ABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo- HSCT) has traditionally involves administering fresh peripheral blood or bone marrow stem cells. At onset of the COVID-19 pandemic in March 2020, the National Marrow Donor Program (NDMP) mandated cryopreservation of all unrelated peripheral blood stem cell (PBSC) products to prevent interruptions in transplant plans by donor COVID-19 infection after recipient's start of conditioning chemotherapy. Since the lifting of this mandate, many centers have continued to cryopreserve grafts prior to initiation of conditioning, but the longer-term clinical outcomes of this practice including chronic graft versus host disease (cGVHD) rates of patients receiving cryopreserved stem cells have not been previously well described. Prior work has raised concern for a deleterious effect of cryopreservation on overall survival and non-relapse mortality (PMID: 33865804). However, heterogeneity in the patient population and reason for cryopreservation suggest that further study is needed to assess these outcomes. Here we report our single-institution experience of clinical outcomes using cryopreserved versus fresh URD PBSCs for allo-HSCT. We examined long-term outcomes in 387 patients who received unrelated donor (URD) PBSCs (136 cryopreserved, 251 fresh) between January 1, 2019 and July 31, 2021. The cohorts had similar baseline characteristics including donor/recipient age/sex, disease, conditioning regimen/intensity, and GVHD prophylaxis regimens. Two-year OS, PFS, relapse, NRM, and acute GVHD rates were not different between recipients of fresh versus cryopreserved PBSCs. Strikingly, 2-year incidence of cGVHD (28% vs 52%, p=0.00001) and moderate/severe cGVHD (9% vs 24%, p=0.00016) was substantially lower in recipients of cryopreserved PBSCs compared to fresh, respectively (Figure 1). This difference was only noted in patients receiving a GVHD prophylaxis regimen without post-transplantation cyclophosphamide (PTCY) (no PTCY 2-year cGVHD incidence cryopreserved vs fresh: 29% vs 57%, p=0.000016), moderate/severe cGVHD 16% vs 34%, p=0.0006) (Figure 2). For patients receiving a PTCY-containing GVHD prophylaxis regimen, there was no difference in cGVHD incidence (cGVHD cryopreserved vs fresh: 24% vs 27%, p=0.56, moderate/severe cGVHD 7% vs 9.3%, p=0.3, Figure 3). (Figure Presented) (Figure Presented) (Figure Presented) While survival and relapse rates are not different, cryopreservation is associated with a marked reduction in cGVHD rates in the setting of non-PTCy based GVHD prophylaxis. Larger multicenter or registry analyses are needed to confirm these observations and may prompt a re-assessment of the role of cryopreservation of stem cell products in clinical practice. If confirmed, it will be critical to understand the immunologic consequences of cryopreservation and how they might influence the clinical impact on chronic GVHDCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background: Intensive care unit (ICU) admission during hematopoietic stem cell transplant (HSCT) is associated with poor prognosis1,2. Published series report a range of ICU admission rates from 24-40% of transplant patients, most frequent reasons involving septic shock, respiratory failure and veno-occlusive disease3. In addition, patients undergoing HSCT are at a high risk of severe morbidity and mortality associated with COVID-194. Aims: The aim of this study was to analyze outcome of HSCT patients requiring ICU admission in our center. Methods: We retrospectively analysed outcome of 752 patients who underwent HSCT in our centre from January/2008 to June/2021. Data were collected from patients' clinical histories. Results: 103 (14%) patients required ICU admission (baseline and HSCT characteristics on table). Median time to ICU admission was 42 days (-2-1765). Seven of these patients were admitted to ICU on two occasions giving a total of 110 consecutive ICU admissions available for analysis. Main reason for ICU admission was respiratory distress (74;67%), mainly due to pneumonia (53%) including a 3% caused by COVID19, pulmonary edema (26%) and pulmonary haemorrhage (8%). Septic shock was second most common cause for ICU admission (26;24%) due to gram-negative bacilli (47%), fungal (15%) gram-positive bacteria (13%), virus (10%) and others/idiopathic (16%). Other less frequent causes were veno-occlusive disease (11;10%), hepatic failure/encephalopathy (8;7%), haemorrhagic complications (6;5%), cardiorespiratory arrest (2%), GVHD (2%), cardiogenic shock (2%). Of the 110 ICU admissions, 37 (34%) required hemofiltration, of which 30 (81%) died;and 77 (70%) required orotracheal intubation, of which 59 (77%) died. During the 110 ICU admissions, 67 patients (61%) died in the ICU;of these, 40 (37%) received unrelated donor HSCT, 36 (33%) sibling donor, 16 (15%) haploidentical and 17 (16%) autologous. Median ICU length of stay of these patients was 13 days (range 1-76). The cause of death was the same reason for ICU admission. Eighteen (16%) patients were discharged from ICU and died prior to Hospital discharge and 24 (22%) survived to Hospital discharge and were classified as post-discharge survivors. Of these 24 cases, 19 (79%) remain alive while the others (5;21%) succumbed to underlying disease or complications post-HSCT. Off note, both patients with COVID19 pneumonia (haploidentical and autologous HSCT respectively) were discharged from ICU and remain alive to date, without major complications. Summary/Conclusion: In our study 14% of transplant recipients required ICU admission, slightly lower than previous reports. Most common cause of admission was respiratory failure, consistent with reported. Mortality rate during ICU admission was 61%;higher death rate observed in allogeneic transplantation and those requiring aggressive ICU treatments such as mechanical ventilation or hemofiltration. Although patients with COVID19 pneumoniae who require ICU admission are usually associated with adverse outcome, in our series they responded successfully to intensive treatment. ICU admission following HSCT is associated with poor prognosis, but should not be considered futile. (Table Presented).
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Background: In the largest study of Baliakas et al. (2019) the presence of at least 5 abnormalities, was associated with dismal clinical outcome, independently of the somatic hypermutation status and TP53 status. The presence of 3 or 4 aberrations is defined as clinically relevant in the absence of TP53. Studies by Kittai (2021) and Al-Sawaf (2020) showed the impact of karyotypic complexity on survival in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib or venetoclax. The complex karyotype (CK) is a topic that is being intensively researched, both in the aspect of increasing karyotypic complexity stratification and clonal evolution. Optimal therapy for patients with CLL has not yet been developed. The combination therapy of ibrutinib and venetoclax was superior to chlorambucil and obinutuzumab in terms of undetectable minimal residual disease (MRD) responses according to data from the GLOW trial (Tunir, 2021). The importance of achieving a complete response with undetectable MRD as the goal of therapy in CLL was proposed (Montserrat, 2005). Aims: The aim of our study is to evaluate the effectiveness of therapy with ibrutinib and venetoclax in combination for the patients with CLL and CK. Methods: This ambilinear observational study included patients with CLL with high genetic complexity (high-CK), defined as >=5 aberrations or CK (>=3 aberrations) in combination with a 17p deletion (CK+del17p). The first retrospective cohort included patients treated with ibrutinib monotherapy (Imono) to progression or intolerable toxicity since May 2015. The second prospective cohort included patients receiving ibrutinib in combination with venetoclax (IVen) since July 2019. Venetoclax therapy was started at the 3rd month of ibrutinib (from the escalation phase). Combination therapy was continued until a complete response, defined as three consecutive PET-CT-negative and MRD-negative results 3 months apart. If this criterion was not achieved at 24th month of therapy, venetoclax was discontinued and ibrutinib continued indefinitely. Results: Seventy-nine patients are included in the study. Twenty-nine patients in the first cohort and 50 patients in the second cohort. The characteristic is presented in Table. At the current follow-up periods, there were no significant differences in PFS and OS regarding a follow-up period <= 24 months (with the exception of death from COVID-19, since patients were not observed at parallel time intervals). In the group of patients treated with Imono, the majority of patients achieved partial remission or partial remission with lymphocytosis by 12 months. In 21 patients from Iven group, with a median follow-up of 7.4 months, a complete remission was achieved (72.4%);of these, 8 had unmeasurable MRD. Four patients did not complete the escalation period. There was a significant difference in the median MRD response achieved between 3 (log10>10) and 12 (log10<0,1) months in IVen group (p=0,03). In 2 patient from the IVen group progression of the disease was noted. Summary/Conclusion: Combination therapy with ibrutinib and venetoclax is an effective oral regimen for high-risk patients with complex karyotype disorders. PFS in both groups is currently not significantly different, which is obviously due to the short follow-up period. Patients receiving the IVen regimen achieve a significantly better response, which paves the way for allogeneic transplantation in these patients.
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Background: In March 2020, specialists in the field of oncohematology faced the problem of severity of coronavirus infection in patients after high-dose course of chemotherapy and autologous or allogeneic bone marrow transplantation. This required a revision of a number of issues related to the selection of patients for bone marrow transplantation (BMT), the development of new preventive and therapeutic tactics aimed at the treatment of infectious and immunological complications in this category of patients, depending on the nature of the underlying disease, the status of the disease and the timing of the treatment. Aims: To assess the severity, the most typical complications and the COVID 19 severity aspects in patients in early and late post-transplant periods to develop the most optimal tactics for the prevention and treatment of COVID 19 in this group of patients. Methods: An analysis was made of patients after HSCT with active coronavirus infection from 2020 to 2021, hospitalized in the hematology department of the Moscow multidisciplinary hospital (the hospital was completely redesigned to work on the COVID19 profile). A total number of hospitalized patients after HSCT was 25: 4 patients after allogeneic transplantation, 21 -after autologous. According to the timing of HSCT, patients were divided into 2 groups -early post-transplant period (ETP) (2-90 days after HSCT) -14 patients, and late post-transplant period (LTP) (3-24 months) -11 patients. According to nosology, patients were divided into following groups: lymphomas -72%, MM -12%, AA and CML 8% each. All patients were admitted with a positive PCR test (0-7 days of COVID). COVID therapy was carried out according to the protocols adopted in the Russian Federation using antiviral drugs, biological therapy, corticosteroids, anticoagulants. If necessary, the required supportive therapy was carried out for this period of HSCT. Results: Severe COVID19 (CT 3-4 severity) was more often observed in patients in ETP (100%) than in LTP (45%) (p=0.021). The incidence of respiratory failure is 70% and 36% in ETP and LTP, respectively. According to the analysis in ETP, agranulocytosis was observed in 65% of cases, for LTP group -in 18% (p = 0.022). Development of severe infectious complications (bacterial, fungal and viral) was detected in 100% of patients in ETP, in 45% of patients in LTP (p = 0.002). Antifungal therapy was required in 100% of cases in ETP, and only in 27% of the LTP group (p=0.001). 90% of patients in both groups required biological therapy. Mortality in the group of patients in ETP was 35%, while no deaths were registered in the group of patients in LTP (p=0.027). Median of hospitalization period for ETP and LTP patients was 20 and 13 days, respectively. Summary/Conclusion: Patients in the early period after HSCT have a higher risk of developing lower respiratory tract infection, more likely to require antifungals, reserve group antibiotics, and have a greater risk of death from COVID-19. Biological therapy is not contraindicated in case of leukopenia and agranulocytosis in this group of patients.
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Background: Prognosis of r/r B-NHL is detrimental. Potentially curative therapeutic approaches, such as autologous stem cell transplantation and innovative CAR-T cell therapy, require maximum disease control to achieve optimal results. Glofitamab is a new bispecific antibody, with a unique 2:1 molecular configuration resulting in superior potency compared with other CD20xCD3 bispecific antibodies with a 1:1 format. Aims: Based on these encouraging results, we included 5 heavily pretreated patients in the early access program of Glofitamab, available in our country. Methods: We collected the data of 5 consecutive patients with r/r B-NHL, who were treated with Glofitamab in our department during the last 15 months. Results: Three men and 2 women, median age of 57 years (38-62), were resistant to 4 (n = 3) and 5 (n = 2) previous lines of treatment. The underlying lymphoma was Richter's transformation of CLL after allogeneic transplantation (alloHSCT), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), r/r diffuse large B-cell lymphoma (DLBCL) after CAR-T therapy and gray zone lymphoma (GZL) transformed to DLBCL. The median number of Glofitamab cycles administered was 3 (2-7). All 5 patients responded early to treatment, which became apparent immediately after the first dose of 2.5 mg. The patient with Richter's syndrome achieved metabolic remission after the 4th cycle and underwent second alloHSCT after the 7th cycle. Unfortunately, he passed away 8 months after alloHSCT due to disseminated atypical mycobacterial infection, remaining however disease free. The patient with tFL also achieved metabolic remission, but the drug was discontinued after the 7th cycle due to COVID-19 infection. He died two months after Glofitamab interruption due to disease progression and CMV encephalitis. The patient with PMBCL, responded partially after Glofitamab and had mediastinal radiotherapy as bridging therapy to CAR-T therapy. As the latter was delayed due to CMV reactivation and CMV enteritis, our patient deceased due to progressive disease. The patient with DLBCL after CAR-T therapy had initial clinical response after two Glofitamab cycles. Due to severe COVID-19, we decided to hold Glofitamab. COVID-19 and disease progression led to his death, a few weeks after COVID-19 diagnosis. Finally, the patient with transformed GZL had Glofitamab administered as bridging therapy prior to CAR-T treatment. After 3 cycles, while she was prepared to proceed to CAR-T therapy, she was diagnosed with invasive aspergillosis. She is currently been treated with antifungal agents, whereas disease is still active. Cytokine release syndrome (CRS) occurred in 3 out of 5 patients. In all cases it was grade 1-2 and manifested at the first administration of the drug, after 4, 32 and 10 hours respectively, from infusion initiation. CRS was managed with antipyretics and steroids, whereas none patient required Intensive Care Unit support. Only one patient required tocilizumab. No Immune effector cell-Associated Neurotoxicity Syndrome (ICANS) was observed. Summary/Conclusion: Glofitamab is effective in treating patients with r/r aggressive B-cell NHL. Efficacy makes it an appropriate bridging tool to autologous, alloHSCT or CAR-T therapy. Nevertheless, relapse remains a challenge for r/r disease. Adverse events, such as CRS, were generally manageable. Given the fact that it was administered to heavily pretreated patients, caution to opportunistic pathogens should be paid. Indeed, toxicity profile may be proven to be more favorable if the agent is being administered earlier in therapeutic algorithms.
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Hemophagocytic lymphohistiocytosis (HLH) is a condition of overexpressed inflammatory response resulting in hypercytokinemia, macrophages infiltration and subsequent multiple organ failure. Without treatment, it leads to death. The main etiological factors include: viral, bacterial and parasitic infections, malignancies and autoinflammatory diseases. The main clinical manifestations are: high fever ≥38°C, lymphadenopathy, splenomegaly, and hepatomegaly. Central nervous system involvement occurs in 30-70% of cases. Less common symptoms include: dyspnea, cough, arrhythmias, jaundice, peripheral edema, rashes, albinism and diarrhea. The picture of the disease seen in laboratory tests consists of: duopenia, hypofibrinogenemia (<150 mg/dL) high D-dimers level, and hyperferritinemia. Other abnormalities include hypertriglyceridemia, elevated liver enzymes, hyperbilirubinemia, hypoalbuminemia and hyponatremia. Diagnostics include: laboratory tests, histopathological examination, lumbar puncture, radiological imaging, functional test and genetic checking. It is important to rule out factors mimicking HLH. Some of the old, well-known criteria are of less relevance nowadays. The aim of the therapy is immunosuppressive, immunomodulatory and anti-cytokine treatment, using the HLH-2004 protocol. In secondary HLH, elimination of the causative agent is critical. In primary HLH, or relapse of secondary forms, allogeneic transplantation is the only curative treatment. The prognosis is uncertain.
