Durable graft‐versus‐leukaemia effects without donor lymphocyte infusions – results of a phase II study of sequential T‐replete allogeneic transplantation for high‐risk acute myeloid leukaemia and myelodysplasia

Abstract

Allogeneic haematopoietic stem-cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high-risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T-cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft-versus-leukaemia effects. T-replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single-arm prospective Phase II clinical trial of sequential chemotherapy and T-replete transplantation using reduced-intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty-seven patients with relapsed/refractory AML or high-risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment-related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late-onset graft-versus-host disease protected against relapse. In conclusion, a T-replete sequential transplantation using reduced-intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft-versus-leukaemia effects without DLI.

Very early lineage-specific chimerism after reduced intensity stem cell transplantation is highly predictive of clinical outcome for patients with myeloid disease

“…Previous studies have found that a decline in donor T cell chimerism is a risk factor for relapse in T replete RIC HSCT [24][25][26][27] and ATG-conditioned RIC HSCT 12,13 . In contrast, mixed T cell chimerism in alemtuzumab-conditioned T cell-depleted RIC HSCT has not been associated with an increased risk of disease relapse 14,15,17,28 .…”

The role of allogeneic stem cell transplantation in the management of acute myeloid leukaemia: a triumph of hope and experience

“…The optimal RIC regimen in older adults with AML has not been established. It is clear that Flu‐based regimens, typically formulated as Flu/Bu 2 (6·4 mg/kg, two days of IV busulfan) (Slavin et al, ), Flu/melphalan (140 mg/m 2 ) (Giralt et al, ) or Flu/Cy (1 g/m 2 × 2) (Davies et al, ), differ in terms of both anti‐tumour activity and toxicity. There are regrettably very few randomised trials of RIC regimens in AML, but it is of interest that a randomised comparison between the widely‐used Flu/Bu 2 regimen and the Seattle Flu/2 Gy TBI NMA regimen demonstrated equivalent overall survival, but an increased NRM and reduced relapse rate with the Flu/Bu 2 regimen compared with the NMA regimen, underlining the importance of comparing specific reduced‐intensity regimens in the future (Blaise et al ., ).…”

From remission to cure: bypass or detour?

“…In this issue, Davies et al () report the results of a prospective clinical phase II trial in which r/r AML and high‐risk myelodysplastic syndrome patients underwent sequential chemotherapy and subsequent T‐replete allogeneic haematopoietic stem cell transplantation (AHST). Traditionally, T‐cell deplete AHST is given in a sequential manner after delivering remission‐inducing chemotherapy (Schmid et al , ).…”

“…In view of the fact that many high‐risk AML patients do not proceed to AHST because they do not achieve a remission and considering that most of us know patients who achieved cure by AHST although they were not in remission before transplantation, the study by Davies et al () is a step in the right direction. The authors demonstrate that a sequential therapy in a T‐replete AHST setting is feasible, results in acceptable rates of transplantation‐related mortality (which seem to be mostly relevant in the elderly proportion of the patients in this trial), low viral reactivations and without the necessity of DLI.…”

“…The incorporation of post‐transplantation cyclophosphamide in a sequential setting to reduce the time of exposure to immunosuppressive therapy, as demonstrated recently (Mielcarek et al , ), and the role of haploidentical AHST (in case of unavailability of a matched donor) (Bashey et al , ) in a sequential setting have not been investigated thus far. Furthermore, it has not been defined whether both, high‐risk and very high‐risk AML patients would benefit from a transplantation strategy like the one reported by Davies et al () or whether this approach is also only indicated for certain cyto‐/genetically defined subsets of AML patients. In the meantime, instead of waiting for a remission that might or might not occur and therefore denying patients the opportunity for a potential curative therapy, bypassing this scenario with a sequential T‐cell replete AHST strategy currently seems to be the most valid approach in this setting.…”