Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation.

STUDY QUESTION: How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy? SUMMARY ANSWER: Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC. STUDY DESIGN, SIZE, DURATION: This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density). MAIN RESULTS AND ROLE OF CHANCE: The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group 'no previous chemotherapy', and 32% (7/22) in the group 'previous chemotherapy'. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients. LIMITATIONS, REASONS FOR CAUTION: The pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Agence de la Biomédecine (France's biomedical office). There are no competing interests to report. TRIAL REGISTRATION NUMBER: NCT02184806.

[Not-for-profit: A report from the fourth annual symposium of ethics held by the National Institute for Blood Transfusion (France)]. / À propos du non-profit : rapport du quatrième symposium annuel d'éthique transfusionnelle de l'Institut national de la transfusion sanguine.

The not-for-profit issue has been debated in November 2016 in Paris; this issue is one of the four canonical pillars of ethical blood donation. It is intimately bound to benevolence though it is distinct, as not-for-profit calls for institutions while benevolence calls for individuals. It is indeed intended that voluntary blood donors do not benefit from their donation and are thus non-remunerated. Not-for-profit is essential since it refers to the public character of blood as a putative public resource aimed at being shared as a tribute of solidarity. A central question however is linked to the capacity- or not -of public sectors to ensure that blood components are universally available, with special mention to plasma derived drugs, without the contribution of the for profit, private sector.

First French experiences of total body irradiations using helical TomoTherapy®.

PURPOSE: Dynamic conformal radiotherapy with helical TomoTherapy® (HT) offers a more quantitative paradigm for total body irradiation. Treatment planning, delivery, dose verification of the first French experiences of total body irradiation using helical TomoTherapy® are presented. MATERIALS AND METHODS: Patients planned for total body irradiation at our institution from February 2012 to May 2013 were reported. Total body irradiation consisted in a single fraction of 2Gy. Planning target volume was divided in two due to the limited translation length of the table. Delivery quality assurance was performed with cylindrical phantom, ionization chamber and films. Thermoluminescent dosimeters and radiochromic films were used for in vivo dosimetry and junction region heterogeneity assessment. RESULTS: Six patients were included. One finally did not receive the treatment but dosimetric data were analyzed. Planned V95% was covered by D95% and V2% did not exceed D107% for five of the six patients. The mean relative difference between measured and calculated absolute dose of the Delivery quality assurance was always less than 2.5% (mean value±SD: 1%±0.67%). Gamma index (3%; 3mm) was less than 1 for at least 93% of the points (value±SD: 97.4±1.6% and 96.6±2.5% for upper and lower part of treatment respectively). Difference between in vivo measured and calculated dose was above 5% for only two out of 15 points (maximum: 10.2%, mean: 0.73±4.6%). Junction region heterogeneity was in average 5.8±1%. The total treatment session of total body irradiation lasted 120min, with a mean beam on time of 17.2±0.6 and 11.2±1.6min for upper and lower part of the body respectively. CONCLUSION: Total body irradiation using helical TomoTherapy® guaranteed high dose homogeneity throughout the body and dose verification was achievable, showing small difference between planned and delivered doses.

[Voluntariness and blood donation: Proceedings of an ethics seminar held at the National Institute for Blood Transfusion]. / Volontariat et don de sang : compte rendu d'un séminaire de l'Institut national de transfusion sanguine.

Voluntariness stands for one of the four pillars of ethics in blood donation; it is, however, more related to tradition than to legislation. Because it seems necessary to apply "marketing" techniques to blood collection in order to meet the needs in blood components, both in terms of quantity and quality, one wonders if this may be at the expense of this principle of voluntariness. This seminar-belonging actually to a series of seminars in Ethics in Transfusion Medicine-aimed at questioning the possible weakness of voluntariness in the field of blood donation. To achieve this goal, specialists of numerous disciplines in medical sciences, law and humanities gathered to discuss all related issues to voluntariness in blood donation.

Chimerism analysis in peripheral blood using indel quantitative real-time PCR is a useful tool to predict post-transplant relapse in acute leukemia.

