Hematology Patient Explorer - an Informatics Infrastructure and Web Application Empowering Clinicians and Researchers to Use Electronic Health Record Information to Identify Clinical Cohorts of Interest

Abstract Introduction: The widespread adoption of electronic health records (EHR) in the US (Adler-Milstein and Jha 2017) presents an opportunity to transform healthcare into rapidly learning health organizations and systems (Etheredge 2007; Abernethy et al. 2010) that use routinely collected clinical data in the course of care to generate evidence, address information disparities in patients underrepresented in clinical trials, such as those who are older, belong to ethnic minorities, or are in medically underserved areas, and continuously improve the quality of care delivered.(Rivera et al. 2019; Penberthy, Rivera, and Ward 2019) Unfortunately, this potential remains largely unrealized due to deficiencies in EHR interoperability (Holmgren, Patel, and Adler-Milstein 2017) and usability.(Dunn Lopez et al. 2021) EHR information remains largely unstructured due to the nature of the patient-clinician interaction and current user interfaces where structured data entry is burdensome.(Khairat et al. 2019) At the University of Utah Huntsman Cancer Institute division of Hematology, clinicians as well as clinical and translational researchers often need detailed information on patients seen at the cancer center to plan and conduct research and evaluate and improve the quality of care delivered. Previous efforts to address these needs relied on a clinical data science and health informatics staff working with clinicians to identify patient cohorts of interest. As part of an effort to improve the efficiency of this service, decrease the latency in information provision, and serve a larger number of clinicians and researchers, we designed and implemented a highly usable, scalable, health information technology solution that allows clinicians and researchers to identify, in near real time, cohorts of interest, based on patient and disease characteristics. Methods: Common information needs at the division were assessed by identifying key stakeholders, including division leadership, clinicians, researchers, and health informatics leadership and staff. A team was formed to include overlapping expertise in Hematology, clinical informatics and data science, and prior experience in extraction of clinical information from EHR data warehouses to generate evidence on patient practices and outcomes. Information sources and architectures were evaluated on their comprehensiveness, validity, extensibility, and ability to integrate multiple data sources. A modern web-based interface was designed to mirror the steps clinicians and clinical researchers frequently used to identify cohorts of interest, provide guidance for these users, and generate population level and patient level information. Usability testing included rounds of initial internal testing, followed by a round of closed beta testing. Results: A data lake architecture was implemented to ingest, harmonize and stage information from various data sources, including the Enterprise Data Warehouse, Tumor Registry, and other data silos. Data cleaning and harmonization was done using Python. A web application using 'Dash' was implemented with four steps split into four consecutive panes. The first two focused on cohort identification using diagnosis (first pane), and patient and disease characteristics (pane 2). Users first input keywords that allow them to identify diagnoses of interest based on ICDO-3 codes. Users can select multiple codes at this stage. In the next step, users can filter down their cohort based on patient and disease characteristics, such as sex, age, year of initial diagnosis, grade and stage of disease, and others. Once all desired refinements to the pilot cohort are made, users move on to the third tab, which displays customizable population level information, such as number of diagnoses by year, sex, or age. Finally, the fourth tab presents individual level data such as Patient Medical Record Numbers, age, or ICDO-3 diagnosis descriptions. Based on this output, users can return to the initial selection criteria and adjust them. Users are able to download or export selection criteria and query results for future work. Conclusion: We describe the process, roles, and informatics infrastructure and tools to implement a web interface that allows clinicians and researchers to leverage EHR information to identify cohorts of patients for research and quality improvement. Further research will focus on tool usability and scope. Disclosures Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fusion Pharma, Medscape, DisperSol: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding.

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Revised-MALT-IPI: A New Predictive Model That Identifies High-Risk Patients with Extranodal Marginal Zone Lymphoma (EMZL)

Blood ◽

10.1182/blood-2019-125008 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4010-4010

Author(s):

Juan Pablo Alderuccio ◽

Isildinha M Reis ◽

Thomas M. Habermann ◽

Brian K. Link ◽

Catherine Thieblemont ◽

...

Keyword(s):

