ABSTRACT
BACKGROUND: Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. METHODS: In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. RESULTS: A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). CONCLUSIONS: Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bendamustine Hydrochloride/administration & dosage , Bendamustine Hydrochloride/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm, Residual/diagnosis , Rituximab/administration & dosage , Rituximab/adverse effectsABSTRACT
Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Aged , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Quality of Life , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Fatigue/chemically inducedABSTRACT
Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Large B-Cell, Diffuse , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Humans , Lenalidomide/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Prednisone/therapeutic use , Prospective Studies , Rituximab/therapeutic use , Treatment Outcome , Vincristine/therapeutic useABSTRACT
Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of 90 Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after 90 Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of 90 Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Rituximab/administration & dosage , Stem Cell Transplantation , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Autografts , Carmustine/administration & dosage , Carmustine/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Female , Humans , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/adverse effects , Rituximab/adverse effects , Survival Rate , Vindesine/administration & dosage , Vindesine/adverse effectsABSTRACT
This prospective, multicenter, phase II study investigated the use of four cycles of bortezomib-dexamethasone induction treatment, followed by high-dose melphalan and autologous stem cell transplantation (SCT) in patients with newly diagnosed light chain amyloidosis. The aim of the study was to improve the hematologic complete remission (CR) rate 6 months after SCT from 30% to 50%. Fifty patients were enrolled and 72% had two or more organs involved. The overall hematologic response rate after induction treatment was 80% including 20% CR and 38% very good partial remissions (VGPR). Fifteen patients did not proceed to SCT for various reasons but mostly treatment-related toxicity and disease-related organ damage and death (2 patients). Thirty-one patients received melphalan 200 mg/m2 and four patients a reduced dose because of renal function impairment. There were no deaths related to the transplantation procedure. Hematologic responses improved at 6 months after SCT to 86% with 46% CR and 26% VGPR. However, due to the high treatment discontinuation rate before transplantation the primary endpoint of the study was not met and the CR rate in the intention-to-treat analysis was 32%. Organ responses continued to improve after SCT. We confirm the high efficacy of bortezomib-dexamethasone treatment in patients with AL amyloidosis. However, because of both treatment-related toxicity and disease characteristics, 30% of the patients could not proceed to SCT after induction treatment. (Trial registered at Dutch Trial Register identifier NTR3220).
Subject(s)
Bortezomib/therapeutic use , Hematopoietic Stem Cell Transplantation , Immunoglobulin Light-chain Amyloidosis/therapy , Aged , Biomarkers , Bortezomib/administration & dosage , Bortezomib/adverse effects , Combined Modality Therapy , Disease Progression , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Immunoglobulin Light-chain Amyloidosis/diagnosis , Immunoglobulin Light-chain Amyloidosis/mortality , Immunophenotyping , Male , Middle Aged , Severity of Illness Index , Transplantation, Autologous , Treatment OutcomeABSTRACT
The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Drug Resistance, Neoplasm , Multiple Myeloma/drug therapy , Prednisone/therapeutic use , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/adverse effects , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Lenalidomide , Male , Maximum Tolerated Dose , Middle Aged , Prednisone/adverse effects , Prognosis , Thalidomide/adverse effects , Thalidomide/therapeutic use , Treatment OutcomeABSTRACT
There is little evidence on the costs associated with the route of administration of oncology drugs. We investigated time and resource use for hospitals and patients and compared healthcare and societal costs for intravenous (IV) and subcutaneous (SC) administration of trastuzumab and rituximab. Data for the preparation and administration of both drugs were collected at the hospital pharmacy and at the oncology day care unit. Patients completed a questionnaire for obtaining information on societal costs (productivity losses, informal care and traveling expenses). A total of 126 patients were recruited in six hospitals; 82 received trastuzumab (37 IV and 45 SC) and 44 received rituximab (23 IV and 21 SC). The costs per administration (including societal cost but excluding drug costs) were &OV0556;167 and &OV0556;264 for IV and &OV0556;76 and &OV0556;146 for SC trastuzumab and rituximab, respectively. The costs for SC administration were lower in all categories. The largest cost component was related to time spent at the day care unit (overhead costs). This resulted in savings of &OV0556;47 for SC trastuzumab and &OV0556;69 for SC rituximab. The costs related to time of healthcare professionals was &OV0556;9 lower for both drugs. The costs for consumables resulted in another &OV0556;12 savings. Societal costs were &OV0556;22 lower for SC trastuzumab and &OV0556;28 lower for SC rituximab. Although administration costs are relatively a small part of the total costs, important savings can be generated by switching to an SC route of administration especially because a large number of patients receive oncology drugs and patients receive more than one administration.
Subject(s)
Rituximab/administration & dosage , Rituximab/economics , Trastuzumab/administration & dosage , Trastuzumab/economics , Aged , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/economics , Drug Costs , Female , Humans , Infusions, Intravenous/economics , Infusions, Subcutaneous/economics , Injections, Subcutaneous/economics , Male , Middle Aged , Netherlands , Retrospective StudiesABSTRACT
BACKGROUND/OBJECTIVES: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) often receive medical nutrition therapy (MNT) during intensive remission-induction treatment. Since little is known about changes in nutritional status, specifically body composition, in this patient population, these changes and their associations with physical and clinical outcomes were assessed. SUBJECTS/METHODS: In this multicenter prospective observational study, newly diagnosed AML/MDS patients who received intensive remission-induction chemotherapy, routine dietary counseling by a dietician and MNT immediately upon inadequate nutritional intake, were included. At treatment initiation and discharge, nutritional status, including Patient-Generated Subjective Global Assessment (PG-SGA)-scores and body composition, physical outcomes and fatigue were assessed. Associations of nutritional status/body composition with physical outcomes, fatigue, fever duration, number of complications, time to neutrophil engraftment and hospital length of stay (LOS) (collected from medical records) were examined using multiple regression analysis. RESULTS: In >91% of the 126 AML/MDS patients included, nutritional intake was adequate, with 61% receiving MNT. Nevertheless, body weight decreased significantly (p < 0.001) and mainly consisted of a loss of muscle/fat-free mass (FFM) (p < 0.001), while fat mass (FM) remained unchanged (p-value range = 0.71-0.77). Body weight and waist circumference showed significant negative associations with fever duration and/or number of complications. Significant positive associations were found between mid-upper arm muscle circumference (MUAMC) and physical functioning and between PG-SGA-scores and fatigue. Body weight and MUAMC were also negatively associated with LOS. CONCLUSION: Despite MNT in AML/MDS patients undergoing intensive chemotherapy, muscle/FFM decreased while FM remained unchanged. Maintenance of nutritional status was associated with improved physical and clinical outcomes.
ABSTRACT
ABSTRACT: Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T cells and natural killer (NK) cells of patients with HGBL-MYC/BCL2 (n = 66), patients with DLBCL NOS (n = 53), and age-matched healthy donors (HDs; n = 16) by flow cytometry and performed proliferation, cytokine production, and cytotoxicity assays. Compared with HDs, both lymphoma subtypes displayed similar frequencies of CD8+ T cells but decreased CD4+ T cells. Regulatory T-cell (Treg) frequencies were reduced only in patients with DLBCL NOS. Activated (HLA-DR+/CD38+) T cells, PD-1+CD4+ T cells, and PD-1+Tregs were increased in both lymphoma subtypes, but PD-1+CD8+ T cells were increased only in HGBL-MYC/BCL2. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of senescent T cells than HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1+ T cells of patients with HGBL-MYC/BCL2 were exhausted with impaired cytokine production and degranulation. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of NK cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM-3+- and DNAM-1+-expressing NK cells. Although NK cells of patients with HGBL-MYC/BCL2 showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T cells of patients with HGBL-MYC/BCL2. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance of investigating potential immune evasion in the microenvironment of MYC-rearranged lymphomas.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Programmed Cell Death 1 Receptor , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Proto-Oncogene Proteins c-bcl-2/genetics , T-Lymphocytes/pathology , Killer Cells, Natural/pathology , Cytokines , Tumor MicroenvironmentABSTRACT
PURPOSE: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages. METHODS: We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses. RESULTS: After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m2 doxorubicin (Ptrend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR]age <21 years, 1.5 [95% CI, 0.9 to 2.6]; HRage ≥21 years, 1.3 [95% CI, 0.9 to 1.9) or chest RT (HRwithout mantle/axillary field RT, 1.9 [95% CI, 1.06 to 3.3]; HRwith mantle/axillary field RT, 1.2 [95% CI, 0.8 to 1.8]). CONCLUSION: This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.