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Background and study design: Patients with immunodeficiencies including CLL have an increased risk of severe infections and may not respond well to conventional vaccines. Two early international surveys reported that hospital-admitted Covid-19 patients with CLL had a high fatality rate (Mato et al., 2020;Scarfo et al., 2020). We recently showed that a robust and durable B and/or T cell immunity occurred in most convalescent CLL patients (Blixt et al., 2021). In contrast, the first publication on vaccination against SARS-CoV-2 in CLL reported seroconversion in only 39.5% of patients (Herishanu et al., 2021). We conducted a prospective clinical trial (COVAXID, clinicaltrials.gov: NCT04780659) in patients with various types of immunodeficiency and matched controls (n=539). Five equally sized cohorts were included: primary immunodeficiency, HIV, allogeneic transplantation or CAR-T, solid organ transplantation as well as CLL. The primary endpoint was seroconversion measured 2 weeks after the 2nd dose of the Pfizer-BioNTech vaccine (Comirnaty). Antispike antibodies in saliva (which may better correlate with protection, Khoury et al., 2020) and T cells (IFN-gamma ELISpot) were also measured. We report here the results of the CLL cohort. Results: Ninety CLL patients were included in four predefined subgroups: indolent untreated disease (n=30);prior chemoimmunotherapy including a CD20 mAb 9-30 months ago (n=20);ongoing BTKi therapy (n=30);and stopped/paused ibrutinib (all >3 months ago) (n=10). The median age was 70 years (range 23-87) and 67% were men. Median IgG was 6.7 g/L (range 1.0-20.8) and 50% had a value below the lower normal range. Reactogenicity occurred in 82.9 and 77.1% of the CLL patients and 81.6 and 85.0% of the controls after doses 1 and 2, respectively. The severity of reactogenicity was similar in patients and controls. AEs≥grade 2 was seen in five patients within 2 weeks after dose 2 but none was considered related to the vaccine. No hematological toxicity was observed. Data analysis on seroconversion is ongoing. Preliminary analysis of saliva showed that on D35 (i.e. 14 days after 2nd dose) 62% of CLL patients (95% of healthy controls) had developed IgG to S1S2 spike antigen compared to only 23% on D21 (i.e. 21 days after dose 1). Subgroup analysis (D35) indicates that ibrutinib-treated patients showed the lowest response in saliva whilst indolent and prior chemoimmunotherapy-treated groups were the best responders. A different pattern was observed for IFNgamma positive T cells with the highest responses in the (few) patients who had paused/stopped ibrutinib with other subgroups having lower T cell responses. Conclusions: This prospective clinical trial verified that the BNT162b2 mRNA vaccine was well-tolerated in patients with CLL. Our preliminary results indicate that anti-spike antibodies in saliva and T cell responses were frequently observed after full vaccination but with different response patterns in CLL subgroups. Details of the study including seroconversion and the overall response rate will be presented at the meeting.
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Onkopedia has been established more than ten years ago with the aim to provide comprehensive evidence-based guidelines on diagnosis and therapy of malignant and benign hematological diseases, as well as of solid tumors. Meanwhile, Onkopedia comprises more than 140 regularly updated guidelines. These include the frequently diagnosed hematological and oncological disorders, but also rare diseases. Specific therapies as allogeneic transplantation as well as innovative therapies (e.g. CAR T cell therapy) are included in separate sections. Special guidelines on supportive therapy report on details of the routine therapy and of recommended interventions in the case of complications. A further section gives an overview on complementary and alternative treatment modalities. A special guideline with recommendations for hematological and oncological patients with COVID19 infection was first available in July 2020 and updated in April 2021. The broad spectrum of the cited literature attached to each guideline indicates the scientific background. The quality and actuality of the Onkopedia guidelines is basing on the contributions of more than 500 experts from Germany, Austria and Switzerland, nominated by the leading persons of the DGHO, OeGHO and SGH+SSH and on mandatory updates in short intervals (routinely every two years, or immediately in the case of treatment-changing therapies). In dependence on the specific problems of each disease, besides hematologists and oncologists, colleagues of other disciplines (pathology, radiotherapy, surgery and others) are included to approach complex questions on an interdisciplinary basis. It is a definite aim to keep the content and the formal quality of the manuscripts on a high level. Clear algorithms and tables are required for easy use and understanding. Furthermore, the Onkopedia team continuously optimizes the technical background of the online platform corresponding to the ongoing progress. Thus, Onkopedia has developed to a valuable tool for the management of patients with hematological disorders or solid tumors.
