Determining Clinical Course of Diffuse Large B-Cell Lymphoma Using Targeted Transcriptome and Machine Learning Algorithms

Abstract Introduction: Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology. However, these biological subgroups overlap clinically. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for treating patients with DLBCL, predicting which patients will not benefit from such therapy is important so that alternative therapy or clinical trials can be considered. Most of the studies stratifying patients select biomarkers first, then explore how these biomarkers can stratify patients based on outcome. We explored the potential of using machine learning to first group patients with DLBCL based on survival, then isolating the biomarkers necessary for predicting these survival subgroups. Methods: RNA was extracted from tissue paraffin blocks from 379 R-CHOP treated patients with de novo DLBCL, and from 247 patients with extranodal DLBCL. A targeted hybrid capture RNA panel of 1408 genes was used for next generation sequencing (NGS). Sequencing was performed using an Illumina NextSeq 550 System platform. Ten million reads per sample in a single run were required, and the read length was 2 × 150 bp. An expression profile was generated from the sequencing coverage profile of each individual sample using Cufflinks. A machine learning system was developed to classify patients into four groups based on their overall survival. This machine learning approach based on Naïve Bayesian algorithm was also used to discover the relevant subset of genes with which to classify patients into each of the four survival groups. To eliminate the underflow problem commonly associated with the standard Naïve Bayesian classifiers, we applied Geometric Mean Naïve Bayesian (GMNB) as the classifier to predict the survival group for each patient. Results: Using machine learning, patients were first divided into two groups: short survival (S) and long survival (L). To refine this model, we used the same approach and divided the patients in each group into two subgroups, generating four groups: long survival in the long group (LL), short survival in the long group (LS), long survival in the short group (SL), and short survival in the short group (SS). The hazard ratio for this model was 0.174 (confidence interval: 0.120-0.251), and P-value <0.0001. After defining these four groups, a machine learning algorithm was used to discover the biomarkers from the expression data of the 1408 genes from NGS data. To reduce the effects of noise and avoid overfitting, we employed a 12-step cross validation to obtain a robust measure. For an individual gene, a generalized Naïve Bayesian classifier was constructed on the training of one of the 12 subsets and tested on the other 11 testing subsets. This allowed us to limit the prediction process to 60 genes for each separation step. Using the selected biomarkers, we classified the patients in the original set (379 patients) into LL, LS, SL, and SS groups and then evaluated the survival pattern of these groups. As shown in Fig. 1A, the selected biomarkers predicted survival as expected in the overall survival groups prior to biomarker selection. For additional validation of the system, we used the selected biomarkers to classify a completely new set of 247 samples of patients with extranodal DLBCL. As shown in Fig. 1B, these selected biomarkers successfully predicted the overall survival in this group of patients with an HR of 0.530 (confidence interval: 0.234-1.197, P=0.005). This classification correlated with cell of origin classification, TP53 mutation status, MYC expression, and IRF4 expression. However, in a multivariate analysis, only TP53 mutation was independent in predicting prognosis (P=0.005) and age (below or over 60) (P=0.01) along with the survival grouping (P<0.000001). Conclusions: Using a novel machine learning approach with the expression levels of 180 genes, we developed a model that can reliably stratify patients with DLBCL treated with R-CHOP into four survival subgroups. This model can be used to identify patients who may not respond well to R-CHOP to be considered for alternative therapy and clinical trials. Figure 1 Figure 1. Disclosures Hsi: AbbVie Inc, Eli Lilly: Research Funding. Ferreri: Ospedale San Raffaele srl: Patents & Royalties; BMS: Research Funding; Pfizer: Research Funding; Beigene: Research Funding; Hutchison Medipharma: Research Funding; Amgen: Research Funding; Genmab: Research Funding; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees. Piris: Millenium/Takeda, EUSA, Jansen, NanoString, Kyowa Kirin, Gilead and Celgene.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria.

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Bone Marrow-Based Biomarkers for Predicting aGVHD Using Targeted RNA Next Generation Sequencing and Machine Learning

Blood ◽

10.1182/blood-2021-147583 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2892-2892

Author(s):

Maher Albitar ◽

Hong Zhang ◽

Andrew L. Pecora ◽

Andrew Ip ◽

Andre H. Goy ◽

...

