Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy

Abstract

Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)‐related karyotype, or history of prior MDS. We evaluated 415 patients with AML‐MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML‐MRC, therapy type and mutation profile. Criteria for AML‐MRC included: cytogenetic abnormalities (AML‐MRC‐C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML‐MRC‐H) and 28 (7%) with previously treated MDS (AML‐MRC‐TS), and 97 (23%) with multilineage dysplasia (AML‐MRC‐M). Median age was 70 years (range 18‐94). Among 95 evaluable patients, a total of 37 (39%) had secondary‐type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML‐MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML‐MRC‐M (HR 0.56, CI 0.38‐0.84, P = .004) and AML‐MRC‐H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML‐MRC‐M/AML‐MRC‐H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML‐MRC‐M (HR 0.42, CI 0.19‐0.94, P = .036) and with improved EFS in AML‐MRC‐M and AML‐MRC‐H (HR 0.26, CI 0.10‐0.63, P = .003). This data suggests that not all diagnostic criteria for AML‐MRC define high‐risk patients and that specific subgroups may benefit from different therapeutic interventions.

Acute myeloid leukemia: 2021 update on risk‐stratification and management

“…Therefore, CPX appears superior to 7 + 3 in AML‐MRC regardless of whether defined by a history of MDS, including patients who have and have not received HMAs, or only by MDS‐cytogenetic changes 20 although it is unclear whether the same is true in patients whom MRC is defined only by morphologic dysplasia. The latter appear to have a better prognosis than other AML‐MRC patients, 21 possibly suggesting AML with MRC defined only by dysplasia is not truly secondary AML. Because the annual rate of relapse or death in CR does not decline to <5% until 3 years have elapsed from remission, 22 the CPX data might be viewed as more stable than the venetoclax data (median follow‐up 20 months), although it is unknown whether the failure rates will decline at the same rate after less intense therapy such as venetoclax as after more intense therapy such as CPX.…”

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances

“…As compared to non-MRC AML, AML-MRC has, overall, been associated with inferior outcomes such as lower remission rates, ranging between 30-50%, and shorter overall survival [6,[19][20][21]. For AML-MRC patients able to receive intensive chemotherapy, the overall response rate (ORR) is 69%, with a complete response (CR) rate of 40-51% [21][22][23]. This is compared to less intensive regimens where the ORR and CR rate are, respectively, 69% and 19-32% with single agent hypomethylating agent, 81% and 38-67% with hypomethylating agent in combination, and 69% and 12-36% with low dose cytarabine therapies [22,[24][25][26].…”

“…For AML-MRC patients able to receive intensive chemotherapy, the overall response rate (ORR) is 69%, with a complete response (CR) rate of 40-51% [21][22][23]. This is compared to less intensive regimens where the ORR and CR rate are, respectively, 69% and 19-32% with single agent hypomethylating agent, 81% and 38-67% with hypomethylating agent in combination, and 69% and 12-36% with low dose cytarabine therapies [22,[24][25][26]. Furthermore, median overall survival for AML-MRC patients is typically only 9 to 12 months even in those patients that are able to tolerate intensive induction chemotherapy, which has traditionally yielded the best outcomes for these patients [19,22,27].…”

“…One of the main challenges of treating patients with AML-MRC is that, compared to non-MRC AML which typically has a flatter incidence of occurrence, AML-MRC tends to occur in an older patient population [19,22,28]. The median age at diagnosis of AML-MRC in general is 70 years old (vs. 67 years old for non-MRC AML) and the median age of diagnosis of AML-MRC with a previous diagnosis of MDS is 74 years old [22]. Patients who are older tend to have more co-morbidities and poorer overall performance status and, thus, are less likely to successfully undergo intensive chemotherapy [1,29,30].…”

“…Although such patients are technically considered to have therapy-related AML (t-AML), there is significant overlap between t-AML and AML-MRC [32]. A recent retrospective study of 415 patients with AML-MRC summarized the most common therapies given prior to their diagnosis of AML-MRC [22]. In this analysis, 22% of patients had received treatment with hypomethylating agents (HMAs), 3% with ruxolitinib, 1% with lenalidomide, and 1% with 7 + 3 for MDS or MDS/MPN treatment prior to their AML-MRC diagnosis [22].…”