Tumor-Confirmed Follicular Lymphoma Mutations Are Detectable in Peripheral Blood Years Prior to Clinical Diagnosis

Abstract Background: Mutations in chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 have been inferred as early events in follicular lymphoma (FL) by truncal status in mature tumors and persistence between diagnosis and relapse. We previously reported frequent detection of CREBBP lysine acetyltransferase (KAT) domain mutations in pre-diagnostic blood and tissue specimens from individuals later developing FL (Schroers-Martin et al, ASH Annual Meeting 2017). However, the limited availability of paired tumor biopsies has precluded confirmation of concordance between precursor lesions and subsequent clinical malignancy. Methods: The American Cancer Society (ACS) Cancer Prevention Study-II (CPS-II) LifeLink cohort collected screening blood or saliva samples from over 100,000 cancer-free American participants between 1998 and 2002. To evaluate detection of tumor-confirmed variants in pre-diagnostic specimens, we identified 29 FL patients with available FFPE tumor biopsy and screening sample (Fig A). The median age at screening was 71 years (range 56-83) with a median time to FL diagnosis of 56 months (TTD, range 6-139). Tumor biopsies were sequenced utilizing hybrid capture sequencing for commonly mutated lymphoma genes. DNA extracted from pre-diagnostic blood or saliva cell pellet specimens was sequenced utilizing error-corrected CAPP-Seq (Newman et al Nat Biotech 2016) to a median depth of 5204x. We sequenced to similar depths peripheral blood DNA from control cohorts of individuals with detectable t(14;18) but no subsequent lymphoma diagnosis (n=14) and healthy individuals without detectable t(14;18) by PCR (n=20). Results: Coding mutations were identified from all tumors with a mutational distribution similar to prior FL sequencing studies. Tumor-derived variants were detected in 7 of 29 paired pre-diagnostic specimens (24%) at a median TTD of 44 months (range 11-112 months, Fig B). The statistical significance of detection was assessed using a previously described approach based on Monte Carlo sampling (Newman et al Nat Biotech 2016) and the error distribution of affected loci in control cohorts. While an outlier case contained concordant TNFRSF14, FOXO1, and STAT6 mutations 90 months pre-diagnosis at an elevated allelic fraction (AF) of 1.8%, the mean AF of other detected precursor variants was 0.091%. Individuals with detected variants were not older (Fig C) nor significantly closer to clinical diagnosis (Fig D). The most frequently detected lesions were CREBBP (6/15 cases, 40%) and BCL2 (3/13, 23%) with one case demonstrating a fuller mutational profile including FOXO1 and ARID1A at 44 months before diagnosis. All detected precursor CREBBP variants localized to the KAT domain, reflecting prior observations in pre-diagnostic samples without confirmatory biopsy (Fig E). Of note, saliva cell pellets may contain 30% or more hematopoietic DNA (Kaur et al Chimerism 2012) and we detected tumor-confirmed variants in both saliva and blood screening specimens (Fig F) with no significant difference in AF (Fig G). In an illustrative independent case with available imaging, a patient undergoing radical prostatectomy was found to have involvement of a pelvic lymph node with in situ follicular neoplasia (ISFN). Staging PET/CT showed no evidence of FL (Fig H) and he was followed expectantly for 4 years without emergent disease. Eight years after surgery he presented with inguinal swelling and bilateral FDG-avid adenopathy on PET/CT. Excisional biopsy confirmed low grade FL and sequencing for M7-FLIPI revealed a CREBBP KAT domain variant. Retrospective sequencing of serial peripheral blood specimens from his initial surveillance showed detectable CREBBP R1446C at the earliest collected time point (AF range 0.019-0.046%) rising to AF 0.082% after clinical diagnosis. Conclusions: Precursor FL mutations are detectable in peripheral blood and saliva years prior to clinical diagnosis with a spectrum of variants enriched in CREBBP and BCL2 and concordant with subsequent FL tumors. Such lesions may assist in stratifying individuals at elevated risk of clinical malignancy, including after identification of pathologic precursors such as ISFN. Figure 1 Figure 1. Disclosures Kurtz: Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Roche: Consultancy; Genentech: Consultancy. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees. Diehn: Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy; Varian Medical Systems: Research Funding; Illumina: Research Funding; CiberMed: Current holder of stock options in a privately-held company, Patents & Royalties; Foresight Diagnostics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Roulland: BMS: Research Funding. Alizadeh: Bristol Myers Squibb: Research Funding; Gilead: Consultancy; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Celgene: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

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Profiling of Circulating Tumor DNA for Noninvasive Disease Detection, Risk Stratification, and MRD Monitoring in Patients with CNS Lymphoma

Blood ◽

10.1182/blood-2021-149644 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 6-6

Author(s):

Jurik Andreas Mutter ◽

Stefan Alig ◽

Eliza Maria Lauer ◽

Mohammad Shahrokh Esfahani ◽

Jan Mitschke ◽

...

