Clinical and Economic Burden During Hospitalizations Among Cancer Patients with Febrile Neutropenia: Evidence From U.S. Hospitals, 2007–2010

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 239-239
Author(s):  
Brian Dulisse ◽  
Xiaoyan Li ◽  
Julie A. Gayle ◽  
Richard L. Barron ◽  
Frank R. Ernst ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Hodgkin Lymphoma ◽  
Economic Burden ◽  
Case Fatality ◽  
Tumor Type ◽  
Index Hospitalization ◽  
Employment Equity ◽  
Equity Ownership ◽  
Infection Types ◽  
Tumor Types

Abstract Abstract 239 Background: Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy that often requires hospitalization. Published burden-of-illness estimates for FN-related hospitalizations were either based on clinical practice more than a decade ago (Caggiano et al Cancer 2005, Kuderer et al Cancer 2006) or derived from small samples (Schilling et al Exp Ther Med 2011). Methods: A retrospective cohort study was conducted to provide updated estimates using 2007–2010 hospital discharge data from a database maintained by Premier and containing service records of over 400 geographically diverse hospitals. It is one of the largest hospital databases in the U.S. The study population included adult patients with 1 of 6 tumor types (breast, lung, colorectal, ovarian cancers; non-Hodgkin lymphoma [NHL]; and Hodgkin lymphoma), discharge diagnoses of neutropenia (ICD-9 code 288.0x) with fever or infection, and receipt of intravenous antibiotics. The average hospitalization cost, case fatality rate, and average length of stay (LOS) associated with each patient's first FN-related hospitalization (index hospitalization) were computed with associated 95% confidence intervals (CIs) for all tumor types combined and stratified by tumor type. Detailed costs and resource utilization components within index hospitalizations were also examined and tallied. Tumor-type-specific multivariate linear regressions (for costs and LOS) and logistic regressions (for mortality) were conducted to assess the effect of infection types and comorbidities on study outcomes, adjusting for other patient and hospital characteristics. FN-related 30-day readmission rates after index hospitalizations were also estimated. All cost measures reflected actual direct costs to hospitals and were adjusted to 2010 dollars. Results: Hospitalization with FN was identified in 16,273 cancer patients. The mean (SD) age was 63 (14) years; 49% were aged ≥65 years; and 60% were female. Hospitalization costs and clinical outcomes of index hospitalizations varied by tumor type and by discharge status (Table). For all tumor types combined, 19% of patients were treated in an intensive care unit (ICU) setting during index hospitalizations, with average LOS of 5.2 days spent in ICU. The estimated models identified certain infection types and comorbidities as potential risk factors for inpatient mortality and predictors of higher economic burden. Of note, breast cancer patients with diagnosed septicemia/bacteremia (N=656) had average costs that were $5,664 (95% CI: $4,233–$7,095) higher than those with other infections (N=2,623), average LOS that was 1.7 days (95% CI: 1.0–2.3) longer, and a higher case fatality rate (risk ratio [as approximated by odds ratio]: 4.12, 95% CI: 2.6–6.5), after adjusting for other observed potential confounders. Higher average costs were also observed in NHL patients with diagnosed renal disease (N=1,263) than in those without renal disease (N=4,174) (adjusted difference: $10,408, 95% CI: $8,391–$12,425). The FN-related 30-day readmission rate after index hospitalization was 5.9% for all tumor types combined. The rate was 9.9% for NHL and 8.6% for Hodgkin lymphoma, higher than that in patients with other tumor types (2.3%–4.1%). Conclusions: FN-related hospitalizations among cancer patients are expensive, resource-intensive, and associated with considerable mortality risk. Substantial differences in the clinical and economic burden of FN exist depending on tumor types, infection types, and comorbidities. Disclosures: Dulisse: Premier healthcare alliance: Employment. Li:Amgen Inc.: Employment, Equity Ownership. Gayle:Premier healthcare alliance: Employment. Barron:Amgen Inc.: Employment, Equity Ownership. Ernst:Premier healthcare alliance, which contracted with Amgen to conduct this study.: Employment. Rothman:Dr. Rothman is an employee of RTI Health Solutions, an independent non-profit research organization that does work for government agencies and pharmaceutical companies.: Employment. Legg:Amgen Inc.: Employment, Equity Ownership. Kaye:RTI Health Solutions (a business unit of RTI International): Employment.

ONC201 Exhibits Mutation-Independent Efficacy with Superior Potency in Non-Hodgkin Lymphoma and Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3873-3873
Author(s):  
Joshua Allen ◽  
Rohinton Tarapore ◽  
Mathew J Garnett ◽  
Cyril Benes
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Stress Response ◽  
Tumor Type ◽  
Integrated Stress Response ◽  
Employment Equity ◽  
Phase Ii Clinical Trials ◽  
Equity Ownership ◽  
Tumor Types ◽  
Novel Agent

