Publications by authors named "Sandy Amorim"

23 Publications

  • Page 1 of 1

Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort.

Ann Hematol 2021 Apr 25;100(4):987-993. Epub 2021 Jan 25.

Service d'Hématologie clinique adultes et thérapie cellulaire, Hôpital Estaing, CHU Clermont-Ferrand, 1 place Lucie Aubrac, 63000, Clermont-Ferrand, France.

The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.
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http://dx.doi.org/10.1007/s00277-021-04419-wDOI Listing
April 2021

Presence of T cells directed against CD20-derived peptides in healthy individuals and lymphoma patients.

Cancer Immunol Immunother 2019 Oct 7;68(10):1561-1572. Epub 2019 Sep 7.

Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Inserm UMRS 1138, "Cancer, Immune Control and Escape" Laboratory, Centre de Recherche des Cordeliers, Paris, France.

Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4 T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2-DR1 transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.
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http://dx.doi.org/10.1007/s00262-019-02389-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805815PMC
October 2019

BAM conditioning before autologous transplantation for lymphoma: a study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Ann Hematol 2019 Aug 20;98(8):1973-1980. Epub 2019 May 20.

Centre Hospitalo-Universitaire Tours, Tours, France.

High-dose chemotherapy before autologous transplantation is a therapeutic option as consolidation in primary or relapsed lymphoma. Even if BEAM conditioning is generally used, alternative conditioning regimens have been published. The purpose of this study was to assess the outcome of 177 adult patients with lymphoma whose conditioning treatment included a BAM (busulfan, aracytine, and melphalan) regimen. With a median follow-up of 17.4 months, 2-year estimates of overall survival and progression-free survival for the entire group were 87% and 70.5%, respectively. Mucositis was the main reported complications and infectious episodes were described in 80.2% of patients. According to multivariate analysis, high performance status and age at diagnosis were adverse factors for survival and increased the risk of disease relapse and death. Despite its limitations, this retrospective study suggests that BAM combination is a valid conditioning regimen in lymphoma patients, with an acceptable rate of toxicity.
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http://dx.doi.org/10.1007/s00277-019-03704-zDOI Listing
August 2019

L’arrivée de l’immunothérapie dans le lymphome de Hodgkin.

Bull Cancer 2018 Dec;105 Suppl 1:S50-S58

Service d'onco-hématologie - Hôpital Saint-Louis, AP-HP, Paris, France.

Immunotherapy Of Hodgkin Lymphoma: Classical Hodgkin lymphoma (HL) is a rare hematological cancer, affecting preferentially young adults. Using a risk-adapted approach, HL has become highly curable (>80%) with front-line chemotherapy in addition with radiotherapy, despite long term significant toxicity. Some patients are primary refractory or relapse after first-line chemotherapy, requiring high dose chemotherapy with serious side effects. Studies of the microenvironment from HL tissue reveal ineffective inflammatory and immune cell infiltrate surrounding Reed-Sternberg cells, involving the Programmed cell Death 1 (PD-1)/PD-ligand-1 checkpoint pathways. Recently, immune checkpoint inhibitors demonstrated high efficacy for relapsed and refractory patients, with a favorable safety profile but indeterminate long term outcome. Guidelines for nivolumab or pembrolizumab treatment in HL remain to be established.
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http://dx.doi.org/10.1016/S0007-4551(18)30390-4DOI Listing
December 2018

Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study.

Br J Haematol 2018 12 8;183(5):755-765. Epub 2018 Nov 8.

Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m  days 1, 2) and rituximab (375 mg/m  day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77-96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients.
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http://dx.doi.org/10.1111/bjh.15641DOI Listing
December 2018

Intensive care unit admission in patients with T cell lymphomas: clinical features and outcome.

Ann Hematol 2019 Jan 14;98(1):195-203. Epub 2018 Sep 14.

Medical Intensive Care Unit, AP-HP, Saint-Louis University Hospital, 1 avenue Claude Vellefaux, 75010, Paris, France.

