Time to Post-Remission Therapy (PRT) Is an Independent Prognostic Factor for Relapse and Overall Survival in Adults with Acute Lymphocytic Leukemia (ALL).
Authors: Advani Anjali , Jin Tao , Tiu Ramon , Ramsingh Giridharan , Lowe Christopher , Saber Wael , Sobecks Ronald , Sekeres Mikkael , Sungren Shawnda , Kalaycio Matt 
Published: October 2019

Abstract
Only 30% of adults with ALL are cured. The identification of modifiable prognostic factors is important in designing future treatment paradigms, and improving the outcome of patients. PRT is integral in the treatment of ALL, and eradicates minimal residual disease (MRD) after complete remission (CR) has been achieved with induction chemotherapy (IC). Decreasing the time from the start of IC to the initiation of PRT may improve prognosis by eradicating MRD at an earlier stage, and preventing the development of resistant leukemic clones. The goal of this study was to retrospectively evaluate the impact of time from the start of IC to PRT, and determine whether or not this affects progression-free survival (PFS) and overall survival (OS).
Methods: We retrospectively evaluated adults with newly diagnosed ALL treated at CCF between the years 1996–2005. 116 patients with ALL were seen. 57 patients were newly diagnosed and received IC and PRT. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, OS, relapse after remission, and PFS. Only variables significant in the univariate setting were included in multivariate analysis. Results were summarized as the hazard ratio (HR) with 95% confidence intervals (CI). The following variables were used in the analysis: pre-treatment characteristics (age, WBC, cytogenetic (CG) risk group, LDH), time to WBC recovery (time from the initiation of IC to an ANC of 500 after IC), CD20 expression, and time from the initiation of IC to start of PRT. CG risk was defined by CALGB criteria.
Results: Characteristics at diagnosis: median age of 38 years [range 16–72], median LDH 673 U/L [112–5753], and median WBC 17.8 × 103/L [1.2–364]. 33.6% of patients had poor risk CG, 22.4% normal CG, 15% miscellaneous, and 29% unknown. Most patients received a vincristine/prednisone based IC (88%). However, 12% received high dose cytarabine/mitoxantrone IC. The CR rate was 75.3% for patients age < 60, and 60% for age ≥ 60. Median disease-free survival was 20.2% at 5 years. The median time from IC to PRT was 7.0 weeks [4.1–17.0]. On univariate analysis, increased age and increased time to WBC recovery were associated with a lower CR rate. Age and time from IC to PRT (per week increase (PWI)) [HR 1.17(CI 1.04–1.32), p=0.009] were significant predictors for relapse after remission. Increased age, poor risk CG, and time from IC to PRT (PWI) [HR 1.13(1.02–1.25), p=0.024] predicted decreased PFS. All of these factors (including time to WBC recovery) predicted decreased OS, with time from IC to PRT (PWI) having a HR of 1.11[(1.01–1.23), p=0.039]. On multivariate analysis, there was a trend for longer time from IC to PRT (PWI) [HR 1.53(0.92–2.54, p=0.10] predicting decreased OS and increased chance of relapse (PWI) [HR 1.12(0.98–1.29), p=0.09]. When patients age > 60 and poor risk CG were excluded, time from IC to PRT (PWI) was the only factor associated with decreased OS [HR 1.34(1.08–1.67), p=0.009], PFS [HR 1.27(1.04–1.55, p=0.019)], and an increased chance of relapse [HR 1.26(0.99–1.61), p=0.06].
Conclusions: Strategies to improve the prognosis of ALL are needed. Time from IC to PRT is an independent prognostic factor for treatment outcome, and administering PRT on time may improve our outcomes in adult patients with ALL.