Keyword(s):

Machine Learning ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Leadership Role ◽

Advisory Committees ◽

Naive Bayesian ◽

Naïve Bayesian ◽

Fold Cross Validation ◽

Generation Sequencing

Abstract Introduction: Acute graft-vs.-host disease (aGVHD) remains a major diagnostic and clinical problem in patients after allogenic hematopoietic stem cell transplant (HSCT). Finding biomarkers that play a role in aGVHD not only helps in predicting and diagnosing aGVHD, but might help in developing prophylaxis and therapeutic approaches. Using Next Generation Sequencing (NGS) and targeted RNA sequencing along with a machine learning approach to predict, we investigated the potential of discovering new biomarkers that can predict aGVHD. Methods: RNA extracted from bone marrow aspiration samples collected around day 90 post HSCT from 46 patients were sequenced using 1408 targeted genes. cDNA was first generated, then adapters were ligated. The coding regions of the expressed genes were captured from this library using sequence-specific probes to create the final library. Sequencing was performed using an Illumina NextSeq 550 platform. Ten million reads per sample in a single run were required. Read length was 2 × 150 bp. Expression profile was generated using Cufflinks. A machine learning system is developed to predict the GVHD cases and to discover the relevant genes. A subset of genes relevant to GVHD is automatically selected for the classification system, based on a k-fold cross-validation procedure (with k=10). For an individual gene, a Naïve Bayesian classifier was constructed on the training of k-1 subsets and tested on the other testing subset. To eliminate the underflow problem commonly associated with the standard Naïve Bayesian classifiers, we applied Geometric Mean Naïve Bayesian (GMNB) as the classifier to predict GVHD. The processes of gene selection and GVHD classification are applied iteratively to obtain an optimal classification system and a subset of genes relevant to GVHD. Results: The analyzed bone marrow samples included patients transplanted for aplastic anemia (#1), acute lymphoblastic leukemia (#9), acute myeloid leukemia (#16), mixed phenotype acute leukemia (#1), myelodysplastic syndrome (#10), chronic myelomonocytic leukemia (#5), and myeloproliferative neoplasm (#4). Of the 46 patients, 30 (65%) had a diagnosis of aGVHD (grade 2-4). The GMNB modified Bayesian model selected 7 genes as top classifiers. These top classifier genes included Class II Major Histocompatibility gene (CIITA), B-cell markers genes (CD19 and CD22), early T-cell related gene (TCL1A), hematopoietic-specific transcription factor (IKZF3), a gene involved in protein-protein interaction, and a gene involved in DNA helicase nucleotide excision repair (ERCC3). When these 7 genes were used in GMNB-modified classifier with 10-fold cross validation to predict aGVHD, the model classified 28 of the 30 positive cases accurately and 14 of the 16 negative cases accurately. The sensitivity was 93% (95% CI, 76%-99%). The specificity was 87.5% (95% CI: 60%-97%). The positive predictive value (PPV) was 93% (95% CI: 76%-99%) and the negative predictive value (NPV) was 87.5% (95% CI: 60%-98%). Conclusion: While most biomarker discovery has been focused on inflammatory cytokines, chemokines, and their receptors, our data suggest that hematopoietic proliferation and transcription regulators in bone marrow might provide important information for the diagnosis and prediction of aGVHD. This data suggests that biomarkers related to B-cell, T-cell, and MHC play a role in aGVHD at the bone marrow level. These findings also suggest that targeting these biomarkers in the bone marrow might be a realistic approach for prophylaxis and treatment that needs to be explored. Although further validation is needed, this study suggests that targeted RNA sequencing by NGS combined with machine learning algorithm can be a practical and cost-effective approach for the diagnosis and prediction of aGVHD. Figure 1 Figure 1. Disclosures Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Goy: Rosewell Park: Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Acerta: Consultancy, Research Funding; Genentech/Hoffman la Roche: Research Funding; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xcenda: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive Peer Exchange: Honoraria; Xcenda: Consultancy, Honoraria; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Infinity/Verastem: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Honoraria, Other; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Hoffman la Roche: Consultancy; Michael J Hennessey Associates INC: Consultancy; LLC(Targeted Oncology): Consultancy; Medscape: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Constellation: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Phamacyclics: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Rowley: ReAlta Life Sciences: Consultancy.

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Patient Reported Financial Toxicity in Acute Leukemia

Blood ◽

10.1182/blood-2018-99-119163 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4796-4796 ◽

Cited By ~ 1

Author(s):

Thomas G. Knight ◽

Myra Robinson ◽

Michael R. Grunwald ◽

Lauren M. Bohannon ◽

Erin Blackwell ◽

...

Keyword(s):

Acute Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Financial Toxicity ◽

Advisory Committees ◽

Data Safety ◽

Safety Monitoring Board ◽

Data Safety Monitoring

Abstract Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients <65 years of age were 2.7 times the odds of FT in those ≥65, adjusting for race, insurance, and time since first treatment (95% CI: 0.884 - 8.438, p = .081). The odds of FT in African American patients were 4.3 times the odds of FT in Caucasian patients, adjusting for age, insurance, and time since first treatment (CI: 0.408 - 44.824, p = .150). The odds of FT in patients with Medicaid insurance were 14.2 times the odds of FT in patients with commercial insurance, adjusting for age, race, and time since first treatment (CI: 1.658 - 121.862, p = .106). Gender, distance from the hospital, type of acute leukemia, history of blood/marrow transplant, and history of relapsed disease were not found to be significant. There was a significant correlation for both the PROMIS global physical (p < .001) and mental (p < .001) scores with the FT score. Lower FT score (higher degree of FT) was associated with lower mental and physical scores. There was no statistically significant difference in survival between patients with FT scores >4 compared to patients with FT scores <=4; however, there was a trend toward decreased survival in those with lower FT scores (Figures 1 and 2). Conclusions: Patients with acute leukemia represent an extremely vulnerable population for financial toxicity with rates of distress even higher than other reported malignancies. Urgent interventions are indicated in this population. Disclosures Grunwald: Medtronic: Equity Ownership; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Five Prime Therapeutics: Other: Data Safety Monitoring Board ; Boston Biomedical: Other: Data Safety Monitoring Board ; Eli Lily & Co: Other: Data Safety Monitoring Board; Immatics: Other: Data Safety Monitoring Board.

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Systematic Review of the Published Evidence on the Pharmacokinetic Characteristics of Factor VIII and IX Concentrates

Blood ◽

10.1182/blood.v124.21.2818.2818 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2818-2818

Author(s):

Menchen Xi ◽

Tamara Navarro-Ruan ◽

Sunil Mammen ◽

Victor S. Blanchette ◽

Cedric R. Hermans ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Committees ◽

Safety Monitoring Board ◽

Population Pk ◽

Viii And Ix ◽

Factor Concentrate

Abstract Introduction: The efficacy of factor VIII and IX concentrates administered to prevent bleeding episodes in patients with hemophilia A and B is correlated with the plasma levels measured over time after the infusion. The inter-patient variability of pharmacokinetic (PK) parameters is large, and it is difficult to assess individual PK profiles due to the need for multiple time points. This is often not feasible, particularly for pediatric patients. Population PK modeling potentially provides a practical solution to this problem. The successful modelling of PK parameters at the population level requires knowledge of disposal characteristics and relevant covariates. We performed a systematic review of the available evidence in order to identify available PK data for factor VIII and IX concentrates to facilitate the implementation of a population PK approach. Methods: We conducted a literature search in MEDLINE and EMBASE from January 1997 to May 2014, using the keywords "hemophilia" and "pharmacokinetic". We included only articles that published original PK data for factor VIII and IX concentrates in humans and published in English. Two authors independently screened the studies and extracted the relevant data. Results: We retrieved 237 unique articles published between 1998 and 2013. We excluded 185 articles that did not meet our research criteria. We included 52 articles, with a total of 1365 patients included in PK analyses. 26 articles reported PK data on factor VIII concentrates, 18 articles report PK data on factor IX concentrates, and one article reported on both factor VIII and IX concentrates. Seven articles reported pharmacokinetic data on both factor VIII and Von Willebrand factor concentrates. We extracted the following data: number of patients, type and severity of hemophilia, patient age, factor concentrate infused, dose infused, sampling data points, half-life, clearance, recovery and the model used for pharmacokinetics, and inclusion of patients undergoing surgery or with inhibitors. The main results are summarized in table 1. Conclusions: This review provides the first systematic appraisal of the methods and results of published papers in the field. The data gathered confirms the intra-patient variability of factor concentrate PK and provides useful information on which to build population based PK models. *3 FIX articles and 2 FVIII articles did not report lab test; one article reported PK data for both FIX and FVIII †11 articles reported FVIII PK data for both one-stage clotting and chromogenic assays ǂPapers reporting on long-acting FVIII and FIX were included in the review, but not summarized in the table. For this reason, not all 1365 patients are accounted for in the table §Estimate of the range of the means found in the papers Disclosures Xi: Baxter: Research Funding. Navarro-Ruan:Baxter: Research Funding. Mammen:Baxter: Research Funding. Collins:Baxter: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL: Consultancy, Honoraria, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: data safety monitoring board, data safety monitoring board Other; Biogen IDEC: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Pfiser: consultancy, data and safety monitoring board Other; Octapharma: Research Funding. Dunn:CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Iorio:Baxter: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; NovoNordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Pfiser: Honoraria, Research Funding.

