Predictors of Outcomes in Adult AML with MLL Rearrangements

Background: Rearrangements of the mixed-lineage leukemia gene (MLLr) cause a unique group of acute leukemias with variable phenotypes but a universally adverse prognosis. Determinants of response in AML with rearrangements of the MLL gene are unknown.

Objective: To determine the mutational profile, phenotypic and clinical characteristics of MLLr AML.

Methods: We screened adult patients (pts) with AML treated at our center between 1990 and 2019. 393/9465 pts (4%) with MLLr AML were identified. Among them, 174 pts had newly diagnosed AML and are the focus of this analysis; we compared their outcomes to 522 age-matched pts (19%) with newly diagnosed AML and diploid karyotype (DK). From 2012, next-generation sequencing panels were used to detect genes recurrently mutated in myeloid neoplasms. Baseline characteristics were assessed and overall survival (OS) was calculated using the Kaplan-Meier method and compared using the log-rank test.

Results: MLLr patients were younger than Pts with DK (median age: 51 vs 61 years, P<0.0001) and had higher baseline LDH (median: 1783 vs 1358 U/L for DK), and bone marrow blast % (median: 66% vs 53%), but lower platelet counts (median: 57 vs 71 x10⁹/L, P< 0.02). Most common rearrangements were due to t(9;11) in 97 pts (56%), t(11;19) in 30 pts (17%), t(6;11) in 19 pts (11%), and (v;11q23.3) in 28 pts (16%). 65 (37%) MLLr patients had therapy-related (t-AML) (vs 9% of DK, P<0.0001). Pts with MLLr AML had fewer mutations than DK (median 0.5 vs 1.2 mutation/patient P<0.0001), most commonly affecting the RAS and TP53 genes. Notably, compared to DK, mutations in FLT3 (12% vs 34%, P<0.0001), IDH1/2 (7% vs 32%, P<0.0001) and DNMT3A (5% vs 30%, P<0.0001) were less frequent in MLLr. The majority of pts with MLLr had a monocytic/myelomonocytic phenotype (64% vs 28%, P=<0.0001). Blasts in MLLr had lower expression of CD7 (median: 6% vs 14%), CD13 (median: 58% vs 74%), and CD34 (median: 16% vs 38%), and higher CD33 (median: 94% vs 82%) (P<0.001).

Pts with MLLr had a similar response rate to age matched pts with DK (CR/CRi: 82 vs 80%, P=0.7) but worse OS (median: 0.9 vs 2 years, P<0.0001). Pts with t-AML and MLLr had significantly worse OS vs non-t-AML with MLLr (median OS of 0.5 vs 1.2 years, P<0.0001). In a landmark analysis, allogeneic hematopoietic stem cell transplant (HSCT) in first complete response (CR) was associated with markedly improved outcomes in MLLr AML (median OS of 10.7 vs 1.1 years, P<0.0001). In a multivariate analysis of factors predicting overall survival in MLLr AML, HSCT was associated with a lower risk of death with a HR of 0.38 (95% CI 0.24 - 0.58, P <0.0001). The only other predictors identified were elevated creatinine (HR of 1.43, 95% CI 1.12 - 1.83, P=0.004) and an elevated WBC (HR of 1.00, 95% CI 1.00 - 1.01, P<.0002).

Conclusion: MLLr is an uncommon subtype of AML with characteristic molecular and phenotypic features and dismal outcomes. Allogeneic HSCT in first CR is associated with a significantly improved survival. Given the limited progress made in treatment of this entity, novel approaches are needed.