Leukemia (blood Cancer)
Bharat R Agarwal
Pediatric Hematologist- Oncologist, Division of Pediatric Hem-Onco, B.J. Wadia Hospital for Children, Mumbai, India
First Created: 02/02/2001 

Acute Lymphoblastic Leukemia (ALL)

ALL is the commonest childhood cancer. The peak age is between 2-6 years. Boys are affected more frequently as compared to girls.

Acute Myeloid Leukemia (AML)

Cancer of the non-lymphoid series of the blood is called myeloid leukemia. It is also called acute myelogenous leukemia or AML, acute nonlymphocytic leukemia, or ALL. It accounts for almost 15- 20% of all childhood leukemia. The ratio of ALL: AML is 4:1.

Etiology:
Though the etiology is still unknown, it is associated with various environmental and genetic factors. It has been seen increasingly in patients with:
Genetic disorders

  • Down's syndrome
  • Bloom's syndrome
  • Fanconi's anemia

However, the majority of children with Down's syndrome and AML can be cured of their leukemia. Neonates with Down's syndrome may manifest a transient myeloproliferative syndrome which mimics congenital AML but improves spontaneously with 4-6 weeks.

Environmental factors

  • Exposure to ionizing radiation
  • Chemical exposure to benzene & hydrocarbons
  • Treatment with alkylating agents

Patients with acquired diseases such as myelodysplastic syndromes, myeloproliferative disorders and other pre-leukemic states are at an increased risk.

Chronic Myelogenous Leukemia (CML)

Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease of childhood, accounting for 2-5% of cases. There are two main types of chronic myeloid leukemia:

  • Adult type (Ph1 positive)
  • Juvenile type (JMML)

These diseases, in the early phase, are associated with an increased number of mature cells in the blood. There is a sequential orderly maturation of cells of myeloid lineage. JMML is characterized by monocytosis and this helps differentiate it from the adult type of CML.

Adult-Type Chronic Myelogenous Leukemia (Ph1 positive)

Chronic myelogenous leukemia is a clonal myeloproliferative disorder of the primitive hematopoietic stem cell and is characterized by:

  • The presence of the Philadelphia (Ph1) chromosome
  • Involvement of the myeloid, erythroid, megakaryocytic, B-, and sometimes T-lymphoid elements in the disease process.
  • A biphasic (chronic and blastic phase) or triphasic clinical course.

The chronic phase with a massive accumulation of granulocyte elements at all stages responds relatively easily to cytoreductive therapy. The phase lasts for months to years. Virtually all patients with CML (chronic, accelerated, and blastic phase) eventually develop an acute (blastic) phase, relatively resistant to therapy.

Pathology

Cytogenetics: The Ph1 chromosome is the result of breaks on chromosomes 9 and 22, with a reciprocal translocation involving the distal genetic material on chromosomes 9 and 22 designated as t(9;22) (q34;q11).

Molecular abnormalities: As a consequence of this translocation, the c-abl proto-oncogene is transposed from its normal position on chromosome 9 to a new position on chromosome 22, adjacent to the breakpoint cluster region (bcr) of the BCR gene. With the juxtaposition of c-abl to the bcr region, a new fusion (chimeric) bcr/abl oncogene is formed. The bcr/abl gene encodes a 210-kDa protein, which, through its properties of increased tyrosine kinase activity and ability to autophosphorylate, changes normal hematopoietic cells into CML cells.

Growth Advantage of the Chronic Myelogenous Leukemia Clone

CML cells express the transmembrane cellular adhesion molecules but lack the expression of the phosphatidylinositol glycan anchor. This results in reduced adherence and decreased interaction of the CML cells to the stromal matrix of the bone marrow. Consequently, CML cells remain in the late progenitor phase for a longer time before differentiation. Reduced adherence also leads to the release of immature CML cells into the circulation and facilitates extramedullary hematopoiesis. Even though the CML progenitor cells divide more slowly than normal hematopoietic progenitor cells, they are capable of producing CFU-GM in excessive quantities, which results in hyperproduction of myeloid cells in CML. The average half-life of CML granulocytes is 5-10 times longer than normal granulocytes. This suggests that the CML cells may live longer by not undergoing programmed cell death (apoptosis).

CML cells may derive their growth advantage by modifications of feedback regulatory pathways of myelopoiesis such as1 deficient lactoferrin production by polymorphonuclear cells and2 decreased sensitivity of progenitor cells to prostaglandin E and acidic isoferritins because of a deficiency of HLA-DR antigen expression on their cell surface.

