Risk of Incident Diabetes and Dysregulated Pre-Existing Diabetes Mellitus in Newly Diagnosed Lymphoma Patients Treated with Steroid-Containing Immunochemotherapy: A Danish Population-Based Study

Introduction Prednisolone has important potential side-effects, one of which is steroid-induced diabetes mellitus (DM). Due to the exposure to a high cumulative dosage of steroids during first-line treatment, patients with non-Hodgkin lymphoma (NHL) could face increased risk of new onset steroid-induced DM or dysregulation of a pre-existing DM. This nationwide observational cohort study evaluated the risk of new onset DM in lymphoma patients and the impact on pre-existing DM in lymphoma survivors following treatment with steroid-containing regimens. Methods Adult NHL patients (≥18 years) treated with ≥3 cycles of steroid-containing immunochemotherapy, such as R-CHOP(-like) and R-CVP, between 2002 and 2015 were identified in the Danish Lymphoma Register and matched to five random individuals from the general population on birth year, sex, Charlson Comorbidity Index score, baseline DM status (DM or not), and DM duration. NHL patients and matched comparators were followed from start of treatment for the patients until the event of interest (DM, insulin prescription), death, relapse, NHL diagnosis (for matched comparators), or censoring (emigration, missing, or end of study on 31 December 2018), whichever came first. DM was captured by either a diagnosis of any DM (ICD-10 codes: E10-E14) in the Danish National Patient Register or any redeemed anti-diabetic prescription registered in the National Prescription Register (insulin or oral anti-diabetic medicine; ATC A10A or A10B). In the analysis of insulin prescriptions following lymphoma treatment initiation, patients with any redeemed prescription of insulin prior to start of lymphoma treatment were excluded. Time-varying incidence rates (IRs) per 1,000 person years and incidence rate ratios (IRRs) with 95% confidence intervals were estimated using a spline-based Poisson regression approach with two-month time splits and five knots. The Aalen-Johansen estimator was used to compute the cumulative risk of an event treating death, relapse, and NHL diagnosis (in comparators) as competing events. Risk differences at specific time points were calculated using pseudo-observations. Crude and adjusted cause-specific hazard ratios (HR) were obtained using Cox regression. Results A total of 4,703 NHL patients were included in the present study. Median age was 66 years and median follow-up was 8.5 years. Among the NHL patients, 4,325 patients did not have pre-existing DM and were matched to 21,625 comparators without DM. The time-varying IR of DM among comparators was 8-10 cases/1000 person years. The IRR of DM for patients vs comparators was higher for patients in the first year following treatment initiation (maximum IRR: 2.40), lower from 1 to 5 years (minimum IRR: 0.52), and higher from 5 to 10 years (maximum IRR: 1.18) (Fig. 1). The cumulative incidence of DM was higher for NHL patients at six months (0.58 percentage units (%U), p <0.01), but lower at 5 years (-1.17%U, p <0.01) and 10 years (-2.09%U, p <0.01) compared to the matched comparators (p <0.01 for the whole period, Fig. 2). Among the NHL patients, 378 had pre-existing non-insulin dependent DM and were matched to 1,890 comparators. The cumulative incidence difference of any insulin use was higher for patients at 6 months (14.29%U, p <0.01), 5 years (9.95%U, p <0.01), and 10 years (4.61%U, p =0.15) (p <0.01 for the whole period, Fig. 3). However, when events were limited ≥5 prescriptions of insulin, no difference was found (p =0.84 for the whole period). The crude HR for ≥5 prescriptions of insulin was 1.42 [1.10;183] for patients compared to the matched comparators and the HR adjusted for sex, age, and comorbidities was 1.39 [1.08;1.79]. Conclusion In conclusion, patients treated with steroid-containing immunochemotherapy did not experience a higher risk of diabetes mellitus compared to matched comparators beyond the first year. Matched comparators had a higher cumulative incidence of diabetes mellitus after 2 years, which was partly explained by the high competing risk of death in the patient group. NHL patients with pre-existing non-insulin dependent diabetes mellitus had an increased cumulative incidence of any insulin prescriptions; however, the difference was diminished when assessing the risk of at least five insulin prescriptions, suggesting that the impact of steroids on diabetes regulation is limited in time when taking competing risks into account. Figure 1 Figure 1. Disclosures Øvlisen: Abbvie: Other: Travel expenses. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Vestergaard: Novo Nordisk Foundation: Other: Head of Research at Steno Diabetes Center North Jutland funded by the Novo Nordisk Foundation, Research Funding. Jørgensen: Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy; Celgene: Consultancy. Clausen: Gilead: Consultancy, Other: Travel expences 15th ICML ; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee.

A Decade of Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: Does the Outcome Improve?

To investigate the potential treatment evolution and outcome improvement, we retrospectively compared clinical characteristics, therapeutic strategies, treatment responses, and overall survival (OS) in patients diagnosed and treated with lymphoma-associated HLH between 2004–2012 (n = 30) and 2013–2021 (n = 26). Our study showed that the clinical characteristics of lymphoma-associated HLH did not substantially change over the past two decades. However, more patients diagnosed in 2013–2021 were tested for Epstein–Barr virus than those diagnosed in 2004–2012 (69.3% vs. 33.3%; p = 0.021). In addition, Eastern Cooperative Oncology Group performance status 3–4 (hazard ratio (HR): 5.38; 95% confidence intervals (CI): 2.49–11.61; p < 0.001) and jaundice (HR: 2.91; 95% CI: 1.37–6.18; p = 0.006) were poor prognostic factors for lymphoma-associated HLH. With a comparable response rate of lymphoma treatment, patients treated in 2013–2021 had a numerically greater median OS than those treated in 2004–2012 (23.6 ± 19.8 vs. 9.7 ± 4.5 months). However, the difference was not statistically significant (p = 0.334). In conclusion, early diagnosis and tailored treatments that balance efficacy and adverse events remain the key to obtaining a better outcome in lymphoma-associated HLH.

A prognostic model for patients with lymphoma and COVID-19: a multicentre cohort study

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behaviour and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not admitted cohort, n=388), or required hospitalization (n=468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95%CI 11-15%) and 23% (95%CI 20-27%), respectively. Anti-lymphoma treatment, including anti-CD20 containing regimens, did not impact on survival. Patients with Hodgkin's lymphoma had the more favourable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment for their underlying disease, and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Primary leptomeningeal lymphoma masquerading as infectious tubercular meningitis

Primary central nervous system lymphoma (PCNSL) is infrequent and often poses diagnostic conundrums due to its protean manifestations. We present the case of a South Asian young man presenting with raised intracranial pressure and a lymphocytic cerebrospinal fluid (CSF) with pronounced hypoglycorrhachia. Progression of the neuro-ophthalmic signs while on early stages of antitubercular treatment led to additional investigations that produced a final diagnosis of primary leptomeningeal lymphoma. Treatment with chemoimmunotherapy (methotrexate, cytarabine, thiotepa and rituximab (MATRix)) achieved full radiological remission followed by successful autologous transplant. This case highlights the difficulties and diagnostic dilemmas when PCNSL presents as a chronic meningeal infiltrative process. While contextually this CSF is most often indicative of central nervous system tuberculosis and justifies empirical treatment initiation alone, it is essential to include differential diagnoses in the investigation work-up, which also carry poor prognosis without timely treatment. High suspicion, multidisciplinary collaboration and appropriate CSF analysis were the key for a correct diagnosis.