recent advances esp, in fanconi anemiaicksh.org/2018/data/ss06-3_hoon_kook.pdf · 2019. 11. 4. ·...
TRANSCRIPT
![Page 1: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/1.jpg)
Inherited BMFS: Recent Advances esp, in Fanconi Anemia
Hoon Kook, M.D.
Chonnam National University Children’s Hospital Gwangju, Korea
Scientific Session 2018. 3. 30.
![Page 2: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/2.jpg)
Introduction
• IBMFSs: genetic heterogeneous group of disorders
– Bone marrow failure
– One or more somatic abnormality
– Inherited or early embryonic development
• The precise incidence/prevalence: unclear
• Usually presents in childhood
but the age at presentation variable
• Malignant transformation
– MDS, AML, various epithelial cancers
![Page 3: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/3.jpg)
IBMFS
• IBMFS associated with pancytopenia – Fanconi anemia
– Dyskeratosis congenita
– Shwachman-Diamond Syndrome
– Cartilage-Hair Hypoplasia
– Pearson's syndrome
– Down syndrome
– Familial marrow dysfunction
• IBMFS associated with isolated cytopenia – Diamond-Blackfan Anemia
– Congenital dyserythropoietic anemia
– Severe congenital neutropenia
– Inherited thrombocytopenia
– Amegakaryocytic thromobocytopenia
– Thrombocytopenia with absent radii
![Page 4: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/4.jpg)
Fanconi Anemia (FA)
![Page 5: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/5.jpg)
Introduction
Inherited bone marrow failure syndrome characterized by - Pancytopenia - Predisposition to malignancy - Physical abnormalities
In 1927, Guido Fanconi first reported 3 brothers with macrocytosis, pancytopenia, and physical abnormalities.
![Page 6: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/6.jpg)
Clinical features of FA
1/200,000; estimated carrier frequency of 1/181 in North Am.
(1) Somatic abnormalities
- No overt physical/somatic abnormalities: 1/4~1/3
(2) Bone marrow failure
- Cytopenia: at 5-10 yrs of age
- Macrocytosis, thrombocytopenia: often
- Risk of full blown marrow failure: 50% at age of 40.
(3) Malignancies
- RR for AML & MDS: 700-6,000 x higher (Alter, 2014)
cf. CI of AML at age 40: 15-20%; CI of MDS at age 50: 40% (Alter, 2010)
- RR for H&N SCC (600 x); Esophagus (2,000 x); Vulva (3,000 x)
cf. Median age of SCCs: 33 yr for FA vs. 60-70 yr for general (Velleur, 2014)
CI of gynecological & H&N cancer: 30% at age 40 (Alter, 2014)
BRCA2 biallelic mutation: CI of cancers at age 7: 90%; CI of AML at age 10: 80% (Alter, 2014)
![Page 7: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/7.jpg)
Alter, Cancer in Fanconi anemia, 1927-2001, Cancer, 2003
37% 50%
46%
76%
![Page 8: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/8.jpg)
Incidence of Functional & Somatic Abn in FA
Dufour , Br J Haematol, 2017 No or subtle abnormalities in 25-30% of FA
![Page 9: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/9.jpg)
Facial features, short stature, typical radial ray abnormalities and café au lait
spots and hypopigmentation in patients with FA.