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Hemophilia Prophylaxis No Longer Just for Children without Inhibitors - Increasing Use of Prophylaxis in Other Groups (children with inhibitors and adults with and without inhibitors)

Blood ◽

10.1182/blood.v126.23.3535.3535 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3535-3535 ◽

Cited By ~ 2

Author(s):

Manuel Carcao ◽

Maria L. Avila ◽

Victor S. Blanchette ◽

Elena Santagostino ◽

Carmen Escuriola-Ettingshausen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Committees ◽

Data Safety ◽

Safety Monitoring Board ◽

Data Safety Monitoring ◽

Adults And Children

Abstract Background: Long-term prophylaxis is standard of care in children with severe hemophilia A (SHA) and B (SHB) without inhibitors. Studies have shown benefit from long-term prophylaxis in adults with SH and in both adults and children with SH and inhibitors. Yet there is little data on the prevalence of prophylaxis in these groups. Aim/Methods: To understand the current use of long-term prophylaxis in these groups of patients in countries capable of underwriting the high cost of prophylaxis we surveyed (2013) hemophilia treatment centers (HTCs) in countries where long-term prophylaxis in children is routinely used. Results: 134 HTC from 14 countries in North America, Australasia, and Western Europe reported on 4,763 adults with SH (4,011 SHA; 752 SHB) and on 751 children and adults with inhibitors. Prophylaxis use in these groups is shown in table 1: Table 1. Prophylaxis use in adults with SH (without inhibitors). Adults without inhibitors Children and adults with inhibitors HA HB In ITI setting In non-ITI setting % on Prophylaxis 59 49 29 28 Most common regimen EOD 2 d/wk FEIBA EOD or 3 d/wk FEIBA EOD or 3 d/wk EOD, every other day Adults without inhibitors: A higher proportion of SHA (59%) vs SHB adults (49%) were on prophylaxis (Χ2 p<.001). This was particularly true in the age group of 18-30 y [74% (SHA) vs 60% (SHB)]. For SHA the use of prophylaxis was progressively less in older age groups: 31-40 y (55%), 41-50 y (47%), 51-70 y (39%) and >70 y (29%). There was little drop in the proportion of SHB adults on prophylaxis with increasing age. 67% of SHA adults on prophylaxis were receiving ≥3 infusions/wk while 80% of SHB adults on prophylaxis were receiving ≥2 infusions/wk. Once/wk prophylaxis was reported in 3% of SHA and by 19% of SHB patients on prophylaxis. Daily prophylaxis was rarely reported in both groups. Children and adults with inhibitors: Data was available on 407 children and 344 adults with SH and inhibitors. Table 2 shows the proportion of children and adults on/not on Immune tolerance induction (ITI) and on/not on bypassing agent prophylaxis (BA-P). Most children (78%) were on either ITI (with or without BA-P) or on BA-P alone and as such were having some bleed protection. In contrast only 28% of adults were on either ITI (with or without BA-P) or on BA-P and as such most adults with inhibitors are not on any bleed protection. Table 2. Use of ITI and of BA-P in children and adults with SH (+ inhibitors). 403 children 344 adults On ITI. Not on BA-P 43% 8% On ITI. On BA-P 17% 4% Not on ITI. Not on BA-P 23% 71% Not on ITI. On BA-P 18% 16% In total, 185 patients had received FEIBA prophylaxis while 70 had received rFVIIa prophylaxis. FEIBA prophylaxis was particularly more common (vs. rFVIIa prophylaxis) in the non-ITI setting [FEIBA (n=107 pts) vs rFVIIa (n=33 pts)]. The most common prophylactic FEIBA regimen was EOD or 3/wk while the most common rFVIIa prophylaxis regimen was daily. Conclusions: This survey captured data on 4,763 adults with SHA/SHB and on 751 adults and children with SH and inhibitors. This is the largest survey of prophylaxis in these 2 groups of patients. Given the benefits of prophylaxis in children it is reassuring to observe that prophylaxis in adults (without inhibitors) is more prevalent than previously reported. Use of BA-P in patients with inhibitors still however lags far behind the use of prophylaxis in non-inhibitor patients - particularly in adults. FEIBA is more commonly used for prophylaxis than rFVIIa. Our survey did not capture longterm patient outcome data; this needs evaluation. Note: This abstract includes data presented as separate abstracts at the ISTH 2015 meeting. The data has been combined and analyzed in this abstract to show the increasing use of prophylaxis outside of children without inhibitors. Disclosures Blanchette: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data Safety Monitoring Board; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding. Santagostino:CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biogen/Sobi: Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Kedrion: Speakers Bureau; Biotest: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau. Leissinger:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Aledort:Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation; Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Using Machine Learning Methods to Explore the Role of Non-Coding RNAs in DLBCL

