Isocitrate Dehydrogenase (IDH) 1 and 2 Mutations Predicts Better Outcome in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation: a study of the ALWP of the EBMT

doi:10.21203/rs.3.rs-4209680/v1

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Isocitrate Dehydrogenase (IDH) 1 and 2 Mutations Predicts Better Outcome in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation: a study of the ALWP of the EBMT

https://doi.org/10.21203/rs.3.rs-4209680/v1

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published 14 Aug, 2024

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Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1 and IDH2 mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with IDH1 mutation (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95%CI 0.47–0.91), p = 0.011; HR = 0.73 (95%CI 0.56–0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95%CI 0.48–0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95%CI 0.34–0.7), p < 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95%CI 0.55–0.9), p = 0.004) and OS (HR = 0.74 (95%CI 0.56–0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes. In conclusion, our data suggest that IDH1 and IDH2 mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1.

Health sciences/Medical research/Stem-cell research

Biological sciences/Stem cells/Haematopoietic stem cells

Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia

The outcome of patients with acute myeloid leukemia (AML) has improved over the years, primarily due to a better understanding of the molecular and cytogenetic heterogeneity of this disease and its prognostic implications (1–3). More recently, three classification systems have updated the classification and risk stratification of AML based on recurrent genetic abnormalities (4–6). However, several mutations have not yet been incorporated into the risk stratification, including isocitrate dehydrogenase 1 and 2 (IDH1/2) gene mutations.

IDH1/2 have been described in AML since 2008, when the first AML genome was sequenced (7). They encode the isocitrate dehydrogenase enzymes. Mutations in these genes impair normal hematopoietic differentiation and promote leukemogenesis through competitive inhibition of αKG-dependent enzymatic activities (8, 9). Approximately 20% of patients with AML carry IDH1 or IDH2 mutations (10). They tend to present at an older age, have a higher blast percentage, carry a higher platelet count, and usually present with diploid or intermediate-risk cytogenetics (11). Several studies have assessed the predictive and prognostic implications of IDH1/2 mutations in AML (12, 13). Despite being targetable mutations, the prognostic impact of IDH1/2 mutations in AML remains controversial, which may explain their omission from AML risk stratification (14). In a meta-analysis by Qingyu et al., including 12,747 patients with AML, overall survival (OS) and event-free survival (EFS) were worse in patients with IDH1 mutation, whereas IDH2 mutation was associated with favorable prognosis in terms of OS (15). The uncertainty regarding the prognosis of patients with AML carrying IDH1/2 mutations may be influenced by co-occurring mutations, notably NPM1, DNMT3A, and FLT3 (16, 17). For instance, IDH-mutated AML with NPM1 co-mutation in the absence of FLT3 mutation seems to carry a more favorable prognosis (18). Studies assessing the outcomes of patients carrying these mutations in the allogeneic hematopoietic cell transplantation (allo-HCT) setting are limited to single center studies and/or include a small number of patients (19–21).

ln this large retrospective registry-based analysis, we assessed the prognostic impact of IDH1/2 mutations on patients with AML undergoing allo-HCT in first complete remission (CR1).

Study Design and Eligibility Criteria

This is a retrospective registry-based analysis of patients who underwent allo-HCT in CR1 between 2015 and 2022 and were reported to the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). The group comprises over 600 primarily European transplant centers, collecting data from consecutive HCTs in a centralized database. Independent systems are utilized for quality control purposes. EBMT centers commit to obtaining informed consent according to the local regulations applicable at the time of transplantation to report pseudonymized data to the EBMT. The review committee of the ALWP of the EBMT registry approved this study.

This retrospective study included 1515 consecutive patients from the EBMT registry who met the following inclusion criteria: a) adult (≥18 years) diagnosed with AML, b) recipient of allo-HCT between 2015 and 2022, c) allo-HCT at CR1, d) availability of reported information on IDH1 or IDH2 mutations. Cord blood transplants, ex-vivo graft manipulation, patients with favorable cytogenetics, and those with concomitant IDH1 and IDH2 mutations were excluded from the study due to limited numbers. Patients were divided into three groups based on IDH1 and IDH2 mutation status: no-IDH mutation, IDH1 mutation, and IDH2 mutation

Definitions

CR denotes complete hematologic remission. Leukemia-free survival (LFS) was defined as survival without evidence of relapse or progression. OS was defined as the time from intervention (allo-HCT) to death, regardless of the cause. Relapse was defined as leukemia recurrence at any site. Non-relapse mortality (NRM) was defined as death without any evidence of relapse or disease progression. Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was defined as time being alive with neither grade III-IV acute GVHD nor severe chronic GVHD nor disease relapse at any time point. Performance status was assessed using the Karnofsky performance status (KPS) score.

