R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial.

BACKGROUND: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens. METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27. FINDINGS: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group). INTERPRETATION: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement. FUNDING: The Dutch Cancer Society and the Schumacher-Kramer Foundation.

Medical nutrition therapy during intensive remission-induction treatment and hematopoietic stem cell transplantation in acute myeloid leukemia patients: Hematologists' experiences and perspectives.

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.

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial.

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.

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.

Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia.

PURPOSE: The applicability of FLT3-internal tandem duplications (FLT3-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based FLT3-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant NPM1 and multiparameter flow cytometry. METHODS: In 161 patients with de novo FLT3-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. FLT3-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS). RESULTS: NGS-based FLT3-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3-ITD MRD v 33% no FLT3-ITD MRD; P < .001) and inferior OS (4-year OS, 31% FLT3-ITD MRD v 57% no FLT3-ITD MRD; P < .001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P < .001) and OS (hazard ratio 2.51; P = .002). Strikingly, FLT3-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or multiparameter flow cytometry. CONCLUSION: NGS-based detection of FLT3-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.

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.

Nutrition-related problems, nutritional support practices and barriers to adherence to nutritional guidelines during intensive treatment for acute myeloid leukemia: Patients' and hematology nurses' perspectives and experiences.

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.

Clinical impact of assessing thrombus age using magnetic resonance venography prior to catheter-directed thrombolysis.

OBJECTIVES: Magnetic resonance venography (MRV) is underutilized in the evaluation of thrombus properties prior to endovascular treatment but may improve procedural outcomes. We therefore investigated the clinical impact of using a dedicated MRV scoring system to assess thrombus characteristics prior to endovascular intervention for iliofemoral deep vein thrombosis (DVT). METHODS: This is a post hoc analysis of data from the CAVA trial ( Clinicaltrials.gov :NCT00970619). MRV studies of patients receiving ultrasound-accelerated catheter-directed thrombolysis (CDT) for iliofemoral DVT were reviewed. Thrombus age-related imaging characteristics were scored and translated into an overall score (acute, subacute, or old). MRV scores were compared to patient-reported complaints. MRV-scored groups were compared for CDT duration and success rate. RESULTS: Fifty-six patients (29 men; age 50.8 ± 16.4 years) were included. Using MRV, 27 thrombi were classified acute, 17 subacute, and 12 old. Based on patient-reported complaints, 11 (91.7%) of these old thrombi would have been categorized acute or subacute, and one (3.7%) of the acute thrombi as old. Average duration of CDT to > 90% restored patency differed significantly between groups (p < 0.0001): average duration was 23 h for acute thromboses (range: 19-25), 43 h for subacute (range: 41-62), and 85 h for old thromboses (range: 74-96). CDT was almost eleven times more successful in thromboses characterized as acute and subacute compared to old thromboses (OR: 10.7; 95% CI 2.1-55.5). CONCLUSION: A dedicated MRV scoring system can safely discriminate between acute, subacute, and old thromboses. MRV-based selection is predictive of procedural duration and success rate and can help avoid unnecessary complications. KEY POINTS: • Thrombus age, characterized by MRV as acute, subacute, and old, can predict CDT duration and probability of success. • Accurate pre-interventional MRV-based thrombus aging has the potential to facilitate identification of eligible patients and may thus prevent CDT-related complications.

Comparing Survivors of Cancer in Population-Based Samples With Those in Online Cancer Communities: Cross-sectional Questionnaire Study.

BACKGROUND: Most Western countries have websites that provide information on cancer and the opportunity to participate in online cancer communities (OCCs). The number of patients with cancer that participate in these OCCs is growing. These patients are relatively easy to approach for research purposes. OBJECTIVE: The objective of this study is to determine the differences and similarities between survivors of cancer in population-based samples and survivors participating in OCCs who use the internet in relation to their illness. METHODS: In 2017, we drew a sample of 539 population-based patients and 531 OCC patients. The population-based patients were sent a paper-based questionnaire, and the OCC patients were sent the same questionnaire on the web. In the questionnaire, we asked patients about their sociodemographics, internet use, sources of information, media use, and wishes regarding future internet use for health care-related purposes, and the effect of internet use on their health care consumption. RESULTS: The response rate of population-based internet users was 47% (233/496), and that of the OCC group was 40.3% (214/531). The OCC group had a significantly higher education level (P<.001), was younger (P<.001), had more survivors that were employed (P<.001), and attached greater importance to the internet (171/214, 79.9% vs 126/233, 54.1%; P<.001) and fellow survivors (107/214, 50% vs 60/233, 25.8%; P<.001). Compared with the population-based group, the OCC group reported more intensive internet use immediately after diagnosis, during treatment, and during follow-up (P<.001 in each case). There were similarities in terms of the relative importance that survivors attach to the various sources of information, the topics on which they seek information, and their wishes for future eHealth possibilities. The OCC group reported a greater need to participate in a web-based class or chat with others (92/214, 43% vs 44/233, 18.9%). CONCLUSIONS: We conclude that survivors who are members of an OCC are not representative of survivors of cancer in general. There are significant differences in sociodemographic characteristics, internet use during their treatment journey, internet search frequency during their cancer journey, and participation wishes. Using web-based information and communication can support shared decision-making and may facilitate the active participation of patients during their treatment. For research purposes, it is important to take the bias in OCC groups into account.