Keyword(s):

Clinical Outcomes ◽

Stock Options ◽

Research Funding ◽

Circulating Tumor Dna ◽

Tumor Burden ◽

Independent Validation ◽

Tumor Biopsies ◽

Tumor Dna ◽

Privately Held

Abstract Introduction: Clinical outcomes for patients with central nervous system lymphoma (CNSL) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure remains challenging with existing methods. In addition, diagnosis of CNSL requires invasive neurosurgical biopsies that carry procedural risks and often cannot be performed in frail or elderly patients. Circulating tumor DNA (ctDNA) has shown great potential as a noninvasive biomarker in systemic lymphomas. Yet, previous studies revealed low ctDNA detection rates in blood plasma of CNSL patients. In this study, we utilized ultrasensitive targeted high-throughput sequencing technologies to explore the role of ctDNA for disease classification, MRD detection, and early prediction of clinical outcomes in patients with CNSL. Methods: We applied Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) and Phased Variant Enrichment and Detection Sequencing (PhasED-Seq, Kurtz et al, Nat Biotech 2021) to 85 tumor biopsies, 131 plasma samples, and 62 CSF specimens from 92 CNSL patients and 44 patients with other brain cancers or inflammatory cerebral diseases, targeting 794 distinct genetic regions. Concentrations of ctDNA were correlated with radiological measures of tumor burden and tested for associations with clinical outcomes at distinct clinical time points. We further developed a novel classifier to noninvasively distinguish CNS lymphomas from other CNS tumors based on their mutational landscapes in plasma and CSF, using supervised training of a machine learning approach from tumor whole genome sequencing data and own genotyping analyses, followed by its independent validation. Results: We identified genetic aberrations in 100% of CNSL tumor biopsies (n=63), with a median of 262 mutations per patient. Pretreatment plasma ctDNA was detectable in 78% of plasma samples and in 100% of CSF specimens (Fig. 1a), with ctDNA concentrations ranging from 0.0004 - 5.94% allele frequency (AF, median: 0.01%) in plasma and 0.0049 - 50.47% AF (median: 0.62%) in CSF (Fig. 1b). Compared to ctDNA concentrations in patients with systemic diffuse large B-cell lymphoma (DLBCL, data from Kurtz et al., J Clin Oncol, 2018), plasma ctDNA levels in CNSL were in median more than 200-fold lower (Fig. 1b). We observed a significant correlation of ctDNA concentrations with total radiographic tumor volumes (TRTV) measured by MRI (Fig. 1c,d), but no association with clinical risk scores (i.e., MSKCC score) or concurrent steroid treatment. Assessment of ctDNA at pretreatment time points predicted progression-free survival (PFS) and overall survival (OS), both as continuous and binary variable (Fig. 1e,f). Notably, patients could be stratified into risk groups with particularly favorable or poor prognoses by combining ctDNA and TRTV as pretreatment biomarkers (Fig. 1g). Furthermore, ctDNA positivity during curative-intent induction therapy was significantly associated with clinical outcomes, both PFS and OS (Fig. 1h). Finally, we applied our novel machine learning classifier to 207 specimens from an independent validation cohort of CNSL and Non-CNSL patients. We observed high specificity (100%) and positive predictive value (100%) for noninvasive diagnosis of CNSL, with a sensitivity of 57% for CSF and 21% for plasma, suggesting that a significant subset of CNSL patients might be able to forego invasive surgical biopsies. Conclusions: We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings suggest that ctDNA accurately mirrors tumor burden and serves as a valuable clinical biomarker for risk stratification, outcome prediction, and surgery-free lymphoma classification in CNSL. We foresee an important potential future role of ctDNA as a decision-making tool to guide treatment in patients with CNSL. Figure 1 Figure 1. Disclosures Esfahani: Foresight Diagnostics: Current holder of stock options in a privately-held company. Kurtz: Genentech: Consultancy; Roche: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company. Schorb: Riemser Pharma GmbH: Honoraria, Research Funding; Roche: Research Funding; AbbVie: Research Funding. Diehn: BioNTech: Consultancy; RefleXion: Consultancy; Roche: Consultancy; AstraZeneca: Consultancy; Foresight Diagnostics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CiberMed: Current holder of stock options in a privately-held company, Patents & Royalties; Illumina: Research Funding; Varian Medical Systems: Research Funding. Alizadeh: Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Gilead: Consultancy; Roche: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Janssen Oncology: Honoraria; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Bristol Myers Squibb: Research Funding.

