Hereditary myeloid malignancies (HMMs) are myeloid neoplasms that arise in individuals with germline mutations associated with increased risk of myeloid malignancies. The first report of HMMs were published in 1861, although the causality remained unclear (1); HMMs had been considered an extremely rare disease for a long time. In 1999, germline RUNX1 mutation was identified, for the first time, as the genetic background of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). Subsequent advent of next-generation sequencing (NGS) era unraveled HMMs as much more manifold and common diseases than considered earlier (2–6). In 2016, HMMs were defined as “myeloid neoplasms with germline predisposition” in the revised fourth edition of the World Health Organization (WHO) classification of myeloid neoplasms (7), and were renamed as “myeloid neoplasms associated with germline predisposition” in the fifth edition of WHO classification (8). Candidate genes associated with HMMs, such as GATA2, CEBPA, ETV6, ANKRD26, SAMD9, and SAMD9L, have been discovered subsequently (9). Recent reports have shown that approximately 5–10% of patients with hematological malignancy carry a germline variant (10). However, the penetrance is not 100% in HMMs, since not all patients with a germline variant develop hematological malignancy. Moreover, de novo germline variant may occur where an obvious family history could be lacking. Some cases with HMMs are often elderly-onset, especially in individuals with germline DDX41 mutations (11). Therefore, the accurate and prompt diagnosis of HMMs is often challenging.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative intervention for HMMs. However, the optimal strategy for HSCT, including indication, timing, donor selection, conditioning regimen, and toxicity management has not been fully elucidated yet. Although many guidelines recommend HSCT for HMMs, data regarding transplant outcome are highly limited (12). In this manuscript, we reviewed the pathophysiology, clinical characteristics, and recent evidence regarding HSCT for HMMs. The review focused on adult-onset HMMs, which often get involved with solitary adult myeloid malignancies in clinical practice. Some child-onset hereditary disorders are beyond the scope of the current review, and the relevant guidelines should be perused in that regard.

In general, HMMs are classified into three groups ( Table 1 ), namely (1) myeloid neoplasms with germline predisposition and pre-existing platelet disorder (RUNX1, ANKRD26, and ETV6), (2) myeloid neoplasms with germline predisposition and potential organ dysfunction (GATA2, SAMD9, SAMD9L, etc.), and (3) myeloid neoplasms with germline predisposition without a preexisting platelet disorder or organ dysfunction (CEBPA and DDX41). Four representative genes responsible for adult-onset HMMs, namely RUNX1, GATA2, CEBPA, and DDX41, are described in detail below.

Considering the low prevalence of hematological neoplasms, family history of hematological disorder is a key circumstantial evidence of HMMs, and mutation analysis should be done; however, it should be noted that lack of family history cannot deny the possibility of HMMs completely (53). Patients with signs/symptoms indicative of HMMs and those younger than 50 years should undergo genetic testing (12). However, considering the frequent absence of family history and the elderly onset in patients with germline DDX41 mutations (51), genetic tests can be also applied for patients older than 50 years old.

Genetic testing of non-hematological tissue is the standard option to confirm the diagnosis of HMMs, and the most authorized method is a culture of fibroblasts obtained from a skin biopsy (54, 55). Although the technique can avoid contamination of blood cells, it is complicated, and buccal swab, nails, or hair roots are often used as alternatives (21).

In addition, if NGS panel in clinical sequencing detects a suspected mutation with variant allele frequency close to 50 or 100%, further testing should be done. Mutations remaining in hematologic complete remission (CR) also suggested the possibility of germline origin (37), although clonal hematopoiesis (CH) can as well persist (56, 57). The NGS panel approaches are able to efficiently identify single nucleotide variants and small insertion/deletion in target region, but can overlook copy number variants or loss of heterozygosity (58–60). Especially when the patient could be a candidate for HSCT, early diagnosis of HMMs is important, since the diagnosis can affect donor selection, as described below.

There is mostly no evidence about first-line therapy about HMMs and the optimal treatment strategies for HMMs have not been sufficiently established. However, in general, patients with HMMs, who developed myeloid malignancies, are treated as the patients with sporadic myeloid malignancies, i.e., intensive chemotherapy for fit patients with AML and using demethylating agents for patients with MDS (21). Targeted therapy can also be administered when adequate molecular target is available, although specific data for HMMs are not yet available. Whether chemosensitivity in patients with HMMs is different from that in sporadic cases is unclear, except that CR rate of patients with AML having germline DDX41 mutations after induction chemotherapy was higher than that of patients with wild-type DDX41 (94% vs. 69%) (16). More vigorous studies to explore the suitable initial treatment strategies are warranted.

The suitable indication and timing of HSCT is still unclear. However, in general, long-term remission can only be obtained by allogeneic HSCT, and HSCT should be considered soon after diagnosis of myeloid malignancy, except for cases with germline CEBPA mutations (61).

