Summary
Elderly patients with primary central nervous ystem lymphoma (PCNSL) do not tolerate treatment with combined radio‐chemotherapy well because of leuco‐encephalopathy; they are usually treated ...initially with chemotherapy or radiotherapy alone. Little is known about the efficacy and toxicity of these treatments outside clinical studies. This study was a retrospective analysis of all patients aged 60 years or over who were admitted with PCNSL to one of five Dutch centers between 1998 and 2007. A total of 74 patients were identified. Twenty‐nine were treated with radiotherapy only (Group A), in 36 the intended treatment was chemotherapy alone (Group B), and nine were planned to receive chemotherapy followed by radiotherapy (Group C). Median overall survival was 20 months; 4 months in patients with a Karnofsky performance status (KPS) <70, 25 months in patients with a KPS ≥ 70 (P < 0·001). Treatment modality was not an independent prognostic factor. Forty patients were treated with methotrexate 3 g/m2: there were two toxic deaths. Ten patients discontinued chemotherapy because of toxicity. Delayed encephalopathy was reported in 10 patients. In conclusion, community hospitals still frequently utilize whole brain radiotherapy in elderly PCNSL patients, though a majority tolerates chemotherapy well. Performance status was the most important variable determining prognosis. Short and long term toxicities must be weighed against possible clinical benefits of each treatment, making treatment decisions a highly individualized process.
Background
Keeping the balance between long-term efficacy and toxicity of treatment in patients with chronic lymphocytic leukemia (CLL) is of utmost importance. Ibrutinib impacts BCR/adhesion ...signaling resulting in efficient lymph node (LN) responses and prolonged disease control despite a lack of deep remissions. Venetoclax directly kills CLL cells by antagonizing the pro-survival Bcl-2 protein leading to deep remissions (undetectable minimal residual disease (uMRD)) in the blood and bone marrow (BM) but incomplete LN clearance. Synergy between these agents is shown in our relapsed/refractory CLL HOVON 141 study with complete remission (CR) rates of 69% and blood uMRD rate of 55% after 12 full dose combination cycles with acceptable toxicity (abstract submitted; Niemann et al.). Extrapolating these data, we hypothesize that a fixed duration of a combination of venetoclax and ibrutinib will result in a substantial proportion of patients in CR and with undetectable MRD, who will have very good outcome after treatment cessation. Yet, not all patients will achieve this level of disease clearance and therefore, intensification approaches are of interest.
A prior study has shown that addition of the CD20 antibody obinutuzumab lead to considerably higher uMRD rates when added after 1 year of prior ibrutinib monotherapy than when given simultaneously (BM uMRD rate of 50% versus 6% respectively; Hillmen et al. 2018). This suggests an opportunity for treatment intensification in the subset of patients who do not respond optimally to initial I+V combination treatment.
In CLL, 3 compartments exist with putative differential sensitivity for targeted agents. Although the predictive role of residual leukemia cells in blood and bone marrow, as measured by MRD is increasingly appreciated, the biological and prognostic relevance of residual LN, which is often observed in venetoclax treated patients, is uncertain. 18F-fluorodeoxyglucose (FDG) PET-CT is widely used for response evaluation of lymphoma, but has not proven its value in CLL. (Conte et al. 2014) However, radiomics with computational processing of the PET/CT may provide biologic and clinical relevant information on the characteristics of residual LN and warrants exploration for guidance of treatment intensification as an MRD proxy for spleen and LN. (Lee et al. 2018)
Objectives
To evaluate the efficacy of 6 cycles ibrutinib+obinutuzumab in converting patients who are not in CR or who have detectable MRD after 12 cycles of ibrutinib+venetoclax to a CR with uMRD (BM). Moreover, PET/CT with radiomics is employed to assess clearance of CLL from LN and spleen.
Primary endpoint
CR with uMRD (BM) 3 months after end of intensification with ibrutinib+obinutuzumab in patients who are not in CR and/or uMRD on combination ibrutinib/venetoclax.
Design
The trial is designed as a single arm phase 2 study for treatment naïve CLL patients requiring treatment according to IWCLL criteria. 85 patients will be included.
Study Treatment
Patients will receive 3 lead-in cycles of ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day including a ramp up of 5-weeks starting in cycle 4 day 1. Patients with measurable disease at evaluation after 15 cycles will continue with 6 intensification cycles of ibrutinib/obinutuzumab. day 1, 2, 8, 15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles in combination with ibrutinib (Figure 1).