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Quantitative Real-Time PCR of Peripheral Blood t(14;18) Positive Cells Predicts Treatment Response and Long-Term Outcome in Patients with Follicular Lymphoma.

Blood ◽

10.1182/blood.v114.22.441.441 ◽

2009 ◽

Vol 114 (22) ◽

pp. 441-441

Author(s):

Fabian Zohren ◽

Ingmar Bruns ◽

Juergen Barth ◽

Sabrina Pechtel ◽

Roland Fenk ◽

...

Keyword(s):

Follicular Lymphoma ◽

Treatment Response ◽

Peripheral Blood ◽

Research Funding ◽

Molecular Remission ◽

Long Term Outcome ◽

Free Survival ◽

Significant Difference

Abstract Abstract 441 Introduction: By means of standard chemotherapy advanced stage follicular lymphoma (FL) is an incurable disease. Clinical courses are characterized by a continuous tendency to relapse caused by residual neoplastic cells. Quantitative polymerase chain reaction (qPCR) to detect lymphoma cell that carry the t(14;18) translocation is a suitable method to measure minimal residual disease (MRD) in patients with FL. Despite several reports dealing with MRD qPCR in FL, its role in the clinical management of patients is still not clearly defined. Therefore, we carried out a multicenter study, to assess the prognostic value of sequential quantitative MRD detection in first-line treatment of FL using an improved version of a LightCycler based qPCR specific for the major breakpoint region (MBR) positive IgH/bcl2 translocation, provided by Roche Diagnostics® (Penzberg Germany). Patients and Methods: We analysed 718 blood (PB) samples of 179 patients with newly diagnosed FL treated within the multicenter randomized trial NHL1, conducted by the German StiL group (Study group indolent Lymphomas), comparing 6 cycles of R–CHOP versus R–Bendamustin (R-B). Samples were taken at diagnosis, after 6 cycles of either R–CHOP or R–B immuno-chemotherapy and every three months during follow-up. All samples were analyzed in the department of Hematology at Heinrich-Heine University in Duesseldorf. Results: At diagnosis, 112 out of 179 patients (62.6%) were positive for IgH/bcl2 within the MBR in the peripheral blood. Significantly higher amounts of bcl2/IgH positive cells were found in patients with bone marrow infiltration (p=0.012) and depending on the number of lymphatic nodes (LN) with disease involvement (>3 LN p=0.003; >5 LN p=0.0009; >7 LN p=0.022). Overall, a remarkable inter-individual variation of bcl2/IgH positive cells in the PB at diagnosis, reflected by ratios from 0.000281 to 81, was found. The estimated event free survival (EFS) at 2 years of patients who presented at diagnosis low to normal amounts of bcl2/IgH positive cells in the PB (ratio < 2, n=83) was 82% (SE 0.045), which was significantly better than the 47% (SE 0.11) observed in patients showing the highest amount of bcl2/IgH positive cells (ratio >2, n=24) in the PB (p=0.003). By univariate and multivariate analysis, we found that the amount of bcl2/IgH positive cells in the PB at diagnosis (p=0.001) as well as the achievement of a negative MRD status after therapy (p=0.0001) were significant predictors for relapse free survival. Monitoring of MRD levels before and after therapy revealed that 6 cycles of immuno-chemotherapy significantly reduced the amount of bcl2/IgH positive cells in the PB compared with pre-treatment MRD levels (p=0.0001; median bcl2/IgH/tPA ratio: before treatment 0.0734, range: 0.000281–81, after treatment negative, range: negative–0.17). After treatment, 86% of the patients (n=82) achieved a molecular remission in the PB defined as qPCR negative, whereas 14% (13 patients) remained PCR positive. Not reaching a molecular remission in the PB at the end of therapy had a significant negative influence on PFS. After a median follow-up of two years, patients who remained MRD positive in the first measurement after therapy had a significant lower PFS than MRD negative patients (p=0.0001; 9 months vs. not reached). There was no significant difference in the degree of tumor cell depletion in the PB induced by the two different regimens. So far, 539 follow-up samples from 3 up to 39 months after therapy were analyzed. Patients with a consistent negative MRD status throughout follow-up showed a trend towards longer PFS. After 38 months follow-up, MRD positive patients had a PFS of 54% compared to 78% in the group of MRD negative patients (p=0.066). Conclusion: QPCR for the t(14;18) performed at diagnosis and during follow-up on PB samples predicts treatment response and long-term clinical outcome of patients with FL. Disclosures: Zohren: Roche: Honoraria, Research Funding. Rummel:Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Kobbe:Roche: Research Funding.

