ALBERT

Description: We measured Mössbauer spectra and the acquisition of saturation isothermal remanent magnetization in alternating steps on the same sample of polycrystalline, multidomain iron metal powder in a diamond anvil cell across the body centered cubic (bcc) to hexagonal closed packed (hcp) phase transition at room temperature up to 19.2 GPa. Within the bcc stability field indicated by the presence of magnetic hyperfine splitting, saturation remanent magnetization and sextet area were well correlated during compression and decompression. The areas and dips of the outer (first and sixth) and middle (second and fifth) components of the sextet changed in relative proportion as a function of pressure, which was attributed to rotation of the magnetization direction perpendicular to the gamma-ray source. Sextet peaks disappeared above ∼15 GPa, yet magnetic remanence persisted. Magnetic remanence intensity divided by the fractional area of the sextet, taken to represent bcc Fe, attained maxima at pressures near the boundaries of the hysteretic transition, which we attribute to strain-related magnetostriction effects associated with a distorted bcc-hcp phase. Magnetic remanence observed within the hcp stability field, as defined by the absence of sextet peaks, could be due to a previously described, distorted bcc-hcp phase whose hyperfine field was below detection limits of Mössbauer spectroscopy. Our study suggests that distorted bcc-hcp Fe holds magnetic remanence and leaves open the possibility that this phase carries magnetic remanence into the pressure range where only pure hcp Fe is considered stable.

Description: Background: Outcomes to salvage therapy for patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) are suboptimal. Checkpoint blockade therapy (CBT) has been explored in the relapsed/refractory (R/R) NHL population, but response rates to single agent CBT therapy are modest. To date, there is no literature on whether treatment with CBT may sensitize NHL patients to subsequent therapy. We investigated the outcome of subsequent treatment in patients with R/R NHL who had received CBT in a large multicenter international retrospective analysis. Methods: Seventeen centers across the US and Canada are participating in this study to date. Medical records of each institution were queried to identify lymphoma patients who received CBT and were subsequently treated with an additional line of therapy. The primary aim of the current analysis was to determine the best response to post-CBT treatment in patients who discontinued CBT due to progression of disease (PD) or toxicity. Patients who discontinued CBT due to a complete response (CR), or patients whose best response to post-CBT therapy could not be determined due to death from another cause, were excluded from analysis. Responses were assessed using Lugano criteria. Survival status to date was analyzed for the entire study population and stratified by post-CBT treatment regimen categories and disease subgroups using the Kaplan-Meier method. Progression free survival (PFS) and overall survival (OS) were calculated for patients with at least stable disease (SD) to post-CBT treatment. Log rank tests were performed to test for statistical significance. Two-sided P

Description: Background: BL is associated with a high risk of primary or secondary CNS involvement, warranting intrathecal (IT) and/or systemic therapy that penetrates the blood-brain barrier (BBB). The lower-intensity DA-EPOCH-R regimen has recently shown high survival rates in BL (Dunleavy, NEJM 2013), but it omits drugs traditionally used for CNS prophylaxis (like high-dose methotrexate [HDMTX]). The objective of this multi-institutional retrospective study was to examine treatments, risk factors, and CNS-related outcomes among patients (pts) with BL. Methods: We collected data from 26 US centers on adult BL pts diagnosed (dx) in 6/2009-6/2018. Using institutional expert pathology review and 2016 WHO criteria, we excluded other high-grade lymphomas (including BL-like/unclassifiable), or cases with inadequate clinicopathologic data. We studied factors associated with baseline CNS involvement (CNSinv) using logistic regression reporting odds ratios (OR). Progression-free (PFS), overall survival (OS), and cumulative incidence function of CNS recurrence (in a competing risk analysis) were examined in Cox or Fine-Gray models reporting hazard (HR) or subhazard ratios (SHR), respectively. All estimates report 95% confidence intervals (in square brackets). Results: Among 557 BL pts (median age, 47 years [yr], 24% women, 23% HIV+), 107 (19%) had CNSinv at dx, including 89 (16%) with leptomeningeal, and 15 (3%) with parenchymal CNS disease. In a multivariable model, factors significantly associated with CNSinv at dx included stage 3/4 (OR, 11.2 [1.47-85.9]), poor performance status (PS; OR, 2.12 [1.22-3.69]), ≥2 extranodal sites (OR, 3.77 [2.02-7.03]), or marrow involvement (OR, 2.44 [1.35-4.39]), whereas intestinal involvement conferred low risk of CNSinv (OR, 0.27 [0.11-0.65]). CNSinv at dx was not significantly associated with use of specific chemotherapy regimens (Fig. A,P=.75) or receipt of IT chemotherapy (91% vs 84%, P=.065). Pts with CNSinv were less likely to achieve a complete response (62% vs 76%, P=.005), had worse 3 yr PFS (47% vs 69%; P3x]; see Evens AM et al, ASH 2019 for further details). With median follow up of 3.6 yrs, 33 pts (6%) experienced a CNS recurrence (82% within 1 yr from dx; 79% purely in CNS, and 21% with concurrent systemic BL). The cumulative risk of CNS recurrence was 6% [4-8%] at 3y (Fig. D). Univariate significant predictors of CNS recurrence included baseline CNSinv, HIV+ status, stage 3/4, poor PS, LDH〉3x, involvement of ≥2 extranodal sites, marrow, or testis. However, in a multivariate model only baseline CNSinv (SHR, 3.35 [1.53-7.31]) and poor PS (SHR, 2.24 [1.03-4.90]) retained significance. The 3 yr risk of CNS recurrence varied from 3% for pts with no risk factor, to 10% with one, and 17% with both factors (Fig. E). In addition, the risk of CNS recurrence differed according to chemotherapy regimen, and was significantly higher for pts treated with DA-EPOCH (12% at 3y [8-18%]; Fig. F) compared with CODOX-M/IVAC (4% [2-8%]) or hyperCVAD/MA (3% [1-6%]; SHR for DA-EPOCH vs. others, 3.50 [1.69-7.22]). All pts recurring after DA-EPOCH had received IT chemotherapy. Higher risk of CNS recurrence persisted with DA-EPOCH regardless of baseline CNSinv (Pinteraction=.70), poor PS (Pint=.14), or HIV status (Pint=.89). Baseline CNSinv was the strongest factor associated with CNS recurrence after DA-EPOCH (3 yr risk, 30% vs 8%, P