Blood ◽

10.1182/blood-2021-152315 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4324-4324

Author(s):

Inbar Cohen ◽

Mali Salmon-Divon ◽

Sapir Peled ◽

Irit Avivi ◽

Yael C Cohen ◽

...

Keyword(s):

Machine Learning ◽

Overall Survival ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Information Gain ◽

Complete Response ◽

Advisory Committees ◽

Machine Learning Methods ◽

Non Coding Rnas

Abstract Diffuse large B-cell lymphoma (DLBCL) is a complex and aggressive malignancy. The standard-of-care chemo-immunotherapeutic regimen, which consists of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), leads to a complete response in most patients. Unfortunately, 30-40% of patients are either refractory to the current treatment regimen or experience disease relapse after complete response, and thus, these patients exhibit a dismal prognosis. Gene expression profiling has delineated two distinct molecular subtypes of DLBCL, the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype; 10 to 15% of cases are unclassifiable, these groups differ in survival, and could potentially direct therapy (Alizadeh, Nature 2000). A study by Schmitz et al have used whole exome and transcriptome of 574 DLBCL tumors to refine the abovementioned genetic subtypes, in attempt to improve prognostic capacity, focusing on protein coding genes (Schmitz, N Engl J Med. 2018) . Non-coding RNAs (ncRNAs) has been shown to be differentially expressed and clustered across different groups of DLBCL samples, suggesting that these ncRNAs may also participate in DLBCL pathogenesis (Shi, OncoTargets and therapy 2020) . In this study, we applied machine learning methods for classification of DLBCL genetic subgroups based on ncRNA expression, and proposing a clinical-genetic survival predictive model. Out of 1866 ncRNAs from the study by Schmitz et al, 377 were selected using information gain algorithm, and were used to classify 234 DLBCL tumors to the different genetic subgroups (ABC, GCB, Unclassified). Classification models were trained using K Nearest Neighbor (KNN) (K=5), decision tree, random forest and multilayer perceptron algorithms leading to a weighted area under the ROC curve of 0.895, 0.749, 0.924 and 0.965 respectively. Using the information gain algorithm, we identified 28 ncRNAs which have an information gain score of >0 in classifying patients to either having achieved survival of three years or not. Of these, seven ncRNAs were found to have a significant correlation to overall survival (OS) (p<0.05 for each) using cox regression survival analysis. In multivariate analysis, including age, gender, ECOG, IPI, genetic subgroups and these seven ncRNAs, we found only age and three ncRNAs (NR_026893, NR_002939, NR_002186) to be significantly associated with OS, figure 1A. We performed Kaplan Mayer analysis using these three genes as binary variables (medians were used for cutoff), dividing the cohort into three groups (all three ncRNA up regulated, one/two down regulated and all three ncRNAs down regulated) with robust difference in overall survival (median OS was not reached, 5.5 CI 95% (1.1-9.9) years 1.5 CI 95% (0.4-2.7) years, respectively), as presented in figure 1B. In conclusion, we detected novel diagnostic and prognostic ncRNAs biomarkers which potentially be able to inform clinical management for patients with DLBCL. Further studying of ncRNAs expression profile and cellular mechanisms could help improve our understanding of the disease and potentially identify new therapeutic targets and support the development of new therapies. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Karophram: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 1 Trial of Regorafenib in Advanced Myeloid Malignancies

