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347 SHORT COMMUNICATION Allogeneic Haematopoietic Cell Transplantation for Epidermolysis Bullosa: the Dutch Experience Katarzyna B. GOSTYŃSKA 1# , Vamsi K. YENAMANDRA 1# , Caroline LINDEMANS 2,3 , José DUIPMANS 1 , Antoni GOSTYŃSKI 1 , Marcel F. JONKMAN 1 and Jaap-Jan BOELENS 2–4 * Center for Blistering Diseases, Departments of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, Department of Immunology/Stem Cell Transplantation, University of Utrecht, University Medical Center Utrecht, Wilhelmina Children’s Hospital, 3 Princess Maxima Center and University Medical Center Utrecht, Blood and Marrow Transplantation Program, Utrecht, The Netherlands, and 4 Department of Stem Cell Transplant and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. E-mail: [email protected] # These authors contributed equally to this study. 1 2 Accepted Nov 28, 2018; E-published Nov 28, 2018 Efforts to find a cure for the devastating inherited bliste- ring disease, epidermolysis bullosa (EB), have received much attention in recent years. The extremely poor long-term prognosis of EB has motivated many patients and clinicians to pursue high-risk experimental thera- pies (1–6). One such therapeutic strategy is allogeneic haematopoietic cell transplantation (HCT) in recessive dystrophic epidermolysis bullosa, generalized severe, (RDEB-gen-sev) patients (1), who completely or partially lack type VII collagen (Col7) at the dermo–epidermal junction (DEJ). Based on encouraging results in mice (7, 8) and humans (1), we designed a study in the Netherlands. We aimed to treat 11 RDEB-gen-sev patients using a previously described HCT protocol (9, 10) (Fig. S1 1 ). Between May 2014 and October 2017, 2 RDEB-gen- sev patients were enrolled and treated following the study protocol. Unfortunately, both patients died due to transplantation-related complications after 50 and 283 days after cord blood transplantation (CBT), respectively. We wish to report detailed results of this trial which has now been prematurely closed. CASE REPORTS The first patient (#1; EB109-01) was a 13-year-old girl with an extensive RDEB-gen-sev phenotype due to homozygous mutation in intron 20 of COL7A1 gene (NM_000094.3); c.[2710+1G>A];[2710+1G>A] with no Col7 expression in im- munofluorescence antigen mapping (IFM; monoclonal antibody LH7:2, Sigma-Aldrich, Poole, UK). Minimal toxicity was noticed with conditioning and the skin condition slightly improved with reduced blistering and inflammation. Unfortunately, the 4/6 cord blood graft (6/10 matched on high resolution molecular typing; NC/kg=6.4 × 10 7 /kg) was rejected (bone marrow aspirate con- firmed day +25, 85% patient chimerism) with the course being further complicated by very early cytomegalovirus reactivation (day +2), prolonged neutropaenia without autologous recovery, followed by multiple bacterial- and therapy-resistant aspergillus infections, resulting in her death (day +50). The study was put on hold and the treatment protocol was adjusted to improve safety by adding: cryopreservation of an autologous back-up graft (for rescue in case of non-engraftment), targeting the pre-HCT ATG to high exposure > 80 AU*d/l (while assuring low post-HCT exposure < 10 AU*d/l) to reduce the probability of donor-graft https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3097 1 rejection and anti-fungal prophylaxis with liposomal amphotericin B instead of fluconazole. The second child (#2; EB402-01), was an 8-month-old boy, with a homozygous large deletion starting in intron 12 and ending in exon 24 of the COL7A1 gene; c.[1637-240_3252del4061],[1637- 240_3252del4061] resulting in no Col7 expression on IFM (Fig. S2 1 ). At baseline, he had minimal cutaneous involvement, severe mucosal (oral and ocular) erosions and nail dystrophy (Fig. S2 1 ). The conditioning was well tolerated and he engrafted quickly (day +17) with a 5/6 unrelated cord blood unit (matched 7/10 on high- resolution molecular typing; NC/kg = 15.1 × 10 7 /kg). However, the treatment course was complicated with several transplantation- related toxicities, requiring resuscitation and multiple intensive care admissions. These included refractory grade III skin graft vs. host disease (GvHD), acute oesophageal bleeding, gastric paresis, capillary leak syndrome, pneumothorax and severe re- spiratory insufficiency. Several switches in immunosuppression were necessary due to medication-induced transplantation-related microangiopathy and kidney toxicity. Acute GvHD was controlled with 3 additional mesenchymal stromal cell infusions (outside the treatment protocol) and basiliximab. Gastroenteral GvHD was suspected, but never proven, despite extensive endoscopic evaluation. Similar to patient 1, patient 2 also developed cytome- galovirus reactivation, even before transplant, which was treated pre-emptively. The load waxed and waned over the disease course, but was never higher than log3 IU/ml. He also had multiple bacterial infections, which were well-controlled. The respiratory problems, however, persisted and required ventilation (4 separate episodes) and oxygen support, leading to progressive decline in lung function and ultimately death (day +283). We are unable to fully explain whether all these complications were related to the immunological phenomena of a CBT or EB. In addition to the multiple life-threatening complications in patient 2, there was clear lack of clinical or biological evidence of efficacy in ameliorating the EB disease course, despite >97% donor peripheral blood chimerism and 9 months’ follow-up. Mu- cosal blistering flared up and persisted throughout the treatment period. Cutaneous blistering was seen during hospital admission, largely explained by iatrogenic trauma. The mini-skin rub test was persistently positive (day +180) (11). Neither Col7, nor its main constituent anchoring fibrils were detected at the various time-points, including post-mortem (day +283) (Fig. S2 1 ). Unfor- tunately, we could not assess dermal chimerism (with X-Y FISH), as the donor and recipient were the same sex. DISCUSSION The first HCT trial in 2010, described treatment of 6 RDEB-gen-sev patients, with transplantation-related mortality in one patient and clinical improvement in the remaining 5 patients, including presence of donor cells in the injured skin and increased Col7 deposition at the DEJ This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3097 Acta Derm Venereol 2019; 99: 347–348