Abstract ONC201 is a first-in-class small molecule inducer of the integrated stress response that is currently in phase II clinical trials in select advanced cancers with promising early clinical results. The efficacy of this novel agent has been demonstrated in numerous preclinical advance cancer models in multiple indications with an exceptional safety profile that has translated well to the clinic. To determine the preclinical sensitivity profile of ONC201 in cancer, we performed an in vitro efficacy screen across >1,000 human cancer cell lines that represent a diverse array of tumor types and genetic aberrations. Sensitivity profiling was assessed by cell viability assays using dose responses curves at concentrations up to 20uM and at 72 hours post-treatment. Ranking the sensitivity dataset by tumor type, non-Hodgkin's lymphomas and multiple myeloma were the most sensitive tumor type to ONC201. The mutation-agnostic efficacy that is most pronounced in lymphomas and multiple myeloma is in accordance with the recent findings that ONC201 induces the integrated stress response through a novel target to trigger is downstream late apoptotic effects. B-cell malignancies are particularly susceptible to induction of apoptosis via the integrated stress response, as they have relatively high basal activation of this pathway due to ER stress conferred by immunoglobulin production. Confirmatory studies revealed that multiple myeloma cell lines indeed possess pronounced sensitivity with nanomolar GI50s, unlike most other tumor types, that is particularly encouraging given the systemic concentrations observed in the first-in-man study. Together, these studies suggest specific advanced cancer indications, such as non-Hodgkin's lymphoma and multiple myeloma, as promising lead indications for this novel agent that are being evaluated in phase II clinical trials. Disclosures Allen: Oncoceutics, Inc: Employment, Equity Ownership. Tarapore:Oncoceutics, Inc: Employment, Equity Ownership.

Incidence of Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified As High-Risk in Guidelines for Myeloid Growth Factor Use: Importance of “Risk Factor Stacking”

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4824-4824
Author(s):  
Derek Weycker ◽  
Xiaoyan Li ◽  
Rich Barron ◽  
Hongsheng Wu ◽  
Phuong Khanh Morrow ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Clinical Practice ◽  
High Risk ◽  
Febrile Neutropenia ◽  
Cancer Patients ◽  
Research Funding ◽  
Tumor Type ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background: Clinical practice guidelines recommend primary prophylactic colony-stimulating factor (CSF) when risk of febrile neutropenia (FN) is ≥20%. Evaluating FN risk among patients who receive regimens that are not documented as high risk in guidelines can be challenging, as some patients may be at a high risk based on a combination of the regimen and their risk factors. Methods: A retrospective cohort design and data from two US private healthcare claims repositories (2003-2012) were employed. The study population comprised cancer patients aged ≥18 years who initiated a course of chemotherapy with a regimen classified as “low” or “intermediate”, or that was unclassified, in terms of FN risk based on guidelines for CSF use. For each subject, the first qualifying chemotherapy course, and each cycle and FN episode within the course, was identified; use of CSF prophylaxis also was identified. FN was ascertained using diagnosis codes for neutropenia, fever, and/or infection; for FN requiring outpatient care only, receipt of intravenous antimicrobials also was required. FN incidence proportion was evaluated during the course within cohorts stratified by tumor type and regimen, for all patients in each cohort and by FN risk factor. Risk factors—documented in guidelines and the published literature, and listed in the Table herein—were evaluated during the 12-month pre-chemotherapy period. Unadjusted relative risks of FN for patients with versus without risk factors, and by the number of risk factors (i.e., “risk factor stacking”), were estimated. Only results for the five most frequently observed tumor/regimen combinations are reported herein. Results: Among patients with one of the five most frequently observed tumor/regimen combinations (n=84,252), 74-97% had ≥1 risk factor for FN and 42-88% had ≥2 (Table). Among patients with ≥1 risk factor, FN incidence ranged from 11-25% (relative risk vs. those without risk factors, 1.4-2.1), and increased in a graded and monotonic fashion with the number of risk factors present (Figure). Conclusion: In this retrospective evaluation of nearly 85,000 cancer patients receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, the large majority had at least one risk factor for FN and many had two or more. FN incidence was found to be markedly elevated in these patients, especially those with multiple risk factors (i.e., “risk factor stacking”). Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Weycker: Amgen: Research Funding. Li:Amgen: Employment, Equity Ownership. Barron:Amgen: Employment, Equity Ownership. Wu:Amgen: Research Funding. Morrow:Amgen: Employment, Equity Ownership. Xu:Amgen: Employment, Equity Ownership. Reiner:Amgen: Employment, Equity Ownership. Garcia:Amgen: Employment, Equity Ownership. Mhatre:Amgen: Employment. Lyman:Amgen: Research Funding.

The Economic Burden of Short-Term Adverse Events Associated with the CHOP Chemotherapy Regimen in Patients with Lymphoproliferative Disorders in the United States: A Comprehensive Literature Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5826-5826
Author(s):  
Crystal Watson ◽  
Arie Barlev ◽  
Jodie Worrall ◽  
Steve Duff ◽  
Rachel Beckerman
Keyword(s):  
Adverse Events ◽  
Resource Utilization ◽  
Economic Burden ◽  
Healthcare Resource ◽  
The United States ◽  
Healthcare Resource Utilization ◽  
Short Term ◽  
Employment Equity ◽  
Comprehensive Literature Review ◽  
Equity Ownership