High Risk ◽

Family Member ◽

Board Of Directors ◽

Risk Score ◽

Research Funding ◽

Stage Iii ◽

Advisory Committees ◽

High Risk Patients ◽

Disease Characteristics ◽

Risk Patients

INTRODUCTION: EMZL is a heterogeneous disease with variable risk for relapse and progression. Based on age ≥70 years, stage III-IV and elevated LDH, Thieblemont et al (Blood. 2017) developed the MALT-IPI to identify high-risk patients. In this index, disease characteristics (stage and LDH) account for 66% while a disease nonspecific characteristic (age) for 33% of the index score. We reported (Am J Hematol. 2019) that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival and increased incidence of higher grade transformation. To better recognize disease-attributable high-risk patients, we developed a new EMZL prognosis score chiefly based on patient's disease characteristics. METHODS: The revised (R)-MALT-IPI was developed using a retrospective data set of 405 EMZL patients treated at the University of Miami (UM) from 1995 to 2017. Cox proportional hazards regression analysis was conducted to evaluate the effect of the potential prognostic variables on progression-free survival (PFS) and overall survival (OS) and to develop the new index R-MALTI-IPI based on PFS. Model validation was performed in two independent cohorts of EMZL patients from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) database (n=297) and the IELSG-19 study (n=400) used for the development of MALT-IPI. Performance of various prognostic indices was compared using AIC statistics, and concordance c-statistics by Harrell (CH) and by Gonen and Heller (CGH). RESULTS: Among the candidate variables tested in univariable analysis, the following were statistically significant predictors of shorter PFS: age >60, age ≥70, anemia (Hb<12g/dL), stage III-IV, ECOG PS ≥2, elevated serum LDH, number of extranodal sites >1, number of nodal sites >4, and presence of MMS at diagnosis, defined as EMZL with ≥2 different extranodal sites excluding spleen and bone marrow. A stepwise Cox regression analysis yielded a multivariable model with four independent predictors of shorter PFS: age >60 (HR=1.53, p=0.010), elevated LDH (HR=1.73, p=0.004), stage III-IV (HR=2.03, p=0.0003) and presence of MMS (HR=2.78, p<0.0001). Based on this, a new index R-MALT-IPI was developed with scores ranging from 0 to 5, calculated as a sum of 1 point for age >60, elevated LDH, stage III-IV, and 2 points for MMS. The R-MALT-IPI defined 4 risk groups: low-risk (score 0 (35%), reference group), low-medium risk (score 1 (39%), HR=1.91, p=0.005), medium-high risk (score 2 (13%), HR=3.77, p<0.0001), and high-risk (score 3+ (13%), HR=8.54, p<0.0001). When compared with MALT-IPI, R-MALT-IPI better stratifies and separates high risk patients (26%) into medium-high risk and high-risk patients with a median PFS of 5.8 years (2.9-9.1) and 1.8 years (1.3-2.6) respectively, compared to 2.6 years (1.8-4.7) in the high-risk MALT-IPI patients (16.8%). The R-MALT-IPI index also distinguished patients with different OS. For validation, we analyzed R-MALT-IPI index performance in independent Iowa/Mayo Clinic MER and IELSG-19 cohorts. Both R-MALT-IPI and MALT-IPI were useful in distinguishing PFS and OS in all the cohorts. In the UM training cohort, the concordance c-statistics' values for the two indices were similar: for PFS, CH=0.6893 and CGH=0.6611 for R-MALT-IPI, and CH=0.6551 and CGH=0.6367 for MALT-IPI; for OS, CH=0.7017 and CGH=0.6813 for R-MALT-IPI, and CH=0.7029 and CGH=0.67715 for MALT-IPI. In the validation cohorts, the concordance c-statistics' values for the two indices were also similar, but slightly lower than in the UM cohort for PFS. When comparing medium-high to high-risk R-MALT-IPI groups, there was a reduction of 4 years in median PFS in the UM cohort, and reduction in median EFS of 5.6 years in the MER cohort, an important difference between these risk groups identified by the R-MALT-IPI index. CONCLUSIONS: R-MALT-IPI is a new index for EMZL centered principally on disease characteristics. Overall, there is a similar prediction of PFS (EFS) by R-MALT-IPI and MALT-IPI indexes; however, R-MALT-IPI better recognizes a high-risk group accounting for 13% of EMZL patients with short median PFS and thus obviates the waiting period needed to recognize patients with shorter EFS24. Collaborative studies addressing best treatment approach for these high-risk EMZL patients are eagerly needed. Disclosures Alderuccio: Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; OncLive: Consultancy; Targeted Oncology: Honoraria; Puma Biotechnology: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member. Thieblemont:Cellectis: Membership on an entity's Board of Directors or advisory committees; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Zucca:Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.

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Multiple Myeloma Oligosecretory Relapse, a Non-Negligible Phenomenon. Frequency, Clinical Characteristics and Outcomes in a Single Center

Blood ◽

10.1182/blood-2021-151255 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3772-3772

Author(s):

Itai Zamir ◽

Tamir Shragai ◽

Svetlana Trestman ◽

Tomer Ziv Baran ◽

Efrat Luttwak ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

M Protein ◽

Advisory Committees ◽

Monoclonal Protein ◽

Disease Characteristics ◽

Comparator Group ◽

Measurable Disease

Abstract Introduction: Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials. Methods: Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP > 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups. Results: One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A). Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p<0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively. Conclusions: Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Bortezomib in Combination with Dexamethasone and Pegylated Liposomal Doxorubicin (DoVeD) Breaks Plateau Responses Following Initial Induction Therapy in Multiple Myeloma: Results of a Phase II Pilot Study.