For patients with AML having a germline CEBPA mutation, HSCT in CR1 is not routinely recommended because of modest survival outcome after chemotherapy and the risk of morbidity and mortality after HSCT (12, 21, 45). However, the appropriateness of refraining from HSCT in CR1 has not been sufficiently validated yet, because prospective and/or controlled studies are still lacking due to the rarity of the disease. Considering the high relapse rate and/or secondary leukemia development after chemotherapy (14), availability of a suitable donor, low dose intensity/density of chemotherapy due to side effects, and development of safer HSCT strategy may rationalize HSCT in CR1. In addition, prognostic impact of the mutation site has been reported in sporadic AML with CEBPA mutation (62, 63). Clinical consequences of CEBPA mutation site in AML with germline mutation should be clarified, although it is difficult due to the remarkable rarity of C-terminal CEBPA germline mutation.

Prophylactic HSCT before transformation is another strategy, but it is not commonly performed due to the risk of morbidity and mortality. However, different from other HMMs, GATA2 deficiency can be treated with HSCT before transformation. Although optimum timing and indication of HSCT in GATA2 deficiency is still unclear, frequent/severe infection and serious organ damage, such as pulmonary function, can be a trigger for launching HSCT (64). Norwegian nationwide survey revealed that approximately 80% of patients with symptomatic GATA2 deficiency need HSCT (65).

In cases with a germline variant but without cytopenia and/or dysplasia, bone marrow should be assessed at the time of diagnosis, and be followed every six months or every year (53).

HSCT from a donor with predisposition to myeloid malignancy should be withheld due to the risk of donor cell leukemia (DCL) (66–68). DCL is a rare post-HSCT complication and cumulative incidence has been estimated to be approximately 0.16-0.70% 15 years after HSCT (69, 70). The exact incidence of DCL in HMMs setting is unknown, but Williams et al. reviewed 19 DCL cases with genetic sequencing results and at least three of them had germline predisposing mutations (71); it suggested significant proportion of DCLs to have been derived from donors with germline mutation.

Related donor candidates of patients with HMMs should undergo genetic testing as well as HLA typing; importantly, genetic counseling before testing is also essential (12). When only a matched related donor with predisposing germline mutation is available and the relapse risk without HSCT is very high, there is no consensus about necessary and sufficient condition of the donor because the quantitative risk of DCL has not been clarified.

Genetic testing of a donor might add fuel to the problems. Gibson et al. had shown donor CH to be associated with improved recipient survival due to reduced relapse risk (70). They also showed donor DNMT3A-CH to be associated with lower relapse risk and superior survival only when post-transplant cyclophosphamide (PT-CY) GVHD prophylaxis was not used. The situation is more complicated, since Crysandt et al. suggested germline predisposition to be extended to polymorphisms (21). Inamoto et al. had reported the association between donor/recipient polymorphisms and the risk of sclerotic GVHD after HSCT (72). Should a donor candidate test HLA, germline predisposition, CH, and polymorphisms? The obligation of the bona fide donor is large, and exploration of the “perfect” donor can reduce donor availability. Suitable biomarkers for quantitative evaluation of the relevant risks are highly required.

Among alternative donors, comparison between umbilical cord blood (UCB) and haploidentical donor remains a matter of debate (73). In most patients with HMMs, little evidence exists about alternative donor selection. However, in patients with GATA2 deficiency, Grossman et al. reported poor outcome of UCB transplantation (73) and Nichols-Vinueza et al. reported excellent outcome of haploidentical transplantation with PT-CY GVHD prophylaxis (74). At least in HSCT for GATA2 deficiency, haploidentical transplantation with PT-CY may be more suitable compared with UCB transplant.

There is no recommended conditioning regimen yet specific for patients with HMMs. In general, adult patients with HMMs are younger than patients with sporadic myeloid malignancies, and myeloablative conditioning can be applied in more cases than in sporadic cases. However, reduced intensity conditioning is preferred in patients with GATA2 deficiency due to comorbidities such as concomitant infections and PAP (73).

High-dose total body irradiation (TBI)-regimens are avoided in cases with germline DNA damage response gene mutations due to the risk of second cancer after HSCT. For example, in patients with Fanconi anemia, non-TBI- or low dose-TBI (4 Gy)-containing regimens are usually employed (75). Although some categories of HMMs, such as Fanconi anemia and Li-Fraumeni syndrome, indicate high-risk feature (19, 76), the risk of second cancer after HSCT in most patients with HMMs is unclear, and further accumulation of cases would be necessary to answer these questions.

In patients with myeloid neoplasms and germline predisposition without potential organ dysfunction (i.e., patients with germline mutation in RUNX1, DDX41, CEBPA and so on), no specific complication after HSCT has been reported till date. However, there is no prospective as well as large-scale retrospective study which focus on transplant complications in patients with HMMs; therefore, we have limited data about post-HSCT complications in HMMs and future studies in these settings are necessary.

Adult patients with germline predisposition and potential organ dysfunction practically refer to patients with GATA2 deficiency, since nearly all patients with SAMD9/SAMD9L germline mutations, i.e. MIRAGE syndrome and Ataxia pancytopenia syndrome, are diagnosed and treated in their childhood (23). For HSCT in patients with GATA2 deficiency, variable comorbidities could complicate the transplantation procedures. For example, many patients with GATA2 deficiency suffer from nontuberculous mycobacteria (NTM) and human papillomavirus (HPV) infections in their clinical courses. However, previous reports had suggested that reactivation of NTM during HSCT could be quite rare under appropriate antimycobacterial therapy up to at least three months after transplantation (73). Drug interaction between calcineurin inhibitors (CIs) and anti-NTM drugs might affect the concentration of CIs (77), and hepatic toxicity due to anti-NTM drugs should also be noted. Reactivation of HPV after HSCT seems to be also rare (73). Patients with GATA2 deficiency frequently develop PAP, which can cause severe respiratory failure. Early HSCT may be better for lower post-HSCT morbidity and mortality in patients with PAP, although pulmonary dysfunction can also be corrected to some extent after HSCT (73, 78).

Nichols-Vinueza et al. reported the outcome of 59 HSCT recipients with GATA2 deficiency and compared transplant outcome based on GVHD prophylaxis (PT-CY vs. tacrolimus and methotrexate-based prophylaxis). PT-CY resulted in a significantly reduced incidence of grade III–IV acute GVHD (0 vs. 32%) and moderate-to-severe chronic GVHD (9 vs. 42%) without increase of relapse (0 vs. 5.2%) compared to that in patients who were administered tacrolimus and methotrexate-based prophylaxis (74). PT-CY may be a promising HSCT strategy in patients with GATA2 deficiency, although the exact mechanism of deteriorating GVHD is still unclear. Hofmann et al. comparatively analyzed the transplant outcomes of pediatric patients with GATA2 deficiency with those of patients without, and revealed that neurologic toxicities (six of 15 cases) and thrombotic events (eight out of 15 cases) were more common in patients with GATA2 deficiency, although the underlying mechanism is uncertain (79). The risk of acute and chronic GVHD was not different based on the existence of germline GATA2 mutation, and second malignancy was rare with a median follow up of nearly six years after HSCT.

Most reports about HMMs are case reports and case series, and large-scale prospective study of HSCT outcome for HMMs is lacking. Even retrospective analysis is highly limited due to its rarity ( Table 2 ).

Since the prevalence of patients with germline DDX41 mutations is relatively high among patients with HMMs, retrospective comparison of patients with and without germline DDX41 mutations using large-scale data of some clinical trials was recently reported by Duployez et al.; 191 patients with AML having DDX41 germline mutations and 1,604 DDX41 wild-type patients with AML were compared (16). Interestingly, AML with germline DDX41 mutation displayed a specific relapse kinetics, with a lower short-term relapse rate and higher late relapse risk. Some previous reports had suggested apparently favorable outcomes in AML with germline DDX41 mutations (11, 51, 80); however, long-term follow up may be necessary to evaluate the genuine prognosis of AML with germline DDX41 mutations. Regarding the role of HSCT, Duployez et al. showed that HSCT in first CR for AML with germline DDX41 mutation may contribute to the suppression of late relapse, although OS was not significantly different (16).

Transplantation outcomes in GATA2 deficiency have been prospectively analyzed in some clinical trials (73, 74, 78), perhaps because the unique clinical features promoted participation in clinical trials. Many of the studies on GATA2 deficiency included tens of patients, mostly children, adolescents, or young adults. In children and adolescents, OS and disease-free survival (DFS) after HSCT in bone marrow failure, MDS, or AML in patients with GATA2 deficiency were 65% and 51%, and those were comparable to the values in patients without GATA2 deficiency (81). Other studies also reported good survival rate after HSCT; four- or five-year OS was 78–93% (64, 74). However, reported HSCT outcomes for GATA2 deficiency should be interpreted with caution, since the proportion of MDS with high-risk features, such as monosomy 7, and severity of concomitant organ dysfunction can affect the outcomes.

Transplant outcomes for FPD-MM, AML with germline CEBPA mutations, and other HMMs have not been reported yet, and HSCT outcomes of patients with sporadic relevant mutations still need to be extrapolated. Waidhauser et al. analyzed 674 patients with AML, who underwent HSCT in first CR (RUNX1 mutation; positive 183, negative 491). Two-year overall survival (OS) was not significantly different between RUNX1 mutation-positive and -negative (67.7 vs 66.1%, p = 0.7). Considering the poor prognosis of AML with RUNX1 mutation (33), HSCT in first CR was considered to overcome the unfavorability. In patients with AML having somatic biallelic CEBPA mutations and having underwent HSCT, five-year OS was 71.8%, which was not significantly different from that in patients with AML having somatic biallelic CEBPA mutations and receiving consolidation chemotherapy alone (82).

We summarized the concurrent available reports about HSCT in patients with HMMs. Although HMMs have recently been noticed more widely, there is too little evidence about recipients as well as donors. Increasing awareness of HMMs would ensure better management by physicians, which could surely improve patient outcomes.

TT wrote the manuscript. HH and YH critically revised the paper and approved the final version. ND supervised the study. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.