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.

Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial.

Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004.

Combining Ixazomib With Subcutaneous Rituximab and Dexamethasone in Relapsed or Refractory Waldenström's Macroglobulinemia: Final Analysis of the Phase I/II HOVON124/ECWM-R2 Study.

PURPOSE: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction (P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.

CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis on Preventing Post-Thrombotic Syndrome) Trial: Long-Term Follow-Up Results.

Background The CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome) trial did not show a reduction of post-thrombotic syndrome (PTS) after additional ultrasound-accelerated catheter-directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1-year follow-up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long-term follow-up. Methods and Results Patients aged 18 to 85 years with a first-time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow-up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow-up of 39.0 months (interquartile range, 23.3-63.8), 120 patients (79.8%) participated in the final follow-up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of -14.2% (95% CI, -32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19-0.84 [P=0.01]) with an absolute difference between groups of -22.2% (95% CI, -39.8% to -2.8%). No new major bleedings occurred following the 12-month follow-up. Conclusions The impact of additional ultrasound-accelerated catheter-directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.

Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial.

IMPORTANCE: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade. OBJECTIVE: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis. INTERVENTIONS: Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks. MAIN OUTCOMES AND MEASURES: Three-year EFS, OS, and safety. RESULTS: A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P = .04). Two patients treated with anthracyclines developed acute leukemia. CONCLUSIONS AND RELEVANCE: This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01996267.

Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial.

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.

Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter HOVON phase II trial.

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).

Adherence to guidelines on nutrition support during intensive treatment of acute myeloid leukemia patients: A nationwide comparison.

BACKGROUND & AIMS: The level of adherence to the updated guidelines of The European Societies for Clinical Nutrition and Metabolism (ESPEN) and for Blood and Marrow Transplantation (EBMT) on nutrition in intensively treated adult acute myeloid leukemia (AML) patients in clinical practice is unknown. The aim of this nationwide survey was to investigate ESPEN/EBMT nutritional guideline adherence during intensive AML treatment, variation in nutrition support practices among hospitals and whether these practices changed after guideline publication. METHODS: All 22 Dutch hospitals providing (aftercare following) high-dose chemotherapy and/or hematopoietic stem cell transplantation for adult AML patients were surveyed on nutrition support practices during these intensive AML treatments. We used an online questionnaire in 2015 and semi-structured telephone interviews in 2018-2019. Both surveys were completed by registered dieticians and addressed the use of enteral (EN) and parenteral (PN) nutrition. The ESPEN/EBMT nutritional guideline adherence was investigated through the telephone interviews. RESULTS: High-level ESPEN/EBMT guideline adherence and/or uniformity among hospitals regarding nutrition support practices during intensive AML treatment were observed for nutritional screening, -aims, safe food handling and exercise training. Adherence to ESPEN/EBMT recommendations that were not implemented into national guidelines, including nutritional assessment and use of medical nutrition, was poor. All hospitals assessed nutritional intake, -impact symptoms and body weight, but muscle mass, physical performance and degree of systemic inflammation were rarely and variably monitored. Although the number of hospitals using EN as first-choice nutritional intervention increased from 3 hospitals in 2015 to 8 in 2019, PN remained the preferred method of nutrition support. Furthermore, the timing of medical nutrition varied. CONCLUSIONS: Although the use of EN increased after publication of the updated ESPEN/EBMT nutritional guidelines, adherence to these standards was limited and there was heterogeneity in nutrition support practices during intensive AML treatment among hospitals. Incorporating international nutritional standards into national guidelines by nutrition expert groups immediately upon publication may improve adherence.

Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84).

PURPOSE: Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP. PATIENTS AND METHODS: A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat. RESULTS: CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections. CONCLUSION: Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.