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Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽

10.1182/blood-2021-155156 ◽

2021 ◽

Vol 138 (Supplement 2) ◽

pp. LBA-5-LBA-5

Author(s):

Lynn Malec ◽

An Van Damme ◽

Anthony Chan ◽

Mariya Spasova ◽

Nisha Jain ◽

...

Keyword(s):

Half Life ◽

Stock Options ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

High Dose ◽

Severe Hemophilia ◽

First Time ◽

Inhibitor Titer ◽

Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

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Clinical and Biological Prognostic Factors in Follicular Lymphoma Patients During Treatment

10.21203/rs.3.rs-275643/v1 ◽

2021 ◽

Author(s):

Ádám Jóna ◽

Anna Kenyeres ◽

Sándor Barna ◽

Árpád Illés ◽

Zsófia Simon

Keyword(s):

Prognostic Factors ◽

High Risk ◽

Follicular Lymphoma ◽

Risk Group ◽

Standardized Uptake Value ◽

Progression Free Survival ◽

High Risk Group ◽

Pet Ct ◽

Significant Difference ◽

Biological Prognostic Factors

Abstract Introduction: Follicular lymphoma (FL) is an indolent yet heterogeneous B-cell lymphoproliferative disorder. Most people respond to treatment well. However, a particular group of patients has a poor prognosis, and these patients are difficult to define.Patients and methods: We retrospectively analyzed FL patients treated at the University of Debrecen in the past 20 years. We investigated prognostic factors that may influence the survival of FL patients.Results: We found a standardized uptake value (SUV)max cut-off value of 9.85 at the staging PET/CT to significantly separate FL patients’ progression-free survival (PFS) (p=0.0003, HR: 0.2560, 95%CI: 0.1232-0.5318). Lymphocyte/ monocyte (Ly/Mo) ratio of 3.45 drawn at diagnosis also significantly predicted PFS (p=0.0324, HR: 1.806, 95% CI: 1.051-3.104). Combining patients’ with staging SUVmax >9.85 and Ly/Mo < 3.45 a high-risk group of FL patients can be identified (p<0.0001, HR: 0.1033, 95%CI: 0.03719-0.2868). Similarly, a significant difference was shown with a SUVmax cut-off of 3.15 at the interim PET/CT (p<0.0001, HR: 0.1535, 95%CI: 0.06329-0.3720). Combining patients with staging SUVmax >9.85 and interim SUVmax >3.15, a high-risk group of FL patients can be identified (p<0.0001, HR: 0.1037, 95%CI: 0.03811-0.2824). The PFS difference is translated into overall survival advantage (p=0.0506, HR: 0.1187, 95%CI: 0.01401-1.005).Discussion: Biological prognostic factors, such as the Ly/ Mo ratio, may improve the prognostic assessment of staging PET/CT. Nevertheless, PFS difference is translated into OS when using a combination of staging and interim SUVmax. We consider investigating additional biological prognostic factors while currently highlighting PET/CT's role in FL.

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Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry

Blood ◽

10.1182/blood-2021-154314 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4997-4997

Author(s):

Surbhi Shah ◽

Shuchi Gulati ◽

Ang Li ◽

Julie Fu ◽

Vaibhav Kumar ◽

...

