The impact of CHOP versus bendamustine on bone mineral density in patients with indolent lymphoma enrolled in the GALLIUM study.

Standard CHOP treatment includes a high cumulative dose of prednisone, and studies have shown increased fracture risk following CHOP. It is unclear whether reductions in bone mineral density (BMD) are caused by glucocorticoids or by the combination with chemotherapy. Our objective was to determine the effect of obinutuzumab (G)/rituximab (R)-bendamustine versus G/R-CHOP on BMD in follicular lymphoma patients. Patients in this GALLIUM post hoc study were ≥60 years old and in complete remission at induction treatment completion (ITC), following treatment with G or R in combination with bendamustine or CHOP. To assess BMD, Hounsfield units (HU) were measured in lumbar vertebra L1 on annual computed tomography. Furthermore, vertebral compression fractures were recorded. Of 173 patients included, 59 (34%) received CHOP and 114 (66%) received bendamustine. At baseline, there was no difference in HU between groups. The mean HU decrease from baseline to ITC was 27.8 after CHOP and 17.3 after bendamustine, corresponding to a difference of 10.4 (95% CI: 3.2-17.6). Vertebral fractures were recorded in 5/59 patients receiving CHOP and in 2/114 receiving bendamustine. CHOP was associated with a significant greater decrease in BMD and more frequent fractures. These results suggest that prophylaxis against BMD loss should be considered.

Primary gastric diffuse large B-cell lymphoma: A multicentre retrospective study.

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) accounts for the majority of extra-nodal DLBCL. Even so, literature is lacking on early, localised presentations. We studied a cohort of patients with stage I disease, diagnosed between 2006 and 2018, from six centres between Australia, Canada and Denmark. Our goal was to characterise outcomes, review treatment and investigate the role of interim positron emission tomography (iPET). Thirty-seven eligible patients were identified. The median duration of follow-up was 42.2 months. All received chemoimmunotherapy with 91.9% (n = 34) given rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 35.1% (n = 13) underwent consolidative radiotherapy. Eighteen patients were H. pylori positive and 11 had the documentation of H. pylori eradication therapy. The 4-year progression-free survival and overall survival of R-CHOP was 88% (95% CI: 71-95) and 91% (95% CI: 75-97) respectively. All patients who achieved a partial metabolic response or complete metabolic response on iPET went on to achieve complete response at the end of treatment. R-CHOP-based therapy with iPET assessment appears to offer favourable outcomes, with radiotherapy and H. pylori eradication therapy implemented on a case-by-case basis.

Bone health and glucocorticoid-containing lymphoma therapy - a review of risk factors and preventative measures.

With survival outcomes ever improving for patients with a wide range of lymphoma histologies, the focus on reducing long-term complications of therapy has increased. Recently published, complimentary population and retrospective series have highlighted the importance of considering bone health in patients treated for lymphoma. Fracture-related events or the requirement for secondary bone prophylaxis, likely linked to glucocorticoid-induced osteoporosis (GIO) are substantial and clinically meaningful in a significant minority of patients following routinely employed steroid-containing immunochemotherapy. In this review, we describe the pathophysiology of GIO, the risk of GIO in observational front-line lymphoma studies and efficacy of prophylactic measures from several prospective clinical trials are summarized. Finally, areas of importance for future research are discussed and recommendations for GIO risk assessment and management in lymphoma are provided based on the current available literature.

Direct costs of antineoplastic and supportive treatment for progressive multiple myeloma in a tax-based health system.

Aim: To estimate current real-world costs of drugs and supportive care for the treatment of multiple myeloma in a tax-based health system. Methods: Forty-one patients were included from a personalized medicine study (2016-2019). Detailed information was collected from patient journals and hospital registries to estimate the total and mean costs using inverse probability weighting of censored data. Results: Total observed (censored) costs for the 41 patients was €8.84 million during 125 treatment years, with antineoplastic drugs as the main cost driver (€5.6 million). Individual costs showed large variations. Mean 3-year cost per patient from first progression was €182,103 (€131,800-232,405). Conclusion: Prediction of real-world costs is hindered by the availability of detailed costing data. Micro-costing analyses are needed for budgeting and real-world evaluation of cost-effectiveness.