Objectives: CHOP (vincristine, cyclophosphamide, prednisone, doxorubicin) is a treatment option for post-transplant lymphoproliferative disorder (PTLD) following solid organ transplant, an aggressive and potentially fatal disease. The most common and impactful CHOP-related adverse events (AEs) are febrile neutropenia (FN), chemotherapy-induced (CI) peripheral neuropathy (PN), infection, CI-anemia (A), and CI-nausea and vomiting (NV). These CHOP-related AEs have a large humanistic burdensignificant impact to quality of life (QoL) of patients, especially shortly after treatment. The evidence for a positive QoL benefit associated with some AE treatments (e.g., erythropoietin stimulating agents [ESA], granulocyte colony stimulating factors) is inconsistent and many patients likely remain with QoL deficits even after treatment. The impact of these short-term CHOP-related AEs is likely to be accompanied by an increase in healthcare resource utilization and costs. The objective of this study was to explore the economic burden of short-term CHOP-associated AEs in PTLD patients. Since PTLD is a rare disease with limited available data, we expanded our search to include all patients with lymphoproliferative disorders (LPD). Methods: Short-term (within several months after treatment) AEs associated with CHOP with an incidence of >4% in patients with LPDs were determined and sourced from the published literature and cancer websites. A comprehensive literature search was conducted using PubMed and EMBASE to identify economic burden studies published from 2010 to 2018 of the AEs associated with CHOP and its components in the United States (US). Studies incorporating rituximab alongside CHOP (CHOP + R) were also included as this is a valid treatment option for PTLD patients. Economic burden was defined as the management costs and resource utilization associated with treating CHOP-emergent adverse events. The conduct of this comprehensive literature review was guided by the PRISMA protocol wherein the research question (using the PICOS format), search strategy, target short-term AEs, and inclusion and exclusion criteria were pre-specified in detail. Results: Overall, 3,946 non-duplicate citations were screened, 39 studies were included for abstraction and no studies included patients with PTLD. Studies were methodologically heterogenous, with approximately half (56%) based on some form of retrospective analysis or prospective observational study. FN was the AE most commonly encountered, followed by CIA, infection, CI-nausea and vomiting, and CIPN. FN was an important driver of hospitalization (proportion of FN patients with hospitalization was up to 83.2%) and extended length of stay (LOS) was substantial for several AEs (LOS range in days: infection, 8.4-23.6; FN, 7.9-19.7). Mean LOS was longer in FN patients with multiple hospitalizations as well as in FN patients with comorbidities. Rates of transfusion in CI-anemia patients varied dramatically, from 10.8% to 47.4%. Transfusion rates were attenuated by ESA use in LPD patients, although a significant proportion of anemic cancer patients receiving ESAs still required transfusions. Total management costs were highly variable, ranging from nominal for events such as CIPN to over $197,000 in hospitalization costs per infection discharge per patients complicated with clostridium difficile. One recent study showed the inpatient costs attributable to FN were $33,006 per patient per episode. Studies identified CINV as a top reason for unplanned service use, but no studies were identified assessing its economic impact in LPD patients. Outpatient care costs for each AE varied but tended to have a low to moderate economic impact. The costs attributable to several AEs (FN, infection) were highest in the first cycle of chemotherapy. Conclusions: Several common short-term AEs due to CHOP in the LPD population were associated with substantial healthcare resource utilization and costs that were primarily driven by increased hospitalization and length of inpatient stays. Costs for FN and infections associated with CHOP ranged from $33,000 to over $197,000, demonstrating the high economic burden to the US healthcare system. No PTLD-specific studies were found, highlighting the absence of published data addressing the economic burden associated with chemotherapy in PTLD patients and the need for effective and tolerable therapies. Disclosures Watson: Atara Biotherapeutics: Employment, Equity Ownership. Barlev:Atara Biotherapeutics: Employment, Equity Ownership. Worrall:Atara Biotherapeutics, Inc: Consultancy. Duff:Atara Biotherapeutics, Inc: Consultancy. Beckerman:Atara Biotherapeutics, Inc: Consultancy.

The Combined Safety and Tolerability Profile of Vorinostat-Based Therapy for Solid or Hematologic Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1710-1710 ◽  
Author(s):  
David Siegel ◽  
Pamela N Munster ◽  
Eric Rubin ◽  
Marian Iwamoto ◽  
Simon van Belle ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Hematologic Malignancies ◽  
Tolerability Profile ◽  
Employment Equity ◽  
Advisory Committees ◽  
Common Drug ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Modifications

Abstract Abstract 1710 Poster Board I-736 Introduction Treatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. Methods Safety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events) In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval) A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was <10 msec at every timepoint, no patient had a QTcF change-from-baseline value >30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE) A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients (<5.8%) reported TEE as a serious AE (SAE), 47 (<2.6%) of which were recorded as being related to vorinostat, and 4/47 (<0.3%) TEE SAEs were fatal. Conclusions In this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. Disclosures Siegel: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

