Noteworthy HSCT Outcomes in Fanconi Anemia based on Protocols with or without Fludarabine: A Systematic Review

  

    
Group
    
Study

      (First Author, Year)
    
Median HSCT FU

      (Range) (yr.)
    
OS (Time)
    
Transplant-Related Morbidity
    
Secondary Malignancy
  
  

    
FLU-based
    
S. Chaudhury, 2008
    
3.2 (1 - 6.5)
    
72.2 (5-yr.)
    
GvHD, Infection, ARDS, MOF, Relapsed AML
    
SCC (V)
  
  

    
B. Kuskonmaz, 2016
    
4.5 (0.83 - 10.9)
    
96 (5-yr.)
    
GF, Infection
    
None
  
  

    
P. Anur, 2016
    
7.45 (2.2 - 15.3)
    
100, 84 (5-, 10-yr.)
    
Secondary Malignancy
    
SCC, MDS (XRT-)
  
  

    
G. M. Fathy, 2017
    
N. M.
    
68.3 (6-yr)
    
GF, Infection, Intracranial H, aGVHD, VOD, Relapsed AML
    
AML
  
  

    
C. L. Ebens, 2018
    
7 (3.9 - 9.6)
    
90 (5-yr)
    
GvHD, GF, Infection, MOF
    
N. M.
  
  

    
M. Ayas, 2019
    
3.1 (2.7 - 3.6)
    
89.5 (5-yr.)
    
GvHD, Recurrence Leukemia
    
None
  
  

    
G. Tuysuz, 2019
    
3 (0.08 - 13.25)
    
70.5 (3-yr.)
    
Infection, GvHD, HC
    
None
  
  

    
R. Uppuluri, 2020
    
2.5
    
68.4 (2.5-yr.)
    
GvHD, Infection, GF, Ruptured Peliosis Hepatis
    
N. M.
  
  

    
L. Murillo-Sanjuán, 2021
    
6.5 (0.27 - 11.1)
    
73 (5-yr.)
    
Infection, GF, PTLD, Relapse, Secondary Malignancy
    
SCC
  
  

    
O. Fink, 2023
    
2.1 (0 - 20.1)
    
82.9 (2-yr.)
    
Infection, ARDS, Secondary Malignancy
    
SCC (O), Burkitt Lymphoma
  
  

    
non-FLU-based
    
M. Kohli-Kumar, 1994
    
2.25 (0.5 - 6.25)
    
100 (2-yr.)
    
None
    
N. M.
  
  

    
E. Gluckman, 1995
    
2.75 (0.3 - 13.5)
    
86 (2.75-yr.); 

      82, 70 vs. 55 (XRT-); 

      91 vs. 70 (ATG-) (2-yr.)
    
N. M.
    
SCC (T, L), AML

      (XRT- (LFI))
  
  

    
C. Dufour, 2001
    
3 (0.1 - 16.3)
    
80.8 (3-yr.)
    
cGvHD, ARSD, MOF
    
None
  
  

    
A. Farzin, 2007
    
10.2 (2.5 - 15.9)
    
89 (10-yr.)
    
MOF (ARDS, Cerebral Infarcts, Fulminant Hepatic Failure, Autoimmune    Anemia, Autoimmune Thrombocytopenia, Interstitial Pneumonia), Relapsed AML
    
SCC (T, A, HN)
  
  

    
C. M. Bonfim, 2007
    
3.7 (0.6 - 7.9)
    
93 (3.7-yr.)
    
GF, MOF, Infection, NC, RRT
    
SCC (T)
  
  

    
T. Rostami, 2022
    
2 (0.2 - 8.5)
    
84.14, 82.16 (1-, 5-yr.)
    
Infection, GvHD, GF, Toxicity (CNS)
    
N. M.
  
  

    
Both
    
F. Locatelli, 2007
    
6 (0.25 - 16)
    
86 vs. 59 (FLU-) (8-yr.)
    
