Acute Lymphoblastic Leukemia

Introduction
FAB classification
Biological classification
ALL derived from B cells
   Cell surface markers and B cell differentiation
   pre-pre-B ALL
   pre-B ALL
   B cell ALL
ALL derived from T cells
Clinical Presentation
Laboratory Tests
Treatment

Introduction

The acute leukemias account for about one third of childhood cancer, and about three quarters of these leukemias are ALL (the others being AML or acute undifferentiated leukemia). In general, ALL has a better outcome than AML. Lymphoblasts can be distinguished from myeloblasts in a number of ways:

Characteristic	Lymphoblasts	Myeloblasts
Chromatin	smooth, homogenous	more fine
Nucleoli	indistinct	punched out
Cytoplasm	small rim	more abundant
Granules	rare	yes sometimes Auer rods
PAS	positive glycogen globs	small, fine PAS staining
MPO	Negative	Most positive
Sudan Black	Negative	Cytoplasmic lipid stains positive

FAB Classification of ALL

The FAB Classification relies on morphology, dividing blasts into L1, L2 and L3 by their appearance. These categories are not well related to biology or outcome except for the L3 blasts. These are derived from immunophenotypically distinct mature B cells.

L1	L2	L3
Small	Larger	Large
Almost no cytoplasm	About 20% cytoplasm	Basophilic Cytoplasm Cytoplasmic vacuolization
Round to cleaved nucleoli Perinuclear chromatin	More prominent nucleoli

Biological Classification of ALL

ALL blasts are derived from either B-cell or T-cell lineages, as determined by cell surface and other markers. A small percentage of the cells are either so primitive that they do not express enough markers to identify, and these comprise the AUL category. As more markers are elucidated, the number of leukemias falling into this wastebasket category is declining. The mixed cell leukemias represent another difficulty for classification: they are not clearly B or T cells and may represent a very early precursor (perhaps of both lines) or lineage infidelity.

ALL derived from B cells

As B cells differentiate, they change their cell surface markers in a predictable fashion. The B-cell leukemias are divided into four major stages as seen in the table below. In general, the earlier the B-cell lineage, the younger the population of patients affected by it.

        pre-pre-B      pre-B     immature    mature
      (precursor B)
                    |         |            |        
TdT     xxxxxxxxxxxx|xxxxxxxxx|xxxxxxxxxxxx| 
CD19    xxxxxxxxxxxx|xxxxxxxxx|xxxxxxxxxxxx|xxxxxxxx
CD24      xxxxxxxxxx|xxxxxxxxx|xxxxxxxxxxxx|xxxxxxxx
CD10        xxxxxxxx|xxxxxxxxx|xxxxxxxxxxxx|xxxxxxxx
CD20          xxxxxx|xxxxxxxxx|xxxxxxxxxxxx|xxxxxxxx
CD21            xxxx|xxxxxxxxx|xxxxxxxxxxxx|xxxxxxxx
CD22              xx|xxxxxxxxx|xxxxxxxxxxxx|xxxxxxxx
cIg                 |xxxxxxxxx|            |        
kappa               |  xxxxxxx|xxxxxxxxxxxx|xxxxxxxx
sIg                 |    xxxxx|xxxxxxxxxxxx|xxxxxxxx
lambda              |       xx|xxxxxxxxxxxx|xxxxxxxx

Pre-Pre B-ALL (Precursor B ALL)
There are two major populations within this stage. Blasts which are positive for CD19 and CD22, but not for CD10 (and thus very early) are common in infantile leukemia and are prognostically bad. Infantile leukemia is associated with high tumor burden, high white counts, organomegaly and CNS involvement. Those that are positive for CD10 are somewhat later in the lineage; these are termed common ALL (c-ALL) and make up more than half of all ALLs. CNS involvement is infrequent. These have a generally good prognosis.

Pre-B cell ALL
Almost all of the Pre-B ALLs have L1 morphology. This stage is defined by the production of cytoplasmic Ig. The presence of a t(1;19) translocation in considered prognostically bad. Both c-ALL and pre-B tend to occur in children between one and ten years of age.

B cell ALL
The minority of B-cell ALLs with surface Ig expression (most commonly IgM) have L3 morphology; on a bone marrow biopsy they are identical to Burkitts lymphoma. Often these cells have a translocation involving myc on chromosome 8. There is a strong male predominance for B-cell ALL. These leukemias behave differently than the other B-cell leukemias: they have a high mitotic rate, frequently invade the CNS, and often cause abdominal disease. The treatment for B-cell ALL is shorter and more intense than the other earlier B-cell ALLs. Relapses tend to occur within the year following cessation of treatment and are fatal with the exception of treatment by bone marrow transplant.

ALL Derived from T cells

The pre-T and T cell ALLs are grouped together in terms of biological behavior and treatment. Like mature B-cell ALL, the majority of the patients are male. The patients tend to be older than other ALL patients, commonly teenagers. They often present with mediastinal masses, high WBC counts, and substantial lymphadenopathy. T-cell ALL commonly invades the CNS and may also occur in the testes.

Clinical Presentation

ALL may present in almost any system. Common early symptoms include limping or bone pain secondary to marrow infiltration, signs of ICP if the CNS is involved, and other symptoms attributable to anemia, granulocytopenia, thrombocytopenia or coagulopathy.

Laboratory Tests

Patients with ALL may have a normal peripheral smear despite marrow involvement. More often, a normochromic/normocytic anemia is present with a decreased reticulocyte count. Dacryocytes, seen in any condition where functional marrow is displaced, may be present along with nRBCs. The white count is generally elevated, and platelets are often decreased. By definition the marrow has more than 25% blasts. If less, the condition is stage IV Non-Hodgkins Lymphoma. Cytogenetic and immunophenotyping studies help classify the type of leukemia and may determine treatment options.

Treatment

Aside from the treatment of mature B-cell ALL as described above, treatment of ALL involves four phases: Induction of remission, intensification, CNS and testicular prophylaxis or treatment, and continuation therapy. The goal of induction is to achieve maximum early cell kill and is successful about 95% of the time. This results in a two or three log decrease in tumor cell burden. Common regimens usually include L-asparaginase and an anthracycline, and often vincristine and prednisone. Intrathecal treatment with methotrexate, ara C and hydrocortisone may also be given. In the intensification phase was instituted to prevent early relapses and involves additional chemotherapy. If CNS disease is present, cranial irradiation and additional intrathecal chemotherapy may be given. The radiation treatments often result in a "somnolence syndrome" 6 to 8 weeks after treatment which is characterized by lethargy, anorexia, EEG changes, CNS pleocytosis and fever. Continuation therapy is designed to have minimal impact on normal cells while holding neoplastic cells in check. 6-mercaptopurine and methotrexate are often used as oral agents in an outpatient setting. The duration of treatment is variable, and multiple protocols come into play in the event of recurrence.

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Last modification: May 5, 1999