ABSTRACT
Background
GATA binding protein 2 (GATA2) plays a crucial role in the differentiation, proliferation, and maintenance of hematopoietic stem cells (HSCs). GATA2 mutations have been identified in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but the impact of somatic GATA2 mutations on prognosis remains controversial, especially on patients who undergo allogeneic hematopoietic stem cell transplantation (allo‐HSCT).
Objectives
The aim of this retrospective case–control study was to explore the prognostic significance of somatic GATA2 mutations in MDS/AML patients who underwent allo‐HSCT.
Study Design
Propensity score matching (PSM) analysis was used to match patients with wild‐type GATA2 as the control group (ratio 1:3). A total of 14 patients with somatic GATA2 mutations and 39 patients with wild‐type GATA2 were enrolled.
Results
The baseline characteristics were comparable between the two groups. However, patients with GATA2 mutations had a higher frequency of WT1 mutations and relapse rate (p = 0.036 and p = 0.008, respectively). Compared to patients with wild‐type GATA2, patients with GATA2 mutations had shorter progression‐free survival (PFS) and overall survival (OS), and post‐transplant PFS (p < 0.001, p = 0.030, and p = 0.004, respectively). Subgroup analysis showed that the PFS, OS, post‐transplant PFS, and OS of patients with GATA2 non‐zinc finger domain 1 (non‐ZF1) mutations (p < 0.001, p = 0.004, p < 0.001, and p = 0.049, respectively), but not those of patients with somatic GATA2 ZF1 mutations, were shorter than that of patients with wild‐type GATA2. Moreover, somatic GATA2 mutations and WBC count ≥ 20.86 × 109/L were independent adverse prognostic factors for PFS (p = 0.005 and p = 0.020, respectively). Relapse before transplantation was an independent adverse prognostic factor for OS (p = 0.009).
Conclusions
Our preliminary study revealed that somatic GATA2 mutations, especially non‐ZF1 mutations, may be associated with unfavorable outcomes in patients with MDS/AML, even for patients who underwent allo‐HSCT.
Keywords: allogeneic stem cell transplantation, GATA2 non‐zinc finger 1 mutation, myeloid malignancy, prognosis, somatic GATA2 mutations
1. Introduction
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are highly heterogeneous hematopoietic stem cell (HSC) disorders, both classified as myeloid malignancy [1, 2]. AML is characterized by extensive genomic changes and molecular mutations [3]. MDS are characterized by peripheral blood (PB) cell reduction, ineffective hematopoiesis, bone marrow (BM) dysplasia, and high risk of AML transformation [2].
The differentiation, proliferation, and malignant transformation of hematopoietic stem cells are closely regulated by a variety of transcription factors. According to previous studies, the occurrence of AML and MDS is related to mutations in transcription factors, such as RUNX1 and CEBPA [4]. GATA binding protein 2 (GATA2), another hematopoietic transcription factor belonging to the GATA family, is located at chromosome 3q21 and encodes a hematopoietic zinc finger transcription factor essential for the development and maintenance of HSC [5]. Somatic GATA2 mutation clusters are most frequently found in the zinc finger 1 (ZF1) domain and ZF2 domain [6]. ZF1 mutations are the most common in AML patients [7]. Hahn et al. [8], Mansour et al. [9], and other studies [10] found that germline GATA2 mutations are associated with predisposition to MDS and AML as well as other syndromes, such as monocytopenia and mycobacterial infection (MonoMAC) syndrome and dendritic cells, monocytes, and B and NK lymphoid cells (DCML) syndrome [9], which have a tendency to develop AML and MDS. In addition, somatic GATA2 mutations have also been reported in patients with AML or MDS [11, 12]. During the disease progression, the original GATA2 mutation may be lost, and new GATA2 mutations may emerge in patients with wild‐type GATA2 at relapse [13, 14].
However, the prognostic impact of GATA2 mutations and overexpression in AML and MDS [13, 15, 16] remains controversial. Hou et al. [13] found that GATA2 mutations are associated with favorable prognosis in AML patients. Tien et al. [14] revealed that patients with GATA2 ZF1 mutations had not only better overall survival (OS) and disease‐free survival (DFS) but also a significantly higher frequency of CEBPA double mutations compared with patients with GATA2 ZF2 mutations. Although others report adverse prognostic implications, Vicente et al. [15] demonstrated that both GATA2 mutations and high expressions predict an adverse prognosis in AML patients. Zhu et al. [17] suggested that there were no significant differences in OS and DFS between patients with and without GATA2 mutations. A recent meta‐analysis [18] revealed that GATA2 mutations are a negative prognostic factor for OS and event‐free survival (EFS) in MDS/AML patients. Therefore, further exploration of the role of somatic GATA2 mutations is of great significance for the precise guidance and treatment of myeloid malignancy. Furthermore, only a small number of patients who received allo‐HSCT were included in the above‐mentioned studies. The role of somatic GATA2 mutations in HSCT remains unclear. Given this, we conducted a retrospective case–control study to investigate the prognostic significance of somatic GATA2 mutations in patients diagnosed with MDS/AML who underwent HSCT.