Detection of increasing mixed chimerism (IMC) using standard PCR correlates with relapse after allo-SCT for acute leukemias (ALs). Quantitative real-time PCR of insertion/deletion polymorphism (indel qrtPCR) is a much more sensitive method, which can be performed on peripheral blood. We studied the significance of low increases of recipient cells (0.1%) detected by indel qrtPCR in a cohort of 89 transplants. We did not observe relapse among the 32 patients with no IMC. Fifty-seven patients presented a first IMC, which was followed by four different scenarios: a decreasing MC (26 cases, no relapse), a stable MC (1 case, 1 relapse), a second IMC (24 cases, 15 relapse) or no control of chimerism (6 cases, 5 relapses). In multivariate analysis, detection of two successive IMCs was strongly associated with relapse (hazard ratio (HR): 9.4, 95% confidence interval (CI): 3.8-23; P<0.0001). Among the 57 patients who presented at least one IMC, 27 underwent immunomodulation (tapering of immunosuppression or donor lymphocyte injection), leading to a 1-year relapse rate of 15.7% vs 57.6% in the 30 other patients (P=0.0007). Altogether, these results indicate that chimerism analysis using indel qrtPCR in peripheral blood is a useful tool for detection of relapse in patients transplanted for AL.

The impact of total body irradiation on the outcome of patients with follicular lymphoma treated with autologous stem-cell transplantation in the modern era: a retrospective study of the EBMT Lymphoma Working Party.

BACKGROUND: The aim of this study was to investigate the impact of the high-dose regimen on the outcome of patients with follicular lymphoma (FL) having had autologous stem-cell transplantation (ASCT) in a recent time period. PATIENTS: Between 1995 and 2007, 2233 patients with FL had their first ASCT with either a total body irradiation (TBI)-containing regimen or carmustin, etoposide, cytarabine and melphalan (BEAM), of which 47% were autografted in first remission. RESULTS: After a median observation time of 73 months (interquartile range 30-107), 5- and 10-year non-relapse mortality (NRM) was similar (6% and 10% in both groups). No significant NRM differences became evident after multivariate adjustment for confounders. Secondary malignancies were observed in 9.7% and 7.9% of the patients after TBI and BEAM (P = 0.19), which were treatment-related myelodysplastic syndromes/acute myelogenous leukaemia (t-MDS/AML) in 3.4% and 2.8% (P = 0.57). The median time to t-MDS/AML was around 50 months in both groups. Because of a lower relapse incidence, TBI was associated with better event-free survival reaching statistical significance in the patients transplanted in first remission but not in those transplanted beyond first remission. CONCLUSIONS: In patients with FL who received TBI-based ASCT after 1995 increased NRM and t-MDS/AML risks did not emerge compared with BEAM while disease control was at least equivalent.

Matched unrelated donor allogeneic transplantation provides comparable long-term outcome to HLA-identical sibling transplantation in relapsed diffuse large B-cell lymphoma.

The objective of this retrospective analysis was to compare outcomes of patients with diffuse large B-cell lymphoma (DLBCL) who received either a matched sibling (sib) or an unrelated donor (URD) allogeneic hematopoietic cell transplantation (allo-HCT). Long-term outcome of 172 DLBCL patients receiving URD-HCT between 2000 and 2007 and reported to the European Group for Blood and Marrow Transplantation, was compared with that of 301 subjects, allografted from sib-HCT. With a median follow-up of 45 months, 3-year PFS approached 35% for both groups; overall survival (OS) was 42% for sib-HCT versus 37% for URD (NS). Multivariate analyses confirmed that donor type was not associated with differences in non-relapse mortality (NRM), relapse rate (RR), PFS or OS. Poor performance status (PS) and refractory disease adversely affected PFS and OS. Prior auto-SCT and multiple previous therapies predicted for shorter PFS. NRM was adversely affected by older age (⩾50 years), poor PS and refractory disease, and RR by time from diagnosis to allo-HCT of <36 months, prior auto-SCT, refractory disease, poor PS and in vivo T-cell depletion with alemtuzumab. This large study shows for the first time that URD-HCT is not inferior to sib-HCT, providing a reasonable therapeutic approach for DLBCL patients, having no HLA-identical sibling available.

Extensive chronic GVHD is associated with donor blood CD34+ cell count after G-CSF mobilization in non-myeloablative allogeneic PBSC transplantation.

