Superior survival with paediatric-style chemotherapy for AYA’s with Ph-negative ALL in first complete remission

August 2021 Clinical trials Tobias Rawson

For adolescents and young adults with Philadelphia-negative acute lymphoblastic leukaemia in first complete remission, the optimal post-remission therapy remains unknown. However, an analysis from CALGB 10403 and the CIBMTR now demonstrates that post-remission therapy with paediatric-style chemotherapy is superior to myeloablative allogeneic haematopoietic stem cell transplantation for overall survival, disease-free survival and non-relapse mortality.

EXPERT OPINION OF PROF. ANN JANSSENS, HAEMATOLOGIST, UZ LEUVEN

“The analysis of the CALGB 10403 and CIBMTR shows that AYA (16-39 years) ALL Ph-negative patients in CR1 treated with post remission paediatric-style chemotherapy have a better overall survival, disease-free survival and a lower non-relapse mortality compared to myeloablative allogeneic stem cell transplantation. The authors claim that allogeneic SCT is warranted for patients refractory or relapsing after paediatric style chemotherapy and for high risk MRD-positive patients in CR1. A randomised controlled trial with matched patient populations could hopefully end the debate definitely on the best treatment for AYA ALL patients in CR1.”

The optimal post-remission therapy for adolescents and young adults (AYAs) with Philadelphia (Ph)-negative ALL in first complete remission (CR1) is not yet established. Therefore, Wieduwilt et al. conducted a study that compares survival outcomes in AYA Ph-negative ALL patients in CR1 receiving post-remission therapy with paediatric-inspired chemotherapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic HCT. The study enrolled 263 AYA (ages 16-39) Ph-negative ALL patients from the phase II CALGB 10403 study who had received post-remission chemotherapy, and 217 patients receiving post-remission MA allogeneic HCT, reported to the CIBMTR.

Superior OS with paediatric-style chemotherapy

The chemotherapy and MA HCT cohorts had a median age of 24 years and 27 years, and median follow-up times of 65 months and 98 months, respectively. Some significant differences in baseline characteristics existed between the two cohorts, including race (Caucasian: 75% vs. 89%), Karnofsky performance score ≥80 (91% vs. 88%), white blood cell count at diagnosis, cytogenetics, extramedullary disease at diagnosis (48% vs. 19%) and weeks from diagnosis to CR1 (median 4.4 vs. 7.6 weeks).

In univariate analysis, at 100 days after the initiation of post-remission therapy, no differences in overall survival (OS), relapse, or non-relapse mortality (NRM- were observed between MA HCT and chemotherapy. At 3 and 5 years, OS was superior with chemotherapy compared to MA HCT (3-year OS: 77% vs. 53%, P< 0.001; 5-year OS: 66% vs. 47%, P< 0.001). Similarly, both 3- and 5-year DFS was significantly improved with chemotherapy, compared to MA HCT (3-year DFS: 68% vs. 50%, P< 0.001; 5-year DFS: 58% vs. 44%, P= 0.004). NRM was also lower with chemotherapy at both 3 and 5 years (3-year NRM: 6% vs. 24%, P< 0.001; 5-year NRM: 8% vs. 29%, P< 0.001). However, cumulative relapse at 5 years was significantly higher in patients treated with chemotherapy, compared to those who received HCT (34% vs. 23%, P= 0.011).

Multivariate analysis of the entire study population (N= 480) revealed that OS was worse with allogeneic HCT (HR[95%CI]: 2.00[1.5-2.66], P< 0.001) and obesity (BMI ≥30kg/m2: HR[95%CI]: 2.17[1.63-2.89], P< 0.001). Obesity was also associated with inferior DFS (HR[95%CI]: 1.97[1.51-2.57], P< 0.001), a greater risk of relapse (HR[95%CI]: 1.84[1.31-2.59], P< 0.001) and greater rates of NRM (HR[95%CI]: 2.10[1.37-3.23], P< 0.001). Treatment with allogeneic HCT in the post-remission setting resulted in inferior DFS compared to chemotherapy (HR[95%CI]: 1.62[1.25-2.12], P< 0.001) and a higher risk of NRM (HR[95%CI]: 5.41[3.23-0.96], P< 0.001). Interestingly, in the first 15 months after CR1, relapse was more likely in patients treated with HCT (HR[95%CI]: 1.78[1.10-2.88], P= 0.02) while beyond 15 months post-CR1, relapse was more likely in patients who received chemotherapy (HR[95%CI]: 0.34[0.19-0.62], P< 0.001). Multivariate analysis of HLA-identical siblings and well-matched unrelated donors bore comparable results to the complete transplant cohort. Additionally, multivariate analysis of cytogenetic risk (standard vs. poor) and HCT time period (2002-2006 vs. 2007-2021) revealed similar results to the full study population.

Conclusion

For AYA Ph-negative ALL patients in CR1, post-remission therapy with paediatric-style chemotherapy offers superior survival outcomes, compared to MA allogeneic HCT. Allogeneic HCT may still be useful to patients refractory to or relapsing after paediatric-style chemotherapy and may be warranted for high-risk MRD-positive patients in CR1. Finally, obesity in AYA Ph-negative ALL patients is a potentially modifiable risk factor that warrants further investigation.

Reference

Wieduwilt M, Stock W, Advani A, et al. Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR. Leukemia. 2021;35:2076-2085.  

X