2. Patients and Methods
2.1. Patients
Clinical data from Peking University First Hospital's medical database from March 2015 and September 2024 was retrospectively analyzed. The inclusion criteria for the study were as follows: (1) diagnosis of a myeloid neoplasm according to the WHO criteria [19]; (2) confirmation of somatic GATA2 mutation at diagnosis by Next‐generation sequencing (NGS); (3) receipt of chemotherapy and allo‐HSCT; and (4) adequate follow‐up. Fourteen patients with somatic GATA2 mutations were enrolled in this study. Based on the mutation pattern, somatic GATA2‐mutated cases were classified into two subgroups: ZF1 and non‐ZF1. Propensity score matching (PSM) analysis with a 1:3 matching ratio was used to select matched patients with wild‐type GATA2 as the control group. The propensity score was calculated using a linear regression model, including age, sex, WBC count, ASXL1 mutation, CEBPA‐bZIP mutation, RUNX1 mutation, NPM1 mutation, and TP53 mutation. A 1:3 matching ratio was applied, and the caliper width was set at 0.03. Finally, 39 patients with wild‐type GATA2 were included as the control group. The median age at diagnosis of patients with somatic GATA2 mutations was 43 years (range, 17–65 years). Among the 14 patients, 78.6% (11/14) were male and 21.4% (3/14) were female. In contrast, the median age at diagnosis of patients with wild‐type GATA2 was 38 years (range, 15–64 years). Among the 39 patients, 64.1% (25/39) were male and 35.9% (14/39) were female. The research was in compliance with the Declaration of Helsinki and approved by the ethics committee of the Peking University First Hospital.
2.2. Chemotherapy Regimens
Most patients received induction chemotherapy with the standard “7 + 3” regimen, consisting of a 3‐day course of an anthracycline combined with a 7‐day course of cytarabine. Other chemotherapy regimens included HAA (homoharringtonine, aclarubicin, cytarabine), CAG (aclarubicin, cytarabine, granulocyte colony‐stimulating factor [G‐CSF]), and VA (venetoclax plus azacitidine). Central nervous system leukemia (CNSL) was regularly monitored, and prophylactic lumbar puncture with intrathecal chemotherapy, including cytarabine, methotrexate, and dexamethasone, was performed.
2.3. Conditioning Regimen, Stem Cell Source, and GVHD Prophylaxis and Diagnosis
Regarding the conditioning regimen, 43 patients received a modified Bu/Flu regimen (busulfan 3.2 mg/kg/day for 3 days; fludarabine 200 mg/m2 total dose), 8 patients received a modified Bu/Cy regimen (cytarabine 2 g/m2/day for 3 days; busulfan 3.2 mg/kg/day for 3 days; cyclophosphamide 1.8 g/m2/day for 2 days), and 2 patients received a modified Cy/TBI regimen (cytarabine 2 g/m2/day for 3 days; cyclophosphamide 1.8 g/m2 for 2 days; total body irradiation 10 Gy administered over 2 days). During the conditioning period, ganciclovir was administered as prophylaxis for cytomegalovirus (CMV) reactivation at a dose of 10 mg/kg/day for 7–10 days. One patient died during the conditioning phase. Among the remaining 52 patients, 39 received grafts containing both bone marrow (BM) and peripheral blood stem cells (PBSCs), 12 received grafts of PBSCs alone, and 1 patient received umbilical cord blood. A total of 47 patients (90.38%) received stem cells from related donors, including 12 with HLA‐matched donors and 35 with HLA‐mismatched donors.
Female‐to‐male transplantation was performed in 12 cases. The GVHD prophylaxis consisted of cyclosporin (CsA), mycophenolate mofetil (MMF), and a short course of methotrexate (MTX). The dose of CsA was 3 mg/kg/day and was adjusted according to the blood concentration of 150–250 ng/mL. The dose of MMF was 0.5 g twice daily from the conditioning regimen to day +30 after transplantation. MTX was given 15 mg/m2 at day +1, 10 mg/m2 at day +3, +5, +11. ATG was administered in cases involving unrelated or HLA‐mismatched donors, with a total cumulative dose ranging from 7.5 to 10 mg/kg. The diagnosis of aGVHD was based on clinical criteria, and the severity was graded from I to IV using a standardized system that evaluates three principal organs (skin, gastrointestinal tract, and liver) [20]. The diagnosis and grading of cGVHD were based on the traditional grading criteria [21] and the latest NIH grading system [22].