Blood ◽

10.1182/blood.v114.22.2311.2311 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2311-2311

Author(s):

Megan C. Manco ◽

Tomer Mark ◽

David S Jayabalan ◽

Faiza Zafar ◽

Roger Pearse ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Liposomal Doxorubicin ◽

M Protein ◽

Long Term Outcomes ◽

Advisory Committees ◽

Disease Characteristics ◽

Grade 3

Abstract Abstract 2311 Poster Board II-288 Improved quality of response to induction therapy has been shown to be associated with improved long-term outcomes, including prolonged progression-free (PFS), event-free, and overall survival (OS), in newly diagnosed multiple myeloma (MM) patients (pts). Induction regimens incorporating the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have demonstrated high overall response rates (ORR), and substantial complete response (CR) and very good partial response (VGPR) rates in MM; however, while a large majority of pts respond, a proportion does not achieve ≥VGPR. Per the Norton–Simon hypothesis, the sequential, dose dense, use of agents or regimens that are not cross-resistant may improve the proportion of pts achieving CR or VGPR to induction therapy, and subsequently improve long-term outcomes. This phase II pilot study investigated the efficacy and safety of bortezomib + dexamethasone ± liposomal doxorubicin (DoVeD) in MM pts who had reached a response plateau (<25% change in M-protein level for three successive assessments) after achieving a partial response (PR) to initial induction with IMiD-containing therapy. All pts proceeded to high-dose therapy and stem cell transplantation. Pts received six 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, plus dexamethasone 40 mg on days 1–4, 8–11, and 15–18. Pts achieving <PR after two cycles or <CR after four cycles received liposomal doxorubicin 30 mg/m2 on day 4 for the remaining four or two cycles, respectively. Response to DoVeD was assessed relative to baseline prior to start of DoVeD therapy according to IMWG uniform response criteria. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 34 pts were enrolled; baseline demographics and disease characteristics are shown in the Table. Initial induction therapy comprised lenalidomide–dexamethasone in 22 pts, thalidomide–dexamethasone in 5 (followed by VAD in 1), thalidomide in 2, and thalidomide–lenalidomide–dexamethasone in 5. At data cut-off, 3 pts remained on DoVeD therapy and were not evaluated for response. The other 31 pts received a median of 6 cycles of DoVeD; liposomal doxorubicin was added in 22/31 (71%) pts, 11 after cycle 2 and 11 after cycle 4. Best responses to DoVeD were 5 (16%) stringent CR, 2 (6%) CR, 6 (19%) VGPR, and 12 (39%) PR, for a ≥VGPR rate of 42% and an ORR of 81%. Four (13%) pts achieved a minimal response, and 2 (6%) had disease progression. Median PFS was 1,210 days (95% CI: 387–1311) and 3-year PFS was 57% (95% CI: 27%–73%). Four pts died during the follow-up period. Median survival was not reached; 4-year OS was 83% (95% CI: 60%–94%). A Cox proportional hazards model controlling for age, sex, and ISS showed that only a ≥90% reduction in M-protein significantly correlated with reduction in disease progression (p=0.014). Among 33 pts who had completed one cycle of DoVeD and were thus evaluable for safety, all experienced at least one AE, including 23 (70%) who experienced at least one grade 3/4 AE. Hematologic grade 3/4 AEs during DoVeD therapy included 9/3% neutropenia and 9% grade 4 thrombocytopenia; non-hematologic AEs included fatigue, pneumonia, infection (9% each), diarrhea, constipation, irritability, hypotension (6% each), hand–foot syndrome, chest pain, and myopathy (3% each). In total, 23 (70%) pts experienced peripheral neuropathy, including 9 (27%) grade 2 and 3 (9%) grade 3 (no grade 4 PN). In conclusion, DoVeD therapy can result in further substantial reductions in tumor burden, including additional CRs and VGPRs, in MM pts whose response has reached a plateau following PR with prior IMiD-containing induction. The additional cytoreduction and increase in CR/VGPR rates achieved with this tandem approach, plus the potential associated improvement in long-term outcomes, suggest a possible paradigm shift for MM induction therapy in general. Table Patient baseline demographics and disease characteristics Characteristic* N=34 Age, years 60.5 (27-76) Male, n (%) 19 (56) B2-microglobulin, mg/L 2.1 (1.0-10.2) Albumin, g/dL 3.5 (2.0-4.3) Durie-Salmon Stage Ia / IIa / IIIa / IIIb, n 2 / 14 / 17 / 1 ISS Stage I / II / III, n 16 / 15 / 3 Abnormalities by FISH, n (%) del 13q14 13 (38) Trisomy 11 6 (18) Hyperdiploidy 5 (15) t(4;14) 4 (12) p53 3 (9) t(11;14) 2 (6) t(14;16) 2 (6) None 16 (47) * Median (range) shown unless stated Disclosures: Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Crann:Milllennium: Membership on an entity's Board of Directors or advisory committees. Leonard:Milllennium: Consultancy; Johnson & Johnson: Consultancy. Coleman:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau; Immunomedics: Membership on an entity's Board of Directors or advisory committees. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.

