Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)

INTRODUCTION — Inherited bone marrow failure syndromes (IBMFS) are rare disorders characterized by varying degrees of bone marrow failure (BMF), predisposition to hematologic malignancies and solid tumors, a range of congenital abnormalities, and other features. The four most common syndromes are Fanconi anemia (FA) and dyskeratosis congenita (DC), which are caused by aberrant DNA repair, and Diamond-Blackfan anemia (DBA) and Shwachman-Diamond syndrome (SDS), which are associated with disordered ribosome assembly and/or function. Allogeneic hematopoietic cell transplantation (HCT) can cure hematologic aspects of IBMFS, but it does not correct the various nonhematologic manifestations. There are distinctive aspects of selecting a graft donor, the conditioning regimen, and other aspects of management and surveillance for patients who will undergo HCT for an IBMFS.

This topic discusses allogeneic HCT for FA, DC, DBA, and SDS.

Indications for HCT in these conditions and selection of transplantation versus other available treatments are discussed in the individual IBMFS topics.

●(See "Management and prognosis of Fanconi anemia".)

●(See "Dyskeratosis congenita and other telomere biology disorders".)

●(See "Shwachman-Diamond syndrome".)

●(See "Diamond-Blackfan anemia".)

PRETRANSPLANT EVALUATION — Patients with a known or suspected IBMFS should be evaluated at a medical center experienced with that disorder and with allogeneic HCT for IBMFS.

A multidisciplinary team should include experts in potentially affected organs (eg, dermatology, dentistry, gastroenterology, medical genetics, otolaryngology, pulmonary) and should include visual, hearing, endocrine, nutritional, and neuropsychologic evaluation.

Clinical and laboratory — History and physical examination should evaluate both hematologic and non-hematologic manifestations, especially liver and lung disorders that might affect tolerance for transplantation conditioning or increase the risk for late complications.

Pretransplant evaluation for all patients with IBMFS should include [1]:

●History and examination – History and physical examination should consider findings associated with the specific IBMFS.

•Family history should seek to identify relatives who may share the patient's condition and genotype. These syndromes are often clinically heterogeneous, may have variable penetrance, and manifestations can differ between the patient and relatives with the same genotype. These features may be relevant to donor selection, as discussed below. (See 'Matched sibling donor choice' below.)

Family history should review hematologic manifestations, somatic features, lung and liver disease, hematologic malignancies, and solid tumors in family members.

•Medications – Androgens and/or glucocorticoids are often used to ameliorate cytopenias associated with IBMFS. Doses, duration, and adverse effects of androgens (eg, virilization, growth problems, liver dysfunction) and glucocorticoids (eg, Cushing's syndrome, hyperglycemia, hypertension, immunosuppression, metabolic syndrome, avascular necrosis, adrenal insufficiency) should be reviewed.

•Hematology – The duration and severity of cytopenias and prior evidence of clonality, including progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), should be assessed.

The number and type of transfusions, serum ferritin levels, liver and cardiac iron levels by magnetic resonance imaging (MRI), and chelation history should be obtained to assess possible iron overload. Alloimmunization and presence of donor-specific antibodies should be evaluated.

•Lifestyle – Smoking and alcohol consumption, oral hygiene, sunscreen use, diet, and exercise should be reviewed, as appropriate.

•Fertility – Options for fertility preservation should be considered prior to HCT. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

•Details of clinical manifestations of the specific syndromes are described separately:

-(See "Clinical manifestations and diagnosis of Fanconi anemia".)

-(See "Dyskeratosis congenita and other telomere biology disorders".)

-(See "Diamond-Blackfan anemia".)

-(See "Shwachman-Diamond syndrome".)

●Laboratory – Laboratory studies include:

•Complete blood count (CBC), differential, and reticulocyte count

•Coagulation studies – Prothrombin time (PT) and partial thromboplastin time (PTT)

•Chemistries – Serum electrolytes, glucose, kidney function (ie, creatinine, blood urea nitrogen [BUN]), liver function tests (eg, transaminases, fractionated bilirubin)

●Bone marrow examination – Evaluation should include microscopy, cytogenetics, and molecular studies and flow cytometry to assess for early dysplastic changes and emergence of clonality, myelodysplasia, or leukemia.

●Other studies are guided by the clinical condition, and may include:

•Cardiac function – Echocardiogram, cardiac MRI, or rarely, radionuclide ventriculogram to assess ejection fraction and other measures of myocardial function

•Pulmonary function tests  

•Imaging should be guided by clinical findings. As examples:

-Substantial transfusion history – We obtain MRI of the chest and abdomen for patients with significant history of transfusions (eg, ≥20 units of red blood cells) to examine iron overload of the liver, heart, or other organs. Especially for patients with Diamond-Blackfan anemia, we perform MRI regardless of the level of serum ferritin, as it can be an insensitive test and pretransplantation chelation therapy for patients with iron overload can avert transplant-related morbidity.

-Organomegaly or unexplained fever – Computed tomography (CT) of the abdomen and/or chest may be useful for identifying a cause for organomegaly or fever.

-Abnormal neurologic findings – MRI can be useful for assessment of abnormal findings on neurologic examination.

Some centers routinely perform brain MRI and/or magnetic resonance angiography (MRA) in patients with FA to evaluate pituitary/brain or central nervous system (CNS) vascular malformations.

•Lumbar puncture (LP) should be performed for children with abnormal neurologic examination and/or CNS imaging.

Identification of a suitable donor — The search for a transplant donor should be initiated promptly. It should begin with evaluations of siblings, but it may require a search for unrelated donors and other alternate graft sources. (See 'Graft' below.)

Testing family members — Family members who are potential graft donors must be carefully evaluated to determine if they carry the same pathogenic variant (ie, mutation) as the transplant recipient [2-5]. Evaluation of potential donors should include:

●Clinical evaluation for the patient's IBMFS. Most IBMFS are detected in children or adolescents, but these syndromes are increasingly first recognized in children and adults with an atypical presentation, manifestations that differ from the transplant recipient, or genetic testing of a seemingly unaffected relative of a patient.

●Mutation testing – Potential donors must be tested for the pathogenic variant associated with the patient's syndrome; it is reasonable to limit genetic testing to the specific abnormality found in the transplant candidate. Implications of identifying the pathogenic variant in potential donors are discussed below. (See 'Matched sibling donor choice' below.)

