Mogamulizumab efficacy is underscored by its associated rash that mimics cutaneous T-cell lymphoma: a retrospective single-centre case series.

BACKGROUND: Mogamulizumab is a humanized antibody against chemokine receptor type 4. It was recently approved by the US Food and Drug Administration for relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS). The most commonly reported adverse event in the phase III licensing trial was drug eruption (28%), now termed mogamulizumab-associated rash (MAR). Clinical recommendations about MAR and its treatment differ between the current package insert and postapproval insights reported from two single-centre studies that focused on its characterization, but less so on outcomes and clinicopathological differentiation from cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To describe our experience in the diagnosis of MAR and treatment of patients with CTCL with mogamulizumab. METHODS: This is a single-centre retrospective case series study. RESULTS: We found a higher incidence of MAR in patients with CTCL (17 of 24, 68%) than previously reported. MAR development is associated with complete (11 of 17) or partial (four of 17) responses, with an overall response rate of 88%, compared with 29% (two of seven) in patients without MAR. Diagnosis of MAR may be obscured by its ability to mimic key CTCL features both clinically and histologically, but an absence of T-cell-receptor clonality and relatively decreased CD4 : CD8 ratio compared with baseline lesions strongly favour MAR over recurrent disease. CONCLUSIONS: MAR has the potential to create a significant management problem for patients on mogamulizumab. Misidentification of MAR as recurrent CTCL may detrimentally result in the premature discontinuation of mogamulizumab in patients whose disease is historically hard to treat. Thorough clinicopathological investigation of new lesions during treatment with mogamulizumab is required to inform ideal treatment decisions and achieve better outcomes.

Risk of stillbirth in singleton gestations following in vitro methods of conception: a systematic review and meta-analysis.

BACKGROUND: In vitro methods of conception are associated with adverse perinatal outcomes. It is unclear if the risk of stillbirth is increased also. OBJECTIVE: This systematic review and meta-analysis aimed to estimate the risk of stillbirth in singleton gestations following in vitro methods of conception compared to non-in vitro conceptions. SEARCH STRATEGY: A comprehensive search in PubMed, Embase, CINAHL, and Cochrane Library was undertaken from database inception to February 2021, with backward citation tracking. SELECTION CRITERIA: Eligible studies included randomized controlled trials, cohort studies, or case-control studies that assessed stillbirth following in vitro fertilisation and/or intracytoplasmic sperm injection in comparison to non-in vitro methods of conception, including spontaneous conceptions, intrauterine insemination, and ovarian stimulation. DATA COLLECTION AND ANALYSIS: The Newcastle-Ottawa Scale was used to assess risk of bias. A summary odds ratio (OR) for stillbirth following in vitro methods of conception compared to non-in vitro methods was calculated using a random-effects model for meta-analysis. MAIN RESULTS: Thirty-three cohort studies met inclusion criteria. There was an increased risk of stillbirth with in vitro methods: OR 1.41 (95% CI 1.20-1.65); however, the crude baseline risk of stillbirth was low (4.44/1000 total births). Subgroup analysis did not demonstrate an increased risk when in vitro methods were compared to conception without in vitro methods in the context of subfertility. CONCLUSIONS: Compared to non-in vitro conceptions, in vitro conceptions have an increased risk of stillbirth. However, there is insufficient evidence to demonstrate whether this risk is associated with in vitro techniques or underlying subfertility. TWEETABLE ABSTRACT: This meta-analysis found an increased risk of stillbirth in singletons from in vitro methods of conception.

Toll-like receptor 2 activators modulate oral tolerance in mice.

BACKGROUND: Toll-like receptor 2 (TLR2) is a widely expressed pattern recognition receptor critical for innate immunity. TLR2 is also a key regulator of mucosal immunity implicated in the development of allergic disease. TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood. OBJECTIVE: The purpose of this study was to evaluate the impacts of TLR2 expression and TLR2 activation on oral tolerance to food antigens in a murine model. METHODS: Mice were fed ovalbumin (OVA) or peanut butter with or without the addition of low doses of TLR2 activators Pam3 CSK4 or FSL-1. Oral tolerance was assessed by analysing antibody responses after a systemic antigen challenge. OVA-specific Tregs were assessed in the Peyer's patches, mesenteric lymph nodes, and spleen in wild-type and TLR2(-/-) mice. Low-dose Pam3 CSK4 was also tested as an oral adjuvant. RESULTS: Oral tolerance was successfully induced in both wild-type and TLR2(-/-) recipient mice, with an associated regulatory T-cell response. Oral TLR2 activation, with low-dose Pam3 CSK4 or FSL-1, during oral antigen exposure was found to alter oral tolerance and was associated with the development of substantial IgE and IgA responses to foods upon systemic challenge. Low-dose oral Pam3 CSK4 treatment also selectively enhanced antigen-specific IgA responses to oral antigen exposure. CONCLUSIONS AND CLINICAL RELEVANCE: TLR2 is not necessary for oral tolerance induction, but oral TLR2 activation modulates humoral IgE and IgA responses during tolerance development. Low-dose Pam3 CSK4 is also an effective oral adjuvant that selectively enhances IgA production. These observations are pertinent to the optimization of oral allergen immunotherapy and oral vaccine development.