Subject(s)
Breast Neoplasms , Cancer Survivors , Doxorubicin , Hodgkin Disease , Humans , Hodgkin Disease/epidemiology , Hodgkin Disease/drug therapy , Female , Doxorubicin/adverse effects , Doxorubicin/administration & dosage , Adolescent , Adult , Breast Neoplasms/epidemiology , Breast Neoplasms/drug therapy , Cancer Survivors/statistics & numerical data , Middle Aged , Young Adult , Antibiotics, Antineoplastic/adverse effects , Incidence , Netherlands/epidemiology , Risk FactorsSubject(s)
Anemia, Aplastic , Antilymphocyte Serum , Aged , Humans , Immunosuppressive Agents , PatientsSubject(s)
Drug Resistance , Lenalidomide/pharmacology , Multiple Myeloma/drug therapy , Peptide Hydrolases/deficiency , Adaptor Proteins, Signal Transducing , Adult , Aged , Aged, 80 and over , Bone Marrow Examination , Female , Humans , Lenalidomide/metabolism , Male , Middle Aged , Multiple Myeloma/pathology , Proto-Oncogene Proteins c-myc/metabolism , Ubiquitin-Protein Ligases , Up-RegulationABSTRACT
Background: Multiple myeloma (MM) is a hematologic malignancy, characterized by clonal proliferation of plasma cells in the bone marrow. These plasma cell proliferations frequently result in scattered osteolytic bone lesions and extensive skeletal destruction. Myeloma bone lesions are frequently located in the spine, and are associated with debilitating bone pain and an increased rate of pathologic fractures and mortality. The aim of this study was to investigate the incidence of vertebral compression fractures (VCFs) and spinal instability in patients with MM. Patients and methods: Newly diagnosed patients with MM with computed tomography (CT) scans of the spine within three months of diagnosis were identified through an electronic patient database. Clinical baseline data were manually extracted from the patient charts. Fractured levels were graded on CT scans following the Genant grading system, and spinal instability was assessed through the Spinal Instability Neoplastic Score (SINS). Results: A total of 385 patients with 6289 eligible vertebrae were eligible for inclusion. The mean age at diagnosis was 67 years, and 60% were male. At least one VCF was present in 180 patients (47%). A quarter of fractures were classified as severe. The incidence of fractures increased with more advanced disease stages, and men were more likely to have a fracture than women. Conclusions: Our data show that 47% of MM patients present with one or more VCFs at the onset of their disease, of which 20% were classified as unstable, meaning a surgical consultation is recommended.
