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Despite an increasing desire to use historical cohorts as “synthetic” controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012–2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty‐six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26‐78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2‐year progression‐free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2‐year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation. Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. In this multicenter retrospective study of 26 patients, the estimated 2‐year overall survival rate was 80%. Outcomes appear favorable, particularly among the subset of patients with primary dural presentation.

Purpose We report that hemodialysis clears Ara-U from the blood after high-dose Ara-C treatment in a patient with lymphoma and end-stage renal failure. Methods The patient received two doses of Ara-C 1 g/m 2 24 h apart and was hemodialyzed at about 6 h after each dose and subsequently as per her usual dialysis schedule. Multiple blood samples were collected after dosing. Blood and dialyzate were also collected from the dialysis circuit during a second identical treatment cycle. Ara-C and its metabolite Ara-U in plasma and dialyzate were measured chromatographically, and the data subjected to pharmacokinetic analysis. Results The distribution and elimination half-lives, steady-state volume of distribution and clearance values were 0.5 h, 7 h, 181 L and 307 l/h for Ara-C and 4.1 h, 34 h, 118 L and 2.64 l/h for Ara-U, respectively. The dialysis sessions immediately after the first and second doses cleared 39 and 52% (as Ara-U) of the respective Ara-C doses. Some 63% of Ara-U in plasma was extracted by dialysis. The patient showed no signs of neurotoxicity or other drug-related adverse effects. Conclusion Hemodialysis is very effective in clearing Ara-U from the plasma in renal failure, and this maneuver could easily be used routinely to prevent Ara-U accumulation and minimize adverse effects in patients with renal failure.

The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood–brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma. This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18–70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group–WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m2 on days 1 and 15, intravenous carmustine 100 mg per m2 on day 4, intravenous teniposide 100 mg per m2 on days 2 and 3, and oral prednisone 60 mg per m2 on days 1–5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m2 on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing. Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55–67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9–51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39–58) in the MBVP group (no rituximab) and 52% (42–61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70–1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes. We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma. Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren.

The role of HAT-PCR (High A/T or High Annealing Temperature–PCR) in the quantification of minimal residual disease (MRD) was investigated in chronic lymphocytic leukemia (CLL) and myeloma. The IGH gene sequence was determined by next-generation sequencing (NGS), either by the Lymphotrack kit or by preparing libraries using an in-house two-round PCR protocol which enabled successful sequencing in 37/37 CLL marrow samples and 34/35 myeloma marrow samples. MRD was quantified by HAT-PCR in 125 CLL marrow or blood samples from 36 patients, with 2 results being less than 10−6 and in 63 myeloma marrow samples from 35 patients, with 10 results being less than 10−6. Measurement of MRD in 113 pairs of CLL samples and 51 pairs of myeloma samples showed that HAT-PCR was significantly more sensitive than flow. Compared to marrow MRD, blood MRD was relatively high in CLL but very low or undetectable in myeloma. Flow-positive HAT-PCR negative samples were not seen in myeloma, although the literature review suggested that flow-positive NGS-negative myeloma samples are sometimes observed. The ability of HAT-PCR to quantify down to and below 10−6 and the practical advantages of PCR suggest that HAT-PCR could be used widely for the quantification of MRD in lymphoid malignancy.

Background Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6 th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly diverse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and other research activities. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process. Methods The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre. Results To date more than 5,300 patients have been enrolled from 28 sites in Australia and New Zealand. Multiple challenges arose during the development, which we describe, along with approaches used to overcome them. Several confirmed international collaborations are now in place, and the registry is providing valuable data for clinicians, researchers, industry and government, including through presentations of results at major national and international conferences. Conclusion Challenges in establishing the LaRDR have been successfully overcome and the registry is now a valuable resource for lymphoma clinicians, researchers, health economists and others in Australia, New Zealand and globally.

A 75-year-old man with stage IV chronic kidney disease due to type 2 diabetes mellitus, presented with increasing proteinuria and rapidly declining renal function despite excellent glycaemic control. Investigations organised to assess his suitability for renal transplantation included an abdominal CT scan, which revealed extensive intra-abdominal lymphadenopathy. A 17fluorodeoxyglucose (FDG)-positron emission tomography scan to further characterise the lymphadenopathy demonstrated activity in the lymph nodes, as well as both kidneys. Following a lymph node biopsy and flow cytometry he was diagnosed with a marginal zone lymphoma. A subsequent kidney biopsy confirmed lymphomatous infiltration of the kidney. Marginal zone lymphoma is an uncommon type of non-Hodgkin's lymphoma, and renal involvement is rare. This case highlights the importance of considering alternative diagnoses when there is deviation from the expected clinical trajectory and the importance of liaising with colleagues in other disciplines to enable an accurate diagnosis to be made.

Background Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. Objective The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. Methods Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. Results CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. Conclusion This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients.