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Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder caused by defects in the nucleotide excision repair (NER) pathway [1]. NER is responsible for removing bulky DNA lesions including the ultraviolet-induced ones but also the majority of DNA damage caused by DNA-targeted chemotherapies. Therefore, XP patients are extremely sensitive to chemotherapies. Classical XP results from germline mutations in one of the seven XP genes (XPA-XPG), with XPC being the most frequently affected in France due to a common founder mutation in North Africa [2]. Clinically, XP is characterized by photosensitivity, progressive cutaneous and eye abnormalities, and early onset of skin cancers in the absence of strict photoprotection [3, 4]. Hematologic malignancies have emerged as an additional, severe complication in XP-C [5, 6]. In a cohort of 161 XP patients reported in 2019, 13 individuals developed myelodysplastic syndrome (MDS) or acute leukemia (AL) between the ages of 7 and 29 years. These malignancies exhibited high-risk oncogenic features, including a high prevalence of complex karyotypes and somatic TP53 deleterious mutations. Clinical outcomes were extremely poor: all but one patient died, either from severe chemotherapy-related toxicity (n = 2) or refractory/relapsed disease (n = 10). The sole survivor had undergone reduced intensity conditioning regimen (RIC) and allogeneic hematopoietic stem cell transplantation (HSCT), but with a follow-up of 3 months at the time of the publication [5]. In this context, we report the French experience of 4 XP-C patients who underwent allogeneic HSCT for hematologic malignancies, with the aim of assessing the feasibility and outcomes of transplantation using adapted RIC in this high-risk DNA-repair-deficient population. All patients from the national French XP-C cohort who underwent allogeneic HSCT for a malignant hematologic disorder were eligible to inclusion. This study was approved by the SFGM-TC committee and registered on the Health Data Hub (n. 25837244). The data were collected from medical records and from the ProMISe database. All patients or their legal representatives provided informed consent for anonymously collecting their personal data in the ProMISe database. Key clinical features and transplant modalities are summarized in Table 1. AML (16 years) 2002 AML (29 years) 2018 Azacitidine 4 cycles MDS (18 years) 2023 Azacitidine + Venetoclax 3 cycles Complete donor chimerism; CR Grade III aGVHD (skin). CR. Mild–moderate cGVHD (vulvovaginal) MDS and B-cell ALL (21 years) 2023 Complete donor chimerism; CR, MRD IG/TR undetectable Grade III aGVHD (skin, gastrointestinal), CR. Mild–moderate cGVHD (eyes, vulvovaginal) The four XP patients harbored the homozygous founder germline XPC mutation, c.1643_1644delTG; p.Val548fsX572. All patients had a history of cutaneous carcinoma treated surgically prior to the diagnosis of the hematologic malignancy. Patient no. 3 had a history of angiosarcoma, also treated by surgical excision. No patient had received anticancer chemotherapy prior to the diagnosis of hemopathy. Two of the four patients (Patients no. 1 and no. 2) had been partially reported in the previously published cohort [5]; one of them died early after HSCT (Patient no. 1), while the surviving patient is presented here with substantially extended follow-up (Patient no. 2). The present report also includes two additional, previously unreported XP-C sisters (Patients no. 3 and no. 4). Indications of HSCT were two acute myeloid leukemias (AML), one high-risk MDS with excess blast, and 1 combined MDS and refractory acute lymphoblastic leukemia (ALL). TP53 somatic mutations were detected in three cases, consistent with the very-high risk profile of XP-C-associated malignancies [5]. All patients received treatment prior to HSCT. Patient no. 1 was treated with intensive chemotherapies combining anthracycline and cytarabine. Patient no. 2 received 4 cycles of azacitidine. Patient no. 3 received 3 cycles of azacitidine in combination with venetoclax. Patient no. 4, who presented with B-cell ALL, was treated according to Down-Syndrome-adapted pediatric protocol with consolidation using blinatumomab [7]. Due to an increase in minimal residual disease, she was subsequently treated by inotuzumab ozogamicin and daratumumab, achieving a molecular response before HSCT. Three patients were in complete remission prior to HSCT, whereas Patient no. 2 was in partial remission (persistence of 7% blasts). Outside the context of XP, TP53-mutated MDS or AL are characterized by universally poor outcomes across and not all Available frontline therapies, and allogeneic HSCT emerges as the only intervention associated with a meaningful improvement in long-term survival [8, 9]. All 4 XP-C patients received a RIC specifically designed to reduce toxicity related to the underlying DNA-repair defect, inspired by