presentation of leukemia

AMANDA S. DAVIS, MD, ANTHONY J. VIERA, MD, MPH, AND MONICA D. MEAD, MD

A more recent article on leukemia is available.

Am Fam Physician. 2014;89(9):731-738

Patient information : See related handout on leukemia , written by the authors of this article.

Author disclosure: No relevant financial affiliations.

Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow. The four broad subtypes most likely to be encountered by primary care physicians are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Acute lymphoblastic leukemia occurs more often in children, whereas the other subtypes are more common in adults. Risk factors include a genetic predisposition as well as environmental factors, such as exposure to ionizing radiation. Symptoms are nonspecific and include fever, fatigue, weight loss, bone pain, bruising, or bleeding. A complete blood count usually reveals leukocytosis and other abnormally elevated or depressed cell lines. Patients with suspected leukemia should be referred promptly to a hematologist-oncologist. The diagnosis is confirmed by further examination of the bone marrow or peripheral blood. Treatment may include chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation. Complications of treatment include tumor lysis syndrome and serious infections from immunosuppression. Leukemia survivors should be monitored closely for secondary malignancies, cardiac complications, and endocrine disturbances such as metabolic syndrome, hypothyroidism, and hypogonadism. Five-year survival rates are highest in younger patients and in patients with chronic myelogenous leukemia or chronic lymphocytic leukemia.

Leukemia is a common malignancy in children and adults that occurs when alterations in normal cell regulatory processes cause uncontrolled proliferation of hematopoietic stem cells in the bone marrow. The age-adjusted incidence rate of leukemia in the United States is 12.8 per 100,000 persons each year. 1 The prevalence of leukemia is generally higher in whites and in males, and increases with age. 1 Approximately one in 70 persons develops leukemia in his or her lifetime. 1 The four subtypes of leukemia most often encountered by primary care physicians are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Family physicians should be able to recognize the common presentations of leukemia, perform the initial diagnostic evaluation, and understand how to care for leukemia survivors.

Risk Factors

Several genetic syndromes, including Down syndrome and neurofibromatosis, are associated with an increased risk of childhood acute lymphoblastic leukemia and acute myelogenous leukemia. 2 Persons exposed to ionizing radiation, such as atomic bomb survivors, medical radiation workers before 1950, and patients with cancer who are receiving radiation treatment, have an increased risk of developing acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia. 2 , 3 Evidence from epidemiologic studies suggests that the amount of radiation from two or three computed tomography scans is associated with a statistically significant increase in the risk of cancer, including leukemia, with a greater risk in younger persons. 4

Occupational and environmental exposure to benzene (a chemical used in the manufacturing of paints and plastics, and released with the combustion of petroleum and coal) is an established risk factor for leukemia in adults, particularly acute myelogenous leukemia. 5 , 6 Household pesticide exposure in utero and in the first three years of life has been associated with an increased risk of childhood acute lymphoblastic leukemia. 6 Obesity may also increase the risk. Aggregate data from a meta-analysis of cohort studies suggest that an increase of 5 kg per m 2 in body mass index is associated with a 13% relative increase in the risk of leukemia. 7 A history of hematologic malignancy is also a risk factor for developing a different subtype of leukemia later in life. 8

Clinical Presentation

Acute leukemia.

Children . According to three retrospective case reviews of childhood leukemia (in which 75% to 100% of the cases were acute lymphoblastic leukemia), common presenting signs and symptoms include fever (17% to 77%), lethargy (12% to 39%), and bleeding (10% to 45%). 9 – 11 About one-third of children had musculoskeletal symptoms, particularly in the spine and long bones, 9 – 11 75% had an enlarged liver or spleen, and nearly 60% had lymphadenopathy. 9 , 10 Central nervous system involvement is present in approximately 7% of children at diagnosis. 10

Adults . Acute myelogenous leukemia accounts for 80% of acute leukemia in adults. 12 Adults also present with constitutional symptoms such as fever, fatigue, and weight loss. They may have anemia-related symptoms, such as shortness of breath or chest pain, or symptoms related to thrombocytopenia, such as excessive bruising, nosebleeds, or heavy menstrual periods in women. Adults are less likely to present with bone pain. Hepatosplenomegaly and lymphadenopathy are rare in adults with acute myelogenous leukemia, but are present in about 50% of adults with acute lymphoblastic leukemia. 12 Central nervous system involvement occurs in approximately 5% to 8% of adults with acute lymphoblastic leukemia. 12

CHRONIC LEUKEMIA

The chronic leukemia subtypes occur almost exclusively in adults. Patients with chronic leukemia may be asymptomatic at the time of diagnosis. Approximately 50% of patients with chronic lymphocytic leukemia and 20% of patients with chronic myelogenous leukemia receive the diagnosis incidentally when marked leukocytosis is found on a complete blood count obtained for an unrelated reason. 13 , 14 Constitutional symptoms are less common, occurring in 15% of patients with chronic lymphocytic leukemia and in approximately one-third of patients with chronic myelogenous leukemia. 13 , 14 Hepatosplenomegaly and lymphadenopathy are common physical examination findings in persons with chronic lymphocytic leukemia. 14 Splenomegaly is common in those with chronic myelogenous leukemia; in one large, retrospective review, 75% of patients had a palpable spleen. 13 Bleeding and bruising are less common presenting features in the chronic leukemia subtypes. Characteristics of the major subtypes of leukemia are listed in Table 1 . 1 , 9 – 18

Laboratory Findings and Diagnosis

If leukemia is suspected, a complete blood count should be obtained. Marked leukocytosis, often greater than 100,000 white blood cells per μL (100.0 × 10 9 per L), is the hallmark laboratory finding in chronic myelogenous leukemia and chronic lymphocytic leukemia. More than 96% of patients with chronic myelogenous leukemia have white blood cell counts greater than 20,000 per μL (20.0 × 10 9 per L), compared with only 34% to 38% of patients with acute myelogenous leukemia or acute lymphoblastic leukemia. 9 , 10 , 13 Acute leukemia can also present with leukopenia, combined with anemia or thrombocytopenia. Other helpful initial laboratory tests include measurement of serum electrolyte and creatinine levels, liver function tests, and coagulation studies. If the patient appears ill or is febrile, the physician should evaluate for infection with urinalysis, urine culture, blood cultures, and chest radiography.

The next step in diagnosis involves a peripheral blood smear and usually a bone marrow specimen (an aspirate or core biopsy). Figure 1 details the initial steps in the evaluation of possible leukemia. 15 – 17

Acute leukemia should be suspected when a peripheral blood smear or bone marrow specimen is overpopulated with blast cells (the earliest form of hematopoietic precursor cells). Classically, acute myelogenous leukemia is characterized by the presence of Auer rods on a peripheral smear. However, because Auer rods are not commonly detected, immunophenotyping by flow cytometry and cytogenetic testing are required to distinguish between acute leukemia subtypes such as acute myelogenous leukemia or acute lymphoblastic leukemia. 15 , 16 Table 2 describes the current approaches to the laboratory diagnosis of the leukemia subtype.

The diagnosis of chronic lymphocytic leukemia is based on a clonal expansion of at least 5,000 B lymphocytes per μL (5.0 × 10 9 per L) in the peripheral blood, confirmed by immunophenotyping. A bone marrow specimen is not required for diagnosis of chronic lymphocytic leukemia, but can be obtained to determine the extent of marrow involvement for prognosis. 17 The diagnosis of chronic myelogenous leukemia requires cytogenetic or molecular testing of the bone marrow or peripheral blood for a specific abnormality called the Philadelphia chromosome, or the BCR-ABL1 fusion gene. 16 In chronic myelogenous leukemia, a reciprocal translocation between chromosomes 9 and 22 results in the formation of the BCR-ABL1 fusion gene that disrupts the normal cell regulatory processes in the bone marrow. The shortened chromosome 22 (Philadelphia chromosome) is found in 95% of patients with chronic myelogenous leukemia. 19 The remaining 5% of patients have a different chromosomal rearrangement, but still form the abnormal BCR-ABL1 fusion gene.

A patient with suspected leukemia should be referred to a hematologist-oncologist to confirm the diagnosis and initiate treatment. Treatment for acute leukemia may include chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation. The type of treatment depends on the leukemia subtype, cytogenetic and molecular findings, patient age, and comorbid conditions.

Early-stage chronic lymphocytic leukemia (i.e., no anemia or thrombocytopenia and less than three areas of nodal involvement) can be monitored without treatment. Active-stage disease is defined as worsening thrombocytosis, thrombocytopenia, or anemia; progressive lymphadenopathy or splenomegaly; or the presence of constitutional symptoms. 17

The discovery of tyrosine kinase inhibitors revolutionized the treatment of chronic myelogenous leukemia. The abnormal fusion gene created by the translocation of chromosomes 9 and 22 codes for tyrosine kinase, an enzyme that activates signal transduction cascades that cause uncontrolled cellular proliferation. This targeted approach of inhibiting the tyrosine kinase enzyme is not curative but can maintain long-term control of the disease without the adverse effects of chemotherapy. Curative treatment consists of hematopoietic stem cell transplantation, which is usually reserved for younger patients or when the disease does not respond to tyrosine kinase inhibitors. 20

Treatment Complications

Tumor lysis syndrome occurs as a result of chemotherapy (or rarely, spontaneously) when widespread cellular destruction releases intracellular contents into the bloodstream. The result is high potassium, phosphorus, uric acid, and blood urea nitrogen levels. Treatment is aimed at preventing renal failure, and includes aggressive intravenous fluid administration plus allopurinol (Zyloprim) or rasburicase (Elitek), a recombinant urate oxidase that breaks down uric acid. 21

Immunosuppression from chemotherapy, hematopoietic stem cell transplantation, or the leukemia itself may increase the risk of serious infections. In patients with leukemia, fever with neutropenia (fewer than 500 neutrophils per μL [0.5 × 10 9 per L]) should prompt an evaluation for infection source and the initiation of empiric broad-spectrum antibiotic therapy, such as imipenem/cilastatin (Primaxin), meropenem (Merrem), piperacillin/tazobactam (Zosyn), or cefepime. 22

Prognosis and Long-Term Sequelae

Prognosis depends on factors such as age, comorbid disease, leukemia subtype, and cytogenetic and molecular characteristics ( Table 1 1 , 9 – 18 ) . Survivors of leukemia have an increased risk of subsequent cancers, likely because of the cellular damage caused by chemotherapy or radiation. In the Childhood Cancer Survivor Study (a cohort of more than 17,000 childhood cancer survivors in North America treated between 1970 and 1986), the 30-year cumulative incidence of neoplasm after leukemia was 5.6%, and the median time to occurrence of the subsequent cancer was nine years. 23 The most common second neoplasms in childhood leukemia survivors are different subtypes of leukemia, or lymphoma. Other second neoplasms include bone, soft tissue, or central nervous system tumors. Guidelines recommend age- and sex-specific cancer screening, routine complete blood count to monitor for relapse or occurrence of a subsequent hematologic malignancy, and a low threshold for brain imaging for neurologic symptoms in patients who have received cranial or craniospinal irradiation. 8 , 24 , 25

Childhood survivors of leukemia are at increased risk of osteonecrosis of joints such as the hip, shoulder, and knee. Adolescent survivors of acute lymphoblastic leukemia are at highest risk, with a 20-year cumulative incidence of 2.8%. 26 Guidelines recommend bone density testing one year after hematopoietic stem cell transplantation. 27 Treatment with certain chemotherapeutic agents or radiation can affect cardiac function, including ejection fraction and electrical conduction of the heart. For example, 20 to 30 years after treatment with anthracyclines (e.g., daunorubicin, doxorubicin [Adriamycin]), 5% to 10% of patients develop congestive heart failure. 8 Guidelines recommend periodic cardiac evaluation in leukemia survivors. 28 , 29 Endocrine abnormalities are also common after leukemia treatment, including metabolic syndrome, thyroid function abnormalities, and gonadal failure. Monitoring and treatment for these and other complications are summarized in Table 3 . 24 , 25 , 27 – 30

Data Sources : We searched PubMed using the key word leukemia. We also performed a search in Essential Evidence Plus. We accessed the National Cancer Institute's Surveillance Epidemiology and End Results Program online database of cancer statistics, and the National Comprehensive Cancer Network database. Search dates: September and December 2011, January 2012, and January 2014.

National Cancer Institute. SEER cancer statistics review 2006–2010. http://seer.cancer.gov/statfacts/html/leuks.html . Accessed January 9, 2014.

Bhatia S, Robison LL. Epidemiology of leukemia and lymphoma. Curr Opin Hematol. 1999;6(4):201-204.

Yoshinaga S, Mabuchi K, Sigurdson AJ, Doody MM, Ron E. Cancer risks among radiologists and radiologic technologists: review of epidemiologic studies. Radiology. 2004;233(2):313-321.

Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277-2284.

Khalade A, Jaakkola MS, Pukkala E, Jaakkola JJ. Exposure to benzene at work and the risk of leukemia: a systematic review and meta-analysis. Environ Health. 2010;9:31.

Buffler PA, Kwan ML, Reynolds P, Urayama KY. Environmental and genetic risk factors for childhood leukemia: appraising the evidence. Cancer Invest. 2005;23(1):60-75.