Description: Background: Hydroxyurea (HU) therapy in children with sickle cell disease (SCD) produces positive hematological and clinical improvements similar to those seen in adults. Increases in HbF levels while receiving HU therapy, reported in pediatric studies varies from a low of 10%-15% to a high that occasionally exceeds 40% (Ware et al. 2011). Approximately 30% of sickle cell disease patients co-inherit α-thalassemia and prior studies have demonstrated conflicting results with regard to its impact on response to HU. Vasavda et al. reported a significantly blunted clinical and laboratory response to HU treatment in adult patients who carried the α-globin gene deletion (Vasavda et al. 2008 & 2012). A more recent report by Darbari et al. analyzed data from the adult MSH cohort and reported a smaller interaction of change in %HbF in patients with α-globin deletion; however these results did not achieve statistical significance (Darbari et al. 2014). Two pediatric studies have evaluated the impact of α- thalassemia on HU response in SCD. A recent analysis of the BABY HUG data, looking at the effect of genetic modifiers of SCD on HU treatment in a cohort of very young patients, found a significant laboratory as well as a clinical response to HU in SCD infants regardless of α-thalassemia status (Sheehan et al. 2013). Ware et al. reported on the association of α-thalassemia status with MTD (maximum tolerated dose) %HbF level (HUSTLE data) (Ware et al. 2011). They showed that α-thalassemia status had no significant association with MTD HbF, but did not report on the clinical efficacy or change in %HbF. While our study examines a similar age cohort as the HUSTLE study, the effect of α-thalassemia status is assessed in the context of routine clinical care. Patients in this cohort were not treated at MTD (maximum tolerated dose), but based on clinical response. We further evaluate the magnitude of reduction in vaso-occlusive events and examine the effect of older age within the pediatric cohort. Methods: This is a retrospective, single institution study. Patients with SCD were included if they were between the ages of 5 and 21, on HU treatment for at least 6 months, had been genotyped for α-thalassemia, and had data on % HbF prior to, and during HU therapy. For both pre and post HU periods, the extreme values were taken (minimum and maximum) so as to capture the maximum effect possible from the HU therapy and minimize the impact of variable adherence. Other parameters that were assessed included hemoglobin, MCV, WBC, ANC and reticulocyte count, HU dose and number of vaso-occlusive pain events. Results: 36 patients without α-thalassemia trait and 26 patients that were heterozygous for the trait were eligible for inclusion. Analysis of the entire cohort revealed no difference in the increase in HbF% between the two groups (Table 1, p=0.3). Surprisingly a greater reduction in vaso-occlusive events in patients with α-thalassemia was seen (p=0.03). Of note, patients that were 〉 12, and had α-thalassemia trait, had a blunted response with regard to change in HbF% (12.5 +/- 5.4) versus those without the mutation (18.9 +/- 7.1, p=0.02). In these patients that were 〉 12 years old, this was associated with a loss of the clinical advantage with no statistical difference in the reduction of vaso-occlusive events (p=0.08). Conclusions: Young patients with α-thalassemia trait have an equivalent hematologic response and better clinical response to HU than patients without α-thalassemia. In contrast, patients 12-21 years of age with α-thalassemia have a blunted hematologic response to HU when not treated at MTD. Increasing HU dose to MTD may be more important in older patients with alpha thalassemia. Table 1: Delta HbF% and VOC rate on HU in SCD patients with and without α-thalassemia trait Variables Age αα/α- αα/αα P-value Change in %HbF 5-21 12.5 (+/- 8.4) 9.9 (+/- 6.3) 0.3 Mean (+SD) 12-21 12.5 (+/- 5.4) 18.9 (+/- 7.1) 0.02 VOC rate on HU 5-21 0 (0-1.3) 1 (0-2.8) 0.03 Median (25-75 percentile) 12-21 0 (0-2) 1 (1-5) 0.08 Disclosures No relevant conflicts of interest to declare.