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Favorable Patient Survival after Failure of Venetoclax (ABT-199/ GDC-0199) Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v126.23.2939.2939 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2939-2939 ◽

Cited By ~ 7

Author(s):

Constantine Tam ◽

Mary Ann Anderson ◽

David S. Ritchie ◽

E. Henry Januszewicz ◽

Dennis Carney ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Disease Characteristics ◽

Btk Inhibitor ◽

Btk Inhibitors ◽

Support Research

Abstract Introduction Targeted inhibitors of BTK, PI3K or BCL-2 all induce durable responses in patients with chemotherapy-refractory CLL. In the case of the BTK inhibitor ibrutinib, two patterns of resistance have emerged: early (<12 - 24 months) progression with RichterÕs Syndrome (RS), and late progression with CLL often carrying BTK and/or PLCγ mutations. The survival of patients with disease progression after ibrutinib is reported to be poor, particularly for those with RS (median overall survival (OS) 2.6 - 3.5 months)(Blood 2015:2062, JAMA Oncol 2015:80). There are no available data in the context of venetoclax failure. Methods We analyzed our institutional experiences with 70 patients with relapsed / refractory CLL enrolled across 3 venetoclax studies between 2011 and 2015 (2 single agent, 1 rituximab combination). Twenty-eight patients (40%) ceased venetoclax for reasons other than voluntary drug hold after achieving complete remission; these patients had received a median 7.5 (range, 1 - 38) months of venetoclax therapy prior to cessation. Results Of 28 patients, 7 (25%) had CLL progression, 16 (57%) developed RS (3 Hodgkin, 13 DLBCL), and 5 (18%) ceased for other reasons. Patients who ceased therapy typically had high-risk disease characteristics including del(17p)/TP53 mutation or complex cytogenetics in 70%, unmutated IgHV in 88%, and a median of 4 (range 1 - 12) prior therapies before venetoclax. After a median survivor follow-up of 12.5 months (range 0 - 34), the median post-progression survival of patients who progressed with CLL and RS were: not reached (1 year OS 69%) and 12 months, respectively (p=0.88, Figure). Post-progression survival did not statistically differ by any of the following factors: response to venetoclax, progression on venetoclax before or after 12 months, cytogenetic risk, or the number of prior therapies (all p-values >0.18). Of the 7 patients with CLL progression, 5 remain alive on next-line ibrutinib (n=4) or corticosteroids (1). Of the 16 patients with RS, 15 received salvage therapy; R-CHOP (n=6) and R-ICE (3) being the most commonly used regimens. 4 received consolidation with stem cell transplantation. One allogeneic stem cell recipient died at 12 months from transplant-related complications, and the other remains alive and free of disease at 34 months. Both autologous transplant recipients have relapsed with CLL and were successful salvaged with BTK inhibitors. Conclusion Failure of venetoclax does not automatically portend a poor prognosis. The survival of patients who progress with CLL or RS on venetoclax therapy may be superior to that reported for BTK inhibitors. Figure 1. Figure 1. Disclosures Tam: Janssen: Consultancy, Honoraria, Research Funding. Off Label Use: Venetoclax is not licensed for treatment of CLL. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Seymour:Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Effect of High Intensity Chemotherapy Vs Targeted Therapy on Survival in AML Patients Aged 60-75

Blood ◽

10.1182/blood-2021-148676 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4125-4125

Author(s):

Kieran D Sahasrabudhe ◽

Melanie T Rebechi ◽

Ying Huang ◽

Greg K. Behbehani ◽

Bhavana Bhatnagar ◽

...

Keyword(s):

Clinical Trial ◽

Targeted Therapy ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Treatment Intensity ◽