Lichtman MA. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist. 2010;15(10):1083-1101.

Diller L. Clinical practice. Adult primary care after childhood acute lymphoblastic leukemia. N Engl J Med. 2011;365(15):1417-1424.

Sinigaglia R, Gigante C, Bisinella G, Varotto S, Zanesco L, Turra S. Musculoskeletal manifestations in pediatric acute leukemia. J Pediatr Orthop. 2008;28(1):20-28.

Ma SK, Chan GC, Ha SY, Chiu DC, Lau YL, Chan LC. Clinical presentation, hematologic features and treatment outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in Hong Kong. Hematol Oncol. 1997;15(3):141-149.

Rogalsky RJ, Black GB, Reed MH. Orthopaedic manifestations of leukemia in children. J Bone Joint Surg Am. 1986;68(4):494-501.

Cornell RF, Palmer J. Adult acute leukemia. Dis Mon. 2012;58(4):219-238.

Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Br J Haematol. 1997;96(1):111-116.

Yee KW, O'Brien SM. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2006;81(8):1105-1129.

National Comprehensive Cancer Network. Clinical practice guidelines in oncology: acute myeloid leukemia. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf (subscription required). Accessed January 9, 2014.

Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951.

Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines [published correction appears in Blood . 2008;112(13):5259]. Blood. 2008;111(12):5446-5456.

National Cancer Institute. SEER fast stats 1975–2005. http://seer.cancer.gov/faststats/selections.php . Accessed January 22, 2014.

Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340(17):1330-1340.

Moen MD, McKeage K, Plosker GL, Siddiqui MA. Imatinib: a review of its use in chronic myeloid leukaemia. Drugs. 2007;67(2):299-320.

Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review [published correction appears in J Clin Oncol . 2010;28(4):708]. J Clin Oncol. 2008;26(16):2767-2778.

National Comprehensive Cancer Network. Clinical practice guidelines in oncology: prevention and treatment of cancer-related infections. http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf (subscription required). Accessed January 9, 2014.

Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102(14):1083-1095.

Children's Oncology Group Nursing Discipline Clinical Practice Subcommittee/Survivorship; Late Effects Committee. Establishing and enhancing services for childhood cancer survivors: long-term follow-up program resource guide. http://www.survivorshipguidelines.org . Accessed January 22, 2014.

Tsimberidou AM, Wen S, McLaughlin P, et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2009;27(6):904-910.

Kadan-Lottick NS, Dinu I, Wasilewski-Masker K, et al. Osteonecrosis in adult survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2008;26(18):3038-3045.

Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2006;12(2):138-151.

Steinherz LJ, Graham T, Hurwitz R, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics. 1992;89(5 pt 1):942-949.

Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10:337.

Sinisalo M, Aittoniemi J, Käyhty H, Vilpo J. Vaccination against infections in chronic lymphocytic leukemia. Leuk Lymphoma. 2003;44(4):649-652.

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Overview of Leukemia

• Classification of Leukemia |
• Risk Factors for Leukemia |
• More Information |

Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms related to cytopenias.

Malignant transformation usually occurs at the pluripotent stem cell level, although it sometimes involves a committed stem cell with more limited capacity for self-renewal. Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells.

The American Cancer Society estimates that in the United States in 2023 there will be about 60,000 new cases of leukemia (of all types) in adults and children and about 24,000 deaths.

Classification of Leukemia

The current approach to classifying leukemia is based on the 2016 World Health Organization (WHO) system ( classification for hematopoietic neoplasms ). The WHO classification is based on a combination of clinical features and morphology, immunophenotype, and genetic factors. Other less commonly used classification systems include the French-American-British (FAB) system, which is based on the morphology of the abnormal leukocytes.

Leukemias are commonly also categorized as

Acute or chronic: Based on the percentage of blasts or leukemia cells in bone marrow or blood

Myeloid or lymphoid: Based on the predominant lineage of the malignant cells

The four most common leukemias and their distinguishing features are summarized in the table Findings at Diagnosis in the Most Common Leukemias .

For 2023, the American Cancer Society estimates the distribution of new cases in the United States by leukemia type as follows ( 1 ):

Acute myeloid leukemia (AML): 34%

Acute lymphoblastic leukemia (ALL): 11%

Chronic myeloid leukemia (CML): 15%

Chronic lymphocytic leukemia (CLL): 31%

Other leukemias: 8%

Findings at Diagnosis in the Most Common Leukemias

Acute leukemias

Acute leukemias consist of predominantly immature, poorly differentiated cells (usually blast forms). Acute leukemias are divided into

Acute lymphoblastic leukemia (ALL)

Acute myeloid leukemia (AML)

Chronic leukemias

Chronic leukemias have more mature cells than do acute leukemias. They usually manifest as leukocytosis with or without cytopenias in an otherwise asymptomatic person. Findings and management differ significantly between

Chronic lymphocytic leukemia (CLL)

Chronic myeloid leukemia (CML)

Myelodysplastic syndromes

Myelodysplastic syndromes are a group of clonal hematopoietic stem cell disorders unified by the presence of distinct mutations of hematopoietic stem cells. They involve progressive bone marrow failure but with an insufficient proportion of blast cells ( < 20%) for making a definite diagnosis of acute myeloid leukemia; 40 to 60% of cases evolve into acute myeloid leukemia.

Leukemoid reaction

A leukemoid reaction is a neutrophil count > 50,000/mcL (> 50 × 10 9 /L) not caused by malignant transformation of a hematopoietic stem cell. It can result from a variety of causes, particularly other cancers or systemic infection. Usually the cause is apparent, but apparent benign neutrophilia can be mimicked by chronic neutrophilic leukemia or chronic myeloid leukemia.

General reference

1. American Cancer Society: Cancer Facts and Statistics. https://www.cancer.org/research/cancer-facts-statistics.html

Risk Factors for Leukemia

Risk of developing leukemia is increased in patients with

History of exposure to ionizing radiation (eg, post–atom bomb in Nagasaki and Hiroshima) or to chemicals (eg, benzene, some pesticides, polyaromatic hydrocarbons in tobacco smoke); exposure can lead to acute leukemias

Infection with a virus (eg, human T lymphotropic virus 1 or 2, Epstein Barr virus) can rarely cause certain forms of ALL; this is seen mainly in regions where such infections are common, such as Asia and Africa

History of antecedent hematologic disorders, including myelodysplastic syndromes and myeloproliferative neoplasms , which can lead to AML

Preexisting genetic conditions (eg, Fanconi anemia , Bloom syndrome, ataxia-telangiectasia , Down syndrome , xeroderma pigmentosum, Li-Fraumeni syndrome), which predispose to acute myeloid leukemia and acute lymphoblastic leukemia

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Leukemia and Lymphoma Society: Resources for Healthcare Professionals : Provides information on education programs and conferences and resources for referrals to specialty care

Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.

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Acute Lymphoblastic Leukemia (ALL)

(acute lymphocytic leukemia).

• Pathophysiology |
• Classification |
• Symptoms and Signs |
• Diagnosis |
• Treatment |
• Prognosis |
• Key Points |
• More Information |

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived hematopoietic progenitor cell results in a high circulating number of blasts, replacement of normal marrow by malignant cells, and the potential for leukemic infiltration of the central nervous system (CNS) and testes. Symptoms include fatigue, pallor, infection, bone pain, CNS symptoms (eg, headache), easy bruising, and bleeding. Examination of peripheral blood smear and bone marrow is usually diagnostic. Treatment typically includes combination chemotherapy to achieve remission, intrathecal and systemic chemotherapy and/or corticosteroids for CNS prophylaxis, and sometimes cerebral irradiation for intracerebral leukemic infiltration, consolidation chemotherapy with or without stem cell transplantation, and maintenance chemotherapy for up to 3 years to avoid relapse.

(See also Overview of Leukemia .)

The American Cancer Society estimates that in the United States in 2023 there will be over 6500 new cases of acute lymphoblastic leukemia (ALL) and almost 1400 deaths will have occurred. Sixty percent of all ALL cases occur in children, with a peak incidence at age 2 to 5 years; a second peak occurs after age 50. ALL is the most common cancer in children, and represents about 75% of leukemias among children ARID5B gene.

Pathophysiology of ALL

Similar to acute myeloid leukemia , acute lymphoblastic leukemia is caused by a series of acquired genetic aberrations. Malignant transformation usually occurs at the pluripotent stem cell level, although it sometimes involves a committed stem cell with more limited capacity for self-renewal. Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells.

Classification of ALL

In acute lymphoblastic leukemia, the precursor lymphoid neoplasms are broadly categorized based on their lineage into

B-lymphoblastic leukemia/lymphoma (B-ALL/LBL)

T-lymphoblastic leukemia/lymphoma (T-ALL/LBL)

Disease can manifest as a leukemia when neoplastic cells (lymphoblasts) involve blood and bone marrow (defined as > 20% bone marrow blasts) or as a lymphoma when blasts infiltrate mainly extramedullary tissue.

The 2016 World Health Organization (WHO) classification of lymphoid neoplasms incorporates genetic data, clinical features, cell morphology, and immunophenotype, all of which have important implications for disease prognosis and management.

Symptoms and Signs of ALL

Symptoms and signs of acute lymphoblastic leukemia may be present for only days to weeks before diagnosis.

The most common presenting symptoms are due to disrupted hematopoiesis with ensuing

Thrombocytopenia

Granulocytopenia

Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain.

Thrombocytopenia can cause mucosal bleeding, easy bruising, petechiae/purpura, epistaxis, bleeding gums, and heavy menstrual bleeding. Hematuria and gastrointestinal bleeding are uncommon. Patients can present with spontaneous hemorrhage, including intracranial or intra-abdominal hematomas.

Granulocytopenia or neutropenia can lead to a high risk of infections, including those of bacterial, fungal, and viral etiologies. Patients may present with fevers and a severe and/or recurrent infection.

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. CNS penetration and meningeal infiltration are common and can result in cranial nerve palsies, headache, visual or auditory symptoms, altered mental status, and transient ischemic attack/stroke.

Diagnosis of ALL

Complete blood count (CBC) and peripheral blood smear

Bone marrow examination

Histochemical studies, cytogenetics, and immunophenotyping

A diagnosis of acute lymphoblastic leukemia is made when blast cells of lymphoid origin are ≥ 20% of marrow nucleated cells or ≥ 20% of non-erythroid cells when the erythroid component is > 50%. If marrow cells are insufficient or unavailable, diagnosis can be made by the same criteria using a peripheral blood sample.

By permission of the publisher. From Chang K, Forman S. In Atlas of Clinical Hematology . Edited by JO Armitage. Philadelphia, Current Medicine, 2004.

CBC and peripheral smear are the first tests done; pancytopenia and peripheral blasts suggest acute leukemia. Blast cells in the peripheral smear may approach 90% of the white blood cell (WBC) count. Aplastic anemia , viral infections such as infectious mononucleosis , and vitamin B12 deficiency , and folate deficiency should be considered in the differential diagnosis of severe pancytopenia. Unlike in AML, Auer rods (linear azurophilic inclusions in the cytoplasm of blast cells) are never present in acute lymphoblastic leukemia.

Bone marrow examination (aspiration and needle biopsy) is routinely done. Blast cells in the bone marrow are typically between 25 and 95% in patients with ALL.

Histochemical studies, cytogenetics, and immunophenotyping studies help distinguish the blasts of ALL from those of AML or other disease processes. Histochemical studies include staining for terminal deoxynucleotidyl transferase (TdT), which is positive in cells of lymphoid origin. Detection of specific immunophenotypic markers such as CD3 (for lymphoid cells of T cell origin) and CD19, CD20, and CD22 (for lymphoid cells of B cell origin) is essential in classifying the acute leukemias. Common cytogenetic abnormalities in ALL include t(9;22) in adults and t(12;21) and high hyperdiploidy in children (see table Common Cytogenetic Abnormalities in ALL ).

Common Cytogenetic Abnormalities in ALL

Less common cytogenetic abnormalities include the following:

t(v;11q23) / MLL or KMT2A rearranged, including t(4;11)/ KMT2A-AF4

t(1;19)/ E2A-PBX1 ( TCF3-PBX1 )

t(5;14)/ IL3-IGH

t(8;14), t(8;22), t(2;8)/ C-MYC rearranged

BCR-ABL -like acute lymphoblastic leukemia overlaps phenotypically with ALL in which the Philadelphia chromosome [a reciprocal balanced translocation between chromosomes 9 and 22, t(9;22)] is present (Ph+ ALL).

Other laboratory findings may include hyperuricemia, hyperphosphatemia , hyperkalemia , hypocalcemia , and elevated lactate dehydrogenase (LDH), which indicate a tumor lysis syndrome . Elevated serum levels of hepatic transaminases or creatinine, and hypoglycemia may also be present. Patients with Ph+ ALL and patients with t( v ;11q23) involving MLL rearrangements often present with hyperleukocytosis.

CT of the head is done in patients with CNS symptoms. CT of the chest and abdomen should be done to detect mediastinal masses and lymphadenopathy and may also detect hepatosplenomegaly. Echocardiography or multi-gated acquisition (MUGA) scanning is typically done to assess baseline cardiac function (prior to administration of anthracyclines, which are cardiotoxic).