The Economic Burden of Pleural Effusions (PE) In Patients with Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3841-3841
Author(s):  
Eric Qiong Wu ◽  
Annie Guerin ◽  
Vamsi Bollu ◽  
Denise Williams ◽  
Amy Guo ◽  
...  
Keyword(s):  
Resource Utilization ◽  
Medical Cost ◽  
Economic Burden ◽  
Regression Models ◽  
Index Date ◽  
Healthcare Resource ◽  
Healthcare Resource Utilization ◽  
Total Medical Cost ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 3841 Background: Ph+ CML patients may develop PE, as an adverse event of some tyrosine kinase inhibitors (TKI) drug therapy. PE is characterized by an excessive accumulation of fluid in the fluid-filled space that surrounds the lungs. PE requires medical care, may compromise the course of CML treatment, and have economic consequence beyond the costs of treating PE. Aim: To compare healthcare resource utilization and costs between CML patients treated with a TKI who developed PE and their matched PE-free controls. Methods: MarketScan and Ingenix Impact databases (2001-2009) were combined to identify adult CML patients (ICD-9CM code 205.1×) who received ≥1 prescription of imatinib, dasatinib, or nilotinib before the index date and had continuous enrollment ≥6 months prior to and after the index date. The index date was defined as 30 days before the first PE diagnosis (ICD-9CM code 511.9×) for patients with PE and was randomly selected among all the eligible calendar dates (i.e., following a prescription for a TKI and a diagnosis for CML) for the PE-free controls. Patients were followed for 6 months after the index date. PE and PE-free patients were matched on a 1:1 ratio using propensity score matching. PE-related (i.e., medical claims with a PE diagnosis) resource utilization (inpatient [IP], outpatient [OP], emergency room [ER] and other medical visits) and costs were estimated for PE patients. To estimate the overall incremental impact of PE, all-cause and CML-related (i.e., medical services associated with a diagnosis code of 205.1×) resource utilization and costs were compared between PE and PE-free controls. All costs were reported in 2009 US dollars. Incidence rate ratios (IRR) for healthcare resource utilization were estimated by Poisson regression models. Incremental costs were estimated using generalized linear models or two-part models. Multivariate regression models controlled for age, gender, treatment duration with tyrosine kinase inhibitor, other chemotherapy, bone marrow or stem cell transplant, CML complexity, Charlson comorbidity index, adverse events, and comorbidities. Results: The study included 179 matched pairs. On average, patients were 63.4 and 63.8 years old with 41% and 49% of the population being female for PE-free and PE patients, respectively. During the study period, PE patients were estimated to have an average of 0.62 PE-related IP admissions, 8.43 IP days, 0.06 ER admissions, and 1.76 OP visits. Compared to PE-free patients, PE patients had more than 7 times as many IP days (IRR=7.23; p<.01), almost 3 times as many IP admissions (IRR=2.96; p<0.01), almost twice as many OP visits (IRR=1.98; p<.01) and ER visits (IRR=1.77; p<.01). Especially, PE patients had almost 10 times as many CML-related IP days (IRR=9.91; p<.01), more than 3 times as many CML-related IP admissions (IRR=3.95; p<0.01), twice as many CML-related OP visits (IRR=2.16; p<.01), and almost 6 times as many CML-related ER visits (IRR=5.60; p<.01). On average, PE-related medical costs were estimated at $11,015 per patient, where 84.2% was accounted for by IP costs. Total costs for all-cause related medical services were estimated at $37,566 for PE patients and $14,841 for PE-free patients. After adjusting for confounding factors, the incremental total medical cost of PE patients was $22,299 (p<.01), mostly due to the incremental OP cost ($12,931; p<.01) and IP cost ($8,737; p<.01). Similarly, PE patients incurred higher CML-related medical costs compared to PE-free patients, with a $15,859 (p<.01) incremental cost. Conclusion: Compared to PE-free patients, PE patients have a substantial economic burden with higher PE-related costs, CML-related costs, and total medical cost. Disclosures: Wu: Analysis Group, Inc.: Employment. Guerin:Analysis Group, Inc.: Employment. Bollu:Novartis: Employment, Equity Ownership. Williams:Novartis: Employment, Equity Ownership. Guo:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ponce de Leon Barido:Analysis Group, Inc.: Employment. Yu:Analysis Group, Inc.: Employment.

scholarly journals Serum Proteomics Reveals Distinct Subtypes Associated with Treatment Response in Idiopathic Multicentric Castleman Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3716-3716
Author(s):  
Dustin Shilling ◽  
Jason R Ruth ◽  
Christopher Sheild Nabel ◽  
Sheila K Pierson ◽  
Mary Guilfoyle ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Treatment Options ◽  
Castleman Disease ◽  
Employment Equity ◽  
Multicentric Castleman Disease ◽  
Serum Proteomics ◽  
Equity Ownership