Keyword(s):

Mechanical Ventilation ◽

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Tumor Board ◽

Bleeding Complications ◽

Advisory Committees ◽

Icu Admission ◽

Patients With Cancer ◽

Privately Held

Abstract Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p<0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Phase I/II Study of IPH1101, γσ T Cell Agonist, Combined with Rituximab, in Low Grade Follicular Lymphoma Patients.

Blood ◽

10.1182/blood.v114.22.1649.1649 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1649-1649 ◽

Cited By ~ 4

Author(s):

Guy Laurent ◽

Sylvie Lafaye de Micheaux ◽

Philippe Solal-Celigny ◽

Pierre Soubeyran ◽

Vincent Delwail ◽

...

Keyword(s):

T Cells ◽

Follicular Lymphoma ◽

Research Funding ◽

Low Grade ◽

Low Doses ◽

Open Label ◽

Independent Panel ◽

Pharmacodynamic Profile ◽

Previously Treated Patients ◽

Previously Treated

Abstract Abstract 1649 Poster Board I-675 Non-conventional γσ T lymphocytes are innate immunity effectors bearing potent anti-tumoral activity, particularly against malignant B cells. IPH1101 is an agonist of γσ T cells, which in the presence of low doses of IL-2 potentiates their direct cytotoxic activity. ADCC is a major molecular mechanism underlying rituximab's efficacy. Increasing the number and the activation state of killer lymphocytes mediating ADCC is therefore believed to be beneficial for therapeutic potency. Since γσ T cells have been found to be capable of mediating ADCC, modulating γσ T cells in the context of rituximab is worth being tested in a clinical trial. The main purpose is to assess the clinical efficacy of IPH1101 with low doses of IL-2, combined with a standard rituximab treatment, in patients (pts) with follicular lymphoma. This is an open label, multinational study consisting of a dose escalation Phase (ph) I-like part followed by a ph II part. The ph I part has shown a good safety and immuno-biological efficacy profile for the highest dose of IL-2. Consequently, the pts of the phase II part were treated with the combination of rituximab (375 mg/m2) administered 4 times weekly, IPH1101 (750 mg/m2) administered i.v. 3 times (every 3 weeks) and IL-2 (8 MIU) administered daily s.c. for 5 days starting on the day of each IPH1101 administration. All pts presented low grade FL which had relapsed after 1 to 4 lines of previous therapy including at least one rituximab-containing line. Inclusion criteria set forth that pts should have no lesion > 7 cm. Results We report here the end of recruitment and updated data on 45 patients and more than 100 cycles of IPH1101. Overall safety was good, and most of the drug-related adverse events were, as expected, flu like symptoms of grade 1 or 2. The SAEs reported were 2 hypotensions, 1 bronchospasm, 1 allergic reaction (back pain), 1 glomerular filtration decrease, 1 ALAT elevation, 1 hypertension and 1 asthenia. The immuno-biological follow up demonstrated the very good pharmacodynamic profile of IPH1101 in these patients and these data are presented in details in another abstract from Lucas et al. To date, in the first set of evaluable patients (12 pts) and after at least 3 months post treatment, investigators reported about 75% of response and 50% of CR. Most of the responses are already confirmed by an independent panel. Conclusion These observations confirm the good safety and the biological rationale of this approach. Furthermore, the response rate in this first set of pts is encouraging in the context of previously treated patients. Updated results will be presented at the meeting. Disclosures Laurent: Innate pharma: Honoraria. Lafaye de Micheaux:Innate Pharma: Employment. Solal-Celigny:Innate Pharma: Research Funding. Soubeyran:Innate Pharma: Research Funding. Delwail:Innate Pharma: Honoraria. Ghesquières:innate pharma: Honoraria. Thieblemont:Innate Pharma: Honoraria. Jourdan:Innate Pharma: Honoraria. Beautier:Innate Pharma: Employment. Squiban:Innate pharma: Employment. Rossi:Innate Pharma: Honoraria.

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Bortezomib Added to CVP-R Is Safe and Effective for Previously Untreated Advanced Stage Follicular Lymphoma: A Phase II Study by the NCIC Clinical Trials Group.

Blood ◽

10.1182/blood.v114.22.407.407 ◽

2009 ◽

Vol 114 (22) ◽

pp. 407-407

Author(s):

Laurie H. Sehn ◽

David A Macdonald ◽

Sheldon H. Rubin ◽

Guy Cantin ◽

Morel Rubinger ◽

...