Details of genetic testing are discussed in the individual IBMFS topics.

●HLA typing – Matching donor and recipient human leukocyte antigen (HLA) types is discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

Databases for unrelated donors — Unless a suitable HLA-matched related (sibling) donor is identified promptly, a preliminary search for an unrelated donor should be initiated.

Evidence-based guidelines for optimal selection of unrelated donors and umbilical cord blood (UCB) donors are available from the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research (CIBMTR) [6]. The NMDP Office of Patient Advocacy can be reached at 1-888-999-6743 or a preliminary search request form can be submitted through the NMDP website. Other United States-based and international registries are available.

Eligibility for HCT — Details of the clinical and laboratory assessment, pretransplant counseling, and eligibility for allogeneic HCT are discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Pretransplant assessment'.)

GENERAL CONSIDERATIONS — HCT in an individual with an IBMFS requires aspects of preparation, management, and surveillance that differ from transplantation in other patients. It must be understood that HCT can cure the hematologic disorders associated with an IBMFS, but it does not correct and may exacerbate the non-hematologic manifestations, such as associated organ dysfunction, cancer risk, or somatic abnormalities.

For all patients with an IBMFS, the potential for cure with HCT must be balanced against the natural history of that condition and the short-term and long-term toxicity of transplantation. The decision to pursue transplantation must be individualized, with consideration of the current clinical status; likelihood of disease progression and complications of the underlying IBMFS; transplant-related risks, including effects on growth and development, graft-versus-host disease (GVHD), endocrine dysfunction, and exacerbation of cancer risk; and the patient's/family's wishes. These decisions should be made in consultation with specialists at a center experienced with the specific disorder and with transplantation for IBMFS.

The most robust and long-standing data for transplantation with IBMFS come from patients with Fanconi anemia. Many of the general considerations about transplantation that follow are drawn from the experience with HCT for Fanconi anemia; where indicated, data are derived from HCT for dyskeratosis congenita or other IBMFS.

Graft — A suitable transplant donor can be identified for nearly all patients with an IBMFS. For patients who do not have a suitable sibling donor, alternative donor sources can provide outcomes that approach those of a sibling donor.

Donor — For patients with a human leukocyte antigen (HLA)-matched sibling donor (MSD), we suggest an MSD graft, rather than an alternative donor graft. No randomized trial has directly compared these graft sources, but outcomes with MSD grafts are similar or superior to those using alternative donor grafts in retrospective and prospective studies, as discussed below. (See 'Outcomes with MSD grafts' below.)

Matched sibling donor choice — It is important to assess potential donors for the presence of the same pathogenic variant (ie, inherited mutation) as the transplant recipient. (See 'Testing family members' above.)

●Selection of an MSD donor – The response to the detection of the pathologic variant varies with the specific IBMFS:

•Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC) – DBA and some DC pathologic variants can act as dominant traits. Patients who carry the pathologic variant should be excluded as donors, to avoid reconstituting the marrow with the same condition.

•Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS) – FA and SDS act as recessive traits, as do some DC variants, so a sibling who is heterozygous for the pathogenic variant (ie, a carrier) is generally acceptable as a transplant donor.

If multiple acceptable sibling donors are identified, selection should favor an individual in good health and of the same sex as the patient (to lessen immunologic mismatch) and should consider cytomegalovirus (CMV) serologic status of donor and recipient. Occasionally, a sibling donor may not be appropriate because of poor health, indeterminate IBMFS genotype status, or absence of consent/assent to donate. For patients without an HLA-matched sibling, extended family searches occasionally identify another relative who is HLA-matched. Consideration of age, sex, and CMV status of the donor is discussed separately. (See "Donor selection for hematopoietic cell transplantation", section on 'CMV status'.)

In some cases, pre-implantation genetic diagnosis (PGD) has been used to select an embryo from in vitro fertilization (IVF) to provide an MSD graft [7,8]. However, a survey of North American FA support group members reported that only one-third of families were aware of this option [9]. The need for IVF/PGD has diminished with improved outcomes using alternative donor sources. (See 'Alternative donors' below.)

Outcomes with MSD grafts — Five-year overall survival (OS) is approximately 90 percent with MSD HCT for patients with FA. Historically, survival with MSD grafts was superior to alternative donor grafts, but outcomes with alternative donors now approach those with MSD HCT.

The following studies compared outcomes with MSD versus alternative donor grafts for patients with FA:

●A retrospective single institution study (2009 to 2014) reported that outcomes were comparable for recipients of MSD grafts versus alternative donor grafts [10]. For 17 recipients of MSD grafts, five-year OS (94 percent [95% CI 65-99 percent]) did not differ significantly from that of 57 recipients from an alternative donor (86 percent [95% CI 74-93 percent]). There was also no difference in engraftment, infectious complications, or GVHD between MSD and alternative donor grafts.

●A large registry study reported superior survival for 211 recipients of MSD grafts versus 179 with matched unrelated donor (MUD) grafts for transplants performed between 2000 and 2009 [11]. Compared with MUD grafts, OS for recipients of MSD grafts was superior at one year (83 percent [95% CI 76-88 percent] versus 68 percent [95% CI 61-75 percent]) and at five years (76 percent [95% CI 70-83 percent] versus 64 percent [95% CI 57-72 percent]). There was no difference in engraftment, chronic GVHD (cGVHD), or non-relapse mortality (NRM), but grade ≥2 acute GVHD (aGVHD) at day 100 was lower with MSD (19 percent [95% CI 13-24 percent] versus 36 percent [95% CI 28-43 percent]).

Studies of HCT for other IBMFS included too few patients to make valid comparisons between outcomes with MSD and alternative donors. Transplant outcomes for specific disorders are described below. (See 'Specific disorders' below.)

Alternative donors — For patients who do not have a suitable MSD, we suggest a MUD graft, rather than a mismatched unrelated donor (mMUD), umbilical cord blood (UCB) graft, or haploidentical donor. No prospective studies have directly compared these sources for transplantation in IBMFS and it is difficult to compare outcomes across different studies, but graft failure and GVHD generally increase with greater immunologic mismatch and with UCB grafts. There is more experience with MUD for HCT with IBMFS than other alternative sources.