Major inclusion criteria•Treatment naïve CLL or SLL patients requiring treatment by iwCLL•WHO performance status 0-3
Adequate BM function defined as: •Hb > 8 g/dL•Neutrophil count ≥75 x 109/L•Platelet count ≥ 50,000 /μL•creatinine clearance ≥ 30ml/min
Major exclusion criteria•Active fungal, bacterial, and/or viral infection that requires systemic therapy;•Patients requiring treatment with strong cytochrome P450 (CYP) 3A inhibitor or with vitamin K antagonists
Statistical methods
For the primary endpoint analyses, all patients registered and eligible for intensification treatment with ibrutinib+obinutuzumab (not in complete remission and/or uMRD) will be included.
Perspective
This trial helps in personalizing CLL treatment by selecting sequential time limited therapies guided by MRD.
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Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Niemann:Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Abbvie: Consultancy, Other: Travel grant, Research Funding. Kater:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Consultancy, 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.
Combination of ibrutinib and venetoclax Combination of ibrutinib and obinutuzumab
•A local dose-response relationship of ORN in the mandible was derived.•Pre-RT extractions increase risk of ORN, but only close to the site of extraction.•Smoking increases risk of ORN in the ...mandible.•Selective sparing of the mandible near extractions may decrease the risk of ORN.
Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy of the head and neck, but not all regions of the mandible may be equally at risk. Therefore our goal was to explore a local dose response relationship for subregions of the mandible.
All oropharyngeal cancer patients treated at our hospital between 2009 and 2016 were reviewed. Follow-up was cut-off at 3 years. For patients that developed ORN, the ORN volume was delineated on the planning CT. Each mandible was divided into 16 volumes of interest (VOIs) based on the location of the dental elements and the presence of ORN in each was scored. Generalized estimating equations were used to build a model for the probability of developing ORN in an element VOI.
Of the 219 included patients, 22 developed ORN in 89 element VOIs. Mean dose to the element VOI (odds ratio (OR) = 1.05 per Gy, 95% confidence interval (CI): (1.04,1.07)), pre-radiotherapy extractions of an element ipsilateral to element of interest (OR = 2.81, 95% CI: (1.12,7.05)), and smoking at start of radiotherapy (OR = 3.37, 95% CI: (1.29,8.78)) were significantly associated with an increased probability of ORN in the VOI.
The developed dose-response model indicates that the probability of ORN varies within the mandible and strongly depends on the local dose, the location of extractions, and smoking.
•Interest in hypofractionated radiotherapy with more heterogeneous dose distributions is increasing.•Existing osteoradionecrosis (ORN) risk models cannot be applied to non-standard fractionation ...schemes and dose distributions.•EUD can be used to better distinguish between ORN and non-ORN in a single model.•EUD(a = 8), teeth extraction, and mandibular volume were factors significantly associated to ORN.
Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD).
We performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/β = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis.
A total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN.
Risk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments.
The clinical value of allogeneic hematopoietic stem cell transplantation (alloHSCT) and autologous hematopoietic stem cell transplantation (autoHSCT) in the subtype of acute myeloid leukemia (AML) ...with double mutant CEBPA (CEBPAdm) has remained unsettled. Among 2983 patients analyzed for CEBPA mutational status (age 18-60 years) treated on 4 published Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) and 3 German-Austrian AML Study Group (AMLSG) protocols (2 published, 1 registered, clinicaltrials.gov NCT00151255), 124 had AML with CEBPAdm and achieved first complete remission (CR1). Evaluation of the clinical impact of alloHSCT and autoHSCT vs chemotherapy was performed by addressing time dependency in the statistical analyses. Thirty-two patients proceeded to alloHSCT from a matched related (MRD, n = 29) or a matched unrelated donor (MUD, n = 3), 20 to autoHSCT in CR1 and 72 received chemotherapy. Relapse-free survival was significantly superior in patients receiving an alloHSCT or autoHSCT in CR1 as compared with chemotherapy (P < .001), whereas overall survival was not different (P < .12). Forty-five patients relapsed. Of 42 patients treated with reinduction therapy, 35 achieved a second CR (83%) and most patients (n = 33) received an alloHSCT MRD, n = 11; MUD, n = 19; haplo-identical donor, n = 3). Survival of relapsed patients measured from date of relapse was 46% after 3 years. Adult AML patients with CEBPAdm benefit from alloHSCT and autoHSCT; relapsed patients still have a favorable outcome after reinduction followed by alloHSCT.
•In AML with bialleleic CEBPA-mut relapse-free survival was improved by allogeneic and autologous hematopoietic stem cell transplantation.•In relapsed patients second complete remission rate was high and survival was favorable after an allogeneic transplantation.
