Ambroise Marçais

Early posttransplantation donor-derived invariant natural killer T-cell recovery predicts the occurrence of acute graft-versus-host disease and overall survival

Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graft-versus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T- and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P = .003) and after a reduced-intensity conditioning regimen (P = .03). Low posttransplantation iNKT/T ratios (ie, < 10(-3)) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P = .001). Inversely, reaching iNKT/T ratios > 10(-3) before day 90 was associated with reduced nonrelapse mortality (P = .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P = .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 × 10(-3) was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival.

Impact of disease status and stem cell source on the results of reduced intensity conditioning transplant for Hodgkin’s lymphoma: a retrospective study from the French Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)

The role of reduced intensity allogeneic stem cell transplantation for the treatment of relapsed/refractory Hodgkin’s lymphoma remains controversial. We retrospectively analyzed 191 patients who underwent reduced intensity allogeneic stem cell transplantation between 1998 and 2008 for relapsed or refractory Hodgkin’s lymphoma and whose data were reported to the French registry. The median follow-up was 36 months. The estimated 3-year overall survival rate, progression-free survival rate, cumulative incidence of relapse and cumulative incidence of non-relapse mortality were 63%, 39%, 46%, and 16%, respectively. There was no difference in outcome between patients in complete response and in partial response at the time of transplantation with regards to overall survival (70% versus 74%, no significant difference) and progression-free survival (51% versus 42%, no significant difference). Patients with chemoresistant disease had a shorter overall survival (39% at 3 years; P=0.0003) and progression-free survival (18% at 3 years; P=0.001) than patients in complete remission. The use of umbilical cord blood as the source of stem cells was associated with a poor outcome with an increased risk of death with a hazard ratio of 3.49 (95% confidence interval: 1.26 to 9.63; P=0.016). The use of peripheral blood was associated with a better outcome for patients who where alive 1 year after transplantation with a hazard ratio of 0.38 (95% confidence interval: 0.17 to 0.83; P=0.016). Disease status at transplantation remains the most important risk factor for outcome. Our data suggest that the use of peripheral blood should be preferred whereas umbilical cord blood should be used with caution.

Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group

We assessed the long-term results of autologous stem-cell transplantation for patients with first-relapsed or refractory Hodgkin lymphoma included in the prospective Lymphoma Study Association/Société Française de Greffe de Moelle H96 trial. This large multicenter phase II trial evaluated a risk-adapted strategy with single or tandem autologous stem-cell transplantation for 245 Hodgkin lymphoma patients. Poor-risk patients (n=150) had primary refractory Hodgkin lymphoma (n=77) or ≥2 risk factors at first relapse (n=73) and were eligible for tandem autologous stem-cell transplantation. Intermediate-risk patients (n=95) had one risk factor at first relapse and were eligible for single autologous stem-cell transplantation. With a median follow-up of 10.3 years, 10-year freedom from second failure and overall survival rates were, respectively: 64% (95% CI, 54% to 74%) and 70% (95% CI, 61% to 80%) for the intermediate-risk group, and 41% (95% CI, 33% to 49%) and 47% (95% CI, 39% to 55%) for the poor-risk group. Considering only patients who did not relapse after completing autologous stem-cell transplantation, the 15-year cumulative incidences of second primary malignancies were 24% for the 70 intermediate-risk patients and 2% for the 75 poor-risk ones. With long-term follow-up, the risk-adapted strategy remains appropriate. Tandem autologous stem-cell transplantation can still be considered an option for poor-risk patients, but integration of positron-emission tomography findings and new drugs may help to refine the need for a second autologous stem-cell transplant and possibly improve outcomes of patients with first-relapsed or refractory Hodgkin lymphoma.

Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE…). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins… Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.RésuméLa transplantation allogénique de cellules souches hématopoïétiques est pratiquée dans les dysfonctions de moelle osseuse liées à des hémopathies, mais également dans certaines maladies rares (adrénoleucodystrophie, encéphalomyopathie mitochondriale gastro-intestinale ou MNGIE…). Après quelques décennies, ce traitement a fait la preuve de son efficacité au prix d’un certain nombre d’effets secondaires précoces ou plus tardifs tels qu’infection, réaction greffon-contre-hôte, complications cardiovasculaires et cancers secondaires. Ces complications sont principalement liées au conditionnement, qui requiert une chimothérapie puissante associée à une irradiation corporelle totale (conditionnement myélo-ablatif) ou une immunosuppression (conditionnement non myélo-ablatif). Parmi ces effets secondaires, les complications endocrines peuvent être classées en 1) déficits hormonaux endocrines (particulièrement gonado- and somatotropes) liés aux conséquences de la chimio- et surtout de la radiothérapie, avec ses effets propres sur la croissance, la puberté, l’os et la fertilité; 2) maladies auto-immunes, particulièrement dysthyroidies; 3) tumeurs secondaires impliquant soit les glandes endocrines (cancer thyroidien) ou dépendant du statut hormonal (cancer du sein, méningiome), favorisées par la dysrégulation immunitaire et la radiothérapie; 4) complications métaboliques, spécialement diabètes cortico-induits et dyslipidémies qui s’accompagnent d’un risque cardiovasculaire accru. Ces complications sont intriquées. De plus, l’hormonothérapie substitutive peut moduler le risque cardio-vasculaire et tumoral de ces patients, déjà accru par la radiothérapie et la chimothérapie, notamment les glucocorticoides et les anthracyclines… C’est pourquoi ces personne et leur famille doivent être informées de ces effets secondaires et de l’intérêt d’un suivi multidisciplinaire à long-terme.