Statistical Methods

The three groups were defined by the absence or presence of IDH1 or IDH2 mutations. Patient-, disease-, and transplant-related characteristics were compared between the three mutation status groups using the chi-square or Fisher's exact test for categorical variables and the Kruskal Wallis test for continuous variables. Probabilities of OS, LFS, and GRFS were calculated using the Kaplan-Meier method, and cumulative incidence (CI) curves were used for NRM, relapse, acute (a) and chronic (c) GVHD to accommodate for competing risks (22). Death and relapse were considered competing events for GVHD. Univariate analyses were performed using the log-rank test for OS, LFS, GRFS, and Gray's test for CI estimates. A Cox proportional hazards model was used for multivariate regression. All variables differing significantly between the three groups and variables conceptually important, plus a center ‘frailty’ effect to take into account the heterogeneity across centers, were included in the Cox model (23, 24). Results were expressed as the hazard ratio (HR) with a 95% confidence interval (95% CI). Tests were two-sided, and p < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS 25.0 (SPSS Inc, Chicago, IL, USA) and R 4.2.3 (R Core Team, 2021, R Foundation for Statistical Computing, Vienna, Austria).

Patients and disease characteristics

We identified 1515 consecutive adult patients with AML who had received allo-HCT at CR1. Patients were categorized into three groups according to IDH1 and IDH2 mutational status: 57.82% (n = 876) did not carry any of these mutations (no-IDH mutation), 15.91% (n = 241) had IDH1 mutation (mIDH1), and 26.27% (n = 398) had IDH2 mutation (mIDH2). The median age of all patients at the time of allo-HCT was 58.3 years (range, 18–77), with patients in the no-IDH group being of younger age (p = 0.004). Patients in the no-IDH group were more likely to be male compared to mIDH1 and mIDH2 groups (59.6% vs 55.8% vs 51.5%, p = 0.025), and carry poor risk cytogenetics (28.9% vs 19.1%, 18.1%, p < 0.0001), respectively. The no-IDH, mIDH1, and mIDH2 groups were comparable with regard to donor source (p = 0.83), and intensity of the conditioning regimen (myeloablative conditioning [MAC], 44.1% vs 39.4% vs 42%, p = 0.4), respectively. Post-transplant cyclophosphamide (PTCy) was more likely to be used in the no-IDH compared to mIDH1 and mIDH2 groups (32.4% vs 27.9% vs 23.5%, p = 0.005), whereas in vivo T cell depletion was mainly used in the mIDH2 groups (57.2% vs 61.3% vs 66.5%, p = 0.007), respectively. Minimal residual disease (MRD) data were available for 755 patients, 49.8% of which 334 (44.2%) were MRD-positive at time of allo-HCT. Patient, disease-, and transplant-related characteristics of both groups are summarized in Tables 1 and 2.

Table 1

Patient and disease characteristics of all patients and according to mutation status group
Patient Characteristics	All patients	No IDH mutation	IDH1 mutation	IDH2 mutation	p-value
Patient Characteristics	N (%)	N (%)	N (%)	N (%)	p-value
N	1515	876	241	398
Follow-up, months [IQR]	23.5 [21–26]	24 [22–26]	22 [10–33]	20 [13–27]	0.11
Age at HSCT, Median [IQR]	58.3 [48.1–65.2]	57.2 [45.6–65.1]	58.6 [50-65.3]	59.2 [50.9–65.5]	0.004
18–39	217 (14.3%)	161 (18.4%)	18 (7.5%)	38 (9.5%)	< 0.0001
40–59	642 (42.4%)	349 (39.8%)	117 (48.5%)	176 (44.2%)
60+	656 (43.3%)	366 (41.8%)	106 (44%)	184 (46.2%)
Patient Sex
Male	861 (56.9%)	522 (59.6%)	134 (55.8%)	205 (51.5%)	0.025
Female	653 (43.1%)	354 (40.4%)	106 (44.2%)	193 (48.5%)
FLT3-ITD
No	1121 (74%)	638 (72.8%)	174 (72.2%)	309 (77.6%)	0.15
Yes	394 (26%)	238 (27.2%)	67 (27.8%)	89 (22.4%)
NPM1
No	1084 (71.6%)	659 (75.2%)	138 (57.3%)	287 (72.1%)	< 0.0001
Yes	431 (28.4%)	217 (24.8%)	103 (42.7%)	111 (27.9%)
Cytogenetics (per ELN2017)
Intermediate	1144 (75.5%)	623 (71.1%)	195 (80.9%)	326 (81.9%)	< 0.0001
Poor	371 (24.5%)	253 (28.9%)	46 (19.1%)	72 (18.1%)
CMV patient
Negative	592 (39.3%)	342 (39.3%)	94 (39.3%)	156 (39.3%)	1
Positive	914 (60.7%)	528 (60.7%)	145 (60.7%)	241 (60.7%)
missing	9	6	2	1
Minimal residual disease
No	421 (55.8%)	210 (54.3%)	78 (52%)	133 (61%)	0.16
Yes	334 (44.2%)	177 (45.7%)	72 (48%)	85 (39%)
missing	760	489	91	180
Abbreviations: IQR: interquartile range, IDH: isocitrate dehydrogenase, HSCT: hematopoietic stem cell transplantation, CMV: cytomegalovirus, AML: acute myeloid leukemia; ELN: European LeukemiaNet