T cell non-Hodgkin lymphomas (T-NHLs) are aggressive malignancies which have a high risk of life-threatening complications. However, their prognosis in the intensive care unit (ICU) setting has not yet been assessed. We conducted a study including 87 ICU patients either with newly diagnosed T-NHLs or those undergoing first-line therapy admitted between January 1, 2000, and December 31, 2014. The primary subtypes were peripheral T cell lymphoma (PTCL) (n = 41, 47%), anaplastic large-cell lymphoma (ALCL) (n = 13, 15%), and adult T-leukaemia/lymphoma (ATLL) (n = 11, 13%). Six in every ten patients had malignancy-related complications (haemophagocytic syndrome 37%, tumour lysis syndrome 18% and hypercalcaemia 9%), while infections accounted for one quarter of ICU admissions. Nine fungal infections were documented, including six invasive aspergillosis. Urgent chemotherapy was started in the ICU in 59% of the patients, and urgent surgery was required in 13%. ICU and day-90 mortality were 22% and 41%, respectively. Multivariate analysis showed that SOFA score at day 1, age, sepsis and haemophagocytic syndrome were independent predictors of day-90 mortality. Compared to 66 ICU-matched controls with non-Hodgkin B cell lymphomas, patients with T-NHLs had a similar ICU survival. Overall survival rates of patients with T cell NHLs and B cell NHLs were 20% and 46%, respectively (hazard ratio for death associated with T cell NHLs 2.00 [1.12-3.58]). Patients with T cell NHLs had a very poor long-term outcome. Although the high rate of short-term survival suggests that an ICU trial is a reasonable option for patients newly diagnosed for the malignancy, extended stay in the ICU or further readmission should be considered only for highly selected patients who respond to the haematological treatment.
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http://dx.doi.org/10.1007/s00277-018-3496-1DOI Listing
January 2019

Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study.

Br J Haematol 2018 05 2;181(3):341-349. Epub 2018 Apr 2.

Hopital Saint Louis, Paris, France.

Tandem stem cell transplantation (SCT) is an option for high-risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14-56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow-up was 43 months (4.8-73.7 months). The two-year progression-free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46-65%) and 71% (95% CI: 49-84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant-related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high-risk relapsed/refractory HL patients, although transplant-related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin-based post-transplant consolidative strategies in high-risk relapsed/refractory HL patients.
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http://dx.doi.org/10.1111/bjh.15184DOI Listing
May 2018

The value of molecular techniques to diagnose Ureaplasma urealyticum and Nocardia farcinica pleuropneumonia in a patient with diffuse large B-cell lymphoma.

Int J Infect Dis 2017 Nov 22;64:93-95. Epub 2017 Sep 22.

Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre-Cochin, Fédération d'Infectiologie, Paris, France; INSERM 1181 Biostatistics, Biomathematics, Pharmacoepidemiology, and Infectious Diseases (B2PHI), Paris, France.

An unusual case of pleural empyema related to Nocardia farcinica and Ureaplasma urealyticum, occurring after autologous haematopoietic stem cell transplantation in a 30-year-old patient with lymphoma, is reported. This case illustrates the role of repeated and comprehensive microbiological investigations and the contribution of molecular techniques in reaching the aetiological diagnosis.
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http://dx.doi.org/10.1016/j.ijid.2017.09.015DOI Listing
November 2017

Long-term outcomes of adults with first-relapsed/refractory systemic anaplastic large-cell lymphoma in the pre-brentuximab vedotin era: A LYSA/SFGM-TC study.

Eur J Cancer 2017 09 20;83:146-153. Epub 2017 Jul 20.

Hematology Department, Necker University Hospital, Greater Paris University Hospitals (AP-HP), Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France. Electronic address:

Background: Long-term outcomes of adults with first-relapsed/refractory (R/R) systemic anaplastic large-cell lymphoma (ALCL) are not definitively established and should be evaluated.

Patients And Methods: We previously published the long-term outcomes of adults with ALCL initially treated with polychemotherapy in LYmphoma Study Association (LYSA) prospective clinical trials conducted during the pre-brentuximab vedotin era. Herein, we report the long-term outcomes of those patients after the first-relapsed/refractory (R/R) events.

Results: Among the 138 (64 (anaplastic lymphoma kinase (ALK(+)) and 74 ALK(-) ALCL) adults initially treated in clinical trials, 40 (14 ALK(+) and 26 ALK(-)) first-R/R ALCL patients and their long-term outcomes were analysed. Median follow-up from the first-R/R events was 12.5 years. For ALK(+) and ALK(-) patients, respectively, median [range] findings were as follows: age at first-R/R event: 35 [19-76] and 61 [34-81] years; time between inclusion in first-line clinical trials and first-R/R events was 6 [1.5-34] and 11.1 [1-67] months (P = 0.36); with median (95% confidence interval) progression-free survival after the first-R/R events: 3.8 (0.7-14.8) and 5.3 (2.4-8.4) months (P = 0.39); and overall survival: 13.6 (0.7-89) and 8.1 (3.3-25) months (P = 0.96). ALCL was the main cause of death.

Conclusion: Most adults with first-R/R ALCL have poor outcomes, with no significant differences between patients with ALK(+) or ALK(-) disease. These results could be used as reference for the evaluation of new drugs to treat R/R ALCL.
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http://dx.doi.org/10.1016/j.ejca.2017.06.026DOI Listing
September 2017

Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study.

Lancet Haematol 2016 Apr 18;3(4):e196-204. Epub 2016 Mar 18.

Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

Background: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results from a cohort of patients with lymphoma or multiple myeloma (non-leukaemia cohort).

Methods: In this dose-escalation, open-label, phase 1 study, we recruited patients from seven university hospital centres (in France [four], Switzerland [one], UK [one], and Italy [one]). Adult patients with non-leukaemia haematological malignancies who had disease progression on standard therapies were eligible to participate. Patients were treated with oral OTX015 once a day continuously over five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg), using a conventional 3 + 3 design, with allowance for evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity (DLT) in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

Findings: Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3-5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3-4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria.

Interpretation: The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects.

Funding: Oncoethix GmbH (a wholly owned subsidiary of Merck Sharp & Dohme Corp).
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http://dx.doi.org/10.1016/S2352-3026(16)00021-1DOI Listing
April 2016

Does bendamustine impact the mobilization of peripheral blood stem cells? A multicenter retrospective study of 23 cases.

Leuk Lymphoma 2016 May 15;57(5):1149-53. Epub 2016 Feb 15.

a Institut D'hématologie De Basse Normandie, Centre Hospitalier Universitaire , Caen , France ;

Bendamustine is used in the treatment of different relapsing or refractory subtypes of lymphoma. Its impact on the yield of peripheral blood stem cells is not well known. Twenty three patients who received bendamustine followed immediately or after another chemotherapy by stem cell mobilization (SCM) were included. The patients were divided into two groups: group 1 (n=17), in whom SCM was performed immediately after bendamustine chemotherapy, and group 2 (n=6), in whom SCM was performed after another cycle of chemotherapy. The success rate of mobilization after Bendamustine+/-plerixafor was 36% (eight cytapheresis succeeded for a total number of 22 cytapheresis); and 75% after other approaches (chemotherapy based or steady state) used for patients who received bendamustine previously. Although bendamustine used alone was not an effective drug to mobilize stem cells, this agent does not seem to have detrimental effects on subsequent SCM.
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http://dx.doi.org/10.3109/10428194.2016.1140160DOI Listing
May 2016

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study.

Lancet Haematol 2015 Apr 17;2(4):e160-5. Epub 2015 Mar 17.

Department of Hematology, Hospices Civils de Lyon and University Lyon 1, Lyon, France. Electronic address:

Background: Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease.

Methods: We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526.

Findings: Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia.

Interpretation: Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial.

Funding: Celgene.
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http://dx.doi.org/10.1016/S2352-3026(15)00023-XDOI Listing
April 2015

Rituximab-ABV(D) for patients with Nodular lymphocyte predominant Hodgkin lymphoma ineligible for radiation therapy.

Br J Haematol 2016 11 18;175(4):735-737. Epub 2015 Dec 18.

Department of Haematology, APHP, Hôpital Saint-Louis, Paris, France.

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http://dx.doi.org/10.1111/bjh.13879DOI Listing
November 2016

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse.

Blood 2015 Oct 3;126(14):1695-8. Epub 2015 Aug 3.

Hemato-oncology Department, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Paris, France; Paris Diderot Université, Sorbonne Paris Cité, Paris, France;

The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.
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http://dx.doi.org/10.1182/blood-2015-05-647834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591793PMC
October 2015

Diagnostic Yield and Safety of Computed Tomography-guided Mediastinal Core Needle Biopsies.

J Thorac Imaging 2015 Sep;30(5):319-27

Departments of *Radiology †Hematology ‡Pulmonology §Pathology, Hôpital Saint Louis, Paris, France.

Purpose: Mediastinal masses of various origins can be encountered on imaging in symptomatic or asymptomatic patients. We aimed to evaluate the diagnostic yield and complication rate of computed tomography (CT)-guided mediastinal core needle biopsies in a large population of patients presenting with mediastinal masses and to identify the factors that could influence these results.

Materials And Methods: In total, 293 consecutive CT-guided mediastinal biopsies, performed in 285 patients with equivocal masses at a single center from 2006 to 2011, were included. Lesion characteristics, technical biopsy parameters, final diagnoses, diagnostic yields (number of biopsies that yielded a complete diagnosis divided by the total number of biopsies), and complication rates were recorded.

Results: Malignant diagnoses, including lymphoproliferative disorders (N=151, 53%) and lung cancers (N=54, 19%), were established in 233 cases (82%). Benign lesions were found in 52 procedures (18%), including sarcoidosis (N=19, 7%) and infections (N=17, 6%). The overall diagnostic yield was 87% and was lower for lymphoma residual masses (57%) than for initial diagnosis or relapses of known disease (90%). Complications occurred in 21 patients (7%), but only 2 patients (0.7%) required hospitalization for >12 hours. Neither the diagnostic yield nor the complication rate was influenced by the target characteristics or by technical parameters.

