Fanconi anemia - learning from children

Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Clinical features of FA are somatic malformations, progressive bone marrow failure and cancer proneness, however there is wide clinical heterogeneity. The symptom most frequently and early associated with morbidity and mortality is progressive pancytopenia in the first decade of life although acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) can appear before aplastic anemia. Squamous cell carcinoma (SCC) of the head-neck, intestinal or genital tract has a very high incidence in FA and can appear at young age. This paper will focus on treatment of bone marrow failure in FA.

Download Full-text

Long-term bone marrow culture in persons with Fanconi anemia and bone marrow failure

Blood ◽

10.1182/blood.v83.2.336.336 ◽

1994 ◽

Vol 83 (2) ◽

pp. 336-339 ◽

Cited By ~ 6

Author(s):

A Butturini ◽

RP Gale

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Bone Marrow Failure ◽

Myelogenous Leukemia ◽

Acute Myelogenous ◽

Nonadherent Cells

Abstract Fanconi anemia is an autosomal recessive disease characterized by a high risk of developing bone marrow (BM) failure and acute myelogenous leukemia. We studied growth of hematopoietic progenitor cells in long- term BM culture (LTBMC) in 8 persons with Fanconi anemia and BM failure. Although LTBMC were initiated with very few BM cells, an adherent layer formed in cultures from 7 persons. In these cultures, the number of nonadherent cells increased for 10 to 15 days. Cell growth continued until cultures were terminated at day 35 to 40. During the first 2 weeks of culture, most nonadherent cells were differentiated myeloid cells. By days 35 to 40, the adherent layer contained cells able to initiate secondary LTBMCs. These data indicate that hematopoietic precursors cells able to proliferate and differentiate in vitro are present in the BM of persons with Fanconi anemia and BM failure. They suggest that mechanisms other than absent precursor cells are responsible for BM failure in Fanconi anemia.

Download Full-text

Long-term bone marrow culture in persons with Fanconi anemia and bone marrow failure

Blood ◽

10.1182/blood.v83.2.336.bloodjournal832336 ◽

1994 ◽

Vol 83 (2) ◽

pp. 336-339

Author(s):

A Butturini ◽

RP Gale

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Bone Marrow Failure ◽

Myelogenous Leukemia ◽

Acute Myelogenous ◽

Nonadherent Cells

Fanconi anemia is an autosomal recessive disease characterized by a high risk of developing bone marrow (BM) failure and acute myelogenous leukemia. We studied growth of hematopoietic progenitor cells in long- term BM culture (LTBMC) in 8 persons with Fanconi anemia and BM failure. Although LTBMC were initiated with very few BM cells, an adherent layer formed in cultures from 7 persons. In these cultures, the number of nonadherent cells increased for 10 to 15 days. Cell growth continued until cultures were terminated at day 35 to 40. During the first 2 weeks of culture, most nonadherent cells were differentiated myeloid cells. By days 35 to 40, the adherent layer contained cells able to initiate secondary LTBMCs. These data indicate that hematopoietic precursors cells able to proliferate and differentiate in vitro are present in the BM of persons with Fanconi anemia and BM failure. They suggest that mechanisms other than absent precursor cells are responsible for BM failure in Fanconi anemia.

Download Full-text

Cancer incidence in persons with Fanconi anemia

Blood ◽

10.1182/blood-2002-05-1498 ◽

2003 ◽

Vol 101 (3) ◽

pp. 822-826 ◽

Cited By ~ 309

Author(s):

Philip S. Rosenberg ◽

Mark H. Greene ◽

Blanche P. Alter

Keyword(s):