Treatment of ALL

Systemic chemotherapy

Prophylactic CNS chemotherapy and sometimes CNS radiation

For Ph+ ALL, also a tyrosine kinase inhibitor

Supportive care

Sometimes immunotherapy , targeted therapy , stem cell transplantation , and/or radiation therapy

Treatment for newly diagnosed acute lymphoblastic leukemia generally consists of 3 to 4 cycles of chemotherapy blocks of non–cross-resistant chemotherapy for the first 9 to 12 months, followed by 2.5 to 3 years of maintenance chemotherapy.

Chemotherapy

The 4 general phases of chemotherapy for acute lymphoblastic leukemia include

Remission induction

Postremission consolidation

Interim maintenance and intensification

Maintenance

The goal of induction treatment is complete remission, defined as 1000/mcL (> 1 × 10 9 /L), a platelet count > 100,000/mcL (> 100 × 10 9 /L), and no need for blood transfusion. In patients with complete remission, a low measurable residual disease (also known as minimal residual disease or MRD) is the most important prognostic factor ( 1 ). Measurable or minimal residual disease is microscopic disease that is not detected by standard assays but can be measured by more sensitive assays. A low measurable residual disease (MRD negativity) is defined variably (based on the assay used) as

Components of induction therapy include

The goal of consolidation is to prevent leukemic regrowth. Consolidation therapy usually lasts a few months and combines regimen-specific courses of non–cross-resistant drugs that have different mechanisms of action. For adults with Ph+ ALL, allogeneic stem cell transplantation is recommended as consolidation therapy.

Interim maintenance and late/delayed intensification therapy are used after consolidation therapy. These phases of therapy incorporate a variety of chemotherapeutic agents with different doses and schedules that are less intense than induction and consolidation.

Most regimens include maintenance therapy

CNS prophylaxis

Medically frail patients with ALL

About one third of patients with acute lymphoblastic leukemia are older adults (> 65). Older ALL patients are more likely to have precursor B-cell ALL and have higher risk and more complex cytogenetics, including Philadelphia chromosome positive (Ph+) or t( v ;11q23) MLL or KMT2A rearranged disease.

hematopoietic stem cell transplantation is an option.

Targeted immunotherapy drugs that are available for treatment of relapsed or refractory ALL are increasingly used for treatment of older patients with ALL in clinical trials or clinical practice.

Older patients with ALL probably tolerate asparaginase more poorly than younger patients do.

Relapsed or refractory ALL

Leukemic cells may reappear in the bone marrow, CNS, testes, or other sites. Bone marrow relapse is particularly ominous. Although a new round of chemotherapy may induce a second remission in the majority of children and about one third of adults, subsequent remissions tend to be brief. Chemotherapy helps only a few patients with early bone marrow relapse to achieve long disease-free second remissions or cure.

Chimeric antigen receptor T (CAR-T) cells, engineered and generated from the patient's T cells, induce remission in patients with relapsed ALL with remarkable efficacy, albeit with significant toxicity ( 2 ).

Available immunotherapies for relapsed or refractory ALL include

a biospecific CD19-directed CD3 T-cell engager, prolongs overall survival for children and adults with relapsed or refractory B-cell precursor ALL, whether Ph+ or Ph-. Life-threatening toxicities may include cytokine release syndrome 3 ).

4 ). Inotuzumab may cause hepatotoxicity, including fatal and life-threatening veno-occlusive disease and is associated with higher post-transplant non-relapse mortality.

a CD19-directed genetically modified autologous T-cell immunotherapy, is available for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in a 2nd or later relapse. Life-threatening toxicities may include cytokine release syndrome and neurologic toxicities ( 5 ).

Brexucabtagene autoleucel , a CD19-directed genetically modified autologous T cell immunotherapy, can be used to treat adult patients with relapsed or refractory B-cell precursor ALL. Complications, including cytokine release syndrome and neurologic toxicities, may be life threatening.

Other agents have been available, but clinically meaningful outcomes have not been convincingly demonstrated (ie, the approvals were based upon response rate but there were no trials verifying an improvement in disease-related symptoms or increased survival) for these. Examples include:

Stem cell transplantation following reinduction chemotherapy or immunotherapy offers the greatest hope of long-term remission or cure if an HLA-matched sibling is available. Cells from other relatives or from matched, unrelated donors are sometimes used. Transplantation is rarely used for patients > 65 years because it is much less likely to be successful and because adverse effects are much more likely to be fatal.

CNS relapse

Testicular relapse may be evidenced clinically by painless firm swelling of a testis or may be identified on biopsy. If unilateral testicular involvement is clinically evident, the apparently uninvolved testis should undergo biopsy. Treatment is radiation therapy of the involved testis and administration of systemic reinduction therapy.

Supportive care is similar in the acute leukemias and may include

Transfusions

Antimicrobials

Hydration and urine alkalinization

Psychologic support

Transfusions of red blood cells and sometimes platelets are administered as needed to patients with bleeding or anemia. Prophylactic platelet transfusion is done when platelets fall to < 10,000/mcL ( 9 /L). Anemia (hemoglobin < 7 or 8 g/dL [

Antimicrobials are often needed for prophylaxis and treatment because patients are immunosuppressed; in such patients, infections can progress quickly with little clinical prodrome. After appropriate studies and cultures have been done, febrile patients with neutrophil counts < 500/mcL ( < 0.5 × 10 9 Pneumocystis jirovecii infection or a viral infection should be suspected and confirmed by bronchoscopy and bronchoalveolar lavage and treated appropriately.

Aspergillus and Candida P. jirovecii

Hydration, tumor lysis syndrome G6PD deficiency

Psychologic support may help patients and their families with the shock of illness and the rigors of treatment for a potentially life-threatening condition.

Treatment references

1. Berry DA, Zhou S, Higley H, et al : Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: A meta-analysis. JAMA Oncol 3(7): e170580, 2017. doi:10.1001/jamaoncol.2017.0580

2. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al : T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967) :517–528, 2015.

3. Kantarjian H, Stein A, Gökbuget N, et al : Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376(9):836–847, 2017.

4. Kantarjian HM, DeAngelo DJ, Stelljes M, et al : Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375(8):740–753, 2016.

5. Maude SL, Laetsch TW, Buechner J, et al : Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378(5):439–448, 2018.

Prognosis for ALL

Prognostic factors help determine treatment protocol and intensity.

Favorable prognostic factors are

Age 3 to 9 years

WBC count < 25,000/mcL ( 9 /L) or 9 /L) in children

Leukemic cell karyotype with high hyperdiploidy (51 to 65 chromosomes), t(1;19), and t(12;21)

No CNS disease at diagnosis

Unfavorable factors include

Leukemic cell karyotype with 23 chromosomes (haploidy), with

Leukemic cell karyotype with t( v ;11q23) MLL ( KMT2A ) rearranged, including t(4;11)/ KMT2A-AF4

Leukemic cell karyotype t(5;14)/ IL3-IG

Leukemic cell karyotype t(8;14), t(8;22), t(2;8) C-MYC rearranged

Presence of the Philadelphia (Ph) chromosome t(9;22) BCR-ABL1

Increased age in adults

BCR/ABL1 -like molecular signature

Regardless of prognostic factors, the likelihood of initial remission is ≥ 95% in children and 70 to 90% in adults. Of children, > 80% have continuous disease-free survival for 5 years and appear to be cured. Of adults,

Less ability to tolerate intensive chemotherapy

More frequent and severe comorbidities

Higher risk ALL genetics that confer chemotherapy resistance

Poorer adherence to ALL treatment regimens, which include frequent (often daily or weekly) out-patient chemotherapy and doctor visits

Less frequent use of pediatric-inspired treatment regimens

Most investigatory protocols select patients with poor prognostic factors for more intense therapy because the increased risk of and toxicity from treatment are outweighed by the greater risk of treatment failure leading to death.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children but also occurs in adults.

Central nervous system (CNS) involvement is common; most patients receive intrathecal chemotherapy and corticosteroids and sometimes CNS radiation therapy.

Response to treatment is good in children, with cure possible in > 80% of children but in

Repeat induction chemotherapy, immunotherapy, and stem cell transplantation may be helpful for relapse.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Leukemia and Lymphoma Society: Resources for Healthcare Professionals : Provides information on education programs and conferences and resources for referrals to specialty care

Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.

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Acute lymphocytic leukemia.

Yana Puckett ; Onyee Chan .

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Last Update: August 26, 2023 .

• Continuing Education Activity

Acute lymphocytic leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a characteristic disease pattern. ALL accounts for approximately 2 percent of lymphoid neoplasms in the United States and occurs slightly more frequently in males than females and three times as frequently in Caucasians as in African Americans. Patients typically present with symptoms related to anemia, thrombocytopenia, and neutropenia due to the replacement of the bone marrow with the tumor. Symptoms can include fatigue, easy or spontaneous bruising and/or bleeding, and infections. Additionally, B-symptoms, such as fever, night sweats, and unintentional weight loss, are often present but may be mild, and hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half of adults on presentation. Central nervous system (CNS) involvement is common and can be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to increased intracranial pressure. This activity examines when acute lymphocytic leukemia should be considered on differential diagnosis and how to properly evaluate it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

• Identify the epidemiology of acute lymphocytic leukemia.
• Outline the exam findings typically seen in patients with acute lymphocytic leukemia.
• Review the management of acute lymphocytic leukemia.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by acute lymphocytic leukemia.
• Introduction

Acute lymphocytic leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors, which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a typical disease pattern characteristic of acute lymphocytic leukemia. ALL accounts for approximately 2 percent of the lymphoid neoplasms diagnosed in the United States. Acute lymphocytic leukemia occurs slightly more frequently in males than females and three times as frequently in Whites as in Blacks. Patients with acute lymphocytic leukemia typically present with symptoms related to anemia, thrombocytopenia, and neutropenia due to the replacement of the bone marrow with the tumor. Symptoms can include fatigue, easy or spontaneous bruising/bleeding, and infections. B-symptoms, such as fever, night sweats, and unintentional weight loss, are often present but may be mild. Hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half of adults on presentation. Central nervous system (CNS) involvement is common and can be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to increased intracranial pressure. [1] [2] [3]

The etiology of acute lymphocytic leukemia is unknown. However, certain environmental factors have been implicated in the etiology of Acute Lymphocytic Leukemia, such as exposure to benzene, ionizing radiation, or previous exposure to chemotherapy or radiotherapy.

Genomic studies have noted that somatic, polymorphic variants of ARD5B, IKZF1 (the gene encoding Ikaros), and CDKN2A are associated with an increased risk of ALL (odds ratio 1.3 to 1.9). Other rare germline mutations in PAX5, ETV6, and particularly p53 can also strongly predispose to the development of leukemia.

Acute lymphoblastic leukemia is not considered a familial disease, and no screening programs have been developed to test for it in childhood. 

• Epidemiology

It is diagnosed in about 4000 people in the United States each year, with the majority being under the age of 18. It is the most common malignancy of childhood. The peak age of diagnosis is between two and ten years of age. Acute Lymphocytic Leukemia is more common in children with Trisomy 21 (Down syndrome), neurofibromatosis type 1, Bloom syndrome, and ataxia telangiectasia. All are common in children between two and three years of age. Prognosis is diminished in children when diagnosed in infants less than one year of age and in adults. It is more favorable in children. The association of the MLL gene in children at the 11q23 chromosome is associated with poor prognosis. Acute lymphocytic leukemia is a disease with low incidence overall in population studies. The incidence of acute lymphocytic leukemia is about 3.3 cases per 100,000 children. Survival rates for ALL have improved dramatically since the 1980s, with a current five-year overall survival rate estimated at greater than 85 percent.

• Pathophysiology

Acute lymphocytic leukemia is thought to occur after damage to DNA causes lymphoid cells to undergo uncontrolled growth and spread throughout the body. Splenomegaly and hepatomegaly occur due to sequestration of platelets and lymphocytes in the spleen and liver; as the white blood cells are not typical, the spleen reacts to them by trying to remove them from the blood. [4] [5] [6]

• Histopathology

On peripheral blood smears of acute lymphocytic leukemia patients, lymphoblasts vary in size. Various CD cytokines must be tested to evaluate for what kind of acute lymphocytic leukemia the patient has developed

• History and Physical

The most common presenting symptoms of acute lymphocytic leukemia are nonspecific and may be difficult to distinguish from common, self-limited diseases of childhood. In a meta-analysis, more than half of children with childhood leukemia had at least one of the following five features on presentation: palpable liver, palpable spleen, pallor, fever, or bruising. ALL patients typically present with symptoms of night sweats, easy bruising, skin pallor, unexplained lymphadenopathy, weakness, weight loss, hepatosplenomegaly, or difficulty breathing. Some patients may present with superior vena cava syndrome. Bone pain, mental changes, and oliguria may also be present. ALL can also present with testicular enlargement, musculoskeletal pain, mediastinal mass, and incidentally found peripheral blood cell abnormalities. 

Acute Lymphocytic Leukemia diagnosis should be explored initially with a laboratory evaluation consisting of a CBC, electrolyte and renal panel, and LDH level. Additionally, imaging, such as a chest x-ray for symptoms of shortness of breath, may be obtained. If abdominal fullness, tenderness, or abdominal mass are symptoms, then a CT scan of the abdomen and pelvis should be obtained. This can also help with the staging of the disease.