Intensive Chemotherapy ◽

Blood Cell Count ◽

Advisory Committees ◽

Disease Characteristics

Abstract Introduction The FDA has recently approved several oral targeted therapies for Acute Myeloid Leukemia (AML). These therapies have been approved in patients with relapsed/refractory disease and as frontline therapy in patients ineligible for intensive induction chemotherapy. These agents are also being increasingly utilized as frontline therapy in patients of all ages and fitness levels on clinical trials and through off label prescribing. The decision to use intensive chemotherapy vs targeted therapy is particularly relevant in patients aged 60-75 due to the heterogeneous nature of this population with respect to disease characteristics, performance status, and comorbidities. However, the relative survival impact of intensive chemotherapy vs targeted therapy in this patient population has not been extensively studied. We conducted a retrospective analysis to compare survival outcomes of these treatment approaches and to determine the relative impact of treatment intensity compared to other variables that are known to affect survival in AML patients. Methods In this single-center, retrospective study, patients aged 60-75 diagnosed with AML from 2016-2020 were included if they received treatment with high intensity chemotherapy (HiC), low intensity targeted therapy (LITT), or both during the course of treatment and prior to transplant. HiC was defined as a regimen containing cytarabine + an anthracycline given on a "7+3" based schedule. Patients treated with liposomal cytarabine-daunorubicin were excluded. LITT was defined as venetoclax, gilteritinib, enasidenib, or ivosidenib alone or in combination with a hypomethylating agent. Between-group analysis was conducted for patients who had received HiC at any point during treatment (any HiC) vs patients who had not (LITT only). Overall Survival (OS) was analyzed by Kaplan-Meier method with log-rank test used for between-group comparisons. Cox regression model was used to associate risk factors with OS. Univariable models were first fit, then a multivariable model was built using backward selection. Transplant status was included as a time-dependent variable. Results A total of 141 patients were included, 80 received any HiC and 61 received LITT only. Compared with the any HiC group, patients in the LITT only group demonstrated older age, a higher percentage of secondary AML, a lower percentage of FLT3 ITD mutations, a higher percentage of IDH1 and IDH2 mutations, a lower white blood cell count, and a trend toward higher ELN risk classification at baseline (Table 1). Median OS was significantly longer in the any HiC group (21.8 months vs 13.6 months). A significantly higher percentage of patients receiving any HiC underwent allogeneic stem cell transplantation, but post-transplant OS was not significantly different between the two groups (Table 2). On univariable analysis, receipt of HiC, lower ELN risk classification, and receipt of transplant were all significantly associated with superior OS. Age, performance status, secondary AML, and white blood cell count at diagnosis notably did not have a significant association with OS in this cohort. On multivariable analysis, treatment intensity was no longer found to have an independently significant impact on survival after accounting for ELN risk (hazard ratio (HR) for unfavorable 3.02, p<0.01) and receipt of transplant (HR 0.25, p<0.01) (Table 3). Discussion The results of this study show that baseline disease characteristics and receipt of transplant were the most important predictors of survival in this cohort of AML patients aged 60-75. These factors were notably more impactful than treatment intensity and chronological age. These findings support the use of transplant in this patient population regardless of treatment intensity, especially in those with higher risk disease. Limiting factors in this study include the retrospective design and relatively small sample size. Ultimately, larger trials with more patients will be needed to confirm these findings including prospective, randomized trials comparing intensive chemotherapy to lower intensity targeted therapy in patients who are transplant-eligible at baseline. Figure 1 Figure 1. Disclosures Bhatnagar: Novartis: Honoraria; Pfizer: Honoraria; Kite: Honoraria; Celgene: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding. Blachly: INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; KITE: Consultancy, Honoraria. Borate: Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Mims: Glycomemetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Aptevo: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Xencor: Research Funding; Kartos Pharmaceuticals: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Walker: Novartis: Other: clinical trial support; Geron: Other: clinical trial support; Newave: Other: clinical trial support.

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Rapid Reduction of Anti-Sars-Cov-2 Antibodies in Convalescent Plasma Donors; Results of a Phase 2 Clinical Study

Blood ◽

10.1182/blood-2020-136940 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Evangelos Terpos ◽

Marianna Politou ◽

Theodoros N Sergentanis ◽

Andreas Mentis ◽

Vassiliki Pappa ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Antibody Titer ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Rapid Reduction ◽