Lay abstract In recent years, there has been a dramatic improvement in the treatment of multiple myeloma due to the introduction of new drugs. These drugs have significantly increased survival but have also had an immense impact on healthcare budgets. In this study, we used detailed treatment information for multiple myeloma patients in combination with billing data from the hospital pharmacy at a Danish hospital to calculate individual cost histories for both drugs and supportive care. Using these data, we estimated the mean 3-year cost of a multiple myeloma patient to be €182.103, but we also found large variation between patients, causing an uncertainty of €50.000 in either direction. We believe that detailed costing studies, similar to the present one, are necessary for evaluation of cost-effectiveness of drugs in clinical practice.

Shared care follow-up of patients with B-cell neoplasms based on nurse-led telephone consultations and PRO-data: a feasibility study from the North Denmark Region.

BACKGROUND: Patients with B-cell neoplasms in remission are monitored with regular physician visits at the hospital. The current standard follow-up procedure is not evidence-based or individualized to patient needs. To improve and individualize the follow-up, we investigated the feasibility of a shared care follow-up initiative, with alternating physician visits and nurse-led telephone consultations and assessments based on patient-reported outcome (PRO) data. METHODS: Patients ≥18 years diagnosed with B-cell neoplasms were eligible for the study when they were in remission and stable without treatment for at least 6 months. Patients were assigned to alternating visits with physicians and nurse-led telephone consultations. The nurse-led telephone consultations were based on PROs, which were collected with the European Organization for Research and Treatment of Cancer questionnaire (EORTC-QLQ-C30), the Myeloproliferative Neoplasm - Symptom Assessment Form, and the Hospital Anxiety and Depression Scale. Patients completed questionnaires before every nurse-led consultation. We also applied the Patient Feedback Form to survey patient acceptance of the requirement of questionnaire completion. We applied descriptive statistics, in terms of counts (n) and proportions (%), to describe the study population and all endpoints. RESULTS: Between February 2017 and December 2018, 80 patients were enrolled. Adherence, measured as the recruitment rate, was 96% (80/83), and the drop-out rate was 6% (5/80). During the study period, 3/80 (4%) patients relapsed, and 5/80 (6%) patients returned to the standard follow-up, because they required closer medical observation. Relapses were diagnosed based on unscheduled visits requested by patients (n = 2) and patient-reported symptoms reviewed by the nurse (n = 1). The response rate to questionnaires was 98% (335/341). A total of 58/79 (74%) patients completed the Patient Feedback Form; 51/57 (89%) patients reported improved communication with health care professionals; and 50/57 (88%) patients reported improved recollection of symptoms as a result of completing questionnaires. CONCLUSION: Based on patient adherence, a low relapse rate, and positive patient attitudes towards completing questionnaires, we concluded that a shared care follow-up, supported by PROs, was a feasible alternative to the standard follow-up for patients with B-cell disease in remission.

Use of WGS data for investigation of a long-term NDM-1-producing Citrobacter freundii outbreak and secondary in vivo spread of blaNDM-1 to Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca.

