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1.
Cancers (Basel) ; 13(12)2021 Jun 12.
Article in English | MEDLINE | ID: mdl-34204600

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1-0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04-0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.

2.
Leukemia ; 35(8): 2332-2345, 2021 08.
Article in English | MEDLINE | ID: mdl-33483613

ABSTRACT

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adult , Aged , Aged, 80 and over , Cytarabine/administration & dosage , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Imatinib Mesylate/administration & dosage , Interferon-alpha/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Prognosis , Prospective Studies , Recombinant Proteins/administration & dosage , Survival Rate , Young Adult
3.
Haematologica ; 106(3): 701-707, 2021 03 01.
Article in English | MEDLINE | ID: mdl-32241844

ABSTRACT

Next-generation sequencing (NGS) is used to investigate the presence of somatic mutations. The utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains unclear. We report the findings of an observational, multicenter study that aimed to assess the impact of somatic mutation testing by NGS in a reallife setting of chronic myeloid malignancies. A total of 177 patients were enrolled, partitioned into two overlapping groups. In group A (n=94), the indication was to search for clonal hematopoiesis, in a context of suspected myelodysplastic syndrome or myeloproliferative neoplasia. In group B (n=95), the theranostic impact of somatic mutations was studied. A panel of 34 genes was used on DNA extracted from blood or bone marrow samples. Within group A, the detection of clonal hematopoiesis supported the diagnosis of chronic myeloid malignancies for 31 patients while the absence of clonal hematopoiesis ruled out the suspected diagnosis in 47 patients. Within group B, NGS identified prognostically relevant somatic mutations in 32 patients, which had a therapeutic impact in 18 cases. By determining the presence or absence of somatic mutations, the application of NGS in daily practice was found to be useful for an integrated final diagnosis in 83% of the patients. Moreover, the search for somatic mutations had a prognostic impact that led to treatment modification in 19% of the cases. This study outlines the fact that adequate implementation of new investigations may have a significant positive medico-economic impact by enabling appropriate management of patients.


Subject(s)
Myelodysplastic Syndromes , Myeloproliferative Disorders , Neoplasms , High-Throughput Nucleotide Sequencing , Humans , Mutation , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Prognosis
5.
Eur J Haematol ; 105(2): 223-230, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32302426

ABSTRACT

BACKGROUND: The R-DHAP regimen (rituximab, cisplatin, dexamethasone, and high-dose cytarabine) is standardly used to treat relapsed Non-Hodgkin lymphoma (NHL). Despite scarce data, cisplatin is frequently substituted with oxaliplatin (R-DHAOx) to avoid nephrotoxicity. We compared nephrotoxicity of cisplatin and oxaliplatin based on creatinine-based trajectory modeling. METHODS: All patients with NHL treated by R-DHAP or R-DHAOx in Angers hospital between January 01, 2007, and December 31, 2014, were included. Patients received cisplatin 100 mg/m2 or oxaliplatin 130 mg/m2 (d1) with cytarabine (2000 mg/m2 , two doses, d2), dexamethasone (40 mg, d1-4), and rituximab (375 mg/m2 , d1). Creatinine levels were recorded before each cycle. Individual profiles of trajectories were clustered to detect homogeneous patterns of evolution. RESULTS: Twenty-two patients received R-DHAP, 35 R-DHAOx, 6 switched from R-DHAP to R-DHAOx due to nephrotoxicity. Characteristics of patients were similar between two groups. Patients receiving R-DHAP experienced more severe renal injury than patients receiving R-DHAOx (68% vs. 7.7%, P < .001). Two homogeneous clusters appeared: cluster A, with a majority of R-DHAOx (32, 91.4%), was less nephrotoxic than B, with a majority of R-DHAP (19, 86.4%), with a decreased average serum creatinine level (P < .0001). There were no other differences between clusters. CONCLUSIONS: Our study confirms that R-DHAOx regimen causes less nephrotoxicity than R-DHAP regimen.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, B-Cell/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Clinical Decision-Making , Cytarabine/administration & dosage , Dexamethasone/administration & dosage , Disease Management , Disease Progression , Female , Humans , Kidney Diseases/diagnosis , Kidney Diseases/etiology , Lymphoma, B-Cell/diagnosis , Lymphoma, B-Cell/mortality , Male , Middle Aged , Neoplasm Staging , Oxaliplatin/administration & dosage , Rituximab/administration & dosage , Survival Analysis , Treatment Outcome
6.
Ann Hematol ; 98(8): 1973-1980, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31111177

