Fanconi anemia (FA) has long been considered a severe inherited bone marrow failure (BMF) disorder of early childhood. Thus, management of this multisystem disorder has previously been unfamiliar to many hematologists specializing in the care of adolescents and young adults (AYA). The increased diagnosis of FA in AYA patients, facilitated by widely available germline genomic testing, improved long-term survival of children with FA following matched sibling and alternative donor hematopoietic stem cell transplantation (HSCT) performed for BMF, and expanding need in the near future for long-term monitoring in patients achieving hematologic stabilization following ex vivo gene therapy are all reasons why management of FA in AYA populations deserves specific consideration. In this review, we address the unique challenges and evidence-based practice recommendations for the management of AYA patients with FA. Specific topics addressed include hematologic monitoring in AYA patients yet to undergo HSCT, management of myeloid malignancies occurring in FA, diagnosis and management of nonhematologic malignances and organ dysfunction in AYA patients with FA, and evolving considerations for the long-term monitoring of patients with FA undergoing gene therapy.

1.
Dufour
C
,
Pierri
F.
Modern management of Fanconi anemia
.
Hematology Am Soc Hematol Educ Program
.
2022
;
2022
(
1
):
649
-
657
.
doi:10.1182/hematology.2022000393
.
2.
Fanconi Anemia Clinical Care Guidelines
. 5th ed.
Fanconi Anemia Research Fund
;
Eugene, OR
,
2020
.
3.
Sevilla
J
,
Navarro
S
,
Rio
P
, et al.
Improved collection of hematopoietic stem cells and progenitors from Fanconi anemia patients for gene therapy purposes
.
Mol Ther Methods Clin Dev
.
2021
;
22
:
66
-
75
.
doi:10.1016/j.omtm.2021.06.001
.
4.
Brosh
RM
,
Bellani
M
,
Liu
Y
,
Seidman
MM
.
Fanconi Anemia: a DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging
.
Ageing Res Rev
.
2017
;
33
:
67
-
75
.
doi:10.1016/j.arr.2016.05.005
.
5.
Hira
A
,
Yabe
H
,
Yoshida
K
, et al.
Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients
.
Blood
.
2013
;
122
(
18
):
3206
-
3209
.
doi:10.1182/blood-2013-06-507962
.
6.
Casado
JA
,
Valeri
A
,
Sanchez-Domínguez
R
, et al.
Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia
.
J Clin Invest
.
2022
;
132
(
15
).
doi:10.1172/JCI142842
.
7.
Kutler
DI
,
Singh
B
,
Satagopan
J
, et al.
A 20-year perspective on the International Fanconi Anemia Registry (IFAR)
.
Blood
.
2003
;
101
(
4
):
1249
-
1256
.
doi:10.1182/blood-2002-07-2170
.
8.
Nicoletti
E
,
Rao
G
,
Bueren
JA
, et al.
Mosaicism in Fanconi anemia: concise review and evaluation of published cases with focus on clinical course of blood count normalization
.
Ann Hematol
.
2020
;
99
(
5
):
913
-
924
.
doi:10.1007/s00277-020-03954-2
.
9.
Wang
YM
,
Loveless
M
,
Miller
E
, et al.
Phenotypes of adults with Fanconi anaemia
.
Br J Haematol
.
2023
;
201
(
1
):
133
-
139
.
doi:10.1111/bjh.18603
.
10.
Steinberg-Shemer
O
,
Goldberg
TA
,
Yacobovich
J
, et al.
Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population
.
Haematologica
.
2020
;
105
(
7
):
1825
-
1834
.
doi:10.3324/haematol.2019.222877
.
11.
Risitano
AM
,
Marotta
S
,
Calzone
R
,
Grimaldi
F
,
Zatterale
A
;
RIAF Contributors
.
Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned
.
Haematologica
.
2016
;
101
(
3
):
319
-
327
.
doi:10.3324/haematol.2015.133520
.
12.
Río
P
,
Navarro
S
,
Wang
W
, et al.
Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia
.
Nat Med
.
2019
;
25
(
9
):
1396
-
1401
.
doi:10.1038/s41591-019-0550-z
.
13.
Bierings
M
,
Bonfim
C
,
Peffault De Latour
R
, et al
;
EBMT SAA WP
.
Transplant results in adults with Fanconi anaemia
.
Br J Haematol
.
2018
;
180
(
1
):
100
-
109
.
doi:10.1111/bjh.15006
.
14.
Ebens
CL
,
MacMillan
ML
,
Wagner
JE
.
Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations
.
Expert Rev Hematol
.
2017
;
10
(
1
):
81
-
97
.
doi:10.1080/17474086.2016.1268048
.
15.
Mehta
PA
,
Davies
SM
,
Leemhuis
T
, et al.
Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study
.
Blood
.
2017
;
129
(
16
):
2308
-
2315
.
doi:10.1182/blood-2016-09-743112
.
16.
Nassani
M
,
Fakih
RE
,
Passweg
J
, et al.
The role of androgen therapy in acquired aplastic anemia and other bone marrow failure syndromes
.
Front Oncol
.
2023
;
13
:
1135160
.
doi:10.3389/fonc.2023.1135160
.
17.
Pollard
JA
,
Furutani
E
,
Liu
S
, et al.
Metformin for treatment of cytopenias in children and young adults with Fanconi anemia
.
Blood Adv
.
2022
;
6
(
12
):
3803
-
3811
.
doi:10.1182/bloodadvances.2021006490
.
18.
Paustian
L
,
Chao
MM
,
Hanenberg
H
, et al.
Androgen therapy in Fanconi anemia: a retrospective analysis of 30 years in Germany
.
Pediatr Hematol Oncol
.
2016
;
33
(
1
):
5
-
12
.
doi:10.3109/08880018.2015.1129567
.
19.
Alter
BP
.
Fanconi anemia and the development of leukemia
.
Best Pract Res Clin Haematol
.
2014
;
27
(
3-4
):
214
-
221
.
doi:10.1016/j.beha.2014.10.002
.
20.
Flatt
T
,
Neville
K
,
Lewing
K
,
Dalal
J.
Successful treatment of Fanconi anemia and T-cell acute lymphoblastic leukemia
.
Case Rep Hematol
.
2012
;
2012
:
396395
.
doi:10.1155/2012/396395
.
21.
Byrd
PJ
,
Stewart
GS
,
Smith
A
, et al.
A hypomorphic PALB2 allele gives rise to an unusual form of FA-N associated with lymphoid tumour development
.
PLoS Genet
.
2016
;
12
(
3
):
e1005945
.
doi:10.1371/journal.pgen.1005945
.
22.
Behrens
YL
,
Göhring
G
,
Bawadi
R
, et al.
A novel classification of hematologic conditions in patients with Fanconi anemia
.
Haematologica
.
2021
;
106
(
11
):
3000
-
3003
.
doi:10.3324/haematol.2021.279332
.
23.
Sebert
M
,
Gachet
S
,
Leblanc
T
, et al.
Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia
.
Cell Stem Cell
.
2023
;
30
(
2
):
153
-
170.e9170e9
.
doi:10.1016/j.stem.2023.01.006
.
24.
Choijilsuren
HB
,
Park
Y
,
Jung
M.
Mechanisms of somatic transformation in inherited bone marrow failure syndromes
.
Hematology Am Soc Hematol Educ Program
.
2021
;
2021
(
1
):
390
-
398
.
doi:10.1182/hematology.2021000271
.
25.
Quentin
S
,
Cuccuini
W
,
Ceccaldi
R
, et al.
Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions
.
Blood
.
2011
;
117
(
15
):
e161
-
e170
.
doi:10.1182/blood-2010-09-308726
.
26.
Marion
W
,
Koppe
T
,
Chen
C-C
, et al.
RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia
.
Leukemia
.
2023
;
37
(
8
):
1698
-
1708
.
doi:10.1038/s41375-023-01945-6
.
27.
Peffault de Latour
R
,
Soulier
J.
How I treat MDS and AML in Fanconi anemia
.
Blood
.
2016
;
127
(
24
):
2971
-
2979
.
doi:10.1182/blood-2016-01-583625
.
28.
Alter
BP
,
Caruso
JP
,
Drachtman
RA
,
Uchida
T
,
Velagaleti
GV
,
Elghetany
MT
.
Fanconi anemia: myelodysplasia as a predictor of outcome
.
Cancer Genet Cytogenet
.
2000
;
117
(
2
):
125
-
131
.
doi:10.1016/s0165-4608(99)00159-4
.
29.
MacMillan
ML
,
DeFor
TE
,
Young
J-A
, et al.
Alternative donor hematopoietic cell transplantation for Fanconi anemia
.
Blood
.
2015
;
125
(
24
):
3798
-
3804
.
doi:10.1182/blood-2015-02-626002
.
30.
Strocchio
L
,
Pagliara
D
,
Algeri
M
, et al.
HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia
.
Blood Adv
.
