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Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3–4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.

Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax–obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions. In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic hospitals in Boston, MA, USA. Eligible patients were aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0–2, and were treatment naive. Patients were treated in 28 day cycles. Acalabrutinib monotherapy was given orally at 100 mg twice daily for cycle 1, then combined for six cycles with intravenous obinutuzumab (100 mg on cycle 2 day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 and on day 1 of cycles 3–7); and from the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Patients continued on acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until day 1 of cycle 16 or day 1 of cycle 25. If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission). The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as <1 chronic lymphocytic leukaemia cell per 10 000 leucocytes as measured by four-colour flow cytometry), at cycle 16 day 1. Safety and activity endpoints were assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT03580928, and is ongoing. Between Aug 2, 2018, and May 23, 2019, 37 patients with chronic lymphocytic leukaemia were enrolled and all received at least one dose of any study drug. The median age of patients was 63 years (IQR 57–70), and ten (27%) were female and 27 (73%) were male. Median follow-up was 27·6 months (IQR 25·1–28·2). At cycle 16 day 1, 14 (38% [95% CI 22–55]) of 37 participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 haematological adverse event was neutropenia (16 [43%] of 37 patients). The most common grade 3–4 non-haematological adverse events were hyperglycaemia (three [8%]) and hypophosphataemia (three [8%]). Serious adverse events occurred in nine (24%) patients; the most common was neutropenia in three (8%) patients. There have been no deaths on study. Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for chronic lymphocytic leukaemia. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib–venetoclax and chemoimmunotherapy in an ongoing phase 3 study (NCT03836261). AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award.

Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4 + T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL. Compared with non-responders, responding patients have more circulating CD4 + naïve and central memory T cells and B cells, as well as more diverse CD4 + T cell and B cell receptor repertoires. Importantly, a population of circulating and tumor-infiltrating IL1β + monocytes/macrophages is detectable in patients with cHL but not healthy donors, and a proinflammatory, tumor-promoting signature of these circulating IL1β + monocytes is associated with resistance to PD-1 blockade in cHL. Altogether, our findings reveal extensive immune rewiring and complementary roles of CD4 + T cells, B cells and IL1β + monocytes in the response to PD-1 blockade and suggest that these features can be captured with a peripheral blood test. Patients with classic Hodgkin lymphoma (cHL) respond well to PD-1 blockade, but the underlying cellular insights are still lacking. Here, the authors use single-cell transcriptome and spatial analyses to identify distinct circulating and tumor-infiltrating CD4 + T cell, B cell and IL1β + monocyte/macrophage features associated with response to PD-1 blockade in cHL.

Background Hepatitis E virus (HEV) is a major public health disease causing large outbreaks and sporadic cases of acute hepatitis. We investigated an outbreak of HEV infection that occurred in September 2018 in the health district (HD) of Bocaranga-Koui, located in the northwestern part of Central African Republic (CAR). Methods Blood samples were collected from 352 patients aged 0–85 years suspected to be infected with yellow fever (YF), according to the World Health Organization YF case definition. The notification forms from recorded cases were used. Water consumed in the HD were also collected. Human samples found negative for anti-YF IgM were then tested by ELISA for anti-HEV IgM and IgG antibodies. Positive anti-HEV (IgM and/or IgG) samples and collected water were then subjected to molecular biology tests using a real time RT-PCR assay, followed by a nested RT-PCR assay for sequencing and phylogenetic analysis. Results Of the 352 icterus patients included, anti-HEV IgM was found in 142 people (40.3%) and anti-HEV IgG in 175 (49.7%). Although HEV infection was detected in all age groups, there was a significant difference between the 0–10 age groups and others age groups ( P  = 0.001). Elevated levels of serum aminotransferase were observed in anti-HEV IgM-positive subjects. Phylogenetic analysis showed HEV genotype 1e in infected patients as well as in the contaminated water. Conclusion This epidemic showed that CAR remains an HEV-endemic area. The genotype 1e strain was responsible for the HEV outbreak in Bocaranga-Koui HD. It is necessary to implement basic conditions of hygiene and sanitation to prevent further outbreaks of a HEV epidemics, to facilitate access to clean drinking water for the population, to launch intensive health education for basic hygiene measures, to sett up targeted hygiene promotion activities and, finally, to ensure that formal health care is available.

The worldwide prevalence of Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) is undetermined. There is no clearly defined cut-off for EBV-encoded RNA (EBER) positivity in tumor cells by in-situ hybridization. The purpose of this study was to establish the proportions of EBV+ DLBCL patients and influence of the different cut-offs for EBER positivity, geographical location, and age on the prevalence of EBV+ DLBCL. PubMed and EMBASE were searched for studies published up to May 28, 2020 that reported proportions of EBER positivity in immunocompetent and de novo DLBCL patients. The pooled proportions were computed by an inverse variance method for calculating the weights and the DerSimonian–Laird method. Multiple subgroup analyses were conducted to explore any heterogeneity. Thirty-one studies (8249 patients) were included. The pooled proportion of EBV+ DLBCL was 7.9% (95% CI, 6.2–10.0%) with significant heterogeneity among studies (p < 0.001). The prevalence of EBV+ DLBCL was significantly higher in Asia and South America compared with Western countries (p < 0.01). The cut-offs for EBER positivity (10%, 20%, 50%) and patients’ age (≥50 years vs. <50 years) did not significantly affect the prevalence (p ≥ 0.10). EBV+ DLBCL is rare with a pooled proportion of 7.9% in patients with DLBCL and the geographic heterogeneity was confirmed.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.

Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma. We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0–2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m 2 once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262. 20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m 2 bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21–47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less). mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids. Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society.