Discontinuation of tyrosine kinase inhibitor in chronic myeloid leukemia: a retrospective cohort in east occitania.

Tyrosine kinase inhibitor (TKI) discontinuation in chronic phase chronic myeloid leukemia (CML) patients has been examined in a real-life setting in the east occitania region of France. We have collected sex, age, prognostic scores, pre-TKI treatment, TKI length and response, relapse data from patients who had stopped TKI in prolonged complete molecular remission (CMR), and analyzed relapse risk factors. Sixty consecutive patients were included from january 2010 to december 2016. Sixteen received pre-TKI treatment. Fifty-three received a first-generation TKI, and seven had a second-generation TKI in first-line therapy. The median TKI time to achieve CMR was 20.5 months [5-137]. The median TKI length before discontinuation treatment was 73 months [12-158]. Twenty-two patients (37%) relapsed with a median time to relapse of 6 months [3-27]. An intermediate or high Sokal score was the only relapse risk factor (HR = 3.32, p < 0.05) associated with relapse after TKI discontinuation. TKI discontinuation was possible without relapse for half of the patients in chronic phase CML. In a real-life cohort, a high-risk Sokal score at diagnosis appears to be an adverse prognosis feature for TKI discontinuation.

Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers.

Background: Peripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem-cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methods: In the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to-treat (ITT). Results: Among 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients ≤65 years old with PTCL-not otherwise specified (NOS) (N = 78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N = 123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N = 68, 25%) with partial (N = 52, 19%) or complete responses (N = 217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR = 1.02; 95% CI: 0.69-1.50 for PFS and HR = 1.08; 95% CI: 0.68-1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P = 0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. Conclusions: The present data do not support the use of ASCT for up-front consolidation for all patients with PTCL-NOS, AITL, or ALK-ALCL with partial or complete response after induction.

Clinical characteristics and prognostic factors of plasmablastic lymphoma patients: analysis of 135 patients from the LYSA group.

Background: Plasmablastic lymphoma (PBL), initially described in 1997 in the oral cavity of HIV positive patients, is now recognized as a distinct aggressive and rare entity of diffuse large B-cells lymphoma by the World Health Organization (WHO) classification. Since the original description, others cases have been reported. However, these are largely derived from case reports or small series limiting any definitive conclusions on clinical characteristics and outcome. Patients and methods: The clinical, biological, pathological features and outcome of a cohort including 135 patients with PBL, from LYSA centers in France and Belgium, were reported and analyzed. Results: The median age was 58 years, with a male predominance. The cohort was divided into 56 HIV-positive patients, 17 post-transplant patients and 62 HIV-negative/non-transplanted patients. Within HIV-negative/non-transplanted, a relative immunosuppression was found in most cases (systemic inflammatory disease, history of cancer, increased age associated with weakened immune system). We have also described a new subtype, PBL arising in a chronic localized inflammatory site, without any sign of immunosuppression. At presentation, 19% of patients showed oral involvement. Immunophenotype showed CD138 positivity in 88% of cases and CD20 negativity in 90% of cases. Chemotherapy was administered to 80% of patients, with a complete response (CR) rate of 55%. The median overall survival (OS) was 32 months. In univariate analysis, HIV positive status showed better OS when compared with HIV negative status. In multivariate analysis, International Prognostic Index score, chemotherapy and CR were associated with survival benefit. Conclusion(s): This cohort, the largest reported to date, increases the spectrum of knowledge on PBL, rarely described. However, specific guidelines to clarify treatment are lacking, and may improve the poor prognosis of this rare disease.

Treatment Response and Outcomes in Post-transplantation Lymphoproliferative Disease vs Lymphoma in Immunocompetent Patients.