Bone Marrow ◽

Solid Tumors ◽

Fanconi Anemia ◽

Solid Tumor ◽

Cumulative Incidence ◽

Bone Marrow Failure ◽

Adverse Outcomes ◽

Relative Risks ◽

Autosomal Recessive Condition ◽

Progressive Pancytopenia

Abstract Fanconi anemia (FA) is an autosomal recessive condition associated with congenital abnormalities, progressive pancytopenia, and a predisposition to leukemia and solid tumors. We studied a retrospective cohort of North American patients with FA. We calculated relative risks of cancer compared to the general population and cause-specific hazards of the first major adverse outcomes of FA: bone marrow transplantation (BMT) for marrow complications, acute myeloid leukemia (AML), solid tumors, or death from bone marrow failure. We also estimated the cumulative incidence of each adverse event in the presence of the competing risks. Among 145 patients with FA, 9 developed leukemia and 14 developed a total of 18 solid tumors. The ratio of observed to expected cancers (O/E ratio) was 50 for all cancers, 48 for all solid tumors, and 785 for leukemia; these increased risks were statistically significant. The highest solid tumor O/E ratios were 4317 for vulvar cancer, 2362 for esophageal cancer, and 706 for head and neck cancer. Cause-specific hazards of both death and AML peaked at 1%/y in teenage years; the hazard of BMT peaked at 4%/y at age 7. In contrast, the hazard of a solid tumor approached 8%/y by age 40 years. The cumulative incidence to age 48 was 10% for leukemia, 11% for death from marrow failure, 29% for a solid tumor, and 43% for BMT. The risk of a solid tumor may become even higher as death from aplastic anemia is reduced and as patients survive longer after BMT.

Download Full-text

Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor

Blood ◽

10.1182/blood-2002-10-3243 ◽

2003 ◽

Vol 101 (10) ◽

pp. 3872-3874 ◽

Cited By ~ 75

Author(s):

Holger Tönnies ◽

Stefanie Huber ◽

Jörn-Sven Kühl ◽

Antje Gerlach ◽

Wolfram Ebell ◽

...

Keyword(s):

Bone Marrow ◽

Risk Factor ◽

Fanconi Anemia ◽

Bone Marrow Cells ◽

Bone Marrow Failure ◽

Molecular Cytogenetics ◽

Complementation Group ◽

Significant Survival ◽

High Incidence ◽

Marrow Cells

Abstract Fanconi anemia (FA) is a condition that induces susceptibility to bone marrow failure, myelodysplastic syndrome (MDS), and leukemia. We report on a high incidence of expanding clonal aberrations with partial trisomies and tetrasomies of chromosome 3q in bone marrow cells of 18 of 53 FA patients analyzed, detected by conventional and molecular cytogenetics. To determine the clinical relevance of these findings, we compared the cytogenetic data, the morphologic features of the bone marrow, and the clinical course of these patients with those of 35 FA patients without clonal aberrations of 3q. The 2 groups did not differ significantly with respect to age, sex, or complementation group. There was a significant survival advantage of patients without abnormalities of chromosome 3q. Even more pronounced was the risk assessment of patients with gains of 3q material with respect to the development of morphologic MDS and acute myeloid leukemia (AML). Thus, our data from 18 patients with 3q aberrations reveal that gains of 3q are strongly associated with a poor prognosis and represent an adverse risk factor in FA.

Download Full-text

Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study [see comments]

Blood ◽

10.1182/blood.v84.5.1650.bloodjournal8451650 ◽

1994 ◽

Vol 84 (5) ◽

pp. 1650-1655 ◽

Cited By ~ 8

Author(s):

A Butturini ◽

RP Gale ◽

PC Verlander ◽

B Adler-Brecher ◽

AP Gillio ◽

...

Keyword(s):

Bone Marrow ◽

Confidence Interval ◽

Myelodysplastic Syndrome ◽

Fanconi Anemia ◽

Myelogenous Leukemia ◽

Registry Study ◽

Cytogenetic Abnormalities ◽

Risk Of Death ◽

Acute Myelogenous ◽

Actuarial Risk

We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.

Download Full-text

Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study [see comments]

Blood ◽

10.1182/blood.v84.5.1650.1650 ◽

1994 ◽

Vol 84 (5) ◽

pp. 1650-1655 ◽

Cited By ~ 265

Author(s):

A Butturini ◽

RP Gale ◽

PC Verlander ◽

B Adler-Brecher ◽

AP Gillio ◽

...

Keyword(s):

Bone Marrow ◽

Confidence Interval ◽

Myelodysplastic Syndrome ◽

Fanconi Anemia ◽

Myelogenous Leukemia ◽

Registry Study ◽

Cytogenetic Abnormalities ◽

Risk Of Death ◽

Acute Myelogenous ◽

Actuarial Risk

Abstract We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.

Download Full-text

Phase I study of recombinant human interleukin-3 in patients with bone marrow failure.

