In Adults with Standard-Risk Acute Lymphoblastic Leukemia (ALL) the Greatest Benefit Is Achieved from an Allogeneic Transplant in First Complete Remission (CR) and an Autologous Transplant Is Less Effective Than Conventional Consolidation/Maintenance Chemotherapy: Final Results of the International ALL Trial (MRC UKALL XII/ECOG E2993).
Authors: Rowe Jacob M. , Buck Georgina , Fielding Adele , Tallman Martin S. , Burnett Alan K. , Chopra Raj , Wiernik Peter H. , Richards Susan M. , Lazarus Hillard M. , Foroni Letizia , Paietta Elisabeth , Litzow Mark R. , Marks David , Durrant Jill , Goldstone Anthony H. 
Published: October 2019

MRC UKALL XII / ECOG E2993 was initiated in 1993, to prospectively define the role of allogeneic transplant (allo), autologous transplant (auto) or chemotherapy in adult ALL in first CR up to age 60 (65 since 2004). All patients received two phases of induction and, if in CR, patients <50 yrs (55 since 2004) were assigned to allo if they had a compatible sibling donor. The other patients were randomized to consolidation/maintenance therapy (chemo) for two and a half years or a single autologous transplant. Prior to the assigned or randomized therapy all patients received intensification with 3 courses of high-dose methotrexate. Over 1,980 patients have been entered on study. The data on induction for all patients and post-remission for Ph-positive ALL were previously reported (Blood.2005;106:3760 and Blood.2003; 104:268a). This report describes the post-remission data for Ph-negative patients entered as of October 31, 2005. The data are summarized in the table. High-risk patients are those with either age > 35 or a high WBC (>30,000 for B-lineage or >100,000 for T-ALL). In a donor versus no donor analysis, patients with a sibling donor had improved OS and EFS and the relapse rate post allo was very significantly lower than for any other therapy. However, this advantage was confined to standard-risk patients. The lack of demonstrable survival benefit in high-risk patients was due to high mortality associated with age >35 years; the 2-year non-relapse mortality for patients with a donor was 39% (high-risk) and 20% (standard-risk) compared with 12% (high-risk) and 7% (standard-risk) among those without a donor. In an intention-to-treat analysis of chemo versus auto, patients receiving chemo had significantly better EFS. The difference between these 2 groups was not due to a higher mortality of auto but due to a higher relapse rate. Molecular monitoring of minimal residual disease (MRD) after induction phase II and intensification was highly predictive of outcome among the non-allo patients (OS 70% vs 22%; p=.0012). In summary, the data demonstrate that sibling allogeneic transplants for ALL in CR1 provide the most potent anti-leukemic therapy and considerable OS and EFS benefit for standard-risk patients. In contrast, the transplant-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. Furthermore, the data show that there is no evidence that a single auto can replace consolidation/maintenance therapy in any risk group. Large collaborative trials are necessary, and feasible, to define the optimal therapy in uncommon disorders.

5-year data No. of Patients OS (%) EFS (%) Relapse (%) * P = < .05 ** Autograft patients excluded Donor vs no donor 388 vs 527 *53 vs 45 *50 vs 41 *29 vs 54     High risk 170 vs 230 39 vs 36 38 vs 32 *36 vs 63     Standard-risk 218 vs 286 *63 vs 51 *59 vs 48 *25 vs 48 Randomized auto vs chemo 220 vs 215 37 vs 46 *33 vs 42 *61 vs 54 Donor vs no donor (chemotherapy)** 384 vs 418 *54 vs 44 *50 vs 40 *29 vs 55     High-risk 168 vs 190 41 vs 35 38 vs 31 *36 vs 63     Standard risk 216 vs 223 *64 vs 51 *59 vs 47 *24 vs 48