Table 2

Transplant and donor characteristics for all patients and according to mutation status group
Transplant Characteristics	All patients	No IDH mutation	IDH1 mutation	IDH2 mutation	p-value
Transplant Characteristics	N (%)	N (%)	N (%)	N (%)	p-value
N	1515	876	241	398
Year HSCT (range)	2020 (2015–2022)	2020 (2015–2022)	2020 (2015–2022)	2020 (2015–2022)	0.56
HCT-CI score
0	623 (45.2%)	356 (45.1%)	95 (43.4%)	172 (46.4%)	0.86
1–2	372 (27%)	207 (26.2%)	63 (28.8%)	102 (27.5%)
> 3	384 (27.8%)	226 (28.6%)	61 (27.9%)	97 (26.1%)
missing	136	87	22	27
Female to male donor	250 (16.5%)	155 (17.7%)	37 (15.4%)	58 (14.6%)	0.34
CMV positive donor	741 (49.2%)	439 (50.4%)	125 (52.1%)	177 (44.9%)	0.12
Type of donor
MSD	337 (22.2%)	196 (22.4%)	48 (19.9%)	93 (23.4%)	0.83
UD	924 (61%)	529 (60.4%)	152 (63.1%)	243 (61.1%)
Haploidentical	254 (16.8%)	151 (17.2%)	41 (17%)	62 (15.6%)
Stem cell source
BM	85 (5.6%)	50 (5.7%)	15 (6.2%)	20 (5%)	0.8
PB	1430 (94.4%)	826 (94.3%)	226 (93.8%)	378 (95%)	0.8
Conditioning intensity
MAC	648 (42.8%)	386 (44.1%)	95 (39.4%)	167 (42%)	0.4
RIC	867 (57.2%)	490 (55.9%)	146 (60.6%)	231 (58%)	0.4
GVHD prophylaxis
Use of PTCY	441 (29.3%)	281 (32.4%)	67 (27.9%)	93 (23.5%)	0.005
In vivo T-cell depletion	910 (60.3%)	499 (57.2%)	147 (61.3%)	264 (66.5%)	0.007
CsA	258 (17.1%)	173 (19.8%)	28 (11.7%)	57 (14.4%)
CsA + MTX	376 (24.9%)	191 (21.9%)	64 (26.7%)	121 (30.5%)
MTX + Tacro	12 (0.8%)	4 (0.5%)	3 (1.2%)	5 (1.3%)
CsA + MMF	604 (40%)	353 (40.5%)	104 (43.3%)	147 (37%)
CsA + Tacro	3 (0.2%)	2 (0.2%)	0 (0%)	1 (0.3%)
CsA + MTX + MMF	10 (0.7%)	3 (0.3%)	4 (1.7%)	3 (0.8%)
Tacro + MMF	145 (9.6%)	82 (9.4%)	20 (8.3%)	43 (10.8%)
MMF + Siro	22 (1.5%)	15 (1.7%)	4 (1.7%)	3 (0.8%)
CsA + Tacro + MMF	6 (0.4%)	5 (0.6%)	0 (0%)	1 (0.3%)
Tacro + Siro	9 (0.6%)	8 (0.9%)	1 (0.4%)	0 (0%)
Other	64	36	12	16
missing	6	4	1	1
HSCT: hematopoietic stem cell transplantation, CR: complete remission, HCT-CI: hematopoietic cell transplantation-specific comorbidity index, CMV: cytomegalovirus, BM: bone marrow, PB: peripheral blood, MSD: Matched sibling donor; UD: unrelated donor, MAC: myeloablative conditioning, RIC: reduced-intensity conditioning, PTCY: post-transplant cyclophosphamide, ATG: anti-thymocyte globulin, GVHD: graft-versus-host disease, CsA: cyclosporine, MTX: methotrexate, Tacro: tacrolimus, MMF: mycophenolate mofetil, Siro: sirolimus