Secondary Malignancy (non-FLU)
    
SCC (T)
  
  

    
J. E. Wagner, 2007
    
14.6 (6.1 - 19.3)
    
52 vs. 13 (3-yr.)
    
GF: 2 vs. 6, GvHD: 5 vs. 3, Interstitial Pneumonitis: 0 vs. 1, OF: 2    vs. 0, Recurrent Leukemia: 1 vs. 1 (non-FLU-)
    
None
  
  

    
E. Gluckman, 2007
    
1.8 (0.25 - 10)
    
50 vs. 25 (FLU-) (3-yr.)
    
Infection, GF, HC, aGvHD, MOF, VOD, ARDS
    
N. M.
  
  

    
M. Akif Yesilipek, 2009
    
2.6 (0.25 - 7.5)
    
90 vs. 50 (3-yr.)
    
VOD vs. Infection (FLU- vs. non-FLU-)
    
AML (non-FLU-)
  
  

    
P. Stepensky, 2011
    
2.6 (0 - 12.4)
    
83 vs. 35 (FLU-) (10.9-yr.)
    
GvHD: 1 vs. 9, Infection: 2 vs. 1, Secondary Malignancy: 0 vs. 1
    
Yes (non-FLU-)
  
  

    
A. A. Hamidieh, 2011
    
1.1 (0.25 - 13.5)
    
36.4 vs. 70 (3-yr.)
    
GF, GvHD (n = 1), PTLD vs. Infection, GvHD (n = 5), H, TTP, ARDS (FLU-    vs. non-FLU)
    
N. M.
  
  

    
R. Peffault de Latour, 2013 (13)
    
6 (0 - 28)
    
65, 52, 36 (FLU-) 

      (5-, 15-, 20-yr.)
    
GvHD, Infection, GF, Toxicity, Relapse, Secondary Malignancy
    
SCC (Mo, T, O, L, V-Vg), ST, Lymphoma, AL, MDS
  
  

    
S. E. Smetsers, 2016
    
5.5 (0 - 23.5)
    
76.4; 87.8 vs. 59.3 (5-yr.)
    
Relapsed Leukemia, aGVHD, Infection, MOF, Secondary Malignancy
    
 SCC (HN, O, Vg)
  
  

    
F. Bernard, 2021
    
6.2 (5 - 7.3)
    
79.9; 88.3 vs. 27.3 (5-yr.)
    
Relapse, Gliomatosis cerebri, cGVHD, BOS
    
SCC (Gingival, T, O), Gliomatosis cerebri
  
  

    
M. Yabe, 2021
    
8.7 (0.1 - 28.6)
    
81; 87.1 vs. 66.7 (FLU-); 

      87.5 vs. 59.4 (ATG/ALG-); 

      77, 72 

      (5-, 10-, 15-yr.)
    
MOF, Relapse, GvHD, Infection, PTLD, Secondary Malignancy
    
SCC (T, M, O), donor-type AML, non-Hodgkin Lymphoma
  
  

    
Abbreviations: FU: Follow Up;    Yr.: Year; R: Range; OS: Overall Survival; CY: Cyclophosphamide; ATG:    Anti-thymocyte Globulin; TAI: Thoracoabdominal Irradiation; cGy: Centi Grays;    S: Shielding; LFI: Limited Field irradiation; TBI: Total Body Irradiation;    Ara-c: Cytarabine; FLU: Fludarabine; ALEM: Alemtuzumab; SDTBI: Single Dose    Total Body Irradiation; RT: Radiation Therapy; BU: Busulfan; SFTBI: Single    Fraction Total Body Irradiation; PTCY: Post Transplant Cyclophosphamide; N. M.: Not Mentioned; GF: Graft Failure; aGvHD: Acute    Graft versus Host Disease; VOD: Veno Occulsion Disease; MOF: Multiple Organ    Failure; ARDS: Acute respiratory distress    syndrome; AML: Acute Myeloblastic Leukemia; HC:    Hemorrhagic Cystitis; SCC: Squamous Cell Carcinoma;    T: Tongue; L: Larynx; A: Anus; HN: Head and Neck; V: Vaginal; AL: Acute    Leukemia; M: Myeloid; ML: Mixed Lineage; MDS:    Myelodysplastic Syndrome; N. M.: Not Mentioned. 
  

