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

Abstract

Allogeneic stem cell transplantation is still the only curative treatment option, and the number of allografts is steadily increasing in international registries [1Kroger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome.Blood. 2012; 119: 5632-5639Crossref PubMed Scopus (54) Google Scholar]. Since large retrospective studies from european society for blood and marrow transplantation (EBMT) and center for international blood and marrow transplant research (CIBMTR) have shown that the number of blasts in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) at the time of transplantation has a significant impact on outcome because of a higher risk of relapse [2Sierra J. Perez W.S. Rozman C. et al.Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia.Blood. 2002; 100: 1997-2004PubMed Google Scholar, 3Symeonidis A. van Biezen A. de Wreede L. et al.Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia: a study of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation.Br J Haematol. 2015; 171: 239-246Crossref PubMed Scopus (71) Google Scholar], attempts have been made to reduce the number of blasts before transplantation by induction chemotherapy or hypomethylating agents (HMAs). Despite the lack of randomized studies, international experts recommend performing cytoreductive therapies before allogeneic stem cell transplantation in high-risk patients with MDS with ≥10% marrow blasts [4de Witte T. Bowen D. Robin M. et al.Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel.Blood. 2017; 129: 1753-1762Crossref PubMed Scopus (203) Google Scholar]. The study from Schroeder et al. [5Schroeder T. Wegener N. Lauseker M. et al.Comparison between upfront transplantation and different pretransplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia.Biol Blood Marrow Transplant. 2019; 25: 1550-1559Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] 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. Other retrospective studies already have reported that HMAs before allogeneic stem cell transplantation did not improve outcome in comparison to upfront transplantation [6Damaj G. Mohty M. Robin M. et al.Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.Biol Blood Marrow Transplant. 2014; 20: 1349-1355Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 7Field T. Perkins J. Huang Y. et al.5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation.Bone Marrow Transplant. 2010; 45: 255-260Crossref PubMed Scopus (121) Google Scholar]. 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. [5Schroeder T. Wegener N. Lauseker M. et al.Comparison between upfront transplantation and different pretransplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia.Biol Blood Marrow Transplant. 2019; 25: 1550-1559Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar], 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 [8Dinmohamed A.G. van Norden Y. Visser O. et al.Effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes in daily practice: results from the Dutch population-based PHAROS MDS registry.Leukemia. 2015; 29: 2449-2451Crossref PubMed Scopus (30) Google Scholar]. 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 [9Damaj G. Duhamel A. Robin M. et al.Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies.J Clin Oncol. 2012; 30: 4533-4540Crossref PubMed Scopus (165) Google Scholar, 10Gerds A.T. Gooley T.A. Estey E.H. Appelbaum F.R. Deeg H.J. Scott B.L. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS.Biol Blood Marrow Transplant. 2012; 18: 1211-1218Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar]. In a recent EBMT registry study, patients who received induction chemotherapy or HMA had a similar outcome after transplantation, and only primary refractory disease resulted in worse outcome [11Potter V.T. Iacobelli S. van Biezen A. et al.Comparison of intensive chemotherapy and hypomethylating agents before allogeneic stem cell transplantation for advanced myelodysplastic syndromes: a study of the Myelodysplastic Syndrome Subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplant Research.Biol Blood Marrow Transplant. 2016; 22: 1615-1620Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Also in studies comparing induction with no-induction therapy, no clear benefit could be observed for those who received induction therapy [6Damaj G. Mohty M. Robin M. et al.Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.Biol Blood Marrow Transplant. 2014; 20: 1349-1355Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 12Alessandrino E.P. Della Porta M.G. Pascutto C. Bacigalupo A. Rambaldi A. Should cytoreductive treatment be performed before transplantation in patients with high-risk myelodysplastic syndrome?.J Clin Oncol. 2013; 31: 2761-2762Crossref PubMed Scopus (30) Google Scholar]. Any benefit was seen only in those who achieved a complete remission. As in other retrospective studies, a major concern is patient selection and those who received some form or induction or bridging therapy but did not undergo allogeneic stem cell transplantation because of reduced performance status caused by long-lasting myelosuppression and organ toxicity or treatment-related mortality. Treatment-related mortality up to 16% has been reported in patients with high-risk MDS who were candidates for allogeneic stem cell transplantation [13Nakai K. Kanda Y. Fukuhara S. et al.Value of chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome.Leukemia. 