When a suitable MUD graft is not available, the next choice of graft is guided by institutional preferences and experience.

●Alternative donor options:

•Matched unrelated donor – MUD is defined by 8/8 or 10/10 allele-based HLA-matched compatibility at the HLA-A, -B, -C, -DQ, and -DRB1 loci. MUD grafts are generally associated with low rates of graft failure and acceptable rates of GVHD. (See "Donor selection for hematopoietic cell transplantation", section on 'HLA gene haplotypes'.)

•Mismatched unrelated donor – An HLA-mismatched unrelated donor should be ≥8 of 10 HLA match, but mMUD grafts are associated with a high risk for GVHD.

•Umbilical cord blood – It is important to select a UCB unit with an adequate cell dose (>3 x 10⁷ nucleated cells/kg body weight of recipient) and ≥5/6 HLA-match (using antigen level typing for HLA A and B, and allele level typing for HLA DRB1). Even with adequate cell doses, UCB grafts are prone to graft failure and GVHD.

•Haploidentical donors – There is limited experience with haploidentical grafts for HCT with IBMFS. Post-transplantation cyclophosphamide (PTCy) is regularly employed to prevent GVHD with haploidentical grafts in other transplant settings (ie, for non-IBMFS conditions). However, caution is necessary in using PTCy for transplantation with IBMFS because FA and other DNA repair disorders are especially vulnerable to alkylating agents and require dose adjustment [12].  

●Outcomes with alternative donor grafts – Advances in donor selection, graft manipulation (eg, T cell depletion), and GVHD management have dramatically improved outcomes with alternative grafts.

As discussed above, outcomes using alternative donor grafts now approach those using MSD grafts. (See 'Matched sibling donor choice' above.)

•Various alternative graft sources:

-A prospective multicenter study reported 80 percent three-year OS for 45 patients with FA who received an alternative donor graft; one-quarter of the patients had already progressed to myelodysplastic syndrome (MDS) prior to HCT [13]. All grafts were CD34-selected/T cell-depleted; MUD was the graft source for 56 percent, while the remainder received mMUD (31 percent) or mismatched related (13 percent) grafts. Outcomes were not reported according to the type of graft. No patients developed grade ≥3 GVHD.

-A single institution study reported 86 percent five-year OS and 7 percent cGVHD for 57 patients with FA who were transplanted with alternative donor grafts, including 32 with mMUD and 20 with UCB sources [10]. Outcomes with an alternative graft source were similar to those for patients who received MSD grafts, but the study did not compare outcomes between various alternative donor sources.

•UCB grafts – A registry study reported outcomes of 64 patients transplanted with UCB grafts for IBMFS, other than FA [14]. For patients who received a related UCB graft, three-year OS was 95 percent and cumulative incidence of cGVHD was 11 percent. By contrast, those who received an unrelated UCB graft had 61 percent three-year OS and 53 percent cGVHD. Three-year OS was related to graft dose; 81 percent for ≥6.1 x 10⁷ nucleated cells/kg body weight versus 37 percent for lower doses.

A single institution study reported that nine patients with FA who received an unmanipulated matched related UCB graft had 89 percent three-year OS, 11 percent had grade ≥3 aGVHD at day 100, and none had cGVHD [15]. The same institution reported that using unrelated UCB grafts (three with 6/6 HLA-match, 15 with 5/6 HLA-match, and two with 4/6 HLA-match) in 20 patients with FA, three-year OS was 71 percent, 84 percent engrafted, and grade ≥3 aGVHD or cGHVD developed in 10 and 12 percent, respectively [15].

•Haploidentical grafts – In a report of haploidentical HCT using PTCy in 26 patients with FA, one-year OS was 73 percent; there were high rates of GVHD, cytomegalovirus reactivation, and hemorrhagic cystitis [16]. In a study of 12 patients with FA who received CD34+ selected haploidentical grafts, five-year OS was 83 percent, 25 percent had graft failure, and none had grade ≥3 cGVHD [17].

Source — We consider either bone marrow or peripheral blood stem/progenitor cells (PBSPC) acceptable as the graft source for transplantation, based on comparable survival. Some studies of transplantation for IBMFS have reported differences in the incidence of GVHD or secondary cancers according to graft source, but the effects have been inconsistent across studies.

GVHD has been associated with increased incidence of secondary cancers in patients with FA and DC [11]. In transplantation for acquired aplastic anemia in children, bone marrow has been associated with less GVHD than PBSPC [18,19]. However, for HCT with IBMFS, there is no consistent difference in survival, GVHD, or cancer incidence according to the graft source.

In a registry study that included 795 patients transplanted for FA, compared with marrow grafts, PBSPC grafts were associated with more secondary cancers (hazard ratio [HR] 3.29; 95% CI 1.30-8.35) [11]. Graft source was not independently associated with OS, incidence of GVHD, NRM, or engraftment. Solid tumors (especially squamous cell carcinoma) accounted for 89 percent of all secondary malignancies in this report.

Dose — For bone marrow grafts, transplantation should use >3 x 10⁸ total nucleated cells/kg of recipient body weight [20]. For UCB grafts, the dose should be >3 x 10⁷ total nucleated cells/kg; if the UCB cell dose is inadequate, supplemental bone marrow may be added. These dose thresholds are based on expert opinion and have not been rigorously tested.

T cell depletion — T cell depletion can reduce the incidence of GVHD with all donor types, but it is typically avoided for UCB grafts and when the patient has developed MDS or leukemia prior to HCT. Preferred methods vary between institutions and may differ according to the graft or donor source.

T cell depletion can be achieved by in vivo methods or ex vivo techniques.

●Ex vivo T cell depletion – Ex vivo CD34+ enrichment (ie, positive selection for CD34+ nucleated cells) depletes most T cells, while permitting limited add-back of T cells (eg, ≤1 x 10⁵ CD3+ cells/kg recipient body weight), if desired [17,21-24]. TCR alpha/beta depletion retains TCR-gamma-delta cells, which may enhance engraftment and retain graft-versus-leukemia (GVL) effects [25,26]. CD34+ enrichment has replaced earlier techniques, such as sheep erythrocyte resetting, soybean lectin agglutination, and counterflow centrifugal elutriation [27,28].