Disease Characteristics ◽

Asymptomatic Patients ◽

Antibody Titers

Introduction: Convalescent plasma is a promising therapeutic option for corona virus disease 2019 (COVID-19). A recent study in 34 COVID-19 patients showed a reduction of recovered patients antibodies within 3 months of infection. The aim on this analysis was to evaluate the antibody titers and explore possible correlations with disease characteristics in volunteer donors, who participated in a phase 2 study for the use of convalescent plasma for the treatment of severe COVID-19 infection. Patients and Methods: This in an ongoing phase 2 study (NCT04408209) for the use of convalescent plasma for severe COVID-19. This analysis reports the results of the first part of the study, regarding the presence of anti-SARS-CoV-2 antibodies in volunteer plasma donors and their correlation with disease characteristics. The main Inclusion criteria for plasma donors included: (i) confirmed SARS-CoV-2 infection by PCR of the nasal/pharyngeal swab; (ii) interval of at least 14 days after complete recovery from COVID-19; (iii) presence of anti-SARS-CoV-2 antibodies; (iv) two negative SARS-CoV-2 PCR results (the second at least 7 days prior to plasmapheresis). For the detection of anti-SARS-CoV-2 antibodies we used two commercially developed assays: one ELISA assay (Euroimmun Medizinische Labordiagnostika AG, Lubeck, Germany), which detects antibodies against the recombinant Spike protein of the virus (S1 domain) and a multiplex assay (ProtATonce Ltd, Athens, Greece) based on the Luminex® xMAP™ technology that detects total antibodies (IgG/IgM/IgA) and individual antibody isotypes IgG, IgM and IgA against 3 SARS-CoV-2 antigens (S1, basic nucleocapsid (N) protein and receptor-binding domain (RBD). Results: To-date, 260 (137M/123F) possible plasma donors were tested for the presence of anti-SARS-CoV-2 antibodies. At the time of their COVID-19 diagnosis, 20 (7.7%) were asymptomatic, 157 (60.3%) were symptomatic but did not need hospitalization and 83 (32%) were hospitalized. Median time from the day of their first symptom or PCR+ (for asymptomatic patients) till the day of screening was 62 (range: 14-104) days. Anti-SARS-CoV-2 antibodies were detected in 229 (88%) donors with the Euroimmun assay and in 238 (91.5%) with the multiplex assay (including the 229 who had antibodies with the Euroimmun method). Univariate analysis showed that donors who had asymptomatic COVID-19 had lower antibody titer compared to those who had symptomatic disease but did not need hospitalization or those who hospitalized (Fig. A-D). Donors <50 years had lower antibody titer compared with older patients [for Euroimmun method, median (IQR): 3.94 (5.10) vs. 7.34 (6.16); p<0.0001], while patients who were tested within 60 days from the first day of symptom or PCR+ (for asymptomatic patients) had higher antibody titer [6.09 (6.52) vs. 4.68 (6.12); p=0.024]. The multivariate analysis showed that age ≥50 years (OR 2.88, 95% CI:1.60-5.18; p<0.001) and need for hospitalization (OR 4.11, 95% CI:2.13-7.90; p<0.001) correlated with higher antibody titers, while asymptomatic phase (OR 0.10, 95% CI:0,01-0.82; p<0.001) and testing within ≥60 days post symptoms onset (OR 0.36, 95% CI:0.20-0.66; p=0.001) correlated with lower antibody titers. In the multivariate logistic regression analysis examining associations between individual symptoms and antibody levels, there was strong correlation between anti-SARS-CoV-2 antibodies and anosmia (OR 11.14, 95% CI:3.92-31.67; p<0.001), loss of taste (OR 5.50, 95% CI:2.23-13.56; p<0.001), fever (OR 4.25, 95% CI:1.90-9.51; p<0.001), and headache (OR 2.34, 95% CI:1.09-5.03; p=0.029). To-date, plasmapheresis was performed in 74 patients with anti-SARS-CoV-2 antibodies, within a median time of 12 (8-19) days after screening; the respective median time (range) from the first day of symptoms or PCR+ was 52 (14-84) days. Interestingly, there was a significant reduction in the antibody titers between the day of screening and the day of plasmapheresis [Fig. E]. Conclusion: Lower anti-SARS-CoV-2 antibody titers, against all studied epitopes, are found in asymptomatic patients, in patients <50 years and in those who were tested ≥60 days post onset of first symptoms. The rapid reduction of anti-SARS-CoV-2 antibodies in our cohort reveals a time pattern of reduction, although we do not know if neutralizing antibodies share the same trend or if this reduction affects the host immunity against SARS-CoV-2. Disclosures Terpos: Amgen: Honoraria, Research Funding; BMS: Honoraria; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria. Pappa:Genesis pharma SA: Research Funding. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau.

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Essential Thrombocythemia (ET) and Polycythemia Vera (PV) Symptom Burden: Phenotypic Cluster Analysis Among an International Sample of 1,141 ET and PV Patients

Blood ◽

10.1182/blood.v120.21.1726.1726 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1726-1726

Author(s):

Robyn M. Emanuel ◽

Amylou C. Dueck ◽

Holly Lynn Geyer ◽

Jean-Jacques Kiladjian ◽

Stefanie Slot ◽

...

Keyword(s):

