The influence of immunodeficiency, disease features, and patient characteristics on survival in plasmablastic lymphoma.

ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes.

Modifiable lifestyle risk factors and survival after diagnosis with multiple myeloma.

BACKGROUND: While remaining incurable, median overall survival for MM now exceeds 5 years. Yet few studies have investigated how modifiable lifestyle factors influence survival. We investigate whether adiposity, diet, alcohol, or smoking are associated with MM-related fatality. RESEARCH DESIGN AND METHODS: We recruited 760 incident cases of MM via cancer registries in two Australian states during 2010-2016. Participants returned questionnaires on health and lifestyle. Follow-up ended in 2020. Flexible parametric survival models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lifestyle exposures and risk of all-cause and MM-specific fatality. RESULTS: Higher pre-diagnosis Alternative Healthy Eating Index (AHEI) scores were associated with reduced MM-specific fatality (per 10-unit score, HR = 0.84, 95%CI = 0.70-0.99). Pre-diagnosis alcohol consumption was inversely associated with MM-specific fatality, compared with nondrinkers (0.1-20 g per day, HR = 0.59, 95%CI = 0.39-0.90; >20 g per day, HR = 0.67, 95%CI = 0.40-1.13). Tobacco smoking was associated with increased all-cause fatality compared with never smoking (former smokers: HR = 1.44, 95%CI = 1.10-1.88; current smokers: HR = 1.30, 95%CI = 0.80-2.10). There was no association between pre-enrollment body mass index (BMI) and MM-specific or all-cause fatality. CONCLUSIONS: Our findings support established recommendations for healthy diets and against smoking. Higher quality diet, as measured by the AHEI, may improve survival post diagnosis with MM.

Painless progressive mononeuritis multiplex secondary to AML associated neuroleukemiosis.

Neuroleukemiosis describes peripheral nerve involvement secondary to leukemic infiltration, a rare complication of leukemia with various clinical presentations, leading to diagnostic challenges for hematologists and neurologists. We present two cases of painless progressive mononeuritis multiplex secondary to neuroleukemiosis. A literature review of previously reported cases of neuroleukemiosis was undertaken. Neuroleukemiosis may present as a progressive mononeuritis multiplex. The diagnosis of neuroleukemiosis requires a high index of suspicion and be aided by repeated CSF analysis.

A phase 1, open-label, randomized drug-drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies.

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib.

Real-world efficacy and safety outcomes of imatinib treatment in patients with chronic myeloid leukemia: An Australian experience.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. To investigate the real-world use and outcomes of imatinib in patients with CML in Australia, a retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, and survival and molecular response were evaluated. 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32%-53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92%-100%) and 81% (95% CI, 72%-92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50%-73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. In conclusion, imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Development and implementation of venous thromboembolism stewardship across a hospital network.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of preventable death in hospital. Ensuring all hospitalized patients are assessed for VTE risk and given appropriate prophylaxis can reduce the burden of VTE on patients and the healthcare system. This is the first study to explore the effectiveness of a VTE stewardship program using electronic clinical decision support (eCDS) to provide oversight of hospital initiatives to prevent VTE. AIM: To determine if a VTE stewardship program can increase risk-appropriate VTE prophylaxis, VTE risk assessment using eCDS, any documented risk assessment and risk assessment within 24 h of admission, plus reduce the incidence of hospital acquired VTE (HA-VTE). METHODS: Education, daily medication chart auditing, weekly clinician performance feedback, health promotion and gamification were deployed over 6 months by two multidisciplinary VTE stewardship teams across four hospitals. Service impact was assessed through cross-sectional audits of electronic medical records every 3 months and review of HA-VTE events pre- and post-intervention. Implementation costs were calculated. RESULTS: A total of 1622 patients were audited in separate cohorts at baseline, 3, 6 and 9 months. There was significant improvement in the prescription of appropriate prophylaxis (78%, 83%, 84%, and 88%, p = 0.004), VTE risk assessment using the eCDS tool (20%, 50%, 81% and 87%, p < 0.001), any documented risk assessment (71%, 82%, 95% and 93%, p < 0.001) and any documented risk assessment within 24 h of admission (54%, 56%, 65% and 63%, p = 0.001). Use of eCDS was associated with prescription of risk-appropriate VTE prophylaxis (p < 0.001). Annual incidence of HA-VTE decreased from 7.88 to 6.99 events per 10,000 discharges pre- to post-intervention (Odds Ratio (OR) 0.89, 95 %CI 0.66-1.18, p = 0.43). The cost of implementing the program across 133,078 episodes of care during the study period was AUD$108,167 (mean cost of $0.82 per patient).

Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukemia.

