Comparison between Upfront Transplantation and different Pretransplant Cytoreductive Treatment Approaches in Patients with High-Risk Myelodysplastic Syndrome and Secondary Acute Myelogenous Leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P < .0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P = .116), whereas RFS rates were 38%, 41%, and 38% (P = .926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (>10% versus <10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P = .0346) and by clear trend in HMA nonresponders (42% versus 61%, P = .073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P = .0005) and a higher 2-year OS rate after relapse (59% versus 19%, P = .0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT.

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation

“…Indeed, this has mainly contributed to a CR rate of 41% and 2-year OS rate of 38%, including 17 patients alive in ongoing remission without any further anti-leukemic treatment for >5 years (up to 10 years). Overall, these results appear to be not only favorable when compared to the previous reports on the use of Aza [ 9 , 10 , 11 , 12 , 17 ], but also when considering outcome after alternative approaches, such as intensive chemotherapy or second transplantation [ 28 , 29 , 30 ]. Still, the retrospective nature of these indirect comparisons and potential selection bias have to be taken into account.…”

“…Finally, in patients with MDS there is controversy among experts regarding the value of pretransplant cytoreduction by intensive chemotherapy and hypomethylating agents [ 15 , 16 ]. Preliminary data from our group suggested that in contrast to upfront transplantation, pretransplant cytoreduction may negatively impact response and survival to HMA in case of relapse after allo-HSCT [ 17 ]. To address these issues and to expand the knowledge about predictive factors, we analyzed data from a well-annotated cohort of 151 patients with a long follow-up, including a relevant fraction of patients with molecular relapse, treated with Aza for relapse after allo-HSCT at our center.…”

Induction, Bridging, or Straight Ahead: The Ongoing Dilemma of Allografting in Advanced Myelodysplastic Syndrome

“…One might argue that the potency of HMA to induce complete remission is significantly lower than intensive chemotherapy and that HMAs are more likely used for "bridging" rather than "induction," aiming to avoid disease progression until a suitable donor is found. Indeed, also in the reported study by Schroeder et al [5], the median number of HMA cycles was only 4, although it is known that most remission after HMA therapy was seen between 4 and 6 cycles or even beyond 6 cycles [8]. However, in the presented study as well as in line with other studies, induction chemotherapy induces a higher rate of complete remission than HMA, but this did not translate into a better outcome after transplantation [9,10].…”

“…They showed that a small subclone before transplant could drive progression after allografting, but also newly acquired structural variants were present in expanding subclones at progression, and pretransplant therapy with 5-azacitidine influenced the mutation spectrum and evaluation of the subclone postallografting [15]. This might explain-but does not prove-why upfront transplant patients responded better to HMA salvage therapy after relapse than others in the reported study from D€ usseldorf [5].…”

“…The study from Schroeder et al [5] in this issue compared retrospectively upfront transplantation with induction chemotherapy and HMAs before stem cell transplantation in 165 patients with MDS and secondary acute myeloid leukemia (sAML). Despite a trend for improved survival in patients receiving upfront transplantation, no significant difference could be seen for upfront versus chemoinduction versus HMA induction with respect to overall survival and relapse-free survival.…”