Subtype Adjusted Therapy Improves Outcome of Elderly Patients with Acute Lymphoblastic Leukemia (ALL).
Authors: Hoelzer Dieter , Goekbuget Nicola , Beck Joachim , Burmeister Thomas , Giagounidis Aristoteles , Glasmacher Axel , Pfeifer Heike , Rieder Harald , Schmid Mathias , Thiel Eckhard , Wassmann Barbara , Ottmann Oliver 
Published: April 2020

Abstract
Despite the major peak of ALL in childhood the incidence also increases in the elderly beyond 50 yrs. Outcome of these elderly ALL pts is very poor. In a survey including 12 studies with 370 pts (50–88 yrs) the mean CR rate was 50% and the rate of continuous CR (CCR) 13%. Also in a first prospective pilot study of the German Multicenter Study Group for Adult ALL (GMALL) for elderly ALL pts &gt; 65 yrs with a moderate intensive chemotherapy regimen (Blood, 96(11): 3104a, 2000) the results in 94 pts were poor with a CR rate of 48% and a survival (OS) &lt;10%.
Therefore in 2003 the GMALL started new therapeutic approaches with subgroup adapted protocols for elderly pts &gt; 55 yrs (age limit for allo SCT) according to status for 1) Ph/BCR-ABL, 2) CD20 expression and 3) a separate protocol for mature B-ALL. For 1) and 2) chemotherapy was similar to the pilot study (induction I,II consol. I–V with 2xIDMTX/MP,2xVM26/AC and reinduction). Out of a total of 824 pts recruited for the GMALL 06/99 109 were older than 55 yrs.
1) Imatinib in Ph/BCR-ABL+ ALL: In a prospective randomized trial pts received a 4 wk induction with 600 mg/d Imatinib (ImInd) compared to chemotherapy without Imatinib (ChInd). 36 pts (median age 67y) were evaluable (18 ImInd; 18 ChInd). The CR rate was higher for the Imatinib arm with 93% compared to only 44% with chemotherapy (p=.003). 3 of the 4 failure pts in the ChInd arm achieved CR after cross-over to ImInd. There were more non-hematologic severe (grade III/IV) adverse events during ChInd (pneumonia N=6 sepsis 2, enteritis 2, hepatotoxicity 1) versus ImInd (N=0). After induction both arms received the consolidation cycles parallel with Imatinib 600 mg/d for 1 yr. After a median follow-up of 4.3 mo (0.5–20+) 21 pts are in CCR and 6 relapsed. 7 pts died in CR. The OS at 18 mo is 47%. 3 pts (11%) achieved molecular remissions.
2) Rituximab in CD20+ ALL: In the 2nd study pts with CD20+ B-prec. ALL (Ph/BCR-ABL neg) received 375 mg rituximab before each cycle (induction I, II, consolidations). The small group of CD20neg ALL received the similar chemotherapy regimen without rituximab. 26 pts are evaluable (19 with rituximab and 7 with CD20 neg B-prec. or T-ALL). The median age is 66 (55–79) yrs. The CR rate in CD20+ pts is 63% and the OS after 1 yr is 54%. No pts died in CR so far.
3) Rituximab in mature B-ALL, Burkitt or other high-grade NHL: Elderly pts &gt; 55 yrs with these diseases had a poor outcome with the former protocol B-NHL90 (Blood100(11):159a, 2002). The CR-rate in 45 pts was 71% and the OS 39% at 6 yrs. Therefore in the subsequent trial B-NHL2002 pts with mature B-ALL/B-NHL &gt;55 yrs (86% CD20 pos) received a total of 8 cycles rituximab (375 mg), 6x before each chemotherapy cycle (day −1) and 2x rituximab only. In 26 evaluable pts the CR-rate increased to 81% and the OS at 1.5 yr is 84% (p=.03 compared to study B-NHL90). Out of 21 CR pts 19 are in CCR, 1 relapsed and 1 went off-study.
Conclusion: In elderly ALL pts the application of Imatinib in Ph/BCR-ABLpos or rituximab in CD20+ pts led to a stubstantially improved antileukemic activity with high CR and low failure rates. The risk of infections remains a major problem and improved supportive measures are needed. Hopefully this risk stratified approach with targeted therapies will translate into improved long-term outcome in this age category (partly supported by Novartis Pharma and Hoffmann-La-Roche)