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Introduction: While the approval of three commercial vaccines for the SARS-CoV-2 virus has provided upwards of 95% protection against the coronavirus for healthy subjects, the efficacy among patients with hematologic malignancies remains unknown. Immune dysfunction and impaired humoral responses to other vaccines are well documented in patients with CLL and B-cell lymphomas. Furthermore, they suffer increased risk of morbidity and mortality with Covid-19 infections compared to healthy controls. As such, the immune response elicited by the available Covid-19 vaccines in these patients is of utmost importance to investigate. Methods: We performed a prospective exploratory analysis in CLL and B-cell lymphoma patients to evaluate humoral and T-cell responses to the commercially available mRNA Covid-19 vaccines. The objective was to obtain samples at baseline and 2-3 weeks post-vaccination, although some samples were obtained outside of this timeframe. IgG to the SARS-CoV-2 spike receptor-binding domain (RBD) was quantified using the ImmunoCAP platform (Thermo Fisher);results were compared to data from 167 subjects in a healthy vaccine cohort at the University of Virginia. T-cell responses to spike protein of SARS-CoV-2 were measured in 3 NHL patients and 3 matched healthy controls at 2-3 weeks post-2nd vaccine dose, by T cell receptor dependent activation-induced marker (AIM) assay using pooled peptides spanning spike protein. Results: Among 18 patients currently evaluable, median age is 67 y and 72% are male. Diagnoses include CLL (5), marginal zone lymphoma (MZL;4), diffuse large B-cell lymphoma (3), follicular lymphoma (1), mantle cell lymphoma (MCL;4), and Waldenstrom's macroglobulinemia (1). All patients except 1 MZL patient are currently receiving or have received systemic treatment for their hematologic malignancy. Treatments include immunochemotherapy in 5 patients, Bruton's tyrosine kinase inhibitors (BTKi) with or without anti-CD20 monoclonal antibody therapy in 5, single agent anti-CD20 monoclonal antibody in 4, and other targeted therapy in 4 patients including venetoclax, lenalidomide, and bortezomib. Two patients had received prior autologous stem cell transplantation, 1 patient allogeneic transplantation, and 1 patient chimeric antigen receptor T-cell therapy. Among patients on therapy (n=10), median time from start of current treatment to Covid-19 vaccine was 136 days (range 13 - 829d). In patients who had completed therapy (n=8), median time from end of last treatment to vaccine was 153 days (range 37 - 355d). Seven patients had a blood sample drawn between 1 week and 1 month post-second mRNA vaccine dose. IgG antibody levels to spike RBD were markedly lower in NHL/CLL patients compared to those observed in the control cohort (median 2.1 µg/mL [IQR 0.23-7.6 µg/mL] versus 60.3 µg/mL [IQR 42.5-87.0 µg/mL], Mann-Whitney P<0.001, Figure 1). Of the 16 samples that were obtained post-vaccine dose 2, nine had IgG levels less than 2 µg/mL (manufacturer lower threshold of detection), whereas only 5 of 252 samples from the control cohort were less than this level (Chi-square P<0.001, RR =39.6 (95%CI 15.1-100)). Antibody responses were independent of type of therapy (Figure 2). The percentage of total lymphocytes and T cells was generally reduced in NHL patients versus controls;however, CD4+ T cells responding to spike protein were readily detected, despite the absence of antibody responses in 2 of these patients, both of whom had MCL. Curiously, 2 patients (1 MZL with and 1 MCL patient without antibodies) displayed a higher percentage of activated CD4+ T cells compared to controls, and CD8+ T cells also responded in each of these patients. T-cell responses were specific for spike protein as evidenced by no response to peptides of whole nucleoprotein. Conclusions: Compared to a reference cohort, patients with B-cell malignancies, both treatment-naïve and on treatment, have impaired antibody response to the commercially available mRNA Covid-19 vaccines. Despite this, virus-responsive T-cells can be readil detected, even in the absence of antibodies. Further research is needed to determine whether antibody levels can be used as a biomarker for vaccine efficacy, whether the presence of virus-specific T-cells confers protection in the absence of antibodies, and to determine the effect of booster doses of vaccine on immune response. [Formula presented] Disclosures: Wilson: Thermo-Fisher Phadia: Research Funding. Woodfolk: Regeneron: Other: Salary Support, Research Funding;NIH/NIAID: Other: Salary support, Research Funding;University of Virginia: Other: Salary Support;Regeneron: Other: research sponsor and salary support;FDA: Membership on an entity's Board of Directors or advisory committees;Clinical and Experimental Allergy: Other: Editorial Board. Portell: Abbvie: Research Funding;Aptitude Health: Honoraria;Merck: Honoraria, Research Funding;Xencor: Research Funding;Pharmacyclics: Honoraria;BeiGene: Honoraria, Research Funding;Targeted Oncology: Honoraria;Morphosys: Honoraria;SeaGen: Research Funding;TG Therapeutics: Honoraria, Research Funding;Acerta/AstraZeneca: Research Funding;Kite: Honoraria, Research Funding;Genentech: Research Funding;VelosBio: Research Funding. Williams: Janssen: Consultancy, Research Funding;Pharmacyclics: Research Funding.