ABSTRACT

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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bone Marrow Transplantation , Lymphoma/diagnosis , Lymphoma/therapy , Mucositis/diagnosis , Transplantation Conditioning/methods , Adult , Age Factors , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Busulfan/administration & dosage , Busulfan/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Female , France , Humans , Lymphoma/classification , Lymphoma/mortality , Male , Melphalan/administration & dosage , Melphalan/adverse effects , Middle Aged , Mucositis/chemically induced , Mucositis/pathology , Multivariate Analysis , Prognosis , Retrospective Studies , Risk Factors , Survival Analysis , Transplantation, Autologous
7.
Leuk Lymphoma ; 60(11): 2802-2805, 2019 11.
Article in English | MEDLINE | ID: mdl-31014144
8.
Bone Marrow Transplant ; 54(10): 1586-1594, 2019 10.
Article in English | MEDLINE | ID: mdl-30770870

ABSTRACT

Several approaches have been developed to overcome historical barriers associated with poor outcomes in the setting of HLA-haploidentical allogeneic transplantation (HaploSCT). Here, we examine the outcome of patients with various hematological disorders undergoing HaploSCT with high-dose, post-transplantation cyclophosphamide. We performed a retrospective study on 381 patients from 30 centers between January 2013 and December 2015. At the last follow-up, a total of 1058 infectious episodes were diagnosed, affecting 90.3% of the cohort. Median time to first infection was 13 days for bacterial, 32 days for viral and 20 days for fungal infections. Around 41% of these infections were of bacterial origin and 35% of viral origin, among which 48.8% of patients presented CMV reactivation. Median of GVHD relapse-free survival, progression-free survival and overall survival were 7.1 months, 19.9 months and 33.5 months, respectively. HSCT procedure was the primary or contributing cause of death (55.6%), followed by relapse of the original disease (34.2%). Infections accounted for 45.7% of the HSCT-related deaths. The present multicenter data on a large cohort of patients receiving HaploSCT with PTCy confirmed the feasibility of the procedure with an acceptable incidence of infectious complications, not different as compared to other haploidentical platforms or HLA-matched transplantation.


Subject(s)
Communicable Diseases/etiology , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Conditioning/adverse effects , Transplantation, Haploidentical/adverse effects , Adult , Communicable Diseases/pathology , Cyclophosphamide/pharmacology , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Middle Aged , Retrospective Studies , Transplantation Conditioning/methods , Transplantation, Haploidentical/methods
9.
J Viral Hepat ; 26(2): 278-286, 2019 02.
Article in English | MEDLINE | ID: mdl-30339311

ABSTRACT

Nucleoside and nucleotide analogues (NUCs) targeting hepatitis B virus are capable of selecting resistant viruses upon long-term administration as monotherapies. The prevalence of resistance-associated substitutions (RASs) and fitness-associated substitutions at baseline of NUC therapy and their impact on treatment responses remain unknown. A total of 232 treatment-naïve patients chronically infected with hepatitis B virus (HBV) consecutively referred for the first time to one of French reference centres were included. The nearly full-length HBV reverse transcriptase was sequenced by means of deep sequencing, and the sequences were analysed. RASs were detected in 25% of treatment-naïve patients, generally representing low proportions of the viral quasispecies. All amino acid positions known to be associated with HBV resistance to currently approved NUCs or with increased fitness of resistant variants were affected, except position 80. RASs at positions involved in lamivudine, telbivudine and adefovir resistance were the most frequently detected. All patients with RASs detectable by next-generation sequencing at baseline who were treatment-eligible and treated with currently recommended drugs achieved a virological response. The presence of pre-existing HBV RASs has no impact on the outcome of therapy if potent drugs with a high barrier to resistance are used.


Subject(s)
Antiviral Agents/therapeutic use , Drug Resistance, Multiple, Viral/genetics , Hepatitis B virus/drug effects , Nucleosides/therapeutic use , Nucleotides/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Genetic Fitness , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Prospective Studies , RNA-Directed DNA Polymerase/genetics
10.
Ann Hematol ; 97(12): 2391-2401, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30091022

ABSTRACT

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7-73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3-60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2-46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials.