IDH1, IDH2 and co-occurring mutations

IDH1 and IDH2 mutations were more frequently encountered in middle-aged patients (40–59 years) (no-IDH 39.8%, mIDH1 48.5%, mIDH2 44.2%, p < 0.0001). Data were available for the co-occurring mutations: FLT3-ITD, NPM1, ASXL1, and DNMT3A. NPM1 mutation was more frequent in the mIDH1 group (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). Among patients with available data for ASXL1 and DNMT3A mutations, IDH1 and IDH2 mutations were frequently associated with ASXL1 (present in 20.3% in no-IDH group, 43.3% in mIDH1 group and 36.9% in mIDH2 group ; p < 0.0001) and DNMT3A mutations (35.4% in no-IDH, 86.5% in mIDH1 and 75.6% in mIDH2; p < 0.0001) (Data not shown). However, no association were observed between IDH1 and IDH2, and FLT3-ITD mutations (no-IDH group, 27.2% vs. mIDH1, 27.8% vs. mIDH2, 22.4%, p = 0.15) (Table 1).

Engraftment and GVHD

The rate of engraftment was 98.7%, with only 19 (1.3%) patients experiencing graft failure in the entire group. Similar rates were observed in both the no-IDH (n = 13, 1.5%) and mIDH2 (n = 6, 1.5%) groups (p = 0.13). No graft failure was observed in the mIDH1 group. (Results not shown)

At day 180, the CI of grade II-IV acute GVHD was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (21% vs. 20.8% vs. 28.8%, respectively, p = 0.003) (Fig. 2A). However, there was no significant difference in the CI of grade III-IV aGVHD at day 180 between the three groups (5.9% vs. 7.1% vs 8.9%, p = 0.28) (results not shown). No significant difference was noted in the 2-year CI of all grade chronic GVHD (38.1% vs. 37.7% vs. 40.1, p = 0.52) (Fig. 2B) and extensive chronic GVHD (19.9% vs. 19.4% vs. 18.4, p = 0.95) rates (results not shown) between the three groups, respectively.

Survival Outcomes

The median duration of follow-up for the entire population was 23.5 (IQR, 21–26) months. The median duration of follow-up for the no-IDH, mIDH1, mIDH2 groups was 24 (IQR, 22–26), 22 (IQR, 10–33), and 20 (IQR,13–27) months, respectively (p = 0.11) (Table 1). Overall, 364 (24%) patients died, 237 (27%) in the no-IDH, 44 (18%) in the mIDH1, and 83 (21%) in the mIDH2 groups. The most common cause of death was disease relapse (n = 158, 46.7%), followed by infection (n = 82, 24.3%) and GVHD (n = 51, 15.1%) (results not shown).

Results of the multivariate analysis are shown in Table 3. The presence of IDH2 mutation was associated with a lower risk of relapse (HR = 0.49 [95%CI 0.34–0.7], p < 0.001) (Fig. 1A), grade II-IV acute GVHD (HR = 0.73 [95%CI 0.56–0.96], p = 0.025) (Fig. 2A), which translated into a better LFS (HR = 0.7 [95%CI 0.55–0.9], p = 0.004) (Fig. 1C), GRFS (HR = 0.76 [95%CI 0.62–0.94], p = 0.01) (Fig. 2C), and OS (HR = 0.74 [95%CI 0.56–0.97], p = 0.027) (Fig. 1D) compared to the no-IDH group. The presence of IDH2 mutation did not significantly impact NRM (HR = 1.05 (95%CI 0.74–1.48), p = 0.8) (Fig. 1B) or rate of chronic GVHD (HR = 0.87 [95%CI 0.68–1.11], p = 0.26) (Fig. 2B). IDH1 mutation was associated with a lower rate of grade II-IV acute GVHD (HR = 0.66 [95%CI 0.47–0.91], p = 0.011) (Fig. 2A) and an improved OS (HR = 0.68 [95%CI 0.48–0.94], p = 0.021) compared to no-IDH (Fig. 1D). The presence of IDH1 mutation did not significantly impact relapse (HR = 0.79 [95%CI 0.55–1.14], p = 0.2) (Fig. 1A), NRM (HR = 0.92 [95%CI 0.59–1.42], p = 0.71) (Fig. 1B), LFS (HR = 0.83 [95%CI 0.63–1.1]), p = 0.19) (Fig. 1C), GRFS (HR = 0.87 [95%CI 0.69–1.1], p = 0.25) (Fig. 2C), or chronic GVHD (HR = 0.87 [95%CI 0.65–1.17], p = 0.36) (Fig. 2C).

Table 3

Multivariate analysis of AML outcomes after allo-HCT
	RELAPSE		NRM		LFS		OS		GRFS		Acute GVHD II-IV		Acute GVHD III-IV		chronic GVHD		extensive chronic GVHD
	HR (95% CI)	p-value	HR (95% CI)	p value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p value	HR (95% CI)	p-value	HR (95% CI)	p-value
no IDH mutation (ref)	1		1		1		1		1		1		1		1		1
IDH1 mutation	0.79 (0.55–1.14)	0.2	0.92 (0.59–1.42)	0.71	0.83 (0.63–1.1)	0.19	0.68 (0.48–0.94)	0.021	0.87 (0.69–1.1)	0.25	0.66 (0.47–0.91)	0.011	0.65 (0.36–1.2)	0.17	0.87 (0.65–1.17)	0.36	1.04 (0.69–1.57)	0.84
IDH2 mutation	0.49 (0.34–0.7)	< 0.001	1.05 (0.74–1.48)	0.8	0.7 (0.55–0.9)	0.004	0.74 (0.56–0.97)	0.027	0.76 (0.62–0.94)	0.01	0.73 (0.56–0.96)	0.025	0.81 (0.51–1.28)	0.36	0.87 (0.68–1.11)	0.26	1.02 (0.72–1.45)	0.91
Age (per 10 year)	0.95 (0.86–1.06)	0.36	1.57 (1.33–1.86)	< 0.0001	1.11 (1.02–1.21)	0.013	1.24 (1.12–1.37)	< 0.0001	1.08 (1-1.16)	0.042	1.06 (0.96–1.17)	0.24	1.04 (0.88–1.23)	0.64	0.98 (0.9–1.06)	0.61	1.04 (0.92–1.17)	0.57
Adverse cytogenetics	1.88 (1.43–2.48)	< 0.0001	1.05 (0.73–1.52)	0.79	1.51 (1.22–1.87)	0.0002	1.56 (1.23–1.99)	0.0003	1.38 (1.14–1.66)	0.0009	1.17 (0.91–1.51)	0.21	1.2 (0.78–1.84)	0.4	1.07 (0.84–1.36)	0.57	1.34 (0.95–1.88)	0.094
FLT3-ITD	1.47 (1.05–2.04)	0.023	1.24 (0.83–1.86)	0.3	1.35 (1.05–1.75)	0.021	1.41 (1.05–1.88)	0.021	1.24 (0.99–1.54)	0.058	1.14 (0.86–1.5)	0.36	1.12 (0.67–1.86)	0.67	0.93 (0.71–1.22)	0.59	1.05 (0.71–1.54)	0.81
NPM1	0.72 (0.5–1.03)	0.069	0.9 (0.6–1.34)	0.6	0.78 (0.6–1.02)	0.073	0.8 (0.59–1.08)	0.15	0.79 (0.63–0.99)	0.04	1.03 (0.78–1.36)	0.81	0.65 (0.38–1.11)	0.12	0.98 (0.75–1.27)	0.87	1.01 (0.7–1.47)	0.94
MSD donor (ref)	1		1		1		1		1		1		1		1		1
UD	0.68 (0.51–0.91)	0.009	1.21 (0.8–1.83)	0.37	0.85 (0.67–1.07)	0.18	1.01 (0.77–1.33)	0.92	0.83 (0.68–1.01)	0.069	1.39 (1.04–1.86)	0.027	1.08 (0.66–1.77)	0.76	0.84 (0.66–1.08)	0.17	0.68 (0.49–0.97)	0.031
Haploidentical	0.61 (0.4–0.93)	0.021	1.26 (0.74–2.14)	0.4	0.81 (0.59–1.12)	0.2	0.87 (0.6–1.26)	0.46	0.7 (0.53–0.92)	0.011	1.23 (0.85–1.79)	0.27	0.99 (0.53–1.88)	0.98	0.71 (0.5–0.99)	0.046	0.39 (0.23–0.64)	0.0003
Female to male	0.88 (0.63–1.24)	0.47	1.03 (0.7–1.54)	0.87	0.95 (0.73–1.22)	0.67	0.93 (0.7–1.25)	0.63	0.93 (0.74–1.16)	0.53	0.95 (0.71–1.28)	0.75	1.04 (0.63–1.72)	0.87	1.38 (1.07–1.78)	0.013	1.11 (0.76–1.63)	0.59
KPS > = 90	0.91 (0.69–1.21)	0.52	0.62 (0.45–0.84)	0.002	0.76 (0.62–0.94)	0.011	0.66 (0.53–0.83)	0.0004	0.75 (0.62–0.9)	0.002	0.88 (0.69–1.12)	0.3	0.72 (0.47–1.09)	0.12	1.07 (0.84–1.36)	0.6	0.79 (0.56–1.12)	0.18
in vivo TCD	0.92 (0.69–1.24)	0.58	1.07 (0.75–1.55)	0.7	0.97 (0.77–1.21)	0.77	0.78 (0.61-1)	0.054	0.68 (0.55–0.84)	0.0004	0.75 (0.56-1)	0.052	0.78 (0.49–1.26)	0.31	0.78 (0.6–1.02)	0.07	0.39 (0.26–0.58)	< 0.0001
RIC vs MAC	1.12 (0.84–1.49)	0.44	1.18 (0.83–1.68)	0.36	1.17 (0.94–1.45)	0.17	1.17 (0.91–1.5)	0.21	1.1 (0.9–1.33)	0.36	1.14 (0.87–1.5)	0.33	0.82 (0.53–1.29)	0.4	1.12 (0.88–1.43)	0.36	1.15 (0.81–1.63)	0.43
Abbreviations: ref: referent group, NRM: non-relapse mortality, LFS: leukemia-free survival, OS: overall survival, GRFS: graft-versus-host disease-free, relapse-free survival, GVHD: graft-versus-host disease, HR: hazard ratio, CI: confidence interval, AML: acute myeloid leukemia, CR: complete remission, MSD: matched sibling donor, UD: unrelated donor, KPS: Karnofsky performance status, TCD: T cell depletion, RIC: reduced-intensity conditioning, MAC: myeloablative conditioning

