Efficacy of Plasmapheresis in Nivolumab-Associated ANCA Glomerulonephritis: A Case Report and Pathophysiology Discussion

Immune checkpoint inhibitors (ICIs) have revolutionized solid organ and hematologic cancer treatments by improving overall prognoses. However, they can lead to overactivation of the immune system and several immune-related adverse events and sometimes affecting the renal system. Although acute interstitial nephritis is well described, we know little about ICI-associated glomerular injury. Herein, we report an exceptional case of renal ANCA positive-associated vasculitis (AAV) after nivolumab therapy. Three weeks after the last nivolumab injection, the patient presented with proteinuria at 1.73 g/g of creatininuria, hematuria, and acute kidney injury needing dialysis associated with lung hemorrhage; anti-neutrophil cytoplasmic antibody (ANCA titer ≥1,280 with myeloperoxidase specificity of 780 U/mL) was positive, and kidney biopsy confirmed glomerular injury with crescents. The patient underwent treatment with steroid pulses, rituximab, and plasmapheresis, resulting in an improvement of the renal function and lung hemorrhage and produced a negative ANCA titer. Despite the results of the PEXIVAS study and the absence of clear benefit of plasmapheresis demonstrated in idiopathic AAV, we suggest that drug-induced AAV may be effectively treated by plasmapheresis, steroids, and rituximab.

Monitoring Energy Balance Through Clinical and Serum Biomarkers in Patients with Hmatologic Malignancies during Chemotherapy

Background: Many cancer patients experience energy imbalance due to the tumor or chemotherapy-related side effects. Chemotherapy could make significant metabolic changes leading to energy imbalance. However, the variations in energy input, metabolic rate, and physical activity are not known in detail. This study aimed to identify changes in energy balance components and serum biomarkers during chemotherapy of patients with hematologic cancer. Methods: This prospective study included 40 patients with hematologic malignancies hospitalized for chemotherapy. Energy balance components, physical function, and serum biomarkers, such as albumin, total protein, CXCL13, GDF15 and leptin, were measured weekly after chemotherapy for 3 weeks. Results: Significant body weight loss, representing negative energy balance, occurred at 2 and 3 weeks after chemotherapy. A statistically reduced oral intake was observed at week three. However, total energy intake did not show any statistical change during the study period due to parental support. Resting energy expenditure statistically decreased according to the Harris-Benedict (HB) equation, but not for the Penn State University (PSU) equation. Physical activity measured by daily steps showed no statistical difference. However, physical function according to the DEMMI score indicated a significant decrease at 3 weeks. Over half of the patients (65.0 %, n = 26) were found to have at least one of energy balance problem according to subgroup classification.Our serum biomarker analysis demonstrated significant differences in serum albumin, total protein, CXCL13, and GDF15 levels, with the exception of leptin. All three subgroups exhibited statistically significant decreases in albumin and total protein. However, only CXCL13 levels in the weight loss group and GDF level in the anorexia and impaired physical function groups were found to be significantly altered by subgroup analysis.Conclusions: The results indicated that 65 % of hematologic cancer patients suffered from energy imbalances during chemotherapy associated with weight loss and anorexia. Significant changes in albumin, total protein, CXCL13, and GDF15 were found. Additionally, subgroup analysis suggested that CXCL13 and GDF15 were associated with weight loss and appetite loss, respectively. Monitoring the energy balance of clinical and serum biomarkers together can help identify the need for nutritional intervention in patients undergoing chemotherapy.

