Decitabine in Older Patients with AML: Quality of Life Results of the EORTC-GIMEMA-GMDS-SG Randomized Phase III Trial.

We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes compared to those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) to IC (3+7) in older fit AML patients. HRQoL was a secondary endpoint, and it was assessed with the EORTC QLQ-C30 and the QLQ-ELD14. The following scales were a priori selected for defining the primary endpoint: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also prior to allo-HSCT and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm (76% [95% CI, 69 to 82] v 88% [95% CI, 82 to 93]; odds ratio, 0.43 [95% CI, 0.24 to 0.76], P=.003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and post-allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, while this was the case for those in the 3+7 arm, in four out of the five primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC, may be preferable to current standard IC (3+7), in fit older AML patients. ClinicalTrials.gov (NCT02172872).

Doxorubicin Exposure and Breast Cancer Risk in Survivors of Adolescent and Adult Hodgkin Lymphoma.

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.

10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes. METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants. FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group. INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics. FUNDING: Janssen Pharmaceuticals.

The course of self-perceived cognitive functioning among patients with lymphoma and the co-occurrence with fatigue and psychological distress.

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.

Measuring chronic myeloid leukaemia TKI-related toxic effects in the real world: a systematic review and critical assessment of content validity of patient-reported outcome measures.

Insight into real-world treatment-related toxic effects reported by patients has the potential to improve care, benchmark trials, and fill knowledge gaps, especially in patients with chronic myeloid leukaemia, which is treated in the majority of patients continually with tyrosine-kinase inhibitors (TKIs). The aim of our systematic review was to investigate the content validity of instruments that elicit TKI-related toxic effects reported by patients with chronic myeloid leukaemia in the real world. We searched PubMed and Embase from Jan 1, 2017 to Oct 21, 2022. Studies on instruments used in or developed for patients with chronic myeloid leukaemia that assess a patient's symptoms were eligible. Content validity was assessed according to the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN): none of the six identified instruments were rated as sufficient. Five instruments (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire for chronic myeloid leukaemia with 24 items [EORTC QLQ-CML24], EORTC symptom set, Functional Assessment of Cancer Therapy-Leukaemia [FACT-LEU], haematological malignancies patient-reported outcomes [HM-PRO], and MD Anderson Symptom Inventory for chronic myeloid leukaemia [MDASI-CML]) were rated as inconsistent due to not being evaluated by professionals post-development, having very few patients with chronic myeloid leukaemia involved, or missing key symptoms. Moderate-quality to very low-quality evidence underpinned these ratings. The two EORTC instruments were the only ones not to miss key toxic effects (eg, muscle cramps). However, their relevance was rated as inconsistent: the QLQ-CML24 includes questions on health-related quality-of-life, whereas the symptom set includes items sourced from solid cancer treatments. This Review shows the need for an instrument with sufficient content validity to measure toxic effects from TKI treatment in patients with chronic myeloid leukaemia. Until then, stakeholders can make an informed choice from currently used instruments with our assessment.

Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL.

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.

Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019.

The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59-1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62-1.77), for male individuals (SIR, 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SIR, 1.92; 95% CI, 1.79-2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96-2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53-1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.

Conditional relative survival among patients with chronic lymphocytic leukaemia: A population-based study in the Netherlands.

Studies on conditional relative survival (CRS) in chronic lymphocytic leukaemia (CLL) have hitherto been lacking in the literature. We predicted up-to-date estimates of 5-year RS at diagnosis and for each additional year survived (i.e., CRS) up to 15 years post-diagnosis among CLL patients diagnosed during 2007-2020. We showed that 5-year CRS continues to decline gradually with each additional year survived in a contemporary era with access to novel-based agents, irrespective of age. This finding indicates that CLL patients continue to experience substantial excess mortality compared to an age- and sex-matched group from the general population.

Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group.

Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.

Persistent symptoms of fatigue, neuropathy and role-functioning impairment among indolent non-Hodgkin lymphoma survivors: A longitudinal PROFILES registry study.

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.

Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989-2018.

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.

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial.

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.

Conditional relative survival in Waldenström's macroglobulinaemia: a population-based study in The Netherlands.

Contemporary diagnosed WM patients, compared to the general population, continue to experience excess mortality regardless of having survived up to 15 years post-diagnosis. This gradual increase in excess mortality might result from the incurable nature of this disease characterized by multiple relapses throughout the disease course with limited efficacious treatment options in the released/refractory setting.

Primary therapy and relative survival in patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia: a population-based study in the Netherlands, 1989-2018.

It is unclear how treatment advances impacted the population-level survival of patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first-line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66-75 and >75 years) and four calendar periods. Overall, treatment with anti-neoplastic agents within 1 year post-diagnosis gradually decreased over time, following a broader application of an initial watch-and-wait approach. Approximately 40% of patients received anti-neoplastic therapy during 2011-2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014-2018 revealed that dexamethasone-rituximab-cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5-year RS increased significantly over time, particularly since the introduction of rituximab in the early-mid 2000s. The 5-year RS during 1989-1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011-2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab-containing therapy. The lack of survival improvement in the post-rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/WM.