NCCN diagnosis guidelines:

• Have presence of more than 20% bone marrow lymphoblasts
• Hematoxylin and eosin-stained bone marrow clot and biopsy sections
• Morphology of bone marrow aspirate assessed with Wright/Giemsa
• Complete flow cytometric immunophenotyping
• Baseline evaluation of the leukemic clone

Lumbar puncture is used to evaluate CNS involvement. The fluid is checked for the presence of lymphoblasts.

• Treatment / Management

Children who are suspected of having acute lymphocytic leukemia should be referred to a pediatric center that specializes in cancer for evaluation and treatment.

For children with Acute Lymphocytic Leukemia, induction therapy consists of anthracycline, vincristine, 1-asparaginase, and a corticosteroid.

Today consolidation therapy is widely used and includes therapy with a variety of chemotherapeutic drugs with good results.

Maintenance therapy utilizes oral 6-mercaptopurine or methotrexate delivered once weekly or once monthly.  Successful treatment of children with acute lymphocytic leukemia involves the administration of a multidrug regimen that is divided into several phases (i.e., induction, consolidation, and maintenance) and includes therapy directed to the central nervous system (CNS).

Most treatment protocols take two to three years to complete.

CNS prophylaxis is done via an intrathecal approach. Patients often require 8 to 16 intrathecal treatments.

If the patient has Ph-chromosome positive ALL, the current treatment includes the use of tyrosine kinase inhibitors like imatinib, nilotinib, dasatinib, or ponatinib. Several trials have shown a good response to these agents.

Stem cell transplantation can sometimes be used as a treatment in which a patient's normal source of blood cells (bone marrow) is replaced by healthy young blood cells (stem cells) from a healthy well-matched donor. However, with improvements in chemotherapy, the role of transplantation is declining in ALL.

Recently CAR-T cell therapy has been investigated in ALL with excellent results. Several studies show high rates of remission. Unfortunately, CART is also associated with serious toxicity that includes cerebral edema and cytokine release syndrome, which can be fatal.

All blood products must be irradiated prior to transfusion to prevent transfusion-related graft versus host disease, which is universally fatal.

Splenectomy is rarely required for acute lymphocytic leukemia. Splenectomy can help boost platelet count but does not affect the outcome of leukemia itself. Splenectomy can be performed for severe symptoms that are not amenable to chemotherapy treatment, such as abdominal pain. Radiation can also be used in cases of enlarged spleen to try and reduce the size of the spleen in most cases. [7] [8] [9]

Tumor lysis syndrome is a life-threatening complication that occurs in patients receiving chemotherapy. It is characterized by hyperuricemia, elevated potassium and phosphate, and decreased levels of calcium. Renal failure is invariably present.

• Differential Diagnosis
• B cell lymphoma
• Acute myeloid leukemia
• Non-Hodgkin lymphoma

Current World Health Organization Classification of ALL [10]

B-lymphoblastic leukemia/lymphoma

• B-lymphoblastic leukemia/lymphoma, NOS
• B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
• B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);  BCR-ABL1
• B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged
• B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);  ETV6-RUNX1
• B-lymphoblastic leukemia/lymphoma with hyperdiploidy
• B-lymphoblastic leukemia/lymphoma with hypodiploidy
• B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3);  IL3-IGH
• B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);  TCF3-PBX1
• Provisional entity: B-lymphoblastic leukemia/lymphoma,  BCR-ABL1-like
• Provisional entity: B-lymphoblastic leukemia/lymphoma with  iAMP21

T-lymphoblastic leukemia/lymphoma

• Provisional entity: Early T-cell precursor lymphoblastic leukemia
• Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

Only about 30% of adults with ALL can be cured today. Criteria for good prognosis include:

• Age of less than 30
• No abnormal cytogenetics
• WBC count less than 30,000
• Complete remission within 4 weeks
• High hyperdiploidy with 51–65 chromosomes in children
• t(12;21)(p13;q22) in children

Poor prognostic factors include:

• Age of more than 60
• Presence of abnormal cytogenetics (t(9:22), t(4:11)
• Failure to achieve remission within 4 weeks
• Precursor B-cells more than 100,000
• Pearls and Other Issues

Despite improvements in supportive care, death resulting from treatment toxicity remains a challenge. It is important to watch out for tumor lysis syndrome, which occurs when chemotherapy causes cancer cells to lyse, releasing certain intracellular elements such as potassium, calcium, uric acid, and phosphorus. These elements, in large numbers, result in toxicity that can often lead to renal failure. Pretreatment with fluids and steroids typically prevents Tumor Lysis Syndrome. However, if it occurs, aggressive fluid therapy is the treatment. 

Even after treatment, acute lymphocytic leukemia can relapse. Relapses can occur as far back as 21 years. It is important to address other issues associated with cancer treatment in a young child, including providing psychological support to the child, parents, and family. 

• Enhancing Healthcare Team Outcomes

Like all malignancies, the management of acute leukemia is with an interprofessional team dedicated to the management of cancer patients; an interprofessional team includes an oncologist, an internist, an infectious disease expert, and a hematologist. The primary care provider and nurse practitioner may be responsible for follow-up after treatment and report back to the interprofessional team. These patients need close monitoring as they are prone to infections, coagulation dyscrasias, and relapse. Team conferences should be held while the patient is being treated, and any problems should be conveyed to the team.

The pharmacist should educate the patient on chemotherapy medications, their adverse effects, and their benefits. The dietitian should encourage a healthy diet. To prevent infections, the nurse practitioner should encourage hand washing, washing of fruits and vegetables, and maintaining good personal hygiene.

The oncology nurses should monitor the patient for adverse effects of the drug, including tumor lysis syndrome. Patients should be given consistent messages, and one should avoid offering unrealistic expectations. To improve outcomes, the team should keep updated on the latest clinical trials.

Despite improvements in supportive care, death resulting from treatment toxicity remains a challenge. It is important to watch out for tumor lysis syndrome, which occurs when chemotherapy causes cancer cells to lyse, releasing certain intracellular elements such as potassium, calcium, uric acid, and phosphorus. These elements, in large numbers, result in toxicity that can often lead to renal failure. Pretreatment with fluids and steroids typically prevents tumor lysis syndrome. However, if it occurs, aggressive fluid therapy is the treatment.

Even after treatment, acute lymphocytic leukemia can relapse. Relapses can occur as far back as 21 years. It is important to address other issues associated with cancer treatment in a young child, including providing psychological support to the child, parents, and family. 

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Disclosure: Yana Puckett declares no relevant financial relationships with ineligible companies.

Disclosure: Onyee Chan declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Puckett Y, Chan O. Acute Lymphocytic Leukemia. [Updated 2023 Aug 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• Review [Chronic lymphocytic leukemia]. [Dtsch Med Wochenschr. 2013] Review [Chronic lymphocytic leukemia]. Maurer C, Hallek M. Dtsch Med Wochenschr. 2013 Oct; 138(42):2153-66. Epub 2013 Oct 8.
• Acute hepatitis A induction of precursor B-cell acute lymphoblastic leukemia: a causal relationship? [Case Rep Oncol. 2010] Acute hepatitis A induction of precursor B-cell acute lymphoblastic leukemia: a causal relationship? Senadhi V, Emuron D, Gupta R. Case Rep Oncol. 2010 Sep; 3(3):505-9. Epub 2010 Dec 24.
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Bone marrow exam

In a bone marrow aspiration, a healthcare professional uses a thin needle to remove a small amount of liquid bone marrow. It is usually taken from a spot in the back of the hipbone, also called the pelvis. A bone marrow biopsy is often done at the same time. This second procedure removes a small piece of bone tissue and the enclosed marrow.

Doctors may find chronic leukemia in a routine blood test, before symptoms begin. If this happens, or if you have signs or symptoms that suggest leukemia, you may undergo the following diagnostic exams:

• Physical exam. Your doctor will look for physical signs of leukemia, such as pale skin from anemia, swelling of your lymph nodes, and enlargement of your liver and spleen.
• Blood tests. By looking at a sample of your blood, your doctor can determine if you have abnormal levels of red or white blood cells or platelets — which may suggest leukemia. A blood test may also show the presence of leukemia cells, though not all types of leukemia cause the leukemia cells to circulate in the blood. Sometimes the leukemia cells stay in the bone marrow.
• Bone marrow test. Your doctor may recommend a procedure to remove a sample of bone marrow from your hipbone. The bone marrow is removed using a long, thin needle. The sample is sent to a laboratory to look for leukemia cells. Specialized tests of your leukemia cells may reveal certain characteristics that are used to determine your treatment options.
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• Bone marrow biopsy

Treatment for your leukemia depends on many factors. Your doctor determines your leukemia treatment options based on your age and overall health, the type of leukemia you have, and whether it has spread to other parts of your body, including the central nervous system.

Common treatments used to fight leukemia include:

Chemotherapy. Chemotherapy is the major form of treatment for leukemia. This drug treatment uses chemicals to kill leukemia cells.

Depending on the type of leukemia you have, you may receive a single drug or a combination of drugs. These drugs may come in a pill form, or they may be injected directly into a vein.

• Targeted therapy. Targeted drug treatments focus on specific abnormalities present within cancer cells. By blocking these abnormalities, targeted drug treatments can cause cancer cells to die. Your leukemia cells will be tested to see if targeted therapy may be helpful for you.

Radiation therapy. Radiation therapy uses X-rays or other high-energy beams to damage leukemia cells and stop their growth. During radiation therapy, you lie on a table while a large machine moves around you, directing the radiation to precise points on your body.

You may receive radiation in one specific area of your body where there is a collection of leukemia cells, or you may receive radiation over your whole body. Radiation therapy may be used to prepare for a bone marrow transplant.

Bone marrow transplant. A bone marrow transplant, also called a stem cell transplant, helps reestablish healthy stem cells by replacing unhealthy bone marrow with leukemia-free stem cells that will regenerate healthy bone marrow.

Prior to a bone marrow transplant, you receive very high doses of chemotherapy or radiation therapy to destroy your leukemia-producing bone marrow. Then you receive an infusion of blood-forming stem cells that help rebuild your bone marrow.

You may receive stem cells from a donor or you may be able to use your own stem cells.

• Immunotherapy. Immunotherapy uses your immune system to fight cancer. Your body's disease-fighting immune system may not attack your cancer because the cancer cells produce proteins that help them hide from the immune system cells. Immunotherapy works by interfering with that process.
• Engineering immune cells to fight leukemia. A specialized treatment called chimeric antigen receptor (CAR)-T cell therapy takes your body's germ-fighting T cells, engineers them to fight cancer and infuses them back into your body. CAR -T cell therapy might be an option for certain types of leukemia.
• Clinical trials. Clinical trials are experiments to test new cancer treatments and new ways of using existing treatments. While clinical trials give you or your child a chance to try the latest cancer treatment, treatment benefits and risks may be uncertain. Discuss the benefits and risks of clinical trials with your doctor.
• Biological therapy for cancer
• Bone marrow transplant
• Chemotherapy
• Radiation therapy

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Coping and support

A diagnosis of leukemia may be devastating — especially for the family of a newly diagnosed child. With time you'll find ways to cope with the distress and uncertainty of cancer. Until then, you may find it helps to:

Learn enough about leukemia to make decisions about your care. Ask your doctor about your leukemia, including your treatment options and, if you like, your prognosis. As you learn more about leukemia, you may become more confident in making treatment decisions.

The term "leukemia" can be confusing because it refers to a group of cancers that aren't all that similar except for the fact that they affect the bone marrow and blood. You can waste a lot of time researching information that doesn't apply to your kind of leukemia. To avoid that, ask your doctor to write down as much information about your specific disease as possible. Then narrow your search for information accordingly.

• Keep friends and family close. Keeping your close relationships strong will help you deal with your leukemia. Friends and family can provide the practical support you'll need, such as helping take care of your house if you're in the hospital. And they can serve as emotional support when you feel overwhelmed by cancer.

Find someone to talk with. Find a good listener who is willing to listen to you talk about your hopes and fears. This may be a friend or family member. The concern and understanding of a counselor, medical social worker, clergy member or cancer support group also may be helpful.

Ask your doctor about support groups in your area. Or check your phone book, library or a cancer organization, such as the National Cancer Institute, the American Cancer Society or the Leukemia & Lymphoma Society.

• Take care of yourself. It's easy to get caught up in the tests, treatments and procedures of therapy. But it's important to take care of yourself, not just the cancer. Try to make time for yoga, cooking or other favorite diversions.

Preparing for your appointment

Start by seeing your family doctor if you have signs or symptoms that worry you. If your doctor suspects you have leukemia, you may be referred to a doctor who specializes in diseases of the blood and bone marrow (hematologist).

Because appointments can be brief, and because there's often a lot of information to discuss, it's a good idea to be prepared. Here's some information to help you get ready, and know what to expect from your doctor.