Subject(s)
Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/mortality , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/mortality , Methotrexate/administration & dosage , Aged , Aged, 80 and over , Central Nervous System Neoplasms/immunology , Disease-Free Survival , Female , Follow-Up Studies , Humans , Lymphoma, Non-Hodgkin/immunology , Male , Middle Aged , Survival Rate
11.
Ann Hematol ; 97(9): 1601-1609, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29717367

ABSTRACT

The benefit of early admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) as soon as they develop organ injury is unknown. We performed a retrospective study on 92 patients admitted to the ICU to determine the impact of time from organ injury to ICU admission on outcome. The number of organ injuries prior to ICU admission was associated with an increased in-hospital mortality (OR 1.7, 95% CI 1-2.7, p = 0.04). Time between first organ injury and ICU admission was also associated with an increased in-hospital survival (OR 1.4, 95% CI 1.1-1.8, p = 0.02). A score combining these two covariates-the number of organ injuries/day (sum of days spent with each individual organ injury)-further improved the prediction of hospital survival. Patients with more organ injuries/day had significantly higher in-hospital mortality rate even after adjustment for refractory acute GVHD and the SOFA (OR 1.3, 95% CI 1-1.7, p = 0.02). Early ICU admission of allogeneic SCT recipients to the ICU as soon as they develop organ injury is associated with decreased in-hospital mortality.


Subject(s)
Critical Care/statistics & numerical data , Graft vs Host Disease/mortality , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hospitalization/statistics & numerical data , Time-to-Treatment , Adult , Female , Graft vs Host Disease/diagnosis , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/mortality , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Lymphoproliferative Disorders/mortality , Lymphoproliferative Disorders/therapy , Male , Middle Aged , Retrospective Studies , Risk Factors , Time Factors , Time-to-Treatment/statistics & numerical data , Transplantation, Homologous/adverse effects , Transplantation, Homologous/mortality
12.
Bone Marrow Transplant ; 53(6): 749-755, 2018 06.
Article in English | MEDLINE | ID: mdl-29523884

ABSTRACT

Renal impairment is a common complication of multiple myeloma (MM), accounting for 20-30% of MM patients at diagnosis and 40-50% of patients during the course of their disease. This feature is associated with poor prognosis and shorter survival as compared to patients with normal renal function (NRF). Therefore, therapeutic management is challenging as autologous stem cell transplantation (ASCT) is often not considered as a valuable strategy, mainly due to concerns of toxicity. In this retrospective and multicenter study, we included 55 MM patients with dialysis-dependent or independent renal failure who underwent high-dose melphalan-based ASCT in order to assess the efficacy outcomes and toxicities of this strategy. Response to ASCT was at least VGPR (very good PR) in 58% of patients and 96% of patients who also received bortezomib-based induction were at least in PR after ASCT. Median OS was 76 months and median PFS was 55 months, similarly to MM patients with NRF. In multivariate analysis, dose of melphalan (140 mg/m2) was correlated with better PFS (18 months, P = 0.005). Toxicities included febrile neutropenia (75%) and severe mucositis (34%). Overall, this work confirmed that ASCT conditioned by 140 mg/m2 melphalan is a beneficial procedure for MM patients with renal failure.


Subject(s)
Multiple Myeloma/therapy , Renal Insufficiency/therapy , Transplantation, Autologous/methods , Adult , Aged , Female , Humans , Male , Middle Aged , Multiple Myeloma/complications , Multiple Myeloma/pathology , Renal Insufficiency/pathology , Retrospective Studies
14.
Am J Hematol ; 93(3): 416-423, 2018 03.
Article in English | MEDLINE | ID: mdl-29226497

ABSTRACT

Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18-50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty-eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow-up of 48 months, 2-year overall survival was 39%, 95% confidence interval (CI) (24-53) in the myeloablative group versus 33%, 95% CI (21-45) in the sequential groups (P = .39), and 2-year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II-IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21-0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Myeloablative Agonists/therapeutic use , Salvage Therapy , Transplantation Conditioning/methods , Adolescent , Adult , Allografts , Antimetabolites, Antineoplastic/therapeutic use , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/etiology , Humans , Immunosuppressive Agents/therapeutic use , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Lymphocyte Transfusion , Male , Middle Aged , Myeloablative Agonists/administration & dosage , Recurrence , Retrospective Studies , Survival Rate , Treatment Outcome , Whole-Body Irradiation , Young Adult
15.
Am J Hematol ; 92(12): 1318-1323, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28960419