2.4. Follow‐Up and Statistical Analysis
The definition of complete remission (CR), relapse, partial remission (PR), no response (NR) followed the recommended criteria [3]. Stable disease (SD) was defined as patients who did not receive chemotherapy before transplantation and whose disease did not progress. Measurable residual disease (MRD) assessment was performed in all patients after induction chemotherapy and after each subsequent chemotherapy cycle, before hematopoietic stem cell transplantation, and monthly during the first year following transplantation. MRD was evaluated by multicolor flow cytometry, real‐time quantitative PCR (qPCR), and next‐generation sequencing (NGS), with sensitivities of approximately 10−4, 10−4–10−5, and up to 10−5, respectively. For GATA2, MRD monitoring was conducted using NGS. MRD negativity was defined as the absence of detectable disease by the most sensitive method available at the corresponding time point. Progression‐free survival (PFS) was defined as the time from diagnosis to relapse, death from any cause, or last follow‐up. Overall survival (OS) was defined as the time from diagnosis to last follow‐up or death from any cause. Post‐transplant PFS was defined as the time from allo‐HSCT to relapse, death from any cause or last follow‐up. Post‐transplant OS was defined as the time from allo‐HSCT to last follow‐up or death from any cause. SPSS software was used for statistical analyses. The Chi‐squared test or Fisher's exact test was used to analyze categorical variables. The independent Samples t‐test or Mann–Whitney U test was used to analyze continual variables. Kaplan–Meier method was used to estimate PFS, OS, Post‐transplant PFS, and Post‐transplant OS. The log‐rank test was used to compare the differences between groups. The Cox's proportional hazard model was used for univariate and multivariate analysis of risk factors for survival. Variables with a p value < 0.05 in univariate analysis were included in the multivariable model. All tests were two‐sided, and a p‐value < 0.05 was regarded as statistically significant.
3. Results
3.1. Clinical Characteristics of the Patients at Diagnosis
The clinical features of all enrolled patients are summarized in Table 1. A total of 53 patients diagnosed with myeloid neoplasms were included in the study. Of these, 14 patients harbored GATA2 mutations at the time of diagnosis, whereas the remaining 39 patients exhibited wild‐type GATA2. The distribution of somatic GATA2 mutation subtypes is presented in Table 2.
TABLE 1.
Clinical characteristics of all patients.
| GATA2‐mutation (n = 14) | GATA2 wild‐type (n = 39) | p | |
|---|---|---|---|
| Age, median (range) | 43 (17–65) | 38 (15–64) | 0.597 |
| Sex, n (%) | 0.508 | ||
| Male | 11 (78.6) | 25 (64.1) | |
| Female | 3 (21.4) | 14 (35.9) | |
| BM blasts, median range (%) | 56.5 (5.0–91.0) | 62 (2–93.5) | 0.968 |
| WBC, median (109/L) | 17.4 (1.7–117.9) | 18.3 (1.3–267.8) | 0.701 |
| HB (g/L) | 102 (49–137) | 90 (36–144) | 0.609 |
| PLT (109/L) | 28.5 (11–125) | 46.0 (7.0–233) | 0.711 |
| ELN risk classification, n (%) | 0.876 | ||
| Favorable | 7 (50.0) | 17 (43.6) | |
| Intermediate | 3 (21.4) | 8 (20.5) | |
| Adverse | 4 (28.6) | 14 (35.9) | |
| WT1 mutation, n (%) | 0.036 | ||
| No | 10 (71.4) | 37 (94.8) | |
| Yes | 4 (28.6) | 2 (5.1) | |
| CEBPA‐bZIP mutation, n (%) | 0.426 | ||
| No | 10 (71.4) | 33 (84.6) | |
| Yes | 4 (28.6) | 6 (15.4) | |
| RUNX1 mutation, n (%) | 0.999 | ||
| No | 13 (92.9) | 34 (87.2) | |
| Yes | 1 (7.1) | 5 (12.8) | |
| NPM1 mutation, n (%) | 0.999 | ||
| No | 11 (78.6) | 32 (82.1) | |
| Yes | 3 (21.4) | 7 (17.9) | |
| ASXL1 mutation, n (%) | 0.660 | ||
| No | 13 (92.9) | 33 (84.6) | |
| Yes | 1 (7.1) | 6 (15.4) | |
| TP53 mutation, n (%) | 0.264 | ||
| No | 13 (92.9) | 39 (100) | |
| Yes | 1 (7.1) | 0 (0) | |
| Remission state before allo‐HSCT, n (%) | 0.008 | ||
| CR1 | 2 (14.3) | 16 (41.0) | |
| CR2 | 2 (14.3) | 11 (28.2) | |
| Relapse | 7 (50.0) a | 3 (7.7) a | |
| PR/SD/NR | 3 (21.4) | 9 (23.1) | |
| MRD before allo‐HSCT, n (%) | 0.410 | ||
| MRD negative | 4 (28.6) | 16 (41.0) | |
| MRD positive | 10 (71.4) | 23 (59.0) |
Abbreviations: allo‐HSCT, allogeneic hematopoietic stem cell transplantation; BM, bone marrow; CR1, first complete remission; CR2, second complete remission; HB, hemoglobin; MRD, measurable residual disease; NR, no response; PLT, platelet; PR, partial remission; SD, stable disease; WBC, white blood cell.
p‐value < 0.05 between the two groups.