ABSTRACT
BACKGROUND: Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear. OBJECTIVES: To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon. METHODS: This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing. RESULTS: We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. ß-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing. CONCLUSION: Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombophilia , Adult , Humans , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Prospective Studies , Factor VIII , Thrombin , von Willebrand Factor , Hydrazines/adverse effects , Thrombophilia/chemically inducedABSTRACT
BACKGROUND & AIMS: The European Societies for Clinical Nutrition and Metabolism (ESPEN) and Blood and Marrow Transplantation (EBMT) recommend enteral nutrition (EN) as the first-choice medical nutrition therapy in acute myeloid leukemia (AML) patients undergoing intensive treatments, including high-dose remission-induction chemotherapy and hematopoietic stem cell transplantation (HSCT). However, parenteral nutrition (PN) remains the preferred method of nutrition support in current clinical practice. The aim of this qualitative study was to gain insight into hematologists' experiences and perspectives regarding the choice and ESPEN/EBMT recommendations on EN versus PN. METHODS: Online semi-structured interviews were conducted with one hematologist from each of the 21 hospitals offering intensive AML treatments in the Netherlands, using Microsoft Teams. Interviews were audio-recorded, transcribed verbatim and thematically analyzed using Atlas. ti. One hundred nineteen hematologists working in the same hospitals were invited to complete a short online questionnaire survey (SurveyMonkey®) regarding their knowledge and opinion on the ESPEN/EBMT guidelines recommending EN over PN during intensive AML treatments. The results of this survey are presented in a descriptive way. RESULTS: Fifty-nine hematologists participated in this study (42% overall response rate), of which 21 in the semi-structured interviews (response rate 100%) and 38 in the online survey (response rate 32%). Hematologists considered medical nutrition therapy important for prevention and treatment of malnutrition and associated adverse outcomes in AML patients undergoing intensive remission-induction treatment and HSCT. However, opposed to the ESPEN/EBMT guidelines, the vast majority of hematologists were hesitant or reluctant to use EN instead of PN as the first-choice medical nutrition therapy in these patients. The most frequently cited barriers to use EN were the expected low feasibility and tolerance of EN, feeding tube-related discomfort and bleeding risk, and patient refusal. Other barriers to follow the guidelines on EN were related to personal factors, including hematologists' knowledge (lack of awareness and familiarity) and attitude (lack of agreement, outcome expectancy, experience, success, motivation, and learning culture), guideline-related factors (lack of evidence and applicability), and external factors (lack of collaboration and resources). Facilitators included strategies for nutrition education and dissemination of nutritional guidelines, interprofessional and patient collaboration, availability of feeding tubes that can be inserted without endoscopy and stronger scientific evidence. CONCLUSIONS: Hematologists recognized the importance of medical nutrition therapy for reducing malnutrition and related negative outcomes during intensive AML treatments. However, contrary to the ESPEN/EBMT guidelines, they preferred PN instead of EN as the medical nutrition therapy of first choice. To reduce compliance barriers, interventions should focus on improving hematologists' knowledge of medical nutrition therapy and dietary guidelines, enhancing success rates of EN by adequately triaging patients eligible for EN and inserting duodenal feeding tubes using an electromagnetic sensing device without endoscopy, developing decision aids and multidisciplinary guidelines and care pathways. Furthermore, future trials should focus on the feasibility and benefits of EN versus PN both during remission-induction treatment and HSCT.
Subject(s)
Enteral Nutrition , Hematopoietic Stem Cell Transplantation , Humans , Parenteral Nutrition , Critical Pathways , NetherlandsABSTRACT
Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Large B-Cell, Diffuse , Humans , Middle Aged , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/therapeutic use , Doxorubicin/adverse effects , Lenalidomide/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Prednisone/therapeutic use , Rituximab/therapeutic use , Treatment Outcome , Vincristine/adverse effects , AgedABSTRACT
Venous thromboembolism (VTE) can be the first presenting symptom in myeloproliferative neoplasms (MPN). Studies have demonstrated a high prevalence of the JAK2V617F mutation in patients with splanchnic vein thrombosis. Fewer studies have been done in patients with thrombosis outside the splanchnic area, showing a lower prevalence although the clinical relevance of the mutation in these patients, e.g., progression to overt MPN, remains unknown. The objective of this study was to determine the effect size of JAK2V617F in prospectively collected DNA samples of patients objectively diagnosed with deep vein thrombosis (DVT) of the leg and controls without DVT, with follow-up on JAK2V617F-positive patients to assess clinical relevance. Presence of JAK2V617F was determined in DNA samples from 187 patients with DVT and 201 controls, using quantitative RT-PCR. Hematological parameters were also analyzed. All initially JAK2V617F-positive patients were reassessed. Of 187 patients with DVT, 178 were analyzed for JAK2V617F, and in four (2.3%; 95% CI 0.1-4.4), JAK2V617F was present. Of 201 controls, 198 were analyzed; one was JAK2V617F positive (0.5%; 95% CI -0.5-1.5, OR 4.5; 95% CI 0.5-40.9). None had MPN features, nor upon reassessment after a median follow-up of 68.5 months. Four JAK2V617F-positive patients with DVT and one control without DVT did not develop overt MPN after a median follow-up of nearly 6 years. Thus, in patients with non-splanchnic venous thrombosis, JAK2V617F appears not to be clinically relevant.