•In this cohort, the cumulative incidence of psPD increases from 13% in the first year to 28% at 10 years.•psPD is asymptomatic in 83% of patients.•1p/19q codeletion and biopsy are associated with an ...increased risk of psPD.•When analyzed as a time-dependent covariate, psPD is not associated with overall survival.•An uniform definition and analysis method for psPD in diffuse glioma is needed for comparisons between photon - and proton beam radiotherapy.
The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy.
We reviewed all follow-up MRI’s of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1–1-2007 and 31–12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD.
A total of 860 MRI’s of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI’s. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients.
The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.
Introduction: The evaluation of novel drugs in hemato-oncology is hampered by relatively large sample sizes needed for sufficiently powered, randomized controlled trials (RCT). External control data ...are increasingly applied in prospective phase II and III studies, and might be derived from Real-World Data (RWD) sources, such as national cancer registries. The HARMONY Alliance recently reported on a big data platform, consisting of data that were generated by cooperative European acute myeloid leukemia (AML) study groups ( Lang et al., Trials, 2020). HARMONY or cancer registry data might supplement prospectively collected trial control data. Here, we investigated whether and to what extent data included in the HARMONY AML database and RWD from the Netherlands Cancer Registry (NCR) compare to the control arm of the recently reported prospective randomized HOVON-103 (H103) study in elderly AML ( Ossenkoppele et al., Leukemia, 2020; Janssen et al., Leukemia, 2022). Methods: The H103 trial consecutively randomized newly diagnosed AML patients aged >65 years between standard induction chemotherapy with or without lenalidomide, tosedostat, or selinexor. External control patients concerned newly diagnosed (HARMONY: 2010-2018; NCR: 2014-2018) and intensively treated (intensified cytarabine/anthracycline) elderly AML patients aged >60 years. H103 were matched 1:1 using nearest neighbor propensity scores with NCR and HARMONY patients for age, European Leukemia Net (ELN) 2022 risk classification, and leukocyte count at diagnosis, while HARMONY patients were additionally matched for WHO performance score. Patients with missing values for propensity score factors were excluded from that analysis. The primary endpoint was overall survival (OS), calculated by the Kaplan-Meier method. Results: 67% of HARMONY patients (n=510) concerned trial patients. Median age was lower for HARMONY patients compared with H103-controls (n=279) (67 vs. 69 years, P<0.01), with also a preponderance of male patients in the H103 cohort (54% vs. 62%, P=0.03). Age and male sex did not differ between H103-controls and NCR patients (n=320) (69 vs. 69 years, P=0.46; 62% vs. 62%, P=1.0) (Table 1). WHO performance score of 0 or 1 was reported in 49% and 41% of H103-controls which was less frequent in HARMONY and NCR data (8% and 31%, P<0.01; 26% and 18%, P<0.01, respectively). Unknown WHO status was more prevalent in the external cohorts than in H103, at 43%, 54%, and 1% for the HARMONY, NCR, and H103 cohorts, respectively. ELN 2022 risk (favorable vs. non-favorable) was reported in 24% vs. 76% of H103 patients, which was similar in HARMONY patients (26% vs. 74%; P=0.73). ELN 2022 risk differed, however, for NCR patients (17% vs 83%; P=0.03). The median leukocyte count at diagnosis was lower for H103-controls than for HARMONY and NCR patients (3.65 vs. 17.1, P<0.01; 3.65 vs. 13.1, P<0.01, respectively). Propensity scores matched 278 HARMONY patients and 278 NCR patients to H103-controls. The 2-year OS (estimate±SE) was 40±3% for H103-controls vs. 35±3% for HARMONY patients (P=0.22), and vs. 30±3% for NCR patients (P=0.052), respectively (Figure 1). Conclusion: Characteristics of H103-controls and HARMONY patients appeared largely comparable, while NCR patients were more frequently ELN 2022 non-favorable risk. Following matching, OS was similar between H103-controls and HARMONY patients, while NCR patients showed inferior OS. The inclusion of a large proportion of trial patients in the HARMONY cohort, adhering to strict inclusion and exclusion criteria and fewer comorbidities compared to RWD patients, might explain these observations. These results suggest that matched data of the HARMONY Alliance might supplement prospectively collected control data in studies evaluating intensive therapy in elderly AML.
Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 ...induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% ± 3 standard error at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ± 2 vs 22% ± 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% ± 4 vs 40% ± 5 at 4 years; Cox P = .002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% ± 5 vs 40% ± 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.
•Clofarabine integrated in standard induction therapy for newly diagnosed AML reduces relapse probability but does not improve survival.•Clofarabine improves survival in intermediate-risk AML categories ELN-1 and the AML genotype without NPM1 and without FLT3-ITD gene mutations.
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