Keyword(s):

Follicular Lymphoma ◽

Phase Ii ◽

Research Funding ◽

Standard Dose ◽

Phase Iii ◽

High Risk Population ◽

Low Grade ◽

Grade 3 ◽

To Receive ◽

Experienced Grade

Abstract Abstract 407 Background: Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R), one of the most commonly used regimens in untreated patients. Methods: This is a phase II multi-centre open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2, capped at 2 mg), prednisone (40 mg/m2 × 5) and rituximab (375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Response was assessed following 4 and 8 cycles. The two co-primary endpoints were complete response rate (CR/CRu) and incidence of grade 3/4 neurotoxicity. Following the final response assessment, patients were permitted to receive maintenance rituximab at the discretion of the treating physician according to local practice. Results: Between March 2007 and February 2009, 95 patients were enrolled. Median age was 56.6 years (range 29.5 – 83.6 years). 48% percent were male and 63% had stage IV disease. FLIPI score at study entry: low 11%, intermediate 43%, high 46%. Safety data was availabel on all patients. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. No pts have developed grade 4 neurotoxicity and only 6/95 (6.3%) have developed grade 3 neurotoxicity (five sensory neuropathy and one neuropathic pain). The incidence of grade I and II neuropathy was 65.3% and 36.8% respectively. Neurotoxicity was largely reversible. Five pts discontinued therapy prematurely (three refused further treatment, one pt was found to have Hodgkin lymphoma as well as FL and one pt was removed from study for non-compliance). 84% of planned bortezomib treatments and 85% of vincristine treatments were administered without dose reduction. Five pts experienced grade 3/4 anemia and 3 pts experienced grade 3/4 thrombocytopenia. Only 4 episodes of febrile neutropenia occurred and 2 grade 3 infections were noted. No grade 4 infections were reported. No serious adverse events were reported. One patient died due to progressive disease. At present, 78/95 patients are evaluable for response. 37/78 (47%) achieved a CR/CRu (95% CI 36.4, 58.5), and 29/78 (37%) achieved a PR with an ORR of 84.6% (95% CI 76.6, 96.6). An additional 5/78 pts had stable disease, while 7/78 progressed on therapy. Complete efficacy data as well as information on quality of life will be availabel within the next few months. Forty-one of 70 pts (58.6%) with availabel follow-up information went on to receive maintenance rituximab. Conclusions: The addition of bortezomib to standard dose CVP-R is feasible and well tolerated with minimal associated toxicity. Neurotoxicity is primarily low grade and reversible and does not limit delivery of either bortezomib or vincristine. The complete remission rate in this high risk population compares favorably to historical results of patients receiving CVP-R. Based on these encouraging results, a phase III trial of CVP-R with or without bortezomib is currently being planned. Disclosures: Sehn: Johnson and Johnson Ortho Biotec: Honoraria. Off Label Use: Velcade for is not yet approved for follicular lymphoma. Chen:Johnson and Johnson Ortho Biotec: Research Funding. Djurfeldt:Johnson and Johnson Ortho Biotec: Research Funding. Shepherd:Johnson and Johnson Ortho Biotec: Research Funding. Crump:Johnson and Johnson Ortho Biotec: Honoraria.

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Rituximab Overcomes Sex as a Strong Adverse Prognostic Factor for Treatment Outcome in Patients with Follicular Lymphoma: Analysis of Patients Treated with Rituximab/CHOP or CHOP in Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽

10.1182/blood.v114.22.3706.3706 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3706-3706 ◽

Cited By ~ 1

Author(s):

Christian Buske ◽

Eva Hoster ◽

Martin H. Dreyling ◽

Roswitha Forstpointner ◽

Michael Kneba ◽

...

