Geriatric assessment in older patients with a hematologic malignancy: a systematic review

The aim of this systematic review is to give an update of all currently available evidence on the relevance of a geriatric assessment in the treatment of older patients with hematologic malignancies. A systematic search in MEDLINE and EMBASE was performed to find studies in which a geriatric assessment was used to detect impaired geriatric domains or to address the association between geriatric assessment and survival or clinical outcome measures. The literature search included 4,629 reports, of which 54 publications from 44 studies were included. Seventy-three percent of the studies were published in the last 5 years. The median age of the patients was 73 years (range, 58-86) and 71% had a good World Health Organization (WHO) performance status. The median prevalence of geriatric impairments varied between 17% and 68%, even in patients with a good WHO performance status. Polypharmacy, nutritional status and instrumental activities of daily living were most frequently impaired. Whereas several geriatric impairments and frailty (based on a frailty screening tool or summarized geriatric assessment score) were predictive for a shorter overall survival, WHO performance status lost its predictive value in most studies. The association between geriatric impairments and treatment-related toxicity varied, with a trend towards a higher risk of (non-)hematologic toxicity in frail patients. During the follow-up, frailty seemed to be associated with treatment non-completion, especially when patients were malnourished. Patients with a good physical capacity had a shorter stay in hospital and a lower rate of hospitalization. Geriatric assessment, even in patients with a good performance status, can detect impaired geriatric domains and these impairments may be predictive of mortality. Moreover, geriatric impairments suggest a higher risk of treatment-related toxicity, treatment non-completion and use of healthcare services. A geriatric assessment should be considered before starting treatment in older patients with hematologic malignancies

Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukemia treated with nilotinib

Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1(IS) at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials. gov identifier: 01061177)Peer reviewe

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.</p

Heterozygosity for bisphosphoglycerate mutase deficiency expressing clinically as congenital erythrocytosis: A case series and literature review

Erythrocytosis is associated with increased red blood cell mass and can be either congenital or acquired. Congenital secondary causes are rare and include germline variants increasing haemoglobin (Hb)-oxygen affinity (e.g., Hb or bisphosphoglycerate mutase (BPGM) variants) or affecting oxygen-sensing pathway proteins. Here, we describe five adults from three kindreds with erythrocytosis associated with heterozygosity for BPGM variants, including one novel. Functional analyses showed partial BPGM deficiency, reduced 2,3-bisphosphoglycerate levels and/or increased Hb-oxygen affinity. We also review currently known BPGM variants. This study contributes to raising awareness of BPGM variants, and in particular that heterozygosity for BPGM deficiency may already manifest clinically

Treatment outcome in a population-based, ‘real-world’ cohort of patients with chronic myeloid leukemia

textabstractEvaluations of the ‘real-world’ efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population-based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second-generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a ‘real-world’ setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients

Omitting cytogenetic assessment from routine treatment response monitoring in chronic myeloid leukemia is safe

OBJECTIVES: The monitoring of response in chronic myeloid leukemia (CML) is of great importance to identify patients failing their treatment in order to adjust TKI choice and thereby prevent progression to advanced stage disease. Cytogenetic monitoring has a lower sensitivity, is expensive, and requires invasive bone marrow sampling. Nevertheless, chronic myeloid leukemia guidelines continue to recommend performing routine cytogenetic response assessments, even when adequate molecular diagnostics are available. METHODS: In a population-based registry of newly diagnosed CML patients in the Netherlands, all simultaneous cytogenetic and molecular assessments performed at 3, 6, and 12 months were identified and response of these matched assessments was classified according to European Leukemia Net (ELN) recommendations. The impact of discrepant cytogenetic and molecular response classifications and course of patients with additional chromosomal abnormalities were evaluated. RESULTS: The overall agreement of 200 matched assessments was 78%. In case of discordant responses, response at 24 months was consistently better predicted by the molecular outcome. Cytogenetic response assessments provided relevant additional clinical information only in some cases of molecular "warning." The development of additional cytogenetic abnormalities was always accompanied with molecular failure. CONCLUSION: We conclude that it is safe to omit routine cytogenetics for response assessment during treatment and to only use molecular monitoring, in order to prevent ambiguous classifications, reduce costs, and reduce the need for invasive bone marrow sampling. Cytogenetic re-assessment should still be performed when molecular response is suboptimal

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

PurposeTo investigate the proportion of patients with lymphoma with persistent clinically relevant cognitive impairment, and its relation to treatment, fatigue, and psychological distress.MethodsPatients with diffuse-large-B-cell-lymphoma (DLBCL), follicular-lymphoma (FL), and chronic-lymphocytic-leukemia (CLL)/small-lymphocytic-lymphoma (SLL), diagnosed between 2004-2010 or 2015-2019, were followed up to 8 years post-diagnosis. Sociodemographic and clinical data were obtained from the Netherlands Cancer Registry and the Population-based HAematological Registry for Observational Studies. The EORTC QLQ-C30 was used to assess cognitive functioning and fatigue, and the HADS to assess psychological distress. Individual growth curve models were performed. Results were compared with an age- and sex-matched normative population.ResultsA total of 924 patients were included (70% response rate). Persistent cognitive impairment was twice as high in patients (30%) compared to the normative population (15%). Additionally, 74% of patients reported co-occurring symptoms of persistent fatigue and/or psychological distress. Patients with FL (- 23 points, p &lt; 0.001) and CLL/SLL (- 10 points, p &lt; 0.05) reported clinically relevant deterioration of cognitive functioning, as did the normative population (FLnorm - 5 points, DLBCLnorm - 4 points, both p &lt; 0.05). Younger age, higher fatigue, and/or psychological distress at inclusion were associated with worse cognitive functioning (all p's &lt; 0.01). Treatment appeared less relevant.ConclusionAlmost one-third of patients with lymphoma report persistent cognitive impairment, remaining present up to 8 years post-diagnosis. Early onset and co-occurrence of symptoms highlight the need for clinicians to discuss symptoms with patients early.Implications for Cancer SurvivorsEarly recognition of cognitive impairment could increase timely referral to suitable supportive care (i.e., lifestyle interventions) and reduce (long-term) symptom burden