Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms

Abstract

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Introduction

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located at the 11.4 locus of short arm of chromosome X.¹ The BCOR gene product is predominantly involved in suppressing myeloid regulatory genes and promotes lymphopoiesis.¹ Grossman et al. first demonstrated the association of somatic BCOR mutations with acute myeloid leukemia (AML).² The recent 2022 European LeukemiaNet (ELN) recommendations on acute myeloid leukemia classifies BCOR-associated AML in the adverse risk category.³ However, the clinical outcomes of BCOR-mutated (mBCOR) AML has primarily been explored in pooled cohorts evaluating multiple other genes. For instance, Papaemmanuil et al. evaluated clinical outcomes of patients with AML stratified by genetic subgroups.⁴ The study included mBCOR AML within the chromatin-spliceosome group, which also included patients with mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6. The study showed adverse outcomes of patients in this mutational group. Similarly, Gardin et al. evaluated the outcomes of a cohort of 471 patients with secondary AML (sAML)-like gene mutations which included 38 patients with mBCOR AML, and a trend towards worse overall survival (OS) in the presence of sAML-like mutations (HR 1.22, P=0.07) was observed.⁵ The outcomes of patients with mBCOR AML were not specifically evaluated in either of the studies. Damm et al. evaluated 15 patients with mBCOR myelodysplastic syndrome (MDS) and demonstrated an inferior OS compared to patients with wild-type BCOR (HR 3.3, 95% CI 1.4-8.1, P=0.008).⁶ Other studies evaluating outcomes of patients with mBCOR MDS are also limited by small sample size and inclusion of other gene mutations.⁷, ⁸

In this study, we evaluated the genetic and clinical features, and factors predicting outcomes of patients with mBCOR AML/MDS.

Methods

Patients

The study was approved by the Mayo Clinic Institutional Review Board. Patients with WHO-defined myeloid neoplasms, including AML and MDS, and found to have a BCOR mutation on next-generation sequencing (NGS) performed between October 2015 to August 2021 on peripheral blood or bone marrow aspirate were included.⁹ Patient demographics, disease characteristics at time of diagnosis and at the time of NGS testing, co-mutations, treatment-related variables and survival outcomes were extracted.

Because patients with mBCOR AML would be considered to have high-risk disease by ELN 2022 risk stratification, the disease risk for baseline characteristics was determined using the Revised International Prognostic Scoring System (IPSS-R) for MDS and the ELN 2017 risk stratification for AML.^3,10,11 However, the survival outcomes of patients with mBCOR AML was compared to a control cohort by both ELN 2017 and ELN 2022 risk stratification.

Consecutive patients who had NGS testing performed from May 2015 to September 2017, and had wild-type (wt) BCOR were considered as control cohort. Data on co-mutations, cytogenetics, and disease risk stratification by ELN 2017, ELN 2022 and IPSS-R criteria were collected for patients in the control cohort.

For patients undergoing alloSCT, a hematopoietic cell transplantation-comorbidity index (HCT-CI) score ≥3 was considered high. Conditioning regimen intensity was defined per the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria.¹² Acute graft-versus-host disease (GvHD) was graded according to Glucksberg criteria and severity of chronic GvHD was determined using the 2014 National Institute of Health consensus criteria.^13,14 Relapse was defined as detection of disease after alloSCT by morphological, cytogenetic, or molecular analysis, as applicable. Relapse incidence (RI) was calculated from the time of alloSCT to the time of relapse detection.

Statistical analysis

Patients’ and disease characteristics were summarized using descriptive statistics. The statistical comparison of categorical variables was performed using χ² test. For continuous variables, Kruskal-Wallis test was used for comparison of medians and t test was used for comparison of means.

Comparison of co-mutations among patients with wtBCOR versus mBCOR was performed using the “epitools” package and evaluated on log10 scale to prevent skewness.¹⁵ Patients were deemed to enter the study at the time of NGS testing. Survival outcomes were analyzed in patients with AML/MDS from timepoint of study entry, unless mentioned otherwise. Kaplan-Meier and log-rank tests were used to estimate OS.¹⁶ Median follow-up time was determined using the reverse Kaplan-Meier method.¹⁷ Cox-proportional hazard model was used to determine the effect on OS. Allogeneic stem cell transplant (alloSCT) was considered a time-dependent covariate for both univariate and multivariate Cox proportional hazard analysis.¹⁸

The cumulative incidence of non-relapse mortality (NRM) and RI in patients undergoing alloSCT was determined using the competing risks method. Fine-Gray analysis was used to determine factors influencing NRM and RI post-alloSCT.