TABLE 2.
The mutation pattern of 14 patients with somatic GATA2 mutations at diagnosis.
| UPN | Age/sex | Type of diseases | Location | GATA2mutation | Other accompanied gene mutations | Survival | ||
|---|---|---|---|---|---|---|---|---|
| DNA change | VAF (%) | Protein change | ||||||
| 1 | 55/M | AML | exon4, ZF1 | c.944TA | 44.56 | p.Leu315Gln | CEBPA a , WT1, KIT | live |
| 2 | 17/M | AML | exon4, ZF1 | c.962 T > C | 41.88 | p. Leu321Pro | CEBPA a , SAMD9 | live |
| 3 | 65/M | MDS | exon3, other | c.359_374dupCCTTCTCCAAGACGCC | 14.26 | p. His127fs | BCOR, ETNK1, RUNX1 | die |
| 4 | 52/M | AML | exon5, other | c.1114G > A | 8.35 | p. Ala372Thr | FLT3 | live |
| 5 | 36/F | AML | exon6, other | c.1162AG | 10.64 | p. Met388Val | no | live |
| 6 | 41/F | AML | exon5, other | c.1032_1033insCG | 3.37 | p. Ala345fs | KRAS | live |
| 7 | 26/M | AML | exon3, other | c.490G>A | 48.31 | p. Ala164Thr | CEBPA a , NF1, WT1, IKZF1, EP300, TP53 | die |
| 8 | 35/M | AML | exon4, ZF1 | c.953C>T | 37.80 | p. Ala318Val | CEBPA a , CUX1 | die |
| 9 | 50/M | AML | _, other | c.1104_1106dup | 41.00 | p.V369dup | NRAS, DNMT3A, WT1, NPM1 | live |
| 10 | 51/M | AML | exon5, other | c.A1052T | 46.57 | p.N351I | DNMT3A, NPM1, WT1, FLT3‐TKD | die |
| 11 | 45/F | AML | exon2, other | c.C187G | 51.20 | p.P63A | DNMT3A, IDH1 | die |
| 12 | 49/M | MDS | exon2, other | c.1160_1177del | 32.23 | p.387_393del | ASXL1, KRAS, NRAS, U2AF1 | die |
| 13 | 27/M | MDS → AML | exon4, ZF1 | c.C1384G | 10.44 | p.A890G:p.N297S | NRAS, WT1 | live |
| 14 | 39/M | AML | exon5, ZF1 | c.1024G> A | 46.08 | p. Ala342Thr | no | live |
Abbreviations: AML, acute myeloidleukemia; F, female; M, male; MDS, myelodysplastic syndromes; VAF, variant allele frequency; ZF1, zinc finger 1.
CEBPA double‐mutated.
Germline GATA2 mutation.
The median white blood cell (WBC) count was 17.4 × 109/L (range, 1.7–117.9 × 109/L) in the GATA2 mutation group and 18.3 × 109/L (range, 1.3–267.8 × 109/L) in the wild‐type GATA2 group. The median bone marrow (BM) blast percentage was 56.5% (range, 5.0%–91.0%) in patients with somatic GATA2 mutations and 62.0% (range, 2.0%–93.5%) in those with wild‐type GATA2. Concomitant CEBPA‐bZIP mutations were identified in 4 patients in the GATA2 mutation group and 6 patients in the wild‐type group. ASXL1 mutations were detected in 1 patient in the GATA2 mutation group and 6 patients in the wild‐type group. A TP53 mutation was observed in 1 patient with a GATA2 mutation. According to the European Leukemia Net (ELN) risk classification, 7 patients with GATA2 mutations were classified as favorable risk, 3 as intermediate risk, and 4 as adverse risk. In the wild‐type group, 17 patients were classified as favorable risk, 8 as intermediate risk, and 14 as adverse risk. Patients with GATA2 mutations had a higher frequency of WT1 mutations (p = 0.036). No significant differences were observed between the two groups in terms of clinical and laboratory characteristics at diagnosis, including age, sex, WBC count, bone marrow blast percentage, ELN risk classification, or the presence of mutations such as CEBPA‐bZIP, RUNX1, ASXL1, and TP53.
