Acute Lymphocytic Leukemia (ALL)
(Acute Lymphoblastic Leukemia)
Acute lymphocytic 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 CNS and abdominal organs. Symptoms include fatigue, pallor, infection, bone pain, and easy bruising and bleeding. Examination of peripheral blood smear and bone marrow is usually diagnostic. Treatment typically includes combination chemotherapy to achieve remission, intrathecal chemotherapy for CNS prophylaxis and/or cerebral irradiation for intracerebral leukemic infiltration, consolidation chemotherapy with or without stem cell transplantation, and maintenance chemotherapy for up to 3 yr to avoid relapse.
Two thirds of all acute lymphocytic leukemia cases occur in children, with a peak incidence at age 2 to 5 yr; ALL is the most common cancer in children and the 2nd most common cause of death in children < 15 yr. A second rise in incidence occurs after age 45.
Prognostic factors help determine treatment protocol and intensity.
Favorable prognostic factors are
Unfavorable factors include
A leukemic cell karyotype with chromosomes that are normal in number but abnormal in morphology (pseudodiploid)
Presence of the Philadelphia (Ph) chromosome t(9;22)
Increased age in adults
B-cell immunophenotype with surface or cytoplasmic immunoglobulin
Early precursor T-cell phenotype; BCR-ABL–like molecular signature
Low chromosome number in the leukemia cells
BCR/ABL-like molecular signature
Regardless of prognostic factors, the likelihood of initial remission is ≥ 95% in children and 70 to 90% in adults. Of children, 75% or more have continuous disease-free survival for 5 yr and appear cured. Of adults, 30 to 40% have continuous disease-free survival for 5 yr. Imatinib improves outcome in adults and children with Ph chromosome–positive ALL. 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.
The 4 general phases of chemotherapy for ALL include
The goal is to induce remission. Several regimens emphasize early introduction of an intensive multidrug regimen. Remission can be induced with daily oral prednisone and weekly IV vincristine with the addition of an anthracycline or asparaginase. Other drugs and combinations that may be introduced early in treatment are cytarabine and etoposide as well as cyclophosphamide. In some regimens, intermediate-dose or high-dose IV methotrexate is given with leucovorin rescue. The combinations and their dosages are modified according to the presence of risk factors. Imatinib can be added to the drug regimen in patients with Ph chromosome–positive ALL.
An important site of leukemic infiltration is the meninges; prophylaxis and treatment may include intrathecal methotrexate, cytarabine, and corticosteroids in combination or methotrexate and cytarabine singly. Cranial nerve or whole-brain irradiation may be necessary and is often used for patients at high risk of CNS disease (eg, high WBC count, high serum LDH, B-cell phenotype), but its use has been decreasing in recent years.
The goal of consolidation is to prevent leukemic regrowth. Consolidation therapy usually lasts a few months and combines drugs that have different mechanisms of action than drugs used in induction regimens. Allogeneic stem cell transplantation is recommended as consolidation therapy for Ph chromosome–positive ALL in adults or for second or later relapses or remissions.
Most regimens include maintenance therapy with methotrexate and mercaptopurine. Therapy duration is usually 2½ to 3 yr but may be shorter when regimens that are more intensive in earlier phases are used. Clinical testing of monoclonal antibodies directed against proteins on the leukemic cell surface are underway, with some new agents showing promise.
Therapy is usually short and intensive for Burkitt leukemia or ALL with mature B-cells (FAB L3 morphology). For patients in continuous complete remission for 1 yr after therapy stops, the risk of relapse is small.
Leukemic cells may reappear in the bone marrow, the CNS, the testes, or other sites. Bone marrow relapse is particularly ominous. Although a new round of chemotherapy may induce a second remission in 80 to 90% of children (30 to 40% of adults), subsequent remissions tend to be brief. Chemotherapy causes only a few patients with early bone marrow relapse to achieve long disease-free second remissions or cure.
New immunotherapy approaches show impressive early results in relapsed/refractory ALL. Antibodies, such as blinatumomab, that bring T-cells in close proximity to leukemic blasts demonstrate activity in relapsed ALL. Chimeric antigen receptor T-cells, generated from pheresed T-cells from the patient, induce remission in relapsed patients with remarkable efficacy, albeit with significant toxicity (1).
If an HLA-matched sibling is available, stem cell transplantation offers the greatest hope of long-term remission or cure. Cells from other relatives or from matched, unrelated donors are sometimes used. Transplantation is rarely used for patients > 65 yr because it is much less likely to be successful and because adverse effects are much more likely to be fatal.
When relapse involves the CNS, treatment includes intrathecal methotrexate (with or without cytarabine or corticosteroids) twice weekly until all signs disappear. Most regimens include systemic reinduction chemotherapy because of the likelihood of systemic spread of blast cells. The role of continued intrathecal drug use or CNS irradiation is unclear.
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 as for isolated CNS relapse.
1. 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. Lancet385(9967) :517–528, 2015
ALL is the most common cancer in children but also occurs in adults.
CNS involvement is common; most patients receive intrathecal chemotherapy and corticosteroids and sometimes CNS radiation therapy.
Response to treatment is good, with cure possible in about 75% of children and 30 to 40% of adults.
Stem cell transplantation and new immunotherapies may be helpful for relapse.