Abstract Human herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood disorder diagnosed in ~1,000 individuals in the USA each year. It involves polyclonal lymphoproliferation, constitutional symptoms, systemic inflammation and an uncontrollable cytokine storm resulting in life-threatening multi-organ failure. Diagnosis and treatment can be difficult due to limited etiological understanding and heterogeneous presentation - clinical, laboratory, and histopathological abnormalities overlap with infectious, autoimmune and oncological diseases. iMCD symptoms and disease progression are largely believed to be driven by interleukin-6 (IL-6). However, approximately 66% of iMCD patients did not respond to anti-IL-6 therapy, siltuximab, the only FDA-approved iMCD therapy, in its phase II study (NCT01024036). Few treatment options exist for anti-IL-6 refractory patients because alternative driver cytokines and signaling pathways are not known. Herein we report the largest study to-date of iMCD serum proteomes with correlative anti-IL6 response data from 92 iMCD patients in disease flare (n=75 of which were collected as part of NCT01024036), in order to: (1) molecularly define iMCD, (2) identify predictors of response to anti-IL6 therapy, and (3) gain insights into the pathogenesis of iMCD. Proteomes of HHV8-positive MCD (n=20), Hodgkin lymphoma (n=20), rheumatoid arthritis (n=20) and healthy individuals (n=44) were also analyzed. Of the ~1,300 analytes measured using SomaLogic SOMAscan, 1,178 passed QC and were included in analyses. Each analyte was log2 transformed and capped at the 2.5th and 97.5th percentiles. Clinical and laboratory data collected at the time of sample draw were used to calculate disease activity following a modified CHAP scale: C-reactive protein, hemoglobin and albumin; missing performance status. Response to siltuximab was determined in NCT01024036. Data analysis was performed using the Medidata Rave Omics machine learning platform and R v3.4.4. Clustering of baseline proteomic data for iMCD patients identified six clusters that ranged in size from seven to 27 subjects. No associations with race, site, sex, age, or batch were found. Analytes identified among the strongest differentiators include cytokines, chemokines and inflammatory molecules. Interestingly, the largest cluster was associated with response to siltuximab (p<0.05; 65% (11/17) vs 19% (5/27) in all others), higher disease activity (p<0.01), and higher IL-6 levels (p<0.01). Analysis of data for the entire study population separated HHV-8-positive MCD, Hodgkin lymphoma, and rheumatoid arthritis into distinct clusters. Of note, iMCD patients did not form a single or unique cluster, reinforcing the heterogeneity of the disease, and a subset of iMCD patients demonstrated similar, but not overlapping, proteomic profiles to those of Hodgkin lymphoma. These results indicate that previously undiscovered proteomically-distinct iMCD subtypes or disease states exist, which can be used to inform treatment options. Given that iMCD may have a sudden and severe onset, predictive markers of anti-IL6 therapy response are critical for timely administration of the correct treatment. Additionally, overlapping proteomic profiles of a subset of iMCD patients with Hodgkin lymphoma provide etiological insights. More broadly, this study represents the first use of high-quality serum proteomics data to study a rare non-malignant lymphoproliferative disorder and to assist with molecularly defining a heterogeneous disease, developing candidate diagnostic biomarkers, predicting response or failure to therapy, and identifying novel candidate therapeutic targets. Disclosures Guilfoyle: Janssen Pharmaceuticals, Inc.: Employment. Tendler:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Reddy:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinblatt:Amgen: Consultancy, Research Funding; Sanofi/Regeneron: Consultancy, Research Funding; Crescendo Bioscience: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; UCB Pharmaceuticals: Consultancy, Research Funding. Bower:Merck: Honoraria; ViiV: Honoraria; Gilead: Honoraria; Janssen Pharmaceuticals: Honoraria. Masaki:Ono: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Beineke:Medidata Solutions: Employment, Equity Ownership. Miljovska:Medidata Solutions: Employment. Katz:Medidata Solutions: Employment. Shenoy:Medidata Solutions: Consultancy. Oromendia:Medidata Solutions: Employment, Equity Ownership. Mezey:Medidata Solutions: Consultancy. Wiser:Medidata Solutions: Employment, Equity Ownership. Benbanaste:Medidata Solutions: Employment, Equity Ownership. Lee:Medidata Solutions: Employment. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Fajgenbaum:Janssen Pharmaceuticals, Inc.: Research Funding.

scholarly journals Safety of Anticoagulant Therapies for Treatment of Venous Thromboembolism in Patients with Cancer

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1178-1178 ◽  
Author(s):  
Michael Streiff ◽  
Dejan Milentijevic ◽  
Keith McCrae ◽  
Daniel Yannicelli ◽  
Jonathan Fortier ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Hazard Ratio ◽  
Control Cohort ◽  
Bleeding Events ◽  
Employment Equity ◽  
Patients With Cancer ◽  
Equity Ownership ◽  
Major Bleeding Events

