ABSTRACT
Historically, double or triple hit lymphoma (DHL and THL) have poor outcomes with conventional chemotherapy, but there is currently no guideline. We report the French experience in managing DHL and THL in first line using collective data on both survival and tolerance. All consecutive patients with newly diagnosis of large B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements, as determined by FISH between January 2013 and April 2019 were included. Based on the eligibility criteria, 160 patients were selected among the 184 patients identified. With a median follow-up of 32 months, 2- and 4-year progression free survival (PFS) rates were 40% and 28% with R-CHOP compared with 57% and 52% with intensive chemotherapy (P = .063). There was no difference in overall survival (OS). For advanced stages, PFS was significantly longer with intensive chemotherapy than with R-CHOP (P = .029). There was no impact of autologous stem cell transplantation among patient in remission. For patients with central nervous system (CNS) involvement, the 2-year PFS and OS rate was 21% and 39%, vs 57% and 75% without CNS disease (P = .007 and P < .001). By multivariate analysis, elevated IPI score and CNS disease were strongly and independently associated with a poorer survival, whereas treatment was not significantly associated with OS. This is the largest series reporting the treatment of DHL and THL in Europe. The PFS was significantly longer with an intensive regimen for advanced stage, but no difference in OS, supporting the need for a prospective randomized trial.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System/pathology , Combined Modality Therapy , Drug Evaluation , Female , Follow-Up Studies , France/epidemiology , Gastrointestinal Diseases/chemically induced , Genes, bcl-2 , Genes, myc , Hematologic Diseases/chemically induced , Hematopoietic Stem Cell Transplantation , Humans , In Situ Hybridization, Fluorescence , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Middle Aged , Progression-Free Survival , Proto-Oncogene Proteins c-bcl-6/genetics , Remission Induction , Retrospective Studies , Salvage Therapy , Transplantation Conditioning , Transplantation, AutologousABSTRACT
Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Initial treatment with fludarabine-based immuno-chemotherapy, with or without intra-CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1-16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From CNSi, 5-year overall survival was 72% and 48% for treatment-naïve and previously treated patients respectively (P = 0·06); 5-year progression-free survival (PFS) was 43% and 0% (P = 0·125). 17p deletion was significantly associated with poor PFS (P = 0·006). CNSi may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.
Subject(s)
Central Nervous System/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Leukemic Infiltration/pathology , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cohort Studies , Disease Management , Disease-Free Survival , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Neoplasm Invasiveness , Piperidines , Prognosis , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Remission Induction , Retrospective Studies , Survival Analysis , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
PURPOSE OF REVIEW: We aimed to produce a comprehensive update on clinical and biological data regarding two rare lymphoid neoplasms, B and T prolymphocytic leukemias, and assess therapeutic management in the light of new molecular insights and the advent of targeted therapies. RECENT FINDINGS: B cell prolymphocytic leukemia (B-PLL) diagnosis remains challenging in the absence of clear immunophenotypic or cytogenetic signature and overlap with mantle cell lymphoma. New molecular defects have been identified in T cell prolymphocytic leukemia (T-PLL), especially in the JAK STAT pathway. Like in chronic lymphocytic leukemia (CLL), B-PLL treatment depends on the presence of TP53 dysfunction. In T-PLL, alemtuzumab still remains the standard of care. Allogeneic transplantation is the only curable option. Thanks to reduced intensity conditioning regimens, it has become accessible to a larger number of patients. PLL prognosis remains poor with conventional therapies. However, great advances in the understanding of both T- and B-PLL pathogenesis lead to promising new therapeutic agents.