3.2. Treatment and Treatment Outcome Pre‐Transplantation
A total of 49 patients received chemotherapy following diagnosis. Most underwent induction chemotherapy of idarubicin‐cytarabine (IA) or daunorubicin‐cytarabine (DA). The median time from diagnosis to transplantation was 5.1 months, during which patients received a median of 3 cycles of chemotherapy. Among patients with GATA2 mutations, 2 achieved first complete remission (CR1), 2 achieved second complete remission (CR2), 7 experienced disease relapses, 1 remained refractory to treatment, and 2 developed central nervous system leukemia (CNSL). In contrast, among patients with wild‐type GATA2, 16 achieved CR1, 11 achieved CR2, 3 relapsed, 2 remained refractory, and 4 developed CNSL. Patients with GATA2 mutations had a significantly higher incidence of relapse compared with those with wild‐type GATA2 (p = 0.008).
3.3. Allogeneic Stem Cell Transplantation
Details of allogeneic stem cell transplantation are summarized in Table 3. One patient died during the conditioning phase before transplantation. Consequently, 52 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). Within 30 days after transplantation, 3 patients died from transplant‐related complications, including severe infection (n = 2) and intracranial hemorrhage (n = 1). Among the remaining 49 patients, including 12 with GATA2 mutations and 37 with wild‐type GATA2, 40 received a busulfan–fludarabine (Bu/Flu) conditioning regimen, while 9 received busulfan–cyclophosphamide (Bu/Cy) or total body irradiation (TBI)–based regimens. Stem cell sources included HLA‐matched sibling donors (n = 12; 1 in the GATA2 mutation group and 11 in the GATA2 wild‐type group), matched unrelated donors (n = 3; all in the GATA2 wild‐type group), and haploidentical donors (n = 34).
TABLE 3.
The characteristics of allogenic stem cell transplantation.
| GATA2‐mutation (n = 14) | GATA2 wild‐type (n = 39) | p | |
|---|---|---|---|
| Donor, n (%) | 0.999 | ||
| Related | 12 (92.3) | 35 (89.9) | |
| Unrelated | 1 (7.7) | 4 (10.3) | |
| Donor sex, n (%) | 0.747 | ||
| Male | 8 (61.5) | 26 (66.7) | |
| Female | 5 (38.5) | 13 (33.3) | |
| Donor age, median (range) | 26 (7–51) | 36 (8–59) | 0.484 |
| Donor/recipient gender, n (%) | 0.254 | ||
| Female to male | 1 (7.7) | 11 (28.2) | |
| Others | 12 (92.3) | 28 (71.8) | |
| HLA matching, n (%) | 0.112 | ||
| HLA‐matched | 1 (7.7) | 14 (35.9) | |
| others | 12 (92.3) | 25 (64.1) | |
| Transplantation conditioning regimens | 0.522 | ||
| Bu/Flu | 10 (71.4) | 33 (84.6) | |
| Bu/Cy | 3 (21.4) | 5 (12.8) | |
| Cy/TBI | 1 (7.2) | 1 (2.6) | |
| Cell source, n (%) | 0.282 | ||
| PB | 5 (38.5) | 7 (17.9) | |
| PB + BM | 8 (61.5) | 31 (79.5) | |
| PB + Cord blood | 0 (0) | 1 (2.6) | |
| Total MNC count, median (108/kg) | 10.9 (4.1–16.5) | 10.7 (4.5–20.3) | 0.161 |
| Total CD34+ cell count, median (106/kg) | 5.5 (2.7–10.5) | 4.8 (2.4–11.8) | 0.886 |
| WBC implantation, median (d) | 12 (10–20) | 11 (9–25) | 0.082 |
| PLT implantation, median (d) | 14 (10–106) | 15 (11–47) | 0.782 |
| aGVHD, n (%) | 0.521 | ||
| no | 5 (38.5) | 19 (48.7) | |
| yes | 8 (61.5) | 20 (51.3) | |
| cGVHD, n (%) | 0.729 | ||
| no | 8 (61.5) | 28 (71.8) | |
| yes | 5 (38.5) | 11 (28.2) |
Abbreviations: aGVHD, acute graft‐versus‐host disease; BM, bone marrow; Bu, busulfan; cGVHD, chronic graft‐versus‐host disease. Cy, cyclophosphamide; Flu, fludarabine; MNC, mononuclear cell; PB, peripheral blood; PLT, platelet; TBI, total body irradiation; WBC, white blood cell.
The median mononuclear cell (MNC) counts of grafts were 10.9 × 108/kg in the GATA2 mutation group and 10.7 × 108/kg in the wild‐type group. The median CD34+ cell counts were 5.5 × 106/kg and 4.8 × 106/kg, respectively. The median neutrophil engraftment time was day +12 in the GATA2 mutation group and day +11 in the wild‐type group, while the median platelet engraftment time was day +14 and day +15, respectively. The cumulative incidence of acute graft‐versus‐host disease (aGVHD) was 61.5% in patients with GATA2 mutations and 51.3% in those with wild‐type GATA2. The incidence of chronic graft‐versus‐host disease (cGVHD) was 38.5% and 48.7%, respectively. No significant differences were observed between the two groups in terms of MNC count, CD34+ cell count, neutrophil or platelet engraftment time, or the incidence of aGVHD or cGVHD.