Variables associated with increased risk of relapse were adverse risk cytogenetics (HR = 1.88 [95%CI 1.43–2.48], p < 0.0001), presence of FLT3-ITD mutation (HR = 1.47 [95%CI 1.05–2.04], p = 0.023), and use of a matched sibling donor (MSD) (unrelated donor [UD] vs MSD, HR = 0.68 [95%CI 0.51–0.91], p = 0.009; haploidentical vs. MSD (HR = 0.61 [95%CI 0.4–0.93], p = 0.021). NRM was higher in patients with older age (HR per 10-year increment = 1.57 [95%CI 1.33–1.86], p < 0.0001), and improved in patients with a KPS ≥ 90% (HR = 0.62 [95%CI 0.45–0.84], p = 0.002). LFS was worse in patients with older age (HR = 1.11 [95%CI 1.02–1.21], p = 0.013), adverse risk cytogenetics (HR = 1.51 [95%CI 1.22–1.87], p = 0.0002), and presence of FLT3-ITD mutation (HR = 1.35 [95%CI 1.05–1.75], p = 0.021), and improved in patients with KPS ≥ 90% (HR = 0.76 [95%CI 0.62–0.94], p = 0.011). OS was worse in patients with older age (HR = 1.24 [95%CI 1.12–1.37], p < 0.0001), adverse risk cytogenetics (HR = 1.56 [95%CI 1.23–1.99], p = 0.0003) and presence of FLT3-ITD mutation (HR = 1.41 [95%CI 1.05–1.88], p = 0.021), and improved in patients with KPS ≥ 90% (HR = 0.76 [95%CI 0.62–0.94], p = 0.011).

Subgroup analyses: Patients with NPM1-negative disease

In order to eliminate the positive effect of NPM1 mutation, we conducted a similar analysis in the group of patients with NPM1-negative disease (n = 1084, 71.6%). In the multivariate analysis of the mIDH1 group, there was a suggestion of improved OS (HR = 0.67 [95%CI 0.45–1.01], p = 0.058). Comparable to the entire cohort, presence of mIDH1 did not impact relapse (HR = 0.84 [95%CI 0.55–1.29], p = 0.43), NRM (HR = 0.82 [95%CI 0.47–1.44], p = 0.5), LFS (HR = 0.84 [95%CI 0.59–1.17], p = 0.3), or GRFS (HR = 0.86 [95%CI 0.64–1.14], p = 0.29). Similarly, the presence of IDH1 mutation decreased the risk of acute GVHD (HR = 0.65 [95%CI 0.43–0.99], p = 0.044). In the mIDH2 group, comparable results were observed pertaining to lower risk of relapse (HR = 0.57 [95%CI 0.38–0.84], p = 0.005), improved LFS (HR = 0.7 [95%CI 0.53–0.93], p = 0.013), OS (HR = 0.69 [95%CI 0.5–0.94], p = 0.02] and GRFS (HR = 0.78 [95%CI 0.61–0.99], p = 0.04). There was no impact on acute GVHD in the mIDH2, NPM1-negative subgroup (HR = 0.77 [95%CI 0.57–1.06], p = 0.11) (results not shown).

This study represents one of the largest series evaluating the prognostic impact of IDH1 and IDH2 mutations on the outcomes of patients with AML undergoing allo-HCT. Our data suggest that the presence of IDH1 or IDH2 mutation are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1. The impact of IDH1 and IDH2 mutations on outcomes of patients with AML has been inconsistent across studies. Meggendorfer et al. evaluated the outcomes of patients with IDH1 or IDH2 mutations compared to wild-type disease and found no difference in OS between presence or absence of IDH mutations (p = 0.976) (25). A more detailed analysis of subgroup mutations found that IDH2R172 mutation carries the best prognosis (p = 0.040). Similarly, Middeke et al. did not observe any difference in CR rate (p = 0.17), median relapse-free survival (RFS, p = 0.52) and OS (p = 0.58) between the IDH mutated and the wild-type groups. Yet, IDH mutational status was prognostic within the ELN2017 favorable risk group; the presence of IDH1/2 mutations was associated with worse OS compared to no-IDH mutations (p < 0.01) (26).

Several studies have reported improved outcomes of patients with IDH1/2 mutations in the setting of allo-HCT (20, 27). Kunadt et al. evaluated the impact of IDH1 and IDH2 mutations on outcomes of patients with AML. When comparing allo-HCT vs. no allo-HCT in CR1, IDH1R132C and IDH2R172 were associated with improved OS and RFS; IDH2R132C improved RFS. There was a trend towards improved OS with IDH1R132H and IDH2R132H. In the multivariate analysis, none of these mutations were associated with improved OS and RFS (20). These results support the role of allo-HCT in CR1 in mitigating the unfavorable prognostic impact of specific IDH mutation subgroups. Chen et al. reported outcomes for 112 patients with mIDH1/2 AML undergoing allo-HCT. They found an RFS of 58% in both mIDH1 and mIDH2 groups, with an OS of 74% for mIDH1 and 68% for mIDH2 groups (21). Our cohort demonstrated a slightly higher LFS (69.6% and 71.8%) and OS (76% and 79.3%) in the mIDH1 and mIDH2 groups, respectively. In contrast to the study reported by Salhotra et al. (19), which found no survival difference between the presence or absence of IDH mutations in the transplant setting, we observed an improved OS in patients carrying IDH1 or IDH2 mutations.

In the ALPHA study, Duchman et al. reported that the presence of IDH1 mutation was associated with a higher risk of relapse and reduced OS and IDH2R172 mutation was associated with a higher risk of early death, whereas, the co-occurrence of NPM1 mutation significantly improved OS (28). In contrast, our results of positive prognostic impact of IDH2 mutation remains consistent in the NPM1 wild-type subgroup, unlike IDH1 which showed only a favorable trend for improved outcomes in this subgroup. This observation suggests that IDH2 mutation independently confer a better prognosis on patients undergoing allo-HCT compared to patients with wild-type disease. The improved prognostic impact of IDH1 mutation may be potentially influenced by the presence of NPM1 mutation.