Abstract Introduction: Anticoagulation is effective for the treatment of venous thromboembolism (VTE) in cancer patients, but it is also associated with an increased risk of bleeding. Previous clinical trials (e.g., CLOT and CATCH) of LMWH and warfarin for the treatment of VTE in cancer patients reported major bleeding in 3% to 6% of treated patients. The objective of this observational study was to compare the risk of major bleeding in cancer patients treated with anticoagulants for VTE in a real world setting. Methods: Medical and pharmacy claims from the Humana Database from 1/1/2013 to 05/31/2015 were analyzed. Newly diagnosed cancer patients with a first VTE diagnosis occurring after their first cancer diagnosis, and with ≥1 dispensing of an anticoagulant within 7 days after their VTE diagnosis, were selected. Based on the first anticoagulant received, patients were classified into one of the following cohorts: LMWH, warfarin, and rivaroxaban (other agents not included due to low utilization). Inverse probability of treatment weights based on propensity score were used to adjust for differences between treatment cohorts for the following comparisons: LMWH vs. rivaroxaban, LMWH vs. warfarin, and rivaroxaban vs. warfarin. Patients were followed up until the earliest event, either treatment non-persistence (gap > 60 days between the end of the days of supply of a dispensing and the start date of the next dispensing), or end of data availability. Major bleeding events were identified using validated criteria (Cunningham et al., 2011). Kaplan-Meier rates at 3 and 6 months and Cox proportional hazards models were used to compare the risk of bleeding between different treatment cohorts. To better understand the risk of major bleeding in cancer patients unrelated to anticoagulation, a cohort of patients with cancer who did not have VTE and did not receive an anticoagulant was added as a control cohort. Results: A total of 2,428 patients (LMWH: n=660; warfarin: n=1,061; rivaroxaban: n=707) were included. Baseline demographic and clinical characteristics were well balanced among treatment cohorts. Median duration of therapy with LMWH was shorter than rivaroxaban (1.0 vs. 3.0 months, p<.0001) and warfarin (1.0 vs. 3.5 months, p<.0001). Rates of major bleeding for LMWH and rivaroxaban were 8.3% and 8.2%, respectively at 6 months with a hazard ratio (HRs [95% CI]) of 1.03 (0.64-1.65; Figure 1A). In the comparison between LMWH and warfarin cohorts, major bleeding rates were 8.5% and 8.6%, respectively at 6 months with hazard ratio (HRs [95% CI]) of 1.04 (0.69-1.57; Figure 1B). The risk of major bleeding was also similar for rivaroxaban and warfarin cohorts, 9.0% and 8.7%, respectively at 6 months with a hazard ratio (HR [95% CI]) of 1.01 (0.71-1.43; Figure 1C). For the control cohort of cancer patients without VTE and not receiving anticoagulation median follow-up was 5.6 months. Rates of major bleeding events for the control cohort were 2.6% and 4.2 % at 3 and 6 months, respectively. Conclusion: This real world study of cancer patients treated for VTE found that the risk of major bleeding was similar for the 3 most widely prescribed anticoagulants in current clinical practice: LMWH, warfarin, and rivaroxaban. The observed rates of major bleeding were generally higher than what has been reported for LMWH and warfarin in the CLOT and CATCH trials. Patient characteristics such as older age (average age 73 years) could have contributed to the higher major bleeding rate seen in this study compared to the CLOT and CATCH trials, respectively. Figure 1 Rates of Major Bleeding Events LMWH vs. rivaroxaban cohorts Figure 1. Rates of Major Bleeding Events. / LMWH vs. rivaroxaban cohorts Figure 2 LMWH vs. warfarin cohorts Figure 2. LMWH vs. warfarin cohorts Figure 3 rivaroxaban vs. warfarin cohorts Figure 3. rivaroxaban vs. warfarin cohorts Disclosures Streiff: Portola: Research Funding; Janssen: Consultancy, Research Funding; Roche: Research Funding; CSL Behring: Consultancy, Research Funding. Milentijevic:Janssen Scientific Affairs: Employment, Equity Ownership. McCrae:Janssen: Membership on an entity's Board of Directors or advisory committees. Yannicelli:Janssen Scientific Affairs: Employment, Equity Ownership. Fortier:Janssen Pharmaceuticals: Research Funding. Nelson:Janssen Scientific Affairs: Employment, Equity Ownership. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Khorana:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Leo: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding.

A Phase 1 Study Of JNJ-40346527, a Colony Stimulating Factor-1 Receptor (CSF-1R) Inhibitor, In Patients With Relapsed Or Refractory Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1812-1812 ◽  
Author(s):  
Bastian von Tresckow ◽  
Franck Morschhauser ◽  
Vincent Ribrag ◽  
Max S. Topp ◽  
Caly Chien ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Phase 1 ◽  
Median Number ◽  
Employment Equity ◽  
Advisory Committees ◽  
Overall Response ◽  
Equity Ownership ◽  
Systemic Therapies

