Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

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.

Diagnosis, management and follow up of peripheral T-cell lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance.

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

COVID-19 vaccination in haematology patients: an Australian and New Zealand consensus position statement.

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high-efficacy COVID-19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID-19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID-19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority.

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.

A multicenter retrospective comparison of induction chemoimmunotherapy regimens on outcomes in transplant-eligible patients with previously untreated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P > .67), or overall survival (OS) (P > .35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.

Defining the clonality of peripheral T cell lymphomas using RNA-seq.

Motivation: In T-cell lymphoma, malignant T cells arising from a founding clone share an identical T cell receptor (TCR) and can be identified by the over-representation of this TCR relative to TCRs from the patient's repertoire of normal T cells. Here, we demonstrate that TCR information extracted from RNA-seq data can provide a higher resolution view of peripheral T cell lymphomas (PTCLs) than that provided by conventional methods. Results: For 60 subjects with PTCL, flow cytometry/FACS was used to identify and sort aberrant T cell populations from diagnostic lymph node cell suspensions. For samples that did not appear to contain aberrant T cell populations, T helper (T H ), T follicular helper (T FH ) and cytotoxic T lymphocyte (CTL) subsets were sorted. RNA-seq was performed on sorted T cell populations, and TCR alpha and beta chain sequences were extracted and quantified directly from the RNA-seq data. 96% of the immunophenotypically aberrant samples had a dominant T cell clone readily identifiable by RNA-seq. Of the samples where no aberrant population was found by flow cytometry, 80% had a dominant clone by RNA-seq. This demonstrates the increased sensitivity and diagnostic ability of RNA-seq over flow cytometry and shows that the presence of a normal immunophenotype does not exclude clonality. Availability and Implementation: R scripts used in the processing of the data are available online at https://www.github.com/scottdbrown/RNAseq-TcellClonality. Contacts: rholt@bcgsc.ca or ksavage@bccancer.bc.ca. Supplementary information: Supplementary data are available at Bioinformatics online.

Relative survival of patients with lymphoma in Queensland according to histological subtype.

OBJECTIVE: To evaluate relative survival of patients in Queensland with different lymphoma subtypes; to determine whether outcomes have improved with recent changes in treatment; to evaluate relative survival according to place of residence and socio-economic status. DESIGN: Retrospective population-based study; analysis of data from the Oncology Analysis System, an online reporting tool for cancer incidence and outcomes in Queensland. PARTICIPANTS: Patients over 15 years of age diagnosed with lymphoma in Queensland during 1993-2012. MAIN OUTCOME MEASURES: Relative survival by lymphoma subtype; influence of place of residence and socio-economic status, age group, sex, year of diagnosis (in 5-year bands), and Pharmaceutical Benefits Scheme funding of rituximab for treating B-cell lymphomas on relative survival. RESULTS: 9509 people (56% men) were diagnosed with lymphoma during 1993-2012. Five-year relative survival improved significantly between 1993-1997 and 2008-2012 for patients with diffuse large B-cell lymphoma (47%; 95% CI, 42-51% v 64%; 95% CI, 61-67%) or follicular lymphoma (62%; 95% CI, 57-66% v 88%; 95% CI, 85-90%; each P < 0.001). Rituximab became available for treating these subtypes during 2003-2006. There was no change in relative survival for patients with Hodgkin lymphoma (81%; 95% CI, 76-85% v 80%; 95% CI, 75-84%; P = 0.22). The only statistically significant difference according to place of residence or socio-economic status was inferior relative survival for rural residents with diffuse large B-cell lymphoma (hazard ratio, 1.14; 95% CI, 1.01-1.28). CONCLUSION: Relative survival for patients with B-cell non-Hodgkin lymphoma improved significantly with the introduction of rituximab as first-line therapy in Australia.

Outcome of primary cutaneous anaplastic large cell lymphoma: a 20-year British Columbia Cancer Agency experience.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare CD30+ lymphoproliferative disorder with excellent outcomes reported despite frequent cutaneous relapses. Limited information exists on the development of systemic lymphoma. The British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify all adults diagnosed with PCALCL from 1993 to 2013. From 2005, the BCCA endorsed radiotherapy (RT) alone for limited stage with data failing to support chemotherapy. Forty-seven patients were identified with a male predominance (n = 31, 66%), median age of 64 years and predominantly limited stage (n = 40, 85%). Median follow-up was 8·4 years. The 5-year time to progression (TTP) was 58% (64% limited versus 29% advanced stage). The 5-year disease-specific survival (DSS) and overall survival was 86% and 75%, respectively. In an as-treated analysis, the 5-year DSS for limited stage patients was similar comparing RT to combined modality treatment or chemotherapy alone but the 5-year TTP favoured RT (82% vs. 33%, P = 0·004). The 5-year cumulative risk of developing systemic lymphoma was 14%. Our results confirm the favourable prognosis of PCALCL despite a high relapse rate. Limited stage patients treated with RT alone have excellent outcomes. There is a small risk of systemic lymphoma in PCALCL.

The biology and management of systemic anaplastic large cell lymphoma.

