S1613 Allogeneic Hematopoietic Cell Transplantation Can Abrogate Increasing Risk of Relapse From Persistent Mutations Measured by Targeted Sequencing at Remission in Normal Karyotype Acute Myeloid Leukemia

Abstract

performed to investigate mutation status of KIT and 32 myeloid genes.Results: The multivariate model identified five independent predictors of survival: age > 60 years (HR 2.4, CI 1.4-5.0, P < .003), hemoglobin < 10 g/dL (HR 2.0, CI 1.3-3.0, P = .002), platelets < 100 x 10 9 /L (HR 1.7, CI 1.1-2.5, P = .02), presence of one high molecular risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1) (HR 2.5, CI 1.6-4.5, P < .0001), and of  2 high molecular risk geme mutations (HR 4.4, CI 2.1-7.3, P < .0001). For assignment of individual scores, we divided the HR value of each variable by the median value of all variables. Accordingly, a weighted score of 1 was assigned to age > 60 years, hemoglobin < 10 g/ dL, platelets < 100 x 10 9 /L, and S/A/R 1 mutation, whereas a score of 2 was assigned to S/A/R  2 mutations. These weighted scores were used to generate three risk groups which comprise the MARS: low-risk, 0 to 1; intermediate risk, 2; high-risk, 3 to 5 with median OS not reached, 3.9 years (95% CI 2.1 to 5.7 years) and 1.9 years (95% CI 1.3 to 2.6 years) (P < .0001) (Figure 1A), respectively. The MARS was independent of the World Health Organization (WHO) classification and was confirmed in an independent validation set (Figure 1B). The MARS was also predictive for leukemia-free survival (P < .0001). On basis of receiver operating characteristic curve analysis, the C-index was 0.42 for the WHO classification and 0.81 for the MARS. Summary/Conclusion:We conclude that the WHO classification remains the pivotal diagnostic and prognostic tool for subtyping of SM into indolent SM and AdvSM. The MARS is a WHO-independent and complementary tool for the heterogeneous cohort of patients with Ad-vSM by defining three risk groups based on a five-parameter prognostic score which may improve upfront treatment stratification for these rare hematologic neoplasms.

Clinical Challenges and Consequences of Measurable Residual Disease in Non-APL Acute Myeloid Leukemia

“…Nevertheless, there is evidence that DTA-mutations might provide MRD information in some situations, e.g., when used in a post-allogeneic-HSCT setting [68]. Despite the still to overcome limitations regarding data sequencing and interpretation, analyzing molecular MRD using NGS already allows identification of patients with a higher relapse risk and shorter OS in the clinical setting of intensive chemotherapy [67,69,70] as well as allogeneic HSCT [62,68,71].…”

“…There are only very limited data on the prognostic significance of MRD assessment at the time-point during aplasia after induction therapy available [85]. For all following time-points during AML therapy—i.e., after induction [19,20,21,22,23,24,25,67,69,70] and consolidation [11,12,20,21,26,52] chemotherapies, prior to [22,27,28,29,30,40,42,45,62,71,86] and after [28,37,68] allogeneic HSCT and during follow up [21]—the predictive value of MRD assessment was extensively published within the last years. However, the optimal timepoints and intervals are yet to be defined and most probably will depend on the underlying AML biology [75].…”

“…For qRT-PCR based MRD analyses, both absolute thresholds (e.g., “negativity”, 0.01% or 0.1%) and log reduction to baseline levels at diagnosis have been identified as clinically relevant. Also for NGS assays, distinct variant allele frequency levels (as negativity, <0.2%, or <2.5%) have been proposed as MRD thresholds [68,69,70,71]. However, in the clinical routine, the sensitivity and threshold applied is most likely of less relevance than the frequency of sampling, the amount, and type of sampled tissue, as well as the clinical interpretation and integration of MRD results into clinical care of patients.…”

“…In general, an improvement of DFS of >10% has been adopted to justify the decision towards an allogeneic HSCT [95]. As previously discussed, many studies reported higher relapse incidences and shorter survival for patients being MRD-positive prior to allogeneic HSCT—irrespective of the used MRD marker or intensity of conditioning regimens [22,27,28,29,30,40,42,44,62,71,96]. One study even showed that MFC-MRD-positive patients had outcomes comparable to patients transplanted with active AML [27].…”

“…Despite the non-randomized treatment approach, the authors were able to show that allogeneic HSCT in MRD-positive intermediate risk patients was able to prolong DFS and OS to rates comparable to favorable risk patients. Finally, two other retrospective studies described a favorable impact of allogeneic HSCT compared to chemotherapy alone on relapse rates and OS in patients with positive but not negative MRD in first CR [69,71]. A potential positive impact of allogeneic HSCT in MRD-positive patients is underlined by the observation that GvL effects after HSCT seem to result in similar relative reduction of relapse risk compared to chemotherapy in MRD-positive and MRD-negative patients [102].…”