What you can do

• Be aware of any pre-appointment restrictions. At the time you make the appointment, be sure to ask if there's anything you need to do in advance, such as restrict your diet.
• Write down any symptoms you're experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
• Write down key personal information, including any major stresses or recent life changes.
• Make a list of all medications, vitamins or supplements that you're taking.
• Consider taking a family member or friend along. Sometimes it can be difficult to remember all the information provided during an appointment. Someone who accompanies you may remember something that you missed or forgot.
• Write down questions to ask your doctor.

Your time with your doctor is limited, so preparing a list of questions can help you make the most of your time together. List your questions from most important to least important in case time runs out. For leukemia, some basic questions to ask your doctor include:

• Do I have leukemia?
• What type of leukemia do I have?
• Do I need more tests?
• Does my leukemia need immediate treatment?
• What are the treatment options for my leukemia?
• Can any treatments cure my leukemia?
• What are the potential side effects of each treatment option?
• Is there one treatment you feel is best for me?
• How will treatment affect my daily life? Can I continue working or going to school?
• I have these other health conditions. How can I best manage them together?
• Should I see a specialist? What will that cost, and will my insurance cover it?
• Are there brochures or other printed material that I can take with me? What websites do you recommend?

In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask other questions during your appointment.

What to expect from your doctor

Your doctor is likely to ask you a number of questions. Being ready to answer them may allow more time later to cover other points you want to address. Your doctor may ask:

• When did you first begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Have you ever had abnormal blood test results? If so, when?
• Kliegman RM, et al. The leukemias. In: Nelson Textbook of Pediatrics. 21st ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Oct. 16, 2020.
• Niederhuber JE, et al., eds. Abeloff's Clinical Oncology. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Oct. 16, 2020.
• Leukemia. American Society of Hematology. https://www.hematology.org/education/patients/blood-cancers/leukemia. Accessed Oct. 16, 2020.
• Warner KJ. Allscripts EPSi. Mayo Clinic. July 9, 2020.
• Pruthi RK (expert opinion). Mayo Clinic. Dec. 2, 2020.

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Home > Books > Leukemia

Acute Leukemia Clinical Presentation

Submitted: 27 April 2012 Published: 15 May 2013

DOI: 10.5772/53531

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Gamal abdul hamid.

• Faculty of Medicine, University of Aden, Yemen

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1. Introduction

Acute leukemias are highly malignant neoplasms and are responsible for a large number of haematopoietic cancer-related deaths ( Jemal et al 2006 ). Although the survival rates have improved remarkably in the younger age group, the prognosis in older patients is still poor ( Redaelli et al 2003 ).

The clinical presentation of acute leukemia results from infiltration of bone marrow or extramedullary sites by blasts. As a result, initial symptoms may be due to the presence of anemia, neutropenia, or thrombocytopenia. Patients generally present with nonspecific complaints including weakness, lethargy, fatigue, dyspnea, fever, weight loss, or bleeding. Blasts may also infiltrate organs or lymph nodes, resulting in hepatosplenomegaly or adenopathy. Bone marrow infiltration with blasts can result in bone pain. Mucosal bleeding, petechiae, ecchymosis, and fundal hemorrhages may occur as a result of thrombocytopenia.

Patients with acute promyelocytic leukemia (APL) characteristically present with coagulopathy and signs of disseminated intravascular coagulation (DIC). It should be noted, however, that rapid cell turnover can result in DIC in any form of acute leukemia.

In acute monocytic leukemia the common findings are weakness, bleeding and a diffuse erythematous skin rash. There is a high frequency of extramedulary infiltration of the lungs, colon, meninges, lymphnodes, bladder and larynx and gingival hyperplasia.

The clinical onset of acute lymphoblastic leukemia (ALL) is most often acute, although a small percentage of cases may evolve insidiously over several months ( Pui 2006 ). The presenting symptoms and signs correlate with the leukemic cell burden and the degree of bone marrow replacement, leading to cytopenias.

Pathophysiology of the clinical manifestations of acute leukemias

2. Signs, symptoms and laboratory features of Acute Myeloblastic Leukemia (AML)

Clinical manifestations of AML result either from the proliferation of leukaemic cells or from bone marrow failure that leads to decrease in normal cells. Leukaemic cells can infiltrate tissues, leading to hepatomegaly, splenomegaly, skin infiltrates and swollen gums. As an indirect effect of the leukaemic proliferation leading to high cell destruction, hyperuricaemia and occasionally renal failure may occur. The haematopoiesis suppression leads to clinical features of anaemia, neutropenia and thrombocytopenia. Signs and symptoms that signal the onset of AML include pallor, fatigue, weakness, palpitations, and dyspnea on exertion. They reflect the development of anemia; however, weakness, loss of sense of wellbeing, and fatigue on exertion may be disproportionate to the severity of anemia. ( Gur et al 1999 ). Easy bruising, petechiae, epistaxis, gingival bleeding, conjunctival hemorrhages, and prolonged bleeding from skin injuries reflect thrombocytopenia and are frequent early manifestations of the disease. Very infrequently gastrointestinal, genitourinary, bronchopulmonary, or central nervous system bleeding can occur at the onset of the disease. Neutropenia translates into infectious manifestations. Pustules or other minor pyogenic infections of the skin and of minor cuts or wounds are most common. Major infections such as pneumonia, pyelonephritis, and meningitis are uncommon as presenting features of the disease, in part because absolute neutrophil counts under 500/μl (0.5 × 10 9 /L) are uncommon until chemotherapy is begun. Anorexia and weight loss are frequent findings. Fever is present in many patients at the time of diagnosis. Myeloid (granulocyte) sarcoma (MS) is an extramedullary tumor that occurs in 2 to 14% of cases of AML ( John et al 2004 ); and is composed of immature and mature granulocytes or monocytes ( Brunning et al 2001 ). These neoplasms are known by a variety of names in the literature, including granulocytic sarcoma, monocytic sarcoma, extramedullary myeloid cell tumor, myelosarcoma, myeloblastoma, and chloroma ( Carneiro et al. 1984 , Valbuena et al 2005 ). Virtually any extramedullary site can be involved by MS. Most patients with MS have a history of a myeloid neoplasm, most often AML and less often a myelodysplastic or myeloproliferative disease ( Brunning et al 2001 ). Alternatively, MS can be the initial manifestation of AML that subsequently involves blood and bone marrow ( Schmitt-Graff et al 2002 ). Very rarely, MS can be the only site of disease. MS is relatively more common in patients who have leukemias with prominent monocytic differentiation, such as acute myelomonocytic or monocytic leukemia and chronic myelomonocytic leukemia ( Menasce et al 1999 , Elenitoba et al 1996). MS manifesting as a testicular mass is uncommon and only rarely has occurred as an isolated mass. The tumors are usually localized ; they often involve bone, periostium, soft tissues, lymph nodes, or skin. Common sites of myeloid sarcoma are orbit and paranasal sinuses. However, it should be noted that according to the WHO classification the infiltrates of any site of the body by myeloid blasts in AML patients are not classified as myeloid sarcoma unless they present with tumor masses in which the tissue architecture is effaced ( Pileri et al 2008 ).

Blasts may infiltrate organs or lymph nodes, resulting in adenopathy or hepatosplenomegaly. Palpable splenomegaly and hepatomegaly occur in about one third of patients. Testicular infiltration is less common in AML than ALL, with an incidence of 1 to 8 % ( Wiernik et al 2001). Meningeal involvement has been reported in 5 to 20% of children and up to 16% of adults with AML ( John et al 2004 ). Leukemic blast cells circulate and enter most tissues in small numbers. Occasionally biopsy or autopsy will uncover marked aggregates or infiltrates of leukemic cells, and less frequently collections of such cells may cause functional disturbances.

3. Signs, symptoms and laboratory features of Acute Promyelocytic Leukemia (APL)

Acute promyelocytic leukaemia (APL) is a distinctive sub-type of acute myeloid leukaemia that has distinct biologic and clinical features.

According to the older French-American-British (FAB) classification of AML, based solely on morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation ( Cheson et al 1990 ), APL is sub-typed as AML-M3. The new World Health Organization (WHO) classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers and is more universally applicable and prognostically valid ( Brunning et al 2001 ). APL exists as 2 types, hypergranular or typical APL and microgranular (hypogranular) APL. APL comprises 5% to 8% of cases of AML and occurs predominately in adults in midlife ( Büchner et al. 1999 ). Both typical and microgranular APL are commonly associated with DIC ( Karp et al. 1987 , Gollard et al 1996 , Davey et al 1986 , Tobelem et al 1980 ). The severe bleeding diathesis associated with APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA), which acts as a differentiating agent ( Licht et al 1995 ). High complete remission rates in APL may be obtained by combining ATRA treatment with chemotherapy ( Brunning et al 2001 ).

4. Signs, symptoms and laboratory features of Acute Myelomonocytic (AML-M4) and Acute Monoblastic/Monocytic Leukemia (AML-M5)

Acute myelomonocytic (M4) and monoblastic/monocytic leukemia (M5), are the morphologic subtype of acute myelogenous leukemia that are most commonly characterized by weakness, bleeding and a diffuse erythematous skin rash and frequently presents with extramedullary involvement, including liver, spleen, lymph nodes, gingiva, skin, eyes, larynx, lung, bladder, meninges and the central nervous system. Involvement of the gastrointestinal tract is rare, the mouth, rectum and anal canal being the most affected sites ( Lichtman et al 1995 ). By contrast, leukemic infiltration of the stomach has been very rarely described, and when it has, it has been mainly in children ( Kasantikul et al 1989 ; Kontny et al. 1995 ; Domingo-Domenech et al 2000 ). Serum and urinary muramidase levels are often extremely high.

Neurological symptoms may occur such as, headache, nausea, vomiting, photophobia, cranial nerve palsies, pupil edema and/ or nuchal rigidity. These symptoms may result from leukostasis, but may also reveal meningeal invasion by myeloblasts or be the presenting symptoms of a "chloroma". These chloromas often have an orbital or periorbital localization, or may arise around the spinal cords causing paraparesis or " Cauda equine" syndrome. CNS leukemic infiltration occurs in 6-16% of AML ( Abbott et al 2003 ), especially in AML-M4.

Renal insufficiency occurs seldom. It is caused by hyperuriccuria and / or hyperphosphaturia, leading to obstructing tubular deposits and oliguria/ anuria.

5. Signs, symptoms and laboratory features of Acute Lymphoblastic Leukemia (ALL)

The clinical presentation of ALL may range from insidious nonspecific symptoms to severe acute life-threatening manifestations, reflecting the extent of bone marrow involvement and degree of extramedullary spread ( Pui et al 2006 ) ( Table 2) . The symptoms at onset are primarily produced by the detrimental effects of the expanding cell population on bone marrow, and secondarily by the infiltration of other organs and by metabolic disturbances ( Henderson et al 1990 , Gur et al. 1999 ). In younger patients the anemia-induced fatigue may be the only presenting feature. Dyspnea, angina, dizziness, and lethargy may reflect the degree of anemia in older patients presenting with ALL. Approximately half of all patients may present with fever attributable to the pyrogenic cytokines, such as IL-1, IL-6, TNF, released from the leukemic cells, infections, or both. Arthralgia and bone pain due to bone marrow expansion by the leukemic cells and occasionally necrosis can be observed, although less commonly in adults compared to children. Pallor, petechiae, and ecchymosis in the skin and mucous membranes due to thrombocytopenia, DIC, or a combination of the above may be observed. ALL may present with either leukopenia (~20%) or moderate (50%–5–25 × 10 9 /L) and severe leukocytosis (10%–>100 ×10 9 /L) with hyperleukocytosis (>100 x 10 9 /L ) present in approximately 15% of the pediatric patients ( Pui et al 2006 ). Neutropenia (less than 500 granulocytes per mm 3 ) is a common phenomenon and is associated with an increased risk of serious infection. Hypereosinophilia, generally reactive, may be present at diagnosis. The majority of patients present with platelet counts less than 100 × 10 9 /L (75%), while 15% have platelet counts of less than 10 × 10 9 /L. Decreased platelet counts (median, 50x10 9 /L) are usually present at diagnosis and can be readily distinguished from immune thrombocytopenia, as isolated thrombocytopenia is rare in leukemia. Severe hemorrhage is uncommon, even when platelet counts are as low as 20x10 9 /L, and infection and fever are absent. Coagulopathy, usually mild, can occur in T-cell ALL and is only rarely associated with severe bleeding. More than 75% of the patients presents with anemia, which is usually normochromic and normocytic and associated with a normal to low reticulocyte count. Anemia or thrombocytopenia is often mild (or even absent) in patients with T-cell ALL. Pancytopenia followed by a period of spontaneous hematopoietic recovery may precede the diagnosis of ALL in rare cases and must be differentiated from aplastic anemia.

