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Conditioning intensity in allogeneic HSCT
In a comparison of conditioning regimen intensities, a correlative analysis was performed of ultra-deep DNA sequencing of blood samples from patients treated in the BMT-CTN trial.26,46 Of the 218 AML patients, 190 patients had blood samples collected prior to HSCT, which were analyzed using a 13-gene, targeted error-cor- rected, next-generation sequencing panel for the pres- ence of genomic MRD. Among these patients, 63% ran- domized to RIC and 68% randomized to MAC had evi- dence of MRD by detection of one or more of the tested genes. It should, however, be pointed out that current European LeukemiaNet recommendations do not sup- port mutations such as FLT3-ITD, NRAS, DNMT3A, or ASXL1, and expression levels of EVI1 as single MRD markers.43 Instead, these markers are suggested to be useful when used in combination with a second MRD marker.
Among MRD-positive patients in this analysis,46 out- comes were dismal for those given RIC, with a 3-year incidence of relapse of 67% versus 19% in the MAC group. After adjusting for disease risk and donor group, RIC was associated with a significantly increased risk of relapse and decreased survival in MRD-positive patients, when compared to MAC. However, the 3-year NRM rate was higher in those who underwent MAC (27%) than in those who received RIC (9%), and this difference was not affected by MRD status. Furthermore, overall survival was comparable in the two groups among patients who were MRD-negative.
In line with these results, an EBMT analysis of 2,292 AML patients in first complete remission showed that less intensive conditioning was only inferior to MAC for patients <50 years old who were MRD-positive, showing higher relapse and lower survival rates.47 Irrespective of age, conditioning intensities were associated with similar outcomes in patients who were MRD-negative. This analysis also revealed the better caption of the “real world” using our proposed balanced conditioning approach, because RIC/MAC groups shared the same heterogeneous spectrum of regimens used, with only dif- ferent distributions of certain regimens. A significant caveat regarding this study is that the MRD methodology and allocation were determined by individual participat- ing centers, utilizing molecular and/or immunophenotyp- ing criteria. An earlier CIBMTR analysis of 197 patients with acute lymphoblastic leukemia showed that MRD- positive patients had a higher risk of relapse with RIC,48 but MRD-negative patients who also received tyrosine kinase inhibitor therapy before HSCT had superior sur- vival after RIC compared to a similar population after MAC. After multivariable adjustment, RIC reduced NRM but increased relapse risk.
In light of these results that suggest benefits of more intensive conditioning primarily for some or all AML patients who were MRD-positive prior to HSCT, a recent analysis suggested that MAC should also be considered for MRD-negative AML patients if tolerated.49
In an analysis of 287 patients with MDS,50 of whom one quarter had >5% marrow blasts and more than a half were MRD-positive at HSCT, as determined by multiparameter flow cytometry and cytogenetics on marrow aspirates, it was found that the risk of overall mortality was higher with lower intensity retimens than with higher intensity regimens among the MRD-positive patients. On the other hand, MRD-negative patients had similar risks of mortali-
Table 4. Risk factors influencing treatment failure (relapse or NRM) after allo- geneic HSCT.
Disease-specific factors
Advanced disease status
Unfavorable cytogenetics/molecular genetics Susceptibility to GVL-effect
Patient-specific risk factors
Age
Performance status Comorbidities
Transplant-specific risk factors
MRD positivity
HLA disparity
CMV incompatibility
Center effect (JACIE accredited)
relapse > NRM relapse > NRM relapse > NRM
NRM > relapse NRM > relapse NRM > relapse
relapse > NRM NRM > relapse NRM > relapse NRM > relapse
NRM, non-relapse mortality; HSCT, hematopoietic stem cell transplantation; GVL, graft-versus- leukemia effect; MRD, measurable residual disease; CMV, cytomegalovirus; JACIE, Joint Accreditation Committee ISCT-Europe & EBMT.
ty. The main reason for mortality after lower intensity con- ditioning in MRD-positive patients was relapse.
Evidence from comparison of conditioning regimens of different intensities according to MRD status in AML is still based on retrospective or post-hoc analyses including heterogeneous use of regimens for each group. Current sig- nals point to a benefit for more intensive approaches in MRD-positive AML patients but the increased risk of NRM needs to be considered. In addition, other factors such as donor selection or graft type may further affect MRD-related outcomes. For example, one retrospective analysis suggested that pre-HSCT MRD-positive patients receiving cord blood as the source of stem cells had a reduced incidence of relapse. in comparison with those receiving transplants from matched unrelated donors and even better survival than those given grafts from mis- matched unrelated donors.51 Another study reported better outcome after haploidentical HSCT in comparison to HLA- identical sibling transplants in MRD-positive AML patients.52
Disease risk
The evidence regarding the impact of conditioning inten- sity on different disease risk index (DRI) groups53,54 is still limited to some retrospective analyses. One analysis eval- uated 380 AML/MDS patients with either high/very high or low/intermediate DRI.55 Among patients with high/very high DRI, there was no difference in outcome between the RIC and MAC groups. For low/intermediate risk DRI, recipients of MAC showed better 3-year overall survival (69% vs. 57%), disease-free survival (65% vs. 51%), and a decreased incidence of relapse (17% vs. 32%) but similar, slightly increased NRM (19% vs. 17%). Except for overall survival, which was not significantly different in multivari- able analysis, results for the remaining outcomes were con- firmed after multivariable adjustment. In a larger, very recent CIBMTR analysis, MAC resulted in an improved survival in comparison to RIC in AML/MDS patients 40 to 65 years old with low/intermediate risk DRI, but similar clinical benefit to RIC despite higher risk of relapse in patients with high/very high risk DRI.56
In conclusion, compared with RIC, MAC may be asso- ciated with improved outcomes among patients with low/intermediate DRI, while no benefit has been noted for any intensity among those in high/very high DRI groups.
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