Matched Unrelated Donor Allogeneic Stem Cell Transplantation in High Risk Acute Lymphoblastic Leukemia (ALL) After a Preparative Regimen of Hyperfractionated Total Body Irradiation and High-Dose Etoposide – A Feasibility Study within the German Multicenter Study Group for Adult ALL.

The optimal preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHCT) using matched unrelated donors (MUD) for adult patients (pts) with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is currently undefined. There is some evidence from one comprehensive retrospective comparative analysis that a higher dose of hyperfractionated total body irradiation (fTBI) or the use of high-dose etoposide instead of cyclophosphamide is able to reduce the leukemic relapse risk of adult pts transplanted in second CR from HLA-identical sibling donors (ISD) (Marks, DI et al. J Biol Blood Marrow Transplant 12: 438-453, 2006).

Within the framework of the German multicenter study group for adult ALL (GMALL) protocols 06/1999 and 07/2003, the combination of 12 Gy fTBI + 120 mg/kg cyclophosphamide is the standard preparative regimen for MUD alloHCT in CR1. In these protocols, a preparative regimen of 12 Gy fTBI + 60 mg/kg etoposide before ISD alloHCT in CR1 has shown particular promising results compared to 12 Gy fTBI + cyclophosphamide. Therefore, this pilot study tested the feasibility of the12 Gy fTBI + etoposide regimen for MUD alloHCT in CR1 adult ALL pts.

In the GMALL protocol 07/2003, alloHCT is generally performed after the first consolidation therapy according to predefined prognostic disease features indicating a high relapse risk for pts up to the age of 55 years (yrs). This study prospectively included 20 consecutive (very) high-risk pts (median age: 39 [range 17 to 55] yrs) from two major GMALL transplant centers, who underwent alloHCT using MUD between 01/07 and 03/09. TBI was applied in 2 daily fractions of 2 Gy on 3 consecutive days (days -6 to -4) followed by etoposide on day -3 (alloHCT on day 0). For prophylaxis of acute graft-versus-host disease (GvHD), 3 × 20 mg/kg antithymocyte globuline was given on days -3 to -1 and ciclosporin combined with prednisone thereafter.

Neutrophil reconstitution > 0.5/nL was reached after a median of 18 (range 12 to 32) days and self-sustaining platelet counts > 20/nL were attained after a median of 25 (range 13 to 36) days. The cumulative incidence of grades I – IV acute GvHD reached 64 %. Three pts. (15 %) developed acute GvHD > grade II. The cause-specific non-relapse mortality (NRM) incidences at 3, 12 and 24 months are 5 %, 18 %, and 22 % (4/20 pts), respectively. Causes of NRM were infections (2 pts), graft failure and toxic epidermiolysis (1 patient each). The cause-specific leukemic relapse incidence reaches 18 % (3/20 pts) after 12 and 24 months. Two pts were successfully rescued by a 2^nd alloHCT after leukemic relapse. After a median follow-up period of 22 months for the 15 surviving pts, the 2-year overall survival estimate is 73 % (95 % confidence limits: 47 % - 89 %).

This pilot study demonstrates that the preparative regimen of fTBI + etoposide before MUD alloHCT is feasible in CR1 adult high-risk ALL pts after intensive induction and consolidation courses as applied in the GMALL protocol 07/2003. The comparatively low relapse rate in high-risk ALL pts further supports that the substitution of cyclophosphamide by etoposide leads to better disease control and may thereby improve transplant outcome in this setting. Based on these results, a prospective study comparing fTBI in combination with either etoposide or cyclophosphamide appears justified.

No relevant conflicts of interest to declare.