●In vivo T cell depletion – In vivo T cell depletion strategies include anti-thymocyte globulin (ATG) and alemtuzumab (CAMPATH; anti-CD52 monoclonal antibody) [29]. These agents can induce cytokine release from the targeted T cells and might slow engraftment or immune recovery.

PTCy (to selectively target rapidly dividing alloreactive T cells) has been employed for in vivo T cell depletion in non-IBMFS settings. However, a benefit of PTCy has not been proven for FA and there is concern about increased risk of alkylating agents in these patients [12].

Transplantation for FA using T cell-depleted MSD grafts was associated with <5 percent grade ≥3 GVHD [30], which is lower than earlier studies without T cell depletion (eg, 30 to 40 percent) [31]. In a multicenter study of 98 patients with FA who received alternative donor grafts, compared with T cell-depleted grafts, aGVHD was higher in patients who received unmanipulated grafts, but there was no adverse effect on hematopoietic recovery or OS [32].

Conditioning regimen — The preferred conditioning regimen varies according to the underlying IBMFS and institutional preference. Total body irradiation should be avoided or dose-adjusted to reduce long-term adverse effects of HCT in patients with IBMFS.

●Fludarabine-based regimens for FA or DC – For patients with FA and DC, we suggest fludarabine-based conditioning, rather than cyclophosphamide- or radiation-based regimens. This suggestion is based on superior survival and faster marrow recovery with fludarabine; furthermore, radiation-based conditioning is associated with increased rates of secondary cancers and other long-term complications with these IBMFS.

Fludarabine-based conditioning was superior to other conditioning regimens in a registry study of HCT for FA; eight-year OS was 86 percent with fludarabine versus 59 percent with non-fludarabine-based conditioning [33]. A study of 98 patients with FA who underwent alternative donor transplantation reported that, compared with other conditioning regimens, fludarabine was associated with superior three-year adjusted OS (52 versus 13 percent), lower day 100 mortality (24 versus 65 percent), and improved recovery of neutrophils and platelets [32].

Superiority of fludarabine over other conditioning regimens has also been reported in other studies [11,34-39]. Outcomes using fludarabine-based conditioning with alternative donor grafts for FA rival those with MSD grafts [34-36]. (See 'Matched sibling donor choice' above.)

It should be noted that for FA and DC, which are associated with defects in DNA repair, fludarabine-based conditioning functions as myeloablative conditioning (MAC), even though it would be considered reduced intensity conditioning (RIC) in other transplantation settings.

Outcomes with HCT for FA and DC are presented below. (See 'Fanconi anemia' below and 'Dyskeratosis congenita' below.)

●RIC regimens for Shwachman-Diamond syndrome – Reduced intensity regimens are preferred for SDS, rather than MAC because of lower rates of transplant-related mortality (TRM). The preferred RIC regimen for SDS varies among institutions.

RIC regimens for HCT with SDS are associated with successful engraftment, little or no GVHD, and long-term survival [40,41]. By contrast, MAC was associated with more than 30 percent TRM in patients with SDS [42].

●Diamond-Blackfan anemia – Most experience has been with MAC, which is associated with high rates of engraftment and low rates of GVHD in patients with DBA [43]. (See 'Diamond-Blackfan anemia' below.)

Timing of transplantation — Transplantation should generally be performed as soon as possible after a decision has been made to proceed to HCT.

Earlier transplantation reduces further complications from cytopenias (eg, infections from neutropenia, iron overload from ongoing transfusions), lessens the likelihood of malignant transformation prior to transplantation, and may avert other complications of the underlying disorder (eg, liver or lung dysfunction associated with some IBMFS). Nevertheless, the decision about timing of transplantation must be nuanced and the risks associated with the underlying IBMFS should be weighed against incremental risks of HCT, itself.

Increasing age is associated with heightened risk for disease progression, potential development of MDS/acute myeloid leukemia (AML), and inferior transplant outcomes:

●Progressive cytopenias – The International Fanconi Anemia Registry (IFAR) reported that among >1300 affected individuals, by age 40, cytopenias from progressive bone marrow failure were present in 90 to 98 percent of patients and occurred at a median age of 7 years [44].

●Increased risk for malignant transformation – IFAR also reported that by age 40, the cumulative incidence of MDS or AML was 33 percent and non-hematologic tumors was 28 percent [44]. In a National Cancer Institute study, among patients with FA who did not undergo HCT, AML was reported in 3 percent (median age 40; range 28 to 56 years) and MDS in 9 percent (median age 31; range 4 to 73 years).

FA may exhibit variable rates of clonal progression. Patients with some genotypes (eg, FANCD1/ BRCA2 or FANCN/PALB2 complementation groups) can rapidly develop leukemia without preceding bone marrow failure; AML developed in 80 percent of patients with FANCD1/BRCA2 before age 10 [45-48].

●Inferior HCT outcomes – In a large registry study, age at transplantation was independently associated with mortality; compared with HCT at age <10 years, risk for death was increased in patients transplanted at age 10 to 20 years (HR 1.39; 95% CI 1.07 to 1.80) and age 20 to 50 years (HR 1.92; 95% CI 1.25 to 2.94) [11]. In a study of 98 patients with FA, patients >10 years old at the time of transplantation had more early deaths (2.1-fold relative risk [RR]) compared with patients ≤10 years [32].

Malignant transformation — Outcomes for patients who are transplanted prior to development of MDS or AML are better compared with transplantation after malignant transformation.

Transplantation prior to malignant transformation is especially important for patients with FA, DC, and SDS, because these syndromes are associated with treatment-resistant AML and excessive toxicity from remission induction therapy.

Among 795 patients transplanted for FA, 58 underwent HCT after progression to MDS or AML [11]. For the entire cohort, 20-year OS was 49 percent and 11 percent experienced graft failure. Compared with patients transplanted for bone marrow failure, those transplanted with MDS/AML had increased risk for graft failure (HR 3.17; 95% CI 1.60-6.28) and death (HR 2.10; 95% CI 1.41-3.11); the 12-month cumulative risk of relapse was 7 to 14 percent (varying with the type of graft donor). Pre-existing clonal evolution was an independent risk factor for development of secondary malignancy (HR 4.56; 95% CI 1.67-12.5). Other small series have reported 33 to 80 percent OS at three to five years for patients transplanted after clonal progression, with most deaths due to relapse or opportunistic infection [49-52].