The Positive Enantiomer of a Novel Chiral DNA Alkylating Agent Exhibits Nanomolar Potency in Hematologic Cancers

LP-184, or (-)-hydroxyurea methylacylfulvene, is a potent DNA alkylating agent that effectively kills solid tumors. It belongs to the acylfulvene compound family known to induce DNA lesions repaired by the Transcription-Coupled Nucleotide Excision Repair (TC-NER) pathway. Here, we show that LP-284, the synthetic positive enantiomer of LP-184, exhibited the greatest and broadest hematologic cancer antiproliferative activities among the 6 acylfulvenes, including illudin S, illudin M, Irofulven (LP-100), the semisynthetic racemic LP-184, the synthetic negative enantiomer LP-184, and LP-284. The distinct pharmacological activities of LP-284 may be due to differences in metabolic activation, transport, or affinity to cellular macromolecules. To determine whether metabolic activation plays a role, we compared the correlation between the expression of Prostaglandin Reductase 1 (PTGR1), the NADPH-dependent oxidoreductase known to convert Irofulven into its active metabolite, and the IC50 of LP-184, Irofulven, and LP-284. We found that the expression level of PTGR1 is highly correlated with LP-184 (r=0.88, p=8.4e-20) and Irofulven (r=0.71, p=4.7e-10) sensitivity, but not with LP-284 (r=-0.01, p=0.93). We also found that the average expression level of PTGR1 is significantly lower in hematologic cancer cell lines (n=180) than in solid tumor cell lines (n=856), indicating the existence of an alternative LP-284 activator in hematologic cells. Next, we checked mutation status, RNA expression, protein expression, and DNA methylation of 489 oxidoreductases, but none of the enzymes was highly correlated with LP-284 activity. To further explore the potential clinical application of LP-284 in hematologic cancers, we conducted cell viability assays in 18 hematologic cancer cell lines and found that LP-284 exhibited nanomolar potency in acute lymphocytic leukemia (average IC50: 351 nM), chronic myeloid leukemia (average IC50: 360 nM), B-cell lymphoma (average IC50: 366 nM), and Multiple Myeloma (MM, IC50: 334 nM). We also investigated the therapeutic potential of LP-284 in combination with spironolactone in treating MM. Spironolactone, an FDA approved drug for hypertension, degrades one of the key TC-NER players ERCC3 in MM, which in turn makes cells more vulnerable to helix-distorting DNA lesions likely caused by LP-284. While Spironolactone alone didn't cause cytotoxicity to the MM cell line RPMI8226, it reduced LP-284 IC50 by 2.4 fold. Taken together, we have demonstrated the importance of stereochemistry in acylfulvene activity. LP-284, likely to be activated through a different route, is a unique and potent acylfulvene for hematologic cancers. Additionally, pharmacological inhibition of the TC-NER pathway greatly promoted LP-284 cytotoxicity. We hypothesize that LP-284 induces DNA lesions, which may be lethal to TC-NER deficient cells and may block transcription of short-lived fusion genes that are essential for cancer cell survival until repaired. Therefore, our discovery of the novel enantiomer LP-284 may provide a targeted therapy option for hematologic cancers with compromised DNA repair. Disclosures Zhou: Lantern Pharma: Current Employment. Biyani: Lantern Pharma: Current Employment. Kathad: Lantern Pharma: Current Employment, Current equity holder in publicly-traded company. Kulkarni: Lantern Pharma: Current Employment. McDermott: Lantern Pharma: Current Employment. Bhatia: Lantern Pharma: Current Employment.

The Relationship between Depression, Anxiety, and Clinical Trial Perceptions Among Patients with Hematologic Cancer

