Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure

Ayas, Mouhab; Nassar, A. M.; Hamidieh, Amir Ali; Kharfan-Dabaja, M.; Othman, Tarek Ben; Elhaddad, Alaa; Seraihy, Amal Al; Hussain, Fazal; Alimoghaddam, Kamran; Ladeb, Saloua; Fahmy, Omar; Bazarbachi, Ali; Mohamed, Said; Bakr, Mohammad; Korthof, Elisabeth T.; Aljurf, Mahmoud; Ghavamzadeh, Ardeshir

doi:10.1038/bmt.2013.35

Cited by 60 publications

(59 citation statements)

References 33 publications

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“…Fludarabine-containing non-myeloablative conditioning regimens are now increasingly used and might give better short-term results [64][65][66]70]. The overall data suggest long-term surveillance is important particularly for cancers and pulmonary complications both of which are likely to be secondary to the genetic defect that is not corrected by HSCT.…”

Section: Dyskeratosis Congenita (Dc)mentioning

confidence: 95%

Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

Dalle

Latour

2016

Int J Hematol

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Section: Dyskeratosis Congenita (Dc)mentioning

confidence: 95%

Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

Dalle

Latour

2016

Int J Hematol

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“…9 The introduction of RIC regimens seems to have played a crucial role in the reduction of toxicity and in the improved outcomes in these patients. 8 A recently published systematic literature review 11 concerning HSCT in DC showed 5-and 10-year overall survival rates of 57% and 23% with the use of alternative donors as the main variable related to worse outcomes (P < .001). In addition, even if 5-year overall survival rates were similar between conditioning regimens (P = .16), the overall survival at last follow-up reported was significantly better after RIC than after myeloablative conditioning regimens (66% vs 40%; P < .01).…”

Section: Discussionmentioning

confidence: 99%

“…Although overall survival has progressively improved over the years with the introduction of reduced intensity conditioning (RIC) regimens, 8 organ toxicities, graft failure, and graftversus-host disease (GVHD) remain important issues. 8,9 Here, we describe an 8-year-old girl with DC who received 2 successive allogeneic HSCTs.…”

Section: Introductionmentioning

confidence: 99%

Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection

Giardino¹,

Faraci²,

Lanino³

et al. 2023

Exp Clin Transplant

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Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Although reduced intensity conditioning regimens seem to be related to better outcomes, a standard regimen for dyskeratosis congenita has never been defined. Here, we report a successful long-term outcome of an 8-year-old girl with dyskeratosis congenita who received 2 consecutive allogeneic hematopoietic stem cell transplants from different unrelated donors, because of rejection after the first one, both conditioned with fludarabine-based reduced intensity conditioning regimen. The second transplant was complicated by severe hemorrhagic cystitis and acute grade IV graft-versus-host disease in the early phase and mild chronic graft-versus-host disease and ureteral stenosis in the late phase. This experience confirms that dyskeratosis congenita is at high risk for transplant-related morbidity but that a fludarabine-based reduced intensity conditioning regimen is a safe and feasible option as a preparative regimen, as shown here in a second transplant after first graft rejection. To reduce the risk of graft-versushost disease, more effective prophylaxis schedules should be chosen in cases of unrelated donor, and haploidentical hematopoietic stem cell transplant with in vitro α/β+ and CD19+ depletion should be considered. Key words: Allogeneic hematopoietic stem cell transplant, Bone marrow failure, Reduced intensity conditioning regimen IntroductionDyskeratosis congenita (DC) is a rare heterogeneous inherited disorder, characterized by abnormal skin pigmentation, oral leukoplakia, nail dystrophy, and bone marrow failure. 1,2 Cancer predisposition with increased risk of squamous cell carcinoma and hepatolymphoid neoplasms and pulmonary fibrosis represent typical severe features of the disease. 3 About 60% to 70% of affected patients carry a mutation in telomerase genes (DKC1, TERC, TERT, NOP10, and NHP2), which are required to synthesize the tandem repeats of the TTAGGG sequencing or of the telosome/shelterin complex proteins (TINF2) acting at chromosome ends. 4 Their defect leads to telomere shortness and consequent chromosomal instability, with premature stem cell exhaustion, tissue failure, and high tissue sensitivity to toxic damage. 5 Moreover, high sensibility to oxidative stress has been demonstrated in DC-cultured cells. 6 Androgen therapy has been reported to improve bone marrow function 7 ; however, allogeneic hematopoietic stem cell transplant (HSCT) still represents the only curative option for DC-related bone marrow failure.Few reports on HSCT for DC have been published so far. Although overall survival has progressively improved over the years with ...

