Citations

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin lymphoma provide expert, multidisciplinary recommendations for the diagnosis and treatment of Hodgkin lymphoma. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Hodgkin Lymphoma focuses on the management of newly diagnosed and relapsed/refractory classic Hodgkin lymphoma in adults aged 18 to 60 years.

Abstract Background and Aims There is a paucity of data on arrhythmia burden in patients with congenitally corrected transposition of the great arteries (ccTGAs). The present study sought to quantify the incidence of atrial arrhythmia (AA), ventricular arrhythmia (VA), and complete atrioventricular block (CAVB) in patients with ccTGA and identify associated factors. Methods An international, multi-centre, retrospective cohort study was conducted in 29 tertiary hospitals (six countries) between 1990 and 2018. Primary analyses consisted of determining the incidence of a combined outcome consisting of AA, VA, or CAVB, along with its individual components. Factors associated with the different types of arrhythmias were assessed by uni-variable and multi-variable Cox regression analyses. Results A total of 1131 patients with ccTGA were followed for 9.0 (interquartile range 4.0–17.2) years. Cumulative rates of the primary endpoint at 10, 15, and 20 years were 44.5%, 51.0%, and 58.8%, respectively. AA, VA, and CAVB occurred in 2.1, 1.4, and 2.0 cases per 100 person-years, respectively. In multi-variable analyses, surgery/intervention conferred a greater than three-fold higher risk of AA [hazard ratio (HR) 3.01, 95% confidence interval (CI) 1.90–4.78, P < .001]. Furthermore, surgery/intervention was significantly associated with a greater risk of VA (HR 1.73, 95% CI 0.98–3.05, P = .003) and CAVB (HR 3.65, 95% CI 2.20–6.05, P < .001). The left bundle branch block was associated with a higher risk of VA (HR 4.03, 95% CI 1.59–10.23, P = .003) and the right bundle branch block with a higher risk of CAVB (HR 3.71, 95% CI 1.81–7.63, P < .001). Conclusions The arrhythmia burden in patients with ccTGA is substantial, with a high incidence of AA, VA, and CAVB.

Background: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. Methods: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. Results: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. Conclusions: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation (“watch and wait”) may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

AbstractConsiderable evidence has accumulated implicating a role for immune mechanisms in moderating the pathology in Alzheimer's disease dementia. However, the appropriate therapeutic target, the appropriate direction of manipulation, and the stage of disease at which to begin treatment remain unanswered questions. Part of the challenge derives from the absence of any selective pressure to develop a coordinated beneficial immune response to severe neural injury in adults. Thus, immune responses to the prevailing stimuli are likely to contain both beneficial and detrimental components. Knowledge gaps include: (1) how a biomarker change relates to the underlying biology, (2) the degree to which pathological stage group differences reflect a response to pathology versus trait differences among individuals regulating risk of developing pathology, (3) the degree to which biomarker levels are predictive of subsequent changes in pathology and/or cognition, and (4) experimental manipulations in model systems to determine whether differences in immune biomarkers are causally related to pathology.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Abstract Background: Checkpoint blockade therapies (CBT) have substantially improved outcomes for patients in a variety of cancers. However, they are associated with a unique spectrum of immune-related adverse events (AEs). Additionally, unlike standard chemotherapy, many patients (pts) remain on CBT for prolonged periods of time, thus immune-related symptomatic AEs may be chronic or low grade therefore important to capture long term tolerability when used as a single agent or in combination with chemotherapy. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which incorporates the dimension of time and includes chronic lower grade events, to the first 6 cohorts (A-F) of a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of Brentuximab Vedotin (BV) and the CBT therapies ipilimumab (Ipi) and nivolumab (Nivo) in pts with relapsed or refractory Hodgkin lymphoma (R/R HL). Methods: Pts with confirmed R/R HL were treated with BV 1.8mg/kg + Ipi 1or 3 mg/kg (n=23); or Nivo 3mg/kg + BV: 1.2 or 1.8 mg/kg (n=19). BV was administered every 21 days for 16 cycles; Ipi every 21 days x 4 and then every 3 months for one year and Nivo every 21 days for up to 2 years. Seven symptomatic (subjective) AEs were selected: fatigue, peripheral sensory neuropathy (PSN), nausea/vomiting (NV), rash/skin (RS), diarrhea, ocular-all types, and hair loss. Treatment-related AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods up to 12 cycles. Using ToxT, mean AE grades over cycles were analyzed for time trend with repeated measures models, time to grade 2 or higher AE (gr2+) was analyzed with time-to-event analysis; AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment groups: BV/Ipi(A-C arms) and BV/Nivo (D-F arms). Results: 9/23 (BV/Ipi) and 6/19 (BV/Nivo) pts completed 10 cycles. For BV/Ipi vs. BV/nivo, ToxC provides overall incidence rates (any grade): fatigue 52% vs 26% (p=0.09); PSN 61% vs 53%; NV 70% vs 53% ; RS 65% vs. 37% (p=0.07); diarrhea 57% vs. 21% (p=0.02); ocular 17% vs. 21% ; and hair loss 17% vs. 0% (p=0.06), respectively. Gr3 AE occurred in 1 pt (2.4%) each for PSN, NV, diarrhea, and 6 pts (14.3%) for RS, and were similar between BV/ipi and BV/nivo. AUC from ToxT which captures chronic lower grade AEs suggested for BV/Ipi: diarrhea (p=0.02) and NV (p=0.03) are significantly more substantial over time with a trend seen for fatigue (p=0.07), RS (p=0.07) and hair loss (p=0.07) . Additionally, ToxT captures the trajectory of AEs, demonstrated a rising incidence and worsening grade of PSN (BV-related) on BV/Ipi (c1: 9% gr1, c2: 21% gr1 5% gr2, c5: 11% gr1 and c10: 22% gr2 [p=0.005], Fig 1a). In contrast there was a slow but significant decreasing incidence of NV on both combinations; for BV/Nivo (c1:52% gr1, c5: 26% gr1 and c10: 22% gr1) and BV/Ipi (c1: 47% gr1 ,c5: 0% and c10 1% gr1) with p=0.006 (Fig 1b). RS and diarrhea appear early on treatment and are not cumulative (Fig1c and 1d). There is no significant difference in the time to gr 2+ toxicities in any of the 7 AE. Combining all 7 AEs and using the maximum grade as a pilot measure of overall AE burden , ToxC indicates no difference in any grade (100% vs 100%) but a significantly higher gr 3+ incidence (35% vs. 11%) for BV/Ipi. Additionally, ToxT further elucidates that BV/Ipi is associated with significantly higher overall AE over time (Fig 2a, p=0.02) and compared to BV/Nivo a significantly higher risk of developing gr 2+ toxicity ( 57% vs 16% gr2 + event by day 50) (HR=0.41, p=0.02, Fig 2b). Conclusions: The CBT therapies Ipi and Nivo, in combination with BV, are overall both well tolerated over time, although BV/Ipi has a higher overall AE burden. Neither regimen has significant cumulative immune toxicity. Results of this analysis should be interpreted in the context of limited number of pts in both cohorts. A larger scale examination of this analysis is planned to incorporate both phase 1 and the ongoing phase 2 components of E4412. Compared with conventional tox analysis, ToxT delineated important additional and clinically relevant depictions of AEs over time and adds a more comprehensive assessment of the tolerability of chronically administered immune therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Ansell:Regeneron: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Advani:Kura: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Forty Seven Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Regeneron: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Kahl:Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. Diefenbach:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Genentech: Consultancy; Denovo: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding.