Posttransplantation lymphoproliferative disorder (PTLD) after solid organ transplantation may carry a poorer prognosis than lymphoma in immunocompetent individuals, but comparative data are lacking. In a retrospective, single-center, case-control study, 21 cases of PTLD were identified in patients undergoing kidney transplantation since 2000, and compared to 42 nontransplanted controls cared for in the same institution and matched for age, prognostic index, and cerebral localization. Two-year and 5-year overall survival was 57% and 44%, respectively, in PTLD patients and 71% and 58% in controls (log-rank test P = .20). On multivariable analysis, overall survival was similar for PTLD and control patients (hazard ratio 1.71, 95% confidence interval 0.81 to 3.61, P = .16). Response rate to first-line chemotherapy was similar between the 2 groups. Death was due to progression of the disease in 46% vs 94% of PTLD and control patients, respectively (P < .01), or sepsis in 31% vs 0% (P = .03). Treatment-related mortality was significantly higher in PTLD (19%) than in controls (0%, P = .03). In conclusion, response to first-line chemotherapy and overall survival are similar in PTLD and control patients, whereas causes of death were significantly different. Better prevention and management of infectious complications could improve the results in PTLD patients.

[Kinetic and organization of granulocytes transfusion: a case report]. / Transfusion thérapeutique de granulocytes : cinétique et aspects organisationnels autour d'un cas clinique.

BACKGROUND: Therapeutic granulocyte transfusion remains an indication for neutropenic sepsis associated with prolonged neutropenia. However, harvest complexity and lack of proved efficacy mark the limits of its development. CASE REPORT: A 58-year old man received allogeneic stem cell transplantation for osteomyelofibrosis. Six months later, after a transplant rejection, he presented with perineal cellulitis from hemorrhoid origin, without any microbiological documentation. The evolution was unfavorable despite antibiotic and antifungal therapy. A set of seven granulocytes transfusions was initiated. Re-circulation of granulocytes analysis showed an initial increase (H2) followed by a decrease (H8) reaching the basal rate at H16. No toxicity has been reported during or following the transfusions. Clinical improvement has been reported five days after the first transfusion, scaring over at D15, without any neutrophil recovery. CONCLUSION: In 2014, granulocyte transfusion therapy is indicated for severe infection associated with long-term neutropenia. Minimal circulation of transfused cells in our observation and fast clinical improvement suggest the concentration of granulocytes on the infected area.

Trends in G-CSF use in 990 patients after EORTC and ASCO guidelines.

BACKGROUND: Although international guidelines have standardised conditions for G-CSF administration, real practice seems to vary. PATIENTS AND METHODS: A large survey was undertaken in France following a three-step method. Data concerning 990 patients in seven main indications were collected prospectively and analysed for their compliance with international guidelines. RESULTS: G-CSF prescription rate varied from 81% in non-Hodgkin lymphoma (NHL), 55% in ovarian, 44% in breast and 21% in colorectal cancer. The main criteria for G-CSF administration were a chemotherapy regimen with a high risk of neutropaenia (65%) and associated risk factors (51%). Public hospital practitioners prescribed G-CSF more frequently as primary prophylaxis, whereas prescriptions of recently graduated practitioners (or=16 years) were often proposed as secondary prophylaxis or as G-CSF therapy, i.e. during ongoing neutropaenia. In prophylactic settings, administration schedules were highly variable depending on molecules, with a first day of administration between days 1 and 3 after chemotherapy in 66%, but before the end of the chemotherapy infusion in 13% of the cases. Concerning lenograstim (38% of prescriptions) and filgrastim (20%), the mean treatment duration was 5.5 days, significantly shorter than in 1999 (7.8 days). CONCLUSION: G-CSF prescription was mainly in compliance with international guidelines. However, some too early administrations during chemotherapy are at risk of increased myelosuppression and should be more clearly disadvised in next international guidelines.

Follicular lymphoma prognostic factors in the modern era: what is clinically meaningful?