Retrotransposons such as LINE-1 and Alu comprise >25% of the human genome. While global hypomethylation of these elements has been widely reported in solid tumours, their epigenetic dysregulation is yet to be characterised in chronic lymphocytic leukaemia, and there has been scant consideration of their evolutionary history that mediates sensitivity to hypomethylation. Here, we developed an approach for locus- and evolutionary subfamily-specific analysis of retrotransposons using the Illumina Infinium Human Methylation 450K microarray platform, which we applied to publicly-available datasets from chronic lymphocytic leukaemia and other haematological malignancies. We identified 9,797 microarray probes mapping to 117 LINE-1 subfamilies and 13,130 mapping to 37 Alu subfamilies. Of these, 10,782 were differentially methylated (PFDR<0.05) in chronic lymphocytic leukaemia patients (n=139) compared with healthy individuals (n=14), with enrichment at enhancers (p=0.002). Differential methylation was associated with evolutionary age of LINE-1 (r2=0.31, p=0.003) and Alu (r2=0.74, p=0.002) elements, with greater hypomethylation of older subfamilies (L1M, AluJ). Locus-specific hypomethylation was associated with differential expression of proximal genes, including DCLK2, HK1, ILRUN, TANK, TBCD, TNFRSF1B and TXNRD2, with higher expression of DCLK2 and TNFRSF1B associated with reduced patient survival. Hypomethylation at nine loci was highly frequent in chronic lymphocytic leukaemia (>90% patients) but not observed in healthy individuals or other leukaemias, and was detectable in blood samples taken prior to chronic lymphocytic leukaemia diagnosis in 9 of 82 individuals from the Melbourne Collaborative Cohort Study. Our results demonstrate differential methylation of retrotransposons in chronic lymphocytic leukaemia by their evolutionary heritage that modulates expression of proximal genes.

Methylation alteration of SHANK1 as a predictive, diagnostic and prognostic biomarker for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the clonal expansion of malignant B cells. To predict the clinical course of the disease, the identification of diagnostic biomarkers is urgently needed. Aberrant methylation patterns may predict CLL development and its course, being very early changes during carcinogenesis. Our aim was to identify CLL specific methylation patterns and to evaluate whether methylation aberrations in selected genes are associated with changes in gene expression. Here, by performing a genome-wide methylation analysis, we identified several CLL-specific methylation alterations. We focused on the most altered one, at a CpG island located in the body of SHANK1 gene, in our CLL cases compared to healthy controls. This methylation alteration was successfully validated in a larger cohort including 139 CLL and 20 control in silico samples. We also found a positive correlation between SHANK1 methylation level and absolute lymphocyte count, in particular CD19+ B cells, in CLL patients. Moreover, we were able to detect gains of methylation at SHANK1 in blood samples collected years prior to diagnosis. Overall, our results suggest methylation alteration at this SHANK1 CpG island as a biomarker for risk and diagnosis of CLL, and also in the personalized quantification of tumor aggressiveness.

The Use of Optimal Treatment for DLBCL Is Improving in All Age Groups and Is a Key Factor in Overall Survival, but Non-Clinical Factors Influence Treatment.

INTRODUCTION: Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma for which a cure is usually the therapeutic goal of optimal treatment. Using a large population-based cohort we sought to examine the factors associated with optimal DLBCL treatment and survival. METHODS: DLBCL cases were identified through the population-based Victorian Cancer Registry, capturing new diagnoses for two time periods: 2008-2009 and 2012-2013. Treatment was pre-emptively classified as 'optimal' or 'suboptimal', according to compliance with current treatment guidelines. Univariable and multivariable logistic regression models were fitted to determine factors associated with treatment and survival. RESULTS: Altogether, 1442 DLBCL cases were included. Based on multivariable analysis, delivery of optimal treatment was less likely for those aged ≥80 years (p < 0.001), women (p = 0.012), those with medical comorbidity (p < 0.001), those treated in a non-metropolitan hospital (p = 0.02) and those who were ex-smokers (p = 0.02). Delivery of optimal treatment increased between 2008-2009 and the 2012-2013 (from 60% to 79%, p < 0.001). Delivery of optimal treatment was independently associated with a lower risk of death (hazard ratio (HR) = 0.60 (95% confidence interval (CI) 0.45-0.81), p = 0.001). CONCLUSION: Delivery of optimal treatment for DLBCL is associated with hospital location and category, highlighting possible demographic variation in treatment patterns. Together with an increase in the proportion of patients receiving optimal treatment in the more recent time period, this suggests that treatment decisions in DLBCL may be subject to non-clinical influences, which may have implications when evaluating equity of treatment access. The positive association with survival emphasizes the importance of delivering optimal treatment in DLBCL.

Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.