Blood ◽

10.1182/blood-2020-140278 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Chi-Joan How ◽

Siyang Ren ◽

Jennifer Lombardi Story ◽

Meghan Bergeron ◽

Julia E. Foster ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Board Member ◽

Safety Monitoring ◽

Advisory Committees ◽

Expansion Phase ◽

Secondary Aml ◽

Myeloid Neoplasms ◽

Safety Monitoring Board

BACKGROUND: Angiogenesis is increasingly known to play a role in pathogenesis of hematologic malignancies, including myeloid neoplasms. Regorafenib is a multikinase inhibitor that targets angiogenic, stromal and oncogenic kinases including VEGF- 1, 2, 3, TIE-2, PDGFR-β,c-KIT, rRET, RAF-1, FGFR-1, BRAF and p38 MAP kinase. As a result of regorafenib's broad inhibition of kinases and its effects on angiogenesis, this drug has the potential to overcome the limitations of more selective kinase inhibitors and may be associated with efficacy in various myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). METHODS: We conducted a single-center, open-label, dose-escalation and expansion phase I trial in patients with relapsed/refractory AML, MPN, or MDS to assess the safety, tolerability, and preliminary efficacy of regorafenib and identify the recommended phase 2 dose (RP2D). A 3+3 dose escalation design was used with 2 planned dose levels (120 mg or 160 mg daily in 28-day cycles), as well as 1 de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. RESULTS: Six patients were enrolled during the dose escalation phase (3 at 120 mg daily followed by 3 at 160 mg daily), with no DLTs, as defined by a Grade >3 toxicity occurring within the first 28 days after initiation of treatment, and unrelated to the myeloid neoplasm. Therefore, the RP2D of regorafenib was identified as 160 mg daily. Ten additional patients were enrolled on this dose during the expansion phase. The median age was 74 (range 36-84), and 13 (81%) patients were male. Diagnoses included 7 AML, 6 MDS, and 3 MPN patients (Table 1). Dose modifications and delays occurred in 5 and 4 patients, respectively. The median duration of treatment was 56 days or 2.5 cycles (range: 5-410 days, 1-15 cycles). Of the 16 patients, the best overall disease response as measured by IWG criteria included partial remission (in 1 patient with AML), stable disease in 12 (2 de novo AML, 2 secondary AML, 3 MPN, and 5 MDS) patients, and progressive disease in 3 (1 MDS and 2 secondary AML) patients. An initial improvement in absolute neutrophil count and/or hemoglobin was observed in the 6 MDS patients, although this did not meet criteria for hematologic improvement by IWG criteria. All patients have discontinued off treatment. The most frequent Grade 3-4 adverse effects (AEs) included liver function test abnormalities (5.1%), fatigue (4.3%), thrombocytopenia (3.4%), and neutropenia (3.4%) (Table 2). The majority of AEs were grades 1-2. CONCLUSIONS: Regorafenib demonstrates an acceptable safety profile in relapsed/refractory myeloid malignancy patients, a population where few treatment options exist. The majority of patients achieved stable disease. Modest improvements in cell counts were observed in MDS patients, and we are performing correlative studies to clarify regorafenib's mechanism of action and identify populations which may benefit from treatment. Disclosures Amrein: AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Fathi:Kura Oncology: Consultancy; Trillium: Consultancy; Boston Biomedical: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Blueprint: Consultancy; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Newlink Genetics: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy, Research Funding. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Neuberg:Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Celgene: Research Funding. Chen:Takeda: Consultancy; Magenta: Consultancy; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Kiadis: Consultancy. Hobbs:Merck: Research Funding; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Jazz: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Bayer: Research Funding. OffLabel Disclosure: Regorafenib was used to assess safety and preliminary efficacy in advanced myeloid malignancies

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Characterizing the Use of Direct Oral Anticoagulants in Children Using the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Blood ◽

10.1182/blood-2019-128324 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1156-1156

Author(s):

Jennifer G. Davila ◽

Dunlei Cheng ◽

Leslie J. Raffini ◽

Courtney D. Thornburg ◽

Fernando F. Corrales-Medina

Keyword(s):