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“…2 Several reports have shown that despite being a bone marrow failure syndrome, the use of reduced intensity conditioning preparative regimens are safer, carries less morbidity and has no increased risk of graft failure or rejection. 1,8,[9][10][11][12][13] In some of these reports, however, the ex vivo T-cell depletion was with ATG and in general, the source of stem cells was nonumbilical cord blood stem cells. In both patients in this report, ATG was replaced with alemtuzumab, which has more in-depth lymphocyte depletion with the hope that this will decrease any chance for rejection.…”

Section: Patientmentioning

confidence: 99%

Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita

Brown

Myers

Shreve

et al. 2016

Bone Marrow Transplant

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Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita Bone Marrow Transplantation (2016) 51, 744-746; doi:10.1038/ bmt.2015; published online 25 January 2016 Dyskeratosis congenita (DC) is a rare genetic disorder characterized by a classic triad of physical findings consisting of nail dystrophy of the hands and/or feet, mucosal leukoplakia and reticular pigmentation of the skin, most commonly on the head, neck and trunk. 1 Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as a myriad of other abnormalities. 2,3 Hematopoietic stem cell transplantation (HSCT) with fully myeloablative regimens has historically been the only curative treatment. 2,3 Attempts at reducing morbidity and mortality post HSCT with reduced intensity conditioning regimens instead of myeloablative regimens have been reported, and over the past decade, experience treating DC associated marrow failure with reduced intensity HSCT has increased. 4 Here we report the HSCT course of two patients with successful restoration of hematopoiesis following reduced intensity conditioning and unrelated cord blood transplant (see Table 1 for patient descriptions).Patient 1 Patient 1 is a 9-year-old white male with a history of macrocephaly. He was diagnosed with severe aplastic anemia at the age of 5 years. Approximately 1.5 years before this diagnosis, he had an event where the tip of his tongue became white, jagged and painful. He presented to his primary care physician where it was treated as a viral infection. Concomitantly, circular flat scalp lesions appeared on his head followed by hair loss and crusted patches. He also had a history of easy bruising for 18 months and dysplastic nails. He was hospitalized multiple times for immunosuppressant therapy with cyclosporine and antithymocyte globulin (ATG) over the previous year. A bone marrow biopsy was obtained and showed markedly hypocellular marrow with cellularity o10% on average and tri-lineage hypoplasia with no evidence of malignancy. Telomere length testing was done and shown to be less than the first percentile in all lymphocyte subset and granulocytes, supporting a diagnosis of DC. Genetic testing revealed heterozygosity for R282H mutation in the TINF2 gene. He was referred for allogeneic stem cell transplantation. He did not have a fully matched sibling and an extensive unrelated donor search did not reveal a fully matched unrelated donor nor a good size, well matched umbilical cord. He received 2 partially matched unrelated umbilical cords; 4/6 with a total neutrophil count (TNC) 9.2 x 10 7 and 5/6 with a TNC of 2.2 x 10 7 /kg. The preparative regimen consisted of cyclophosphamide 50 mg/kg x 1, fludarabine 40 mg/m 2 x 5, low dose TBI at 200cGy, and alemtuzumab 0.2 mg/kg x 5. GvHD prophylaxis consisted of tacrolimus and mycophenolate...

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Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure

Cited by 60 publications

References 33 publications

Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection

Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita

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