Subject(s)
Leukemia, Prolymphocytic, B-Cell/diagnosis , Leukemia, Prolymphocytic, B-Cell/genetics , Leukemia, Prolymphocytic, B-Cell/therapy , Leukemia, Prolymphocytic, T-Cell/diagnosis , Alemtuzumab , Antibodies, Monoclonal, Humanized/therapeutic use , Humans , Immunophenotyping/methods , Leukemia, Prolymphocytic, T-Cell/genetics , Leukemia, Prolymphocytic, T-Cell/therapy , Transplantation, Homologous/methodsABSTRACT
Central nervous system involvement by malignant cells is a rare complication of Waldenström macroglobulinemia, and this clinicopathological entity is referred to as the Bing-Neel syndrome. There is currently no consensus on the diagnostic criteria, therapeutic approaches and response evaluation for this syndrome. In this series, we retrospectively analyzed 44 French patients with Bing-Neel syndrome. Bing-Neel syndrome was the first manifestation of Waldenström macroglobulinemia in 36% of patients. When Waldenström macroglobulinemia was diagnosed prior to Bing-Neel syndrome, the median time interval between this diagnosis and the onset of Bing-Neel syndrome was 8.9 years. This study highlights the possibility of the occurrence of Bing-Neel syndrome without any other evidence of progression of Waldenström macroglobulinemia. The clinical presentation was heterogeneous without any specific signs or symptoms. Biologically, the median lymphocyte count in the cerebrospinal fluid was 31/mm(3). Magnetic resonance imaging revealed abnormalities in 78% of the cases. The overall response rate after first-line treatment was 70%, and the overall survival rate after the diagnosis of Bing-Neel syndrome was 71% at 5 years. Altogether, these results suggest that Bing-Neel syndrome should be considered in the context of any unexplained neurological symptoms associated with Waldenström macroglobulinemia. The diagnostic approach should be based on cerebrospinal fluid analysis and magnetic resonance imaging of the brain and spinal axis. It still remains difficult to establish treatment recommendations or prognostic factors in the absence of large-scale, prospective, observational studies.
Subject(s)
Central Nervous System Neoplasms , Waldenstrom Macroglobulinemia , Aged , Aged, 80 and over , Central Nervous System Neoplasms/cerebrospinal fluid , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/secondary , Central Nervous System Neoplasms/therapy , Female , France , Humans , Male , Middle Aged , Syndrome , Waldenstrom Macroglobulinemia/cerebrospinal fluid , Waldenstrom Macroglobulinemia/mortality , Waldenstrom Macroglobulinemia/pathology , Waldenstrom Macroglobulinemia/therapyABSTRACT
The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second-line options after fludarabine-cyclophosphamide-rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non-randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second-line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second-line regimen, followed by alemtuzumab-based regimens, R-CHOP, and FCR. Median progression-free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression-free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Databases, Factual , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Salvage Therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , France/epidemiology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Middle Aged , Prednisone/administration & dosage , Recurrence , Retrospective Studies , Risk Factors , Rituximab , Survival Rate , Time Factors , Vincristine/administration & dosageSubject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Nervous System Diseases/drug therapy , Nervous System Diseases/etiology , Nervous System/drug effects , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Aged , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Male , Middle Aged , Nervous System Diseases/enzymology , Piperidines , Protein-Tyrosine Kinases/antagonists & inhibitors , Retrospective StudiesSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Cyclophosphamide/therapeutic use , Follow-Up Studies , Humans , Remission Induction , Retrospective Studies , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
Relapsed/Refractory Diffuse Large B Cell Lymphoma have a dismal prognosis in need of innovative treatments. This prospective phase 2 study enrolled 32 patients between 2013 and 2017 with Relapsed/Refractory Diffuse Large B Cell Lymphoma treated with Rituximab and Lenalidomide (R2). Median age was 69 years (40-86), 90.1% had received at least 2 prior lines of treatment, 81% were defined as having High Risk disease according to our criteria and ECOG performance status was > 2 in 51.6%. Patients received a median number of 2 cycles of R2 (1-12). With a median follow up of 22.6 months, the objective response rate was 12.5%. Median progression free survival was 2.6 months (95% CI, [1.7-2.9]) and median overall survival was 9.3 months (95% CI, [5.1-Not estimable]). This study therefore did not achieve its primary endpoint and the R2 regimen cannot be recommended in Relapsed/Refractory Diffuse Large B Cell Lymphoma patients with High Risk features.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Humans , Aged , Rituximab/adverse effects , Lenalidomide/adverse effects , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Lymphoma, Non-Hodgkin/drug therapy , Treatment OutcomeABSTRACT
Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.
