ABSTRACT
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
BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Lymphocytic, Chronic, B-Cell , Piperidines , Sulfonamides , Vidarabine , Humans , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Sulfonamides/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Female , Aged , Middle Aged , Follow-Up Studies , Piperidines/administration & dosage , Vidarabine/analogs & derivatives , Vidarabine/administration & dosage , Rituximab/administration & dosage , Rituximab/adverse effects , Adenine/analogs & derivatives , Adenine/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Progression-Free Survival , Cyclophosphamide/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Immunotherapy , AdultABSTRACT
Little is known about the long-term health-related quality of life (HRQoL) and persistence of symptoms among patients with indolent non-Hodgkin lymphoma (iNHL). This large population-based longitudinal study therefore investigated the long-term HRQoL and persistence of symptoms and identified associated sociodemographic, clinical and psychological factors. Patients diagnosed between 1999 and 2014 and four or more months after diagnosis were invited to participate in a longitudinal survey. Sociodemographic and clinical data were obtained from the Netherlands Cancer Registry. The EORTC QLQ-C30 and CLL-16 were completed by 669 patients (74% response rate). Patients completed on average four questionnaires. Primary treatment was active surveillance (52%), systemic therapy (31%) or radiotherapy (13%). Respectively, 36% reported persistent fatigue, 33% persistent neuropathy and 25% persistent role-functioning impairment. This was 2-3 times higher than in the age- and sex-matched normative population. Up to 10 years after diagnosis, scores remained relatively stable without clinically relevant changes. Comorbidities, psychological distress, shorter time since diagnosis, systemic therapy, younger age, education level and having no partner were associated with worse outcomes (all ps < 0.05). Up to a third of patients with iNHL experience long-term persistent symptoms which do not improve over time. Early recognition of symptoms will help in providing tailored supportive care for those in need.
Subject(s)
Lymphoma, Non-Hodgkin , Peripheral Nervous System Diseases , Fatigue/epidemiology , Fatigue/etiology , Humans , Longitudinal Studies , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/epidemiology , Lymphoma, Non-Hodgkin/therapy , Peripheral Nervous System Diseases/epidemiology , Peripheral Nervous System Diseases/etiology , Quality of Life/psychology , Registries , Surveys and Questionnaires , Survivors/psychologyABSTRACT
BACKGROUND: Randomized controlled trials (RCTs) often provide accurate estimates of the internal validity of an intervention but lack information on external validity (generalizability). We conducted an RCT on the effectiveness of a self-management intervention among patients with lymphoma in a population-based setting. OBJECTIVE: The objectives of the current study were to describe the proportion of RCT participants compared to all patients invited to participate, and compare sociodemographic and clinical characteristics of RCT participants with all respondents, all patients invited to participate, and all patients selected from the Netherlands Cancer Registry (NCR) to determine the reach of the intervention. An additional objective was to assess differences on RCT outcome variables between RCT and paper respondents. METHODS: Patients with lymphoma or chronic lymphocytic leukemia ≥18 years old at diagnosis from 13 hospitals in the Netherlands were selected from the population-based NCR, which routinely collects data on sociodemographic and clinical characteristics. Eligible patients were invited to participate in an RCT and complete a questionnaire. Web-based completion determined RCT enrollment, whereas paper respondents were followed observationally. RESULTS: A total of 1193 patients were selected from the NCR, 892 (74.77%) of whom were invited to participate in the trial by their hematologist after verifying eligibility. Among those invited, 25.4% (227/892) completed the web-based questionnaire and were enrolled in the RCT. The RCT participants were younger and there was a higher proportion of men than nonparticipants (P<.001). In addition, 25.7% (229/892) of those invited opted to participate in the paper-based observational follow-up study. Compared with paper respondents, RCT participants were younger (P<.001), with a higher proportion of men (P=.002), and had higher education levels (P=.02). RCT participants more often wanted to receive all available information on their disease (P<.001), whereas paper respondents reported higher levels of emotional distress (P=.009). CONCLUSIONS: From a population-based sample of eligible patients, the participation rate in the RCT was approximately 25%. RCT participants may not be representative of the target population because of different sociodemographic and clinical characteristics. Since RCT participants represent a minority of the target population, RCT results should be interpreted with caution as patients in the RCT may be those least in need of a self-management intervention. TRIAL REGISTRATION: Netherlands Trial Register NTR5953; https://www.trialregister.nl/trial/5790.
