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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.

•Geriatric assessments can aid in identifying patients with less physical resilience who are at increased risk of grade ≥3 adverse events.•Fixed-duration Ven-O improves HRQoL in patients with CLL with and without geriatric impairments.

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.

Population-based studies that contain detailed clinical data on patients with myelodysplastic syndrome (MDS) are scarce. This study focused on the real-world overall survival (OS) of MDS patients in association with comorbidities, specifically malignancies. An observational population-based study using the HemoBase registry was performed, including all patients with MDS diagnosed between 2005 and 2017 in Friesland, a Dutch province. Detailed information about diagnosis, patient characteristics, previous treatment of malignancies, and comorbidities according to the Charlson Comorbidity Index (CCI) was collected from electronic health records. Patients were followed up until June 2019. Kaplan-Meier plots and Cox regression analyses were used to study survival differences. In the 291 patients diagnosed with MDS, the median OS was 25.3 months (95% confidence interval [CI], 20.3-30.2). OS was significantly better for patients with CCI score <4, age <65 years, female sex, and low-risk MDS. Fifty-seven patients (20%) had encountered a prior malignancy (excluding nonmelanoma skin cancer), and a majority (38 patients; 67%) were therapy related. Both therapy-related and secondary MDSs were associated with worse OS (hazard ratio, 1.51; 95% CI, 1.02-2.23 and 1.58; 95% CI, 0.95-2.65, respectively), as compared with de novo MDS patients (P = .04). Patients in remission at time of MDS diagnosis had a similar median OS compared with patients with de novo MDS (25.5 vs 28.3 months). This population-based study involving all newly diagnosed MDS patients over a 13-year period in Friesland showed that multiple comorbidities, including previous malignancies, are associated with shorter OS. OS was not related to the use of radiotherapy or chemotherapy.

Population-based studies that contain detailed clinical data on patients with myelodysplastic syndrome (MDS) are scarce. This study focused on the real-world overall survival (OS) of MDS patients in association with comorbidities, specifically malignancies. An observational population-based study using the HemoBase registry was performed, including all patients with MDS diagnosed between 2005 and 2017 in Friesland, a Dutch province. Detailed information about diagnosis, patient characteristics, previous treatment of malignancies, and comorbidities according to the Charlson Comorbidity Index (CCI) was collected from electronic health records. Patients were followed up until June 2019. Kaplan-Meier plots and Cox regression analyses were used to study survival differences. In the 291 patients diagnosed with MDS, the median OS was 25.3 months (95% confidence interval [CI], 20.3-30.2). OS was significantly better for patients with CCI score <4, age <65 years, female sex, and low-risk MDS. Fifty-seven patients (20%) had encountered a prior malignancy (excluding nonmelanoma skin cancer), and a majority (38 patients; 67%) were therapy related. Both therapy-related and secondary MDSs were associated with worse OS (hazard ratio, 1.51; 95% CI, 1.02-2.23 and 1.58; 95% CI, 0.95-2.65, respectively), as compared with de novo MDS patients (P= .04). Patients in remission at time of MDS diagnosis had a similar median OS compared with patients with de novo MDS (25.5 vs 28.3 months). This population-based study involving all newly diagnosed MDS patients over a 13-year period in Friesland showed that multiple comorbidities, including previous malignancies, are associated with shorter OS. OS was not related to the use of radiotherapy or chemotherapy.

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.

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.

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfhcell, Treg, and PD-1+CD8+T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells.

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+ T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfh cell, Treg, and PD-1+ CD8+ T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells.

Early data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment.

Early data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment.

Acquired T-cell dysfunction is characteristic of CLL and is associated with reduced efficacy of T-cell based therapies. A recently described feature of dysfunctional CLL-derived CD8 T cells is reduced metabolic plasticity. To what extend CD4 T cells are affected, and if CD4 T-cell metabolism and function can be restored upon clinical depletion of CLL cells is currently unknown. Here we address these unresolved issues by a comprehensive phenotypic, metabolic, transcriptomic and functional analysis of CD4 T cells of untreated CLL patients, and by analyzing the effects of venetoclax + obinutuzumab on the CD4 population. Resting CD4 T cells derived from CLL patients expressed lower levels of GLUT-1, displayed deteriorated oxidative phosphorylation (OXPHOS) and overall reduced mitochondrial fitness. Upon T-cell stimulation, CLL T cells were unable to initiate glycolysis. Transcriptome analysis revealed that depletion of CLL cells in vitroresulted in upregulation of OXPHOS and glycolysis pathways and restored T-cell function in vitro. Analysis of CD4 T cells from CLL patients prior and after venetoclax + obinutuzumab treatment, which led to effective clearance of CLL in blood and bone marrow, revealed recovery of T-cell activation and restoration of the switch to glycolysis, as well as improved T-cell proliferation. Collectively these data demonstrate that CLL cells impose metabolic restrictions on CD4 T cells which lead to reduced CD4 T-cell functionality. This trial is registered in the Netherlands Trial Registry ID: NTR6043.