Table 5: The secondary HSCT outcomes of the cohorts concerning the conditioning regimen protocol group—FLU-, non-FLU-, and both.

The SMNs

Four cohorts in the FLU group who were irradiated with SDTBI 150 – 450 cGy developed squamous cell carcinoma (SCC) [19,27,31,32]. MDS and Burkitt’s lymphoma were reported in two of these studies [27,32]. In an Egyptian study secondary AML was reported in cases without irradiation [24].

SCC was reported in three studies that were non-FLU-based with or without the use of XRT [17,23,33]. Similarly, the Italian cohort, based on a CIBMTR report in 1995, had developed SCC without the utilization of XRT; Secondary AML was also reported in the same study [23]. Two patients who underwent HSCT using non-FLUXRT protocol also developed SCC [17]. The Brazilian study reported SCC development within 5-years post-HSCT with extensive cGvHD occurrence [33].

SCC was reported in five studies [66, 35, 39-41], while secondary AML occurred in two [36,41]. Lymphoma [16,41] and gliomatosis cerebri, nine years post-HSCT [40], were reported in two and one cohorts respectively. Two Japanese boys developed donor-type AML and non-hodgkin lymphoma six and one year after being conditioned with FLU-based TBI and TAI protocols in M. Yabe’s study [41]. A study by P. Stepensky defined SMNs in patients without FLU [38].

The OS and cause of death

Among ten cohorts who received FLU-based conditioning regimen, the average OS rates were reported as following: < 5-year OS at 84.1% (n = 5), 5-year OS at 74% (n = 3), and > 5-year OS was noted at 76.1% (n = 2).

Two studies reported = 90% 5-year OS with a median FU of 4.5 – 7 years in the FLU-based setting (FLU 175 mg/m2) [20,28]; however, three studies with lower dose FLU (140 mg/m2) reported 72.2% – 89.5% OS rate [19,29,31]. Three cohorts transplanted with FLU at 120 – 180 mg/m2 stated < 90% of 3-, 2.5-, and 2-year OS rates, respectively [21,30,32]. Higher OS rate of 84% in the American cohort conditioned within a FLU-based regimen (140 – 150 mg/m2) was reported [27]. Subsequently, the lowest OS within 6 years was 68.3% in the Egyptian cohort [24].

Subsequently, in the non-FLU-based conditioning regimen, the OS rates were at 90% (< 5-year), 82% (5-year), and 89% (> 5-year) in one, four, and one cohort, respectively.

A 5-year OS rate of 82.16% was reported in the Iranian cohort with the non-FLU-non-XRT protocol [34]. Among three studies conditioned with non-FLU-XRT, the longer the time from HSCT, the lower the OS rate. It means that 2-year OS: 100%, 2.75-year OS: 86%, and 3-year OS: 80.8% [22,23,26]. In parallel, a multi-institution study utilizing LDCY calculated the 3.7-year OS rate of 93% [33] Similarly, the 10-year OS of 89% was reported in the American cohort, which is consistence with non-FLU-XRT settings [17].

Nine studies confirmed the profound difference in OS based on FLU-based regimens compared to non-FLU ones with the median FU time of 3 – 10.9 years [16,18,35-41]. All cohorts except one by A.A. Hamidieh reported higher OS rates in patients who received FLU. They did not find a statistically significant difference in 3-year OS (36.4% vs. 70%; P-value = 0.112) [37]. In contrast, The EBMT 2007 report stated a 3-year OS rate of 50% vs. 25% in the FLU- vs. non-FLUbased conditioning regimen, respectively (P-value = 0.01). Howbeit, irradiation usage was not described as a statistically determining factor, 32% vs. 47% (XRT- vs. non-XRT; P-value = 0.21) [25].