![Page 10: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/10.jpg)
PBS
Pancytopenia, and hypocellular BM
Development of AML in FA patient
BM Section
![Page 11: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/11.jpg)
Diagnosis of FA
(1) Suggestive features
- Presence of BMF & somatic malformations - Family history or personal history of BMFS
- Macrocytosis or thrombocytopenia - Spontaneous chromatid breakage
- Unbalanced 1q, 3q or 7q translocations on BM karyotyping during MDS or AML Dx work-up
- Unexpected occurrence of classical FA malignancies in young patients
- Excessive toxicity after standard chemotherapy for acute leukemia
(2) Chromosomal breakage test w/ DNA cross-linking agents - Gold standard for the Dx of FA
- Mitomycin C (MMC) or Diepoxybutane (DEB) exposure on PB lymphocyte culture
Hematopoietic somatic mosaicism: seen in upto 25% of FA cases
- Correction of mutated allele in a HSC or in a lymphocyte progenitor
- eg., back mutation, intragenic crossover, gene conversion or compensating
deletion/insertion
Test on skin fibroblasts to confirm the Dx in mosaic FA patients
cf. Exact correlation btw somatic mosaicism and hematopoietic function: not fully established
(3) Flow cytometry for cell cycle: auxiliary diagnostic test
- S2 delay or block
(4) Complementation analysis
(5) Next generation sequencing
![Page 12: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/12.jpg)
Diagnosis of FA
- ↑ Chr. breakage or aberration (breaks, gaps, rearrangements, radials, exchanges,
endoreduplications) in PB cells after culture w/ diepoxybutane (DEB) or
mitomycin C (MMC)
Blood lymphocytes (~90%) by somatic mosaicism or Skin fibroblasts (100%)
DEB 0.1 μg/mL
Chromosome breakage test (clastogenic assay)
![Page 13: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/13.jpg)
FA genes
Nalepa & Clapp, Nat Rev, 2018
21 genetic subtypes identified - 5 new entities added recently - Autosomal recessive disorder except for FANCB (XR), FANCR (also known asRAD51): dominant-negative mutation - FANCA (60%), FANCC (12%), FANCG (10%)
![Page 14: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/14.jpg)
Genotype-Phenotype correlation
FA: Guidelines for diagnosis and management, 4th edition (2014)
• FANCA – null alleles 1) earlier onset of hematologic abnormalities 2) higher risk of developing MDS &AML 3) shorter survival after diagnosis than with at least one hypomorphic mutation
• FANCC 1) less severe hematologic course 2) lower incidences of congenital microcephaly and radial ray abnormalities
• FANCG 1) more severe cytopenias 2) higher rates of MDS and AML
![Page 15: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/15.jpg)
FANCD2-FANCI ubiquitylation regulates the DNA
damage response
FANCT: E2 ubiquitin-conjugating Enz FANCL: E3 ubiquitin ligase
![Page 16: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/16.jpg)
The FA pathway orchestrates the interphase DNA
damage response (interstrand crosslink repair pathway)
Chromatin localization of FANCD2-FANCI heterodimer
Downstream FA Effector pathway
![Page 17: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/17.jpg)
Function of FA proteins
Multifunctional
(1) DNA repair
- Interstrand crosslink (ICL) repair pathway through mono-ubiquitylation
and chromatin localization of the FANCD2-FANCI heterodimer.
(2) Reactive oxygen species (ROS) detoxification (Zhang, 2005; Du, 2012)
(3) Energy metabolism (Cappelli, 2013)
(4) Cytokine signaling (Li, 2007; Anur, 2012)
![Page 18: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/18.jpg)
Management of FA at Diagnosis
Initial Work-up of FA
patients
Dufour, BJH 2017
Management based on cytopenia severity (at least one of the followings)
- Mild: Hgb (>10, but < lower limit for age);
ANC (1000-1,499), Plt (50k-149k) - Moderate: Hgb (8.0-9.9); ANC (500-999), Plt (20k-49k) - Severe: Hgb (< 8.0); ANC (<500), Plt (<20k) Lowest value of the 3 lineages defines the