Monitoring for development of MDS and AML is described below. (See 'Monitoring' below.)

Management and outcomes with HCT for patients who develop MDS or AML prior to transplantation are discussed below. (See 'IBMFS with AML' below.)

POST-HCT CARE — Long-term management of the patient who undergoes HCT for IBMFS must include management of graft-versus-host disease (GVHD), surveillance for transplant-related adverse effects and complications, and progression of non-hematopoietic effects of the underlying IBMFS.

Monitoring — Patients require ongoing monitoring and management of GVHD and other adverse effects of HCT. They are also at ongoing risk for non-hematologic complications of the underlying IBMFS and late effects of transplantation, some of which are heightened by their underlying inherited disorder. Transitions from pediatric to adult care and from transplant specialists to primary care providers are especially challenging and demand excellent communication and collaboration.

For patients with IBMFS who undergo HCT, ongoing evaluation should monitor growth, development, reproductive/gonadal function, and neurocognitive/psychosocial maturation; long-term screening must also include monitoring of immunity, possible iron overload, organ function (eg, lungs, kidneys, liver), and cancer screening [53]. In addition, evaluation must consider effects of progression of the non-hematologic features associated with the specific underlying IBMFS and interactions of HCT with that disorder (eg, increased risk for cancer or organ dysfunction).

Key aspects of post-HCT care include:

●Graft-versus-host disease – All patients who undergo HCT for IBMFS require monitoring and management for GVHD, as described separately. (See "Treatment of chronic graft-versus-host disease".)

●Secondary malignancies – The incidence of secondary cancers is increased after HCT, and the risk is especially great for patients with intrinsic DNA repair defects, such as Fanconi anemia (FA) and dyskeratosis congenita (DC). Life-long monitoring for secondary cancers is required in all patients who undergo HCT for IBMFS. (See 'Cancer risk' below.)

●Endocrine complications – Transplantation is associated with endocrine abnormalities, including growth hormone deficiency, thyroid dysfunction, dyslipidemia, hypogonadism, infertility, glucose intolerance, insulin resistance, and diabetes [53-55]. Monitoring for endocrine complications of HCT is described separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents" and "Long-term care of the adult hematopoietic cell transplantation survivor".)

Cancer risk — HCT is associated with increased risk for development of secondary cancers in patients with IBMFS. Transplantation is associated with increased incidence of solid tumors, with the degree of risk and the spectrum of cancers varying according to the underlying IBMFS.

Even without HCT, patients with FA have a high risk of squamous cell cancers (SCCs) of the head, neck, and esophagus; this risk is further increased by HCT, according to comparisons of patients who did and did not undergo transplantation. The age-specific hazard of SCC was 4.4-fold higher in 117 patients who underwent transplantation at a center in Paris, compared with 145 patients from North America who did not receive transplantation [56]. In transplanted patients, SCC arose earlier (median 18 versus and 33 years) and presence of GVHD was a significant risk factor for development of SCC. It was not possible to assign cancer risk to specific factors (eg, radiation in conditioning regimens) due to the small numbers of patients and diverse conditioning regimens.

Cancer incidence was reported in long-term follow-up of >500 individuals with IBMFS; approximately one-third underwent HCT [57]. Compared with individuals with FA who were not transplanted, the 63 patients with FA who underwent HCT had an increased relative risk (RR) for cumulative incidence of cancer (RR 3.5 [95% CI 1.2-9.2]) and the cancers arose at younger ages; most common were cancers of the tongue, esophagus, vulva and other anogenital SCC. The cumulative cancer incidence was also higher and occurred earlier in 60 patients transplanted for DC, compared with untransplanted individuals with DC; oral cancers were most common. Non-Hodgkin lymphoma (probably post-transplant lymphoproliferative disorder) arose in one patient each who underwent HCT for FA, DC, and DBA.

Multivariate analysis of a large population of patients transplanted for FA reported that age ≥10 years, longer duration of chronic GVHD, clonal evolution prior to transplantation, and peripheral blood as the graft source were associated with increased risk for secondary malignancies [11].

Other reports also describe the increased risk for secondary cancers in patients who undergo HCT for IBMFS [2,53,58].

SPECIFIC DISORDERS

Fanconi anemia — Fanconi anemia (FA) is the most common IBMFS and there is more experience with transplantation for FA than other IBMFS. HCT is the only curative option for bone marrow failure (BMF) associated with FA, but it is associated with an increased risk for secondary cancers and other complications.

Details of the clinical manifestations, underlying genetic findings, diagnosis, and management of FA are presented separately. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Management and prognosis of Fanconi anemia".)

HCT can cure hematologic manifestations of FA, but the intrinsic DNA repair defects complicate transplantation because of increased sensitivity to alkylating agents and radiation used in some conditioning regimens and heightened tissue damage from graft-versus-host disease (GVHD). Individuals with FA have elevated risk for cancer from the underlying disorder and transplantation and GVHD further increase the risk [57,59].

Considerations for HCT in FA

●Indications for HCT – Indications for HCT for severe BMF or development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) are discussed separately. (See "Management and prognosis of Fanconi anemia".)

Isolated cytogenetic abnormalities without malignant transformation (ie, without AML or MDS) is generally not considered an indication for transplantation, as these findings can persist indefinitely without development of aplasia or leukemia [60]. However, the risk of malignant transformation can vary between FA complementation groups and close observation for development of AML is required [46,61,62].

●Pretransplant considerations – Androgens can alleviate cytopenias while searching for a suitable donor, but the response may be transitory. Androgens can cause significant toxicity (eg, dyslipidemia, liver adenomata, accelerated growth, virilization, especially in young girls) and does not prevent progression to MDS/AML [63,64].

●Timing – We generally proceed with HCT before the patient receives 20 units of transfused red blood cells (RBC) or platelets to limit iron overload and alloimmunization [65]. Older age at transplantation is associated with inferior outcomes with HCT in patients with FA [11,32], as discussed above. (See 'Timing of transplantation' above.)

●Conditioning regimen – Our preference for fludarabine-based conditioning in patients with FA is described above. (See 'Conditioning regimen' above.)

Fludarabine-based conditioning, with or without lower-dose cyclophosphamide or radiation, has been successful with HCT using human leukocyte antigen (HLA)-matched sibling donors (MSD) and alternative donors. Individuals with FA are highly sensitive to DNA damaging agents, and transplantation with conventional doses of cyclophosphamide and/or radiation therapy were associated with excessive treatment-related toxicity, infectious complications, high rates of GVHD, and increased secondary cancers [66]. Compared with standard myeloablative conditioning (MAC), using lower doses of cyclophosphamide (with or without lower dose radiation) partially mitigated these risks and improved outcomes, including longer survival and fewer cancers [67-72].

●Graft – The preference for an MSD donor and acceptable alternatives are discussed above. (See 'Graft' above.)

Outcomes with HCT in FA — By age 50, 70 percent of patients with FA underwent HCT or had died [57]. In a study of 199 adults with FA, nearly half had developed MDS or AML before transplantation, which is associated with inferior outcomes [73].

The most favorable outcomes with transplantation for FA are associated with fludarabine-based conditioning and transplantation before development of MDS/AML:

●Survival – HCT in 20 patients with FA using fludarabine-based conditioning and MSD donors was associated with 95 percent two-year overall survival (OS) [74]. In a study of 25 patients with FA, fludarabine conditioning with either MSD or alternative donor grafts was associated with 86 percent eight-year OS [33]. Other studies report similar outcomes and indicate that, compared with other conditioning regimens, fludarabine-based conditioning is associated with more favorable survival [11,33,38,39,75]. (See 'Conditioning regimen' above.)

In a large registry study, factors independently associated with inferior survival in HCT for FA included age >10 years [37], >20 units RBC transfusion prior to HCT [32], cytomegalovirus (CMV) status [32,38,76], and prolonged chronic GVHD (cGVHD) [11].

●HCT in patients with MDS or AML – Patients with FA who are transplanted after development of MDS or AML have worse outcomes than those transplanted for FA with BMF [50,51,60,77]. Management and outcomes after development of MDS or AML are discussed below. (See 'IBMFS with AML' below.)

●Late effects – HCT for FA is associated with increased risk of secondary cancers and endocrine complications; life-long surveillance for late complications is required (see 'Monitoring' above):  

•Endocrine – Growth hormone deficiency, thyroid dysfunction, dyslipidemia, hypogonadism, glucose intolerance, insulin resistance, or diabetes are increased after transplantation [53-55]; males are generally infertile, but some successful pregnancies have been reported [1,53,54].

•Cancer – There is an increased risk for secondary cancers after HCT for FA, especially squamous cell cancers (SCC) of the head and neck and other regions; the risk may be increased by radiation therapy and/or GVHD [2,53,54,57,78,79].

Screening for late complications after HCT must continue life-long. According to a large FA transplant registry study, only one-half of transplanted patients remained alive after 15 years and only one-third were alive at 20 years, because of high rates of secondary cancers, endocrinologic disorders, GVHD, and other transplant-related complications [11].

Specific guidelines for post-transplant surveillance in patients with FA have been published [2,53].

Dyskeratosis congenita — Patients with dyskeratosis congenita (DC) may present with BMF and a classic diagnostic triad of dysplastic nails, lacy reticular pigmentation, and oral leukoplakia. However, DC is more heterogeneous than previously recognized and patients may have pulmonary or hepatic fibrosis; neurologic, ophthalmic, and immunologic abnormalities; avascular necrosis of the hips; or stenosis of lacrimal ducts, esophagus, and/or urethra. Details of the clinical manifestations, underlying genetic findings, diagnosis, and management of DC are presented separately. (See "Dyskeratosis congenita and other telomere biology disorders".)

HCT is the only curative treatment for the hematologic complications of DC, but survival is limited by a high incidence of both early and long-term complications [2,5,43,54,80]. The risk of secondary cancers is increased, with SCC of the head and neck and anogenital region being most common [5,53,57].

Transplantation in patients with DC is associated with excessive liver, lung, and vascular complications, including hepatic sinusoidal obstruction syndrome (SOS; also called veno-occlusive disease) and hepatopulmonary syndrome (HPS) [2,5,81]. Many transplanted patients die of non-hematologic complications of DC; this issue should be discussed with families of potential HCT candidates.

●Indications – Indications for HCT in patients with DC and BMF and/or development of MDS or AML are discussed separately. (See "Dyskeratosis congenita and other telomere biology disorders".)

●Pretreatment management – A multidisciplinary team approach is important for early detection of liver and lung problems associated with DC. Pulmonary function tests (PFT), liver imaging, and evaluation for vascular abnormalities should be performed before transplantation to screen for pre-existent liver, lung, and vascular complications [2,5,81].

Androgens may improve marrow function prior to HCT, but patients with DC are especially susceptible to liver complications; the risk of splenic peliosis and splenic rupture is increased when growth factors are used simultaneously [5,63,82].

Telomere elongation has been reported in patients with DC who are treated with danazol, but it is unclear if that should affect the timing of transplantation and/or ameliorate post-transplantation complications (eg, pulmonary toxicity/fibrosis) [82].

●Conditioning regimen – Our preference for fludarabine-based conditioning in patients with DC is described above. (See 'Conditioning regimen' above.)

●Graft – The preference for an MSD donor and acceptable alternatives are discussed above. (See 'Graft' above.)

●Outcomes – By age 50, half of patients with DC had severe BMF that led to either transplantation or death [57]. HCT can relieve BMF, but it does not correct non-hematologic DC-related abnormalities; PFTs should be used as a screening tool for early diagnosis of pulmonary failure after transplantation.

The largest study of HCT for DC reported that among 94 patients who underwent non-myeloablative conditioning HCT for BMF (MDS was present in eight), OS at three years was 66 and declined to 62 at five years; crude mortality was 41 percent [80]. Graft failure occurred in 17 percent and GVHD developed in one-third of patients. Early deaths were primarily from infections, while deaths from organ failure appeared later (reaching 25 percent after 10 years) and solid tumors began to appear after five years (reaching 7.5 percent by 10 years). Patients transplanted at age <20 years had more favorable outcomes.