Clinical Trials of Adult T-Cell Leukaemia/Lymphoma Treatment

Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I (HTLV-1). Prognosis is severe because of intrinsic chemoresistance and severe immuosuppression. Four different subtypes are described with different outcomes, and treatment strategies vary according to the different clinical courses. Japanese trials show that combinations of chemotherapy can increase the response rates especially in the lymphoma subtype. However, patients have a high rate of relapse and the outcome remains extremely poor. Recently, a worldwide meta-analysis demonstrated that the combination of Zidovudine and Interferon-alpha (IFN) is effective in the leukemic subtypes (smoldering, chronic, and acute) and influences favorably the course of the disease. In order to prevent relapse, clinical trials testing new drugs such as monoclonal antibodies or combinations such as arsenic/IFN are needed. Finally, allogeneic stem cell transplantation is a feasible option but bears a very high rate of complications.

Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis

Human T-cell leukaemia virus type-1 (HTLV-1) and bovine leukaemia virus (BLV) infect T- and B-lymphocytes, respectively, provoking a polyclonal expansion that will evolve into an aggressive monoclonal leukaemia in ∼5% of individuals following a protracted latency period. It is generally assumed that early oncogenic changes are largely dependent on virus-encoded products, especially TAX and HBZ, while progression to acute leukaemia/lymphoma involves somatic mutations, yet that both are independent of proviral integration site that has been found to be very variable between tumours. Here, we show that HTLV-1/BLV proviruses are integrated near cancer drivers which they affect either by provirus-dependent transcription termination or as a result of viral antisense RNA-dependent cis-perturbation. The same pattern is observed at polyclonal non-malignant stages, indicating that provirus-dependent host gene perturbation contributes to the initial selection of the multiple clones characterizing the asymptomatic stage, requiring additional alterations in the clone that will evolve into full-blown leukaemia/lymphoma.

Overview of Targeted Therapies for Adult T-Cell Leukemia/Lymphoma

Adult T-Cell Leukemia/lymphoma (ATL) is the first human malignancy associated with a chronic infection by a retrovirus, the human T-cell lymphotropic virus type I (HTLV-I). ATL occurs, after a long latency period, only in about 5% of 10-20 millions infected individuals. ATL has a dismal prognosis with a median survival of less than 1 year, mainly due to its resistance to chemotherapy and to a profound immunosuppression. The viral oncoprotein, Tax, plays a major role in ATL oncogenic transformation by interfering with cell proliferation, cell cycle, apoptosis, and DNA repair. The diversity in ATL clinical features and prognosis led to Shimoyama classification of ATL into four clinical subtypes (acute, lymphoma, chronic, and smoldering) requiring different therapeutic strategies. Clinical trials, mainly conducted in Japan, demonstrated that combination of chemotherapy could induce acceptable response rate in the lymphoma subtype but not in acute ATL. However, long-term prognosis remains poor for both subtypes, due to a high relapse rate. Similarly, whether managed by a watchful waiting or treated with chemotherapy, the indolent forms (smoldering and chronic) have a poor long-term outcome. An international meta-analysis showed improved survival in the leukemic subtypes of ATL (chronic, smoldering as well as a subset of the acute subtype) with the use of two antiviral agents, zidovudine and interferon-alpha, and accordingly, this combination should be considered the standard first-line treatment in this context. ATL patients with lymphoma subtype benefit from induction chemotherapy, given simultaneously or sequentially with an antiviral combination of zidovudine and interferon-alpha. Allogeneic hematopoietic stem cells transplantation remains a promising and potentially curative approach but is limited to a small number of patients. Novel drugs such as arsenic trioxide in combination with interferon-alpha or monoclonal antibodies such as anti-CXCR4 have shown promising results and warrant further investigation.

Arsenic trioxyde in the treatment of HTLV1 associated ATLL

Background The prognosis of Adult T-cell leukemia/lymphoma (ATLL) associated with HTLV1 is dismal. The response to conventional chemotherapy ranges between 20 and 70% and relaspe is constant. Median survival is 8 to 13 months. Chronic and smouldering ATLL have a longer survival, ranging from 18 to 72 months at 5 years. Interferon alpha (IFNa) and AZT combination therapy is effective in acute, chronic and smouldering ATLL, sometimes leading to complete response and has a better prognosis than conventional chemotherapy (5 year survival of 82% in acute and 100% in chronic and smouldering forms reaching a complete response). Patients with ATLL/lymphoma do not benefit from IFNa+AZT combination and despite initial response to chemotherapy, all patients eventually relapse. Arsenic trioxyde (AsO3) in combination with IFNa has in vitro activity with a negative regulation of the Tax oncoprotein and leads to apoptosis of HTLV1 transformed lymphocytes. A recent study has showed a benefit in chronic forms of ATLL.

Guidelines SFGMSuivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques : insuffisance gonadique et fertilitéManagement of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: A report of the SFGM-TC on gonadal failure and fertility

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant.

Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy

Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.