A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Outcomes in grade 3B follicular lymphoma: an international study led by the Australasian Lymphoma Alliance.

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between 'lowgrade' (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL.

Clinical characteristics of Australian treatment-naïve patients with classical Hodgkin lymphoma from the lymphoma and related diseases registry.

Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real-world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first-line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced-stage disease, and 48% of patients with the early-stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced-stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early-stage disease, and 88% in advanced-stage disease. Early progression-free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.

Alcohol and tobacco use and risk of multiple myeloma: A case-control study.

Multiple myeloma (MM) is the second most common hematological cancer and causes significant mortality and morbidity. Knowledge regarding modifiable risk factors for MM remains limited. This analysis of an Australian population-based case-control family study investigates whether smoking or alcohol consumption is associated with risk of MM and related diseases. Incident cases (n = 789) of MM were recruited via cancer registries in Victoria and New South Wales. Controls (n = 1,113) were either family members of cases (n = 696) or controls recruited for a similarly designed study of renal cancers (n = 417). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional multivariable logistic regression. Heavy intake (>20 g ethanol/day) of alcohol had a lower risk of MM compared with nondrinkers (OR = 0.68, 95% CI: 0.50-0.93), and there was an inverse dose-response relationship for average daily alcohol intake (OR per 10 g ethanol per day = 0.92, 95% CI: 0.86-0.99); there was no evidence of an interaction with sex. There was no evidence of an association with MM risk for smoking-related exposures (p > 0.18). The associations between smoking and alcohol with MM are similar to those with non-Hodgkin lymphoma. Further research into potential underlying mechanisms is warranted.

Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.

Background: We previously investigated the association between 5 "first-generation" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: PhenoAge, GrimAge, and predicted telomere length. Methods: We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models. We also assessed associations by time since blood draw and by cancer subtype, and we investigated potential nonlinearity. Results: We observed relatively strong associations of age-adjusted PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per SD was approximately 1.2-1.3). Similar findings were obtained for age-adjusted GrimAge, but the association with lung cancer risk was much larger (RR per SD = 1.82, 95% confidence interval [CI] = 1.44 to 2.30), after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables. For cancer overall, the comprehensively adjusted rate ratio per SD was 1.13 (95% CI = 1.07 to 1.19) for PhenoAge and 1.12 (95% CI = 1.05 to 1.20) for GrimAge and appeared larger within 5 years of blood draw (RR = 1.29, 95% CI = 1.15 to 1.44 and 1.19, 95% CI = 1.06 to 1.33, respectively). Conclusions: The methylation-based measures PhenoAge and GrimAge may provide insights into the relationship between biological aging and cancer and be useful to predict cancer risk, particularly for lung cancer.

HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

The influence of unmet supportive care needs on anxiety and depression during cancer treatment and beyond: a longitudinal study of survivors of haematological cancers.

OBJECTIVES: This paper aims to examine the cross-sectional and longitudinal associations between patient-reported unmet needs and anxiety and depression for survivors of diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM). METHODS: In a longitudinal study design, self-reported data were collected through telephone interviews at two time points approximately 7 (T1) and 15 (T2) months post-diagnosis. The sample was recruited through the population-based Victorian Cancer Registry. At T1 and T2, the study outcomes, anxiety and depression, were assessed using the Hospital Anxiety and Depression Scale (HADS) and unmet needs were measured using the Supportive Care Needs Survey (SCNS-SF34). Questions related to social/family problems, relationship problems and financial problems were also asked. A three-step multivariable hierarchical logistic regression analysis examined the relative role of T1 anxiety and depression, T1 and T2 unmet needs and other psychosocial factors with T2 anxiety and depression. RESULTS: Both cross-sectional and longitudinal associations were observed between unmet needs and psychological distress. T2 anxiety was associated with T1 anxiety (OR 4.75, 95% CI 1.86-11.09), T2 psychological needs (OR 1.68, 95% CI 1.34-2.11) and with T1 social problems (OR 2.33, 95% CI 1.03-5.05) in multivariate analysis. T2 depression was associated with both T1 (OR 1.28, 95% CI 1.06-1.57) and T2 psychological needs (OR 1.35, 95% CI 1.06-1.70), T2 physical needs (OR 1.89, 95% CI 1.27-2.81) and T1 depression (OR 4.52, 95% CI 1.88-10.86). CONCLUSIONS: Unmet needs that manifest following diagnosis and treatment may persist into early survivorship and contribute to psychological distress. Addressing these needs during treatment may diminish the risk of current and future anxiety and depression.

The course of anxiety, depression and unmet needs in survivors of diffuse large B cell lymphoma and multiple myeloma in the early survivorship period.

PURPOSE: The purpose of the study is to examine the course of anxiety, depression and unmet needs in diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM) survivors in the first 2 years post diagnosis. METHODS: DLBCL and MM survivors, recruited through the Victorian Cancer Registry, completed two interviews approximately 7 and 15 months post diagnosis. Hospital Anxiety and Depression Scale (HADS) and Supportive Care Needs Survey (SCNS-SF34) were completed at both interviews. Primary outcomes were prevalence of anxiety, depression and unmet needs (any or moderate-high). Generalized estimating equation examined whether course of anxiety, depression and unmet needs differed between the two cancers. RESULTS: Overall, 236 DLBCL and 178 MM survivors completed both telephone interviews. Course of anxiety differed (p < 0.01) with rate increasing in DLBCL (14 to 22%) while remaining stable for MM (15 to 12%). Course of depression also differed (p < 0.01), decreasing for MM (22 to 12%) and remaining stable for DLBCL (15 to 16%) survivors. Change in unmet needs was generally similar for the two cancer groups, except for moderate to high psychological needs (p < 0.05). CONCLUSIONS: Patterns of change in anxiety and depression in first 2 years post diagnosis differ for DLBCL and MM survivors. IMPLICATIONS FOR CANCER SURVIVORS: Studying psychological outcomes in mixed haematological cancer samples may be inappropriate, at least in the early survivorship phase. Separate studies of the experiences of people with the different haematological cancer subtypes are needed to ensure psychosocial and supportive care interventions are appropriate to the needs of individuals with different haematological cancers.

Bortezomib with high dose melphalan conditioning for autologous transplant is safe and effective in patients with heavily pretreated and high risk multiple myeloma.

There are no uniform guidelines for the treatment of relapsed refractory multiple myeloma (MM), however autologous stem cell transplant (SCT) remains an important treatment modality. Although a number of modifications to high dose melphalan (HDM) conditioning have been evaluated, improvement in overall survival has not been demonstrated. We now report our experience of 23 patients with heavily pretreated MM (median lines of prior treatment 3 [range 1-6]) who underwent SCT with bortezomib and high dose melphalan (BorHDM). The overall response rate (at least partial response [PR]) was 65.4%. Median overall survival (OS) was 24 months. A subset of patients who relapsed ≤ 12 months after initial SCT had significantly longer OS after BorHDM SCT compared to a historical control group who received HDM conditioning alone (14.5 vs. 8 months, respectively, p = 0.011). In summary, BorHDM SCT produces very good response rates in heavily pretreated MM, and may increase survival in the salvage setting in patients who relapse early after initial SCT. We propose that its use should be explored as part of a tandem approach in patients undergoing initial SCT who are at high risk of early relapse.