Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Improves Outcome As Compared to Conventional Consolidation in Patients Aged 40–60 Years with AML in CR1 with Apparent Greater Benefit for Reduced Intensity Rather Than Myeloablative Conditioning

Abstract 159

AlloHSCT is considered standard consolidation therapy in adults with intermediate and poor-risk acute myeloid leukemia (AML) in first complete remission (CR1). Myeloablative (MAB) alloHSCT confers a survival advantage in younger AML patients (pts), but non-relapse mortality (NRM) may counterbalance a favorable effect on relapse, resulting in limited benefit in older pts. Meta-analyses have suggested that the advantage may already be limited beyond the age of 40. Reduced intensity conditioning (RIC) regimens were introduced to reduce NRM, while sparing graft versus leukemia (GVL) effects in older pts. Retrospective comparative studies have confirmed less NRM, but suggested that the net result in terms of overall outcome may not differ, as less NRM may be counterbalanced by more relapse. We evaluated within 4 consecutive prospective HOVON/SAKK cooperative studies (H29, H42, H42A, and H92) alloHSCT versus conventional consolidation in AML-CR1 pts between 40–60 years, with integrated comparison of alloHSCT using MAB versus RIC. Outcome measures included overall survival (OS), relapse free survival (RFS), as determined by relapse and NRM. The choice of conditioning regimen prior to alloHSCT (MAB or RIC) was solely based on center preference throughout the study period.

1105 pts between 40 and 60 years of age with newly diagnosed AML receiving consolidation in CR1, were studied, including 237 pts proceeding to MAB and 144 to RIC alloHSCT. 724 pts were consolidated with either a third cycle of chemotherapy (n=470) or an autograft (n=254). More pts with unfavourable karyotype or late CR proceeded to alloHSCT than to alternative consolidation. Recipients of MAB or RIC were comparable with respect to age, leukemia risk-status, donor/recipient gender combination, CMV-serology, time from diagnosis to HSCT, EBMT risk-score, and follow-up (median 24 versus 25 months, in RIC and MAB, respectively). Significant differences with respect to stem cell source, graft manipulation, and year of transplant were observed, with a higher proportion of RIC in recent years.

Pts with alloHSCT showed better OS (55% ± 4) than pts receiving alternative consolidation (46% ±2), p<0.01. In accordance with previous observations, pts in CR1, who received MAB alloHSCT had an OS of 50% (±3) at 5 years post HSCT, which appeared not different from consolidation by autografting, with OS of 49% (±3). However, pts receiving RIC alloHSCT experienced improved outcome with a 5 yr OS of 62% (±4%), p< 0.001, which improvement was noted among intermediate and poor-risk pts. RFS estimated 55% (±5%) versus 47% (±3%), in RIC and MAB pts, and RFS estimated 41% ±3% following autografting, p<0.001. The 5 yr cumulative incidence of relapse was not significantly different between RIC and MAB conditioned pts (36% ±4% versus 29% ±3%, p=0.56), but recipients of RIC alloHSCT experienced significant less NRM (9% ±3% versus 24% ±3%, p<0.001). Cox-regression analysis was performed with alloHSCT as a timedependent covariate and adjustment was done for age, time to CR, and cytogenetic risk. Comparing alloHSCT versus other consolidation treatments with respect to RFS, the overall hazard ratio (HR) for alloHSCT was 0.59 (95% CI, 0.49–0.70), P <.0001, while specific HR's for RIC and MAB alloHSCT were 0.49 and 0.66, respectively, (both with p < 0.001). With endpoint OS, the overall HR for alloHSCT was 0.71 (95% CI, 0.76–0.90), p<0.0001, while the HR for RIC was 0.53 (0.40–0.71), p < 0.001, and for MAB alloHSCT 0.82 (0.66–1.01), p=0.07. In addition, cytogenetic risk appeared an important risk factor, determining RFS and OS (HR 2.08 95%CI, 1.84–2.34, p<0.0001).

In conclusion, consolidation by alloHSCT significantly improves outcome as compared to either chemotherapy or autologous transplantation in CR1 pts aged 40–60 years, which was largely accounted for by RIC alloHSCT. These results suggest that: 1. similar to younger pts, alloHSCT can be considered standard consolidation therapy in intermediate and poor-risk AML in CR1, aged 40–60 years; 2. RIC and MAB alloHSCT may only slightly differ with respect to reduction of relapse in pts having benefited from intensive preceding induction/consolidation chemotherapy, while RIC is additionally associated with a significant reduction of NRM; 3. a prospective randomized trial comparing RIC and MAB in similarly pretreated AML pts, including younger pts in CR1, is advocated.