Systemic anaplastic large cell lymphoma (ALCL) is an aggressive CD30(+) non-Hodgkin lymphoma. Anaplastic lymphoma kinase-positive (ALK+) ALCL is associated with the NPM-ALK t(2;5) translocation, which is highly correlated with the identification of the ALK protein by immunohistochemistry. ALK+ ALCL typically occurs in younger patients and has a more favorable prognosis with 5-year survival rates of 70% to 90% in comparison with 40% to 60% for ALK-negative (ALK-) ALCL. Studies support young age as a strong component of the favorable prognosis of ALK+ ALCL. Until recently, no recurrent translocations were identified in ALK- ALCL. However, emerging data now highlight that ALK- ALCL is genetically and clinically heterogeneous with a subset having either a DUSP22 translocation and a survival rate similar to ALK+ ALCL or a less common P63 translocation, the latter associated with an aggressive course. Anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment choice for systemic ALCL, but in many patients with ALK- ALCL, it is ineffective, and thus it is often followed by consolidative autologous stem cell transplantation. However, selection of appropriate patients for intensified therapy remains challenging, particularly in light of genetic and clinical heterogeneity in addition to the emergence of new, effective therapies. The antibody drug conjugate brentuximab vedotin is associated with a high response rate (86%) and durable remissions in relapsed/refractory ALCL and is under investigation in the first-line setting. In the future, combining clinical and genetic biomarkers may aid in risk stratification and help guide initial patient management.

Diagnostic performance of prospective same-day 18F-FDG PET/MRI and 18F-FDG PET/CT in the staging and response assessment of lymphoma.

BACKGROUND: Accurate staging and response assessment are essential for prognosis and to guide treatment in patients with lymphoma. The aim of this study was to compare the diagnostic performance of FDG PET/MRI versus FDG PET/CT in adult patients with newly diagnosed Hodgkin and Non- Hodgkin lymphoma. METHODS: In this single centre study, 50 patients were prospectively recruited. FDG PET/MRI was performed after staging FDG PET/CT using a single injection of 18F-FDG. Patients were invited to complete same-day FDG PET/MRI with FDG PET/CT at interim and end of treatment response assessments. Performance was assessed using PET/CT as the reference standard for disease site identification, staging, response assessment with Deauville score and concordance in metabolic activity. RESULTS: Staging assessment showed perfect agreement (κ = 1.0, P = 0) between PET/MRI and PET/CT using Ann Arbor staging. There was excellent intermodality correlation with disease site identification at staging (κ = 0.976, P < 0.001) with FDG PET/MRI sensitivity of 96% (95% CI, 94-98%) and specificity of 100% (95% CI, 99-100%). There was good correlation of disease site identification at interim assessment (κ = 0.819, P < 0.001) and excellent correlation at end-of-treatment assessment (κ = 1.0, P < 0.001). Intermodality agreement for Deauville scores was good at interim assessment (κ = 0.808, P < 0.001) and excellent at end-of-treatment assessment (κ = 1.0, P = 0). There was good-excellent concordance in SUV max and mean between modalities across timepoints. Minimum calculated radiation patient effective dose saving was 54% between the two modalities per scan. CONCLUSION: With high concordance in disease site identification, staging and response assessment, PET/MR is a potentially viable alternative to PET/CT in lymphoma that minimises radiation exposure.

The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network.

The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP) (#NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. One hundred twenty-seven patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60 years, elevated LDH and low serum albumin were independent prognostic factors. The model identified 3 groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-year OS of 78% (95% confidence interval [95% CI], 29-127), 46% (95% CI, 24-68), and 25% (95% CI, 20-30), respectively (P < 0.001) and 5-year PFS of 66% (95% CI, 33-99), 37% (95% CI, 9-65), and 17% (95% CI, 9-25), respectively (P < 0.001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the 3 groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T-Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

A cost-effectiveness analysis of front-line treatment strategies in early-stage follicular lymphoma.

Recent data suggest the use of radiotherapy alone (RT) in Early-Stage Follicular Lymphoma is declining. Cost-effectiveness analysis of treatments has not been performed. We constructed a partitioning model (15-year horizon) to compare RT, combined-modality therapy (CMT) and immunochemotherapy with rituximab maintenance (ICT + RM) from a PET-staged cohort from the Australian Lymphoma Alliance. Lifetime direct health care costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. AUD $75,000 was defined as the willingness-to-pay threshold (WTP). The direct healthcare costs were: RT $12,791, CMT $29,391 and ICT + RM $42,644. Compared with RT, CMT demonstrated minimal improvement in QALYs (+0.01) and an ICER well above the WTP threshold ($1,535,488). Compared with RT, ICT + RM demonstrated an improvement in QALYs (+0.41) with an ICER of $73,319. Modeling a 25% cost reduction with a rituximab biosimilar led to further ICER reductions with ICT + RM ($52,476). ICT + RM is cost-effective in early-stage FL from the Australian taxpayer perspective.

Management and Outcomes of Diffuse Large B-cell Lymphoma Post-transplant Lymphoproliferative Disorder in the Era of PET and Rituximab: A Multicenter Study From the Australasian Lymphoma Alliance.

There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET) and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immunosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers: median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5-14.5 y). RIS occurred in 88% of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91% versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure rate for patients achieving complete remission with CNS or systemic PTLD.

Trends in myeloma relative survival in Queensland by treatment era, age, place of residence, and socioeconomic status.

Relative survival (RS) in myeloma has improved in younger but not older patients (≥80 years) with treatment advances. Whether place of residence or socioeconomic status (SES) affect RS is unknown. We used the Queensland cancer registry to calculate the five-year RS of myeloma patients diagnosed between 1982 and 2014. This period was divided into three eras: (1) 1982-1995 chemotherapy alone; (2) 1996-2007 autologous stem cell transplantation; (3) 2008-2014 novel agents (proteasome inhibitors and IMIDs). 6025 patients were diagnosed from 1982 to 2014. RS improved across eras: (1) 30% vs. (2) 43% vs. (3) 53% (p < .001 (2) vs. (1); p < .001 (3) vs. (2)). RS improved across all age groups, including patients ≥80 years. Patients with disadvantaged SES (39% vs. affluent 46%; p < .001) and rural patients (40% vs. urban 45%; p < .001) had an inferior RS. RS has improved across all ages with treatment advances.