Abstract Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (Nivo), and ipilimumab (Ipi) in patients with R/R HL. Here we present the preliminary safety and response data on the full cohort of patients treated in Phase 1 with BV + Ipi + Nivo (Arms G-I). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg, Ipi 1mg/kg and BV 1.2mg/kg (Arm G) or 1.8mg/kg (Arm H) with a 3+3 design, and an expansion cohort (Arm I) of 9 patients with BV at 1.8mg/kg. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional 12 months. Ipi is given every 12 weeks except for the first 2 patients in Arm G who received Ipi every 6 weeks for the first 3 cycles. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 6/30/18 22 patients with a median of 2 prior therapies (range 1-5) have been treated; 7 in Arm G, 6 in Arm H, and 9 in Arm I. Median age was 35, range (19-60); 11 patients were male. Nine patients had prior SCT (1 alloSCT, 8 autoSCT); 1 patient had prior BV. Safety: All 22 enrolled patients are evaluable for safety. There were 3 DLTs, one in each arm. In Arm G one patient experienced grade 4 diabetic ketoacidosis and hyperglycemia, and went off treatment after cycle 1. In Arm H, one patient had transient grade 3 AST elevation; this was of no clinical significance and did not require a delay in therapy. In Arm I a post AlloSCT patient had grade 4 Steven-Johnson syndrome with grade 3 pruritis, rash, and GVHD, and came off therapy. Common toxicities considered at least possibly related to drug, are shown in Table 1, and grade 3 or greater toxicity in Table 2. There were no grade 5 AEs or additional grade 4 AEs. Significant grade 3 AEs were: rash, colitis, gastritis, pancreatitis, and arthritis each in one patient, resulting in dose delays but not discontinuation of therapy. One patient experienced grade 2 angioedema in cycle 1 and came off therapy. No significant infusion reactions were noted. Response: Nineteen of 22 patients are evaluable for response. Three patients discontinued treatment after cycle 1 and are not evaluable for response. For the full population the overall response rate (ORR) was 82% (18/22), with a complete response (CR) rate of 68% (15/22). For patients treated with at least 3 cycles of therapy who were evaluable for response, the ORR is 95% (18/19) with a CR rate of 79% (15/19). Six patients went from treatment to SCT. With a median follow-up of 0.52 years median progression free survival (PFS) has not been reached (Figure 1), and with a median follow-up of 0.82 years overall survival (OS) has not been reached (Figure 2). Conclusion: In this study of the triplet combination of BV, Ipi and Nivo for R/R HL, therapy was generally well tolerated, although more grade 3 AEs were seen than in the doublets. In a heavily pretreated patient population, with 9 patients post SCT, the ORR of 95% and CR rate of 79% in evaluable patients is extremely promising. Data will be updated to include longer term PFS and OS by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-Nivo to the triplet of BV-Ipi-Nivo. Disclosures Diefenbach: Trillium: Research Funding; Incyte: Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Hong:Merck: Consultancy. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Janssen: Research Funding; Millenium: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KITE: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Kahl:Genentech: Consultancy; Abbvie: Consultancy; Acerta: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding.