[Telomeropathies: A study of 15 cases]. / Téloméropathies de recrutement hématologique : étude de 15 cas.

INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.

Chronic graft-versus-host disease and inhibition of interleukin-17: proof of concept in humans.

Psoriasiform chronic graft-versus-host disease (GvHD) is a rare clinical presentation recently described after allogeneic haematopoietic stem cell transplantation. It is characterized by the combination of clinical and pathological characteristics of psoriasis together with pathological features of chronic GvHD. As described for psoriasis, psoriasiform chronic GvHD is characterized by the infiltration of T helper 17 CD8+ T cells producing both interferon-γ and interleukin-17. However, no data are available about the efficacy of interleukin-17 blockade in the treatment of patients with psoriasiform chronic GvHD. What's already known about this topic? Psoriasiform chronic graft-versus-host disease (GvHD) is a rare clinical presentation with a poor durable response to steroids. Animal models and human data suggest that psoriasiform GvHD could be induced through interleukin-17 production by donor T cells. What does this study add? We describe the first case of a patient with psoriasiform GvHD and persistent improvement on treatment with secukinumab, an anti-interleukin-17A antibody.

Cutaneous presentation of adult T-cell leukemia/lymphoma (ATLL). Single-center study on 37 patients in metropolitan France between 1996 and 2016.

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a hematological malignancy associated with chronic HTLV-1 infection. AIM: To describe skin lesions in ATLL. METHODS: A descriptive, retrospective study between 1996 and 2016, including all patients diagnosed with ATLL at Saint-Louis Hospital (Paris, France). RESULTS: Thirty-seven ATLL patients were included. Fifteen patients (41%) had a cutaneous localization of the disease, which was present from the beginning of the disease for two thirds of them. ATLL types in patients with cutaneous localization of the disease were as follows: lymphoma, n=5, chronic, n=4, smoldering, n=4, acute, n=2. Half the patients had 2 or more cutaneous manifestations. The cutaneous localizations observed were as follows: nodulotumoral (n=8), plaques (n=7), multipapular (n=6), macular (n=4), purpuric (n=2). Among the 15 patients with cutaneous localization, median overall survival was significantly shorter in the acute and lymphoma types compared to the smoldering and chronic types (8.7 months vs. 79 months, P=0.003). DISCUSSION: ATLL is a hematologic malignancy with variable expression that is diagnosed only very rarely in metropolitan France, but that should be sought in patients from countries with high HTLV-1 prevalence in the event of a chronic eruption with patches, papules, plaques and/or tumors. The chronic and smoldering types are relatively indolent, whereas the acute and lymphoma forms have a poor prognosis.

Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status.

Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV-seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p <0001). Half-life of CMV under treatment was significantly longer in D-/R+ than in D+/R+. Treatment failure observed in eight recipients was associated with low leucocyte count at reactivation onset, and was significantly more frequent in D-/R+ (six patients) than in D+/R+ (two patients) (p <0.0001). CMV strains resistant to antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare.

Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD.

In a previous study, the fecal biomarkers calprotectin and α1-antitrypsin (α1-AT) at symptom onset were reported to be significantly associated with the response to steroids in gastrointestinal GvHD (GI-GvHD). The purpose of this trial was to evaluate the dynamics of the fecal biomarkers calprotectin and α1-AT throughout the course of GvHD. Patients who were refractory to steroids had initially higher biomarker levels and in the course of GvHD demonstrated a continuous increase in fecal biomarkers. In contrast, the dynamics of calprotectin and α1-AT demonstrated low and decreasing levels in cortico-sensitive GvHD. In steroid-refractory patients who received a second line of treatment, the biomarker levels at the beginning of second-line treatment did not predict the subsequent response. Nevertheless, calprotectin levels progressively decreased in subsequent responders, whereas non-responders demonstrated continuously high levels of calprotectin. α1-AT values correlated to a lesser extent with the response to second-line treatment and remained elevated in both non-responders and responders. In conclusion, calprotectin monitoring can be of use in the management of immunosuppressive treatment in GI-GvHD.

[SFGM-TC recommendation on indications for allogeneic stem cell transplantation in children with congenital neutropenia]. / Indications d'allogreffe dans les neutropénies constitutionnelles : recommandation de la SFGM-TC.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity.

BACKGROUND: According to the National Institutes of Health classification of chronic graft-versus-host disease (cGVHD), skin ulcers after allogeneic haematopoietic stem-cell transplantation (HSCT) are recorded as having the maximal severity score but published data are scarce. OBJECTIVES: To describe skin ulcers related to cGVHD with an emphasis on clinical findings, associated morbidity, management and evolution. PATIENTS AND METHODS: A multicentre retrospective analysis was carried out of patients with a diagnosis of cGVHD skin ulcers. RESULTS: All 25 patients included in the study had sclerotic skin cGVHD and 21 had lichenoid skin lesions associated with the sclerotic skin lesions. Thirteen patients had severe cGVHD without considering the skin, because of the involvement of an extracutaneous organ by cGVHD. The median time from HSCT to the onset of ulcers was 44 months. In addition to scleroderma, initial skin lesions at the site of ulcers were bullous erosive lichen in 21 patients and bullous erosive morphoea in four patients. Fifteen patients had an inaugural oedema. Ulcers were mostly bilateral with a predilection for the lower limbs. They were frequently colonized but few infections occurred. Four patients died during a median follow-up period of 55 months. CONCLUSIONS: Chronic graft-versus-host disease skin ulcers occur in patients with sclerodermatous skin cGVHD, are associated with severe cGVHD, often start with bullous lichenoid lesions or bullous morphoea and seem to cause more morbidity than mortality, given the low rate of mortality observed in our series of patients.