ABSTRACT
Despite recent advances with monoclonal antibody therapy, chronic lymphocytic leukemia (CLL) remains incurable. Natural killer (NK) cells are potent antitumoral effectors, particularly against hematological malignancies. Defective recognition of B-CLL leukemic cells by NK cells has been previously described. Here, we deciphered the mechanisms that hamper NK cell-mediated clearance of B-CLL and evaluated the potential of NK cells as therapeutic tools for treatment of CLL. First of all, leukemic B cells resemble to normal B cells with a weak expression of ligands for NK receptors. Conversely, NK cells from B-CLL patients were functionally and phenotypically competent, despite a decrease of expression of the activating receptor NKp30. Consequently, resting allogeneic NK cells were unable to kill leukemic B cells in vitro. These data suggest that patients' NK cells cannot initiate a proper immune reaction due to a lack of leukemic cell recognition. We next set up a xenotransplantation mouse model to study NK-CLL cell interactions. Together with our in vitro studies, in vivo data revealed that activation of NK cells is required in order to control B-CLL and that activated NK cells synergize to enhance rituximab effect on tumor load. This study points out the requirements for immune system manipulation for treatment of B-CLL in combination with monoclonal antibody therapy.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/pharmacology , Immunologic Factors/pharmacology , Killer Cells, Natural/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Adult , Aged , Animals , Histocompatibility Antigens Class I/immunology , Humans , Killer Cells, Natural/drug effects , Male , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Natural Cytotoxicity Triggering Receptor 3/immunology , Neoplasm Transplantation , Rituximab , HLA-E AntigensSubject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Salvage Therapy , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Female , France , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology , Male , Middle Aged , Piperidines , Treatment OutcomeABSTRACT
The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death. HVEM function was mainly dependent on LIGHT, since other ligands like HSV-glycoprotein D and B and T lymphocyte attenuator were essentially ineffective. In conclusion, we describe a novel, as yet unknown killing effect of LIGHT through HVEM on a lymphoid malignancy, and combined with induction of chemokine release this may represent an additional tool to boost cancer immunotherapy.
Subject(s)
Apoptosis , Hematologic Neoplasms/immunology , Receptors, Tumor Necrosis Factor, Member 14/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 14/metabolism , Adult , Aged , Apoptosis Regulatory Proteins/metabolism , Cytokines/biosynthesis , Cytokines/genetics , Fas-Associated Death Domain Protein/metabolism , Female , Humans , Lymphotoxin beta Receptor/immunology , Lymphotoxin beta Receptor/metabolism , Male , Membrane Potential, Mitochondrial/immunology , Middle Aged , Receptors, Tumor Necrosis Factor, Member 14/antagonists & inhibitors , Receptors, Tumor Necrosis Factor, Member 14/immunology , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 14/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 14/immunologyABSTRACT
As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.
ABSTRACT
BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazines/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Benzamides/adverse effects , Benzamides/pharmacology , Female , Gastrointestinal Diseases/chemically induced , Humans , Male , Middle Aged , Myeloid Differentiation Factor 88/genetics , Neoplasm Proteins/antagonists & inhibitors , Neutropenia/chemically induced , Pain/chemically induced , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Pyrazines/adverse effects , Pyrazines/pharmacology , Quality of Life , Recurrence , Respiratory Tract Infections/etiology , Salvage Therapy , Treatment Outcome , Waldenstrom Macroglobulinemia/enzymology , Waldenstrom Macroglobulinemia/geneticsABSTRACT
This review aimed to inventory and analyze previous studies regarding quality of life (QoL) and psychological outcomes in relation to pancreatectomy. PubMed and PsycInfo databases were reviewed using the Preferred Reporting Items for Systematic review and Meta-Analysis guidelines. Thirteen studies were selected, 9 of which focused on the QoL after surgery. Quality of life significantly improved 3 to 6 months after surgery. Regarding the postoperative experience, one study reported high fear of recurrence of cancer, whereas another emphasized various expressions of patient needs. One study explained how strategy and ability to adapt are not related to the type, the cause, nor the physical condition, but are mainly influenced by the age and the subjective experience of the patients. A last study showed that depression did not affect survival rate after surgery. Our systematic review found only few studies regarding the psychological condition after pancreatectomy and highlights the need to describe and characterize the patients' psychological characteristics in this setting.