Clinical features of adult acute lymphocytic leukemias

Bone marrow is usually infiltrated with >90% blast cells. Infiltration with less than 50% blasts represents only 4% of cases. Though the distinction between lymphoblastic leukaemia and lymphoma is still arbitrary, for many treatment protocols 25% bone marrow blasts is used as threshold for defining leukaemia ( Borowitz & Chan 2008 ). Normal trilineage haematopoiesis is consequently decreased. The classical triad of symptoms related to bone marrow failure are the following: (1) fatigue and increasing intolerance to physical exercise (caused by anaemia), (2) easy bruising and bleeding from mucosal surfaces and skin (caused by thrombocytopenia especially when platelets are < 20 × 10 9 /L), and (3) fever with infections (40% of all cases, caused by absolute granulocytopenia). Hyperleukocytic leukaemias with >100 x 10 9 /L blast cells rarely lead to the leukostasis syndrome and catastrophic early bleeding ( Porcu et al 2000 ). Also malaise, lethargy, weight loss, fevers, and night sweats are often present but typically are not severe. Compared to AML, patients with ALL experience more bone and joint pain. Rarely, they may present with asymmetric arthritis, low back pain, diffuse osteopenia, or lytic bone lesions [ Gur et al 1999 ]. Children experience these symptoms more frequently than adults. Young children may have difficulties in walking due to bone pain [ Farhi et al 2000 ]. Lymphadenopathy, splenomegaly, and hepatomegaly are more common than in AML and affect half of the adults with ALL. CNS involvement is also more common in ALL compared to AML. Patients may present with cranial neuropathies (most often involving the 6th and 7th cranial nerves). Nausea, vomiting, headache, or papilledema may result from meningeal infiltration and obstruction of the outflow of cerebrospinal fluid (CSF) leading to a raised intracranial pressure. Testicular involvement, presenting as a painless, unilateral mass, is noted at diagnosis in approximately 2% of boys. It is associated with infant or adolescent age, hyperleukocytosis, splenomegaly, and mediastinal mass [ Farhi et al 2000 ]. The diagnosis of testicular involvement is made by wedge biopsies. Bilateral biopsies are necessary due to the high incidence of contralateral testicular disease [Amendola et al 1985.[

6. Central nervous system involvement

The incidence of CNS involvement in patients with AML is considerably less common than CNS involvement in both adults and children with ALL (Charles et al 2012). Early CNS leukemia occurs in 8% of patients at the time of the first diagnosis while the percentage of relapsing CNS leukemia is 10%. ( Hardiono et al 2001 ).

Patients with CNS involvement may be asymptomatic or may have symptoms related to increased intracranial pressure (headache, nausea, vomiting, irritability). All patients newly diagnosed with ALL should have a lumbar puncture for cytologic analysis of the cerebrospinal fluid; for AML, however, this is performed only in patients with symptoms indicative of CNS involvement ( Pavlovsky et al 1973 ). There is an association of central nervous system involvement and diabetes insipidus in AML with monosomy 7, abnormalities of chromosome 3 and inversion of chromosome 16. ( Glass et al 1987 ; Lavabre-Bertrand et al. 2001 ; Harb et al 2009 ).

Central nervous system hemorrhage and infection are reported to cause 80% ( Lazarus et al 2006 ) of all deaths in patients with leukemia. The intracerebral hemorrhages that are often related to intravascular leukostases and leukemic nodules, and associated with leukocyte counts more than 100x10 9 /L in peripheral blood ( Phair et al 1964 ).

6.1. Leukemic parenchymal tumor

CNS may be affected as a solid tumors consisting of myeloid leukemic blasts called granulocytic sarcomas or chloromas ( Recht et al 2003 , Teshima et al 1990 ). The term chloroma results from the greenish color of these tumors caused by the presence of myeloperoxidase. Chloromas usually have a dural attachment although parenchymal tumors have rarely been reported. These tumors are hypercellular and avidly enhance with either cranial magnetic resonance imaging (MRI) or cranial computed tomography (CT). Neurologic findings are dependent upon location. Chloromas most often occur in bone that may result in epidural spinal cord compression, the orbit that may result in proptosis and a restrictive ophthalmopathy, or dura, which may simulate a meningioma.

6.2. Intracranial hemorrhage

Hemorrhagic complications are common in patients with acute leukemia (approximately 20%) and constitute the second most common cause of death in such patients (20% of all leukemic deaths result from intracranial hemorrhage) ( Kim et al 2004 , Kawanami et al 2002 ). Intracranial hemorrhage (ICH) is the most common hemorrhagic complication in acute promyelocytic leukemia and is not infrequent in AML and ALL (ranging in occurrence from 2-18% of all patients with acute leukemia). ICH may occur at the time of diagnosis (early hemorrhage) or subsequent to diagnosis and following initial treatment (late hemorrhage) ( Cortes et al 2001 ). DIC, disseminated aspergillosis or mucormycosis, leukemic cell infiltration, thrombocytopenia or L-asparaginase chemotherapy-related consequences, are the most common etiologies for ICH. Both DIC (especially common in the M3 subtype of AML) and thrombocytopenia typically result in a solitary often-massive ICH whereas disseminated fungal infection and ICH occurring during neutropenia and is a result of hemorrhagic infarction. Leukemic cell infiltration occurs with extreme leukocytosis (defined as >300x10 9 leukemic cells/L and increase the risk of multiple intracranial hemorrhages in acute leukaemia( Bunin et al 1985 ). L-asparaginase may induce hyperfibrinogenemia and result in cortical vein or sinus thrombosis complicated with venous infarction. Fungal-related mycotic aneurysms may also lead to ICH and would be a consideration in a patient with blood culture positive for fungus. Topographically the majority of ICH is intraparenchymal with cerebral hemorrhage more common than cerebellar. ( Wolk et al 1974 ).

Subarachnoid hemorrhage occurs in the context of ICH, either in isolation or more frequently as more diffuse hemorrhage secondary to DIC. Spinal subarachnoid hemorrhage may occur in the context of DIC and acute promyelocytic leukemia and present primarily with back pain that migrates rostrocaudally.

Risk - factor analysis revealed that female gender, APL, leukocytosis, thrombocytopenia and prolonged PT were the risk factors for fatal intracranial hemorrhages, while other reports have suggested the significance of serum fibrinogen ( Wide et al 1990 ).

6.3. Leukemic meningitis

Meningeal leukemia appears more often in patients with ALL than in those with AML ( Lazarus et al 2006 ). The manner in which leukemia cells enter the CNS is a subject of controversy, but the likely source include hematogenous spread or direct spread from adjacent infiltrated bone marrow.

Meningitis in leukemia may result from leptomeningeal infiltration of tumor (LM), subarachnoid hemorrhage, chemical (treatment-related following intra-CSF instillation of chemotherapy) or infection (bacterial or fungal) ( Cash et al 1987 , Dekker et al 1985 ). The presence or absence of LM always needs to be ascertained as if diagnosed, prognosis is profoundly affected. Chemical meningitis (typically due to intra-CSF cytarabine or methotrexate and most often given intraventricularly) is temporally related to intra-CSF chemotherapy. Chemical meningitis begins one to two days after intra-CSF chemotherapy administration, It is transient typically lasting less than five days and demonstrates no evidence of infection by CSF culture. Like other meningitis syndromes, patients complain of headache, fever, nausea, vomiting, photophobia and meningismus. Notwithstanding an inflammatory CSF, chemical meningitis rapidly abates and is mitigated by oral steroids. Infectious meningitis occurs in leukemia due to immunosuppression both as a result of the underlying disease and its treatment. Listeria , Candida and Aspergillus are common infectious etiologies however clinical presentation differs. Listeria presents as a meningitise syndrome whereas Candida presents with a diffuse encephalopathy and multiple small brain abscesses and Aspergillus presents with progressive hemorrhagic stroke confined to a single vascular territory ( Gerson et al 1985 , Winston et al 1993 ).

6.4. Cerebrospinal fluid in leukemic patients

The cerebrospinal fluid findings in leukemic patients must be carefully evaluated since bacterial meningitis, abscess formation or fungal disease occur with increased frequency. Cerebrospinal fluid pleocytosis, chemical abnormalities (elevated protein and low sugar) and elevated pressure may be present in these potential complications of the disease or its therapy. Appropriate cultures and stains, are often helpful in diagnosis. Abscesses can often be detected by brain scans, electroencephalograms and arteriography.

6.4.1. Categories of CNS status at diagnosis of acute leukemia

Patients who have nontraumatic diagnostic lumbar punctures at diagnosis may be placed into 3 categories according to white blood cells (WBCs) per microliter and the presence or absence of blasts on the cytospin: central nervous system 1 (CNS1) refers to CSF with <5 WBCs per microliter with cytospin negative for blasts; Cxlink refers to CSF with <5 WBCs per microliter with cytospin positive for blasts; CNS3 refers to CSF with >5 WBCs per microliter with cytospin positive for blasts. Children with ALL who presents with CNS disease at diagnosis (CNS3) are at high risk for treatment failure compared with patients not meeting the criteria of the CNS disease at diagnosis. Patients with Cxlink may be at an increased risk of CNS relapse, although this may not apply to all treatment regimens and can be overcome by more intensive intrathecal treatment ( Burger et al 2003 ).

7. Testicular involvement

Involvement of the testis - one of the most common sites of relapse in acute lymphoblastic leukemia usually presents with painless enlargement of one or both testis. Testicular involvement occurs in 10% to 23% of boys during the course of the disease at a median time of 13 months from diagnosis. Occult testicular involvement is recognized in 10% to 33% of boys undergoing bilateral wedge biopsies performed during the first 3 years of treatment or at any time after cessation of the therapy (Lanzkowsky et al. 1985). In a study in which biopsies were done in boys with newly diagnosed ALL, microscopic testicular involvement was reported to be 21% ( Neimeyer et al 1993 ). Testicular involvement of the endothelial side of the interstitium of one or both testis, leads to increased testicular size and firmness [ Kay et al 1983 ]. Hydrocele resulting from lymphatic obstruction may also present with painless scrotal enlargement and is readily identified by ultrasonography. Overt testicular involvement may occur in any form of acute lymphoblastic leukemia, most commonly in common C-ALL, but also in T-ALL and B-ALL. Rarely it is present when ALL is first diagnosed, but most often it is a late complication and, as with meningeal leukemia, the higher the initial blood blast count is, the earlier the discovery of testicular disease is likely ( Nesbit et al 1980 ).

8. Superior vena cava syndrome

Superior vena cava syndrome comprises the signs and symptoms associated with compression or obstruction to the superior vena cava. Patients with ALL (particularly T-ALL), may present with symptoms of cough, dyspnea, stridor, or dysphagia from tracheal and esophageal compression by a mediastinal mass (15% of patients). Compression of the great vessels by a bulky mediastinal mass also may lead to the life threatening superior vena cava syndrome ( Marwaha et al 2011 ). A child with leukemia may experience anxiety, confusion, drowsiness and sometimes unconsciousness ( Salsali et al 1969 ). There is facial edema, plethora, cyanotic faces. Venous engorgement of neck, chest and arm with collateral vessel and some sign of pleural effusion and pericardial effusion may be present ( Rice et al 2006 ).

9. Skin involvement

Various cutaneous lesions can be observed in patients with acute leukemias. These include specific cutaneous lesions resulting from infiltration of the skin by the leukemic cells, characteristic diseases such as pyoderma gangrenosum and Sweet syndrome, cutaneous signs of infection or hemorrhage resulting from the bone marrow dysfunction induced by the malignant process or chemotherapy.

Skin involvement may be of three types: nonspecific lesions, leukemia cutis, or granulocytic sarcoma of skin and subcutis. Nonspecific lesions include macules, papules, vesicles, pyoderma gangrenosum, or vasculitis ( Bourantas et al. 1994 , Nambiar Veettil et al 2009 ), neutrophilic dermatitis (Sweet's syndrome) ( Cho K-H et al 1997 , Philip R Cohen 2007 ), cutis vertices gyrata, or erythema multiforme or nodosum ( Byrd et al 1995 ). Leukemia cutis lesions usually appear at the time of diagnosis of systemic disease or thereafter, but occasionally can occur before peripheral blood or bone marrow involvement (aleukemic leukemia cutis). ( Christos Tziotzios et al 2011 , Márcia Ferreira et al 2006 ). T-cell ALL may show epidermotropism and monocytic leukemia often involves the entire dermis and the superficial panniculus ( Yalcin et al 2004 ).

10. The gastrointestinal tract

Gastrointestinal (GI) manifestations of leukemia occur in up to 25% of patients at autopsy, generally during relapse. Its presence varies with the type of leukemia and has been decreasing over time due to improved chemotherapy. Gross leukemic lesions are most common in the stomach, ileum, and proximal colon. Leukemia in the esophagus and stomach includes hemorrhagic lesions from petechiae to ulcers, leukemic infiltrates, pseudomembranous esophagitis, and fungal esophagitis. ( Dewar et al. 1981 ) The mouth, colon, and anal canal are sites of involvement that most commonly lead to symptoms. Oral manifestations may bring the patient to the dentist; gingival or periodontal infiltration and dental abscesses may lead to an extraction followed by prolonged bleeding or an infected tooth socket. ( Dean et al. 2003 ). The gingival hyperplasia is most commonly seen with the AML subtypes acute monocytic leukemia M5 (67%), acute myelomonocytic leukemia M4 (18.5%) and acute myelocytic leukemia M1-M2 (3.7%) ( Cooper et al 2000 ). Enterocolitis, a necrotizing inflammatory lesion involving the terminal ileum, cecum, and ascending colon, can be a presenting syndrome or can occur during treatment. Fever, abdominal pain, bloody diarrhea, or ileus may be present and occasionally mimic appendicitis. Intestinal perforation, an inflammatory mass, and associated infection with enteric gram-negative bacilli or clostridial species are often associated with a fatal outcome. Isolated involvement of the gastrointestinal tract is rare.( Tim et al 1984 ).. Neutropenic enterocolitis (NE), which is a fulminant necrotizing process is a well-recognized complication of neutropenia in patients dying from hematologic malignancies especially acute leukemia as indicated by various autopsy series ( Steinberg et al 1973 ). Proctitis, especially common in the monocytic variant of AML, can be a presenting sign or a vexing problem during periods of severe granulocytopenia and diarrhea.( Christos Tziotzios et al. 2011 )

11. Respiratory tract involvement

Infectious and noninfectious pulmonary complications represent a critical problem for patients with leukemia, which itself can be the direct cause of pulmonary leukostasis, pulmonary leukemic infiltration (PLI), and leukemic cell lysis pneumopathy. These disorders are usually more frequent in patients with hyperleukocytic leukemia. Pulmonary leukostasis is characterized by occlusion of the pulmonary capillaries and arterioles by leukemic cells. Leukemic infiltration may lead to laryngeal obstruction, parenchymal infiltrates, alveolar septal infiltration, or pleural seeding. Each of these events can result in severe symptoms and radiologic findings ( Potenza et al 2003 , Wu et al 2008 ).