Subject(s)
Lymphoma/therapy , Self-Management/psychology , Female , Humans , Internet , Male , Middle Aged , Randomized Controlled Trials as TopicABSTRACT
Only a small number of patients with aggressive B-cell lymphoma take part in clinical trials, and elderly patients in particular are under-represented. Therefore, we studied data of the population-based nationwide Netherlands Cancer Registry to determine trends in incidence, treatment and survival in an unselected patient population. We included all patients aged 15 years and older with newly diagnosed diffuse large B-cell lymphoma or Burkitt lymphoma in the period 1989-2010 and mantle cell lymphoma in the period 2001-2010, with follow up until February 2013. We examined incidence, first-line treatment and survival. We calculated annual percentage of change in incidence and carried out relative survival analyses. Incidence remained stable for diffuse large B-cell lymphoma (n=23,527), while for mantle cell lymphoma (n=1,634) and Burkitt lymphoma (n=724) incidence increased for men and remained stable for women. No increase in survival for patients with aggressive B-cell lymphoma was observed during the period 1989-1993 and the period 1994-1998 [5-year relative survival 42% (95%CI: 39%-45%) and 41% (38%-44%), respectively], but increased to 46% (43%-48%) in the period 1999-2004 and to 58% (56%-61%) in the period 2005-2010. The increase in survival was most prominent in patients under 65 years of age, while there was a smaller increase in patients over 75 years of age. However, when untreated patients were excluded, patients over 75 years of age had a similar increase in survival to younger patients. In the Netherlands, survival for patients with aggressive B-cell lymphoma increased over time, particularly in younger patients, but also in elderly patients when treatment had been initiated. The improvement in survival coincided with the introduction of rituximab therapy and stem cell transplantation into clinical practice.
Subject(s)
Lymphoma, B-Cell/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease Progression , Female , History, 20th Century , History, 21st Century , Humans , Incidence , Lymphoma, B-Cell/diagnosis , Lymphoma, B-Cell/history , Lymphoma, B-Cell/therapy , Male , Middle Aged , Neoplasm Staging , Netherlands/epidemiology , Population Surveillance , Registries , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
The increasing number of longer-living patients with diffuse large B-cell lymphoma (DLBCL) and serious side effects of treatment urged us to study the health-related quality of life (HRQoL) and persistent (treatment-related) symptoms in unselected patients after different treatment modalities and compare HRQoL of patients with a normative population. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with DLBCL from 2004 to 2010. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was completed twice, with a 1-year interval. Detailed data on treatment were extracted from the Population-based HAematological Registry for Observational Studies. Two hundred fifty-six patients responded (84 %, T1). Compared to patients treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days ((R-)CHOP21), those who underwent (R-)CHOP14 more often reported tingling in the hands and feet (27 vs 42 %, p = 0.02) and fatigue (35 vs 46 %, p = 0.03) and reported a lower global health status/HRQoL. Mean HRQoL was statistically and clinically relevantly lower among DLBCL patients compared to a normative population (p < 0.01). Persistent tingling in hands/feet was reported more often by older patients and patients treated with (R-)CHOP14 independently of the other characteristics. Furthermore, patients who reported symptoms exhibited significantly lower HRQoL compared to patients without symptoms/worries. Patients treated with (R-)CHOP14 reported more neuropathic symptoms, more fatigue, and a lower HRQoL than patients treated with (R-)CHOP21. Alertness for persistent symptoms that occur during and after treatment of DLBCL patients is needed and may help to avoid lasting negative influence on their HRQoL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Quality of Life , Survivors/psychology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Anxiety/epidemiology , Anxiety/etiology , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Fatigue/chemically induced , Fatigue/epidemiology , Female , Follow-Up Studies , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/epidemiology , Humans , Lymphoma, Large B-Cell, Diffuse/economics , Lymphoma, Large B-Cell, Diffuse/epidemiology , Lymphoma, Large B-Cell, Diffuse/psychology , Male , Middle Aged , Netherlands/epidemiology , Neuralgia/chemically induced , Neuralgia/epidemiology , Paresthesia/chemically induced , Paresthesia/epidemiology , Patient Satisfaction , Prednisone/administration & dosage , Prednisone/adverse effects , Registries , Rituximab , Surveys and Questionnaires , Symptom Assessment , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