Keyword(s):

Treatment Outcome ◽

Prognostic Factor ◽

Follicular Lymphoma ◽

Research Funding ◽

Low Grade ◽

Study Group ◽

Female Patients ◽

Male Patients ◽

Male Sex ◽

Lymphoma Study Group

Abstract Abstract 3706 Poster Board III-642 Sex has been recognized as an important prognostic factor for the treatment outcome of patients with lymphoma. Thus, several retrospective analyses have shown that male sex is associated with an inferior outcome in advanced stage follicular lymphoma. This was confirmed in a retrospective analyses of 1795 patients with follicular lymphoma using Cox regression analysis, in which male sex was independently associated with inferior survival (Solal-Celigny et al., Blood 2004). We now analyzed the prognostic impact of sex on treatment outcome of 1172 patients with follicular lymphoma treated first line with CHOP or R-CHOP in prospectively randomized clinical trials of the German Low-Grade Lymphoma Study Group (GLSG). From these, 616 pts were treated with CHOP, 556 pts with R-CHOP. FLIPI was equally distributed between the two treatment arms (low risk 14% vs. 14%, intermediate risk 42% vs. 41% and high risk 44% vs. 45 %, respectively). 48% of the patients were male (50% in the CHOP and 46% in the R-CHOP arm). For all patients there was a significantly inferior time to treatment failure (TTF) for male patients with a median of 43 months compared to 61 months for female patients (p=0.0035). In the patient group treated with CHOP alone the median TTF was 30 months for male vs. 40 months for female patients (p=0.0041). The observation that male sex was associated with inferior treatment outcome was seen both in the elderly (above 60 yrs of age) as well as the younger patient group (below 60 yrs of age). However, after treatment with R-CHOP sex did not affect treatment outcome anymore with virtually the same results in male vs. female patients (for the total group and for patients < 60yrs TTF median not reached in both arms, p = n.s.; for pts > 60 yrs TTF 81 vs. 84 months, respectively, p=n.s.). In multivariate analysis, also adjusting for FLIPI risk factors, male sex showed up as an independent prognostic factor for patients treated with CHOP alone (HR 1.82; 1.32 – 2.5; p=0.0002), but not for patients treated with R-CHOP (HR 1.06; 0.68 - 1.66, p = 0.79; p=0.0476 for the interaction term of sex with Rituximab). Based on this, male patients had the highest benefit when rituximab was added to CHOP (R-CHOP vs. CHOP: male pts HR 0.31,0.21 - 0.46, p<0.0001 and female pts. HR 0.53, 0.37 - 0.76, p = 0.0005). These data demonstrate that Rituximab functions as an equalizer with regard to sex as a prognostic factor and underlines that well established prognostic factors may lose their predictive power with the emergence of novel effective treatment approaches. Disclosures: Buske: Roche: Honoraria. Hoster:Roche: travel support. Dreyling:Roche: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Research Funding. Unterhalt:Roche: .

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Interim Positron Emission Tomography-Computed Tomography (PET-CT) Is Predictive of Post-Therapy Outcome in High Grade Transformation of Low Grade Lymphoproliferative Disorders

Blood ◽

10.1182/blood.v126.23.5038.5038 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5038-5038

Author(s):

Louise Imlay-Gillespie ◽

David Simon Kliman ◽

Kelly Wong ◽

Christopher Arthur ◽

Luke Coyle ◽

...

Keyword(s):