3.4. Treatment Outcome and Long‐Term Follow‐Up
The median follow‐up time for all 53 patients was 73.8 months (range, 2.9–106.0 months) from diagnosis. Among patients with somatic GATA2 mutations, the median progression‐free survival (PFS) was 6.9 months (95% CI, 4.5–9.2 months), and the median overall survival (OS) was 28.8 months (95% CI, 0.0–63.7 months). In contrast, the median PFS and OS were not reached in the wild‐type GATA2 group because of the limited number of events.
Patients with GATA2 mutations had significantly worse PFS and OS than those with wild‐type GATA2 (p < 0.001 and p = 0.030, respectively; Figure 1A,B). Subgroup analyses further demonstrated inferior PFS in both the GATA2 ZF1 and non‐ZF1 mutation subgroups (p = 0.017 and p < 0.001, respectively; Figure 1C), as well as worse OS in the non‐ZF1 mutation subgroup (p = 0.004; Figure 1D) compared with patients with wild‐type GATA2.
FIGURE 1.
The impact of somatic GATA2 mutations on survival outcomes in patients with myeloid neoplasms following allo‐HSCT. (A) Progression‐free survival (PFS) and (B) overall survival (OS) in patients with somatic GATA2 mutations compared to those with wild‐type GATA2. (C) PFS and (D) OS stratified by somatic GATA2 mutation status, including patients with somatic GATA2 ZF1 mutations, somatic GATA2 non‐ZF1 mutations, and wild‐type GATA2. (E) Post‐transplant PFS and (F) OS in patients with somatic GATA2 mutations compared to those with wild‐type GATA2. (G) Post‐transplant PFS and (H) OS stratified by somatic GATA2 mutation status, including patients with somatic GATA2 ZF1 mutations, somatic GATA2 non‐ZF1 mutations, and wild‐type GATA2.
The median follow‐up time for the 49 patients was 70.1 months (range, 1.4–100.1 months) after allo‐HSCT. Among patients with GATA2 mutations, the median post‐transplant PFS and OS were 12.9 months (95% CI, 5.8–19.9 months) and 47.0 months (95% CI, 2.9–91.0 months), respectively. In contrast, the median post‐transplant PFS and OS were not reached in the wild‐type GATA2 group. Patients with GATA2 mutations had significantly shorter post‐transplant PFS than those with wild‐type GATA2 (p = 0.004; Figure 1E). Subgroup analyses further showed that patients with GATA2 non‐ZF1 mutations had significantly worse post‐transplant PFS and OS compared with those with wild‐type GATA2 (P < and p = 0.049, respectively; Figure 1G,H).
3.5. Analysis of the Prognostic Factors
Univariate analysis showed that somatic GATA2 mutations (hazard ratio [HR], 7.43; 95% CI, 2.81–19.66; p < 0.001), WBC count ≥ 20.86 × 109/L (HR, 2.95; 95% CI, 1.10–7.89; p = 0.031), relapse before transplantation (HR, 19.59; 95% CI, 4.11–93.4; p < 0.001), and MRD positivity (HR, 3.64; 95% CI, 1.05–12.58; p = 0.041) were significantly associated with poorer PFS. GATA2 mutations (HR, 3.12; 95% CI, 1.06–9.21; p = 0.039) and relapse before transplantation (HR,19.93; 95% CI, 2.43–163.31; p = 0.039; Table 4) were also associated with worse OS. Multivariate analysis confirmed that GATA2 mutations (HR, 7.23; 95% CI, 1.83–28.96; p = 0.005) and WBC count ≥ 20.86 × 109/L (HR, 3.61; 95% CI, 1.22–10.71; p = 0.020) were independent adverse prognostic factors for PFS. Relapse before transplantation was an independent adverse prognostic factor for OS (HR, 22.76; 95% CI, 2.21–234.88; p = 0.009).
TABLE 4.
Univariate and Multivariate analysis of the prognosis of acute myeloid leukemia patients.