Pulmonary disease in leukaemia is frequent and often lethal. Lung involvement in leukaemia is primarily due to (a) leukostasis of vessels and (b) true leukaemic infiltration of interstitium and alveoli. ( Majhail et al 2004 , Porcu et al 2000 ) Clinically, leukostasis in leukaemia should be suspected in patients with unexplained fever and cardiopulmonary or cerebral dysfunction. Pulmonary leukostasis was found in about40% of autopsy series. ( Mark et al 1987 ). Maile et al 1983 noted parenchymal opacities on 90% of chest radiographs obtained shortly before death in adult patients with leukaemia. These radiologic opacities on autopsy were attributed to infections, haemorrhages, leukaemic infiltrations and edema. In addition, drug induced pulmonary infiltrates and leukoagglutinin transfusion reactions were also reported ( Mark et al 1987 ). In spite of the above data, pulmonary leukostasis in leukaemia has been mentioned only incidentally as a cause of abnormalities on chest radiography.

12. Cardiac complications

Cardiac complications of the patients with acute leukemia are common. Most of the cardiac complications may be due to chemotherapeutics such as antracyclins, besides anemia, infections, or direct leukemic infiltrations of the heart. Symptomatic pericardial infiltrates, transmural ventricular infiltrates with hemorrhage, and endocardial foci with associated intracavitary thrombi can, on occasion, cause heart failure, arrhythmia, and death. Infiltration of the conducting system or valve leaflets or myocardial infarction may occur. ( Ashutosh et al 2002 , Fernando et al 2004 ). Cardiac and other tissue damage as a consequence of release of eosinophil granule contents can occur in patients with leukemia, associated with eosinophilia ( Kocharian et al 2006 ). Cardiac damage is a major determinant of the overall prognosis.

13. Urogenital involvement

The urogenital organs can also be affected. The kidneys are infiltrated with leukemic cells in a high proportion of cases, but functional abnormalities are rare. Hemorrhages in the pelvis or the collecting system are frequent, however, cases of vulvar, bladder neck, prostatic, or testicular involvement have been described.. ( Quien et al 1996 ).

14. Musculoskeletal system

Musculoskeletal manifestations are the presenting complaint in up to 20% of patients with pediatric leukemia,( Andreas et al 2007 ). The main clinical osteoarticular manifestations in early leukemia include limb pain, nighttime pain, arthralgia, and arthritis. Skeletal manifestations of acute leukaemia (bone or back pain, arthritis or radiographical abnormalities of skeleton) are well described in children ( Barbosa et al 2002 ). Arthritis can occur at any time during the course of acute leukaemia. It may lead to delay in diagnosis and therapy and any delay in therapy is associated with poor prognosis ( Sandeep et al 2006 ). The most common clinical presentation of leukaemic arthritis is additive or migratory asymmetrical oligoarticular large joint arthritis and in some cases juvenile idiopathic arthritis. ( Evans et al. 1994 , Mirian et al. 2011 ). The joints most commonly involved are the knee, followed by the ankle, wrist, elbow, shoulder and hip. Onset of arthritis may be sudden or insidious, and parallel the course of acute leukaemia ( Sandeep et al. 2006 ).

Arthritis as the first manifestation of acute leukaemia is however extremely uncommon in adults.

15. Hyperleukocytosis and leukostasis

Leukostasis is a syndrome, caused by clumping of leukocytes in the vasculature of the lungs and brain, often resulting in hypoxia, dyspnea, confusion, and coma, and may be fatal.

Leukapheresis is indicated in the initial management of leukostasis in patients with hyperleukocytosis in acute leukemias, particularly myeloid leukemias, or in patients who are at high risk of developing such a complication.

Adult T-cell leukemia/lymphoma is a distinct form of ALL that presents with progressive lymphadenopathy, hepatosplenomegaly, and hypercalcemia. It involves the skin, lungs, bone marrow, intestinal tract, and CNS. This disease is associated with HTLV-1 and is endemic in the Caribbean, southeastern United States, Africa, and Japan. Circulating tumor cells have a characteristic “cloverleaf”-shaped nucleus.

The risk factors for leukostasis are acute the leukaemia itself, younger age (most common in infants), certain types of leukaemia like acute promyelocytic (microgranular variants), acute myelomonocytic, acute monocytic leukaemia and T cell type of ALL. Cytogenetic abnormalities – 11q23 translocations and presence of Philadelphia chromosome are also associated with leukostasis ( Porcu et al 2000 ). The pathogenesis of leukostasis is determined by: - 1) sluggish flow with stasis, 2) aggregation of leukaemic cells, 3) formation of microthrombi, 4) release of toxic granules, 5) endothelial damage, 6) oxygen consumption by leukocytes, 7) tissue invasion ( Litchman et al 1987 ). Leukostasis is usually associated with counts of >100 x 10 9 but acute monocytic leukaemia may present with leukostasis with counts of 50 x 10 9 /L. 5-13% of patients of AML and 10-30% of patients of ALL will manifest with hyperleukocytosis. Earlier leukostasis was thought to be due to the presence of critical leukocrit (fractional leukocyte volume) and increased viscosity. Although hyperleukocytosis is also common presenting feature in patients with ALL, particularly with T-cell phenotype, 11q23, and t(9;22) chromosomal rearrangements, symptomatic leukostasis is exceedingly rare [ Porcu et al 2000 ]. While WBC count is a major factor contributing to microvessel occlusion seen with leukostasis, other features, such as activation of adhesion cell surface markers and mechanical properties of the leukemic blasts, are likely to be important. For example, the stiffness of myeloid blasts, as measured by atomic force microscopy, is 18 times that of lymphoid blasts [ Rosenbluth et al 2006 ]. This difference in deformability of the cells may at least partially explain the increased frequency of leukostasis in AML compared to than in ALL. Presence of symptoms suggestive of leukostasis, such as headache, blurred vision, dyspnea, hypoxia, constitute a medical emergency and efforts should be made to lower the WBC rapidly. However, the role of leukapheresis to reduce tumor burden in patients with ALL and leukocytosis remains controversial.

16. Metabolic complications

Hyperuricemia and hyperphosphatemia with secondary hypocalcemia are frequently encountered at diagnosis, even before chemotherapy is initiated, especially in patients with B-cell or T-cell ALL with high leukemic cell burden. Severe metabolic abnormalities may accompany the initial diagnosis of ALL and AML ( Haralampos et al 1999 ). Patients with high leukemic burden are at risk of developing acute tumor lysis syndrome (ATLS). Such metabolic changes may lead to the development of oliguric renal failure due to the tubular precipitation of urate and calcium phosphate crystals, fatal cardiac arrhythmias, hypocalcemic tetany, and seizures ( Jeha 2001 ).

17. Lactic acidosis

Lactic acidosis (LA), as the presenting manifestation of acute leukemia, is rare, but potentially fatal complication of acute leukemia ( Grossman et al 1983 ), characterized by low arterial pH due to the accumulation of blood lactate. It has been suggested that LA occurring in the setting of hematological malignancy is associated with an extremely poor prognosis [ Sillos et al 2001 ]. Lactate, the end product of anaerobic glycolysis, is metabolized to glucose by the liver and kidneys. Because leukemic cells have a high rate of glycolysis even in the presence of oxygen and produce a large quantity of lactate, LA may result from an imbalance between lactate production and hepatic lactate utilization [ Sillos et al 2001 ]. Several factors may contribute to the high rate of glycolysis. Overexpression or aberrant expression of glycolytic enzymes, such as hexokinase, the first rate-limiting enzyme in the glycolytic pathway [ Mazurek et al 1997 ] allows leukemic blasts to proliferate rapidly and survive for prolonged periods [ Mathupala et al 1997 ]. Although insulin normally regulates the expression of this enzyme, insulin-like growth factors (IGFs) that are overexpressed by malignant leukemic cells, can mimic insulin activity [ Werner 1996 ,]. LA is frequently associated with acute tumor lysis syndrome (ATLS) and its extent is correlated with the severity of ATLS.

Typically, the patient with lactic acidosis presents with weakness, tachycardia, nausea, mental status changes, hyperventilation, and hypotension, which may progress to frank shock as acidosis worsens. Laboratory studies show a decreased blood pH (<7.37), a widened anion gap (>18), and a low serum bicarbonates.

Definitions of comorbidities and HCT-CI scores included in the HCT-CI

18. Comorbidity

Many factors have been studied to predict outcome and allocate treatment in acute leukemia. The best established prognostic factors are karyotype and age. However, comorbidity may play an important role in the outcome.

A comprehensive assessment including performance status, evaluation of comorbidities and abilities to perform activities of daily living, geriatric depression scale in elderly patients has been proven to be useful in detecting treatment-related changes in older cancer patients and has been recommended to be incorporated into clinical outcome analysis. An index developed specifically for patients with hematologic malignancies has been developed: the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) presented in Table 3 ( Sorror ML et al 2005 ). This index captures comorbidities that predict non-relapse mortality in patients considered for allogeneic transplant and also proved to be a helpful tool for defining comorbid conditions in elderly untreated AML patients. ( Novotny J et al 2009 ; Sorror ML et al 2007 ). Modifications such as modified EBMT risk score have been developed and evaluated for ALL patients ( Terwey T et al, 2010 ).

Comorbidity scoring is currently still under the investigation in many cooperative groups. It is important to bear in mind that when translating the results from clinical trials into treatment decision-making for the individual patient, many patients with e.g. „unacceptable“ renal, cardial or hepatic abnormalities are generally not included into clinical trials. By such approach at least 20-30% of younger patients and more than 50% of elderly patients with AML are excluded and have not been reported in any results. Because of that it would be important to propose comorbidity score for all leukemia patients and to evaluate how many of the patients are able to receive standard therapy and stem cell transplantation, how many of them are candidate for low-intensity treatment and supportive care.

While acute leukemia patients depend on the expert recommendations from their physicians, knowledge of clinical presentation and patient's related prognostic factors can help to improve treatment decision and to identify patients who would benefit most from either intensive or low-intensive treatment or even best supportive care alone.

• 4. Ashutosh Hardikar Prem Shekar. Cardiac Involvement in a Case of Acute Lymphoblastic Leukemia, Ann Thorac Surg 2002 73 1310 2
• 16. Charles A Schiffer Richard A Larson et al, Involvement of the central nervous system with acute myeloid leukemia, Up-to-date Jan 25, 2012
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Overview of leukaemia

• Overview  
• Resources  

This page compiles our content related to leukaemia. For further information on diagnosis and treatment, follow the links below to our full BMJ Best Practice topics on the relevant conditions and symptoms.

Introduction

Leukaemia is a progressive, malignant disease of the blood-forming organs, characterised by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. In 2019, there were 644,000 new cases of leukaemia globally. [1] Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Compton K, et al. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the global burden of disease study 2019. JAMA Oncol. 2022 Mar 1;8(3):420-44. https://www.doi.org/10.1001/jamaoncol.2021.6987 http://www.ncbi.nlm.nih.gov/pubmed/34967848?tool=bestpractice.com The Surveillance, Epidemiology, and End Results Program estimates that there will be 59,610 new cases of leukaemia in 2023 in the US, representing 3.0% of all new cancer cases. [2] National Cancer Institute: Surveillance, Epidemiology, and End Results Program. National Institute of Health. U.S Department of Health and Human Services. ​Cancer stat facts: Leukemia. [internet publication]. https://seer.cancer.gov/statfacts/html/leuks.html ​ Leukaemia can be classified as acute or chronic, according to the degree of cell differentiation (not the duration of disease), and as myelogenous or lymphocytic, according to the predominant type of cell involved (myeloid or lymphoid). The exact cause of leukaemia is unknown, but genetic and environmental risk factors have been implicated for many sub-types. [3] Bispo JAB, Pinheiro PS, Kobetz EK. Epidemiology and etiology of leukemia and lymphoma. Cold Spring Harb Perspect Med. 2020 Jun 1;10(6):a034819. https://www.doi.org/10.1101/cshperspect.a034819 http://www.ncbi.nlm.nih.gov/pubmed/31727680?tool=bestpractice.com ​ Typical signs and symptoms might include fatigue, weight loss, fever, pallor, ecchymoses, petechiae, dyspnoea, dizziness, palpitations, bleeding, and recurrent infections, although each sub-type has its distinguishing features. Definitive diagnoses often require bone marrow biopsy and/or blood analysis.