Infection and GvHD development were reported as the main TRM in eight [19-21,24,28,30-32] and six [19-21,24,29,30] cohorts with FLU-based protocol. In tandem, five cohorts reported that the FA-HSCT patients died of GF [20,21,24,28,31]. Secondary AML [19,24,29] and SMNs [27,31,32] occurred in three cohorts each.

Two studies defined MOF and ARDS as causes of death [17,26]. The neurological complication and CNS toxicity were reported in patients who were conditioned with CY-and CY-BU-based protocols, respectively [33,34].

Two studies by F. Locatelli and J. E. Wagner (47% vs. 81%; P-value < 0.001) described higher TRM rates in non-FLU- cohorts [18,35]. P. Stepensky and A. A. Hamidieh reported GvHD as TRM in non-FLU groups [37,38].

Discussion

This systematic review is the first conducted on 26 cohorts who underwent HSCT using preparative regimens to investigate post-HSCT complications regarding FLU usage with and without irradiation. FA patients need multidimensional management due to the sophisticated nature of the disease. The disease status, FANC genotypes, and mosaicism are effective factors that physicians have to consider to ensure successful HSCT outcomes. The clonal cytogenetic abnormalities evolution can be challenging. Patients fare better with low-intensity conditioning regimens due to the pathophysiology of This systematic review is the first conducted on 26 cohorts who underwent HSCT using preparative regimens to investigate post-HSCT complications regarding FLU usage with and without irradiation. FA patients need multidimensional management due to the sophisticated nature of the disease. The disease status, FANC genotypes, and mosaicism are effective factors that physicians have to consider to ensure successful HSCT outcomes. The clonal cytogenetic abnormalities evolution can be challenging. Patients fare better with low-intensity conditioning regimens due to the pathophysiology of

Approximately 31% of American transplant recipients with FA had evidence of cytogenetic clones- MDS, or AML; however, no significant difference was found [17], in contrast to S. E. Smetsers’s study [39]. Conversely, The EBMT report in 2013 defined BM status as an imperative factor associated with better OS (AA vs. MDS or AML; hazard ratio: 2.1, (95% confidence interval (1.41 – 3.11)) [16]. On the other hand, a retrospective analysis showed a significantly higher 5-year OS in the AA group rather than in the MDS or AML [40,41]. Since BM cellularity has a vital effect on the outcome of HSCT, we suggest mentioning BM status in every cohort.

The diagnosis and management of FA is contingent on the molecular work-up. FANCA, FANCG, FANCC, FANCD2, and FANCB is distributed in 85%, 9%, 3%, 2%, and 1% of the patients, respectively. The genotype-phenotype association in this disease is vague, which contributes to challenges in prognostic predictions, treatment decisions, and the FU programs [43].

In some studies, the subtype of FA and HSCT association were analyzed indecorously (n= 4). The remaining studies did not mention the subtypes at all (n = 15). In the American cohort it was noted that the complementation group (FANCA vs. non-FANCA) did not influence OS [17]. In parallel, the CIBMTR report in 2007 did not signify a correlation either [18]. Three out of 12 FA-A, one out of three FA-G, and one out of one FA-D1 patients died due to infection and disease relapse in the American cohort; however, it was stated as statistically not significant [19] unlike former studies. The unified multi-centric Spanish study was similar to the American study [31].

Spontaneous HSPC modifications of FANC-A, B, C, D2, N, and -T germline mutations lead to a somatic genetic rescue (SGR) event. It's worth noting that specific genome sequences, molecular defects, and mitochondrial oxidative metabolism contribute to development pathways and the occurrence rate of the aforementioned event in FA individuals. Ultimately an attenuated cellular and clinical phenotype leading to the late onset and diagnosis of FA individuals are associated with HSPC's SGR event. A recently published retrospective review of literature-reported FA mosaicism cases has indicated that mosaicism may be associated with a lower incidence of BMF or hematologic malignancy, lower requirement for HSCT, and relatively lower mortality during the initial two to four decades of life compared to non-mosaic patients [44].