Subject(s)
Janus Kinase 2/genetics , Leg/blood supply , Point Mutation , Venous Thromboembolism/genetics , Venous Thrombosis/genetics , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Splanchnic CirculationABSTRACT
Discrimination between Waldenström macroglobulinemia (WM) and marginal zone lymphoma (MZL) of the bone marrow (BM) can be difficult due to overlap in clinical, histopathologic, and immunophenotypic characteristics. We determined which characteristics can aid in the differential diagnosis of 'gray zone' cases. We compared clinical, histopathologic, immunophenotypic, and molecular features of 222 WM and 65 MZL patients. LASSO regression was employed for variable selection. The most distinguishing clinical features of WM compared to MZL were the presence of the B-symptom weight loss and IgM paraprotein. Histopathological findings were plasmacytoid differentiation, monoclonal plasma cells, and increased mast cells in the BM. Regarding flow cytometry, only CD10 and CD38 were distinguishing markers. Finally, as the expected presence of the MYD88L265P mutation showed to be of great value in the distinction between WM and MZL. Despite the great overlap, WM can often be distinguished from MZL by using a combination of characteristics. These characteristics should be weighed in complex, 'gray zone' cases.
Subject(s)
Lymphoma, B-Cell, Marginal Zone , Waldenstrom Macroglobulinemia , Bone Marrow/pathology , Humans , Immunophenotyping , Lymphoma, B-Cell, Marginal Zone/pathology , Mutation , Myeloid Differentiation Factor 88/genetics , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/genetics , Waldenstrom Macroglobulinemia/pathologyABSTRACT
BACKGROUND & AIMS: The updated guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) and for Blood and Marrow Transplantation (EBMT) on nutrition in intensively treated acute myeloid leukemia (AML) patients recommend enteral nutrition (EN) instead of parenteral nutrition (PN) as the first-choice medical nutrition therapy. Despite this, PN remains the preferred route of nutrition administration in daily practice. The aim of this qualitative study was to gain insight into the patients' and hematology nurses' experiences and perceptions regarding nutritional problems and nutritional support and the reasons for the low adherence to the ESPEN/EBMT guidelines. METHODS: Semi-structured interviews were conducted in 23 patients from various Dutch hospitals who had completed intensive AML treatment. Interviews with 22 patients were audio-recorded and transcribed, one interview was summarized. The transcripts and summary were thematically analyzed using Atlas.ti. From each of the 22 Dutch hospitals providing intensive AML treatment, one hematology nurse participated in a telephone questionnaire survey. The results of this survey are presented in a descriptive way. RESULTS: Nutritional problems were a major source of distress in most participating patients. Nutritional support often led to peace of mind and less concerns, provided that there were no conflicting nutritional support practices among treating hospitals. Patients perceived PN and EN as a life-line and necessary for the prevention of or recovery from physical decline, but they also experienced loss of independence, limited mobility, fear of unwanted body weight gain and problems related to the feeding equipment. Both patients and hematology nurses regarded PN as an easy method of nutrition administration, while EN was often seen as a necessary evil or was even refused by patients, owing to tube-related physical discomfort and EN intolerance. Both patients' and hematology nurses' reluctance to administer EN proved to be barriers to the ESPEN/EBMT nutritional guideline adherence. Among the surveyed hematology nurses, barriers to adherence included personal factors related to their knowledge (lack of awareness) and attitudes (negative outcome expectancy and lack of agreement), guideline-related factors (lack of evidence) and external factors (lack of collaboration). CONCLUSION: Individualized nutritional support, including EN and PN, may reduce nutrition-related distress in intensively treated AML patients, provided that conflicting nutritional support practices among hospitals are avoided or explained. The barriers to adherence to the ESPEN/EBMT guidelines on EN and PN in this patient group may be reduced by enhancing hematology nurses' awareness and knowledge of the guidelines, incorporating the guidelines into multidisciplinary clinical pathways, improving outcome of EN by proper triage of patients eligible for EN and increasing the level of evidence of the guidelines.