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Acute Myeloid Leukemia (AML) Clinical Presentation

• Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
• Sections Acute Myeloid Leukemia (AML)
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Approach Considerations
• Blood Studies
• Flow Cytometry (Immunophenotyping)
• Cytogenetic Analysis
• Molecular Marrow Evaluation
• Other Tests
• Histologic Findings
• Treatment of Acute Myeloid Leukemia
• Treatment of Acute Promyelocytic Leukemia
• Treatment of Relapsed Acute Myeloid Leukemia
• Supportive Care
• Diet and Activity
• Long-Term Monitoring
• Medication Summary
• Antineoplastics, Tyrosine Kinase Inhibitor
• Antineoplastics, Hedgehog Pathway Inhibitor
• Bcl-2 Inhibitor
• IDH Inhibitors
• Questions & Answers

Patients with acute myeloid leukemia (AML) present with signs and symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable. Some patients, particularly younger ones, present with acute symptoms that develop over a few days to 1-2 weeks. Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder, such as myelodysplastic syndrome (MDS).

Symptoms of bone marrow failure

Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia. The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks. Other symptoms of anemia include dyspnea on exertion; dizziness; and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.

Patients with AML often have decreased neutrophil levels despite an increased total white blood cell (WBC) count. Patients generally present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, < 500 cells/µL, especially < 100 cells/µL) have the highest risk of infection. See the Absolute Neutrophil Count calculator.

Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.

Patients may present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both. Potentially life-threatening sites of bleeding include the lungs, gastrointestinal (GI) tract, and central nervous system.

Symptoms of organ infiltration with leukemic cells

Alternatively, disease manifestations may be the result of organ infiltration with leukemic cells. The most common sites of infiltration include the spleen, liver, gums, and skin. Infiltration occurs most commonly in patients with the monocytic subtypes of AML. Patients with splenomegaly note fullness in the left upper quadrant and early satiety. Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.

Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that calls for immediate intervention. Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in AML patients. Fever and other signs of infection can occur, including lung findings of pneumonia.

Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. The petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder (eg, DIC). Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.

Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).

Signs relating to leukostasis include respiratory distress and altered mental status.

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• Table 1. Common Antigens for Immunophenotyping of AML Cells
• Table 2. Cytogenetic Abnormalities in APL
• Table 3 AML Cytogenetic Risk Factors

Contributor Information and Disclosures

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research , American College of Physicians , American Society of Hematology Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science , American Association of Blood Banks , American Clinical and Climatological Association , American Society for Clinical Pathology , American Society of Hematology , College of American Pathologists , International Society of Blood Transfusion , International Society on Thrombosis and Haemostasis , Royal College of Physicians and Surgeons of Canada Disclosure: Nothing to disclose.

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education , American Society of Clinical Oncology , American College of Clinical Pharmacology , American Federation for Medical Research , American Society of Hematology , New York Academy of Sciences Disclosure: Nothing to disclose.

Clarence Sarkodee Adoo, MD, FACP Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program Clarence Sarkodee Adoo, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine , American Society of Hematology , American Society of Clinical Oncology Disclosure: Nothing to disclose.

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Clinical Presentation of Leukemia

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Clinical Presentation of Leukemia. AAP Grand Rounds December 2016; 36 (6): 70. https://doi.org/10.1542/gr.36-6-70

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Clarke   RT , Van den Bruel   A , Bankhead   C , et al . Clinical presentation of childhood leukaemia: a systematic review and meta-analysis . Arch Dis Child . 2016 ; 101 : 894 – 901 : doi: https://doi.org/10.1136/archdischild-2016-311251 Google Scholar  

Investigators from multiple institutions conducted a systematic review to describe how leukemia presents in childhood. They searched MEDLINE and EMBASE databases, using the search terms “leukemia” and “diagnosis” to identify studies that included infants, children, and adolescents. Studies were considered acceptable quality if they defined leukemia according to bone marrow findings, defined at least 2 baseline characteristics of participants, involved a sample that comprised all consecutive cases over the study period, and used a standardized data collection form and/or objectively measured signs. Data on presenting signs and symptoms were then extracted from all included studies that met quality criteria, and pooled proportions of children presenting with each feature were calculated.

Of the 14,963 identified in the original search, 35 studies met eligibility criteria. Of these, 33 met quality criteria and were included in analysis. All included studies were retrospective cohorts, conducted in 21 countries, and described presenting signs and symptoms in a total of 3,084 children. In pooled analysis, the 5 most common presenting signs and symptoms were hepatomegaly (64%), splenomegaly (61%), pallor (54%), fever (53%), and bruising (52%). Other common presenting signs and symptoms were recurrent infections (49%), fatigue (46%), limb pain (43%), hepatosplenomegaly (42%), bruising/petechiae (42%), lymphadenopathy (41%), bleeding tendency (38%), and rash (35%). Only 6% of children were asymptomatic on diagnosis.

The investigators conclude that because >50% of children with leukemia have palpable livers or spleens, children with unexplained illness should receive a focused examination that includes abdominal palpation.

Dr. Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

Leukemia comprises approximately 30% of childhood cancers, affecting an estimated 4,000 children annually. 1  Innate risk factors for leukemia include syndromes of trisomy 21, monosomy 7, immunodeficiency, bone marrow failure, tumor suppressor gene, and DNA repair gene disorders. 2,3  Associated exposure risk factors are chemotherapy agents such as topoisomerase II inhibitors, anthracyclines, and alkylating agents for prior cancers. 1,3,4 

Signs and symptoms at leukemia presentation overlap with indicators of infection, allergy, autoimmune disease, or injury. 1,3,4  Bone or joint pain, limping, adenopathy, fatigue, pallor, petechiae, excessive bruising, and hepatosplenomegaly with or without fever are common. 1,4–6  Rarer symptoms (which include headache, nausea, vomiting, abdominal pain, weight loss, mucosal bleeding, shortness of breath, or skin lesions) need to be taken in context of symptom duration and severity in addition to a thorough physical examination. 1,4,5  Initial investigations may include complete blood count with differential white blood cell count, comprehensive metabolic panel, sedimentation rate, lactic dehydrogenase, and uric acid. 1  Although not diagnostic, a mediastinal mass detected on chest radiograph or hepatosplenomegaly on abdominal ultrasound...

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Clinical presentation of childhood leukaemia: a systematic review and meta-analysis

Affiliations.

• 1 Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
• 2 Department of Paediatric Oncology/Haematology, Children's Hospital, John Radcliffe, Oxford, UK.
• 3 Department of Paediatric Oncology/Haematology, Leeds General Infirmary, Leeds, UK.
• 4 Department of Primary Care Health Sciences, University of Oxford, Oxford, UK Department of Family Medicine, University of Washington, Seattle, USA.
• PMID: 27647842
• DOI: 10.1136/archdischild-2016-311251

Objective: Leukaemia is the most common cancer of childhood, accounting for a third of cases. In order to assist clinicians in its early detection, we systematically reviewed all existing data on its clinical presentation and estimated the frequency of signs and symptoms presenting at or prior to diagnosis.

Design: We searched MEDLINE and EMBASE for all studies describing presenting features of leukaemia in children (0-18 years) without date or language restriction, and, when appropriate, meta-analysed data from the included studies.

Results: We screened 12 303 abstracts for eligibility and included 33 studies (n=3084) in the analysis. All were cohort studies without control groups. 95 presenting signs and symptoms were identified and ranked according to frequency. Five features were present in >50% of children: hepatomegaly (64%), splenomegaly (61%), pallor (54%), fever (53%) and bruising (52%). An additional eight features were present in a third to a half of children: recurrent infections (49%), fatigue (46%), limb pain (43%), hepatosplenomegaly (42%), bruising/petechiae (42%), lymphadenopathy (41%), bleeding tendency (38%) and rash (35%). 6% of children were asymptomatic on diagnosis.

Conclusions: Over 50% of children with leukaemia have palpable livers, palpable spleens, pallor, fever or bruising on diagnosis. Abdominal symptoms such as anorexia, weight loss, abdominal pain and abdominal distension are common. Musculoskeletal symptoms such as limp and joint pain also feature prominently. Children with unexplained illness require a thorough history and focused clinical examination, which should include abdominal palpation, palpation for lymphadenopathy and careful scrutiny of the skin. Occurrence of multiple symptoms and signs should alert clinicians to possible leukaemia.

Keywords: Haematology; Oncology.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PubMed Disclaimer

• When should I suspect childhood leukaemia? Connor P. Connor P. Arch Dis Child. 2016 Oct;101(10):874-5. doi: 10.1136/archdischild-2015-308731. Arch Dis Child. 2016. PMID: 27647841 No abstract available.

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• Childhood acute leukemia in West Bengal, India with an emphasis on uncommon clinical features. Biswas S, Chakrabarti S, Chakraborty J, Paul PC, Konar A, Das S. Biswas S, et al. Asian Pac J Cancer Prev. 2009;10(5):903-6. Asian Pac J Cancer Prev. 2009. PMID: 20104987
• 'Shouting from the roof tops': a qualitative study of how children with leukaemia are diagnosed in primary care. Clarke RT, Jones CH, Mitchell CD, Thompson MJ. Clarke RT, et al. BMJ Open. 2014 Feb 18;4(2):e004640. doi: 10.1136/bmjopen-2013-004640. BMJ Open. 2014. PMID: 24549167 Free PMC article.
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September 23, 2024

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Clinical trial supports adding ruxolitinib to tyrosine kinase inhibitors for chronic myeloid leukemia

by SWOG Cancer Research Network

Researchers leading the SWOG S1712 clinical trial have found that adding ruxolitinib to standard tyrosine kinase inhibitor (TKI) treatment for patients with chronic-phase chronic myeloid leukemia (CP-CML) significantly increased the percentage of patients who had a molecular response deep enough to warrant discontinuing treatment.

Results are being presented at the European School of Haematology's 26th Annual John Goldman Conference on Chronic Myeloid Leukemia, to be held in Prague, September 27–29.

Kendra L. Sweet, MD, a SWOG investigator at Moffitt Cancer Center who was principal investigator on the S1712 trial will deliver the results Friday, September 27, as an oral presentation in the conference's first scientific session, which is devoted to the meeting's top-scoring abstracts.

"Treatment free remission has become a common therapeutic goal for patients with CP-CML. In spite of this, only approximately 40 to 50% of CP-CML patients achieve molecular responses that are deep enough to qualify them for an attempt to discontinue TKI therapy," Sweet said.

"In this study the addition of ruxolitinib to TKIs resulted in significantly more patients with durable, deep molecular responses. Ultimately, this could lead to more patients successfully discontinuing treatment, which has been shown to significantly reduce health care costs and improve health-related quality of life."

CML is often treated with a class of drugs known as tyrosine kinase inhibitors. But leukemic stem cells can hide from TKIs in a patient's bone marrow. Preclinical data suggested that a drug called ruxolitinib can alter the bone marrow microenvironment to sensitize these stem cells to TKIs.

Researchers from SWOG Cancer Research Network hypothesized that adding ruxolitinib to TKI treatment would make TKIs more effective against leukemic stem cells , eradicating measurable residual disease in more patients.

In clinical trial S1712, they randomized 75 eligible patients with CML whose disease was still molecularly detectable on current therapy and who had been undergoing treatment with a TKI for at least one year. All patients continued their TKI treatment, but one half of patients also had the drug ruxolitinib added to their treatment.

After 12 months of on-study treatment, all patients had their blood tested for molecular response (MR), a highly sensitive test for RNA from a gene specific to leukemic cells. A score of MR4.0—considered a deep molecular response—indicates a reduction in this RNA to 0.01% or less of the baseline level. A score of MR4.5 indicates that no such RNA has been detected and is considered a complete molecular response.

The rate of S1712 patients scoring MR4.0 by 12 months was significantly higher on the ruxolitinib arm—46% versus 26% on the TKI-only arm. The rate of patients scoring MR4.5 at 12 months was significantly higher on the ruxolitinib arm as well—14% versus 3% on the control arm.

The addition of ruxolitinib also moved more patients to a remission deep enough that they were able to go off treatment. Two years after randomization, the proportion of patients who met the National Comprehensive Cancer Network (NCCN) guidelines criteria for being able to discontinue treatment was 29% on the investigational arm versus 11% on the control arm.

Toxicities were similar on the two arms. Two patients had grade 3 treatment-related adverse events (side effects) on the ruxolitinib arm. On the TKI-only arm, three patients had grade 3 treatment-related adverse events and one patient had a grade 4 adverse event. Grade 1/2 anemia was more common in patients treated on the ruxolitinib arm of the trial.

Sweet's team is now working to characterize which patients with CML are most likely to benefit from having ruxolitinib added to their TKI treatment. The authors conclude that further trials are warranted to test whether this combination could increase the percentage of these patients who move to treatment-free remission.

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