Subject(s)
Adaptation, Psychological , Pancreatectomy/psychology , Pancreatic Neoplasms/surgery , Quality of Life , Anxiety/diagnosis , Anxiety/psychology , Chemotherapy, Adjuvant , Depression/diagnosis , Depression/psychology , Humans , Outcome Assessment, Health Care , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/psychology , Surveys and QuestionnairesABSTRACT
Myeloid and plasmacytoid dendritic cells (MDC, PDC) play a key role in the initiation of immune responses. We found a reduction of both DC subsets in 42 patients with chronic lymphocytic leukaemia (CLL) at diagnosis (P<0.0001 and 0.0001 vs. controls, respectively), likely related to the high secretion of CCL22 and CXCL12 (P=0.04 and 0.008 vs. controls, respectively) by leukaemic cells. However, CD14+ monocytes from CLL patients could give rise to functional IL-12p70-secreting monocyte-derived DCs, capable of inducing a type 1 polarization immunostimulatory profile. These monocyte-derived DCs from CLL patients efficiently migrate in response to CCL19/MIP-3beta chemokine, suggesting that functional autologous DCs can be generated for immunotherapeutic purposes to circumvent DC defects in CLL.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Lymphocyte Subsets/immunology , Adult , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cytokines/immunology , Dendritic Cells/metabolism , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lymphocyte Subsets/metabolism , Male , Middle AgedABSTRACT
BACKGROUND: Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR). METHODS: This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m2 per day] and oral cyclophosphamide [250 mg/m2 per day] for the first 3 days of each cycle, rituximab at 375 mg/m2 intravenously on day 0 of cycle 1 and subsequently at 500 mg/m2 on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m2) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606. FINDINGS: Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47·7 months (IQR 30·4-65·8), median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6-not estimable) was improved compared with the observation group (49·0 months, 39·9-60·5; hazard ratio 0·55, 95% CI 0·40-0·75; p=0·0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group. INTERPRETATION: 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy. FUNDING: French National Cancer Institute (INCa), Roche, Chugai.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Rituximab/therapeutic use , Aged , Female , Humans , Immunotherapy , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Rituximab/pharmacologyABSTRACT
The association between cancer and sarcoidosis is controversial. Some epidemiological studies show an increase of the incidence of cancer in patients with sarcoidosis but only few cases of sarcoidosis following cancer treatment have been reported. We conducted a retrospective case study from internal medicine and oncology departments for patients presenting sarcoidosis after solid cancer treatment. We also performed a literature review to search for patients who developed sarcoidosis after solid cancer. We describe the clinical, biological, and radiological characteristics and outcome of these patients. Twelve patients were included in our study. Various cancers were observed with a predominance of breast cancer. Development of sarcoidosis appeared in the 3 years following cancer and was asymptomatic in half of the patients. The disease was frequently identified after a follow-up positron emission tomography computerized tomography evaluation. Various manifestations were observed but all patients presented lymph node involvement. Half of the patients required systemic therapy. With a median follow-up of 73 months, no patient developed cancer relapse. Review of the literature identified 61 other patients for which the characteristics of both solid cancer and sarcoidosis were similar to those observed in our series. This report demonstrates that sarcoidosis must be considered in the differential diagnosis of patients with a history of malignancy who have developed lymphadenopathy or other lesions on positron emission tomography computerized tomography. Histological confirmation of cancer relapse is mandatory in order to avoid unjustified treatments. This association should be consider as a protective factor against cancer relapse.
Subject(s)
Neoplasms/complications , Sarcoidosis/etiology , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
BACKGROUND/AIMS: Virological factors associated with hepatitis B virus reactivation (HBV-R), following chemotherapy for cancer in hepatitis B surface antigen (HBsAg)-negative patients, are not well known. MATERIALS AND METHODS: HBV strains from 16 patients presenting HBV-R following chemotherapy were studied and compared to those obtained from 51 HBV chronically-infected patients. RESULTS: HBsAg variability was significantly increased within the major hydrophilic region, the a determinant and the C-terminal region. Amino acid substitutions were more frequently found in HBV-R patients as compared to controls at 17 and 11 positions within HBsAg and HBV-RT, respectively. This resulted in atypical serological testing in 56% of patients and detection of resistance mutation to nucleoside analogs in 12.5%. CONCLUSION: HBsAg and HBV-RT mutations are frequently encountered in patients with HBV-R, resulting in atypical serological testing and emergence of HBV strains resistant to nucleos(t)ides analogs.
Subject(s)
Hepatitis B Surface Antigens/blood , Hepatitis B Surface Antigens/genetics , Hepatitis B virus/physiology , RNA-Directed DNA Polymerase/genetics , Virus Activation , Adult , Aged , Antineoplastic Agents/therapeutic use , Female , Hepatitis B virus/genetics , Humans , Male , Middle Aged , Mutant Proteins/genetics , Neoplasms/drug therapyABSTRACT
The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15-30 years were fully matched to 365 adult patients aged 31-65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.