Venous Thrombosis ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Board ◽

Advisory Committees ◽

Data Safety ◽

Safety Monitoring Board ◽

Data Safety Monitoring

Background: The incidence of venous thromboembolism (VTE) in children has risen significantly. (Raffini, Huang et al. 2009) There are currently four direct oral anticoagulants (DOACs) - apixaban, dabigatran, edoxaban, and rivaroxaban - approved for the acute treatment and prevention of VTE in adults. Advantages of these medications over the traditionally used anticoagulants, enoxaparin and warfarin, include fixed dosing, no need for routine laboratory monitoring, few drug interactions and no dietary restrictions. Despite lack of information on the safety and efficacy of these agents in children, pediatric hematologists across the United States are using DOACs in their patients based on extrapolated data from adult studies. The American Thrombosis and Hemostasis Network (ATHN) is a nonprofit network of over 140 federally funded Hemophilia Treatment Centers (HTCs) which provides the infrastructure for clinical and surveillance-based research. ATHN maintains the ATHNdataset (ADS), a "limited dataset" free of protected health information, with data collected on patients with bleeding and clotting disorders at participating HTCs within the Human Resources and Services Administration (HRSA)-supported regional hemophilia networks across the US. The authors acknowledge ATHN, the ATHN-affiliated U. S. Hemophilia Treatment Centers and their 39,000+ patients who have contributed their demographic, clinical, and genetic information to the ATHNdataset. Methods: The objective of this study was to describe the characteristics of pediatric patients diagnosed with VTE in the ADS, focusing on those patients who received a DOAC. Data were abstracted for patients in the ADS who had acute VTE at age <21 years from January 2010 to March 2019. Data extraction included basic demographics and information about VTE and treatment. Results : A total of 1,094 pediatric VTE cases were captured in the ADS. 577 (52.7%) were male. Caucasians were the most prevalent racial group (n = 809; 74%), followed by African-Americans (n = 203; 18.6%).14.9% (n = 163) were Hispanic. Deep venous thrombosis (DVT) was the most prevalent pediatric VTE reported in the ADS (n=889, 81.3%), followed by pulmonary embolism and cerebral venous thrombosis (n=130, 11.9% and n=40, 3.7% respectively). VTE location by age group is listed in Table 1. The most common DVT location was the lower extremities or pelvis, comprising 37.5% (n = 333) of all reported DVTs. Upper extremities or upper thorax DVT occurred less often (n = 211; 23.8 %). 345 (38.8 %) cases were reported only as "DVT" without a specific thrombus location. We reviewed 1,051 anticoagulant prescriptions for 650 VTE patients (mean 1.6 prescriptions per person). Enoxaparin was the most commonly prescribed anticoagulant (n = 676 prescriptions; 64.3%) followed by warfarin (n = 178 prescriptions, 16.9%). Interestingly, 116 (11%) patients, from 21 HTCs, had a DOAC prescribed as their anticoagulant regimen. Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Further analysis of the DOAC subgroup showed that rivaroxaban was the most prescribed DOAC with 77.6% (n = 90/116) of the patients using this agent. Apixaban and dabigatran use was also reported (n= 23, 19.8% and n= 3, 2.6% respectively). The majority of DOACs were prescribed for patients older than 13 years of (111/116, 95.7 %). In children between 3 to 6 years of age (n = 3), rivaroxaban was the only DOAC prescribed. DOACs were primarily used to treat DVT of the extremities (84/116 patients). Other scenarios in which DOACs were also prescribed were PE and abdominal venous thrombosis patients (26, and 4 patients, respectively). Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Conclusion: DVT of the lower extremities and pelvis is the most prevalent pediatric VTE in the ADS. Enoxaparin and warfarin remain the main anticoagulant agents used for pediatric VTE treatment. Despite lack of an FDA-approved pediatric indication, hematologists in US-based HTCs are already using DOACs in pediatric patients with VTE. As further characterization of DOAC use in children is needed, the authors, in collaboration with ATHN, are currently building a multi-institutional retrospective and prospective registry, ATHN 15. This registry will serve as a resource for pediatric hematologists to collect real-world use of DOACs in children, as we await the results of prospective clinical trials. Disclosures Davila: Octapharma: Other: Grant to attend VWD meeting ; Genentech: Other: Advisory board; Spire Learning: Speakers Bureau. Raffini:Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Roche: Other: Advisory Board. Thornburg:Sanofi Genzyme: Research Funding; Bluebird bio: Other: Data Safety Monitoring Board; Genentech: Speakers Bureau; NovoNordisk: Research Funding; Ironwood: Other: Data Safety Monitoring Board; Sanofi Genzyme: Other: Data Safety Monitoring Board. Corrales-Medina:Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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