Chemoresistance to Prednisolone as Treatment Stratification Criteria In the Adult ALL Therapeutic Approach of the Russian Acute Lymphoblastic Leukemia (RALL) Study Group

Abstract 4333

Adult acute lymphoblastic leukemia (ALL) differs from pediatric ALL by higher frequency of unfavorable biological features including cytogenetics (often t(9;22), rare t(12;21)), slower molecular response (MRD negativity is lower at day near +30 in adults - 47% vs 80%; Bruggemmann, Blood, 2006; Borowitz, Blood, 2010), more toxicity followed by less complience, all this translating in less efficacy. Another very important, early and simple predictor of antileukamia effect in ALL is prednisolone (PRD) sensitivity, that is to say tumor clearance within one week of prephase. It's a well documented fact in childhood ALL, but scarcely characterized in adults. 35% of adults with ALL are considered to be resistant to PRDN compaired to 10% children after evaluation of PB blast count on day +8 (Annino, Blood, 2002; Shrappe, Leukemia 2002), but few data exists about bone marrow blasts clearance. We initiated a prospective multicenter trial for Ph-negative ALL under the age of 55 based on: 1.evaluation of blast clearance in b/m after 7 days of PRD and its substitution by dexamethazone (DEXA) if blast count was 25% and more. 2. “no interruptions” protocol with 8 weeks induction and 5 consolidation phases followed by 2-years maintenance. 3. prolonged L-asparaginase application at 10.000 IU weekly in induction, once in two weeks in consolidations, twice a month in maintenance (total proposed dose 560.000 IU).

The study started in April, 2009. 20 participating centers enrolled 77 patients (median age 27y (16-55), 44f, 33m, 61,5%=B-lin, 38,6%=T-lin; 41% with normal karyotype (NK)). 30,7% of patients were in the standrad risk (SR) group (WBC <30 for B-Lin, <100 for T-Lin, EGIL BII-III, T-III; LDH < 2N, No late CR, t(4;11)-), 69,3% - in the high risk (HR) group (WBC >30 for B-Lin, >100 for T-Lin, EGIL BI, T-I-II-IV; LDH > 2N, No late CR, t(4;11)+). The analysis was performed in June, 2010, and comprised 70 pts.

The data on the day +8 b/m count was reported in 67 pts: 70% of them had b/m blasts 25% and more, thus were considered as non-responders to PRD (60 mg/m²) and were switched to DEXA (10 mg/m²). It's worth to note that the proportion of non-responders to PRD was almost equal in the SR and HR groups: 12 of 20 (60%) in SR and 35 of 47 (74,5%). CR rate was high in both risk groups (SR=95,5%; HR=89,4%) and immunological subsets (B=91,4%;T=91,6%). For the whole group of analysed patients (n=70) there were 5 induction deaths (7,1%) and 1 resistant leukemia (1,4%). Median of days without treatment during induction period was 8 days (0-56). Death in remission was reported in 2 of 64 CR pts (3,1%). Relapses occurred in 4/64 (4,2%). Within the short period of follow-up (14 mo) the probability of OS for 70 patients constituted 78,8%, DFS – 76,7%, continuous CR – 81,2%. The difference in DFS between PRD responders and non-responders was at borderline: 63,3% vs 93,8% (p=0,1), and statistically proved in pts with NK vs all other abnormalities: 100% vs 72% (p=0,03). Age, WBC, immunophenotype, risk group, time without treatment did not influence survival.

We concluded that in adult Ph-negative ALL the proportion of non-responders to PRD is very high (70%), thus providing much poorer results than in children; sensitivity to PRD may still be used as very simple discriminative marker of unfavorable prognosis.