level of severity
![Page 19: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/19.jpg)
Dufour, BJH 2017
![Page 20: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/20.jpg)
Growth factors: G-CSF, EPO
- Not recommended for long-term use d/t potential clonal evolution
- Anti-TNF-α: safe, but not effective against advanced BMF (Mehta, 2012)
Anabolic steroids:
(1) Danazole: 68% response in 37 FA (Paustian, 2016)
but hold d/t cytogen abn, lack of response, liver adenoma, MDS/AML
(2) Oxandrolone: 7/9 early response, but virilization in 3, ↑ LFT in 2 (Rose, 2014)
(3) Oxymetholone (0.5-1 mg/kg/d) in 49 Brazil FA
- Transfusion independence in 83% (median 3 mo), multilineage response, 55%
- 12% maintain hematologic response off Tx; Virilization in 100%
- 29/49 subsequent HSCT & 25/29 (86%), alive (Ribeiro, 2014)
Supportive care
(1) Iron chelation to start if RBC transfused >200 ml/kg or liver iron >7 mg/g dry wt
Or s-ferritin: >1,000 μg/L (Barone, 2015)
TPO mimetics, eltromopag or romiplostim:
Gene therapy using lentiviral vectors w/o conditioning
Treatment options
![Page 21: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/21.jpg)
HSCT
- Only curative option to correct marrow failure
- Better outcomes in last 2 decades
- Fludarabine containing conditioning
- BM preferred to PB due to less GvHD
- Post-transplant HNSCC: 4.4 x ↑ & 16 yr acceleration than non-TPL
- Malignancies: found in 40% 15-20 yr after SCT (Rosenberg, 2005)
34% at 20 yr after SCT (Peffault de Latour; EBMT; 2013)
Treatment options
![Page 22: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/22.jpg)
Peffault de Latour, Blood 2013
Allogeneic HSCT in FA: EBMT N = 795 (1972-2010)
OS = 49% at 20 yr
cGvHD, 2nd mal: time-dependent Poor Px factor
83%
64%
![Page 23: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/23.jpg)
Peffault de Latour, Blood 2013 EBMT
HSCT from an HLA-matched sibling donor
![Page 24: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/24.jpg)
Irradiation vs. Nonirradiation Conditioning
for MST in FA 148 FA from CIBMTR data btw 1990 & 2001
Supporting the use of nonirradiation conditioning Pasquini, BBMT 2008
Patients - All BM graft without T-cell deletion
Results Irradiation Non-irrad P value
Number 77 71
Median ANC recovery day 13 17 NS
ANC recovery 94% 89% NS
Platelet recovery at D+100 92% 92% NS
aGVHD, gr II-IV 23% 21% NS
cGvHD 18% 24% NS
5-yr OS 78% 81% NS
Factors ass w/ high mortality: 1) Age >10 (RR, 4,24; P<0.001) 2) Androgen therapy (RR, 2.62; P= .008) 3) CMV (+) either in donor or recipient (RR, 4.67; P= .39)
![Page 25: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/25.jpg)
Factors for Outcome of Related HSCT for FA
94 FA children: related HSCT at FSPRC, Saudi Arabia
MDS a/o abn cytogenetics / AML: 12 cases
Fluda + CY 20 mg/kg: best survival for
Matched familial donor HSCT for FA
OS: 92.5%, 89%, 86% at 1, 5, 10 yrs
Ayas, BBMT 2014
10 yr OS: CY 60 mg/kg vs. CY 20 mg/kg = 91% vs. 82% (P<.05) Rad conditioning vs. non-rad = 76% vs. 91% (P<.01) Fludarabine + CY 20 mg/kg: highest OS (95.2%; P<.05) Higher CY: ↑ hemorrhagic cystitis (20%) Squamous cell Ca in 3
![Page 26: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/26.jpg)
MSD in 43 FA conditioned w/ Cy 60 mg/kg
Bonfim Brazil, BBMT 2007
43 FA, marrow transplant from HLA-matched related donor
(Sib, 27; others, 6)
Conditioning: Cy alone 60 mg/kg (15 mg/kg x 4 d) GvHD prophylaxis: MTX + CyA Cytogenetic abn in 12 including 3 with rejection OS: 93% (40/43) median f-up 3.7 yr Graft failure: Primary (n=1) - Retransplant : Alive Late (n=4) - Retransplant in 3 : Alive in 2 TRM: 7% aGvHD (III-IV): 2% cGvHD (extensive): 24.5% Mucositis (high grade): 60%
![Page 27: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/27.jpg)
HSCT from an HLA-matched sibling donor