A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma.

BACKGROUND: Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%. PATIENTS AND METHODS: We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m(2) twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function. RESULTS: Among 25 BL patients, the median age was 44 years (23-70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 µg/ml, respectively, versus 131 and 193 µg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 µg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively. CONCLUSIONS: The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. Clinicaltrials.gov NCT00392990.

Incidence of venous thromboembolism in patients with non-Hodgkin lymphoma.

INTRODUCTION: Patients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE). Current risk-prediction models classify NHL as a single entity. We aimed to quantify the difference in VTE risk in follicular lymphoma (FL) versus diffuse large B cell lymphoma (DLBCL). METHODS: Using a prospective cohort study, we identified 2730 patients (2037 DLBCL; 693 FL) within the Veteran's Administration Central Cancer Registry. A competing risk model assessed the association between VTE risk and histology in the first year after NHL diagnosis. We assessed the effect of additional risk factors for VTE in NHL. RESULTS: In univariate analysis, DLBCL was associated with increased risk of VTE compared to FL in the first year after diagnosis; this association was no longer significant in adjusted analysis (adjusted hazard ratio (aHR) 1.52; 95% CI 0.97-2.40). Major risk factors for VTE included history of VTE before NHL diagnosis (aHR 4.73, p≤0.0001) and time period during chemotherapy administration (aHR 7.60, p≤0.0001). Additional risk factors included: stage III/IV disease (p=0.02), BMI≥30 (p=0.02), B-symptoms (p=0.02), and doxorubicin (p=0.04). The cumulative incidence of VTE was highest in the period following diagnosis and decreased over time for both histologies. CONCLUSION: DLBCL is associated with increased risk of VTE compared to FL. This risk is markedly attenuated when adjusting for additional risk factors. The strongest predictors for development of VTE included: time period during chemotherapy administration (especially doxorubicin) and history of VTE. This knowledge can assist clinicians in identifying NHL patients at high risk for VTE.

High-dose therapy and autologous stem cell transplant in older adults with multiple myeloma.

Randomized trials showing that high-dose therapy with autologous stem cell transplant (ASCT) improved the overall survival (OS) in multiple myeloma (MM) excluded patients over age 65. To compare the outcomes of older adults with MM who underwent ASCT with non-transplant strategies, we identified 146 patients aged 65-77 with newly diagnosed MM seen in the Washington University School of Medicine from 2000 to 2010. Survival among patients who did (N=62) versus did not (N=84) undergo ASCT was compared using Cox proportional hazards modeling, controlling for comorbidities, Eastern Cooperative Oncology Group performance status (PS) and the propensity to undergo ASCT. Median age was 68 years (range 65-77). PS and comorbidities did not differ significantly between those who did versus those who did not undergo ASCT. Median OS was significantly longer in patients who underwent ASCT than in those who did not (median 56.0 months (95% confidence intervals (CIs) 49.1-65.4) versus 33.1 months (24.3-43.1), P=0.004). Adjusting for PS, comorbidities, Durie-Salmon stage and the propensity to undergo ASCT, ASCT was associated with superior OS (HR for mortality 0.52 (95% CI 0.30-0.91), P=0.02). In a cohort of older adults with MM, undergoing ASCT was associated with a nearly 50% lower mortality, after controlling for PS, comorbidities, stage and the propensity to undergo ASCT.

The skinny on obesity and plasma cell myeloma: a review of the literature.

Despite tremendous advances in treatments for myeloma in the past decade, the disease remains incurable in the majority of patients. Here, we review recent data demonstrating an association between obesity and increased risk of myeloma development. This may be due to the pro-inflammatory cytokine profile caused by obesity. Currently, there are no screening or prevention strategies for myeloma, but we propose that obesity-associated inflammatory pathways, or obesity itself, may be amenable to intervention, thereby preventing the transition from pre-malignancy to myeloma. In addition, we suggest that the morbidity, mortality and the significant costs associated with myeloma treatment could be reduced by addressing modifiable risk factors, and that research efforts should explore this novel hypothesis.