Abstract Introduction JNJ-40346527 is a selective inhibitor of the colony stimulating factor-1 receptor (CSF-1R) tyrosine kinase. It impairs macrophage recruitment in animal models and reduces viability of Hodgkin lymphoma (HL) cell lines in vitro. Therefore, JNJ-40346527 has two potential targets in HL tumors: tumor associated macrophages and HL cancer cells. This study investigates JNJ-40346527 as a treatment for relapsed or refractory classical HL. Methods The patient population included men and women aged 18 years of age or older with a histopathologically confirmed initial diagnosis of classical HL and who have disease that has relapsed or is refractory after at least 1 appropriate therapy. Patients were assigned to sequential cohorts of oral daily dose of JNJ-40346527 (150, 300, 450, 600 mg QD, and 150 mg BID). Each treatment cycle consisted of 21 days. Dosing was continuous until progressive disease, toxicity or any other reason. Upon completion of 1 cycle (21 days of dosing, this may include any delays occurring during cycle 1) of each dose cohort, a review of all available study data was done by the study evaluation team (SET). The SET consists of the principal investigators (or their designees), the sponsor's medical monitors, and the sponsor's clinical pharmacologist. All (serious) adverse events, occurrence of dose limiting toxicities, pharmacokinetics and overall response rate were considered by the SET before deciding to go to the next dose level. Disease evaluations were done at baseline, end of cycle 2, end of cycle 6, and thereafter at the discretion of the investigator, and included CT/MRI and PET scan. Overall response was based upon both modalities. During the first cycle, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of blood samples was performed on days 1, 7, 14 and 21 and at various timepoints during the day. PD included total and phosphorylated CSF-1R after CSF-1 stimulation. The primary endpoint for dose escalation phase was to establish the recommended phase 2 dose. Secondary endpoints included safety, overall response rate, PK, and PD. Results In this ongoing phase 1 study, 21 patients ([150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3] QD, and 150 mg: 7 BID) were enrolled, 10 men/11 women, median age 40 (range, 19–75) years, and median number of prior systemic therapies were 6 (range, 3–12); 12/21 pts underwent >5 prior systemic therapies and 18/21 pts received autologous stem cell transplant. In addition, 15/21 patients underwent radiotherapy and 3/21 patients had HL related surgery. No dose limiting toxicities were observed. Maximum tolerated dose has not been established yet. As of 01 June 2013, 6 patients are ongoing in the study. Best overall response seen is 1 patient with a complete response, ongoing in the study for 10 months, and 10 patients showing stable disease, varying from 1.5–8 months. A first disease evaluation is still pending for 2 patients. A total of 15 patients discontinued treatment, 13 patients due to progression of disease, 1 patient by investigator decision (increased PET activity), and 1 patient due to treatment-emergent adverse events (TEAEs, lung embolism noted at C1D1, which was a pre-existing event at study entry). Median number of cycles received was 3.5 (range, 1–15). Most common (≥20% of patients) possibly drug-related TEAEs (per investigator assessment) were nausea, headache and vomiting. Serious TEAEs were recorded for 4 patients, none of them related to treatment as per investigator assessment. Preliminary PK analysis showed that JNJ-40346527 exposure increased in a near dose-proportional manner over the dose range of 150–450 mg QD but plateaued out at 600 mg QD. Serum trough levels were within the projected pharmacologically active concentration range at a dose as low as 150 mg QD. Preliminary PD analysis confirmed target engagement and showed >80% inhibition of CSF-1R phosphorylation at 4 hours post dosing in peripheral blood mononuclear cells stimulated with CSF-1. Conclusion Preliminary results indicate that JNJ-40346527 was well-tolerated and may be effective for the treatment of Hodgkin lymphoma. Disclosures: von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Morschhauser: Janssen Research & Development : Honoraria. Ribrag: Bayer: Research Funding; takeda: Membership on an entity’s Board of Directors or advisory committees; Janssen Research & Development: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chien: Janssen Research & Development: Employment, Equity Ownership. Seetharam: Janssen Research & Development: Employment, Equity Ownership. Aquino: Janssen Research & Development: Employment. Kotoulek: Janssen Research & Development: Employment. Khan: Janssen Research & Development: Employment, Equity Ownership. de Boer: Janssen Biologics B.V.: Employment, Equity Ownership. Engert: Millennium, Takeda: Consultancy, Honoraria, Research Funding.

scholarly journals A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1953-1953 ◽  
Author(s):  
Tae Min Kim ◽  
Nehal Lakhani ◽  
Justin Gainor ◽  
Manali Kamdar ◽  
Philip Fanning ◽  
...  
Keyword(s):  
Immune Response ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Marginal Zone ◽  
Tumor Response ◽  
Low Grade ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Mantle Cell ◽  
Equity Ownership