Dufour, BJH 2017
SCT from healthy MSD using non-irradiation regimens with Flu + Cy, and BMT: Tx of Choice w/ excellent OS
![Page 28: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/28.jpg)
UBMT for FA
Wagner, Blood, 2007
CIBMTR: 98 FA UBMT btw 1990-2003
Flu (+) Flu (-) P value
3-yr adjusted OS 52% 13% <.001
ANC recovery 89% 69% .02
Plt recovery 73% 23% <.001
TRM at D+100 24% 65% <.001
Flu-conditioning w/ TCD BM graft Early referral for TPL w/o excessive Tf
![Page 29: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/29.jpg)
Peffault de Latour, Blood 2013
EBMT
77%
57%
![Page 30: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/30.jpg)
HSCT from an HLA-matched unrelated donor
Dufour, BJH 2017
SCT from MUD: Best results w/ Flu-conditioning w/ ex vivo or in vivo TCD before excessive transfusions and clonal abnormalities Inferior OS outcome for MUD (64%) vs. MSD (83%) (P =.011)
![Page 31: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/31.jpg)
Alternative Donor HSCT for FA
130 FA patients at U. Minnesota btw 1995 & 2012
Alternative donor HSCT: excellent for FA w/o prior opport inf. or transfusions
MacMillan, Blood 2015
Patients - Age: 9.0 (1-48) - Clonal abn (28%), late MDS/AML (8%) - Median f-up: 7.7 yr - Conditioning: CY + single TBI + ATG +/- Fluda
Results - 5-yr OS: 58% - aGvHD 2-4, 20%; cGvHD, 10% - Better survival - Flu-containing, esp w/ TBI 3Gy: RR, 0.1 - Higher mortality - Older age (10-17, RR = 2,2; >18, RR = 2.7) - Prior opportunistic infection (11%, RR = 3.5) - CMV + (RR = 2.3) - Prior RBC or Plt transfusions (74%, RR = 2.3)
N= 17
![Page 32: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/32.jpg)
Gluckman, BBMT 2007
HSCT from Cord blood
93 FA patients Eurocord Registry & EBMT
Patients : 93 FA, median age at transplant: 8.6 yr - HLA matching: 6/6, 13%; 5/6, 37%; 4/6, 43%; 3/6, 5% - Median NC: 4.9 x 107/kg of recipient CD34+: 1.9 x 105/kg of recipient - Conditioning: various, but Flu-based in 61%
Flu+Cy±TBI: m.c. (< 5Gy in 13; w/o TBI in 28) - GvHD prophylaxis: CsA + pred ± ATG in 58% Results : - Neutrophil recovery: 60% at D+60 - aGvHD 2-4, 32%; cGvHD, 16% - OS: 40% ± 5%
OS OS OS
Donor selection & Flu-conditioning can improve survival
![Page 33: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/33.jpg)
Zecca, BBMT 2014
Haplo- TCD HSCT in FA
12 FA patients from Pavia & Roma, Italy
Patients : 12 FA, 14 SCT - RI conditioning: Flu (120 mg/m2) + Cy (1200 mg/m2) + fATG (40 mg/kg) ± single TBI (2Gy) (11/14) - TCD (CD34+ selected) PBSC - Donor: Father, 8; Mother, 6 Results : - Graft rejection in 2 (17%) : retransplanted from other parent - aGvHD 2-4, 17%; cGvHD, 35% - No regimen-related mortality - TRM: 17% - 5-yr OS, 83%; EFS, 67%; DFS, 83%
Fluda conditioning + high-dose TCD SC: engraftment w/ good OS & DFS
Haplo SCT in FA: feasible
![Page 34: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/34.jpg)
Haplo-BMT w/ Post-Transplant CY for FA
30 FA patients at Federal Univ. of Parana, Brazil btw 2008 & 2015
Haplo-BMT w/ PT-CY: suitable option for FA w/o MRD or MUD Bonfim, BBMT 2017
Patients - 26 FA w/o MRD or MUD 4 FA w/ graft failure after HSCT - Median age: 10 yrs (4 – 16 yr) - Conditioning 1) CY 10 mg/kg + Flu 150 mg/m2 + TBI 2-3 Gy (n=5) 2) Flu 150 mg/m2 + TBI 2 Gy (n=9) 3) Flu 150 mg/m2 + TBI 2 Gy + rATG 4-5 mg/kg (n=13) 4) Flu 150 mg/m2 + TBI 1 Gy + rATG 4-5 mg/kg (n=3) - Un-manipulated BM - GvHD prophylaxis: PT-CY 25 mg/kg/d on D+3 & D+4 CyA 3 mg/kg from D+5; MMF at 15 mg/kg/d 3 x/d - Donor: mother (n=17), sibling (n=5), father (n=4) - Donor specific Ab (DSA, n=3): Tx w/ rituximab & pheresis
Results 1-yr OS: 72.6% w/ median follow-up of 30 months - CMV reactivation: 75% at D+32 - No PTLD, No VOD - Hemorrhagic cystitis (50%) 14 FA w/o rATG vs. 16 FA w/ rATG - OS, P=NS; severe GvHD ↓ w/ rATG