Cluster Analysis ◽

Board Of Directors ◽

Research Funding ◽

Symptom Burden ◽

Symptom Clusters ◽

Spleen Size ◽

Cognitive Complaints ◽

Advisory Committees ◽

Disease Characteristics ◽

Night Sweats

Abstract Abstract 1726 Background: We previously reported that symptom burden among persons with ET and PV can be severe and adversely affect QOL. The presence of severe symptoms is linked to poor prognosis. There is considerable inter-subject heterogeneity regarding which symptoms are present in which subjects. No studies have empirically evaluated whether disease characteristics can be grouped in related symptom clusters. Using our previously validated 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196), we sought to evaluate symptom burden by means of cluster analysis. Methods: Data was collected from an international cohort of subjects with MPNs including demographics, disease features and the completed BFI and MPN-SAF instruments. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual difficulties, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst-imaginable) scale. Development of symptom clusters was based on consideration of r-squared in hierarchical clustering using Ward linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 1,141 subjects with PV (N=519) and ET (N=622) was prospectively collected (Chinese 236, French 305, German 45, Italian 114, Dutch 191, English 56, Spanish 109, Swedish 85. Age (mean 59, range, 26–87) and gender (54% F) were typical. Five clusters were selected (Figure 1). Frequencies of prior bleeding, spleen size, anemia, presence of any lab abnormality, language, gender, and MPN type varied significantly between clusters (P<0.05). Cluster 1: The “Reduced Symptom” Profile (n=421 (37%; 60% ET, 40% PV) The largest cluster, subjects had increased complaints of sexual difficulties and fatigue. There was a slightly higher proportion of subjects with ET (60%) versus PV. There were fewer lab abnormalities (28% prevalence) and less prior bleeding (3%) compared to other clusters. Spleen size was smallest of the cluster (1 cm below costal margin). Cluster 2: The “Fatigue-dominant” Group (n=286 (25%; 56% ET, 44% PV)). Subjects in this cluster were predominantly female and had relatively few laboratory abnormalities (19%) than other cohorts. They are characterized by high severity of fatigue compared to end-organ symptoms. Symptom profiles emphasize fatigue, QOL and insomnia with some end-organ complaints. The cohor 63% of the cohort. Cluster 3: The “End-Organ Complaints” Group (n=210 (18%; 49% ET, 51% PV)). Male predominant (56%), subjects had mainly macro-vascular symptom complaints including sexual difficulties, insomnia, and overall QOL, with few microvascular related symptoms (low itching/night sweats). Cluster 4: “Cognitive Complaints” Cluster (n=110 (10%; 53% ET, 47% PV)). The smallest cluster and female predominant (64%), main complaints include fatigue, insomnia, loss of concentration, numbness, and sad mood. Cluster 5: The “Highly Symptomatic” Cluster (n=114 (10%; 44% ET, 56% PV)). Subjects had many cognitive complaints and symptoms correlated with severe micro-vascular abnormalities (pruritus) and or splenomegaly. This cluster had the largest spleen sizes (mean 3 cm), the highest prevalence of prior thrombosis (29%), and highest frequency of lab abnormalities (43%). Cognitive and end-organ complaints were rated as most severe. Conclusion: This analysis offers new means of evaluating persons with PV and ET utilizing symptom clusters. Laboratory and physical abnormalities differed significantly between symptom clusters indicating that our groupings likely result from biological alterations present in specific disease phenotypes. Future studies should investigate correlations between clusters and prognosis and genotype. Disclosures: Kiladjian: Celgene: Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

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Intensified Cytarabine Dose during Consolidation Therapy in AML Patients Under 65 Years Is Not Associated with Survival Benefit

Blood ◽

10.1182/blood-2021-146606 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1242-1242

Author(s):

Maher Hanoun ◽

Leo Ruhnke ◽

Michael Kramer ◽

Kerstin Schäfer-Eckhard ◽

Björn Steffen ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

High Dose ◽

Advisory Committees ◽

Disease Characteristics ◽

First Remission

Abstract Background: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive. Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups. Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

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Narratives of Patients with Fatal Outcomes During the Phase 2 TITAN and Phase 3 HERCULES Studies

Blood ◽

10.1182/blood-2019-123124 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4908-4908 ◽

Cited By ~ 1

Author(s):

Spero Cataland ◽

Marie Scully ◽

Flora Peyvandi ◽

Paul Knoebl ◽

Johanna A. Kremer Hovinga ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Fatal Outcome ◽