ABSTRACT

Patients with Acute Myelogenous Leukemia have a better outcome if reaching molecular remission. We compared the outcome of 373 patients autografted and 335 patients allografted with a 10/10 compatible unrelated donor in first molecular remission. Patients were stratified using the ELN European Leukemia Net classification. ELN favorable group: (234 auto and 70 unrelated transplants). By univariate analysis, in the auto group, the Non Relapse Mortality (NRM) was lower (3.7% versus 19%; P < 10-4 ), Relapse Incidence (RI) higher (29% versus 17%, P < 10-4 ), Leukemia Free Survival (LFS) identical (67% versus 64%) and Overall Survival (OS) better than in the allogeneic group (83% versus 62%; P = .008). By multivariate analysis, autologous transplantation was associated with a lower NRM (HR: 4, P = .01) and a better OS (HR: 2.08, P = .04). ELN intermediate group 1: (87 autologous and 172 unrelated transplants). By univariate analysis, in the auto group, NRM was lower (2.5% versus 11.8%; P = .03), RI higher (59% versus 18%, P < 10-6 ), LFS lower (39% versus 70%; P < 10-6 ) and OS lower than in the unrelated donor group (61% versus 74%; P = .005). By multivariate analysis, unrelated donor was superior to autologous transplantation for LFS (HR: 0.36, P < 10-5) and OS (HR: 0.53, P = .01). ELN intermediate group 2: (52 autologous and 93 unrelated donors). The outcome was identical. We conclude that good risk patients get higher benefit from autologous transplantation. Intermediate risk 2 patients have the same outcome and Intermediate risk 1 patients get higher benefit from unrelated donor transplants.


Subject(s)
Leukemia, Myeloid, Acute/therapy , Transplantation, Autologous/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Remission Induction , Retrospective Studies , Risk Assessment , Survival Rate , Transplantation, Homologous , Treatment Outcome , Unrelated Donors , Young Adult
16.
Blood ; 129(19): 2616-2623, 2017 05 11.
Article in English | MEDLINE | ID: mdl-28251914

ABSTRACT

High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab PK and of TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by 18F-fluorodeoxyglucose-positron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m2 rituximab infusions every 2 weeks in combination with chemotherapy in 2 prospective trials. A 2-compartment population model allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV0 increased (R2 = 0.41, P < .0001). A high AUC in cycle 1 (≥9400 mg × h per liter) was associated with better response (odds ratio, 5.56; P = .0006) and longer PFS (hazard ratio [HR], 0.38; P = .011) and OS (HR, 0.17; P = .001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0 was constructed, and the 375 mg/m2 classical dose would be suitable for patients with TMTV0 <281 cm3 In summary, rituximab exposure is influenced by TMTV0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0 should be evaluated in prospective studies. These studies were registered at www.clinicaltrials.gov as #NCT00498043 and #NCT00841945.


Subject(s)
Antineoplastic Agents/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Rituximab/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Positron-Emission Tomography , Rituximab/administration & dosage , Rituximab/metabolism , Rituximab/pharmacokinetics , Treatment Outcome , Tumor Burden/drug effects , Young Adult
17.
Transplantation ; 101(2): 437-444, 2017 Feb.
Article in English | MEDLINE | ID: mdl-26950729

ABSTRACT

BACKGROUND: Admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) remains controversial, especially when graft-versus-host disease (GVHD) is present. METHODS: We performed a retrospective study to assess prognostic factors of survival in all allogeneic SCT recipients admitted to the ICU between 2002 and 2013 in our center which has flexible admission criteria, especially regarding GVHD. RESULTS: Of 349 patients who underwent allogeneic SCT during the study period, 92 patients (26%) were admitted to the ICU. Intensive care unit and hospital discharge rates were 66% and 46%, respectively, whereas 1 year survival was 24%. Acute GVHD, either grade III to IV (30 patients, 33%) or refractory (12 patients, 13%) had a nonsignificant impact on hospital mortality (odds ratio [OR], 2.1; P = 0.1; OR, 5, P = 0.05, respectively). Fifty percent of patients required invasive mechanical ventilation, 30% required vasopressors, 17% required renal replacement therapy, and 28% had liver impairment (bilirubin >34 µmol/L), each of these parameters defining organ failure. Mortality was closely associated with the number of organ failures as hospital discharge rates were 69%, 50%, 42%, and 0% among patients with 0 (26 patients), 1 (26 patients), 2 (26 patients), and 3 to 4 (14 patients) organ failures, respectively (OR, 2.7; 95% confidence interval, 1.6-4.6; P < 0.001 according to the number of organ failures). CONCLUSIONS: Early mortality of allogeneic SCT recipients admitted to the ICU is especially influenced by the number of organ failures and therefore patients with 0 to 2 organ failures should be considered if required. Refractory GVHD affects survival but not within the confined ICU admission.