2005; 19: 396-401Crossref PubMed Scopus (100) Google Scholar]. Investigators tried to overcome long-lasting myelosuppression of induction chemotherapy by a sequential approach using first anthracycline-based chemotherapy, followed after only 3 days of rest by the reduced or myeloablative conditioning regimen, which was also used in 73% of the upfront transplantation patients in the presented study. The impact of this sequential approach is currently being tested in a randomized FIGARO trial (ClinicalTrials.gov 50855000), and results are eagerly awaited. Even after HMAs that in general are considered less toxic, patients might lose their eligibility for allogeneic stem cell transplantation during treatment. In a recent reported prospective trial in older patients with high-risk MDS, allogeneic stem cell transplantation was planned for patients with an HLA-matched donor. During a donor search, 4 cycles of 5-azacitidine were planned as a bridge to transplant to induce remission or at least prevent progression until transplantation. The fact that 33% who started 5-azacitidine treatment could not undergo allogeneic stem cell transplant because of death (19%), progress (10%), or toxicity suggests an advantage for upfront transplantation [14Kroeger N. Sockel K. Wolschke C. et al.Prospective multicenter phase 3 study comparing 5-azacytidine (5-aza) induction followed by allogeneic stem cell transplantation versus continuous 5-aza according to donor availability in elderly MDS Patients (55-70 years) (VidazaAllo Study).Blood. 2018; 132 (208-208)Google Scholar]. Concerns about using pretransplant chemotherapy or HMAs came from recent investigators who analyzed clonal evaluation in patients with MDS who relapsed after allograft. 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 [15Jacoby M.A. Duncavage E.J. Chang G.S. et al.Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant.JCI Insight. 2018; 3: 98962Crossref PubMed Scopus (34) Google Scholar]. 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 Düsseldorf [5Schroeder T. Wegener N. Lauseker M. et al.Comparison between upfront transplantation and different pretransplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia.Biol Blood Marrow Transplant. 2019; 25: 1550-1559Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Overall, after the only randomized study from the EBMT had to be closed because of poor recruitment, all reported retrospective studies did not answer properly whether to induce, bridge, or perform allogeneic stem cell transplantation without any pretransplant in patients with advanced MDS (see Table 1). The available results and the biological clonal evaluation studies question seriously the usefulness of pretreatment in patients with MDS who are considered for an allogeneic stem cell procedure, but they remind us about the still existing clinical need for a well-designed prospective study assessing this issue.Table 1.Retrospective Studies Investigating Induction Therapy before Allogeneic Stem Cell Transplantation in MDSAuthorTreatmentRFSP ValueOSPValueSchroeder et al. [5Schroeder T. Wegener N. Lauseker M. et al.Comparison between upfront transplantation and different pretransplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia.Biol Blood Marrow Transplant. 2019; 25: 1550-1559Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]Upfront (n = 67)5 yr: 38%.905 yr: 61%.10Chemotherapy (n = 64)5 yr: 41%5 yr: 50%HMA (n = 34)5 yr: 38%5 yr: 45%Potter et al. 11Potter V.T. Iacobelli S. van Biezen A. et al.Comparison of intensive chemotherapy and hypomethylating agents before allogeneic stem cell transplantation for advanced myelodysplastic syndromes: a study of the Myelodysplastic Syndrome Subcommittee of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplant Research.Biol Blood Marrow Transplant. 2016; 22: 1615-1620Abstract Full Text Full Text PDF PubMed Scopus (40) Google ScholarHMA (n = 77)3 yr: 29%.603 yr: 42%.30Chemotherapy (n = 132)3 yr: 36%3 yr: 41%Damaj et al. 9Damaj G. Duhamel A. Robin M. et al.Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies.J Clin Oncol. 2012; 30: 4533-4540Crossref PubMed Scopus (165) Google ScholarChemotherapy (n = 98)3 yr: 37%.903 yr: 48%.07HMA (n = 48)3 yr: 42%3 yr: 55%HMA → chemotherapy (n = 17)3 yr: 36%3 yr: 32%Damaj et al. (only RIC/NMA) 6Damaj G. Mohty M. Robin M. et al.Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.Biol Blood Marrow Transplant. 2014; 20: 1349-1355Abstract Full Text Full Text PDF PubMed Scopus (44) Google ScholarUpfront (n = 88)3 yr: 42%.803 yr: 53%.70HMA (n = 40)3 yr: 37%3 yr: 53%Alessandrino et al. [12Alessandrino E.P. Della Porta M.G. Pascutto C. Bacigalupo A. Rambaldi A. Should cytoreductive treatment be performed before transplantation in patients with high-risk myelodysplastic syndrome?.J Clin Oncol. 2013; 31: 2761-2762Crossref PubMed Scopus (30) Google Scholar]Chemotherapy (n = 209)NANAHR: 1.07.50Untreated (n = 148)NANakai et al. [13Nakai K. Kanda Y. Fukuhara S. et al.Value of chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome.Leukemia. 2005; 19: 396-401Crossref PubMed Scopus (100) Google Scholar]RAEB-TNANA54% (only CR).80Chemotherapy (n = 111)NANA20% (if no response).10Untreated (n = 28)NA57%RA + RAEBNA58% (only CR)ChemotherapyNA50% (if no response)UntreatedNA73%Gerds et al. 10Gerds A.T. Gooley T.A. Estey E.H. Appelbaum F.R. Deeg H.J. Scott B.L. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS.Biol Blood Marrow Transplant. 2012; 18: 1211-1218Abstract Full Text Full Text PDF PubMed Scopus (146) Google ScholarChemotherapy (n = 33).101 yr: 36%.20HMA (n = 35)HR: 0.621 yr: 57%Field et al. 7Field T. Perkins J. Huang Y. et al.5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation.Bone Marrow Transplant. 2010; 45: 255-260Crossref PubMed Scopus (121) Google ScholarHMA (n = 30)1 yr: 41%.301 yr: 47%.25Upfront (n = 24)1 yr: 51%1 yr: 60%RFS indicates relapse-free survival; OS, overall survival; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning; NA, not applicable; HR, hazard ratio; RAEB-T, refractory anemia with excess of blasts in transformation; CR, complete remission; RA, refractory anemia; RAEB, refractory anemia with excess of blasts. Open table in a new tab RFS indicates relapse-free survival; OS, overall survival; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning; NA, not applicable; HR, hazard ratio; RAEB-T, refractory anemia with excess of blasts in transformation; CR, complete remission; RA, refractory anemia; RAEB, refractory anemia with excess of blasts.