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P= .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P= .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Background:The majority of patients with myelodysplastic syndromes (MDS) needs regular blood transfusions and becomes transfusion dependent. Blood transfusions temporarily alleviate anemia-related symptoms, but can be accompanied by adverse events, like iron overload. In MDS patients with >20 blood transfusions and plasma ferritin levels >1000 µg/L, (inter)national guidelines advise iron chelation therapy (ICT) to reduce potential organ damage due to transfusion-mediated iron overload. The aim of this study was to determine the adherence to these guidelines, to determine to what extent plasma ferritin levels were monitored in daily practice and which patient-related factors contributed to monitoring plasma ferritin levels during the transfusion period.

Background:

No relevant conflicts of interest to declare.

Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: Roche: Speakers Bureau; Abbvie,: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Hebart: Roche: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Kreuzer: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen: Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau.Ibrutinib in combaintion with Venetoclax + Obinutuzumab is not approved.

Rozema: Celgene: Other: Financial support for visiting MDS Foundation conference.

Bergh: Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; UCB: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee.

No relevant conflicts of interest to declare.

The majority of patients with myelodysplastic syndromes (MDS) require regular red blood cell (RBC) transfusions. Alloimmunization (AI) against blood products is an adverse event, causing time-consuming RBC compatibility testing. The reported incidence of AI in MDS patients varies greatly. Even though different studies on AI in MDS patients have been performed, there are still knowledge gaps. Current literature has not yet fully identified the risk factors and dynamics of AI in individual patients, nor has the influence of disease modifying treatment (DMT) been explored. Therefore, we performed this study to evaluate the effect of DMT on AI.

Introduction

IntroductionBone lesions are one of the primary symptoms in multiple myeloma (MM), and it has been suggested that these lesions adversely impact overall survival (OS). In the last decades, intensified supportive care and new treatment strategies were introduced to improve overall survival and quality of life. Bortezomib may have the capacity to stimulate bone formation, but reduction in skeletal morbidity has not been demonstrated yet. In addition, data on the fracture risk of MM patients in time are lacking. We hypothesized that the improved treatment strategies and supportive care, including the use of bisphosphonates, reduced the risk of fractures in MM patients at the population level. Therefore, the aim of this study is to determine the effect of different treatment periods on the risk of any fracture in patients with MM. Secondary objectives were to determine the risk of vertebral fractures, and the effects of gender and age on the occurrence of all fractures.

Eldering: Celgene: Research Funding. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kater:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction

Introduction.Since publication of the pivotal CLL011 phase 3 trial, combination of chlorambucil and anti-CD20 MAb has become the standard first-line CLL treatment for patients unfit for FCR. Lenalidomide (Len) has been proven effective both as monotherapy and in combination with rituximab. Although recent studies in CLL suggest that Len is mostly beneficial as consolidation treatment, the exact place and duration of this drug is still not optimized. Moreover, Len has shown a distinct and more difficult to manage toxicity profile in the context of CLL, potentially hampering combination treatment with this drug. We therefore conducted a phase 2 study to evaluate efficacy and safety of a combination of chlorambucil, rituximab and individual dosed Len (induction-I) followed by 6 months of Len monotherapy (induction-II).