Only those genes that were mutated in at least 5 patients (approx. 5% of the entire cohort) were included in the univariate analyses. Because BCOR gene is located on X-chromosome, the variant allele frequency (VAF) of BCOR mutation was gender-adjusted for all the analyses. Variables with P<0.20 in univariate analyses were included in multivariate analysis. R 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria) was used to perform all the statistical analyses. P<0.05 was considered statistically significant.^19,20

Results

Out of 6,887 consecutive NGS tests performed, 138 (2%) patients were found to have BCOR mutation. These patients were compared to 275 patients with wtBCOR, who were considered to be the control cohort.

Control cohort

The control cohort consisted of 155 (82 males, 53%) patients with AML, 105 (71 males, 68%) with MDS, and 15 (5.5%) others. Median age at study entry was 74 years (interquartile range [IQR] 67-78 years) for MDS and 65 years (IQR 56-73 years) for AML.

Of the 155 AML patients, 17 (11%) were favorable risk, 61 (39%) were intermediate risk, and 73 (47.1%) were adverse risk by ELN 2022 criteria. By ELN 2017 criteria, 20 (13%) patients had favorable risk, 66 (42%) had intermediate risk, and 65 (42%) patients had adverse risk disease (Table 1). Risk stratification could not be determined for 4 (2.6%) patients. The most commonly mutated gene among patients with AML was DNMT3A (N=33, 21.3%), followed by mutations in genes TET2 (N=29, 18.7%), TP53 (N=27, 17.4%), and IDH2 (N=27, 17.4%) (Online Supplementary Table S1). Among the 105 MDS patients, 27 (25%) were high or very high-risk by the IPSS-R. Fourteen (13%) patients had MDS with increased blasts-type 1 (MDS-IB1), while 15 (14%) patients had MDS-IB2. The most commonly mutated gene among MDS patients was ASXL1 (N=29, 27.6%), followed by mutations in genes TET2 (N=21, 20%) and SF3B1 (N=20, 19%). TP53 gene was mutated in 15 (14.3%) patients (Online Supplementary Table S1).

Table 1.Baseline characteristics of patients stratified by wild-type BCOR and mutated BCOR.

Characteristics of patients with mBCOR acute myeloid leukemia and myelodysplastic syndromes

A total of 138 patients (96 males, 69.6%) with mBCOR hematologic disorders were evaluated. Thirty-six (26.1%) patients had AML and 63 (45.6%) had MDS (Table 2 and Online Supplementary Table S2). Among patients with AML and MDS, 64 (64.6%) had NGS testing performed before the first intervention/treatment.

Most of the patients (N=133, 96.4%) harbored only a single BCOR mutation. A total of 144 BCOR variants were seen across 138 patients. RUNX1 (50/138, 36%) and U2AF1 (38/138, 28%) were among the most commonly co-mutated genes (Figure 1A). Median VAF for BCOR mutation was 34.5% (IQR 16-61%) (Figure 1B); the median gender-adjusted VAF was 24.25% (IQR 11-37%). Mutations in the BCOR gene were present throughout the exon sequence and a particular hotspot could not be identified (Figure 1C). Frameshift variants were most common (82, 57%), followed by nonsense (45, 32%) and splice-site (16, 11%) variants, while only one (0.7%) patient had a missense mutation (Figure 1C).

Sixty-six (47.8%) patients had a normal karyotype: 16 (44.4%) among patients with AML, and 27 (42.9%) among patients with MDS (Figure 1D). None of the mBCOR AML or MDS patients had any abnormalities in chromosome 17. Monosomy 7 was found in 3 (4.8%) patients, and deletion 20q was seen in 8 (12.7%) patients with mBCOR MDS but were not seen in any patient with mBCOR AML. Other cytogenetic abnormalities among patients with mB-COR AML/MDS included trisomy 8 in 16 (16.2%) patients (7 AML, 43.8%; 9 MDS, 56.2%), deletion 5q in 8 patients (3 AML, 37.5%; 5 MDS, 62.5%), and inversion 3 in 2 (2%) patients (1 patient each with AML and MDS). One (1.59%) patient with MDS had rearrangement involving the KMT2A gene locus (11q23). Eighteen (13%) patients had complex karyotype: 7 (19.4%) among the 36 patients with AML and 6 (9.5%) among the 63 patients with MDS (Table 2, Figure 1D). Among the AML patients, one (2.8%) had favorable risk, 14 (38.9%) had intermediate risk, and 19 (52.8%) had adverse risk disease by ELN 2017 criteria; risk stratification could not be evaluated in 2 (5.6%) patients. Among the MDS patients, 43 (68.3%) had an intermediate or higher risk disease by IPSS-R; 20 (31.7%) patients had MDS-IB1, while 23 (36.5%) had MDS-IB2 (Table 2). Median white blood cell (WBC) count was 2.5x10⁶ cells/L (range 0.9 – 98.4x10⁶) in patients with AML and 2.30x10⁶ cells/L (range 0.8 – 14.4x10⁶) in patients with MDS.

Among AML and MDS patients, BCOR mutations were found to be highly associated with mutations in RUNX1 gene (odds ratio [OR] 5.5; P<0.001). BCOR mutations were less commonly associated with TP53 mutations, particularly among patients with MDS (OR 0.21; P=0.02) (Figure 1E, Online Supplementary Table S3). Patients with mBCOR MDS were found to be significantly associated with U2AF1 mutation (OR 3.95; P<0.001). The U2AF1 S34F variant was the predominant mutation (20/24, 83%) in mBCOR MDS patients (Online Supplementary Table S4). Interestingly, none of the patients with mBCOR had an NPM1 co-mutation.

Survival analysis

Median follow-up time after study entry among patients with mBCOR AML/MDS was 3.2 years (95% CI: 2.34-3.82 years). Median survival for the entire cohort of mBCOR AML/MDS patients was 15 months. The survival was lower among patients with AML compared to MDS, but this difference was not statistically significant (median OS: 0.74 vs. 1.53 years; P=0.21) (Figure 2A, Online Supplementary Figure S1A). Complex karyotype (median OS 0.3 vs. 1.5 years; P<0.001) and age ≥70 years (median OS 0.88 vs. 2.04 years; P=0.008) were associated with a worse survival (Figure 2B, C). Patients with mBCOR had similar survival regardless of the presence of additional other high-risk co-mutations by ELN 2022 criteria (median OS 1.26 vs. 1.3 years; P=0.46) (Figure 2D). The median OS from diagnosis among patients with NGS at diagnosis was similar to those who had NGS performed after treatment (median OS 2.07 vs. 2.05 years; P=0.87).

In comparison to wtBCOR patients (control cohort), survival since study entry among mBCOR patients was similar to those with adverse risk AML and numerically inferior to those with favorable or intermediate risk AML by the ELN 2017 criteria (3-year OS 29.5% vs. 24.4% vs. 41.2%; P=0.32) (Figure 2E). Survival from diagnosis among mBCOR AML patients was similar to those with adverse risk AML by ELN 2017 criteria and significantly inferior compared to those with favorable or intermediate risk AML by the ELN 2017 criteria (3-year OS 36.5% vs. 33.5% vs. 52.8%; P=0.03) (Figure 2F); similar findings were seen on evaluating survival by ELN 2022 criteria (Online Supplementary Figure S1B, C). Patients with mBCOR AML with NGS performed at diagnosis or after treatment had survival rates similar to adverse risk AML and inferior to favorable/intermediate risk AML by ELN 2017 criteria (3-year OS rate: 35.4% vs. 38.1% vs. 33.5% vs. 52.8% for mBCOR at diagnosis, mBCOR after treatment, wtBCOR with adverse risk AML and wtBCOR with favorable/intermediate risk AML, respectively; P=0.046). Survival was similar among mBCOR MDS with or without a U2AF1 mutation (P=0.89) (Online Supplementary Figure S2A) and those with mBCOR AML/MDS with or without a RUNX1 co-mutation (P=0.51) (Online Supplementary Figure S2B). Univariate analysis showed that, among patients with mBCOR, complex karyotype (HR 3.17, 95% CI: 1.69-5.96; P<0.001) and age ≥70 years at study entry (HR 2.04, 95% CI: 1.2-3.47; P=0.008) were associated with inferior survival, whereas alloSCT (HR 0.25, 95% CI: 0.11-0.57; P=0.001) was associated with an improved OS. Complex karyotype, age ≥70 years at study entry, alloSCT, and presence of EZH2 and/or KRAS co-mutations were factors included in the multivariate analysis (Online Supplementary Table S5). Multivariate analysis confirmed that complex karyotype was associated with a worse survival (HR 4.92, 95% CI: 2.0811.65; P<0.001), whereas alloSCT was associated with an improved survival (HR 0.38, 95% CI: 0.14-0.996; P=0.049) (Online Supplementary Figure S1D). Upon adjusting the BCOR VAF for gender, a trend towards inferior survival was seen among patients with BCOR VAF ≥40% (Figure 3).