OBJECTIVES: On the basis of two population-based registries, our study aims to calculate the real-world cost-effectiveness of rituximab maintenance compared with observation in relapsed or refractory follicular lymphoma patients who responded to second-line chemotherapy. METHODS: Data were obtained from the EORTC20981 trial, the Netherlands Cancer Registry and two population-based registries. A Markov model was developed to calculate cost per life year gained (LYG) and quality-adjusted life years (QALYs) for three scenarios. RESULTS: Our real-world patients were (62 years) 6 to 7 years older and had higher complete response rates to second-line chemotherapy than the trial population. Differences between the real-world rituximab and observation group were observed for second-line chemotherapy and disease progression. Groups were more balanced after using propensity matching. Relying entirely on updated trial results (scenario1) in combination with local cost data resulted in ratios of 11,259 per LYG and 12,655 per QALY. For scenario2, consisting of trial efficacy and matched real-world costs, ratios of 21,202 per LYG and 23,821 per QALY were calculated. Using real-world matched evidence (scenario3) for both effectiveness and costs showed ratios of 10,591 per LYG and 11,245 per QALY. CONCLUSION: Although differences in real-world and trial population were found, using real-world data as well as results from long-term trial follow-up showed favourable ICERs for rituximab maintenance. Nevertheless, results showed that caution is required with data synthesis, interpretation and generalisability of results. As different scenarios provide answers to different questions, we recommend healthcare decision-makers to recognise the importance of calculating several cost-effectiveness scenarios.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/economics , Antineoplastic Agents/economics , Antineoplastic Combined Chemotherapy Protocols/economics , Cost-Benefit Analysis , Lymphoma, Follicular/economics , Registries , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials as Topic , Disease Progression , Female , Humans , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/pathology , Male , Markov Chains , Middle Aged , Netherlands , Quality-Adjusted Life Years , Recurrence , RituximabABSTRACT
OBJECTIVES: The increasing number of longer living patients with follicular lymphoma (FL) and serious side effects of treatment urged us to study the health-related quality of life (HRQoL) and persistent (treatment-related) symptoms in unselected patients after different treatment modalities and compare HRQoL of patients with a normative population. METHODS: The population-based Eindhoven Cancer Registry was used to select patients diagnosed with FL during 2004-2010. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was completed twice, with a 1-yr interval. This questionnaire was also completed by an age- and sex-matched normative population (N = 580). Detailed data on treatment were extracted from the cancer registry and Population-based HAematological Registry for Observational Studies (PHAROS). RESULTS: Of the 181 patients who were invited, 148 responded (82%, T1). Patients treated with immunochemotherapy reported clinically relevant higher mean fatigue scores than those who underwent radiotherapy (P = 0.02). No differences were observed on the other HRQoL scales between treatment groups. Mean HRQoL scores were worse for FL patients treated with immunochemotherapy compared with a normative population (P < 0.01). A quarter to 50% of patients persistently reported to be slowed down, lethargic, or persistently worried about future health or was limited in social activities. Subsequently, patients reporting these symptoms/worries had a lower global health status/HRQoL. CONCLUSION: Alertness for persistent symptoms that occur during and after treatment of FL patients is needed and may help to avoid lasting negative influence on their HRQoL.
Subject(s)
Lymphoma, Follicular/psychology , Quality of Life/psychology , Registries , Survivors/psychology , Adult , Aged , Antineoplastic Agents/therapeutic use , Anxiety/physiopathology , Anxiety/psychology , Case-Control Studies , Fatigue/physiopathology , Fatigue/psychology , Female , Gamma Rays/therapeutic use , Hematopoietic Stem Cell Transplantation/psychology , Humans , Immunotherapy/psychology , Lymphoma, Follicular/pathology , Lymphoma, Follicular/therapy , Male , Middle Aged , Pain/physiopathology , Pain/psychology , Surveys and QuestionnairesABSTRACT
The course of fatigue and quality of life in survivors of non-Hodgkin's lymphoma is unknown. The aims of this study were, therefore, to assess fatigue and quality of life in patients with non-Hodgkin's lymphoma following primary treatment, compare fatigue and quality of life in these patients with those of an age- and sex matched normative population to assess the severity of concerns and identify associations with fatigue of survivors who remained fatigued. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with non-Hodgkin's lymphoma from 1999-2009. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Fatigue Assessment Scale were completed once by 824 survivors of non-Hodgkin's lymphoma (80% response rate); 434 survivors completed these questionnaires again 1 year later. Survivors of non-Hodgkin's lymphoma reported more clinically relevant fatigue up till 10 years post-diagnosis compared to a normative population (P<0.001). Mean fatigue scores remained fairly stable over time (T1: x=28, SD=26; T2: x=30, SD=27, P=0.14): 22-28% of survivors reported deterioration, 19-23% reported improvement and 44-54% reported constant fatigue. Survivors who reported constant fatigue were more often diagnosed with stage IV disease and had more comorbid diseases. They were additionally more often female and divorced. Having comorbidities and being without a partner were also associated with constant fatigue in the normative population. In conclusion, six out of every ten responding non-Hodgkin's lymphoma survivors reported a high level of fatigue up till 10 years after diagnosis. Mean fatigue scores remained stable over time and survivors reporting constant fatigue more often had stage IV disease at diagnosis and comorbidities.
Subject(s)
Fatigue/epidemiology , Fatigue/etiology , Lymphoma, Non-Hodgkin/complications , Survivors , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Netherlands/epidemiology , Odds Ratio , Population Surveillance , Quality of Life , Registries , Risk Factors , Surveys and QuestionnairesABSTRACT
PURPOSE: To investigate the proportion of patients with lymphoma with persistent clinically relevant cognitive impairment, and its relation to treatment, fatigue, and psychological distress. METHODS: Patients with diffuse-large-B-cell-lymphoma (DLBCL), follicular-lymphoma (FL), and chronic-lymphocytic-leukemia (CLL)/small-lymphocytic-lymphoma (SLL), diagnosed between 2004-2010 or 2015-2019, were followed up to 8 years post-diagnosis. Sociodemographic and clinical data were obtained from the Netherlands Cancer Registry and the Population-based HAematological Registry for Observational Studies. The EORTC QLQ-C30 was used to assess cognitive functioning and fatigue, and the HADS to assess psychological distress. Individual growth curve models were performed. Results were compared with an age- and sex-matched normative population. RESULTS: A total of 924 patients were included (70% response rate). Persistent cognitive impairment was twice as high in patients (30%) compared to the normative population (15%). Additionally, 74% of patients reported co-occurring symptoms of persistent fatigue and/or psychological distress. Patients with FL (- 23 points, p < 0.001) and CLL/SLL (- 10 points, p < 0.05) reported clinically relevant deterioration of cognitive functioning, as did the normative population (FLnorm - 5 points, DLBCLnorm - 4 points, both p < 0.05). Younger age, higher fatigue, and/or psychological distress at inclusion were associated with worse cognitive functioning (all p's < 0.01). Treatment appeared less relevant. CONCLUSION: Almost one-third of patients with lymphoma report persistent cognitive impairment, remaining present up to 8 years post-diagnosis. Early onset and co-occurrence of symptoms highlight the need for clinicians to discuss symptoms with patients early. IMPLICATIONS FOR CANCER SURVIVORS: Early recognition of cognitive impairment could increase timely referral to suitable supportive care (i.e., lifestyle interventions) and reduce (long-term) symptom burden.
ABSTRACT
Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.
ABSTRACT
It is unclear whether survival in diffuse large B-cell lymphoma (DLBCL) continues to increase in an era where rituximab-containing chemotherapy reigns for almost two decades. Therefore, we evaluated trends in primary therapy and relative survival (RS) among Dutch DLBCL patients diagnosed between 1989 and 2018. Analyses were performed separately according to the stage I (N = 6952) and stage II-IV disease (N = 20,676), stratified by calendar period and age (18-64, 65-74, and ≥75 years). The use of chemotherapy ± radiotherapy increased over time across all age and stage groups. As of the mid-2000s, >95% of chemotherapy-treated patients received chemoimmunotherapy, irrespective of age and stage. Overall, RS increased significantly over time across all age groups, especially after 2003 when rituximab-containing chemotherapy had become the standard of care. However, RS increased less pronounced between 2003-2010 and 2011-2018 than between 1989-2002 and 2003-2010. These findings were congruent across all studied stage groups. Five-year RS across the three age groups during 2011-2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II-IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Humans , Immunotherapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Netherlands/epidemiology , Prednisone/therapeutic use , Rituximab/therapeutic use , Treatment Outcome , Vincristine/therapeutic useABSTRACT
BACKGROUND: Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status. METHODS: We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27). FINDINGS: Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths. INTERPRETATION: Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. FUNDING: F Hoffmann-La Roche.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Adolescent , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , SulfonamidesABSTRACT
Randomized controlled trials have studied different dose-intensity and dose-interval regimens of R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL). This study was undertaken to confirm these results in a population-based setting, with special emphasis on the value of 6xR-CHOP21 among patients aged 18-64 years. Two thousand three hundred and thirty-eight stage II-IV DLBCL patients, ≥18 years, we confirmed the similar efficacy of six versus eight cycles of R-CHOP and of R-CHOP21 versus R-CHOP14 regimens across all age groups on overall survival (median follow-up 36.4 (1.3-167.6) months). Nevertheless, overall survival decreased with older age. Interestingly, in patients 18-64 years, the adjusted risk of mortality among recipients of 6xR-CHOP21 compared to other R-CHOP regimens seems to be similar (HR 0.62; 95%CI: 0.38-1.02; p= .059). Although this finding might suggest that 6xR-CHOP21 could be considered as first-line regimen for all stage II-IV DLBCL patients, it should be confirmed in forthcoming population-based studies with larger patient numbers and longitudinal follow-up.