Leonardo Magro

Imatinib mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease

Imatinib is a promising candidate for the treatment of fibrotic diseases. This retrospective study evaluated the use of imatinib for the treatment of refractory sclerotic chronic graft-versus-host disease in 14 patients with different hematologic malignancies. Imatinib was started at a median of 44 months after transplantation (range, 16-119 months after transplantation) and was administered for a median of 5.9 months from time of initiation (range, 2.1-74 months from time of initiation). With a median overall follow-up of 11.6 months from time of initiation (range, 4.1-74 months from time of initiation) of imatinib, 4 patients (29%) had to stop imatinib because of drug intolerance. All other adverse reactions were of mild-to-moderate grade and could be managed symptomatically. Overall, 7 patients responded to imatinib (50%; 95% confidence interval, 24%-76%) with 4 patients improving their Rodman score more than or equal to 90%. In addition, imatinib therapy allowed for a significant reduction of corticosteroid dosage. Despite its limited size, this cohort suggests some beneficial activity of imatinib in sclerotic chronic graft-versus-host disease, warranting further prospective investigations.

Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplantation: the impact of expanding CD28negative CD8+ T cells on relapse.

Allogeneic stem cell transplantation has become standard therapy for hematologic malignancies through the positive immunologic graft-versus-leukemia effect. Initial immune recovery relies on peripheral expansion of infused T cells, which switch to a memory-like phenotype. This study prospectively investigated whether changes in subset composition precedes complications after myeloablative HLA-matched transplantation for hematologic malignancies. Of 80 allograft recipients, 18 were still free of clinical complication throughout 395 to 1564 days of follow-up. Compared with this complication-free subgroup, patients who developed chronic graft-versus-host disease (cGVHD) without relapsing recovered similar numbers of circulating T cells with predominance of CD8+ T cells lacking CC-chemokine receptor-7 and CD28 expression throughout the first year after transplantation. Conversely, poor CD8+ T cell recovery with diminished numbers of CD28neg CD8+ T cells (approximately 1/4th of that of relapse-free patients) preceded occurrence of malignant relapse. In multivariate analysis, lower CD28neg CD8+ T cell counts by day 60 postallograft were associated with a greater risk of subsequent relapse (hazard ratio [HR] 0.33; 95% confidence interval [CI]: 0.14-0.76; P = .01). Enumeration of CD28neg CD8+ T cells in patients could assist in predicting risk of relapse and help build an algorithm for accelerating the immune recovery by reducing the immunosuppressive treatment and considering the introduction of preemptive donor lymphocyte infusions.

Chronic graft-versus-host disease revealed by lichenoid vulvar lesions successfully treated with thalidomide

Sir, Chronic graft-versus-host disease (GVHD) occurs in approximately 60 – 80% of patients who survive for 100 days after allogeneic bone marrow transplantation (BMT) (1). The skin is affected in almost all cases of chronic GVHD, with two distinct phases: the early chronic phase, characterized by lichenoid lesions similar to lichen planus, and the late chronic phase, with sclerodermatous lesions. During the early course, the clinical spectrum of lichen planus may be reproduced, and the initial lesions are usually in the buccal mucosa. Rarely has genital mucosa been reported during chronic GVHD. We describe a case of chronic GVHD in a 40-year-old woman successfully treated with thalidomide at a dose of 100 mg per day. GVHD manifested in erosive lichen-planus-like lesions of the vulva following allogeneic BMT for chronic myeloid leukaemia.

Our experience of solitary plasmacytoma of the bone: improved PFS with a short-course treatment by IMiDs or proteasome inhibitors combined with intensity-modulated radiotherapy

Emmanuelle Le Ray, Lisa Belin, Corine Plancher, Philippe Anract, Antoine Babinet, Val erie Dumaine, J erôme Tamburini, B en edicte Deau Fischer, Lise Willems, Leonardo Magro, Thierry Facon, Xavier Leleu, Didier Bouscary and Youlia M. Kirova Service d’H ematologie, Hôpital Cochin, AP-HP, Paris, France; Facult e de M edecine Sorbonne Paris Cit e, Universit e Paris Descartes, Paris, France; Department of Biostatistics, Institut Curie, Paris, France; Service de chirurgie orthop edique, Hôpital Cochin, AP-HP, Paris, France; Institut Cochin, D epartement D eveloppement Reproduction Cancer, CNRS UMR8104, INSERM U1016, Paris, France; Service d’H ematologie, CHRU Lille, Lille, France; Service d’h ematologie, CHU de Poitiers, Poitiers, France; Department of Radiation Therapy, Institut Curie, Paris, France

Bone marrow graft as a source of allogeneic hematopoietic stem cells in patients undergoing a reduced intensity conditioning regimen

In an attempt to reduce the incidence of chronic GVHD (cGVHD) after reduced-intensity conditioning (RIC), we used BM instead of PBSC and added melphalan 100 mg/m2 to the classical association of fludarabine, 30 mg/m2/day for 3 days and TBI, 200 cGy (FLUIM regimen). Between 2000 and 2012, 51 patients received BM with the FLUIM regimen (group A), and 124 received BM (n=22) or PBSC (n=102) with another RIC regimen (group B). Donors were siblings (n=123) or HLA-matched 10/10 unrelated (n=52). Full donor-type chimerism at day 100 was more often recorded in group A (86%) than in group B (62%); P<0.001. There was no difference between the two groups in terms of OS and EFS, acute GVHD, relapse and non-relapse mortality incidence. cGVHD occurred more often in group B (41%) than in group A (23%); P=0.021. In multivariate analysis, the two risk factors associated with the development of cGVHD were conditioning in group B (hazard ratio (HR)=2.871, 95% confidence interval (CI) (1.372–6.006); P=0.005) and CD34+ count (HR=1.009, 95% CI (1.006–1.011); P<0.001). In conclusion, the FLUIM regimen followed by BM leads to more frequent full-donor chimerism and a reduced incidence of cGVHD without compromising relapse and survival.