OBJECTIVES: An outbreak of NDM-1-producing Citrobacter freundii and possible secondary in vivo spread of blaNDM-1 to other Enterobacteriaceae were investigated. METHODS: From October 2012 to March 2015, meropenem-resistant Enterobacteriaceae were detected in 45 samples from seven patients at Aalborg University Hospital, Aalborg, Denmark. In silico resistance genes, Inc plasmid types and STs (MLST) were obtained from WGS data from 24 meropenem-resistant isolates (13 C. freundii, 6 Klebsiella pneumoniae, 4 Escherichia coli and 1 Klebsiella oxytoca) and 1 meropenem-susceptible K. oxytoca. The sequences of the meropenem-resistant C. freundii isolates were compared by phylogenetic analyses. In vitro susceptibility to 21 antimicrobial agents was tested. Furthermore, in vitro conjugation and plasmid characterization was performed. RESULTS: From the seven patients, 13 highly clonal ST18 NDM-1-producing C. freundii were isolated. The ST18 NDM-1-producing C. freundii isolates were only susceptible to tetracycline, tigecycline, colistin and fosfomycin (except for the C. freundii isolates from Patient 2 and Patient 7, which were additionally resistant to tetracycline). The E. coli and K. pneumoniae from different patients belonged to different STs, indicating in vivo transfer of blaNDM-1 in the individual patients. This was further supported by in vitro conjugation and detection of a 154 kb IncA/C2 plasmid with blaNDM-1. Patient screenings failed to reveal any additional cases. None of the patients had a history of recent travel abroad and the source of the blaNDM-1 plasmid was unknown. CONCLUSIONS: To our knowledge, this is the first report of an NDM-1-producing C. freundii outbreak and secondary in vivo spread of an IncA/C2 plasmid with blaNDM-1 to other Enterobacteriaceae.

Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study.

There is consensus that young patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens, but optimal treatment of elderly patients as well for as patients with limited or indolent disease is not defined. Our aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL in a population-based data set. Data were collected from the Swedish and Danish Lymphoma Registries from the period of 2000 to 2011. A total of 1389 patients were diagnosed with MCL. During this period, age-standardized incidence MCL increased, most prominently among males. Furthermore, male gender was associated with inferior overall survival (OS) in multivariate analysis (hazard ratio [HR] = 1.36; P = .002). Forty-three (3.6%) patients with stage I-II disease received radiotherapy with curative intent, showing a 3-year OS of 93%. Twenty-nine (2.4%) patients followed a watch-and-wait approach and showed a 3-year OS of 79.8%. Among patients receiving systemic treatment, rituximab (n = 766; HR = 0.66; P = .001) and autologous stem cell transplant (n = 273; HR = 0.55; P = .004) were independently associated with improved OS in multivariate analysis. Hence, by a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice.

Bone Marrow Aspiration: A Randomized Controlled Trial Assessing the Quality of Bone Marrow Specimens Using Slow and Rapid Aspiration Techniques and Evaluating Pain Intensity.

BACKGROUND/AIMS: Bone marrow aspiration (BMA) is an essential procedure in the examination of hematological disorders, but there is limited evidence as to whether the aspiration rate affects specimen quality. We aimed to assess the specimen quality and pain intensity using slow (S-technique) or rapid (R-technique) aspiration. METHODS: This was a single-center, prospective, randomized patient- and assessor-blinded study of 482 patients scheduled for BMA. Specimen quality was evaluated by grading bone marrow (BM) cellularity and counting the number of marrow particles. Pain was assessed using a visual analog scale (VAS). RESULTS: We found a significant difference between the 2 groups with regard to the quality of specimens. For cellularity, the odds ratio (OR) for having a poor quality aspirate using the S-technique versus the R-technique was 3.05 [confidence interval (CI) 1.79-5.31]. For BM particles, the quality of specimens with the S-technique proved to be poor compared with the R-technique (OR 2.52; CI 1.51-4.28). We found a statistically significant difference of 1 VAS point (p < 0.001) of the median pain intensity in favor of the S-technique. CONCLUSION: Even though the pain intensity is significantly higher with the R-technique, the median difference is relatively small. We propose that the R-technique is preferable to the S-technique due to better specimen quality.

Role of routine imaging in detecting recurrent lymphoma: A review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma.

After first-line therapy, patients with Hodgkin lymphoma (HL) and aggressive non-HL are followed up closely for early signs of relapse. The current follow-up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non-HL (nodal T-cell and diffuse large B-cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002-2011 and relapsed after achieving complete remission on first-line therapy. Characteristics and outcome of imaging-detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient-reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91-255 depending on the lymphoma subtype. Patients with imaging-detected relapse had lower disease burden (P = 0.045) and reduced risk of death following relapse (hazard ratio = 0.62, P = 0.02 in multivariate analysis). Patient-reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging-detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial.