![Page 35: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/35.jpg)
SCT for FA transformed to MDS/AML
(1) Low-dose chemotherapy followed by SCT
Cincinnati group - 3 AML patients + 1 CMML patient - “mini-FLAG induction regimen Low-dose Flu (30 mg/m2 x 3 d) + Cy (300 mg/m2 x 3 d) + G-CSF (5 µg/kg x 5 d) - Conditioning: Flu + Cy + TBI 450 cGy + ATG Results : - No major toxicity - 2 CR & 1 PR at SCT
- Survival in 1 with a f-up of 8 mo (Mehta, PBC 2007)
Hannover, Germany - 3 AML patients - Minimal antileukemic treatment 6-TG (40 mg/m2 x 8 d) + ara-C (40 mg/m2 x 7 d) + single VCR None 6-TG (40 mg/m2 x 24 d, then half x 30 d) + ara-C (40 mg/m2 x 4 d) - Conditioning: Flu (150-180 mg/m2) + Bu (1.6 mg/kg) + Cy (20-40 mg/kg) ± ATG 40-80 mg/kg or Campath 35 mg/m2 Results : - 2 chemo patients showing marrow aplasia at the time of transplant - 3/3 alive at f-up of 14-174 mo
- All with cGvHD (Beier, BMT 2015)
![Page 36: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/36.jpg)
SCT for FA transformed to MDS/AML
(2) Full-dose chemotherapy followed by Reduced intensity SCT
Saint Louis - 8 patients (AML, 7; MDS, 1) - “Full dose FLAG regimen Flu (30 mg/m2 x 5 d) + ara-C (2.0 g/m2 x 5 d) + G-CSF (5 µg/kg x 5 d) - Reduced intensity conditioning within 3 weeks:
Flu (120 mg/m2) + Cy (40 mg/kg) + TBI 200 cGy + rATG only in MUD Results : - 5/8 alive - Cause of deaths: relapse, 1; cGvHD, 1; infection,1)
(Talbot, Hematologica, 2014; Peffault de Latour, 2016) Saitama, Japan: Addition of Ara-C in conditioning 4 patients (AML, 3; MDS with 12% blasts, 1) - Antileukemic treatment No chemotherapy (MDS, blast 12%) Reduced AML chemo: CR MDS progression: (blast 27%) No chemo AML after ALL: (blast 30%) No chemo - Conditioning: Flu (120-150 mg/m2) + Cy (40 mg/kg) + Ara-C (6-20 g/m2) + TBI (4.5-6 Gy) ± rATG (5 mg/kg in 2) Results : - 4/4 alive (8 mo- 14yr) - SE: Gr IV in 1 (IPS); aGvHD (Gr >2): none; extensive cGvHD; none
(Aoki, BBMT 2016)
![Page 37: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/37.jpg)
SCT for FA transformed to MDS/AML
(3) Full-dose chemotherapy followed by Reduced intensity SCT
Minnesota - 21 patients (AML, 12; ALL, 1; MDS, 8), BRCA2 biallelic mutation in 6 - Chemotherapy prior SCT: 8
Remission in 3 Toxicities in 6, severe in 3 Survival: 2
- 5-yr OS after HSCT: 33% (Mitchell, BJH, 2014)
Current Policy for FA with MDS/AML from Minnesota
- Without chemotherapy prior to SCT - TCD SCT - Conditioning: Flu + Cy+ ATG + TBI 300 cGy
(MacMillan, Blood 2015)
Some subsets might benefit from cytoreduction before HSCT - eg., MDS with excess blast, overt AML or BRCA2/FANCD1 patients (Peffault de Latour 2016)
![Page 38: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/38.jpg)
HSCT for FA w/ Cytogen abn, MDS, or A Leukemia
IBMTR data from 1985 to 2007
113 FA (Cytogen abn, n =54; MDS, n =45; AL, n=14)
Younger patients & HLA-related SCT w/ cytogen abn only:
best survival Ayas, JCO 2013
64%, 55% at 1, 5-yr OS
Patients - Complex cytogen abn (n =18/54, 33.3%) - Acute leukemia (n=14; AML, 12; ALL, 2) - Stem cell: BM, 75%; PB, 12%; CB, 13% - Conditioning: Rad, 60% (TBI, 42%; TLI/TAI, 19%) Fluda, 27%; ATG, 50% Results - Neutrophil engraftment: 78% at D+28, 85% at D+100 - 2ndary GF: 9% - aGvHD ≥ 2 in 26%, ≥ 3 in 12% at D+100 - cGvHD: 20%, 23% at 1, 5 yrs; extensive in 12 Px factors for 5-yr OS - Age < 14 yr: 69% vs. 39%; P<.05 - In related SCT (n=82) Cyt abn only vs. MDS/AL = 67% vs. 43%; P<.05
Related SCT (n=82)
![Page 39: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/39.jpg)
Dufour, BJH 2017
![Page 40: Recent Advances esp, in Fanconi Anemiaicksh.org/2018/data/SS06-3_Hoon_Kook.pdf · 2019. 11. 4. · Clinical features of FA 1/200,000; estimated carrier frequency of 1/181 in North](https://reader035.vdocuments.us/reader035/viewer/2022071000/5fbc094a6d0eeb78bd027546/html5/thumbnails/40.jpg)
Thank you for your attention!