| Univariate analysis | multivariate analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| PFS (n = 53) | ||||||
| GATA2 mutation | 7.43 | 2.81–19.66 | < 0.001 | 7.23 | 1.83–28.96 | 0.005 |
| WBC count ≥ 20.86 × 109/L | 2.95 | 1.10–7.89 | 0.031 | 3.61 | 1.22–10.71 | 0.020 |
| Remission state before allo‐HSCT | < 0.001 | |||||
| CR1 | 1 | |||||
| CR2 | 4.23 | 0.82–21.80 | 0.085 | |||
| Relapse | 19.59 | 4.11–93.4 | < 0.001 | |||
| PR/SD/NR | 1.76 | 0.25–12.50 | 0.572 | |||
| MRD positive | 3.64 | 1.05–12.58 | 0.041 | |||
| OS (n = 53) | ||||||
| GATA2 mutation | 3.12 | 1.06–9.21 | 0.039 | |||
| Remission state before allo‐HSCT | 0.010 | 0.048 | ||||
| CR1 | 1 | 1 | ||||
| CR2 | 4.53 | 0.47–43.59 | 0.191 | 4.587 | 0.48–44.17 | 0.187 |
| Relapse | 19.93 | 2.43–163.31 | 0.005 | 22.76 | 2.21–234.88 | 0.009 |
| PR/SD/NR | 5.29 | 0.55–50.92 | 0.149 | 5.33 | 0.55–51.25 | 0.148 |
| Post‐transplant PFS (n = 49) | ||||||
| GATA2 mutation | 5.86 | 1.50–22.88 | 0.011 | |||
Abbreviations: allo‐HSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CR1, first complete remission; CR2, second complete remission; HR, hazard ratio; MRD, measurable residual disease; NR, no response; OS, overall survival 1; PFS, progression‐free survival 1; PR, partial remission; SD, disease stable.
For post‐transplant outcomes, univariate analysis identified GATA2 mutations as a significant adverse factor for post‐transplant PFS (HR, 5.856; 95% CI, 1.50–22.88, p = 0.011). No other variables were significantly associated with post‐transplant PFS or OS (Table 5).
TABLE 5.
Univariate and multivariate analysis of the prognosis of acute myeloid leukemia patients with post‐transplantation.
| Univariate analysis (n = 60) | multivariate analysis (n = 60) | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| GATA2 mutation (yes vs. no) | 4.499 | 1.530–13.234 | 0.006 | |||
| TP53 mutation (yes vs. no) | 8.714 | 1902–39.918 | 0.005 | |||
| Remission state before allo‐HSCT | 0.008 | |||||
| CR1 | 1 | |||||
| CR2 | 6.686 | 0.747–59.841 | 0.089 | |||
| Relapse | 20.206 | 3.441–265.188 | 0.002 | |||
| PR/SD/NR | 7.185 | 0.803–64.323 | 0.078 | |||
| MRD (positive vs. negative) | 10.860 | 1.420–83.082 | 0.022 | |||
| GATA2 mutation (yes vs. no) | 3.093 | 1.122–8.529 | 0.029 | |||
| TP53 mutation (yes vs. no) | 7.225 | 1.591–32.816 | 0.01 | |||
| Remission state before allo‐HSCT | 0.047 | |||||
| CR1 | 1 | |||||
| CR2 | 1.538 | 0.384–6.153 | 0.547 | |||
| Relapse | 6.166 | 1.596–23.818 | 0.008 | |||
| PR/SD/NR | 1.653 | 0.233–3.723 | 0.478 | |||
Abbreviations: allo‐HSCT, allogeneic hematopoietic stem cell transplantation; CR1, first complete remission; CR2, second complete remission; MRD, measurable residual disease; NR, no response; OS2, overall survival 2; PFS2, progression‐free survival 2; PR, partial remission; SD, disease stable.
4. Discussion
In this study, we investigated the clinical and prognostic significance of somatic GATA2 mutations in adult patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We found that patients harboring somatic GATA2 mutations had significantly worse progression‐free survival (PFS) and overall survival (OS) compared with those with wild‐type GATA2. In addition, GATA2 mutations were associated with a higher relapse rate and a higher frequency of WT1 mutations. Subgroup analyses further suggested that non‐ZF1 GATA2 mutations were particularly associated with inferior survival outcomes after transplantation. These findings indicate that somatic GATA2 mutations may represent an adverse prognostic factor in transplanted AML patients.
Zhu et al. [17] reported that AML patients harboring FLT3 and NPM1 mutations showed elevated GATA2 expression, although the complete remission (CR) rate did not differ between the high‐ and low‐expression groups after induction chemotherapy. A clinical trial that enrolled 89 patients with single CEBPA and 113 patients with double CEBPA mutations reported that the CR rate was comparable between GATA2‐mutated and GATA2‐unmutated patients [11]. A study [13] showed that AML patients harboring GATA2 mutations tended to have higher CR rates and lower relapse rates compared to those without GATA2 mutations. The notable observation in their study was that many patients with GATA2 mutations also harbored favorable prognostic genetic alterations, such as NPM1 mutations and biallelic CEBPA (CEBPA‐bZIP) mutations.
To more accurately assess the independent prognostic impact of GATA2 mutations, we performed a propensity score matching analysis (1:3), adjusting for key clinicopathological and molecular variables, including age, sex, white blood cell (WBC) count, ASXL1 mutation status, CEBPA‐bZIP mutation status, RUNX1 mutation status, NPM1 mutation status, and TP53 mutation status.
Our study cohort included 14 patients with GATA2 mutations, among whom 2 were diagnosed with MDS and 1 with AML evolving from MDS. Of these 14 cases, one patient carried a concurrent TP53 mutation, and four harbored double CEBPA mutations. Additionally, five patients carried mutations located in the GATA2 zinc‐finger 1 (ZF1) domain. No significant differences were observed in baseline clinical or demographic characteristics between the GATA2‐mutated group and the wild‐type group. Contrary to previous studies, patients with somatic GATA2 mutations had a higher rate of WT1 mutations and disease relapse. These findings suggest that patients with somatic GATA2 mutations may represent a high‐risk subgroup, highlighting the need for improved therapeutic strategies.
Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is an important therapeutic strategy for patients with intermediate‐ to high‐risk myeloid malignancies. However, the impact of allo‐HSCT on the clinical outcomes of individuals harboring GATA2 mutations remains unclear. Jørgensen et al. [23] reported that the majority of patients with symptomatic GATA2 deficiency require allo‐HSCT, which is associated with a relatively favorable safety profile. Grossmann et al. [24] demonstrated that GATA2 mutations remained significantly associated with overall survival even when transplanted cases were censored at the time of transplantation. However, Tien et al. reported that allo‐HSCT in CR1 for ZF1‐mutated patients did not offer a survival benefit compared with post‐remission chemotherapy alone [14].
All patients underwent allo‐HSCT in our study. There were no significant differences in baseline characteristics between the two groups, including donor age, donor/recipient sex, HLA matching, conditioning regimens, stem cell source, total mononuclear cell (MNC) count, CD34+ cell count, median time to neutrophil or platelet engraftment, or incidence of aGVHD and cGVHD.
Most importantly, we describe the association between somatic GATA2 mutations and post‐transplant survival outcomes. In our study, prognosis analysis after allo‐HSCT was performed in 12 patients with GATA2 mutations and 37 patients without such mutations. We found that patients with somatic GATA2 mutations who survived more than 1 month post‐allo‐HSCT had significantly shorter PFS and OS compared with those without GATA2 mutations. Subgroup analysis revealed that patients with GATA2 zinc‐finger domain 1 (ZF1) mutations had comparable survival outcomes to patients without GATA2 mutations. However, patients with non‐ZF1 GATA2 mutations exhibited significantly worse PFS and OS compared with those with wild‐type GATA2. Our findings differ from those reported by Grossmann et al. [24], which may be because their study population was restricted to individuals with CEBPA mutations. This discrepancy highlights the need for further research in this patient population and underscores the importance of investigating pretreatment strategies to better inform clinical decision‐making.
In addition, our analysis demonstrated that GATA2 mutations and WBC count ≥ 20.86 × 109/L were independent adverse prognostic factors for PFS. Relapse before transplantation was an independent adverse prognostic factor for OS. However, these factors were not significantly associated with post‐transplant survival outcomes, possibly because of the limited sample size. Therefore, further investigation in larger cohorts is warranted to validate these findings.
5. Conclusions
Our study demonstrates that GATA2 mutations may exert an adverse effect on both progression‐free survival (PFS) and overall survival (OS) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Moreover, patients harboring GATA2 mutations could exhibit poorer clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo‐HSCT). These findings indicate that GATA2 mutation status may serve as a relevant prognostic indicator in the context of myeloid malignancies and support the need for the development of more effective therapeutic strategies for this high‐risk patient subgroup. However, given the retrospective design, relatively small sample size, and long enrollment period of this study, further prospective investigations with larger cohorts are warranted to validate the clinical significance of GATA2 mutations and to refine risk stratification in patients with myeloid neoplasms.
Author Contributions
Xian Zhang: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, writing – original draft. Bingjie Wang: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, writing – original draft. Yujun Dong: conceptualization, resources, project administration. Qian Wang: investigation, project administration, resources, data curation. Na Han: investigation, project administration, resources. Qingya Wang: data curation, investigation, project administration, resources. Qingyun Wang: investigation, project administration, data curation, resources. Yuan Li: conceptualization, data curation, funding acquisition, methodology, project administration, supervision, writing – review and editing. Jialin Zhu: data curation, resources, project administration, investigation.
Funding
This work was supported by National Natural Science Foundation of China, 81970410 Beijing Natural Science Foundation, 7202203 The Beijing Municipal Science and Technology Commission, Z221100007422008 National High Level Hospital Clinical Research Funding, 2023YC02 China University Industry‐University‐Research Innovation Fund (2023GY002).
Ethics Statement
The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board at Peking University First Hospital (No. 2023–279).
Consent
Due to the retrospective nature of the study, the requirement for written informed consent was waived. All data used in this manuscript were anonymized to ensure patient confidentiality.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
This work was financially supported by National Natural Science Foundation of China (No. 81970410); Beijing Natural Science Foundation (No. 7202203); The Beijing Municipal Science and Technology Commission (No. Z221100007422008); National High Level Hospital Clinical Research Funding (Youth Clinical Research Project of Peking University First Hospital, 2023YC02); China University Industry‐University‐Research Innovation Fund (2023GY002).
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.