An Aggressive Course of Transformed Splenic Diffuse Red Pulp Small B-Cell Lymphoma With Novel Somatic Loss-of-Function Mutation in RB1.

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is an extremely rare B-cell lymphoma. The disease is typically indolent and treatment with splenectomy usually results in durable remissions. Here, we present a case of an extremely aggressive course of SDRPL with transformation to diffuse large B-cell lymphoma and multiple relapses immediately following cessation of immunochemotherapy. We provide results from whole-exome sequencing from debut of SDRPL and from following transformed stages and identified a novel somatic mutation in RB1 as the possible driver of this aggressive disease, which has not been reported earlier in SDRPL.

A randomized trial of alendronate as prophylaxis against loss in bone mineral density following lymphoma treatment.

Lymphoma patients often receive high glucocorticoid doses as part of standard therapy. Observational studies have shown a substantial risk of glucocorticoid-induced osteoporosis (GIO) with associated fractures. The aim of the SIESTA trial was to determine if oral alendronate (ALN) is a safe and effective prophylaxis against GIO in lymphoma. SIESTA was a single-center, randomized, double-blinded, phase 2 study of lymphoma patients planned for glucocorticoid-containing chemotherapy. After randomization, patients received weekly ALN 70 mg or placebo for a total of 52 weeks. Bone mineral density (BMD) was assessed at baseline, after completion of chemotherapy (end of treatment [EOT]) (4 to 6 months), and at the end of the study (EOS) (12 months). Vertebral fracture and biomarkers were assessed at baseline and EOS. Patients with baseline BMD assessment and at least 1 follow-up BMD assessment were analyzed for efficacy. The primary endpoint was a change in lumbar spine T-score from baseline to EOS. Of the 59 patients enrolled, 23 of 30 in the ALN arm and 24 of 29 in the placebo arm were analyzed for efficacy. The mean change in T-score from baseline to 12 months at the lumbar spine was +0.15 for ALN and -0.12 for placebo (P = .023). The difference in ΔTEOS between the ALN and placebo groups was larger among females (ALN 0.28; placebo -0.28; P = .01). Biomarker analyses confirmed reduced bone resorption in ALN-treated patients. In conclusion, ALN is a safe and effective primary prophylaxis against loss in BMD following glucocorticoid-containing chemotherapy. Despite reduced BMD loss in the ALN arm, the treatment did not influence fracture risk in this small cohort of patients.

Monoclonal gammopathy of undetermined significance and risk of venous thromboembolism.

BACKGROUND: Patients with multiple myeloma are at increased risk of venous thromboembolism (VTE), but little information is available on VTE risk in patients with the precursor condition monoclonal gammopathy of undetermined significance (MGUS). OBJECTIVE: To evaluate the risk of VTE and its impact on mortality in patients with MGUS. PATIENTS AND METHODS: We identified 1610 patients with MGUS and no prior diagnosis of VTE during the 1978-2005 period in North Jutland County, Denmark. We used the Danish Central Population Registry to select 16,100 general population comparison cohort members with no prior VTE diagnosis, matched with the MGUS patients by age, sex, and comorbidity. Follow-up data on VTE incidence in the two groups were obtained from the Danish National Patient Registry covering all Danish hospitals. Time-varying Cox regression analysis was used to compute the incidence rate ratio (IRR) of VTE and the mortality rate ratio (MRR) for MGUS patients who developed VTE compared to MGUS patients without VTE. RESULTS: In the MGUS cohort, 50 VTE events were identified during 12,594 person-years (PY) of follow-up, corresponding to an incidence rate of 4.0 VTEs/1000 PY. The IRR for VTE among MGUS patients compared to the comparison cohort was 1.37 (95% confidence interval (CI): 1.00-1.88). Of the 50 MGUS patients with VTE, one was later diagnosed with malignant transformation. The adjusted MRR for MGUS patients with VTE compared to MGUS patients without VTE was 1.94 (95% CI: 1.36-2.77). CONCLUSIONS: MGUS is a risk factor for VTE, and VTE is a marker for increased mortality among MGUS patients.