Twenty-two cohorts had not determined mosaicism, despite its importance. The CIBMTR report in 2007 reported on the influence of mosaicism on HSCT outcomes. An observation suggests the higher GF incidence in recipients of non-FLU-XRT may be due to incomplete ablation of DEB-resistant lymphocytes, which the addition of FLU overcame [18]. Furthermore, an American study demonstrated mixed chimerism (91% donor cells) within two years in one patient with a 76% mosaicism history [17]. Two studies mentioned this matter but had not analyzed the relationship [19,20]. Carrying out a FANC group’s analysis and FA/BRCA pathway to determine mosaicism pre-HSCT, contributes to the appropriate conditioning regimen and irradiation usage, leading to better HSCT outcomes. There are contradictory outcomes regarding FLU- and non-FLU-based with or without XRT in the cohorts. The most efficacious engraftments were observed in patients receiving HSCT utilizing FLU-XRT-based (150 mg/m2) preparative regimens [19,27,29]. The use of FLU at 180 mg/m2 associated with 10.5% and 22% of GF in the two studies, respectively, with [21] and without [32] radiotherapy. The EMBT report in 2013 proved the FLU-based regimen has a vital role in efficient engraftment [16]. Unexpectedly, the highest rate of secondary GF (9.5%) was reported in the non-FLU-non-XRT-based protocol in a multiinstitution study [33].

Preparative regimens have similar effects on a-and c-GvHD development. All four studies comparing FLU and non-FLU-based regimens showed lower GvHD development in recipients using FLU [18,36-38]. Two cohorts support ‘the higher the CY dose, the higher the GvHD incidence’ in the non-FLU-non-XRT settings [26,33].

Likewise, post-HSCT toxicities regarding regimens are consistent with the engraftment and GvHD development outcomes; the higher the CY dose, the higher the OM and HC incidences. Overall, a higher OS rate was seen in patients who underwent HSCT in the FLU-non- XRT-based settings. Secondary AML and GvHD are described as the most common TRM in the XRT setting. Howbeit, the patients who were not irradiated expired due to infection and GF. Irradiation can be a risk factor in SCC development [23,27,35,40,41]; however, cohorts with non-XRT-based preparative regimens reported it as well [31-33]. The EBMT report in 2013 could not find a statistically significant relation between XRT-based conditioning regimen with SMNs; although independent risk factors including HSCT age and clonal evolution were an indication.

This is the first systematic review to investigate the effect of preparative regimens on HSCT success, as stated. The evidence was described transparently by ascertaining the scientific goals in advance and employing a systematic approach with precise methods, minimizing the risk of study selection and reporting bias. However, we dealt with several limitations.

The patient's age, disease status and subtypes, the conditioning regimen protocols details, types of irradiations, and incidence of HSCT outcomes were not mentioned in the review of some studies, which restricted conclusions. We did not narrow the inclusion criteria, even though some limitations could be solved and the comparability between cohorts could be enhanced.

The cohorts regarding regimens and their effect on HSCT outcomes are countless, but the evidence is limited due to heterogeneity as well as methodological shortcomings. However, current evidence shows better post-HSCT outcomes in FLU-regimen without irradiation. In addition, evidence suggests a lower risk of developing SMNs in a long-term FU of patients who weren't exposed to irradiation. Due to the heterogeneity of data and the lack of conducive parameters, we suggest future studies prioritize the investigation of the relationship between the patient's genotype and the appropriate conditioning regimen as well as the dosage.

Acknowledgments

I gratefully appreciate Prof. Amir Ali Hamidieh who has been a tremendous mentor to me. Further, I would like to express my deepest appreciation to Dr. Maryam Behfar who nurtured me with neverwavering support. Finally, I cannot forget to thank my colleagues and the PCGTRC committee.

Author Contributions Statement

P.N. conducted electronic search and selection processes, assessed risk of bias, and wrote the manuscript. M. B. supervised the manuscript. H. K. assessed risk of bias and synthesized method. L. J., Z. K., R. M. and M. M. conducted data collection process. Y. K. checked and edited native English. A. A. H. hypothesized the main idea of the manuscript.

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