Interestingly, in the multivariate analysis, the presence of IDH1 mutation was associated with a significantly lower risk of acute GVHD. Similarly, the presence of IDH2 mutation was associated with a significantly lower risk of acute GVHD, relapse, LFS, and OS. This unexpected benefit of IDH1 and IDH2 mutation in relation to the observed low incidence of acute GVHD in our study remains unexplained. There was no difference between the two groups with respect to baseline transplant characteristics that could impact GHVD occurrence, including donor type, stem cell source, and conditioning intensity. PTCy was more frequently used in the no-IDH group, and typically associated with lower incidence of GVHD. We speculate that this could possibly be due to the role of IDH as a key enzyme in the glycosylation and metabolic pathways on T cell function leading to the detected effect on GVHD (29). Given the absence of any other explanation, further studies are warranted to investigate this finding.

Similar to previous reports, we observed a significant association between IDH1/2 mutations and the co-occurrence of NPM1, ASXL1, and DNMT3A mutations, but not FLT3-ITD. In a study by Meggendorfer et al., the majority of patients with AML had co-occurring mutations (n = 236, 67%) (25). The most frequent co-occurring mutation was NPM1 (48%), followed by DNMT3A (42%), SRSF2 (29%), FLT3-ITD (21%), and ASXL1 (16%). Interestingly, in patients with IDH1 and IDH2 mutation, the presence of NPM1 mutation significantly improved OS (25). Additionally, in patients with NPM1-positive disease, the presence of IDH2 mutation was associated with a decreased risk of relapse. Unlike prior studies, we observed a higher frequency of IDH1 and IDH2 mutations in our cohort (42%) compared to previous reports (10–20%) (14, 30). This discrepancy could be attributed to the selection bias of transplant-eligible patients rather than a population of newly diagnosed AML, thereby, excluding unfit patients for whom allo-HCT is not indicated.

In our study, we were able to evaluate the impact of MRD status on outcomes following allo-HCT. MRD positivity at the time of transplant was significantly associated with shorter LFS, highlighting the negative impact of MRD prior to allo-HCT on post-transplant outcomes. Conversely, Ravindra et al. did not show any prognostic impact of IDH MRD on leukemia relapse, RFS, and OS (31). However, it is important to note that the latter study had a limited number of relapsed cases, and patients had received IDH inhibitors pre- and post-allo-HCT, which could have mitigated the impact of MRD on post-transplant outcomes. These findings emphasize the need to investigate the role of maintenance IDH inhibitors, especially in patients with MRD-positive disease. Also, in the era of innovative artificial intelligence and machine learning, predictive models may hypothesize which patient would benefit most from this approach (32).

This study has certain inherent limitations due to its retrospective design. It is a registry study with lack of information on IDH inhibitor use pre- or post-allo-HCT and MRD measurement technique.

In conclusion, we found that IDH1 and IDH2, in addition to being targetable mutations, carry prognostic implications, leading to improved outcomes of patients with AML undergoing allo-HCT. Our study showed a lower risk of relapse, and improved LFS and OS in patients with IDH2 and improved OS in patients with IDH1 mutated AML following allo-HCT, compared to patients without IDH mutations. Further studies investigating allo-HCT outcomes in IDH1 and IDH2 mutated patients with AML in the era of IDH inhibitors (both in the pre- and post-transplant setting) would help define the impact of these mutations in this setting and thus optimize an individualized treatment approach.

Contribution

RM wrote the manuscript, RM and MM designed the study, ML performed the statistical analysis, all authors reviewed its final version and were the principal investigators at the centers recruiting the highest number of patients into the study.

Acknowledgment: No source of funding.

Authors contributions: RM wrote the manuscript, RM and MM designed the study, ML performed the statistical analysis. All the authors reviewed its final version. Co-authors were the principal investigators at the centers recruiting the highest number of patients into the study.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Sources of funding: The authors declare no sources of funding

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Isocitrate Dehydrogenase (IDH) 1 and 2 Mutations Predicts Better Outcome in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation: a study of the ALWP of the EBMT

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Abstract

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Introduction

Materials and Methods

Study Design and Eligibility Criteria

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Statistical Methods

RESULTS

Patients and disease characteristics

IDH1, IDH2 and co-occurring mutations

Engraftment and GVHD

Survival Outcomes

Subgroup analyses: Patients with NPM1-negative disease

DISCUSSION

CONCLUSION

Declarations

References

Additional Declarations

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