Treatment of Older Patients, 40 to 70 Years of Age, with Acute Lymphoblastic Leukemia According to a Chemotherapy Regimen That Includes a Novel Pre-Phase for Rapid Tumor Load Reduction. Results of the Dutch-Belgian HOVON-71 Study.

Based on the dismal outcome of older patients with ALL and a promising pilot study in a single institution, HOVON started a multicenter phase 2 feasibility study to assess efficacy and safety of a novel chemotherapy regimen for patients between 40 and 70 years of age (younger patients being eligible for a pediatric treatment schedule in a parallel study). The innovative part of the study consisted of a relatively intensive “pre-induction” course for rapid reduction of the tumor load.

The pre-induction course consisted of cytarabine 200 mg/m² and etoposide 120 mg/m² on day 1, and 8 and MTX 500 mg/m² on day 4, and 11. This was followed on day 15 by an induction course of vincristine 1 mg/wk x 3, dexamethasone 8-12 mg/d x 21 depending on body weight, and adriamycine 40 mg (>60 yr: 30 mg)/m²/d on day 2-4 (ODA). After regeneration of the bone marrow, ODA was repeated once in patients with at least a partial remission. Subsequently, consolidation with cytarabine 1000 mg/m²/12 hr x 4 followed by asparaginase 6,000 IU/m²/d x 10 was given, and, finally, regular maintenance therapy for 30 cycles. Intrathecal prophylaxis consisted of weekly MTX 15 (>60 yr: 10) mg x 4 followed by monthly MTX 15 (> 60 yr: 10) mg x 6. Patients with t(9;22) also received imatinib 600 mg/d, except during asparaginase administration; patients in complete remission (CR) were eligible for nonmyeloablative allogeneic stem cell transplantation (SCT) using either sibling (sib) or matched unrelated donors (MUD).

Sixty patients, 27 males and 33 females, with a median age of 57 years (range 40–69) were enrolled; 40% were over 60 years. B-lineage ALL was present in 54. Median WBC count at diagnosis was 6.3 × 10⁹/l (range 0.7-186). t(9;22) was present in 16 (34%) and t(4;11) in 4 (9%) of 47 patients with available karyotype or FISH data. Based on WBC, cytogenetics, and time to CR 31 patients (52%) were considered high risk and 29 (48%) standard risk. Fifty-one patients (85%) attained CR, 47 of them after the first ODA course. One patient was a nonresponder. Ten patients (17%) died during the early phases of intensive chemotherapy mainly due to infection. Moreover, treatment had to be withdrawn or delayed in 12 (20%) because of side effects such as grade 3-4 mucositis and infection. Seventeen patients underwent allo-SCT (10 sib, 7 MUD) in first CR. After a median follow-up of 21 months (range 15–37), 37 patients (62%) were alive; 13 (22%) relapsed, 6 of them after SCT. The 2-year EFS was 48% (95% CI 32-63%), 2-year DFS 51% (32-68%), and 2-year OS 61% (47-73%).

Notwithstanding considerable toxicity including early mortality of 17%, this schedule produced high survival and low relapse rates, especially when considering the median age of 57 years and the relatively high number of high risk patients. The pre-induction course induced a rapid reduction of (circulating) blasts in all patients. Based on this phase 2 study a prospective randomized trial has recently been initiated. In order to reduce toxicity the protocol has been amended by replacing dexamethasone by prednisone, allowing time for hematological recovery after the pre-induction course, growth factor support, and optimizing antibiotic prophylaxis.

No relevant conflicts of interest to declare.