Acute lymphoblastic leukemia (ALS) is the most common form of leukemia in childhood with a peak frequency between 2 and 6 years of age. It occurs more frequently in children with some chromosomal abnormalities such as trisomy 21, Fanconi anemia, ataxia-telangiectasis syndrome, Li Fraumeni syndrome or Bloom syndrome.

The etiology of ALL is, on the whole, unknown even though many genetic and environmental factors have a proven association with them. The severity of the disease and its treatment depend on the morphology, surface markers and the cytogenetic characteristics of the hematopoietic cells involved. Surface markers show that ALL derives:

• in 85 % of cases, from progenitors of the lymphocytic B-line,
• in 15 % of cases, from the lymphocytic T-line,
• and in 1 % of cases, from lymphocytic B-line.

In the majority of cases, these cells contain chromosomal abnormalities (translocations, deletions, multiplications) with high prognostic impact.

2016 WHO CLASSIFICATION OF THE ACUTE LYMPHOBLASTIC AND AMBIGUOUS LINE LEUKEMIAS

The terms leukemia or lymphoma can be used interchangeably, depending on the initial presentation of the disease: in both situations the same type of blasts is involved but the presentation is different:

-        ALL: massive medullary involvement and leukemic phase

-        Lymphoblastic lymphomas: milder medullary involvement and sometimes leukemic masses (mediastinum, intestinal wall, lymph nodes,...)

1. ACUTE LEUKEMIA / LYMPHOBLASTIC LYMPHOMA B WITHOUT FURTHER SPECIFICATION

ALL1 [MIM 615 545]: predisposing mutation in 10q21

ALL2 [MIM 613 067]: predisposing mutation in 7p12.2

ALL3 [MIM 615 545]: predisposing mutation in 9p13.2

Burkitt-type ALL (ALL3 - FAB) [MIM 113 970] is a leukemic burkitt lymphoma and it is included in the mature B-cell tumors. It is associated with an infection by the Epstein-Barr virus. Somatic mutations or translocations involving the MYC gene (8q24.21).

2)        ACUTE LEUKEMIA / LYMPHOBLASTIC LYMPHOMA B WITH RECURRENT CYTOGENETIC ABNORMALITIES:

 

• Acute leukemia / B lymphoblastic lymphoma with t (9;22) (q34;q11.2); BCR-ABL1
• Acute leukemia / B lymphoblastic lymphoma with t (v;11q23); MLL (now KMT2A) rearranged
• Acute leukemia / B lymphoblastic lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)
• Acute leukemia / B lymphoblastic lymphoma with hyperdiploidism (> 50 chromosomes)
• Acute leukemia / B lymphoblastic lymphoma with hypodiploidism (< 50 chromosomes) (TP53 mutation)
• Acute leukemia / B lymphoblastic lymphoma with t(5;14)(q31;q32); IL3-IGH
• Acute leukemia / B lymphoblastic lymphoma with t(1;19)(q23 ;p 13.3); TCF3 - PBX1
• provisional entity: acute leukemia/B lymphoblastic lymphoma, BCR-ABL1 - like due to translocations involving tyrosine kinases (ABL1 genes, ABL2, CEBB, NTRK3, TYK2, JAK2, CSFIR) or cytokine receptors (CRLF2, sometimes associated with JAK2 as in trisomy 21).
• provisional entity: acute leukemia / lymphoblastic B lymphoma with iAMP21 (up < 2 %) (intrachromosomal amplification of chromosome 21), especially in the older child

3)        ACUTE LEUKEMIA / LYMPHOBLASTIC LYMPHOMA T

 

• Acute leukemia/ lymphoblastic lymphoma T

• Temporary entity: acute lymphoblastic leukemia with early T precursors (early-T). T differentiation is low, with retention of some myeloid and stem cells characteristics at the immunophenotypic and genotypic levels. Myeloid gene mutations are common: FLT3, NRAS/KRAS, DNMT3A, IDH1, and IDH2.
• Provisional entity: NK-cell acute leukemia/ lymphoblastic lymphoma

Very rare, which expresses CD56.