Journal of Clinical Oncology ◽

10.1200/jco.1991.9.7.1241 ◽

1991 ◽

Vol 9 (7) ◽

pp. 1241-1250 ◽

Cited By ~ 106

Author(s):

R Kurzrock ◽

M Talpaz ◽

Z Estrov ◽

M G Rosenblum ◽

J U Gutterman

Keyword(s):

Bone Marrow ◽

Bone Marrow Failure ◽

High Dose Chemotherapy ◽

Myelogenous Leukemia ◽

Refractory Anemia ◽

High Dose ◽

Low Grade ◽

Interleukin 3 ◽

Acute Myelogenous ◽

Rapid Clearance

Interleukin-3 (IL-3) is a T-cell-derived colony-stimulating factor (CSF) whose primary targets include relatively early, multipotential, hematopoietic progenitor cells. In this trial, we treated 24 patients with recombinant human IL-3 given by a daily 4-hour intravenous infusion for 28 days. The dose levels were 30, 60, 125, 250, 500, 750, and 1,000 micrograms/m2/d. At least three patients were entered at every dose level. Each participant suffered from bone marrow failure, with the underlying diagnosis being myelodysplastic syndrome (13 patients), aplastic anemia (eight patients), or aplasia after prolonged high-dose chemotherapy (three patients) for multiple myeloma, breast cancer, or acute myelogenous leukemia. Most patients tolerated therapy well, with the most frequent side effects being low-grade fever and headaches. Hematopoietic changes included modest increases in neutrophil counts (eight patients), eosinophil counts (six patients), platelet counts (three patients), and reticulocyte counts (two patients). An increase in blasts occurred in one patient who had refractory anemia with excess blasts in transformation and was reversible once IL-3 was discontinued. In addition, one patient with chronic myelomonocytic leukemia showed an increase in monocytes (and granulocytes). Progression to acute leukemia did not occur. Pharmacokinetic analyses showed a rapid clearance with a mean half-life of 18.8 minutes at the 60 micrograms/m2/d dose, and 52.9 minutes at the 250 micrograms/m2/d dose. Serum concentrations of 10 to 20 ng/mL of IL-3 were achievable at the 250 micrograms/m2/d dose. Our observations indicate that recombinant human IL-3 can be given safely at doses of 1,000 micrograms/m2/d or less. In addition, on the basis of preclinical data and the biologic activity observed in this study, further trials of this molecule, alone and in combination with other growth factors, are warranted in patients with pancytopenia.

Download Full-text

Facial palsy: a rare manifestation in Fanconi anaemia

International Journal of Otorhinolaryngology and Head and Neck Surgery ◽

10.18203/issn.2454-5929.ijohns20171209 ◽

2017 ◽

Vol 3 (2) ◽

pp. 440

Author(s):

ArvindKumar B. Sangavi ◽

Nasima Banu ◽

Shashikala P.

Keyword(s):

Fanconi Anemia ◽

Facial Palsy ◽

Genetic Disorder ◽

Myelogenous Leukemia ◽

Fanconi Anaemia ◽

Present Case Report ◽

Epithelial Cancers ◽

Rare Manifestation ◽

Acute Myelogenous ◽

Progressive Pancytopenia

<p class="abstract">Fanconi anemia (FA) is an autosomal recessive genetic disorder characterized by progressive pancytopenia, multiple congenital anomalies, increased susceptibility to acute myelogenous leukemia and epithelial cancers especially in head and neck and GUT. The otologic manifestations in patients with Fanconi anemia is only about 10%. The present case report highlights the rare manifestation of Facial palsy/otologicand other associated anomalies in a 5 year old boy with Fanconi anemia<span lang="EN-IN">.</span></p>

Download Full-text

Bone Marrow Failure as a Risk Factor for Clonal Evolution: Prospects for Leukemia Prevention

Hematology ◽

10.1182/asheducation-2007.1.40 ◽

2007 ◽

Vol 2007 (1) ◽

pp. 40-46 ◽

Cited By ~ 16

Author(s):

Grover C. Bagby ◽

Gabrielle Meyers

Keyword(s):

Bone Marrow ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Myelogenous Leukemia ◽

The Past ◽

Cell Pool ◽

Bone Marrow Failure Syndromes ◽

Acute Myelogenous ◽

Prevention Trials ◽

Stem Cell Pool

AbstractPatients with bone marrow failure syndromes are at risk for the development of clonal neoplasms, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia (MDS), and acute myelogenous leukemia (AML). Approximately 10% to 20% of those who survive acquired aplastic anemia will develop a clonal disease within the decade following their diagnosis. The relative risk of clonal neoplasms is very significantly increased in children and adults with inherited bone marrow failure syndromes as well. Until recently, the mechanisms underlying clonal evolution have been opaque, but a sufficient amount of evidence has now accumulated to support a model in which cells resistant to extracellular apoptotic cues are selected from the stem cell pool. Indeed, in the past two years this paradigm has been validated in preclinical models that are robust enough to reconsider new therapeutic objectives in aplastic states and to support the planning and development of rationally designed leukemia prevention trials.

Download Full-text