Study Drug ◽

Adamts13 Activity ◽

Advisory Committees ◽

Baseline Platelet Count ◽

Disease Characteristics ◽

Patient Narratives

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening thrombotic microangiopathy, with an untreated mortality rate of >90%. Prompt treatment with therapeutic plasma exchange (TPE) and immunosuppression improves outcomes in patients with aTTP, but 10-20% of patients still die acutely from this disease. The aim of this analysis was to describe in more detail the characteristics and disease courses of the patients who died during the caplacizumab clinical development program. Methods: Patient narratives on all deaths occurring during the phase 2 TITAN and phase 3 HERCULES studies were extracted. Results: In the overall study periods, a total of 6 patients died, 2 patients enrolled in TITAN (Patients 1 and 2) and 4 patients enrolled in HERCULES (Patients 3-6). Five patients received placebo, while 1 (Patient 6) received caplacizumab. Demographics and baseline disease characteristics are summarized in Table 1. The patient narratives are provided below. Patient 1 (placebo) was a 57-year-old male, with a recurrent episode of aTTP. Baseline platelet count was 25 x109/L and ADAMTS13 activity <10%. The patient was treated with daily TPE and cyclosporine. Because of lack of response to TPE, treatment was intensified (increased plasma volume exchanged, and rituximab and cyclophosphamide initiated). Still, the patient's clinical condition declined with rising lactate dehydrogenase (LDH) values and persistent thrombocytopenia, with a fatal outcome on Day 23. Patient 2 (placebo) was a 49-year-old female, with an initial presumed aTTP episode. Baseline platelet count was 7 x109/L and baseline ADAMTS13 activity was 75%. The patient did not respond to therapy (TPE and corticosteroids), with platelet counts remaining below 35 x109/L over the whole period. On Day 10 of the study, the patient experienced a cerebral hemorrhage, for which study drug treatment was permanently discontinued. The patient was intubated and died the next day of cerebral hemorrhage. Patient 3 (placebo) was a 62-year-old female with an initial aTTP episode. Baseline platelet count was 18 x109/L and ADAMTS13 activity <10%. The patient was treated initially with daily TPE and corticosteroids. On Day 2 the patient suffered from a massive ischemic stroke with hemorrhagic transformation; TPE was interrupted for 2 days and restarted thereafter. The platelet count improved to 104 x109/L, but fell to 44 x109/L on Day 6. Rituximab was added on Day 8, however, the patient died on Day 14 from the consequences of the stroke. Patient 4 (placebo) was a 72-year-old female with an initial aTTP episode. Baseline platelet count was 21 x109/L and baseline ADAMTS13 activity was <10%. Despite an initial (partial) platelet count response, the disease worsened with coma starting on study Day 6 and severe septic shock 2 days later. The patient died on Day 8 due to these events. Patient 5 (placebo) was a 30-year-old female enrolled with her third aTTP episode. Baseline platelet count was 21 x109/L and ADAMTS13 activity <10%. The patient did not respond to therapy (TPE, corticosteroids, rituximab), with platelet count remaining below 30 x109/L over the whole period. Respiratory failure was reported on study Day 8, likely due to alveolar hemorrhage, with fatal outcome the same day; an autopsy was not performed. Patient 6 (caplacizumab) was a 77-year-old female with her initial aTTP episode. Baseline platelet count was 38 x109/L and ADAMTS13 activity <10%, and was treated with TPE, corticosteroids and caplacizumab. Following daily TPE (for 36 days without tapering), the patient completed 30 days' treatment with caplacizumab, maintaining normal platelet counts during that period. ADAMTS13 activity at the end of study drug treatment was 62%. On follow-up Day 5, the patient was hospitalized with severe cerebral ischemia leading to death 3 days later; the event was considered not related to the study drug. Conclusion: Although the use of TPE and immunosuppression reduces mortality in patients with aTTP, the disease is still associated with a substantial risk of mortality. The fact that all 5 immediate deaths occurred in the placebo arm suggests that the use of caplacizumab has the potential to reduce acute mortality in patients with aTTP. Table 1. Baseline demographics and disease characteristics. Table 1 Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Scully:Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Novartis: Consultancy; Shire/Takeda: Consultancy; Shire: Research Funding. Peyvandi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Knoebl:Roche: Consultancy; Shire/Takeda: Consultancy; Novo-Nordisk: Consultancy, Research Funding; CSL-Behring: Consultancy; Ablynx/Sanofi: Consultancy. Kremer Hovinga:Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Ablynx/Sanofi: Consultancy; Alexion: Consultancy; Shire: Consultancy. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Octapharma: Research Funding; Alexion: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

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Impact of MYD88L265P mutation Status on Histological Transformation of Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-120046 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2884-2884 ◽

Cited By ~ 1

Author(s):

Saurabh Zanwar ◽

Jithma Prasad Abeykoon ◽

Stephen M. Ansell ◽

Rebecca L King ◽

Rong He ◽

...

Keyword(s):

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Cumulative Probability ◽

Proportional Hazard ◽

Advisory Committees ◽

Entire Cohort ◽

Disease Characteristics ◽

Cox Proportional Hazard ◽

Histological Transformation

Abstract Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p<0.0001]. Additionally, serum lactate dehydrogenase (LDH) was higher at diagnosis of WM in patients who transformed, Table 2. On multivariate analysis, MYD88WT status remained an independent predictor of disease transformation [p=0.003; odds ratio 10 (95% CI: 2.1-48)]. On univariate Cox proportional hazard analysis for identifying predictors of time-to-transformation, only MYD88WT mutational status was associated with shorter time-to-transformation with a 5-year transformation rate of 15.5 % for MYD88WT versus 2.6 % with MYDL265P mutated patients [risk ratio 6.2 (95% CI: 2.5-16.4); p<0.0001]. Treatment-related details in the transformed cases were available for 37 (90%) patients; R-CHOP was the most common (41%) frontline therapy for transformation; 33% patients underwent autologous stem cell transplantation for transformed disease during their disease course. Conclusion: Histological transformation is an uncommon event in WM but confers poorer survival. MYD88WT genotype is independently associated with histological transformation a shorter time-to- transformation in patients with WM. Disclosures Ansell: Trillium: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Takeda: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Gertz:Apellis: Consultancy; Alnylam: Honoraria; spectrum: Consultancy, Honoraria; janssen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; celgene: Consultancy; Teva: Consultancy; Medscape: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

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