Conversion from Mycophenolate Mofetil to Enteric-coated Mycophenolate Sodium ( myfortic ®) in a Patient with Graft-versus-host Disease

The patient was 58 years old in September 2002 when he was diagnosed with chronic myeloid leukaemia (CML). He was first treated using IFNa, to which aracytine was soon added. By February 2003, hyperleukocytosis with myelocytosis was still present so the interferon was replaced by imatinib. The patient’s condition continued to deteriorate, and the haematopoietic cell count started to increase in August 2003. In September 2003, the patient underwent allogeneic haematopoietic stem cell transplantation with peripheral stem cells from a human leukocyte antigen-matched brother after a busulfan-based non-myeloablative conditioning regimen. Graftversus-host disease (GVHD) prophylaxis consisted of cyclosporine 3mg/kg per day and short-course methotrexate. Subsequent changes in the immunosuppressive regimen are summarised in table I. On day 15 posttransplant, a differential count clearly indicated recrudescence of the CML, with a total white blood cell count of 65 000 10/l, including 70% myeloid cells. In response to this, cyclosporine was discontinued because there was no evidence of GVHD, and treatment with imatinib (400mg/day) and low-dose busulfan (2mg/day by mouth) was started. A complete cytogenetic and molecular remission was observed unexpectedly within 2 months. On day 19, grade II cutaneous GVHD developed, with no gastrointestinal symptoms. The patient was given methylprednisolone followed by anti-IL-2 antibody therapy (Leucotac) for 4 days. The symptoms failed to improve by day 46, however, and treatment with mycophenolate mofetil (MMF) was started at a dose of 1000mg twice a day. The patient quickly developed severe diarrhoea two to three times a day responsible for a body weight loss of 5% within one week, and 18 days after the introduction of MMF (i.e. on day 64) it was withdrawn and replaced with enteric-coated mycophenolate sodium (EC-MPS; myfortic) at a dose of 720mg twice a day. The gastrointestinal symptoms quickly resolved after conversion from MMF to EC-MPS and the GVHD steadily waned. In January 2004, 4 months posttransplantation, the GVHD flared up again so the corticosteroid dose was increased to 80mg/day, and tacrolimus 2mg twice a day was started. In the face of persistent GVHD, this regimen of EC-MPS 720mg twice a day, prednisolone 80mg/day and tacrolimus 2mg twice a day was maintained until March 2004 when the patient developed acute kidney failure and tacrolimus was discontinued. As the GVHD appeared to be under control, the corticosteroid dose was tapered downwards, starting in May 2004. The patient is still alive in good condition and in complete molecular remission from his CML. CASE REPORT Drugs 2006; 66 Suppl. 2: 29–31 0012-6667/06/0002-0029/

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

44.95/0

Association Between Low Plasma Level of Citrulline Before Allogeneic Hematopoietic Cell Transplantation and Severe Gastrointestinal Graft vs Host Disease

Fingolimod could be efficient to treat GVHD of the central nervous system.Further research should explore the use of fingolimod and other sphingosine-1-phosphate receptor agonists to prevent or treat GVHD.

Carnet de suivi national : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

BACKGROUND & AIMS: The gastrointestinal form of acute graft vs host disease increases morbidity and mortality following allogeneic hematopoietic cell transplantation. Plasma levels of citrulline, a non‐proteinogenic amino acid, indicate functional enterocyte mass. We measured citrulline in patients before allogeneic hematopoietic cell transplantation and investigated its association with incidence and severity of gastrointestinal graft vs host disease. METHODS: We performed a retrospective study with 191 patients (69 women, 122 men; median age of 52 years) who underwent allogeneic hematopoietic cell transplantation for hematological malignancies at a tertiary center of France from January 2013 through April 2015. Levels of citrulline in plasma samples collected 30 days before graft infusion were measured by high performance liquid chromatography with tandem mass spectrometry. We assigned patients to groups with a high level of citrulline (>26 &mgr;mol/L) or low level of citrulline (≤26 &mgr;mol/L). The primary outcomes were difference between groups in incidence of stage 2–4 gastrointestinal graft vs host disease, death without hematological disease relapse (non‐relapse mortality), relapse of the hematological disease, and overall survival through 2 years after transplantation. RESULTS: Ninety‐six patients (50%) developed acute graft vs host disease and 37 (19%) developed a gastrointestinal form. Among patients with gastrointestinal involvement, 33 patients (89%) had stage 2–4 gastrointestinal graft vs host disease. In univariable analysis, low level of citrulline associated with higher cumulative incidence of stage 2–4 gastrointestinal graft vs host disease, non‐relapse mortality, and shorter overall survival. In multivariable analysis, low level of citrulline was the only risk factor independently associated with stage 2–4 gastrointestinal graft vs host disease (hazard ratio, 3.06; 95% CI, 1.37–6.85; P = .007); it also associated with increased non‐relapse mortality (hazard ratio, 2.29; 95% CI, 1.24–4.22; P = .008). CONCLUSIONS: In a retrospective study with 191 patients, we associated a low plasma level of citrulline before allogeneic hematopoietic cell transplantation with a higher risk for stage 2–4 gastrointestinal graft vs host disease and non‐relapse mortality. This marker might be used to manage patients before allogeneic hematopoietic cell transplantation.

Thirteen cases of jaw osteonecrosis in patients on bisphosphonate therapy

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country. Our article discusses the updates and modifications for the 2016 version of the national patient follow-up care logbook.