experience gained in treating Fanconi anemia patients [10-12]. Conditioning included fludarabine and low-dose cyclophosphamide (40 mg/kg) associated with low-dose busulfan (6 mg/kg) for Patient no. 1. Because the mechanisms of damage induced by ionizing radiation differ from those caused by UV and are not essentially repaired by NER, XP patients do not appear to show increased radiosensitivity to therapeutic ionizing radiation. Thus, low-dose total body irradiation (TBI) (2 Grays) was added for Patients no. 3 and no. 4 to prevent graft failure. HSCTs were performed using different donor sources: one matched-related donor (MRD), two matched-unrelated donors (MUD), and one haploidentical donor. The graft types included bone marrow (n = 1), peripheral blood stem cells (PBSC; n = 2), and CD34-selected PBSC (n = 1). The patient transplanted from an MRD received a bone marrow graft with graft-versus-host disease (GVHD) prophylaxis based on cyclosporine and mycophenolate mofetil. Both patients transplanted from MUD donors received PBSC grafts and GVHD prophylaxis consisting of cyclosporin, mycophenolate mofetil, and anti-thymocyte globulin (ATG, thymoglobulin 7.5 mg/kg). The patient who underwent haploidentical transplantation received a CD34-selected PBSC graft and ATG as the sole GVHD prophylaxis. This approach reflected the practices of the time, as the transplant occurred in 2003. Neutrophil engraftment was achieved in 3 patients at a median of 13 days (10–17). Complete donor chimerism (> 95%) at Day +30 was observed in Patients no. 3 and 4, whereas Patient no. 2 exhibited mixed chimerism at Day +40 and +100, with no blast excess but persistent cytogenetic abnormalities at Day +100. In this context, she received one donor lymphocyte infusion (DLI) and 10 cycles of azacitidine, which led to cytogenetic remission and complete donor chimerism. Grade III acute GVHD occurred in Patients no. 3 and no. 4. Both were refractory to systemic corticosteroids and achieved complete response with ruxolitinib. Chronic GVHD developed in three patients: mild-to-moderate in two cases (Patients no. 3 and no. 4) and severe in one case occurring after DLI (Patient no. 2), who also responded to ruxolitinib. At last follow-up, ruxolitinib had been successfully discontinued in all patients. Patient no. 1 presented a relapse at 29 days after HSCT and died 60 days after HSCT (relapse and toxicity). Two patients (no. 2 and no. 3) are alive in complete hematologic remission with sustained donor chimerism at 6 and 2.2 years after HSCT respectively. Patient no. 4 presented a relapse in the form of AML arising from high-risk MDS with the same mutational abnormalities as at diagnosis 1.4 years after HSCT; IG/TCR-based minimal residual disease was undetectable. She was refractory to azacitidine and venetoclax, and died 3.2 months after relapse and 1.7 years after HSCT. This emphasizes the substantial risk of post-HSCT relapse despite pretransplant remission in TP53-mutated hematologic malignancies [9]. No accelerated cutaneous complications (unrelated to GVHD) or secondary malignancies were observed during follow-up, aside from surgically treated uterine myoma and thyroid adenomas in Patient no. 2. Nevertheless, long-term monitoring for secondary cancers is crucial particularly in these patients. As XP-C patients now reach older ages thanks to improved diagnosis, photoprotection and dermatologic surveillance, the incidence of hematologic malignancies in this population is likely to increase, further reinforcing the urgent need for adapted therapeutic strategies. Our experience demonstrates that allogeneic HSCT is feasible in XP-C patients with high-risk hematologic malignancies when performed with carefully tailored RIC. Despite DNA repair deficiency, transplant-related toxicity was acceptable, and durable remission was achieved in two patients. These outcomes contrast sharply with the dismal poor prognosis reported with nontransplant approaches, where relapse is almost inevitable and long-term survivors have been described. Given the exceptional oncogenic risk and aggressive disease course of myeloid malignancies in XP-C patients, allogeneic HSCT currently represents the only potentially curative option and should be systematically considered once remission is achieved, despite the inherent risks of toxicity and GVHD. We thank very much Andrei Yurchenko and Sergey Nikolaev (Gustave Roussy, Villejuif, France) for the information following the WGS of Patient no. 2 AML. ChatGPT (OpenAI) was used solely to assist with linguistic editing and reduction of word count; it did not contribute to the scientific content, analysis, or interpretation of the data. The authors have nothing to report. This study was approved by the SFGM-TC committee and registered on the Health Data Hub (n. 25837244). Written informed consent was obtained from the parents and/or the patients. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.