An overview of developments in reduced intensity conditioning and GvHD prophylaxis

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment of choice for many hematologic malignancies. However, the use of allo-HSCT remains challenging due to its association with high morbidity and non-relapse mortality (NRM) rates. The risk of NRM due to graft-versus-host-disease (GvHD), organ toxicity, and infections increases with age, higher hematopoietic cell transplantation comorbidity index, disease stage, donor type, and conditioning intensity. Although, increasing conditioning intensity elicits high NRM, reducing conditioning intensity increases the risk of relapse.

At the European Hematology Association (EHA) 2021 Virtual Congress, Marie Therese Rubio¹ provided an overview on how reduced intensity conditioning (RIC) regimens and GvHD prophylaxis have progressed and how they can be improved in the future. Outcomes for allo-HSCT treatment have been improved through various ways, including reduced toxicity conditioning, optimization of GvHD prophylaxis, reduction of disease burden before transplantation, and post-transplantation therapeutic strategies. Rubio’s presentation focused on reduced toxicity conditioning and optimization of GvHD prophylaxis. The GvHD Hub is pleased to provide a summary here.

Progress in reducing NRM

A retrospective analysis by Penack et al.² demonstrated that substantial progress has been made in reducing NRM in the last 40 years. This has been possible due to increased use of peripheral blood stem cells, in vivo T-cell depletion, RIC, reduced use of higher doses of total body irradiation, improved human leukocyte antigen (HLA) typing, and improved GvHD prophylaxis and anti-infectious treatments. NRM at 1-year post-transplantation has decreased over time: 29.7% from 1980 to 1989, 24.4% from 1990 to 1999, 14.8% from 2000 to 2009, and 12.2% from 2010 to 2016.

Improved outcomes with RIC

RIC is one of the main factors in attaining NRM not only in elderly patients but also in young patients. In a systematic review and meta-analysis, conducted by Ma et al.³, comparing RIC and myeloablative conditioning (MAC) in relatively young patients (age range, 18–66 years), RIC (fludarabine + busulfan or fludarabine + total body irradiation [8 Gy]) was associated with lower NRM, less acute GvHD (aGvHD), and a lower incidence of chronic GvHD (cGvHD).

Despite the improvements, post-transplant relapse remains a challenge for RIC, especially in patients with low or intermediate disease risk index and detectable measurable residual disease (MRD), as shown by Solh et al.⁴ and Hourigan et al.⁵ In next-generation sequencing (NGS)-assessed MRD-positive patients, RIC was significantly associated with an increased risk of relapse compared with MAC. The study showed that MAC improved survival in patients with acute myeloid leukemia with genomic evidence of MRD before allo-HSCT.

Due to the increased risk of relapse in NGS-assessed MRD-positive patients, RIC has been adapted to slightly intensified conditioning with fludarabine-melphalan 100 or 140 mg/m². Retrospective studies by Peric et al.⁶ and Zhou et al.⁷ show that fludarabine-melphalan reduced the risk of relapse in patients with high-risk acute myeloid leukemia compared with fludarabine-busulfan, albeit with a higher NRM.

The combination of thiotepa-busulfan-fludarabine (TBF) has also been investigated in retrospective studies from the EBMT registry,⁸ showing no difference except in one single-center study, which demonstrated a reduced incidence of relapse and improved overall survival (OS) with TBF versus fludarabine-busulfan).

A meta-analysis by Zhu et al.⁹ showed improved OS with treosulfan-based conditioning regimens compared with busulfan-based regimens. In a single center study by Wedge et al.¹⁰ a higher dose of treosulfan (42 g/m²) with fludarabine compared with non-myeloablative and standard myeloablative conditioning in patients with myelodysplastic syndromes showed significantly improved OS and a lower risk of NRM.

More recently, a phase III trial (NCT00822393)¹¹ of fludarabine-treosulfan compared with fludarabine-busulfan showed that fludarabine-treosulfan was superior for event-free survival and NRM. There were no significant differences in the incidence of aGvHD, cGvHD, or relapse between the two conditioning regimens.

Optimization of GvHD prophylaxis

Several studies^12,13 have shown the benefit of antithymocyte globulin (ATG) in reducing aGvHD, and Grade 3 and 4 cGvHD, as well as improving quality of life, without increasing the risk of relapse, particularly in match-unrelated donors. Therefore, ATG is the preferred option for GvHD prophylaxis in Europe.

Another agent for GvHD prophylaxis is post-transplant cyclophosphamide (PTCy). A study by Rugerri et al.¹⁴ demonstrated a significant improvement in outcomes for haploid transplantation and potential for use in matched-unrelated donors. For GvHD prophylaxis in HLA-matched donors, the addition of other immunosuppressive drugs to PTCy enhances its effect, reduces the risk of severe cGvHD, reduces mortality, and improves survival.

During the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Eolia Brissot¹⁵ presented the results of a multicenter, randomized, phase II trial comparing the efficacy of PTCy versus ATG for GvHD prophylaxis in patients undergoing fludarabine-busulfan RIC allo-HSCT with 10/10 HLA-matched donors. The study demonstrated similar outcomes in both PTCy and ATG arms, supporting their use for GvHD prophylaxis.

In the absence of any prospective studies comparing ATG to anti-T-lymphocyte globulin (ATLG), evidence from a retrospective monocentric study¹⁶ showed that ATLG reduced the incidence of aGvHD, with no difference in cGvHD. There were also no differences in NRM, relapse incidence, and OS, therefore longer-follow up is recommended. In terms of immune reconstitution, there was a more profound depletion of CD8+ T cells and reduced PD1 expression on CD8+ T cells in patients receiving ATLG compared with those receiving ATG, which warrants further exploration; levels of regulatory cells were similar.

Conclusion

A substantial improvement has been made in NRM after allo-HSCT with match-related donors and matched-unrelated donors in the last several years. Taken together, the evidence so far suggests that reduced-toxicity conditioning with fludarabine-treosulfan should be considered as a new standard for HSCT with match-related donors or matched-unrelated donors in elderly patients or those with comorbidities. The use of ATG and PTCy for GvHD prophylaxis has reduced the incidence of severe aGvHD and cGvHD, improving patient quality of life. Further comparisons of ATG versus low-dose ATLG versus PTCy should continue, as well as exploration of optimal ATG dosing.