Blastic Transformation

In the course of CML, there is sequential clonal evolution of stem cells bearing the original Ph1 chromosome. The newly evolved clones suppress the proliferation and differentiation of normal and preexisting Ph1 CML stem cells. Eventually, immature cells accumulate and the acute phase (blast crisis) develops. At a molecular level, there is no change in the bcr/abl gene activity. There is a high incidence of p53 mutations in association with blastic transformation of CML. Thus, it is possible that p53 mutation might complement the preexisting bcr/abl mutation and induce blastic transformation. Hyperploidy is more often associated with the myeloblastic acute phase, whereas hypoploidy or pseudodiploidy is more often associated with the lymphoblastic acute phase. Table 1 shows the poor prognostic factors in CML.

Juvenile Myelomonocytic Leukemia (JMML)

Biology and Pathogenesis:
Malignant monocyte-macrophage proliferation forms the basis for JMML. The biology of JMML cells is characterized by:

  • Monocyte-specific immunophenotype

  • Autocrine production of tumor necrosis factor (Alpha-TNF) by the malignant monocyte-macrophage cells of JMML

  • Selective hypersensitivity of JMML progenitor cells (CFU-GM) to GM-CSF.

The following pathologic events result in the growth of JMML cells:

  • Bi-directional action of TNF:
    • TNF inhibits normal hematopoiesis
    • TNF induces the proliferation of the malignant monocyte-macrophage elements of JMML.

  • Proliferating monocyte-macrophage elements of JMML secrete GM-CSF
  • GM-CSF increases further the proliferation of the hypersensitive population of JMML cells and enhances further the release of TNF.
  • Proliferating monocyte-macrophage cells also generate IL-1

The inhibitory effect of TNF on normal hematopoiesis outweighs the normal stimulatory function of GM-CSF and IL1 and eventually results in bone marrow suppression, anemia, and thrombocytopenia.

Monosomy 7 in Association with Chronic Myeloproliferative or Myelodysplastic Syndrome

Monosomy 7 syndrome and JCML share many common clinical manifestations and hematologic findings. Both can also be classified as refractory anemia, refractory anemia with excessive blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia according to FAB system of myelodysplastic syndrome. However, monosomy 7 syndrome differs from JCML in the following ways:

  • Hemoglobin F is rarely observed to be greater than 10%
  • Thrombocytopenia is usually not an early prominent feature.
  • Many patients progress to AML.
  • Neutrophil function is impaired with defective chemotaxis and killing (normal in JCML).
  • Monosomy 7 occurs in families.

Treatment:
Allogenic bone marrow transplantation is curative therapy. Because of an increased familial incidence of monosomy 7 syndrome, bone marrow cells of a prospective family member donor should have a chromosomal analysis to exclude monosomy 7 prior to bone marrow transplantation.

Chemotherapy:
Chemotherapy is only utilized for cytoreduction and palliation and similar therapy to that recommended for JCML can be employed.

Presentation

These children present either with very few symptoms or with severe sepsis, bleeding, etc, which indicate marrow failure and involvement of extramedullary organs. Certain features are unique to a particular sub-type of AML for e.g.

  • Patients with acute promyelocytic (M3) leukemia may have intravascular coagulopathy due to clotting factor deficiency resulting in severe bleeding.

  • Patients with M4 & M5 AML(monocytic component) may have associated gingival hypertrophy from leukemic infiltration, They may also develop meningeal leukemia, retinal infiltration, leukemia cutis, or other localized leukemia infiltrations. They may also have chloromas, which are granulocytic sarcomas seen commonly in the skin and have a dull green color due to the high peroxidase content in the leukemia cell.

In addition, in patients with AML, 1/3 of patients may splenomegaly. Hyper-uricemia is also very common.

JMML - Clinical Features

JMML is sub classified into

Juvenile chronic myelogenous leukemia (JCML) when there is

  • JMML morphology in the absence of t(9;22) translocation
  • Raised HbF (>10%)
  • No monosomy 7

Infantile monosomy 7 syndrome when there is

  • Presenting age less than 4 years with any type of myelodysplasia
  • Monosomy 7

Frequency:
The incidence of JMML is 0.6 cases per year per million children. JMML accounts for 18% of all cases of myelodysplastic syndrome in children less than 15 years of age.

Genetics:
Seven percent of JMML cases have been associated with neurofibromatosis, type 1. JMML has been described in identical twins.

Age of onset:
Forty percent of cases occur before 1 year of age and 60% of cases occur before 2 years of age.

Sex:
The male: female ratio is 2.1:1

Clinical symptoms :
JMML presents with fever and respiratory symptoms

Physical findings:
These include facial rash, lymphadenopathy, splenomegaly and bleeding problems, pharyngotonsillitis and bronchiolitis


Leukemia (Blood Cancer) Leukemia (Blood Cancer) 02/02/2001
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