The correlation between the incidence of GVHD and the number of infused CD34(+) cells remains controversial for PBSC transplantation after a reduced-intensity-conditioning (RIC) regimen. We evaluated 99 patients transplanted with an HLA-identical sibling after the same RIC (2-Gy-TBI/fludarabine). Donor and recipient characteristics, donor's blood G-CSF-mobilized CD34(+) cell count, and number of infused CD34(+) and CD3(+) cells were analyzed as risk factors for acute and chronic GVHD There was a trend for an increased incidence of extensive chronic GVHD in the quartile of patients receiving more than 10 × 10(6) CD34(+) cells/kg (P = 0.05). Interestingly, the number of donor's blood CD34(+) cells at day 5 of G-CSF mobilization was closely associated with the incidence of extensive chronic GVHD, that is, 48% (95% CI: 28-68) at 24-months in the quartile of patients whose donors had the highest CD34(+) cell counts versus 24.3% (95% CI: 14-34) in the other patients (P = 0.007). In multivariate analysis, the only factor correlating with extensive chronic GVHD (cGVHD) was the donor's blood CD34(+) cell count after G-CSF (HR 2.49; 95% CI: 1.16-5.35, P = 0.019). This study shows that the incidence of cGVHD is more strongly associated with the donor's ability to mobilize CD34(+) cells than with the number of infused CD34(+) cells.

[Bronchiolitis obliterans postallogeneic stem cell transplantation: what is new?]. / Bronchiolite oblitérante après allogreffe de cellules souches hématopoïétiques : quels progrès ?

Bronchiolitis obliterans (BO) is a severe complication of hematopoietic stem cell transplantation (HSCT). It is considered as a respiratory manifestation of chronic graft-versus-host disease. It is quite similar to the bronchiolitis obliterans after lung transplantation. Classical therapy associates steroids and immunosuppressive drugs, however theses procedure showed a modest efficacy and have an important morbidity. Recent progresses in the physiopathology of BO post-HSCT allow to use new treatments: mTOR inhibitors, immunotherapy, extra-corporeal photochemotherapy, and bronchial anti-inflammatory effects of azithromycin, statins or antileucotriens. This review will focus on the use of these new therapies in BO post-HSCT.

Influence on Busilvex pharmacokinetics of clonazepam compared to previous phenytoin historical data.

This study investigated the effect of seizure prophylaxis on busulfan (Bu) plasma exposure. Twenty-four adult patients received an intravenous Bu-cyclophoshamide conditioning regimen prior to bone marrow transplantation. Busilvex (0.8 mg/kg) was administered every six hours during four consecutive days. Clonazepam (0.025 to 0.03 mg/kg/day as a continuous 12-h i.v. infusion) was administered at least 12 hours prior to i.v. Bu dosing and continued until 24 hours after the last dose. Pharmacokinetic (PK) data were compared with those previously collected in patients (n=127) treated with phenytoin for seizure prophylaxis. Through population PK analysis, a 10% average increase (coefficient of variation, RSE=5.35%) in total clearance of Bu was quantified when Bu was associated with clonazepam as compared to phenytoin, which was considered as not being clinically relevant. The suspected induction on Bu metabolism by phenytoin should have resulted in the opposite effect. The patient efficacy and safety profiles were comparable between the two cohorts.

Fully functional NK cells after unrelated cord blood transplantation.

Promising results of umbilical cord blood transplantation (UCBT) from unrelated donors have been reported in patients with hematologic disorders. These transplants, having potential to trigger beneficial donor-versus-recipient natural killer (NK) cell-mediated alloreaction, we have conducted the first extensive analysis of the phenotypic and functional properties of NK cells after UCBT. NK cells from 25 patients with high-risk hematologic malignancies were compared with cells derived from both healthy adult and CB cells. We found that following UCBT, NK cells display not only some phenotypic features associated with maturity but also unique characteristics that make them fully functional against leukemic blasts. We propose that this full functionality of alloreactive donor-derived NK may drive graft-versus-leukemia reactions after UCBT.

HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT.