Conclusions: CT-guided core needle biopsy of equivocal mediastinal masses is a minimally invasive procedure that is effective and safe, even in cases of small targets or targets in challenging locations.
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http://dx.doi.org/10.1097/RTI.0000000000000160DOI Listing
September 2015

Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma.

Leuk Lymphoma 2015 12;56(11):3090-5. Epub 2015 May 12.

a Medical Intensive Care Unit, Saint Louis University Hospital , Paris , France.

Toxic effects of high dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) can lead to life-threatening conditions that may require intensive care unit (ICU) admission. We conducted a retrospective observational study over a 10-year period of all patients admitted to the ICU within 3 months after HDT/ASCT for lymphoma. Among the 532 patients treated by HDT/ASCT at our hospital, 27 (5%) were admitted to the ICU. Infections accounted for 88% (n = 24) of diagnoses, in whom 50% were microbiologically documented. Primary sources of infections were neutropenic enterocolitis (n = 9, 33%) and pneumonia (n = 9, 33%). Bacteria were identified in 83% of documented infections. ICU mortality was 18.5% (n = 5), representing 0.9% of the 532 patients. Among the 22 ICU survivors, 72.7% (n = 16) were alive and in complete remission 6 months after ICU discharge. In our experience, maximal intensive care support is justified for HDT/ASCT recipients with severe complications.
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http://dx.doi.org/10.3109/10428194.2015.1034700DOI Listing
September 2016

Management and prognosis of 66 patients with B-cell non-Hodgkin lymphoma presenting with initial spinal cord compression: a French retrospective multicenter study.

Leuk Lymphoma 2015 Jul 17;56(7):2025-31. Epub 2014 Dec 17.

Hemato-Oncology, AP-HP at Saint-Louis Hospital, Paris VII Diderot- Sorbonne University, IUH , Paris , France.

Initial spinal cord compression (ISCC) in B-cell non-Hodgkin lymphoma (NHL) is rarely present at diagnosis. We performed a multicenter retrospective analysis of 66 patients with ISCC, including diffuse large B-cell (DLBCL) (70%), follicular (20%), small lymphocytic (6%), marginal zone (2%) and B-cell unclassified (2%) lymphomas, with the aim of describing their management and outcomes, as well as the occurrence of central nervous system (CNS) relapses. All but two patients received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens, with rituximab in 61% of cases. Forty-six patients received CNS prophylaxis. The 5-year overall survival and progression-free survival were 78% and 65% for DLBCL, and 60% and 48% for indolent lymphomas, respectively. CNS relapses occurred in four (6%) patients, all with DLBCL and all in the cerebellum. Initial decompressive procedures, intradural involvement, cerebrospinal fluid infiltration and lack of CNS prophylaxis did not influence survival. Adverse prognostic factors were male sex, poor performance status, elevated lactate dehydrogenase and high age-adjusted international prognostic index.
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http://dx.doi.org/10.3109/10428194.2014.977884DOI Listing
July 2015

Outcomes after intensive care unit admission of patients with newly diagnosed lymphoma.

Leuk Lymphoma 2015 May 9;56(5):1240-5. Epub 2014 Oct 9.

Medical Intensive Care Unit.

No data are available on outcomes of patients with lymphoma requiring intensive care unit (ICU) admission. We retrospectively studied 190 patients admitted to our ICU between 2000 and 2010, before or during the first chemotherapy course for lymphoma. Reasons for ICU admission were renal failure (36%), shock (28%), respiratory failure (26%), coma (22%) and monitoring (12%). Mechanical ventilation was needed in 45% of patients, dialysis in 41% and vasoactive drugs in 30%. ICU, hospital and 1-year mortality rates were 22%, 37% and 51%. By multivariate analysis, factors associated with higher hospital mortality were age > 50 years (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.02-4.9), poor performance status (OR, 3.36; 95% CI, 1.47-6.54), high Sequential Organ Failure Assessment (SOFA) score (OR, 1.15/point; 95% CI, 1.04-1.27), hemophagocytic syndrome (OR, 2.57; 95% CI, 1.03-6.40), Burkitt lymphoma (OR, 3.36; 95% CI, 1.38-8.19) and primary cerebral lymphoma (OR, 7.32; 95% CI, 1.06-50.54). Admission after 2004 was associated with better survival (OR, 0.35; 95% CI, 0.15-0.78).
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http://dx.doi.org/10.3109/10428194.2014.922181DOI Listing
May 2015

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.

Lancet Oncol 2014 Aug 17;15(9):1019-26. Epub 2014 Jul 17.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma.

Methods: In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750.

Findings: From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose.

Interpretation: Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial.

Funding: Janssen.
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http://dx.doi.org/10.1016/S1470-2045(14)70311-0DOI Listing
August 2014
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