Page 31 - 2021_07-Haematologica-web

Conditioning intensity in allogeneic HSCT
the median time to initial infection after MAC occurred earlier, at a median of 15 versus 21 days.77 Patients receiv- ing MAC were more likely to experience ≥1 bacterial infection, whereas ≥1 viral infection was more prevalent among those receiving RIC/NMA. Another recent smaller analysis regarding mucositis found infections were less frequent after less intensive conditioning, with the rate being lowest after fludarabine-treosulfan conditioning.78
Evaluations regarding long-term effects of different intensity conditioning regimens are scarce. One study showed similar long-term leukemia-free survival and GvHD-free/relapse-free survival at 10 years for RIC and MAC, with most events occurring within the first 2 years after allogeneic HSCT.79 Relapse was the major cause of late death in both groups; while NRM and especially chronic GvHD as well as second cancers were more fre- quent causes of late death after MAC.
Graft-versus-host disease
Prospective and retrospective comparisons show that
relapse is the major cause of death in RIC patients while most MAC patients die from GvHD. This led to the con- cept of influencing risk of relapse and GvHD to improve outcomes for any given conditioning intensity.80 Regarding the latter, the use of post-HSCT cyclophosphamide signif- icantly reduced the risk of GvHD and was associated with better outcomes when used in haploidentical HSCT, at least compared with transplants from mismatched unrelat- ed donors.81 In view of this consistent effect of post-HSCT cyclophosphamide, no significant differences according to conditioning intensity in haploidentical transplants were found after meta-regression analyses81 and in two large reg- istry analyses.82,83 So far, it has not been possible to confirm the hypothesis of an association between reduced GvHD after post-HSCT cyclophosphamide and better survival in patients treated with MAC regimens, but comparisons still lack stringent control and assessments in specific donor settings. Here, it is important to underscore the complex interplay of GvHD and risk of relapse with the type of dis- ease or tumor burden, including phenomena that are not yet fully clarified.84 In acute lymphoblastic leukemia and BCR-ABL-negative myeloproliferative neoplasms there are similar and obvious correlations between the occurrence of GvHD and risk of relapse when compared with chronic myeloid leukemia, and in MDS and lymphoproliferative disorders there are intermediate correlations between GvHD and relapse risk. Only in AML and plasma cell dis- orders is GvHD associated with only modest reductions in relapse risk.
Maintenance therapy
A more personalized approach might incorporate post- transplant strategies to prevent relapse.85-87 There is accu- mulating evidence regarding the efficacy of post-HSCT
maintenance therapy with tyrosine kinase inhibitors in AML, specifically for patients with FLT3-ITD mutations. Two prospective studies showed that sorafenib mainte- nance was associated with significantly better relapse and relapse-free survival outcomes.88,89 In the Chinese study all patients were given MAC,88 while 58% of patients in the German study received sorafenib and underwent RIC HSCT;89 no stratified comparisons according to condition- ing intensity were conducted within this latter study. Limited indirect comparison of the two studies suggest at least comparable outcomes in both, with 2-year survival rates in the sorafenib arm of 82% in the Chinese study and 90% in the German study. Whether the impressive effect of maintenance on relapse, with a 60% risk reduc- tion, may broaden the utility of less intensive condition- ing, is yet to be determined.
Summary
The answer to “when and f\or whom” with respect to HSCT conditioning intensity is complex, individualized, and constantly evolving. Apart from factors such as pre- treatment, disease risk, donor source, GvHD prophylaxis, and maintenance strategies, the conditioning regimen is only one factor affecting the risk of treatment failure through relapse or NRM after allogeneic HSCT. As of 2021, the traditional, simplified section of a conditioning regimen between RIC and MAC is no longer appropriate because it significantly underestimates the complexity of currently used regimens with respect to toxicity. Updated categorizations from the EBMT15 are one step in the right direction but still provide only modest improvements in facilitating decision-making, considering all outcomes. A critical individual balance between the risk of NRM and the risk of relapse must be inclluded in a personalized medicine approach. These individual and continuous considerations may include diverse factors such as dis- ease burden, MRD status and other disease-specific, patient-specific, and transplant-specific risk factors. Furthermore, recent advances in the incorporation of tox- icity-reduced conditioning regimens (e.g., treosulfan) and improvements in relapse reduction by including mainte- nance strategies, as well as immunotherapy approaches after allogeneic HSCT may further refine considerations regarding conditioning intensity, steering towards the use of less intensive and toxic regimens in the future.
Discosures
No conflicts of interest to disclose.
Contributions
NG and NK drafted the manuscript and approved the final version.
References
1. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplanta- tion: one size does not fit all. Blood. 2014;124(3):344-353.
2. Giralt S, Ballen K, Rizzo D, et al. Reduced- intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Center for International Blood and Marrow Transplant
Research. Biol Blood Marrow Transplant.
2009;15(3):367-369.
3. Champlin R, Khouri I, Kornblau S,
Marrow Transplant. 2009;15(12):1628-1633. 5. Bacigalupo A. Third EBMT/AMGEN Workshop on reduced-intensity condition- ing allogeneic haemopoietic stem cell trans- plants (RIC-HSCT), and panel consensus. Bone Marrow Transplant. 2004;33(7):691-
Molldrem J, Giralt S. Reinventing bone mar-
row transplantation: reducing toxicity using nonmyeloablative, preparative regimens
and induction of graft-versus-malignancy. 696.
Curr Opin Oncol. 1999;11(2):87-95. 4.Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regi- mens: working definitions. Biol Blood
6. Bacigalupo A. Second EBMT Workshop on reduced intensity allogeneic hemopoietic stem cell transplants (RI-HSCT). Bone Marrow Transplant. 2002;29(3):191-195.
haematologica | 2021; 106(7)
1801