• Indolent T lymphoblastic (distinguishable from lymphoblastic T lymphoma). It is a non-tumor entity that mimics T lymphoblastic lymphoma. It usually involves the lymphoid tissue of the upper aerodigestive tract. Local recurrences are possible, but systemic involvement is rare. Lymph node histology shows infiltration and sometimes replacement with lymphoblasts, but they are less morphologically atypical than tumoral T lymphoblasts.

4)        AMBIGUOUS LINE ACUTE LEUKEMIA (< 2 %)

• ACUTE UNDIFFERENTIATED LEUKEMIA

These are rare AL, to be distinguished from AL with dendritic plasmacytoid precursors, or NK cells, or basophiles, and medullar involvement by metastatic cells of solid tumors. The blasts have no myeloid morphological differentiation, are negative for DFO cytochemistry and esterase, and do not express any B, T ,  myeloid, NK, dendritic or basophilic antigen.

 

• MIXED PHENOTYPE WITH T(9;22)(Q34; Q11.2) (B or T MYELOID)

AL that meets the criteria for a mixed AL phenotype, but with a Ph1 chromosome.

 

• MIXED PHENOTYPE WITH t (V;11Q23); REARRANGED MLL (LYMPHOBLASTES - MONOBLASTS)

Found at all ages but especially in early childhood.

It is often a hyperleucocytic AL, with a double population of blasts, one resembling lymphoblasts and the other monoblasts.

The translocation partner is usually AF4 located on 4q21.

 

• MIXED B AND MYELOID PHENOTYPE, WITH NO OTHER SPECIFICATION

Blasts usually resemble lymphoblasts, or are a mixture of lymphoblast-like and myeloblasts- like cells.

 

• MIXED T AND MYELOID PHENOTYPE, WITH NO OTHER SPECIFICATION

The morphological aspect evokes the above category, but may also correspond to a mixture of small and large lymphoblasts all with a very high N/C ratio.

Clinical presentation:

The onset of the clinical manifestations is most often insidious: anorexia, fatigue and progressive irritability sometimes associated with a subfebrile or febrile state. It is often associated with bone or joint pain. The symptomatology is often progressive, dominated by palor, the formation of skin hematomas either spontaneously or following a minor trauma, purpura, mucous bleeding, respiratory infection and a febrile state.

The biological evaluation usually shows hyperleucocytosis (20,000/mm3),anemia and thrombopenia. Bone marrow biopsy confirms the diagnosis and allows specifying the type of the disease. Further examinations will then be performed to specify the extension of the disease in different organs (especially the central nervous system).

Treatment and complications

Treatment is based on sequentially applied chemotherapy protocols ("cures"), depending on the patient's age, histological form and surface markers, and the initial response to treatment. The initial treatment (induction cure, usually lasting about 4 weeks) aims at destroying the malignant hematopoietic line in the bone marrow,and results in bone marrow aplasia.

The most commonly used agents are vincristine, L-asparaginase, daunomycin and, in addition to high-dose corticosteroid therapy (dexamethasone or prednisone). Intrathecal injections of methotrexate and/or cytarabine are also performed, either as a curative (from the induction treatment) or as a preventive measure, after the induction treatment. Induction treatment usually results in 98 % of  remission (defined by the presence of less than 5 % of blast cells in the bone marrow with normalization of blood platelets and polynuclear neutrophils count).

The subsequent stages of treatment follow complex protocols, varying between teams and countries. In general, a consolidation treatment is applied after the induction treatment for a period of several months to several years with regular monitoring for relapses, which occurs in 15 to 20 % of cases and will lead to new particularly aggressive chemotherapy and other treatment methods (radiotherapy, immunotherapy, bone marrow transplantation etc.).