Table 2.Characteristics of patients with mutated BCOR.

Figure 1.Genomic landscape of patients with BCOR mutations. (A) Oncoplot of patients with BCOR mutation; top 15 mutated genes are shown. (B) Top 10 genes with highest median variant allele frequency. (C) Lollipop plot showing various mutations across the BCOR gene. Mutations were most commonly frameshift or nonsense, and spread across the entire gene, without a specific hotspot region. (D) Specific cytogenetic abnormalities stratified by diagnoses: acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or others. Approximately half of the patients had normal karyotype, whereas complex karyotype or chromosome 17 abnormalities were seen in only a minority of patients. (E) Association of BCOR mutation with other genes among patients with MDS and AML. CK: complex karyotype; MK: monosomal karyotype; Ab: abnormal; Chr: chromosome; Diag: diagnosis; Mono: monosomy; N: number; NGS: next-generation sequencing; S: significant (P<0.05); T: trend (0.10 > P≥0.05; NS: not significant (P≥0.10); NA: not applicable.

Transplant outcomes

A total of 30 patients (19 males, 63.3%) underwent alloSCT after study entry. Median age at alloSCT was 65 years (IQR 58-68 years). Ten patients (33.3%) had AML, 17 (56.7%) had MDS, 2 (6.7%) had myeloproliferative neoplasm, and one patient (3.3%) had chronic myelomonocytic leukemia (CM-ML) (Table 3).

The 27 patients with mBCOR AML/MDS were evaluated for post-alloSCT outcomes. Median follow-up time after alloSCT was 2.5 years (95% CI: 1.8-4.0 years). Median HCT-CI score was 3 (IQR 1-3); thirteen (48.1%) patients had a high HCT-CI score. Fifteen (55.6%) patients were in complete remission (CR) at the time of alloSCT, 11 (40.7%) had persistent disease, and the disease status was not known for one patient (3.7%). Among the 10 patients with AML, 5 (50%) had pre-alloSCT minimal residual disease (MRD) testing performed, 4 (40%) of whom were MRD negative and one (10%) patient was MRD positive before transplant. Median survival after alloSCT was not reached; OS rate at three years was 61.1% (Figure 4A). A total of 8 (29.6%) deaths were reported within three years after transplant, of whom 5 patients (62.5%) had NRM and 3 (37.5%) patients died after relapse. The cumulative incidence of NRM was 23.7% and RI was 24.1% at three years after transplant (Online Supplementary Figure S3). Among the 5 patients with NRM, 2 (40%) died of infection, one (20%) died of GvHD, and the cause of death was not known for 2 (40%) patients. There was no significant difference in 3-year NRM (10% vs. 34.5%; P=0.32) and relapse (10% vs. 33.3%; P=0.24) in patients with AML or MDS (Figure 4B).

Given that BCOR is a high-risk mutation, we evaluated factors influencing post-transplant relapse. Univariate competing risk analysis showed that mutation in genes ASXL1, RUNX1 (mRUNX1), melphalan-, or busulphan-based conditioning, and reduced-intensity conditioning were factors significantly affecting post-transplant relapse (Online Supplementary Table S6). Multivariate analysis showed that mRUNX1 was associated with an increased risk of post-transplant relapse (HR 88.0, 95% CI: 1.98-3918; P=0.02), and melphalan-based conditioning was associated with a decreased risk of post-transplant relapse (HR 0.02, 95% CI: 0.001-0.40; P=0.01) (Figure 4C).

Patients with mBCOR AML undergoing alloSCT had a superior post-alloSCT survival compared to those with mBCOR MDS, but it was not statistically different (3-year OS 88.9% vs. 43.2%; P=0.1) (Figure 5A), while complex karyotype was associated with an inferior post-alloSCT survival (median OS 1.24 vs. NA years; P=0.04) (Figure 5B). Multivariate analysis that included complex karyotype and diagnosis (AML vs. MDS) (Online Supplementary Table S7) did not identify either of the 2 to be independently associated with post-alloSCT survival (Figure 5C), suggesting that alloSCT was beneficial regardless of phenotype or cytogenetics.