Hematological cancer survivors' experiences of participating in a shared care follow-up-an exploratory interview study.

PURPOSE: The aim of the present study was to explore hematological cancer survivors' experiences of participating in a shared care follow-up based on alternating routine physician visits and nurse-led telephone consultations at the Department of Hematology, Aalborg University Hospital, Denmark. DESIGN: The design was an exploratory qualitative interview study based on a semi-structured interview guide. METHOD: Twelve patients who had participated in the shared care follow-up were interviewed. The interviews were recorded and transcribed. Data were analyzed using thematic analysis. RESULTS: Our findings suggest that hematological patients found the nurse-led telephone consultations convenient and helped alleviate anxiety. Despite fewer visits to the hospital and less physical examinations, the patients' sense of security was maintained. Furthermore, completing questionnaires and the emotional and psychosocial focus in nurse consultations were considered beneficial. Finally, using the telephone was considered to be personal and an acceptable way of talking about topics of a sensitive nature. CONCLUSIONS: Our findings suggest that hematological cancer survivors value alternating routine visits and nurse-led telephone consultations as part of cancer survivorship care as well as the emotional and psychological focus of the shared care follow-up. It seems that their sense of security was maintained due to retention of physical examinations. IMPLICATIONS FOR CANCER SURVIVORS: The findings from this study underline the importance of the flexibility and adaptability of cancer follow-up in order to meet patients' needs and preferences. Furthermore, this study underlines the importance of cancer survivorship care that goes beyond disease-related support.

[Fever, loss of vision and acute promyelocytic leukemia at the pandemic ward].

This is a case report of a 68-year-old female referred to the SARS-CoV-2 ward with one week of intermittent fever and three days of progressive loss of vision. Laboratory work-up revealed severe coagulopathy, thrombocytopenia and hyperleukocytosis. MRI showed multiple ischaemic cortical lesions. Acute treatment with all-trans retinoic acid and cytoreduction was started and coagulation parameters corrected. Patients referred to pandemic wards must undergo stringent examination and be referred for further evaluation irrespective of suspected severe acute respiratory syndrome coronavirus-2 infection.

Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.

Acute myeloid leukaemia (AML) is characterised by phenotypic heterogeneity, which we hypothesise is a consequence of deregulated differentiation with transcriptional reminiscence of the normal compartment or cell-of-origin. Here, we propose a classification system based on normal myeloid progenitor cell subset-associated gene signatures (MAGS) for individual assignments of AML subtypes. We generated a MAGS classifier including the progenitor compartments CD34+/CD38- for haematopoietic stem cells (HSCs), CD34+/CD38+/CD45RA- for megakaryocyte-erythroid progenitors (MEPs), and CD34+/CD38+/CD45RA+ for granulocytic-monocytic progenitors (GMPs) using regularised multinomial regression with three discrete outcomes and an elastic net penalty. The regularisation parameters were chosen by cross-validation, and MAGS assignment accuracy was validated in an independent data set (N = 38; accuracy = 0.79) of sorted normal myeloid subpopulations. The prognostic value of MAGS assignment was studied in two clinical cohorts (TCGA: N = 171; GSE6891: N = 520) and had a significant prognostic impact. Furthermore, multivariate Cox regression analysis using the MAGS subtype, FAB subtype, cytogenetics, molecular genetics, and age as explanatory variables showed independent prognostic value. Molecular characterisation of subtypes by differential gene expression analysis, gene set enrichment analysis, and mutation patterns indicated reduced proliferation and overrepresentation of RUNX1 and IDH2 mutations in the HSC subtype; increased proliferation and overrepresentation of CEBPA mutations in the MEP subtype; and innate immune activation and overrepresentation of WT1 mutations in the GMP subtype. We present a differentiation-dependent classification system for AML subtypes with distinct pathogenetic and prognostic importance that can help identify candidates poorly responding to combination chemotherapy and potentially guide alternative treatments.

