Phase 2 study of intensified chemotherapy and allogeneic hematopoietic stem cell transplantation for older patients with acute lymphoblastic leukemia

Abstract

BACKGROUND Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi‐agent approach derived from a Dana‐Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752). METHODS The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome–positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment. RESULTS Thirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2‐year OS rate was 52% (n = 30), and the 2‐year disease‐free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy‐related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing. CONCLUSIONS Intensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379–2388. © 2016 American Cancer Society.

Improved prognosis with additional medium‐dose VP16 to CY/TBI in allogeneic transplantation for high risk ALL in adults

“…Therefore, the benefit of additional VP16 may not apply to the cohort composed of older patients, although our results showed that the difference in NRM between the CY/TBI and VP16/CY/TBI regimens was within the negligible range irrespective of patient age. The average age of patients undergoing transplants is currently increasing, so future analyses focusing on older patients will be necessary.…”

Treatment of older patients with acute lymphoblastic leukemia

“…Twelve out of 20 CR patients actually received SCT with no apparent survival advantage for transplanted patients. 21 A retrospective analysis of patients .40 years showed no survival advantage of SCT compared with chemotherapy (40% vs 46%); whereas SCT was associated with a lower relapse rate, but this advantage was offset by the higher mortality experienced by participants. 52 Indication for SCT and the optimal conditioning regimen in older patients need to be defined.…”

“…Therefore induction therapy is the most critical phase for management. In older patients, induction mortality has a wide range (0% to 42%) (Table 2), 14,[16][17][18][19][20][21][22][23][24][25] and early death occurs also before the onset of chemotherapy. The most frequent cause of death in induction is infection.…”

“…20 Furthermore a pediatric-based regimen using pegylated asparaginase during induction in older patients revealed grade 3-4 bilirubin increases in 33% of the patients. 21 Thrombosis and pancreatitis are other relevant toxicities of asparaginase. Altogether, there is some evidence that the use of asparaginase during induction therapy may be associated with increased risks in older patients.…”

Current challenges and opportunities in treating adult patients with Philadelphia‐negative acute lymphoblastic leukaemia

“…This excess toxicity may reflect the effect of comorbidities and co‐medications in older adults as well as pharmacokinetic and pharmacodynamic alterations associated with aging (Gokbuget, ). Asparginase during induction seems to significantly increase toxicity and ED (Sancho et al , ; Fathi et al , ) that can be reduced if asparginase is delayed until the post‐remission phases (Gokbuget et al , ). In many protocols idarubicin is used in lieu of other anthracyclines in older patients to reduce toxicity (Bassan et al , ).…”