Prognostic Features

While several analyses of prognostic features in ALL have been performed, two classic multivariate analyses, one by the German multicenter group and another by the Memorial Sloan-Kettering Cancer Center (MSKCC) group, were reported in 1988. These and other studies indicate the importance of five prognostic features: white blood cell (WBC) count at diagnosis, age, leukemic cell immunophenotype, cytogenetics (particularly Philadelphia-chromosome-positive disease), and the time to achieve CR.4,5

An elevated WBC count at the time of diagnosis is associated with a poor prognosis. The multivariate analyses indicate that there is both a reduced likelihood of achieving a CR, as well as a shorter duration of remission, and ultimately worse overall survival. In part, the poor prognosis associated with an elevated WBC reflects an increased disease burden, but it is also related to the propensity of poor cytogenetic subtypes (i.e., t(4:11) and t(9:22)) to present with hyperleukocy-tosis. Different studies have used different WBC levels as their cutoff for an adverse feature. In the MSKCC study, WBC counts greater than 10,000/^L were associated with a lower frequency of achieving a CR, and counts greater than 20,000/^L were associated with a shorter duration of CR. In the German study, WBC counts greater than 30,000/^L carried an adverse prognosis.

Older age in adult ALL patients is also associated with a worse prognosis, and similar to an elevated WBC count, age is probably a continuous variable (i.e., the older the patient, the worse the prognosis). Different studies have defined different ages as having a poor prognosis; the German group identified age 35, while the MSKCC study identified age 60.

The immunophenotype of the leukemic cell also has prognostic significance.4-6 Traditionally, T-cell disease has had a favorable prognosis, pre-B-cell (common) ALL an intermediate prognosis, and mature B-cell disease was associated with a poorer prognosis (using conventional treatments). Recently, however, modern intensive treatment regimens designed specifically for this rare subtype have improved the prognosis for patients with mature B-cell (Burkitt's type) lym-phoblastic disease, and it is no longer considered to have a comparatively poor prognosis.78

Cytogenetic abnormalities, specifically t(9:22) (Philadelphia-chromosome-positive disease) and t(4;11), portend poor prognoses. These patients are essentially never cured by chemotherapeutic regimens, with 5-year disease-free survival rates of 0-15%, using conventional therapy. A minority may be cured with an allogeneic transplant in first CR.9a-c Also unclear is the impact that therapy with the tyrosine kinase inhibitor imatinib mesylate will have on Philadelphia-chromosome-positive disease. Another karyotype, t(8;14), involving the c-myc locus, has traditionally carried an unfavorable prognosis, though again, this may change with current intensive therapy.

Many studies have shown that the time to achieve a CR during remission induction therapy carries significant prognostic implications. The likelihood of being cured diminishes with the greater amount of time it takes the patient to achieve a CR. Notably, time to CR greater than 4 or 5 weeks substantially diminishes the likelihood of cure.5 However, it is uncertain whether a shorter duration in achieving a CR reflects an innate sensitivity of the disease to the chemotherapeutic agents used, or whether the rapid cytoreduction of the leukemic cell mass minimizes the development of drug resistance and thus ultimately allows for the cure of the patient.

Note however the above-listed prognostic features relate primarily to initial therapy. At relapse, the prognosis is poor, with only a small fraction of patients salvaged. In this setting, long duration of first remission and isolated sanctuary site relapse are the two most important favorable prognostic factors.

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