Chemotherapy has significant toxic effects not only on blast cells but also on many normal cells in the body such as :

• normal hematopoietic cells of the bone marrow, resulting in bone marrow aplasia;
• hair follicle cells, resulting in extensive alopecia;
• mucous and digestive cells that cause very painful mucites, anorexia, food intolerance, sometimes severe various digestive contaminations; 

• neurons of the long spinal tract in case of spinal involvement;
• peripheral neuropathy, drug-induced  pancreatitis with vincristine
• nodal tissue cardiomyocytes with some chemotherapeutic agents.

Brisk cell lysis at the beginning of treatment causes a high elevation of uricemia that needs to be treated preventively (hyperhydration, allopurinol or rasburicase) to avoid kidney failure. The risk of acute tumor lysis syndrome is significant early in treatment and cases of kidney failure and hyperkalemia have been described after usual doses of corticosteroids.

Medullary aplasia or myelosuppression results in:

• significant anemia that requires repeated transfusions (phenotyped, CMV negative and irradiated blood);
• severe thrombopenia that exposes the child to a risk of major bleeding and requires platelet transfusions, especially in cases of invasive procedure or bleeding;
• severe neutropenia that exposes children to a major infectious risk, particularly to usually low-pathogenic agents: broad-spectrum antibioprophylaxis must be introduced in case of fever. Throughout the duration of treatment (induction and consolidation phase), children should receive a prophylactic antibiotic treatment aganint pneumocystis carinii.

Anesthetic implications:

• diagnostic phase: total blood count and chest X-Ray (mediastinal mass?). Hyperleucocytosis can lead to respiratory problems, especially after general anesthesia for diagnostic biopsies or central venous catheter insertion: these complications due to leukostasis in the lung are caused by transfusions and hyperhydration  which are often needed at the beginning of the treatment.

• onset of treatment: major risk of tumor lysis syndrome: uricemia ? kaliemia ? Avoid the administration of corticosteroids (dexamethasone for  antiemetic prevention, for example,) without the advice of a hematologis
• long-term venous access: Broviac or Hickman, "PICC," an acronym for Peripherally Inserted Central Catheters), or implantable chambers (port-a-cath).
• during treatment: total blood count, immunosuppression, side effects of treatment (thrombocytopenia, anemia, febrile neutropenia, neuropathy, mucitis etc), risk of iatrogenic adrenal failure
• in case of treatment with vincristine or cisplatin, check for the absence of any neuropathy before performing a peripheral nerve block
• after recovery/remission: echocardiography (toxicity of anthracyclines)

References : 

 -        Latham GJ, Greenberg RS.
Anesthetic considerations for the pediatric oncology patient- part 1: a review of antitumor therapy.
Pediatr Anesth 2010; 20:295-304.

-        Simbre II VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE.
Cardiotoxicity of cancer chemotherapy : implications for children.
Pediatr Drugs 2005; 7:187-202.

-        Osthaus WA, Linderkamp C, Bünte C, Jüttner B, Sümpelmann R.
Tumor lysis syndrome associated with dexamethasone use in a child with leukemia.
Pediatr Anesth 2008; 18:268-70.

-        McDonnell C, Barlow R, Campisi P, Grant R, Malkin D.
Fatal peri-operative acute tumour lysis syndrome precipitated by dexamethasone.
Anaesthesia 2008; 63:652-5.

-        Fong C, Fung W, McDonald J, Dallapozza L, De Lima J.
Anesthesia for children with hyperleukocytosis: a retrospective review.
Pediatr Anesth 2009; 19:1191-8.

-        Latham GJ, Greenberg RS.
Anesthetic considerations for the pediatric oncology patient- part 2: systems-based approach to anesthesia. 
Pediatr Anesth 2010; 20:396-420.

-        Hebl JR, Horlocker TT, Pritchard DJ.
Diffuse brachial plexopathy after interscalene blockade in a patient receiving cisplatin chemotherapy: the pharmacologic double crush syndrome.
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-        Huettemann E, Sakka SG.
Anaesthesia and anti-cancer chemotherapeutic drugs.
Curr Opin Anaesthesiol 2005;18:307-14.

Updated: March 2021