Follicular lymphomas (FL) account for 30% of non-Hodgkin's lymphomas (NHL). Their evolution is heterogeneous. Some patients present with indolent forms undergoing several relapses while in other patients the disease evolves abruptly toward aggressive NHL. This is why accurate prognostic indices are required so that treatment strategies may be optimized for each patient and so that trials may be conducted in groups of patients that are as homogeneous as possible. The Follicular Lymphoma International Prognostic Index (FLIPI) has been designed to separate patients into 3 groups with significantly different hazard ratios for death. Its accuracy has been confirmed in several studies. The FLIPI2 was designed more recently to separate patients with significantly different hazard ratios for progression/relapse in the era of anti-CD20 monoclonal antibody treatments. Gene profile studies have shown that the prognosis of FL is mainly related to the type, number, and activation of immune cells in the microenvironment of lymphomatous follicles. Immunohistochemical studies suggest that macrophages, CD4+ T cells and among them T-regulatory cells (T-regs) and programed death-1 cells (PD-1 cells) play a major role in the outcome of FLs. However, additional confirmatory studies are required due to discrepancies in results. Up to now, these biological study results are more useful for approaching the pathophysiology of FL rather than to be used as prognostic tools in clinical practice.

[Implications of receptors for the Fc portion of IgG (FcgammaRs) in mechanism of action of therapeutic antibodies]. / Rôle des récepteurs à la portion Fc des IgG (FcgammaRs) dans l'activité des anticorps thérapeutiques.

From several years ago, recombinant monoclonal antibodies have allowed a revolution in therapeutic approach of cancer patients. Whereas the clinical efficacy of many antibodies is now demonstrated, their mechanism of action in patients remains elusive. For antibodies targeting membrane antigens, they particularly resort to cytotoxic effectors, which expressed receptors for Fc portion of IgG (FcgammaRs). This review analyses different functions depending of FcgammaR and their potential role in mechanism of action of therapeutic antibodies. A better knowledge of these functions should allow in the next future the optimisation of these treatments.

[Late post-partum eclampsia: a case report]. / A propos d'un cas d'éclampsie tardive du post-partum.

Post-partum eclampsia is an unfrequent entity (11 to 44 % of eclampsia), which can sometimes occur late, beyond the 48th hour. We report a case of late post-partum eclampsia which occurred 12 days after an uncomplicated pregnancy and delivery. Post-partum eclampsia differs from antepartum by a pauci symptomatic or unexpected context. The mortality rate is comparable with that of the ante-partum eclampsia. Brain MRI appears to be the investigation of choice in case of uncertain diagnosis. Magnesium sulfate treatment should be considered under the same conditions as during pregnancy. Identifying and informing high-risk women would allow early diagnosis, which may improve the prognosis of this atypical type of eclampsia.

Neutrophil role in in vivo anti-lymphoma activity of rituximab: FCGR3B-NA1/NA2 polymorphism does not influence response and survival after rituximab treatment.

BACKGROUND: Neutrophils could play an important role in in vivo rituximab anti-lymphoma activity. FcgammaRIIIb is expressed only by neutrophils and FcgammaRIIIb-neutrophil antigen (NA)1/NA2 polymorphism influenced phagocytosis of immunoglobulin G1-opsonized particles. We formulated the hypothesis that if neutrophils are critical cells for in vivo rituximab activity, FcgammaRIIIb-NA1/NA2 polymorphism could influence the response to rituximab. PATIENTS AND METHODS: FCGR3B-NA1/NA2 genotypes were determined in 46 patients having received rituximab for a previously untreated, follicular, non-Hodgkin's lymphoma. The clinical response and the disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow were evaluated at 2 months (M2) and each year during 7 years. RESULTS: They were 13% homozygous for FCGR3B-NA1, 61% homozygous for FCGR3B-NA1/NA2 and 26% heterozygous. The objective response rates at M2 were 67% in homozygous FCGR3B-NA1 patients compared with 75% in homozygous FCGR3B-NA2 and 75% in heterozygous patients (not significant). We found no difference for progression-free and overall survival by FCGR3B-NA1/NA2 genotypes. CONCLUSION: These results indicate no association between FCGR3B-NA1/NA2 polymorphism and response to rituximab indicating no significant role of phagocytosis mediated by neutrophils in in vivo mechanism of rituximab activity.

A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma.

BACKGROUND: Protein kinase C beta (PKCbeta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCbeta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. PATIENTS AND METHODS: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. RESULTS: Sixty patients, median age 66 years (range 45-85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3-5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for > or =3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. CONCLUSION: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.

Evaluation of a peptide ELISA for the detection of rituximab in serum.

