Stable Long-Term Risk of Leukemia in Patients with Severe Congenital Neutropenia Maintained On G-CSF Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3206-3206 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Cornelia Zeidler ◽  
Audrey Anna Bolyard ◽  
Blanche P. Alter ◽  
Mary Ann Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cumulative Incidence ◽  
Bone Marrow Failure ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hazard Curve ◽  
Number Of Patients ◽  
Increasing Trend

Abstract Abstract 3206 Poster Board III-143 BACKGROUND G-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODS We updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTS The update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONS For SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. Disclosures Boxer: Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

scholarly journals Nontransplant therapy for bone marrow failure

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Danielle M. Townsley ◽  
Thomas Winkler
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Single Agent ◽  
Telomere Attrition ◽  
Long Term Follow Up ◽  
Treatment Naïve

Abstract Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.

The Incidence of Leukemia and Mortality from Sepsis in Patients with Severe Congenital Neutropenia Receiving Long-Term G-CSF Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 669-669 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Blanche P. Alter ◽  
Audrey A. Bolyard ◽  
Mary A. Bonilla ◽  
Laurence A. Boxer ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Intermediate Group ◽  
Cell Counts ◽  
Secondary Analyses ◽  
Shwachman Diamond Syndrome ◽  
Pre Treatment ◽  
Stimulating Factor

Abstract Background: In patients with severe congenital neutropenia (SCN), mortality from sepsis is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported in treated and untreated patients. Methods: We studied 374 patients with SCN and 29 patients with Shwachman-Diamond Syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Results: In SCN, mortality from sepsis was stable at 0.9%/year. The hazard of MDS/AML increased significantly over time, from 2.9%/year after 6 years to 8.0%/year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for mortality from sepsis and 21% for MDS/AML. The hazard of MDS/AML increased with the dose of G-CSF. Twenty-nine percent of SCN patients received more than the median dose of G-CSF (≥8 μg/kg/day), but achieved less than the median absolute neutrophil count (ANC) response (ANC <2188 cells/μL at 6–18 months). In these less responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared to 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. An intermediate group achieved an ANC above the median on doses of G-CSF above the median; among them, the 10 year cumulative incidence was 15% for MDS/AML and 3% for mortality from sepsis. In secondary analyses, we found that pre-treatment blood cell counts could not predict the subsequent clinical outcome. Furthermore, on therapy, patients who were less responsive vis-à-vis their neutrophil counts had similar increases in eosinophils, basophils, monocytes, and lymphocytes, and similar decreases in platelets, as other patients maintained on ≥8 μg/kg/day. Consistent with the SCN results, in SDS patients, the limited available data do not suggest that G-CSF therapy is a risk factor for MDS/AML in SDS. Conclusions: The risk of MDS/AML was similarly low in all patients who achieved an ANC above the median on any dose of G-CSF. It appears that G-CSF has reduced mortality from sepsis, and revealed the underlying leukemic predisposition of SCN.

G-CSFSR Mutations Present in Patients with Severe Congenital Neutropenia Cooperate with PML-RARα To Induce Acute Myeloid Leukemia in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2193-2193
Author(s):  
Jill R. Woloszynek ◽  
Ghada M. Kunter ◽  
Tim Ley ◽  
Dan C. Link ◽  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Transgenic Mice ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Direct Evidence ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Acute Myeloid