Subject(s)
Critical Care , Graft vs Host Disease/therapy , Multiple Organ Failure/therapy , Stem Cell Transplantation/adverse effects , Adult , Chi-Square Distribution , Female , France , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hospital Mortality , Humans , Intensive Care Units , Kaplan-Meier Estimate , Logistic Models , Male , Middle Aged , Multiple Organ Failure/diagnosis , Multiple Organ Failure/etiology , Multiple Organ Failure/mortality , Multivariate Analysis , Odds Ratio , Patient Admission , Patient Discharge , Proportional Hazards Models , Retrospective Studies , Risk Assessment , Risk Factors , Stem Cell Transplantation/mortality , Time Factors , Transplantation, Homologous , Treatment Outcome
18.
Clin Genitourin Cancer ; 15(1): 163-167, 2017 02.
Article in English | MEDLINE | ID: mdl-27444987

ABSTRACT

BACKGROUND: The optimal management of advanced seminoma that relapses after chemotherapy remains unknown. We retrospectively analyzed outcomes with the use of high-dose chemotherapy (HDCT). PATIENTS AND METHODS: Eligibility included adult male patients with pure seminomatous histology and treatment with salvage HDCT. Data of patients who received HDCT from 13 European Society for Blood and Marrow Transplantation (EBMT) centers were used. Multivariable Cox analyses evaluated the association of prespecified factors (line of treatment, prior radiotherapy, and chemosensitivity according to standard definition), with progression-free (PFS) and overall survival (OS). The prognostic ability of the model was assessed through the concordance statistic. RESULTS: From December 2002 to December 2012, 46 cases were identified. Median age was 38 years (interquartile range, 35-46 years). HDCT was provided as second-line therapy (n = 14, 30.4%) and in third-line or beyond third-line therapy (n = 20, 43.5%; 12 had missing information). Sixteen patients (34.8%) received paraortic and/or iliac radiotherapy, and 10 (21.7%) had disease that was cisplatin refractory or absolutely refractory. Median follow-up was 22 months (interquartile range, 8-56). On multivariable Cox analysis, refractory disease was a significantly negative prognostic factor for both PFS (hazard ratio, 6.04; 95% confidence interval, 1.86-19.64) and OS (hazard ratio, 3.93; 95% confidence interval, 1.07-14.45), while prior radiotherapy trended to significance for both. The c index was 0.74 and 0.66 for PFS and OS, respectively. The small numbers and the lack of any comparison with conventional-dose chemotherapy are major study limitations. CONCLUSION: Despite our small sample size, this retrospective analysis suggested that HDCT may represent a valuable therapeutic option for patients with a pure seminoma after standard-dose chemotherapy failure. Our observation requires validation through a prospective study.


Subject(s)
Antineoplastic Agents/administration & dosage , Carboplatin/administration & dosage , Etoposide/administration & dosage , Salvage Therapy/methods , Seminoma/drug therapy , Testicular Neoplasms/drug therapy , Adult , Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Disease-Free Survival , Etoposide/therapeutic use , Humans , Male , Middle Aged , Prognosis , Recurrence , Retrospective Studies , Survival Analysis , Treatment Outcome
19.
Clin Pharmacokinet ; 56(6): 635-647, 2017 06.
Article in English | MEDLINE | ID: mdl-27783363

ABSTRACT

BACKGROUND AND OBJECTIVES: Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL. METHODS: Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance. RESULTS: Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (p = 0.00046) and in patients with the FCGR3A-158VV genotype (p = 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (p = 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (p = 1.3 × 10-5 and 0.0015, respectively). CONCLUSIONS: A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab 'consumption' (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in FCGR3A-158VV patients. CLINICAL TRIAL REGISTRATION: NCT01370772.


Subject(s)
Antigens, CD20/metabolism , Antineoplastic Agents/pharmacokinetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Models, Biological , Receptors, IgG/genetics , Rituximab/pharmacokinetics , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , B-Lymphocytes/metabolism , Body Surface Area , Female , Genotype , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphocyte Count , Male , Middle Aged , Polymorphism, Genetic , Rituximab/blood , Rituximab/pharmacology , Rituximab/therapeutic use
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