Research Funding ◽

Metabolic Response ◽

B Cell Lymphoma ◽

Low Grade ◽

High Grade ◽

Interim Pet ◽

Pet Ct ◽

High Grade Transformation ◽

Post Therapy ◽

Initial Staging

Abstract Background PET-CT has become an essential tool in the management of Lymphoma. PET-CT is utilized in both the initial staging of lymphoma as well as assessing treatment-response. High grade transformation of a low grade lymphoproliferative disorder (LPD) is associated with a poor prognosis. Patients (pts) are usually treated with standard of care for Diffuse Large B-Cell Lymphoma (DLBCL) with R-CHOP but generally have poorer outcomes and can experience relapse of either low or high grade disease. To our knowledge, PET-CT has not been evaluated as a prognostic tool for the subgroup of transformed DLBCL. Methods A retrospective audit was performed of patients treated at Royal North Shore Hospital in Sydney, Australia between 2003-2012. Pts were included if they were treated with Rituximab for DLBCL during the study period and if this occurred on a background of low-grade LPD. Clinical data including LPD type, initial staging, treatment and outcomes were also collected. Treatments were stratified into standard R-CHOP-like versus more intensive regimens including Hyper-CVAD and dose-adjusted R-EPOCH. PET-CT reports were reviewed at staging, interim and post-therapy time points and outcomes stratified to complete metabolic response (CR), partial metabolic response (PR) and progressive disease (PD),based on the nuclear medicine physician's report. Results 64 pts were identified in the study period with median follow up 4.4 yrs (range, 50d-11yrs)Male:female ratio was 1:1. Median age was 65 yrs (range 30-89). LPD diagnosis included Follicular Lymphoma (FL) (75%), Chronic Lymphocytic Leukemia (CLL) (6%) and others (19%) that included Mucosa Associated Lymphoid Tissue and Marginal Zone Lymphomas. 39 pts (61%) had PET-CT reports available for review. 45 pts (70%) were treated with R-CHOP with the remainder having more intensive regimes. 26% of pts received consolidation radiotherapy. 13 pts (20%) underwent autologous and 6 (9%) proceeded to an had an allogeneic transplant. 3 yr OS and EFS was 89% and 73% respectively. Univariate analysis demonstrated both interim and post therapy PET-CT to be significant for both OS and EFS (p<0.01) with three groups identified; CR, PR and PD with 3 year OS for negative interim PET of 100%, 91% and 0% accordingly. CR on end of therapy CT was associated with improved OS (p<0.05) but not interim CT (p=0.967). On multivariate analysis interim PET-CT was the strongest independent predictor for EFS but not OS (p < 0.05). Discussion PET-CT is an invaluable tool in the management of LPD. This retrospective review demonstrates the utility of interim PET-CT in the prognostication of pts with transformed LPD. Larger prospective studies should be considered using PET-CT to more accurately stratify treatment for pts with transformed LPD. Figure 1. Figure 1. Disclosures Imlay-Gillespie: Novartis: Honoraria. Arthur:Amgen: Honoraria; Amgen: Honoraria; BMS: Honoraria. Mackinlay:Sanofi Aventis: Research Funding; Roche: Research Funding. Mulligan:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi Aventis: Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Additive Value of Dynamic FDOPA PET/CT for Glioma Grading

Frontiers in Medicine ◽

10.3389/fmed.2021.705996 ◽

2021 ◽

Vol 8 ◽

Author(s):

Antoine Girard ◽

Pierre-Jean Le Reste ◽

Alice Metais ◽

Nibras Chaboub ◽

Anne Devillers ◽

...

Keyword(s):

Kinetic Analysis ◽

Kinetic Parameters ◽

Area Under The Curve ◽

Compartment Model ◽

Low Grade ◽

Newly Diagnosed ◽

Time To Peak ◽

Positron Emission ◽

Pet Ct ◽

Significant Difference

Purpose: The aim of this study was to assess the value of the FDOPA PET kinetic parameters extracted using full kinetic analysis for tumor grading with neuronavigation-guided biopsies as reference in patients with newly-diagnosed gliomas.Methods: Fourteen patients with untreated gliomas were investigated. Twenty minutes of dynamic positron-emission tomography (PET) imaging and a 20-min static image 10 min after injection were reconstructed from a 40-min list-mode acquisition immediately after FDOPA injection. Tumors volume-of-interest (VOI) were generated based on the MRI-guided brain biopsies. Static parameters (TBRmax and TBRmean) and kinetic parameters [K1 and k2 using full kinetic analysis with the reversible single-tissue compartment model with blood volume parameter and the time-to-peak (TTP)] were extracted. Performances of each parameter for differentiating low-grade gliomas (LGG) from high-grade gliomas (HGG) were evaluated by receiver-operating characteristic analyses (area under the curve; AUC).Results: Thirty-two tumoral VOI were analyzed. K1, k2, and TTP were significantly higher for HGG than for LGG (median K1-value = 0.124 vs. 0.074 ml/ccm/min, p = 0.025, median k2-value = 0.093 vs. 0.063 min−1, p = 0.025, and median TTP-value = 10.0 vs. 15.0 min, p = 0.025). No significant difference was observed for the static parameters. The AUC for the kinetic parameters was higher than the AUC for the static parameters (respectively, AUCK1 = 0.787, AUCk2 = 0.785, AUCTTP = 0.775, AUCTBRmax = 0.551, AUCTBRmean = 0.575), significantly compared to TBRmax (respectively, p = 0.001 for K1, p = 0.031 for k2, and p = 0.029 for TTP).Conclusion: The present study suggests an additive value of FDOPA PET/CT kinetic parameters for newly-diagnosed gliomas grading.

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