Description: Background: Relapsed or refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical problem. Recently checkpoint blockade therapy (CBT) has shown striking activity in this setting, but the complete response (CR) rate is modest. Patients who relapse after CBT have limited therapeutic options. A prior, retrospective study showed that after anti-PD-1 therapy the objective response rate to chemotherapy alone was 61% (Rossi et al 2017). We investigated the effect of treatment subsequent to CBT in a large international multicenter retrospective analysis. Methods: Seventeen centers across the US and Canada are participating in this study to date. Medical records of each institution were queried to identify HL patients who received CBT and were subsequently treated with an additional line of therapy. The primary aim of this analysis was to determine the best response to post-CBT treatment in patients who discontinued CBT due to progression of disease (PD), preparation for stem cell transplant (SCT), or toxicity. Patients who discontinued CBT due to CR, and patients whose best response could not be determined due to death from another cause were excluded from analysis. Responses were assessed using Lugano criteria. Survival status was analyzed for the entire study population and stratified by post-CBT treatment regimen and disease subgroups using the Kaplan-Meier method. Progression free survival (PFS) was calculated for patients with at least stable disease (SD) to post-CBT treatment. Log rank tests were performed to test for statistical significance. Two-sided P

Description: Introduction: Historically, outcomes for BL have improved in adults using dose intensive chemotherapy regimens and early CNS prophylaxis. More recent data using a less intensive regimen, DA-EPOCH, have been reported. We analyzed detailed patient (pt) & disease characteristics and treatment patterns across 26 US CCs over a recent 9 year (yr) period and also determined survival rates & prognostication. Methods: We conducted a large multicenter retrospective study of newly diagnosed (dx) adult BL pts (6/2009 - 6/2018). Dx was established by institutional expert pathology review; all cases were verified for BL based on 2016 WHO criteria (high grade B cell lymphoma, BL like, etc were excluded). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. Univariate (UVA) associations were derived via Cox model with variables P ≤0.05 entered stepwise into a multivariate (MVA) model. Using significant factors from the MVA, a prognostic survival model was constructed. Results: Among N=557 verified BL cases, clinical features included: median age 47 yrs (17-88 yrs; 24% ≥60 yrs); male 76%; HIV+ 22%; ECOG PS 0/1 76%; B symptoms 51%; elevated LDH 78% (3, 5, & 10x elevation: 44%, 29% & 15%, respectively); hemoglobin 1 EN. On MVA, factors associated with inferior survival were: age ≥40 yrs (PFS HR 1.57, P

Description: Introduction: There are few data about prognostication and outcomes in patients (pts) with HIV-BL treated in the cART era. Optimal treatment strategies to minimize treatment-related mortality (TRM) remain unclear and current recommendations are based on small studies. We conducted a multicenter international analysis to identify prognostic factors and outcomes in pts with HIV-BL treated in the cART era. Methods: This retrospective analysis included a subcohort from a recent study across 30 US sites (Evens et al. Blood 2020) augmented by data from 5 UK centers treated 2009-2018. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier & differences assessed by log-rank test. Univariate (UVA) associations were derived via Cox model and multivariable (MVA) models were constructed by forward selection of significant variables with P 3x upper limit of normal (ULN) 49% & 〉5xULN 39%); 〉1 extranodal (EN) site: 60%; any CNS involvement (CNSinv) 25%; and +bone marrow (BM) 46%. MYC rearrangement was reported in 93% of pts with t(8;14) in 49%, break-apart probe in 41% and MYC-light chain in 3%; the rest had classical BL with negative MYC testing (4%) or missing result (3%) (otherwise classical BL). Median CD4 count was 217 (IQR 90-392 cells/µL) with 68% pts having CD4〉100 cells/µL. At BL diagnosis, HIV viral load was detectable in 55%; 39% of pts were on cART. Baseline features were similar between the US & UK cohorts with significant differences only in ECOG PS 2-4 (32% vs 65%; P