pain, especially in children with ALL. [msdmanuals.com]

  and enlarged lymph nodes can be prominent features. [en.wikipedia.org]

• Neutropenia

  Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO ® infusion and interrupt BLINCYTO ® if prolonged neutropenia occurs. [prnewswire.com]

  […] of febrile neutropenia. [search.ndltd.org]

  Adverse events The most common adverse reactions occurring in greater than 20% of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, [adcreview.com]

  35%), haemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), febrile neutropenia (26%), increased transaminases (26%), abdominal pain (23%), increased gamma-glutamyltransferase (21%), and hyperbilirubinaemia (21%). [pfizer.com]

  thrombocytopenia, and neutropenia. [amgen.com]

• Leukopenia

  We present the case of a 9-year-old girl from northwestern Greece admitted to our Hospital because of malaise, low-grade fever, intermittent hip joint pain, anemia, leukopenia and thrombocytopenia. [ncbi.nlm.nih.gov]

  Frequently reported adverse events included thrombocytopenia, neutropenia, leukopenia, infection, anemia, hemorrhage, fatigue, fever, nausea, headache, liver damage, hyperbilirubinemia, and abdominal pain. [cancertherapyadvisor.com]

  Adverse events The most common adverse reactions occurring in greater than 20% of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, [adcreview.com]

  Indications for Testing ALL testing should be considered for patients who present with signs of bone marrow failure (eg, anemia, thrombocytopenia, leukopenia) and constitutional symptoms (eg, fever, lethargy, weight loss). [arupconsult.com]

  Common side effects of Besponsa include low levels of platelets (thrombocytopenia), low levels of certain white blood cells (neutropenia, leukopenia), infection, low levels of red blood cells (anemia), fatigue, severe bleeding (hemorrhage), fever (pyrexia [fda.gov]

• 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 [en.wikipedia.org]

  […] mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered "clonal hematopoiesis of indeterminate potential" (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis [bloodjournal.org]

  In addition, samples that are classified as lymphocytosis contain higher numbers of lymphocytes; however, these samples do not have adequate numbers of precursor B-cells and should not be used. [jove.com]

All types of acute lymphoblastic leukemia are treated according to a specific protocol and B-precursor acute lymphoblastic leukemia constitutes no exception. The particular details of the treatment may be decided based on the type of genetic mutation and other individualized characteristics of the malignancy. Treatment is initiated with an induction phase, which includes various chemotherapeutic and other agents, such as doxorubicin, vincristine, cyclophosphamide, and prednisone. The induction phase is followed by a consolidation phase after remission has been confirmed, whose purpose is to intensify therapy with drugs such as cytarabine and methotrexate. Finally, a long maintenance phase is required, which may contain cycles of intensified induction therapy, since it can greatly contribute to the ultimate therapeutic goal.

Prophylaxis of the central nervous system is mandatory and is achieved with triple intrathecal therapy; the previous option which involved cranial radiation is gradually being rejected due to the negative effect it can have on the CNS [21] [22] [23]. Antimicrobial and antifungal medications are also administered to patients with profound leukocytopenia, as prophylaxis [24]. The ultimate therapeutic option is stem cell transplantation, which is employed in a relative minority of the cases, approximately in 6% of all patients.

B-precursor acute lymphoblastic leukemia is widely viewed in a more positive prognostic light when compared to T-precursor acute lymphoblastic leukemia [18]. One of the factors that greatly influence the outcome are the exact genetic modifications that are held accountable for the malignancy. More specifically, subtypes with a better-expected outcome are associated with:

• Translocation t(12;21) (TEL-AML1(ETV6-RUNX1))
• Translocation t(1;19) (TCF3-PBX1)
• Hyperdiploidy with over 51 chromosomes

On the other hand, genetic alterations that negatively affect prognosis include:

• Hypodiploidy with less than 44 chromosomes
• Translocation t(9;22) (BCR-ABL1)
• Translocation t(4;11) (MLL-AF4) during infancy

A second factor that can determine the outcome is the extent of minimal residual disease (MRD) on the 15th to 19th day of the initial, induction therapy: 1% of MRD during these days and less than 0.01% MRD at the end of the therapy is associated with a better long-term survival and the patients are considered to be low-risk [19]. Other factors that are linked with a better prognosis include the age of onset between 1 and 9 years old and leukocyte count below 50,000.

The majority of acute lymphoblastic leukemia cases that occur in childhood are induced by genetic defects that can be detected by fluorescence in situ hybridization and karyotyping [6]. In B-precursor acute lymphoblastic leukemia open link the genetic background that leads to the onset of the disease includes the following:

• Translocation t(12;21)(p13;q22) (ETV6-RUNX1 (TEL-AML1))
• Translocation t(9;22)(q34;q11) (BCR-ABL1)
• Translocation t(4;11)(q21;q23) (MLL-AFF1(AF4))
• Hyperdiploidy

B-ALL is categorized under the broader group of acute lymphoblastic leukemia, which is the type of cancer most frequently diagnosed in children in an international scale. ALL has been evincing a gradually increasing incidence during the past decades, with individuals of Hispanic ethnicity being more susceptible to developing the disease, followed by Caucasian patients [7] [8].

Similarly to ALL in general, B-ALL is more commonly diagnosed during the ages of 1 to 4 and constitutes the most frequent cause of death amongst children affected by malignancy. The disease exhibits a clear predilection for male patients. From a prognostic aspect, the dimmest prognosis accompanies occurrences in infancy, with the rest of the pediatric cases followed by a high event-free survival (EFS) rate [9] [10] [11] [12].

Hematopoiesis is the process through which every blood cell is produced by the hematopoietic stem cells (hemocytoblasts), in the bone marrow. It is a complicated procedure that is completed in a staged fashion and is strictly regulated by various transcription factors and signal transduction [13]. B-precursor acute lymphoblastic leukemia is a subtype of acute lymphoblastic leukemia and specifically targets the B precursor cells; the latter are derived from the common lymphoid progenitor cells and subsequently give rise to B cells after the maturation process has been completed.

In B-ALL specifically, a developmental arrest is observed in the stage of B-precursor differentiation, which is attributed to various genetic mutations and leads to a considerable heterogeneity on a clinical scale. The mutations known to underlie the clonal disease include hyperdiploidy with over 40 or 50 chromosomes, translocations such as t(12;21), t(1;19) and t(4;11) and other genetic mutations [14] [15]. It is, however, known that the genetic defects alone are not able to initiate the malignant proliferation of cells: it has been hypothesized that defects in the modification of chromatin, tumor suppression and the regulation of the cellular cycle are mandatory in order for the malignancy to fully develop into B-precursor acute lymphoblastic leukemia [16] [17].

The genetic mutations that underlie B-precursor acute lymphoblastic leukemia cannot be prevented. However, any individual can minimize their chances of suffering from B-ALL, if they avoid certain risk factors that have been associated with the malignancy. Those risk factors include exposure to benzene, high dose ionizing radiation and smoking.

B-precursor acute lymphoblastic leukemia (B-ALL) is classified under the category of acute lymphoblastic leukemia (ALL). ALL generally encompasses the wider cancer group of B-cell malignancies, one of which is B-ALL. B-cell leukemia is more commonly diagnosed during childhood and 75% of the cases affect children that are below the age of 6 years old.

Depending on cellular morphology, the FAB classification divides acute lymphoblastic leukemias into 3 categories, namely L1, L2 and L3. L1 comprises round-shaped blasts with clumped chromatin. L2 is the type of leukemia characterized by larger cells with a more delicate arrangement of chromatin and L3 cells contain vacuoles and are generally larger. B-precursor leukemia is an L1 or L2 type malignancy, with cells that express the B-cell antigens and/or surface light chains [1] [2].

The malignancy is characterized by an abnormal genetic background which includes various diverse translocations, hypo- or hyperdiploidy. The Philadelphia chromosome might also be present, and so can the MYC rearrangement [3] [4] [5].

B-precursor acute lymphoblastic leukemia is diagnosed with a standard complete blood count (CBC), which will reveal pancytopenia. The symptoms related to this type of cancer are non-pathognomonic and include manifestations of the existent pancytopenia, such as pallor, fatigue, bleeding tendencies and recurrent infections. Treatment is standardized and aggressive, as it consists of an induction, consolidation and long maintenance phase, which are all met with success in the majority of the cases. Cases of non-responsive B-ALL are treated with a stem cell transplantation, although a relative minority of the patients are required to undergo such a procedure.

Production of cellular components: red blood cells, platelets, and white blood cells takes place in the bone marrow. The process through which every single cell is produced is called hematopoiesis. It is a complex procedure that involves a single type of original bone marrow cell, the hematopoietic stem cell, which undergoes differentiation and produces the final, mature lines of blood cells. Acute lymphoblastic leukemia (ALL) is a type of cancer which causes an increased production of lymphoblasts, which fail to differentiate into mature T or B lymphocytes. B-precursor acute lymphoblastic leukemia (B-ALL) is a subtype of ALL, which leads to an abnormally overproduced line of those cells that differentiate into B lymphocytes. The malignant cells display developmental arrest, in the sense that their maturation process is halted at a prime period. This phenomenon causes a failure of the bone marrow to produce normal lymphocytes and at the same time prevents the other cellular components from developing too.

B-ALL is a result of various genetic mutations and other abnormalities. Additional defects in physiological procedures that have not yet been completely defined also play a role in the onset of the disease. Risk factors that have been associated with B-LL include high dose ionizing radiation, benzene exposure, and smoking.

As mentioned before, B-LL leads to the inability of the bone marrow to produce all three lines of cells: platelets, red blood cells and white blood cells. Consequently, patients affected by the malignancy present with a multitude of non-specific symptoms related to these deficiencies. The most common symptoms associated with B-LL are:

• Weight loss
• Anorexia
• Fatigue, weakness
• Nosebleeds
• Bruises on the body or gums that cannot be otherwise explained
• Swollen lymph nodes in the armpits, neck, groin, that appear as palpable lumps
• Frequent infections
• Pallor
• Headaches
• Vomiting

B-precursor acute lymphoblastic leukemia is diagnosed with blood tests that reveal decreased levels of blood cellular components. It is also required to perform a bone marrow biopsy, as well as a blood smear; the latter is used to observe the shape and structure of the blood cells under a microscope. Finally, genetic testing in order to identify the exact genetic mutation is also mandatory for a definitive diagnosis to be made. B-ALL is treated like all types of ALL, with chemotherapy. Treatment consists of an induction stage, which comprises various medications and, after the disease has subsided, a second round of therapy is administered, which is called the consolidation stage. This is an intensified cycle of chemotherapeutic agents. Treatment is completed with the administration of the final round of therapy, called maintenance therapy; it can last for quite a long time. Due to the aggressive type of treatment that has been designated for B-ALL, the results are usually positive, with patients achieving high survival rates and complete remission. In cases where chemotherapeutic aggressive treatment fails to cure the disease, a stem cell transplantation can be attempted, although it is a last resort therapy reserved for refractory and unresponsive cases.

1. Nelson BP, Treaba D, Goolsby C, et al. Surface immunoglobulin positive lymphoblastic leukemia in adults; a genetic spectrum. Leuk Lymphoma open link. 2006; 47(7):1352–1359.
2. Higa B, Alkan S, Barton K, et al. Precursor B-cell acute lymphoblastic leukaemia with FAB L3 i.e., Burkitt's leukaemialymphoma morphology and co-expression of monoclonal surface light chains and Tdt: report of a unique case and review of the literature. Pathology. 2009; 41(5):495–498.
3. Mann G, Trebo MM, Haas OA et al. Philadelphia chromosome-positive mature B-cell (Burkitt cell) leukaemia. Br J Haematol. 2002;118(2):559–562
4. Dunphy CH, Van Deventer HW, Carder JK, et al. Mature B-cell acute lymphoblastic leukemia with associated translocations (14;18)(q32;q21) and (8;9)(q24;p13): A Burkitt variant?. Arch Pathol Lab Med. 2003; 127(5):610–613.
5. Zhao X, Hassan A, Perry A, et al. C-MYC rearrangements are frequent in aggressive mature B-cell lymphoma with atypical morphology. Int J Clin Exp Pathol. 2008;1(1):65–74.
6. Mullighan CG.The molecular genetic makeup of acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program. 2012; 2012:389–396.
7. Shah A, Coleman MP. Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer. 2007;(7): 1009-12.
8. Smith MA, Ries LA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program; 1999.
9. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2011. Bethesda, MD: National Cancer Institute; 1975.
10. Gatta G, Rossi S, Foschi R, et al. Survival and cure trends for European children, adolescents and young adults diagnosed with acute lymphoblastic leukemia from 1982 to 2002. Haematologica. 2013; 98: 744–752.
11. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012; 30: 1663–1669.
12. Kotecha RS, Gottardo NG, Kees UR, et al. The evolution of clinical trials for infant acute lymphoblastic leukemia. Blood Cancer J. 2014, 4: e200. 10.1038/bcj.2014.17.
13. Zhou Y, You MJ, Young KH, et al. Advances in the molecular pathobiology of B-lymphoblastic leukemia. Hum Pathol. 2012;43:1347–62.
14. Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. 2010;11:429–38.
15. Ma Y, Dobbins SE, Sherborne AL,et al. Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2013;110:7429–33.
16. Lo Nigro L. Biology of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2013;35:245–52.
17. Greaves MF, Maia AT, Wiemels JL, et al. Leukemia in twins: lessons in natural history. Blood. 2003;102:2321–33.
18. Raimondi SC. Cytogenetics of acute lymphoblastic leukemia. New York, NY: Cambrige University Press; 2012.
19. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009; 360: 2730-2741.
20. Pui CH, Carroll WL, Meshinchi S, et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29:551–565.
21. Manabe A, Tsuchida M, Hanada R,et al. Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children's Cancer Study Group study L89-12. J Clin Oncol.2001; 19: 3182-3187.
22. Liu HC, Yeh TC, Hou JY, et al. Triple intrathecal therapy alone with omission of cranial radiation in children with acute lymphoblastic leukemia. J Clin Oncol. 2014; 32:1825-1829.
23. Yeh TC, Liu HC, Hou JY, et al. Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis. Cancer. 2014; 120: 1255-1262.
24. Pui CH. Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia. Front Med. 2015; 9: 1-9.