Imatinib Improves Outcomes in Elderly Patients with Ph+ ALL

Abstract & Commentary

By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Acute lymphocytic leukemia (ALL) in the elderly is not common, but as in younger adults, a subset will be Philadelphia chromosome postitive (Ph+). In young patients with Ph+ ALL, the addition of imatinib has been shown to be effective in enhancing complete response rates and relapse-free survival. The treatment of elderly patients with ALL has not been satisfactory and in this study, for those with Ph+ disease, imatinib was added to the consolidation (or salvage) phase in the overall initial treatment plan. The experience in 30 Ph+ ALL patients older than age 55 was compared by this group of French and Belgian clinical investigators to a series of 18 similar patients previously treated by an analogous protocol but without the imatinib. At the end of one year, relapse-free survival was 58% in the current cohort, which compared favorably with 11% of the historic controls. Thus, imatinib, used during consolidation may benefit older patients with Ph+ ALL.

Source: Delannoy A, et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia. 2006;20:1526-1532.

With advancing age there is increasing prevalence of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). In young patients with Ph+ALL, the addition of imatinib has been shown to be both safe and effective as an adjunct to chemotherapy.1 In the current clinical trial conducted by a consortium of French and Belgium investigators, older patients (55 years and older) with de novo ALL were treated with a combination of initial chemotherapy followed by imatinib as consolidation, maintenance or salvage.

Over an approximate two-year period, 30 eligible (older than 55 years old, documented previously untreated Ph+ ALL) were enrolled in this trial conducted by the Group for Research on Adult Lymphocytic Leukemia (GRAALL). A complex treatment protocol was used that extended treatment over approximately two years. An induction phase consisted of chemotherapy (daunorubicin, vincristine, methylprednisilone) and irrespective of initial response, patients were then given consolidation/salvage therapy including imatinib 600 mg daily and steroids. Only patients in complete remission (CR) after the consolidation/salvage phase were offered to proceed with the maintenance therapy which included several 2-month blocks of chemotherapy and two additional 2-month blocks of imatinib. Treatment response for the included 30 patients was compared to that of 21 historical controls who were similarly aged and treated similarly but without added imatinib.

Of the 29 evaluable patients, 21 (72%) were in CR after induction chemotherapy vs 6/21 (29%) in controls. Five additional CRs were obtained after salvage with imatinib and four after salvage additional chemotherapy in the control group. Overall survival (OS) was 66% at 1 year vs 43% in the control group (P = 0.005). The 1-year relapse-free survival was 58% vs 11% (P = 0.003). Thus, these investigators concluded the use of imatinib was an effective adjunct to standard chemotherapy for Ph+ ALL occurring in elderly patients.

Commentary

Curiously, the relative portion of ALL that is Ph+ increases with age through early adult years, but seems to decline again in late life. Imatinib, an orally administered inhibitor of the BCR/ABL encoded tyrosine kinase, has been demonstrated to be active in patients with Ph+ ALL in patients with relapsed or refractory disease. In one series, 29% of such patients obtained complete hematological remission.1 Accordingly, imatinib has been effectively incorporated into the front line therapy in young adults with previously untreated Ph+ ALL.2,3

Unlike that for younger patients, the presence of the Ph chromosome is of little prognostic consequence in elderly ALL patients, most likely due to the overall poor prognosis of ALL in this age group.4 Thus, a therapeutic advance, particularly one that is fairly well tolerated in this age group, is a welcome advance.

The current trial demonstrated the safety of incorporation of imatinib into the treatment regimen. Patients, in general, did better than historic controls, but it should be noted that there was a significantly higher CR rate during the induction phase for those on this trial than the controls, and it should be emphasized that imatinib was only used during the consolidation/salvage phase. Nonetheless, for those who did not achieve remission during induction, consolidation that included imatinib and steroids proved successful in 5 of 6 patients, whereas salvage chemotherapy was successful in only 4 of 12. Furthermore, overall survival was clearly improved by imatinib (median survival, 23.2 months compared to 11.2 months for the control group) and this would seem a reliable indicator of the efficacy of this consolidation/maintenance approach. Of course, ALL is not common in older people and Ph+ ALL comprises less than 25% of the total ALL population. Thus, a large scale cooperative group trial would seem the only likely mechanism to definitively establish the role for imatinib in the treatment of ALL in the elderly.

References

1. Ottmann OG, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002;100:1965-1971.

2. Towatari M, et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood. 2004;104:3507-3512.

3. Thomas DA, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407.

4. Houot R, et al. Philadelphia chromosome-positive acute lymphoblastic leukemia in the elderly: prognostic factors and treatment outcome. Hematology. 2004;9:369-376.