Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia: results of Cancer and Leukemia Group B Study 19802

Abstract

Background: Cancer and Leukemia Group B (CALGB) Study 19802, a phase 2 study, evaluated whether dose intensification of daunorubicin and cytarabine could improve disease-free survival (DFS) in adults with acute lymphoblastic leukemia (ALL) and whether high-dose systemic and intrathecal methotrexate could replace cranial radiotherapy for central nervous system (CNS) prophylaxis.

Methods: One hundred sixty-one eligible, previously untreated patients ages 16 to 82 years (median age, 40 years) were enrolled, and 33 (20%) were aged ≥60 years.

Results: One hundred twenty-eight patients (80%) achieved complete remission (CR). Dose intensification of daunorubicin and cytarabine was feasible. At a median follow-up of 10.4 years for surviving patients, the 5-year DFS rate was 25% (95% confidence interval, 18%-33%), and the overall survival (OS) rate was 30% (95% confidence interval, 23%-37%). Patients aged <60 years who received the 80 mg/m(2) dose of daunorubicin had a DFS of 33% (95% confidence interval, 22%-44%) and an OS of 39% (95% confidence interval, 29%-49%) at 5 years. Eighty-four patients (52%) relapsed, including 9 patients (6%) who had isolated CNS relapses. The omission of cranial irradiation did not result in higher than historic CNS relapse rates.

Conclusions: Intensive systemic, oral, and intrathecal methotrexate dosing permitted the omission of CNS irradiation in adult patients with ALL. This intensive approach using higher doses of daunorubicin and cytarabine failed to result in an overall improvement in DFS or OS compared with historic CALGB studies. Future therapeutic strategies for adults with ALL should be tailored to specific age and molecular genetic subsets.

Figure 1. Treatment plan

Figure 2. a. and b. Disease-free survival and Overall Survival

One hundred and twenty-eight patients (80%) of the 161 enrolled onto CALGB 19802 achieved CR. The 5-year DFS was estimated at 25% (95% CI, 18–33%) (Figure 2a). Overall survival at 5-years for all 161 patients was 30% (95% CI, 23–37%) (Figure 2b).

Figure 2. a. and b. Disease-free survival and Overall Survival

One hundred and twenty-eight patients (80%) of the 161 enrolled onto CALGB 19802 achieved CR. The 5-year DFS was estimated at 25% (95% CI, 18–33%) (Figure 2a). Overall survival at 5-years for all 161 patients was 30% (95% CI, 23–37%) (Figure 2b).

Figure 3. a. b, c and d. DFS and OS by age and cytogenetic risk group

Disease-free survival (Figure 3a) and overall survival (Figure 3b) by age. Disease-free survival (Figure 3c) and overall survival (Figure 3d) by cytogenetic risk group.

Figure 3. a. b, c and d. DFS and OS by age and cytogenetic risk group

Disease-free survival (Figure 3a) and overall survival (Figure 3b) by age. Disease-free survival (Figure 3c) and overall survival (Figure 3d) by cytogenetic risk group.

Figure 3. a. b, c and d. DFS and OS by age and cytogenetic risk group

Disease-free survival (Figure 3a) and overall survival (Figure 3b) by age. Disease-free survival (Figure 3c) and overall survival (Figure 3d) by cytogenetic risk group.

Figure 3. a. b, c and d. DFS and OS by age and cytogenetic risk group

Disease-free survival (Figure 3a) and overall survival (Figure 3b) by age. Disease-free survival (Figure 3c) and overall survival (Figure 3d) by cytogenetic risk group.

Figure 4. a and b. DFS and OS by daunorubicin dose for patients < 60 years old

Complete remission was achieved in 36 of 39 (92%) patients who received the 60 mg/m² daily dose of daunorubicin. Five-year DFS for these patients was estimated at 18% (95% CI,7–32%) and OS was 29% (16–44%). For the 89 patients who received the 80 mg/m2 daily daunorubicin dose, CR was achieved in 72 (81%). The 5-year DFS for these patients was 33% (95% CI, 22–44%) and OS was 39% (29–49%).

Figure 4. a and b. DFS and OS by daunorubicin dose for patients < 60 years old

Complete remission was achieved in 36 of 39 (92%) patients who received the 60 mg/m² daily dose of daunorubicin. Five-year DFS for these patients was estimated at 18% (95% CI,7–32%) and OS was 29% (16–44%). For the 89 patients who received the 80 mg/m2 daily daunorubicin dose, CR was achieved in 72 (81%). The 5-year DFS for these patients was 33% (95% CI, 22–44%) and OS was 39% (29–49%).