Characteristics of older people in an inpatient haematology unit: A descriptive study.

OBJECTIVE: To characterise older inpatients in a haematology unit. METHODS: Hospital case-mix data of haematology separations of all ages (n = 7419) and more extensive data restricted to older patients (age ≥75 years, n = 1025) were evaluated. RESULTS: From 2000 to 2014, there was a 200% increase in those aged ≥85 years who were more likely to have a geriatric syndrome as the principal diagnosis (P < 0.05), have delirium (P < 0.05), receive less intensive treatment (P < 0.001) and be discharged to a nursing home (P < 0.001). Compared to younger inpatients, those aged ≥75 years were more likely to be emergency admissions (48% vs 37%, P < 0.001) and die during the admission (8% vs 4%, P < 0.001). CONCLUSION: Haematologists care for older inpatients who are complex with multidisciplinary health service needs. There may be value in conducting comprehensive geriatric assessments in this setting.

Distress and unmet needs during treatment and quality of life in early cancer survivorship: A longitudinal study of haematological cancer patients.

OBJECTIVE: To examine the influence of anxiety, depression and unmet supportive care needs on future quality of life (QoL) in multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) patients. METHODS: Multiple myeloma and DLBCL patients recruited through the population-based Victorian Cancer Registry. Data were collected through two telephone interviews: (T1) on average 7 months postdiagnosis, (T2) average 8 months later. QoL was examined at T2 using the Functional Assessment of Cancer Therapy (FACT-G) scale. The Hospital Anxiety and Depression Scale measured anxiety and depression, and the Supportive Care Needs Survey measured unmet needs at T1. Multivariate linear regression examined associations between QoL subscales (physical, emotional, social and functional well-being and overall QoL) and T1 anxiety, depression and unmet needs. RESULTS: Except physical well-being, all other QoL subscales and overall QoL were significantly associated with T1 anxiety. All QoL subscales and overall QoL were significantly associated with T1 depression. Only patient care needs were associated with physical and social well-being and overall QoL. CONCLUSION: Anxiety, depression and patient care unmet needs during treatment are associated with diminished physical and emotional well-being in the following months. Psychological distress and unmet supportive care needs experienced during treatment should be addressed to maximise future QoL.

Global measures of peripheral blood-derived DNA methylation as a risk factor in the development of mature B-cell neoplasms.

AIM: To examine whether peripheral blood methylation is associated with risk of developing mature B-cell neoplasms (MBCNs). MATERIALS & METHODS: We conducted a case-control study nested within a large prospective cohort. Peripheral blood was collected from healthy participants. Cases of MBCN were identified by linkage to cancer registries. Methylation was measured using the Infinium(®) HumanMethylation450. RESULTS: During a median of 10.6-year follow-up, 438 MBCN cases were evaluated. Global hypomethylation was associated with increased risk of MBCN (odds ratio: 2.27, [95% CI: 1.59-3.25]). Within high CpG promoter regions, hypermethylation was associated with increased risk (odds ratio: 1.76 [95% CI: 1.25-2.48]). Promoter hypermethylation was observed in HOXA9 and CDH1 genes. CONCLUSION: Aberrant global DNA methylation is detectable in peripheral blood collected years before diagnosis and is associated with increased risk of MBCN, suggesting changes to DNA methylation are an early event in MBCN development.

Low uptake of upfront autologous transplantation for myeloma in a jurisdiction with universal health care coverage: a population-based patterns of care study in Australia.

BACKGROUND: Guidelines for the management of symptomatic multiple myeloma (MM) recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible patients. PATIENTS AND METHODS: Using population-based data, we examined the characteristics of transplant-eligible patients who do not undergo upfront ASCT. Altogether, 686 newly diagnosed MM cases were identified through the population-based central cancer registry in Victoria, Australia from 2008 to 2009. We performed a detailed review of clinical notes and follow-up for at least 12 months after diagnosis for a subset of 225 patients who were aged < 70 years at diagnosis and had symptomatic MM. RESULTS: Of these 225 patients, 123 (55%) proceeded to receive upfront ASCT. Patient and disease factors associated with not receiving upfront ASCT were the presence of severe medical comorbidities, MM-associated renal impairment, and initial referral to a medical oncologist rather than a hematologist. Place of residence (rural vs. metropolitan) was not significant. Of 121 patients aged < 65 years at diagnosis who had minor or no comorbidities, only 75 (62%) proceeded to upfront ASCT. CONCLUSION: A substantial percentage of apparently transplant-eligible patients with newly diagnosed MM do not proceed to upfront ASCT. Community practice appears to diverge from clinical guidelines. The reasons for this divergence require further study but reasons may include perceptions of toxicity vs. benefits of upfront ASCT.