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N. Gagelmann and N. Kröger
Transplant risk score
Several studies have been published to further aid physi- cians in balancing the risks and benefits of HSCT for patients. The EBMT transplantation risk score,57 initially established for chronic myeloid leukemia, has now been expanded and validated to assess post-transplant risk for multiple hematologic disorders that can be treated with a transplant. The risk score includes: the patient’s age class (<20, 20-40, or >40 years), disease stage (early, intermedi- ate, or advanced), donor type (HLA-identical sibling or unrelated donor), and donor-recipient sex match/mismatch (specifically, an increased score for a male recipient with female donor). The score held for all acquired hematologic disorders (score 0-5) and was independent of the HSCT procedure itself. This risk scheme does not specifically con- sider comorbidities (see below), and notably places all patients >40 years in a high-risk category. Importantly, the EBMT risk score was independently valid, irrespective of the intensity of the conditioning.
In line with these findings, an EBMT mega-file analysis showed that patients' pre-HSCT risk factors determine sur- vival,58 independently of conditioning intensities, suggest- ing that outcomes may be improved more effectively through better identifying patients with their individual pre-HSCT characteristics.
In summary, the recent increased efforts will shape future research to establish more individualized risk mod- els for predicting outcome after HSCT in several diseases, irrespective of conditioning intensity.59–62
Genetic risk
The Japanese Society of Hematopoietic Stem Cell Transplantation reported a significant survival benefit from MAC versus RIC in 840 AML patients with poor cytogenet- ics, irrespective of subgroup analysis for age <60 years or high comorbidity index.63 In contrast, EBMT studies failed to show any survival benefit of either type of conditioning regimen in patients with cytogenetically poor-risk AML64,65 One such study with AML patients 40-60 years old in first complete remssion, stratified according to cytogenetic risk, found better survival with RIC in low-risk patients but not in the intermediate- or poor-risk groups.65 In the latter groups, relapse incidence was lower with MAC, but NRM was higher with MAC in all cytogenetic risk groups. The analysis concluded that in patients 40-60 years old, MAC had no significant advantage. Bornhäuser et al. also report- ed no difference between MAC and RIC for intermediate- and high-risk AML patients in a prospective randomized trial.16
Another very recent study in MDS showed that the adverse impact of shorter telomeres on NRM was more frequently observed in patients receiving more intensive conditioning and was associated with the development of GvHD.66 Thus, strategies in MDS patients with shorter telomere length may focus on minimizing toxicity and reducing conditioning intensity.
Performance status, comorbidities and age
There is conflicting evidence regarding the association of conditioning intensity and comorbidities. As described above, the study by Rambaldi et al. showed significantly reduced NRM after busulfan-fludarabine conditioning compared with busulfan-cyclophosphamide conditioning in patients with a comorbidity index >2.20 A recent analysis in patients ≥50 years old with Philadelphia-positive acute
lymphoblastic leukemia who received tyrosine kinase inhibitor therapy before HSCT and who achieved MRD- negativity showed similar outcomes after RIC or MAC,67 with subgroup analyses suggesting better outcomes for RIC in patients with a poor performance status or a high HCT-Comorbidity Index.68,69 In contrast, the above men- tioned Japanese study in patients with cytogenetically poor-risk AML and first complete remission showed an association with better outcomes for MAC,63 irrespective of subgroup analysis for patients <60 years old or high HCT-Comorbidity Index.
A single-center experience including 875 adults high- lights both the pitfalls of arbitrary dichotomization of con- ditioning intensity and the value of patient-specific bal- anced evaluations.70 The following were classified as RIC: fludarabine 150 mg/m2 with busulfan 6.4 mg/kg; fludara- bine 150 mg/m2 with treosulfan 30 g/m2; and fludarabine 150 mg/m2 with melphalan 100-140 mg/m2. With respect to specific comorbidities in the overall population, which varied widely across regimens, renal dysfunction, hypoal- buminemia, and severe hepatic disease were associated with worse NRM. Notably, the risk was not associated with intensity as classified. Instead, outcome was associat- ed with regimen-specific profiles, showing increased NRM for fludarabine-busulfan in patients with cardiac disease, and for fludarabine-melphalan and fludarabine-treosulfan in patients with severe pulmonary disease and a pre-exist- ing infection. The HCT-Comorbidity Index was only asso- ciated with worse outcome in patients receiving fludara- bine-melphalan conditioning but not in those given other regimens.
With respect to RIC versus MAC, several analyses showed similar outcomes in patients ≥50 years old.47,71 Of note, generally, patients receiving RIC are older by a medi- an of 10 years.72 For the evaluation of less intensive condi- tioning, a retrospective analysis compared the efficacy of RIC in MDS patients >50 years, analyzing patients <65 or ≥65 years at HSCT separately. Subsequently, in patients <65 years, NMA conditioning was associated with higher NRM and shorter survival, while the cumulative incidence of relapse was similar in both the RIC and NMA groups.
The EBMT recently analyzed the outcome of AML patients with reduced performance status according to the Karnofsky performance status of ≤80%. Patients with a Karnofsky performance status of 80% benefited more from MAC, while patients with a performance status <80% benefited more from RIC.73
In conclusion, simple recommendation of RIC/NMA for older unfit patients or MAC for young and fit ones is not reflected by current evidence. Neither age nor comorbidi- ties are associated with significantly different outcomes for these categorizations.74,75 Ultimately, only patients with exceptionally limiting comorbidities/performance may experience different outcomes.
Infections and late effects
Presumably, less intensive conditioning may lead to reduced rates of infection. However, published evidence on this issue remains limited. Early investigations sug- gested that RIC may decrease the risk of dying from an opportunistic infection, reducing the frequency of cytomegalovirus infection/disease.76 In a recent CIBMTR analysis of 1,755 AML patients ≥40 years old, although absolute numbers of patients with ≥1 infection were not different in the RIC/NMA (58%) and MAC (61%) groups,
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haematologica | 2021; 106(7)