Figure 2.Clinical outcomes of patients with BCOR-mutated acute myeloid leukemia or myelodysplastic syndromes. Kaplan-Meier plots for survival since time of BCOR mutation (mBCOR) detection stratified by (A) disease type, (B) complex karyotype at next-generation sequencing (NGS), (C) age at NGS, and (D) presence/absence of high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria. (E and F) Overall survival of patients with mutated (m)BCOR versus wild-type (wt)BCOR, stratified by ELN 2017 risk category. Adv: adverse risk; AML: acute myeloid leukemia; Fav/Int: favorable / intermediate; MDS: myelodysplastic syndromes.

Figure 3.Multivariate analysis of factors affecting post-next-generation sequencing survival in patients with mutated BCOR. adj: adjusted; HR: Hazard Ratio; NGS: next-generation sequencing; VAF: variant allele frequency.

Characteristics of mBCOR myelodysplastic syndromes / myeloproliferative neoplasms overlap syndrome

A total of 11 (7.8%) patients had myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, 6 (54.5%) of whom had CMML. The median age at diagnosis was 75 years (IQR 68-82 years). Of the 11 patients, 8 (72.7%) patients had normal karyotype while trisomy 8 was seen in 2 patients (18.2%); karyotype was not available for one patient (9.1%). ASXL1 (10 patients, 90.9%), SRSF2 (5 patients, 45.5.%) and RUNX1 (4 patients, 36.4%) were among the most commonly mutated genes. Two (18.2%) patients (1 CMML, 9.1%) harbored a mutation in the TET2 gene. Median follow-up time was 1.6 years (95% CI: 1.57-NA). Survival was higher among patients with CMML compared to other MDS/MPN disorders; however, it was not statistically significant (median OS 15 vs. 9 months; P=0.5). Survival from NGS among patients with mBCOR MDS/MPN was similar to patients with mBCOR AML (median 7.5 vs. 9 months; P=0.28), but inferior to patients with mBCOR MDS (median 7.5 vs. 18.6 months; P=0.005) (Online Supplementary Figure S4).

Discussion

We described a cohort of 138 patients with mBCOR, of whom 99 (72%) had AML/MDS. Patients had BCOR mutations detected primarily in their 6^th-7^th decade of life and had low white blood cell (WBC) counts at diagnosis. These findings are parallel to those reported by Papaemmanuil et al.⁴

Studies have shown that a majority of patients with BCOR mutation have normal karyotype.^6,21 Approximately half of the patients in our cohort had normal karyotype and would have been classified in non-high-risk categories in the absence of mBCOR; complex karyotype was seen in only a minority of patients, while abnormality of chromosome 17 was not seen in any patient with mBCOR AML/MDS. We could not identify a specific hotspot of mutations and the BCOR variants were spread throughout the gene. Most of the BCOR mutations were truncating mutations, and missense mutation was a rare finding in our cohort. This is similar to the findings of Grossmann et al., who evaluated 26 patients with mBCOR AML and found 15 frameshift, 6 nonsense, and 4 splice-site mutations, and a mutation pattern that is consistent with a tumor-suppressor function.^2,22,23

Mutations in the BCOR gene have previously been associated with a RUNX1 mutation^.6,21 Damm et al. also showed a strong association of mBCOR MDS with mutations in the DNMT3A gene.⁶ Our study confirms these findings with a significant association of mutations in BCOR and DNMT3A in patients with MDS. A similar trend was also noticed in mBCOR AML in our cohort. Our study confirms that BCOR and NPM1 mutations are mutually exclusive.^6,24 We also found that mBCOR MDS were highly associated with mutations in the U2AF1 gene. This is in contrast to the study by Montgomerry et al., which showed a predominant association of mBCOR with mU2AF1 in lymphoid malignancies and not in myeloid neoplasms.²⁵ In our study, the U2AF1 S34F was the predominant variant. The U2AF1 has been shown to portend poor outcomes in patients with MDS.^26,27 Our study showed that the survival among mBCOR patients was poor, regardless of the presence or absence of the U2AF1 mutation. More importantly, the poor survival among patients with mBCOR AML/MDS was in spite of association with a high-risk co-mutation such as RUNX1 or ASXL1.