Pharmacokinetic studies of therapeutic monoclonal antibodies necessitate the measurement of their biologically active fraction. The aim of this work was to develop an enzyme-linked immunosorbent assay (ELISA) for rituximab, a chimeric anti-CD20 monoclonal antibody, based on its binding to a 20-mer peptide (P20) derived from the extracellular loop of human CD20 (residues 165-184). Derivatives of P20 were prepared by conjugation to bovine serum albumin (BSA-P20ACM) or biotin (Biot-P20ACM). Interactions of P20 and its derived peptides with rituximab were analyzed by surface plasmon resonance (SPR) and by ELISA. A monoclonal anti-idiotype antibody (MB2A4) was used as the reference in each case. SPR analysis showed that P20 (conjugated or unconjugated) had a lower affinity for rituximab than MB2A4. ELISA methods based on P20 or MB2A4 were both highly accurate and reproducible for rituximab measurement in spiked samples, but the MB2A4-based assay had a lower limit of quantification. Interestingly, discrepant results were obtained with the two ELISA methods when analyzing pharmacokinetic samples, with the rituximab concentrations obtained with the MB2A4-based method being systematically higher than those determined by the P20-based method. Possible interference of circulating CD20 with the P20-based method was supported by competition experiments. Rituximab aggregation in the bloodstream may also account for the bias observed in samples from healthy mice. The P20-based ELISA is far less sensitive than the MB2A-based ELISA, thus limiting its utility for pharmacokinetic studies. However, the discrepancy observed between two different approaches for rituximab measurement indicates that data from different studies should be interpreted with care.

[Complications of laparoscopic lymphadenectomy in gynaecologic oncology. A series of 1102 procedures in 915 patients]. / Complications des lymphadénectomies coelioscopiques en oncologie gynécologique: 1102 interventions chez 915 patientes.

OBJECTIVE: Evaluate complications of pelvic and para aortic laparoscopic lymphadenectomies in oncologic gynaecology to confirm the surgical approach and include it in current therapy. PATIENTS AND METHODS: From December 1998 to March 2004, 915 patients underwent pelvic and/or aortic lymphadenectomies by laparoscopy. Among them, 771 were operated on at the centre Oscar-Lambret (Lille, France), whereas 144 underwent surgery at the institut Claudius-Regaud (Toulouse, France). Laparoscopic lymphadenectomies could be indicated along with other procedures in 98 early adnexal carcinomas, in 237 cervical carcinomas and 216 locally advanced cervical carcinomas. It may also be included as part of cancer therapy with (radical) hysterectomy/trachelectomy in 161 endometrial and 203 up front surgical cervical carcinomas. RESULTS: A total of 1102 pelvic and aortic lymphadenectomies have been performed: 714 pelvic (694 trans peritoneal, 20 extra peritoneal) and 388 aortic lymphadenectomies (154 transperitoneal, 234 extraperitoneal). Seventeen open surgeries (1.85%) were necessary for technical reasons or complications. DISCUSSION AND CONCLUSIONS: Laparoscopic lymphadenectomies are safe and accurate with no more complications than by laparotomy and no death up to now.

Visceral leishmaniasis. Persistence of parasites in lymph nodes after clinical cure.

Visceral leishmaniasis (VL) is generally associated with severe immunodeficiency (AIDS; renal, liver, and heart transplantations; haemopoietic malignancies). More rarely it can be related to an immunotolerence status such as pregnancy. Various observations report the development of leishmaniasis several months or even years after exposure to the parasite. Relapses occur rarely in patients not known to be immunocompromised, but are common after incomplete treatment. They are frequent in patients with Leishmania/HIV co-infection. Asymptomatic phases and relapses suggest that parasite can exist in the tissues for a long time before and/or after clinical onset of the disease. The mechanisms of onset of clinical leishmaniasis following exposure and infestation are highly relevant to understanding the pathology of the disease. The survival of Leishmania parasite between infection and disease or after cure is a very important issue for clinicians and epidemiologists. We describe two cases of VL occurring in a patient with lymphoma and in a pregnant woman. In both cases, parasites remained present in the lymph nodes after clinical cure.