Introduction. Despite the fact that thousands of cancer clinical trials (CCTs) are available today, engagement remains low, with only 2-7% of patients with cancer participating in CCTs. Research has shown that this may partially be due to fear-based perceptions around CCTs. Unfortunately, depression and anxiety, two psychological factors that are highly prevalent in the cancer space, are known to bias attention in ways that alter perceptions and are specifically known to amplify fear-based perceptions. Thus, the purpose of this exploratory study was to examine the relationship between depression, anxiety, and perceptions of clinical trials among patients with hematologic cancer. Method: In this observational, cross-sectional study, 625 patients with hematologic cancer (46.4% multiple myeloma; 19.5% CLL; 11.4% non-Hodgkin lymphoma; 4.0% AML; 3.5% Hodgkin lymphoma; 3.2% CML; 1.6% ALL; 1.3% MPN; 7.4% other lymphoma; 1.8% other leukemia) completed the Cancer Support Community's online survey, the Cancer Experience Registry®. Participants provided sociodemographic and clinical history information, rated their level of agreement (0 = strongly disagree to 4 = strongly agree) with 8 statements related to beliefs about CCTs, and completed the Anxiety and Depression subscales (4 items each rated 1 = never to 5 = always) from the Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0). Responses to these 8 PROMIS items were averaged to compute a combined depression and anxiety score on a 5-point Likert scale. To understand the impact of depression and anxiety on perceptions of CCTs, 8 hierarchical regression models were examined; the dependent variable for each model was one of the CCT perception variables. Clinical history (cancer diagnosis, time since diagnosis, type of cancer care facility) and sociodemographic variables (age, gender identity, income, educational attainment, race, ethnicity, geographic area) were controlled for. Results: The sample was 54.9% female, 86.7% Non-Hispanic White, 60.1 years old on average (SD=10.8) and had an average time since diagnosis of 5.3 years (SD=5.3; Median = 3.0 years; IQR = 6 years). 67.7% had a college degree, 20.5% had a gross annual household income of $100,000 or above, 41.4% received cancer treatment at an academic or comprehensive cancer center, and 45.6% lived in a suburban area. Participants' average anxiety and depression score was 1.91 (SD=.93). Hierarchical regression analyses demonstrate that depression and anxiety had a significant effect on 7 of the 8 CCT perceptions assessed, when controlling for sociodemographic and cancer characteristics. Specifically, depression and anxiety were significant predictors of participants' perceptions that, "I would be unable to fulfill trial requirements due to logistical barriers" (ΔR 2=.019, b=.19, p=.003), "I don't trust the medical establishment and fear I will be used as a 'guinea pig'" (ΔR 2=.017, b=.17, p=.006), "I am uncomfortable with being randomly assigned" (ΔR 2=.016, b=.19, p=.01), "I fear receiving a placebo (for example, a sugar pill) in a clinical trial" (ΔR 2=.012, b=.18, p=.024), "I don't understand what clinical trials are" (ΔR 2=.011, b=.13, p=.021), "There are no clinical trials available in my community" (ΔR 2=.010, b=.14, p=.030), and "I fear side effects that might come with treatment on a clinical trial" (ΔR 2=.009, b=.13, p=.047). Thus, depression and anxiety accounted for significant amounts of variance in each of these clinical trial perceptions above and beyond the controls. Depression and anxiety did not have a significant impact on participants' perceptions that their health insurance would not cover a CCT (ΔR 2=.002, b=.05, p=.370). Conclusion. Our findings demonstrate small but significant relationships between depression, anxiety, and perceptions of CCTs among patients with hematologic cancer. While common attempts to alter CCT perceptions often focus on information dissemination, the present study indicates that psychological factors may also need to be considered. While this study is an important first step in considering the relationship between mental health and perceptions of CCT, further longitudinal research is needed to better elucidate these findings. For example, differential analyses should explore if and how these relationships differ among patients with pre-existing clinically-significant levels of depression and anxiety. Disclosures LeBlanc: AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Flatiron: Consultancy, Other: Advisory board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; UpToDate: Patents & Royalties; Pfizer: Consultancy, Other: Advisory Board; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; Helsinn: Consultancy, Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Astellas: Consultancy, Honoraria, Other: Advisory board; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; Jazz Pharmaceuticals: Research Funding; Otsuka: Consultancy, Honoraria, Other; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Other: travel; Heron: Consultancy, Honoraria, Other: advisory board; American Cancer Society: Research Funding; Duke University: Research Funding.