A study of HCT for DC in 34 patients reported five-year OS was 57 percent and 10-year OS was 30 percent [83]. Median age at HCT was 13 years and most conditioning used fludarabine and/or cyclophosphamide, but 10 patients received total body irradiation. Graft failure occurred in 12 percent, mostly in association with HLA-mismatched grafts. High-dose conditioning was associated with severe organ toxicity and death; lower intensity conditioning caused fewer early adverse events but did not eliminate pulmonary toxicity. A single-center study of 28 patients with DC and other telomere biology disorders who were transplanted for BMF reported 53 percent five-year OS; most patients received RIC and half received an HLA-matched unrelated donor (MUD) grafts [1].

Diamond-Blackfan anemia — Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia with macrocytic anemia that is usually diagnosed in infancy or childhood. More than a dozen genes have been identified in the ribosome biogenesis pathway and most pathogenic mutations act in an autosomal dominant manner. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

HCT is the only curative option in transfusion-dependent patients with DBA, but it is associated with heightened risk for secondary cancers. The spectrum of secondary cancers (eg, osteosarcoma, colon cancer, lung cancer) differs from that associated with other IBMFS.

●Indications – Indications for HCT in patients with DBA and inadequate response of anemia to steroids and/or development of MDS/AML are discussed separately. (See "Diamond-Blackfan anemia".)

The optimum time for HCT in DBA is generally after a patient becomes refractory to glucocorticoids, but before 20 RBC transfusions are administered [58].

●Pretreatment management – Glucocorticoids can improve anemia in 60 to 80 percent of patients, but fewer than half can be maintained on doses low enough to avoid long-term toxicity [58]. Furthermore, glucocorticoid treatment in the first year of life may limit linear growth. Chronic transfusion therapy is associated with iron overload of the liver and heart, alloimmunization, and anti-HLA antibodies; chelation therapy may be needed when children are transfused with >200 mL RBC/kg body weight.

Iron can accumulate rapidly, especially in the youngest patients, and we screen with magnetic resonance imaging (MRI) and administer chelation therapy pretransplantation, as appropriate. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Iron chelation in transfusion-dependent thalassemia'.)

●Graft source – The preference for an MSD donor and acceptable alternatives are discussed above. (See 'Graft' above.)

It is essential to exclude a silent DBA phenotype in sibling donors [58,84]; HCT using a similarly affected donor has led to transplant failure or full donor chimerism with a continued need for transfusions [85,86]. (See 'Matched sibling donor choice' above.)

●Conditioning regimen – MAC regimens are most often used, but there is no standard preparative regimen and preferences vary between institutions. Use of MAC for HCT with DBA differs from conditioning for other IBMFS, as described above. (See 'Conditioning regimen' above.)

MAC regimens may lead to infertility, and fertility preservation (when available) should be discussed with the patient or family upfront.

●Outcomes – HCT with MAC is associated with high rates of OS and engraftment and low rates of severe GVHD.

In a registry study, HCT for DBA in 70 children (median age 5.5 years; MSD grafts in two-thirds) was associated with engraftment in 100 percent and little or no cGVHD [87]. Other studies reported high rates of OS for HCT in DBA [88-91]. Outcomes with MUD grafts were similar to those using MSD grafts [86], but use of HLA-mismatched unrelated donor (mMUD) grafts leads to high graft failure and GVHD. A registry study reported 95 percent three-year survival among 21 children with DBA who received umbilical cord blood (UCB) grafts [14]. Other studies have also reported successful use of UCB grafts for HCT with DBA [14,75,86,92-94].

A retrospective study (Italian Association of Pediatric Hematology and Oncology DBA Registry) indicated a worse prognosis for those transplanted after age 10 years [86].

Shwachman-Diamond syndrome — Shwachman-Diamond syndrome (SDS) is a rare IBMFS characterized by exocrine pancreatic insufficiency, cytopenias, and abnormalities of bone. Most patients have biallelic pathogenic variants in the SBDS gene or other genes that affect ribosome biogenesis and mitosis. (See "Shwachman-Diamond syndrome".)

HCT has the potential to cure the hematologic manifestations of SDS, but it does not affect pancreatic exocrine dysfunction or other non-hematologic manifestations.

●Indications – Indications for HCT in patients with SDS and progressive cytopenias, inadequate response to granulocyte colony stimulating factor (G-CSF), and/or progression to MDS/AML are discussed separately. (See "Shwachman-Diamond syndrome".)

●Conditioning regimen – Reduced intensity/lower toxicity regimens are preferred for SDS, because MAC has been associated with excessive transplant-related mortality (TRM; eg, >30 percent) and relapse [41,42,95].

The choice of RIC for SDS varies among institutions. Clinical trials using RIC regimens and other modifications to reduce the toxicity in individuals with SDS are ongoing [40].

●Outcomes – HCT for SDS is associated with approximately 70 percent five-year OS, but outcomes are dismal for those transplanted after development of MDS or AML [96-99]. TRM is high with MAC, but there are only limited data for transplant with RIC.

In a series of seven patients with SDS who underwent HCT with an RIC regimen, all patients had donor-derived hematopoiesis and there was no grade ≥3 GVHD; all patients were alive at a median follow-up of approximately 1.5 years [41]. Transplantation of three patients with MUD grafts using treosulfan, fludarabine, and anti-thymocyte globulin (ATG) conditioning was associated with 100 percent engraftment, no chronic GVHD, and survival >3 years at the time of the report [40]. Small case series described approximately 65 percent one-year OS and 60 percent five-year event-free survival [42,95].  

IBMFS with AML — Outcomes with HCT for patients with IBMFS are inferior after development of MDS or AML, compared with patients who are transplanted for BMF. Malignant transformation can increase infections due to cytopenias, the malignant cells are relatively resistant to conditioning therapy and/or immunologic benefits of transplantation, and some IBMFS (eg, FA, DC, SDS) are excessively sensitive to alkylating agents and other chemotherapy of remission induction therapy.

Management of AML — We strongly favor HCT prior to malignant transformation to MDS or AML, as discussed above. (See 'Malignant transformation' above.)

Conventional induction chemotherapy for AML is associated with significant toxicity and prolonged aplasia in patients with FA, DC, and SDS. It is unclear whether induction therapy prior to HCT is preferable to transplantation with active AML or MDS, but most experts would not treat for chromosomal, immunophenotypic, or molecular findings of clonality alone (ie, without evidence of malignant transformation) to avoid the risk of exacerbating or prolonging cytopenias.