Abstract Severe congenital neutropenia (SCN) is an inherited disorder of granulopoiesis that is associated with a markedly increased risk of developing acute myeloid leukemia (AML) or myelodysplasia (MDS). Somatic mutations of CSF3R, encoding the G-CSF receptor (G-CSFR), are strongly associated with the development of AML/MDS in SCN. These mutations invariably produce a truncated G-CSFR that, though remaining ligand-dependent, transmits a hyperproliferative signal. Transgenic mice carrying a targeted (knock-in) mutation of Csf3r (termed d715) reproducing a mutation found in a patient with SCN have an exaggerated neutrophil response to G-CSF treatment but do not develop AML/MDS. Moreover, we recently showed expression of the d715 G-CSFR confers a strong clonal advantage at the hematopoietic stem cell level that is dependent upon exogenous G-CSF. Collectively, these data suggest that CSF3R truncation mutations are an initiation or early progression factor for leukemic transformation. However, there is, as yet, scant direct evidence supporting this hypothesis. Previous studies have established that activating mutations of receptor tyrosine kinases, such as internal tandem duplications of FLT3, are able to cooperate with PML-RARα to induce AML. Since the CSF3R mutations in SCN also are “activating”, we asked whether the d715 G-CSFR could cooperate with PML-RARα to induce AML in mice. PML-RARα transgenic mice were intercrossed with d715 G-CSFR mice (all inbred > 10 generations onto a C57BL/6 background) to generate the cohorts listed in Table 1. A separate cohort for each genotype was treated chronically with pegylated G-CSF (1 mg/kg every 4–5 days for 6 months) to simulate the high level of serum G-CSF present in patients with SCN. Complete blood counts were performed at 3 months intervals and documented a similar increase in neutrophil counts in all mice treated with G-CSF. The cumulative incidence of AML and median follow-up for each cohort is shown in Table 1. None of the mice without the PML-RARα transgene, regardless of G-CSF treatment, developed AML, confirming that the d715 G-CSFR is not sufficient to induce AML. In mice carrying the PML-RARα transgene but not treated with G-CSF, a nonsignificant trend to increased AML was observed in mice expressing the d715 G-CSFR (P=0.12). However, in mice carrying the PML-RARα transgene and treated with G-CSF, the presence of the d715 G-CSFR significantly increased the penetrance (P=0.009) and reduced the latency of AML. In all cases, the leukemia was characterized by leukocytosis, splenomegaly, and a high percentage of blasts in the bone marrow and spleen that co-express Gr1 and c-Kit. These data provide the first direct evidence that the CSF3R mutations present in patients with SCN are leukemogenic and provide further support for the proposition that patients who acquire CSF3R mutations be considered for early stem cell transplantation. The cumulative incidence of AML and median follow-up for each cohort PML-RAR CSF3R G-CSF Rx N Median follow-up Cumulative AML% No WT No 20 454 0.0% No d715 No 45 250 0.0% No WT Yes 20 488 0.0% No d715 Yes 47 311 0.0% Yes WT No 57 286 6.4% Yes d715 No 67 267 11.9% Yes WT Yes 54 322 20.4% Yes d715 Yes 50 311 44.0%

Significance of Bone Marrow Karyotype and Morphology in Patients with Inherited Bone Marrow Failure Syndromes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3431-3431
Author(s):  
Neelam Giri ◽  
Blanche P Alter ◽  
Helkha Peredo-Pinto ◽  
M. Tarek Elghetany ◽  
Irina Maric ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Myelogenous Leukemia ◽  
Monosomy 7 ◽  
Cytogenetic Abnormalities ◽  
Bone Marrow Failure Syndromes ◽  
Number Of Patients

Abstract Abstract 3431 Recurring clonal cytogenetic abnormalities have been described in patients with Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS). In FA, gains of 3q and monosomy 7 (−7) imply progression to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In SDS, isochromosome 7q and deletion (del) 20q are usually benign. Dyskeratosis congenita (DC) and Diamond-Blackfan anemia (DBA) do not have unique clones. We report here the types and frequencies of cytogenetic clones and their association with morphologic MDS or AML in the major inherited bone marrow failure syndromes (IBMFS), in a prospective/ retrospective study of patients with FA, SDS, DC and DBA enrolled in the NCI IBMFS cohort from 2002–2010. Bone marrow (BM) morphology and cytogenetics (G-banding; selected FISH, CGH, SKY) performed at our institute and all outside cytogenetics reports were centrally reviewed. Cytogenetic abnormalities were defined and karyotypes designated according to ISCN (2009). Two independent blinded hematopathologists reviewed BM morphology. Diagnosis of morphologic MDS was based on a modification of WHO 2008 and required ≥10% dysplasia in 2 cell lineages. Data analysis was both cross-sectional and longitudinal. P values are global comparing all 4 disorders using Fisher's exact test.ParameterAll IBMFSFASDSDCDBAP valueTotal number (N)12835113646–N with clone ever2817 (49%)4 (36%)4 (11%)3 (7%)<0.01N with MDS ever105 (14%)3 (27%)1 (3%)1 (2%)0.01N with clone + MDS75 (14%)2 (18%)00<0.01N with clone alone2112 (34%)2 (18%)4 (11%)3 (7%)<0.01N with MDS alone301 (9%)1 (3%)1 (2%)0.3N with clone at 1st BM179 (26%)4 (36%)3 (8%)1 (2%)<0.01N with clones at follow-up118012<0.01N with follow-up BMs591791716–Median follow-up in years3 (0–19)6 (1–16)2 (1–6)3 (0–19)2 (0–10)– More FA and SDS patients had clones and/or MDS compared with DC or DBA (Table). MDS was always associated with clones in FA but not in the other IBMFS. In FA, bone marrow transplant (BMT) or death occurred with similar frequencies in those with or without clones. Among 17 patients with clones, follow-up cytogenetics were unavailable in 5; of these, 2 with clone alone [one with del 7q and 18p and one with t(3;6)(q?25;p?21)] progressed to AML, while one with clone and MDS died from other causes. Recurring abnormalities in 12 FA patients with clones followed for up to 16 years, included gains of 1q in 4, −7 or del 7q in 3, and deletions of 6p, 13q, 18p and 20q in 2 patients each; only one had gain of 3q. These patients showed fluctuation or disappearance of clones, new appearance of clones, stable clone, or clonal evolution. Progression to MDS occurred with gain of 1q and 6p deletion, gain of 3q, or −7 in 3 patients, respectively; one patient with MDS had clonal persistence. No disease progression was seen in 5 FA patients with clone alone. All 5 SDS patients with clones and/or MDS are alive with no disease progression. The 4 with a clone had stable persistent del 20q as a sole abnormality; 2 had MDS and 2 did not. One had MDS with a normal karyotype. Four DC patients had abnormal clones including 2 with gain of 1q only. One patient with 1q gain died from pulmonary fibrosis. Three others are alive; 2 with stable clones at 7 and 19 years' follow-up, respectively. One additional DC patient has morphologic MDS but no clone. All 3 DBA patients with clones had del 16q, 2 alone and 1 with del 9p; none had MDS. The clones were transient in 2, disappearing within 1–2 years; the third was recently identified. None of these had disease progression. One patient with morphologic MDS alone died from complications of iron overload. This study shows that clonal chromosome abnormalities occur more frequently in FA and SDS than in DC and DBA. Gain of 3q in FA was not as common here as reported by others. This is the first comprehensive study of clones and MDS in DC and DBA. Strengths of this study include the large number of patients, and central review of cytogenetics and morphology. It is unbiased compared with FA literature reports that include many patients referred for BMT. Limitations include a relatively small number of patients with each diagnosis and short follow-up in most. The study demonstrates that clones may fluctuate or disappear, and may not per se portend a bad prognosis. Progression to clinically significant MDS or AML may be related to the severity of cytopenias and not to clone alone, and warrants more extensive long-term studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

