Several groups have reported results from smaller series of AYAs with ALL. Outcomes with so-called protocols for adults were generally inferior compared to so-called pediatric protocols. The GMALL protocols were originally based on pediatric BFM protocols and have been consecutively optimized for adults since 1981. We report the results of two recent protocols 05/93 (Goekbuget et al, Blood 98(11):802a, 2001) and 07/03 (Goekbuget et al, Blood 110(11):12a, 2007). In study 07 high risk (HR) pts were identified by one of the factors: B-lin with WBC>30.000, late CR (>3 wks), pro-B, early T, mature T, MLL1/AF4/t(4;11). Pts without risk factors were standard risk (SR) and those with BCR-ABL/t(9;22) very high risk (VHR). HR/VHR pts were candidates for SCT in CR1. The major innovations in study 07 were: intensified, shortened induction with dexamethasone instead of prednisone, PEG-asparaginase (ASP) instead of native ASP, intensified first consolidation, 6x HDMTX/ASP during consolidation, matched unrelated SCT for HR/VHR pts without sibling donor and SCT indication in pts with persistent MRD. After amendments in trial 07 pts partly also received intensified PEG-ASP, rituximab in CD20+ ALL and imatinib in Ph+ ALL.

Overall, 1529 of 3060 (50%) pts recruited into both trials were aged between 15-35 yrs. 642 pts from 94 centres were recruited to study 05 and 887 pts from 130 centres to study 07. Patient characteristics were similar for both trials. 70% had B-Lin and 30% T-ALL (61% c/preB, 9% proB, 7% early T, 6% mature T, 17% thy T) with no significant differences across age subgroups (15-17,18-25 and 26-35 yrs). Allocation to SR, HR and VHR was 51%, 35% and 14%. VHR incidence increased from 3%, 11% to 19% in age groups (p<.0001).

The CR rate increased in studies 05 to 07 from 88% to 91% (p=.001), most prominently within the age range of 26-35 yrs (86% to 90%;p=.001) (table). The OS increased from 46% to 65% (p<.0001) (significant in all age groups). Remission duration (RD) at 5 yrs increased from 49% to 61% (p=.0001), most prominently within the age range of 26-35 yrs (46% vs 59%; p=.005). OS improved from study 05 to study 07 in B-Lin (45% vs 66%; p<.0001) and T-ALL (47% vs 63%; p=.0007) overall and in subgroups as c/pre B (50% vs 68%;p<.0001), pro B (45% vs 67%;p=.05), mature T (19% vs 61%; p=.005) and thymic T (59% vs 70%;p=.09) but to a lesser extent in early T (35% vs 48%;p>.05). OS increased in SR (58% to 74%; p<.0001), HR (24% to 58%; p<.0001) and VHR (36% vs 55%;p=.0003).

Table 1

Results of Induction and Overall Outcome in GMALL-Studies 05/93 and 07/03

05/9307/03
Total15-1718-2526-35Total15-1718-2526-35
Evaluable 642 106 252 384 887 53 458 376 
CR 88% 91% 88% 86% 91% 94% 91% 90% 
ED 3% 1% 3% 3% 4% 0% 3% 6% 
Failure 9% 8% 8% 11% 5% 6% 5% 4% 
RD at 5y 49% 52% 50% 46% 61% 60% 62% 59% 
OS at 5y 46% 57% 45% 42% 65% 73% 69% 60% 
05/9307/03
Total15-1718-2526-35Total15-1718-2526-35
Evaluable 642 106 252 384 887 53 458 376 
CR 88% 91% 88% 86% 91% 94% 91% 90% 
ED 3% 1% 3% 3% 4% 0% 3% 6% 
Failure 9% 8% 8% 11% 5% 6% 5% 4% 
RD at 5y 49% 52% 50% 46% 61% 60% 62% 59% 
OS at 5y 46% 57% 45% 42% 65% 73% 69% 60% 
View Large

15% vs 43% of all CR pts underwent SCT in CR1 in studies 05 and 07. The proportion of SCT increased from 22% to 68% (p<.0001) in HR and from 62% to 73% (p<.0001) in VHR in studies 05 vs 07. The OS after SCT improved from 36% to 68% (p<.0001), mainly due to a decrease of TRM from 34% to 12% (p<.0001).

In trial 07 MRD in week 16 (after consolidation I) was tested in 353 pts. The proportion of molecular failure (MRD>0.01%) was 26% with no differences across age groups. OS was 90% in pts with mol. CR vs 53% in mol. failure (p<.0001). Amendments in study 07 led to further improvement with an OS of 71% in 274 pts aged between 15-35 yrs treated according to the final protocol version.

We present here results of the so far largest cohort of AYA ALL pts treated according to pediatric-derived adult ALL protocols. Outcomes have significantly improved and reached a 73% OS in pts aged 15-17 yrs. Intensified treatment with ASP, MTX and targeted therapies as rituximab and imatinib and MRD based stratification have contributed to the improvement in study 07. SCT led to improved OS in HR and VHR ALL. Obviously, there is no indication for SCT in CR1 in young SR pts with an OS of 74%. Future GMALL studies will attempt to optimize further the combination of pediatric approaches and targeted therapies in adults.

Supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971.

Disclosures:

Off Label Use: RItuximab in ALL.

Topics:
acute lymphocytic leukemia, adolescent, adult t-cell lymphoma/leukemia, bcr-abl tyrosine kinase, brachial plexus neuritis, dexamethasone, disease remission, imatinib mesylate, molecular targeted therapy, off-label use

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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