2021
;
5
(
5
):
1333
-
1339
.
doi:10.1182/bloodadvances.2020003707
.
31.
Bonfim
C
,
Ribeiro
L
,
Nichele
S
, et al.
Haploidentical bone marrow transplantation with post-transplant cyclophosphamide for children and adolescents with fanconi anemia
.
Biol Blood Marrow Transplant
.
2017
;
23
(
2
):
310
-
317
.
doi:10.1016/j.bbmt.2016.11.006
.
32.
Giardino
S
,
de Latour
RP
,
Aljurf
M
, et al
;
Severe Aplastic Anemia and Chronic Malignancies Working Parties of European Blood and Marrow Transplantation group
.
Outcome of patients with Fanconi anemia developing myelodysplasia and acute leukemia who received allogeneic hematopoietic stem cell transplantation: a retrospective analysis on behalf of EBMT group
.
Am J Hematol
.
2020
;
95
(
7
):
809
-
816
.
doi:10.1002/ajh.25810
.
33.
Bernard
F
,
Uppungunduri
CRS
,
Meyer
S
, et al
;
UK Paediatric BMT group
.
Excellent overall and chronic graft-versus-host-disease-free event-free survival in Fanconi anaemia patients undergoing matched related- and unrelated-donor bone marrow transplantation using alemtuzumab-Flu-Cy: the UK experience
.
Br J Haematol
.
2021
;
193
(
4
):
804
-
813
.
doi:10.1111/bjh.17418
.
34.
Chattopadhyay
S
,
Lionel
S
,
Selvarajan
S
, et al.
Fludarabine-based low-intensity conditioning for Fanconi anemia is associated with good outcomes in aplastic anemia but not in MDS—a single-center experience
.
Mediterr J Hematol Infect Dis
.
2023
;
15
(
1
):
e2023039
.
doi:10.4084/MJHID.2023.039
.
35.
Mitchell
R
,
Wagner
JE
,
Hirsch
B
,
DeFor
TE
,
Zierhut
H
,
MacMillan
ML
.
Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia
.
Br J Haematol
.
2014
;
164
(
3
):
384
-
395
.
doi:10.1111/bjh.12634
.
36.
Lasaga
M
,
Río
P
,
Vilas-Zornoza
A
, et al.
Gene therapy restores the transcriptional program of hematopoietic stem cells in Fanconi anemia
.
Haematologica
.
2023
;
108
(
10
):
2652
-
2663
.
doi:10.3324/haematol.2022.282418
.
37.
Czechowicz
A
,
Sevilla
J
,
Rajni
A
, et al.
Gene therapy for Fanconi anemia [Group A]: interim results of RP-L102 clinical trials
.
Blood
.
2023
;
138
(
suppl 1
):
3968
.
doi:10.1182/blood-2021-147071
.
38.
Altintas
B
,
Giri
N
,
McReynolds
LJ
,
Best
A
,
Alter
BP
.
Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort
.
Haematologica
.
2023
;
108
(
1
):
69
-
82
.
doi:10.3324/haematol.2021.279981
.
39.
Silva de Araujo
BE
,
Markgraf
M
,
de Santana Almeida Araujo
IK
, et al.
A new multi-color FISH assay for brush biopsy-based detection of chromosomal aneuploidy in oral (pre)cancer in patients with Fanconi anemia
.
Cancers (Basel)
.
2022
;
14
(
14
):
3468
.
doi:10.3390/cancers14143468
.
40.
Cappelli
E
,
Bertola
N
,
Bruno
S
, et al.
A multidrug approach to modulate the mitochondrial metabolism impairment and relative oxidative stress in Fanconi anemia complementation group A
.
Metabolites
.
2021
;
12
(
1
):
6
.
doi:10.3390/metabo12010006
.
41.
Webster
ALH
,
Sanders
MA
,
Patel
K
, et al.
Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer
.
Nature
.
2022
;
612
(
7940
):
495
-
502
doi:10.1038/s41586-022-05253-4
.
42.
Koo
J
,
Grom-Mansencal
I
,
Howell
JC
, et al.
Gonadal function in pediatric Fanconi anemia patients treated with hematopoietic stem cell transplant
.
Haematologica
.
2023
;
108
(
9
):
2358
-
2368
.
doi:10.3324/haematol.2022.282094
.
43.
Tsui
V
,
Crismani
W.
The Fanconi anemia pathway and fertility
.
Trends Genet
.
2019
;
35
(
3
):
199
-
214
.
doi:10.1016/j.tig.2018.12.007
.
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