2020 ◽  
Author(s):  
Daijing Nie ◽  
Jing Zhang ◽  
Fang Wang ◽  
Wei Zhang ◽  
Lili Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Basis ◽  
Bone Marrow Failure ◽  
Severe Infection ◽  
Multicenter Studies ◽  
Hematopoietic Stem ◽  
Cytogenetic Abnormalities ◽  
Number Of Patients

Abstract Background: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet. Methods: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA.Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied. Results: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2 -G/A genotype have a significantly younger age of BMF onset ( p =0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection. Conclusion: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

scholarly journals Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

2020 ◽  
Author(s):  
Daijing Nie ◽  
Jing Zhang ◽  
Fang Wang ◽  
Wei Zhang ◽  
Lili Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Basis ◽  
Bone Marrow Failure ◽  
Severe Infection ◽  
Multicenter Studies ◽  
Hematopoietic Stem ◽  
Cytogenetic Abnormalities ◽  
Number Of Patients

Abstract Background: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet. Methods: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA.Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied. Results: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2 -G/A genotype have a significantly younger age of BMF onset ( p =0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection. Conclusion: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

Disease Progression and Clinical Outcomes in Telomere Biology Disorders

Blood ◽  
2021 ◽  
Author(s):  
Marena R. Niewisch ◽  
Neelam Giri ◽  
Lisa J McReynolds ◽  
Rotana Alsaggaf ◽  
Sonia Bhala ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Outcomes ◽  
Bone Marrow Failure ◽  
Solid Organ ◽  
Long Term Study ◽  
Telomere Biology ◽  
Mode Of Inheritance

Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR) or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs [144 male, 86.6% known genotype, median age at diagnosis 19.4 years (0-71.6)], enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up [median follow-up 5.2 years (0-36.7)]. Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure, severe liver disease and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival of 52.8 years [95% confidence interval (CI) 45.5-57.6] and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better overall survival was present in AD versus AR/XLR/TINF2 disease (p&lt;0.01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines, and risk stratification in patients with DC/TBDs. clinicaltrials.gov NCT00027274

scholarly journals Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry

2014 ◽  
Vol 9 (1) ◽  
Author(s):  
Claire Desplantes ◽  
Marie Louise Fremond ◽  
Blandine Beaupain ◽  
Jean Luc Harousseau ◽  
Agnès Buzyn ◽  
...  
Keyword(s):  
Clinical Spectrum ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Long Term Follow Up

scholarly journals Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

2020 ◽  
Author(s):  
Daijing Nie ◽  
Jing Zhang ◽  
Fang Wang ◽  
Wei Zhang ◽  
Lili Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Basis ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Multicenter Studies ◽  
Hematopoietic Stem ◽  
Cytogenetic Abnormalities ◽  
Number Of Patients

Abstract Background: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet.Methods: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied.Results: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p=0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection.Conclusions: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

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