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. ALX148 is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In combination with anti-tumor antibodies, ALX148 enhances the innate and adaptive immune response against cancer. ALX148 has previously been shown to be well tolerated both as a single agent and in combination with pembrolizumab or trastuzumab in a range of solid tumors with no maximum tolerated dose (MTD) identified (SITC 2018 #P335, ASCO 2019 #2514). Characterization of ALX148's safety profile and antitumor activity in combination with rituximab are reported in patients (pts) with both aggressive and indolent histologies of non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety confirmation population was first cycle dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Preliminary clinical data from the fully enrolled cohort is reported as of July 15, 2019. Results: Twenty pts (15 males, 5 females) with NHL were administered ALX148 in combination with rituximab (DLBCL, n=11; mantle cell lymphoma, n=4; follicular lymphoma, n=3; and marginal zone lymphoma, n=2). The pts median age was 66 years (range 32-80) and ECOG PS 0/1 was 7/13. Patients had a median of 3 prior lines of therapy (range 1-7) with 50% having rituximab-refractory tumors. There were no dose limiting toxicities reported and the MTD of ALX148 in combination with rituximab was not reached. The maximum administered dose was 10 mg/kg QW. Sixteen pts experienced any AE, while 11 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (20%, n=4); anemia, fatigue, nausea, neutropenia and decreased platelets (10%, n=2 each). One TRAE ≥ G3 of neutropenia occurred in more than 1 patient (1G3, 1G4). As of the data cut off with a median follow-up time of 3 (0.3-14) months, preliminary tumor response was assessed in 17 evaluable pts using the Lugano Classification, 2014. The ORR was 35% across all tumor histologies, with a 50% ORR reported in indolent (FL+MZL), and 31% ORR reported in aggressive (DLBCL+MCL) histologies. The overall DCR was 41%. Six pts achieved partial response [(2) follicular, (2) DLBCL, (2) mantle cell]. Four pts achieved SD [(1) each of follicular, marginal zone, DLBCL(>1yr), and mantle cell]. Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity in combination with rituximab was observed with objective responses reported in heavily pretreated and rituximab-refractory patients. Clinical trial information: NCT03013218 Disclosures Kim: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Lakhani:ALX Oncology Inc.: Research Funding; Ascentage Pharma: Research Funding; Asana Biosciences: Research Funding; BeiGene: Research Funding; Constellation Pharmaceuticals: Research Funding; Alexion Pharma: Research Funding; Cerulean Pharma: Research Funding; Forty Seven: Research Funding; Loxo: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; TaiRx: Research Funding; Apexian: Research Funding; Formation Biologics: Research Funding; Coordination Therapeutics: Research Funding; Symphogen: Research Funding; CytomX: Research Funding; InhbRx: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Livzon: Research Funding; Northern Biologics: Research Funding; Tesaro: Research Funding; Innovent Biologics: Research Funding. Gainor:BMS: Research Funding; Genentech/Roche: Other: grant; Takeda: Other: grant, personal fees; Blueprint: Research Funding; Loxo: Research Funding; Oncorus: Other: grant , personal fees; Regeneron: Other: grant,personal fees; Pfizer: Other: grant personal fees; Incyte: Other: grant personal fees; Novartis: Other: grant, personal fees; Merck: Other: grant personal fees; Agios: Other: personal fees; Amgen: Other: personal fees; Array: Research Funding; Tesaro: Research Funding; Moderna: Other: grant; Adaptimmune: Other: grant; ALX Oncology: Other: grant; Ironwood Pharma: Equity Ownership. Kamdar:AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Fanning:ALX Oncology Inc: Employment, Equity Ownership. Squifflet:IDDI: Employment; ALX Oncology Inc: Consultancy. Jin:ALX Oncology Inc.: Consultancy. Wan:ALX Oncology Inc.: Employment, Equity Ownership. Pons:ALX Oncology Inc.: Employment, Equity Ownership; venBio: Employment, Membership on an entity's Board of Directors or advisory committees. Randolph:ALX Oncology Inc: Employment, Equity Ownership; venVio: Consultancy; Carrick: Equity Ownership. Kim:Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding.

Identification of a Predictive Factor for Reversible Neurological Adverse Events in a Subset of Non-Hodgkin Lymphoma Patients Treated with CD19-Specific BiTE ® Antibody Blinatumomab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4793-4793 ◽  
Author(s):  
Gerhard Zugmaier ◽  
Dirk Nagorsen ◽  
Matthias Klinger ◽  
Ralf C Bargou ◽  
Mariele Goebeler ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Hodgkin Lymphoma ◽  
Predictive Factor ◽  
Single Agent ◽  
Target Cells ◽  
Speech Impairment ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership

Abstract Abstract 4793 Blinatumomab is a CD19/CD3-bispecific antibody construct of the bispecific T cell engager (BiTE®) class showing as single agent a high rate and duration of responses in patients with relapsed non-Hodgkin lymphoma (NHL) and B-precursor acute lymphocytic leukemia (ALL). Blinatumomab has a favorable safety profile with exception of a subset of patients developing neurological adverse events (AEs) during the first days of treatment, such as confusion, speech impairment or cerebellar symptoms. Thus far, all relevant neurological AEs (11 out of 48 patients) were transient, fully reversible and resolved without sequelae within 3 to 72 hours after stop of infusion. In no case, pathological findings were seen upon cranial magnetic resonance imaging. Despite treatment discontinuation, 4 patients with neurological AEs have achieved an objective lymphoma remission. Analysis of cerebrospinal fluid (CSF) taken within hours after stop of infusion showed detectable levels of blinatumomab in the majority of affected patients, while in one patient without neurological symptoms no blinatumomab was detectable in CSF during infusion. Moreover, increased levels of albumin and T lymphocytes in CSF support a disturbance of the blood brain barrier (BBB) as a possible underlying event. Analyses of patient serum samples for angiopoetin-2 and S100b are ongoing to investigate whether levels of the endothelial stress and BBB integrity marker, respectively, correlate with neurological AEs. In a retrospective analysis of 39 NHL patients, a baseline B cell to T cell (B:T) ratio in peripheral blood at or below 1:10 was identified as the only predictive factor for the subsequent occurrence of neurological AEs. The predictive value was then prospectively confirmed in 8 additional patients. Of note, ALL patients –despite very low B:T ratios– rarely showed neurological AEs, which may relate to previous intrathecal chemotherapy depleting target cells in the brain. Potential mechanisms for the neuroprotective effect of peripheral B cells are being investigated. In conclusion, we identified a simple measure to prospectively identify patients at risk of developing neurological AEs after onset of blinatumomab treatment. Mitigating measures are currently tested in these high-risk patients in order to avoid discontinuation of treatment. Disclosures: Zugmaier: Micromet: Employment, Equity Ownership. Nagorsen:Micromet: Employment, Equity Ownership. Klinger:Micromet: Employment, Equity Ownership. Bargou:Micromet: Consultancy, Patents & Royalties. Baeuerle:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties.

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