Table 3.Characteristics and outcomes of patients with mBCOR undergoing allogeneic stem cell transplantation.

Figure 4.Outcomes of patients with BCOR-mutated acute myeloid leukemia / myelodysplastic syndromes undergoing allogeneic stem cell transplantation. (A) Overall survival after allogeneic stem cell transplantation (alloSCT). Follow-up data available in 26 patients. (B) Competing risk analysis showing cumulative incidence of non-relapse mortality (NRM) and relapse after alloSCT. (C). Multivariate competing risk analysis for relapse incidence at three years after alloSCT showing an overall adverse effect of RUNX1 mutation and a positive effect of melphalan-based conditioning. AML: acute myeloid leukemia; HR: Hazard Ratio; MDS: myelodysplastic syndromes.

Our study shows that patients with mBCOR AML/MDS have poor prognosis. The poor prognosis was seen across all the subgroups of MDS and AML patients, regardless of blast percentage. A comparison with the control cohort showed that survival among mBCOR AML patients parallels those with adverse risk AML patients by both ELN 2017 and ELN 2022 criteria, confirming the adverse prognosis of patients with mBCOR AML. Our study also shows that alloSCT improves survival in patients with mBCOR AML/ MDS, and these patients should be evaluated for alloSCT at the earliest opportunity. More importantly, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse while melphalan-based conditioning was found to have a positive effect on post-alloSCT RI. A few studies have previously evaluated the effect of alloSCT in patients with mBCOR AML.^28,29 In a pooled cohort of de novo AML with secondary-type mutations including BCOR, Song et al. evaluated 15 patients undergoing alloSCT and found a cumulative RI of 33.3% at five years.²⁸ This parallels a 3-year RI of 24.1% reported in our study.

Some of the limitations of our study are that the NGS testing was done at different time points and the relatively small sample size of patients undergoing transplant. However, the former limitation is somewhat offset by the fact that the majority of patients with mBCOR AML/MDS in our cohort had NGS testing carried out before the first intervention/treatment. The time-to-event approach from NGS testing does lead to an underestimation of survival as the duration of disease before testing is not accounted for by this methodology. However, because this bias applies to both the mBCOR and the control cohort, its effect is diminished in a comparative analysis. For the same reason, we evaluated survival outcomes from both the time points, i.e., from diagnosis and from NGS. We further compared the survival outcomes of patients found to have a BCOR mutation at diagnosis versus later in the time-course and found similar survival rates. Given the rarity of BCOR mutations, a small sample size will be a limitation of any single-institutional study.

To our knowledge, this is the largest study specifically evaluating the impact of mBCOR across patients with AML and MDS. Our study also shows that the outcomes mBCOR AML/MDS are poor regardless of the presence or absence of high-risk co-mutations, suggesting an effect of BCOR in determining disease outcomes, while complex karyotype continues to have adverse outcomes. Finally, our study confirms that allogeneic transplant is associated with improved outcomes in patients with mBCOR AML/ MDS; patients harboring a RUNX1 co-mutation are at an increased risk of relapse, while melphalan-based conditioning decreases the relapse risk.

Figure 5.Factors influencing post-allogeneic stem cell transplantation survival in patients with mutated BCOR acute myeloid leukemia / myelodysplastic syndromes. Overall survival after allogeneic stem cell transplantation (alloSCT) stratified by: (A) disease type, (B) complex karyotype. (C) Multivariate analysis for 3-year post-alloSCT survival. AML: acute myeloid leukemia; HR: Hazard Ratio; MDS: myelodysplastic syndromes.

Footnotes

• Received August 29, 2023
• Accepted January 22, 2024

Correspondence

H.B. Alkhateeb Alkhateeb.Hassan@mayo.edu

Disclosures

MVS reports research funding to the institution from Astellas, Abbvie, Celgene, and Marker Therapeutics. All of the other authors have no conflicts of interest to disclose.

Contributions

HBA, MVS and AB contributed to study design. AB, MG, RB and BK contributed to data acquisition and analysis. AB and HBA wrote the first draft. RH, DSV and PG performed molecular testing. JF, TB, HM, CAY, JP, AAM, MMP, MRL, WJH, KB, NG, AT, AA-K, MVS and HBA contributed patients and reviewed the manuscript. All authors approved the final version of the manuscript for publication.