Increased risk of osteoporosis following commonly used first-line treatments for lymphoma: a Danish Nationwide Cohort Study.

High-dose prednisolone is used in first-line treatment for lymphoma, but the potential adverse impact on bone health is unclear. Danish patients with diffuse large B-cell lymphoma or follicular lymphoma diagnosed between 2000 and 2012 were matched to the background population. Osteoporotic events (osteoporosis treatment or low-energy fracture) were identified using the Danish National Patient Registry and Prescription Registry. In total, 2589 patients and 12,945 controls were included. Lymphoma patients had increased risk of osteoporotic events compared to the matched population (hazard ratio 1.61 [95% confidence interval 1.40;1.84]). The 5- and 10-year cumulative risks of osteoporotic events for lymphoma patients were 10.0% [8.6;11.4] and 16.3% [13.8;18.7], whereas corresponding risks in the background population were 6.8% [6.3;7.3] and 13.5% [12.4;14.6]. Patients without osteoporotic event in the first two years after treatment were not at higher risk of osteoporotic events in subsequent years. Risk factors for osteoporotic events were female sex and age >70 years.

Development of a Precision Medicine Workflow in Hematological Cancers, Aalborg University Hospital, Denmark.

Within recent years, many precision cancer medicine initiatives have been developed. Most of these have focused on solid cancers, while the potential of precision medicine for patients with hematological malignancies, especially in the relapse situation, are less elucidated. Here, we present a demographic unbiased and observational prospective study at Aalborg University Hospital Denmark, referral site for 10% of the Danish population. We developed a hematological precision medicine workflow based on sequencing analysis of whole exome tumor DNA and RNA. All steps involved are outlined in detail, illustrating how the developed workflow can provide relevant molecular information to multidisciplinary teams. A group of 174 hematological patients with progressive disease or relapse was included in a non-interventional and population-based study, of which 92 patient samples were sequenced. Based on analysis of small nucleotide variants, copy number variants, and fusion transcripts, we found variants with potential and strong clinical relevance in 62% and 9.5% of the patients, respectively. The most frequently mutated genes in individual disease entities were in concordance with previous studies. We did not find tumor mutational burden or micro satellite instability to be informative in our hematologic patient cohort.

Aspects of vincristine-induced neuropathy in hematologic malignancies: a systematic review.

PURPOSE: Vincristine is widely used as anticancer therapy for a variety of hematological malignancies. The treatment is limited by progressive vincristine-induced neuropathy, possibly including both peripheral sensory and motor nerves, autonomic nervous functions, and the central nervous system. This dose-limiting side-effect can diminish quality of life and, furthermore, cause discontinuation of vincristine treatment. The present review elucidates the current knowledge regarding vincristine-induced neuropathy in hematologic malignancies, focusing on neuropathy assessment, clinical and molecular predictive markers, drug-drug interference, prevention, and treatment. METHODS: This review is conducted by a systematic search strategy for the identification of relevant literature in the PubMed and Embase databases. RESULTS: No clinical parameters displayed convincing potential as predictors of vincristine-induced neuropathy; however, preexisting neuropathy was consistently reported to be associated with an increased risk of neurotoxicity. In contrast, molecular markers, including polymorphisms in genes involved in the pharmacodynamics and pharmacokinetics of vincristine, displayed great potential as predictive markers of neuropathy incidence and severity. Furthermore, antifungal drugs, such as itraconazole and voriconazole, decrease the metabolism of vincristine and consequently lead to severe neuropathy when co-administered with vincristine, underscoring why fluconazole should be the antifungal drug of choice. CONCLUSION: Reports from the 71 included studies clearly emphasize the lack of consistency in neuropathy assessment, grading systems, and reporting, making it difficult to interpret results between studies. Thus, truer clinical and molecular markers could emerge if the consistency of neuropathy detection and reporting increases by the use of conventional standardized neuropathy assessment tools and grading scales.