Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease as well as the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS).[1,2] The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic) and, in some cases, cranial radiation therapy.

Treatment is divided into three phases: remission induction, CNS prophylaxis, and remission continuation or maintenance. The average length of treatment of ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. Younger adults with ALL may be eligible for selected clinical trials for childhood ALL.

It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia chromosome (Ph1).[3] The Ph1 occurs in only 1% to 2% of patients with acute myelocytic leukemia, but it occurs in about 20% of adults and a small percentage of children with ALL.[4] In the majority of children and in more than one half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).

Ph1-positive ALL has a worse prognosis than most other types of ALL, though many children and some adults with Ph1-positive ALL may have complete remissions following intensive ALL treatment clinical trials. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in this disease.[5,6][Level of evidence: 3iiiDiv] In one study, 10 patients with Ph1-positive ALL and 10 patients with CML lymphoid blast crisis were treated with doses of imatinib ranging from 300 mg to 1000 mg per day.[5] Of these 20 patients, 4 had complete hematologic remission and 10 had marrow responses. Responses were short lived, with the majority of these patients relapsing at a median of 58 days after the start of therapy. In another study, 48 patients with Ph1-positive ALL were treated with 400 mg to 800 mg of imatinib per day.[6] The overall response rate was 60%, with 9 out of 48 patients (19%) achieving a complete remission. The responses again were short, with a median duration of 2.2 months. While there are no randomized clinical trials comparing chemotherapy with or without imatinib for this disease, because of the responses observed in monotherapy trials, imatinib is generally incorporated into the treatment of patients with Ph1-positive ALL. If a suitable donor is available, allogeneic bone marrow transplantation should be considered because remissions are generally short with conventional ALL chemotherapy clinical trials. Many patients who have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. Because many patients have a different fusion protein from the one found in CML (p190 vs. p210), the bcr-abl fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction (RT-PCR). These tests should be performed whenever possible in patients with ALL, especially those with B-cell lineage disease. Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(9;22) and t(4;11), patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype. In multivariate analysis, karyotype was the most important predictor of disease-free survival.[7][Level of evidence: 3iiDii] L3 ALL is associated with a variety of translocations which involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus (t(2;8), t(8;12), and t(8;22)). Unlike bcr-abl-positive ALL and t(4;11) ALL, there is some evidence such as was found in a Cancer and Leukemia Group B study (CALGB-9251) that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.[8-10]

References

1. Clarkson BD, Gee T, Arlin ZA, et al.: Current status of treatment of acute leukemia in adults: an overview of the Memorial experience and review of literature. Crit Rev Oncol Hematol 4 (3): 221-48, 1986.  [PUBMED Abstract]
   
   
2. Hoelzer D, Gale RP: Acute lymphoblastic leukemia in adults: recent progress, future directions. Semin Hematol 24 (1): 27-39, 1987.  [PUBMED Abstract]
   
   
3. Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia: a study of 28 patients. Am J Med 60(2): 209-220, 1976. 
   
   
4. Secker-Walker LM, Cooke HM, Browett PJ, et al.: Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72 (2): 784-91, 1988.  [PUBMED Abstract]
   
   
5. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.  [PUBMED Abstract]
   
   
6. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.  [PUBMED Abstract]
   
   
7. Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999.  [PUBMED Abstract]
   
   
8. Fenaux P, Lai JL, Miaux O, et al.: Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases. Br J Haematol 71 (3): 371-6, 1989.  [PUBMED Abstract]
   
   
9. Reiter A, Schrappe M, Ludwig WD, et al.: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 80 (10): 2471-8, 1992.  [PUBMED Abstract]
   
   
10. Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.  [PUBMED Abstract]
    
    

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