Natural killer (NK) cells generated after haploidentical hematopoietic SCT in patients with AML are characterized by specific phenotypic features and impaired functioning that may affect transplantation outcome. We show that IFN-gamma produced by immature CD56(bright) NK cells upregulates cell surface expression of HLA-E on AML blasts and that this upregulation protects leukemic cells from NK-mediated cell lysis through the mediation of CD94/NKG2A, an inhibitory receptor overexpressed on NK cells after haploidentical SCT. Two years after transplantation, however, maturing NK cells were functionally active, as evidenced by high cytotoxicity and poor IFN-gamma production. This implies that maturation of NK cells is the key to improved immune responses and transplantation outcome.

Successful treatment of disseminated Geotrichum capitatum infection with a combination of caspofungin and voriconazole in an immunocompromised patient.

Disseminated Geotrichum capitatum infection is uncommon, and has been reported exclusively in immunocompromised patients. The prognosis is poor with a mortality rate of approximately 50-75%. We report a case of disseminated G. capitatum infection in a severely neutropenic patient who was receiving chemotherapy for acute myeloblastic leukaemia. G. capitatum was isolated from blood cultures, skin lesions, bronchoalveolar lavage fluid, throat swabs and stools. The infection was successfully cured with a combination of voriconazole and caspofungin.

Involvement of mature donor T cells in the NK cell reconstitution after haploidentical hematopoietic stem-cell transplantation.

We previously demonstrated that natural killer (NK) cells generated after haploidentical stem-cell transplantation (SCT) are blocked at an immature state characterized by phenotypic features and impaired functioning and that this may affect transplantation outcome. We hypothesize that the absence of mature donor T cells in the graft may affect NK cell differentiation. NK cells from 21 transplant recipients who underwent either partial (pTCD; n=11) or extensive (eTCD; n=10) T-cell depletion were compared with NK cells from their healthy donors. We report that despite the strong graft-versus-host disease (GvHD) reaction, pTCD patients, with T cells present during SCT, had a better clinical outcome than patients with eTCD transplants. In addition, the frequency of CD3- CD56(bright) and NKG2A+ NK cells was much lower in pTCD than in eTCD patients after transplantation, and the level of cytotoxicity against primary haplo-mismatched blasts was significantly more pronounced after pTCD than eTCD transplants. These finding strongly suggest that mature donor T cells in the graft may play a key role in NK cell differentiation in vivo, after haploidentical SCT.

Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial.

Fifty-four percent of adults with acute lymphoblastic leukemia (ALL) who entered the LALA-94 trial experienced a first relapse. We examined the outcome of these 421 adult patients. One hundred and eighty-seven patients (44%) achieved a second complete remission (CR). The median disease-free survival (DFS) was 5.2 months with a 5-year DFS at 12%. Factors predicting a better outcome after relapse were any transplant performed in second CR (P<0.0001), a first CR duration >1 year (P=0.04) and platelet level >100 x 10(9)/l at relapse (P=0.04). Risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse. The best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation (SCT). Geno-identical allogeneic SCT was performed in 55 patients, and 3 patients received donor lymphocyte infusions. Forty-four transplantations were performed from an unrelated donor (of which four were cord blood). We conclude that most adult patients with recurring ALL could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option.

[Management of the pulmonary complications of haematological malignancy]. / Approche diagnostique d'une pneumopathie chez un malade atteint d'hémopathie maligne.

The high frequency of pulmonary complications of haematological malignancy and the increasing number of patients treated for these disorders make it important that the respiratory physician has a structured diagnostic approach according to: 1 the immune deficiency due to the malignancy and/or the treatment administered; 2 the factors that can modify the risk of infection (anti infection prophylaxis and/or pre-emptive treatment); 3 co-morbidities; 4 extra-pulmonary manifestations. Two main situations can be identified: The patient is aplasic: Initially the pneumonias are predominantly of bacterial origin but may be fungal if the neutropenia is prolonged. The respiratory physician is faced with two problems: 1 the diagnosis of pneumonia; this may be helped by CT scanning; 2 The choice of antibiotics; this will depend on previous investigations. The patient is not aplasic: The lung disease may have many causes, mainly infectious but also drug related, tumoral, haemorrhagic or embolic. The main problem is the correct choice of investigations to establish an aetiological diagnosis. The collection of data according to a pre-established protocol based on simple factors (study of the notes and clinical examination) is one of the key elements for improving the prognosis of these patients whose management should be multidisciplinary following a pre-defined plan.

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.