Effect of COVID-19 Pandemic Control Measures on Diagnoses of Hematologic Cancer Among CMS Population in 2020

Introduction Measures taken to mitigate infection spread during the 2020 COVID-19 pandemic are considered to have caused significant unintended consequences on other diseases. Large decreases in the numbers of symptomatic and asymptomatic people presenting for diagnosis of heart disease, diabetes and cancer have been observed. A recent analysis of solid tumors showed up to 70% reduction in the number of patients presenting for diagnosis. The potential exists for significantly increased morbidity and mortality for these missed or delayed presenting patients. Further, it is important to determine whether infection spread mitigation measures affected the diagnostic testing and treatment decisions for these patients. This study aimed to determine whether pandemic control measures affected presentation, testing and treatment of patients across eight different hematologic cancers. Methods CMS claims data were analyzed for the presence of diagnostic (DX) ICD 10 codes indicative of hematologic cancer. Patients with a DX code first appearing in 2019 or in 2020 were selected to provide newly diagnosed pre-COVID-19 and during COVID-19 cohorts for comparison, with unique patient counts being calculated for each month. A "COVID-19 dip" i.e. a decrease in the number of patients was calculated as the change in number of patients diagnosed in a given month relative to the number for JAN2020. Dip duration was calculated only when the decrease was >10% of the JAN2020 figure. Patients who received treatment via a "J" code Healthcare Common Procedure Coding System (HCPCS) code were extracted from the cohorts and the time taken from initial diagnosis to first treatment calculated. Results Eight hematologic cancers: AML, CLL, CML, HEME (a group of different hematologic cancers), Hodgkins (HOG), Myelodysplasia (MDS), Non-Follicular Lymphomas (NFL), and Non-Hodgkins Lymphoma (NHL) showed a decrease in the number of patients being diagnosed during the early part of 2020 (Fig.1) Fig.1. Change in new patient diagnoses for selected hematologic cancers as a proportion of their JAN2020 value There was some variation in the depth and duration of the COVID-19 dip (Table 1) with MDS having both the longest and deepest dip. Median depth and duration of the dip was 33% and 3.5 months, respectively, with all dips starting either in FEB or MAR2020. Table 1. Duration and depth of COVID-19 dips for selected hematological cancers The proportions of patients receiving therapy via J HCPCS code (JRX) are shown in Table 2 Table 2. Proportions of patients receiving J code therapy Conclusions The decline in new patient diagnoses for heme cancers during the period when COVID-19 control measures were implemented is similar to that seen with solid tumors, although the depth of the COVID-19 dip was generally larger in the latter. There is no evidence of "catch up" diagnosis occurring i.e. patients missing from Q2 2020 are not reappearing en masse in subsequent quarters. The decline for MDS patients has, except for SEP to OCT2020, remained. Collectively, (depending on the calculation method), the COVID-19 dip for these eight heme cancers represents 16,584-33,671 patients who will likely have significantly increased rates of morbidity and mortality due to delayed diagnosis. Analysis of J code treatments show little difference between the proportions of patients receiving these treatments in 2020 compared to 2019 suggesting that at least some aspects of treatment e.g. infused chemotherapy, IO drugs for these patients was relatively unchanged by pandemic control measures. It also suggests that the main cause for decreased patient numbers treated is due to decreased testing for diagnosis, rather than not being treated once diagnosed. This aligns with findings from studies in the US and UK. The results of this study indicate that there may be a "backlog" of tens of thousands of people with cancer whose diagnosis has been significantly delayed and who urgently need to be identified in order to get on proper treatment to lessen the impact of that delay. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Expert Curation of Somatic FLT3 Variants By the Clingen Somatic Hematologic Cancer Taskforce (ClinGen HCT)