The most commonly reported remission induction regimens for AML developing from IBMFS are moderate-dose or low-dose FLAG (fludarabine, cytarabine, G-CSF) [50,51,100,101], but no studies have directly compared induction regimens. Patients in remission after treatment for AML have better survival than those transplanted with active disease, but pretransplant chemotherapy may cause excessive toxicity and prolonged aplasia, especially in patients with FA, DC, and SDS. A multicenter study of 74 patients with transformed FA (35 with MDS, 35 with AML, 4 with cytogenetic abnormalities) reported no difference in survival for recipients of MSD versus alternative donor grafts [33].

Outcomes with AML/MDS — Outcomes are poor for patients transplanted with active MDS or AML and it is not clear if chemotherapy to control the malignancy prior to HCT is associated with improved outcomes.

●HCT for patients with MDS or AML arising from IBMFS – Outcomes with transplantation for MDS are generally better than for AML, but they are rarely analyzed separately. For patients with FA who have MDS or AML, five-year survival averages 33 and 43 percent; outcomes are inferior compared with transplantation for FA without malignant transformation. Analysis of 74 patients (35 with MDS, 35 with leukemia, 4 with cytogenetic abnormalities) in a transplant registry reported that after five years, OS was 42 percent, nonrelapse mortality was 40 percent, and incidence of relapse was 21 percent [102]. Pre-HCT cytoreductive chemotherapy was administered to 22 patients; those transplanted in complete remission (CR) had superior survival compared with those transplanted at the time of active malignant disease (71 versus 37 percent).

Among patients with FA, compared with those transplanted prior to malignant transformation, patients transplanted with MDS or AML had three-fold greater risk for graft failure and two-fold greater risk of death [11]. Other studies also described inferior outcomes after malignant transformation, as described above. (See 'Malignant transformation' above.)

●Effect of chemotherapy prior to HCT – In a small series, sequential induction therapy with FLAG induction followed by HCT reported that all six patients (median age 21 years) were alive and without evidence of clonality after median follow-up of 28 months [101]. Patients received pretransplant FLAG induction therapy (fludarabine 30 mg/m²/d for 5 days plus cytarabine 1 g/m² twice daily for 5 days, with G-CSF support), followed three weeks later by HCT (cyclophosphamide 10 mg/kg for 4 days, fludarabine 30 mg/m² for 4 days, anti-thymocyte globulin [ATG] 3.75 mg/kg, and TBI [2 Gy]) delivered during chemotherapy-induced aplasia. All patients engrafted (median 21 days) and were alive in CR without clonal evolution after median follow-up of 28 months.

●HCT for clonal abnormalities without MDS/AML – One study reported outcomes among patients with FA who had clonal abnormalities: 54 had isolated cytogenetic abnormalities, 45 had MDS, 12 had AML, and 2 had acute lymphoblastic leukemia (ALL) [52]. Induction chemotherapy was given prior to HCT in 6 of the 14 patients with leukemia. OS was 64, 58, and 55 percent at 1, 3, and 5 years, respectively. Inferior survival was associated with older age and development of grade ≥3 GVHD.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

SUMMARY AND RECOMMENDATIONS

●Transplantation for inherited disorders is distinctive – Allogeneic hematopoietic cell transplantation (HCT) can cure hematologic abnormalities of inherited bone marrow failure syndromes (IBMFS); however, HCT does not correct non-hematologic manifestations and increases the risk for secondary cancers and other transplant-related complications. The most common IBMFS are Fanconi anemia (FA) and dyskeratosis congenita (DC), which are associated with DNA-repair defects, and Diamond-Blackfan anemia (DBA) and Shwachman-Diamond syndrome (SDS), which are defects in ribosome formation or function.

●General considerations – A suitable transplant donor can be identified for nearly all patients with an IBMFS. Distinctive aspects for selecting a transplant donor, conditioning regimen, and other aspects of management and surveillance include:

•Graft donor:

-Patients with a human leukocyte antigen (HLA)-matched sibling donor (MSD) are transplanted using the MSD graft. (See 'Donor' above.)

However, potential MSD donors should first be evaluated for the pathogenic variant (ie, mutation) present in the patient; eligibility in the presence of the variant varies according to the inheritance pattern of the specific IBMFS. (See 'Matched sibling donor choice' above.)

-For patients without a suitable MSD donor, we suggest an HLA-matched unrelated donor (MUD), rather than a mismatched unrelated donor (mMUD), umbilical cord blood (UCB) graft, or haploidentical donor (Grade 2C).

•Graft source – We consider either bone marrow or peripheral blood stem/progenitor cells (PBSPC) acceptable as the graft source. (See 'Source' above.)

•Conditioning regimen (see 'Conditioning regimen' above):

-FA, DC, and SDS – For patients with FA, we recommend fludarabine-based conditioning, rather than myeloablative conditioning (MAC) (Grade 1B). We also suggest it for patients with DC or SDS (Grade 2C). Radiation should be minimized or eliminated for conditioning.

-DBA – For patients with DBA, we suggest MAC (Grade 2C) based on more experience with that approach.

•Timing – Transplantation should generally be performed as soon as possible after a decision has been made for HCT to limit complications from ongoing cytopenias, avoid progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), and to transplant before development of other IBMFS-associated complications (eg, DC-associated liver or lung fibrosis). (See 'Timing of transplantation' above.)

•Malignant transformation – Outcomes for patients who are transplanted prior to development of MDS or AML are better than for those who receive transplantation after malignant transformation. Nevertheless, HCT remains an option for patients after transformation, as discussed above. (See 'Malignant transformation' above.)

●Specific scenarios – Distinctive aspects of transplantation and outcomes are discussed for each of the following conditions:

•Fanconi anemia – (See 'Fanconi anemia' above.)

•Dyskeratosis congenita – (See 'Dyskeratosis congenita' above.)

•Diamond-Blackfan anemia – (See 'Diamond-Blackfan anemia' above.)

•Shwachman-Diamond syndrome – (See 'Shwachman-Diamond syndrome' above.)

•HCT for AML in patients with IBMFS – (See 'IBMFS with AML' above.)