This case illustrates the potential for systemic cobalt toxicity in non-metal-on-metal bearings and its potentially devastating consequences. We present a 71-year-old male with grinding sensations in his right hip following ceramic-on-ceramic total hip arthroplasty (THA). After diagnosing a fractured ceramic liner, the hip prosthesis was revised into a metal-on-polyethylene bearing. At one year postoperatively, X-rays and MARS-MRI showed a fixed reversed hybrid THA, with periarticular densities, flattening of the femoral head component, and a pattern of periarticular metal wear debris and pseudotumor formation. Before revision could take place, the patient was admitted with the clinical picture of systemic cobalt toxicity, supported by excessively high serum cobalt and chromium levels, and ultimately died. At autopsy dilated cardiomyopathy as cause of death was hypothesized. A third body wear reaction between ceramic remnants and the metal femoral head very likely led to excessive metal wear, which contributed systemic cobalt toxicity leading to neurotoxicity and heart failure. This case emphasizes that fractured ceramic-on-ceramic bearings should be revised to ceramic-on-ceramic or ceramic-on-polyethylene bearings, but not to metal-on-polyethylene bearings. We aim to increase awareness among orthopedic surgeons for clinical clues for systemic cobalt intoxication, even when there is no metal-on-metal bearing surface.

Hoogendoorn: Novartis: Consultancy; Gilead: Consultancy.

Lugtenburg: Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Purpose:

The ATM-p53 DNA damage response pathway plays a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53and ATM. Identifying and distinguishing TP53and ATMfunctional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as underlying cause of chemoresistance. Also, specific treatments sensitizing TP53-or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53versus ATMand (iii) enable the identification of additional defects in the ATM-p53 pathway. Previously we showed that a reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) procedure which quantifies expression levels of the p53-targets, CDKN1A, BBC3and Bax, in CLL cells following irradiation is able to determine p53 functionality. With the aim of identifying and distinguishing abnormalities of TP53versus ATMand enabling the identification of additional defects in the DDR, we developed a new RT-MLPA based functional assay.

Background:Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation.

Hoogendoorn: Gilead: Consultancy; Novartis: Consultancy.

Hovenga: Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding.

Introduction

Waal de: Jansen Cilag: Research Funding. Munck de:Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. velden Van Der:Jansen Cilag: Research Funding. Tromp:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding. Vellenga:Jansen Cilag: Research Funding. Hovenga:Jansen Cilag: Research Funding.

Introduction: Combination therapy for longer periods but at low dose, also called metronomic scheduling, might be an effective manner to treat patients with relapsing myeloma. In particular if the used agents attack the malignant clone in an alternative manner. Therefore we used the combination of bortezomib, dexametasone and daily low dose of oral cyclophosphamide as an induction regimen followed by one year of maintenance therapy consisting of bortezomib and cyclophosphamide.

Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease and/or a deletion 17p del(17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. There is an unmet need for active salvage regimens for these high-risk patients, but so far prospective data on salvage regimens prior to alloSCT are lacking. Here we report our results with R-DHAP remission-induction studied in a prospective international multicenter phase 2 study. The rationale for R-DHAP is formed by in vitro studies showing that platinum induces p53 independent cell death.Patients up to the age of 70 years with fludarabine refractory CLL (defined, according to the EBMT consensus, as relapse within 1 year after fludarabine monotherapy or within 2 years after fludarabine plus a monoclonal antibody) and/or with relapsed CLL with a del(17p) , and with an indication for treatment were eligible for inclusion. Patients received at least 3 cycles of R-DHAP salvage therapy (rituximab on day 1 (375mg/m2 1st cycle, 500 mg/m2 later cycles), cisplatinum 100mg/m2 (day 1), cytarabine 2x2000mg/m2 (day 2) and dexamethasone 40mg days 1-4) every 4 weeks. Response to R-DHAP was determined according to 2008 IWCLL guidelines.Forty patients have been included from February 2009 till April 2012. One patient was ineligible because of Richter’s syndrome at the time of inclusion. The median age was 59 years (range 43-69) and the median number of prior therapies was 2 (range 1-5).Twenty-four patients completed at least 3 cycles of R-DHAP. Due to long donor search. two of these received 4 cycles, two 5 and 1 six cycles. Nine patients received only one or two cycles of R-DHAP because of toxicity, and two patients never received R-DHAP due to poor performance. Overall response rate (ORR) for all 39 eligible patients was 56%: 6 CR (15%), 16 PR (41%). Five patients had SD (13%) and 2 PD (5%). ORR rates in patients with bulky lymphadenopathy (>5 cm, n=18) and in those having del(17p) (n=17) was 67% and 53% respectively.In the first 16 patients four infection related deaths occurred (3 septic shock and 1 encephalitis). After an amendment optimizing infection prophylaxis, no additional severe bacterial or fungal infections or infection related deaths were observed.Twenty-six patients proceeded to alloSCT (67%). With a median follow-up of 16 months (range 6-42 months) 2-years progression-free survival (PFS) and overall survival (OS) after transplantation is 63% and 72% respectively. Sixteen are free from progression and 3 progressed but are still alive. Seven patients died (3 from acute GVHD, 2 due to encephalopathy, 2 other reasons).R-DHAP is an effective remission-induction regimen for fludarabine-refractory CLL patients even in those having bulky lymphadenopathy and/or del(17p), enabling a high percentage of patients to proceed to alloSCT resulting in a high PFS and OS at 2 years.No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease and/or a deletion 17p del(17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. There is an unmet need for active salvage regimens for these high-risk patients, but so far prospective data on salvage regimens prior to alloSCT are lacking. Here we report our results with R-DHAP remission-induction studied in a prospective international multicenter phase 2 study. The rationale for R-DHAP is formed by in vitrostudies showing that platinum induces p53 independent cell death.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. The optimum salvage therapy for these patients is not known. Treatment results with second-line chemotherapy have generally been disappointing. In some centers in the Netherlands PECC (Prednisone, Etoposide, Chlorambucil and Lomustine) combination chemotherapy is used as salvage treatment for such patients. PECC is a completely oral schedule. The efficacy and toxicity of PECC in this patient category has not been evaluated systematically before. 90Y-ibritumomab tiuxetan (Zevalin®) showed clinical activity as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating induction therapy with Rituximab (R)-PECC followed in responsive patients by 90Y-ibritumomab tiuxetan consolidation.Patients aged ≥ 18 years with refractory CD20 positive DLBCL or first or second relapse, more than one year after or not eligible for ASCT, were enrolled. Treatment consisted of R-PECC (Prednisone 40 mg/m2 po D1–5; Etoposide 100 mg/m2 po D1–5; Chlorambucil 8 mg/m2 po D1–5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1), every 28 days for 4 cycles. Patients with progressive disease after 2 cycles went off protocol. Patients in complete or partial remission after 4 cycles received consolidation treatment with 90Y-ibritumomab tiuxetan at the standard single dose of 15 MBq/kg (0.4 mCi/kg) 6 to 12 weeks after start of the last R-PECC cycle. Response to treatment was evaluated according to the revised 2007 Cheson criteria.Between November 2008 and February 2012 64 patients were enrolled. We report preliminary data for the first 50 patients evaluable for response and toxicity after the induction treatment with R-PECC. The median age was 70 years (range, 45–82) and median time since first diagnosis was 17 months (range 3–172). All patients had been treated with CHOP as first-line treatment and 8 patients (16%) had not been exposed to rituximab at first-line. Prior therapies consisted of (R)-CHOP (72%), R-CHOP and R-DHAP/VIM (16%) or R-CHOP and R-DHAP/VIM plus ASCT (12%). Eleven patients (22%) were refractory to their last prior systemic therapy. According to the secondary IPI, 26%, 28%, 34% and 8% of the patients belonged to the low-, low-intermediate-, high-intermediate-, and high risk group, respectively. Median relative dose intensities for the myelosuppressive agents of the PECC regimen were 93.7% (90% CI = 62.8–106.9%), 94.3% (90% CI = 71.6–104.7%) and 97.4% (90% CI 76.0–104.7%) for Lomustin, Etoposide and Chlorambucil, respectively. Progressive disease occurred in 14 patients (28%). Overall response rate (ORR) after induction treatment was 52%, including 34% complete response and 18% partial response. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (64% vs. 9%, p=0.099). Patients more than one year from start of upfront treatment had a significant higher ORR than that of patients less than one year from start of upfront treatment (81% vs 21%, p=0.005). Median response duration was 13 months. One patient died because of treatment related toxicity due to sepsis and pneumonia after the first R-PECC cycle. The most common grade 3 or 4 adverse event was haematological toxicity (42%), followed by infection (14%), malaise (13%) and gastro-intestinal toxicity (6%). Eighteen serious adverse events (SAEs) occurred in 14 patients, 14 of the SAEs were possibly related to treatment (mainly hospitalisations because of infections). Approximately half of the patients (46%) have entered the 90Y-ibritumomab tiuxetan consolidation phase of the study.The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile.Off Label Use: 90Y-ibritumomab tiuxetan is not registered for DLBCL.