Clinical significance of somatic gene variants needs to be comprehensively characterized for their diagnostic, prognostic and/or therapeutic actionability in patient management. However, challenges remain due to discrepancies in interpretation and reporting of these somatic variants among different testing labs. Therefore, standardized curation, clinical interpretation and reporting of somatic variants in hematologic cancers is critical. To address this issue, the Hematologic Cancer Taskforce (HCT), composed of 52 multi-disciplinary experts including oncologists, molecular pathologists, lab directors, genomic scientists and biocurators, was formed in January 2020 within the ClinGen Somatic Cancer Clinical Domain Working Group (CDWG) with a goal to undertake systematic curation and evidence-based clinical interpretation of genes/somatic variants associated with hematologic malignancies. In collaboration with the Clinical Interpretation of Variants in Cancer (CIViC) (civicdb.org) knowledgebase, HCT members curate, edit, and verify Evidence Items for each variant extracted from peer-reviewed publications. Monthly discussions based on these Evidence Items lead to the preparation of variant Assertions, which summarize the state of the field consensus variant interpretation and include tiering based on the AMP/ASCO/CAP guidelines (PMID: 27993330). FMS-like tyrosine kinase 3 (FLT3) encodes a class III receptor tyrosine kinase expressed in hematopoietic cells. FLT3 mutations, including both internal tandem duplication (ITD) and mutations in the tyrosine kinase domain (TKD), are the most common mutations in acute myeloid leukemia (AML), occurring in approximately 30% of all AML cases. Implementing FLT3 tyrosine kinase inhibitors (TKIs) in different treatment regimens for FLT3 mutated AML patients has led to significantly improved overall survival. Type I FLT3 inhibitors, including midostaurin, gilteritinib, sunitinib, lestaurtinib, and crenolanib, bind to the ATP-binding site when the receptor is in active conformation. Type II FLT3 inhibitors, including sorafenib, ponatinib, and quizartinib, interact with a hydrophobic region directly adjacent to the ATP-binding domain that is only accessible when the receptor is inactive, which prevents receptor activation. Generally in AML cells, type I FLT3 inhibitors prevent activity for both ITD and TKD mutations, while Type II inhibitors target ITD but lack efficiency against TKD mutations. The development of TKD mutations in AML cells with ITD have proved to be a mechanism of acquired, or secondary resistance to Type II FLT3 inhibitors. The HCT is piloting curation assessments of FLT3 alterations, including ITD, TKD and non-TKD variants, in AML. So far, the HCT has curated 75 evidence items for FLT3 somatic variants. FLT3-ITD, as well as D835 and I836 were asserted as tier 1 level A variants based on the prediction of response to gilteritinib in relapsed/refractory AML (PMIDs: 27993330, 31665578, 28645776, 28516360, 27908881). Recent curation activities are focused on FLT3 D839G and N676K, as clinical trials using large AML patient cohorts are lacking in their ability to validate drug response/resistance associations of these two TKD variants due to their low frequency. Functional studies showed both variants result in increased proliferation and protection from apoptosis, supporting the oncogenic potential of these two variants (PMIDs: 26891877, 2468088). FLT3 D839G combined with ITD confers resistance to pexidartinib and ponatinib, both Type II FLT3 inhibitors (PMIDs: 25847190, 23430109). FLT3 N676K predicts response to the Type I FLT3 inhibitor, gilteritinib, when N676K is present alone or in combination with ITD. Interestingly, FLT3 N676K in the absence of ITD predicts response to sorafenib, a Type II FLT3 inhibitor (PMIDs: 32040554, 32984009). However, these results are mostly derived from in vitro studies. Two separate Tier II, Level D Assertions have been submitted for FLT3-ITD&D839G for its response to pexidartinib and ponatinib, and more evidence is being collected to form an Assertion for FLT3 N676K. The complexity of the prediction of response/resistance associated with FLT3 D839G and N676K supports the importance of evidence-based curation and collection for these variants in the context of the overall mutation profile, disease context and specific FLT3 TKIs to clearly define their clinical impact. Disclosures Pullarkat: Stemline Therapeutics: Honoraria.