Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 20 ( 2017-07-10), p. 2260-2267

Abstract: Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2017.72.2157

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2017

detail.hit.zdb_id: 2005181-5

In: Applied Immunohistochemistry & Molecular Morphology, Ovid Technologies (Wolters Kluwer Health), Vol. 19, No. 1 ( 2011-01), p. 62-69

Type of Medium: Online Resource

ISSN: 1541-2016

URL: Article

DOI: 10.1097/PAI.0b013e3181ed47bc

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2011

detail.hit.zdb_id: 2052398-1

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1500-1500

Abstract: Background: Central nervous system (CNS) relapse in pts with aggressive non-Hodgkin lymphoma (NHL) is a generally fatal complication, with median overall survival (OS) of less than six months (Abramson et al., 2010). Several studies have identified features associated with increased risk of CNS relapse, such as extranodal (EN) sites of disease, elevated lactate dehydrogenase (LDH), presence of B symptoms, and bone marrow involvement (Bernstein et al., 2009; van Besien et al., 1998). Moreover, multivariate analyses have suggested that LDH greater than 3x upper limit of normal (ULN) is strongly associated with increased risk of death or progression among patients with aggressive NHL (Zhou et al., 2014). Despite little evidence on its true efficacy, prophylaxis (ppx) intrathecal (IT) chemotherapy, most frequently with methotrexate (MTX), is often used to among pts thought to be at high risk for CNS relapse. Data on efficacy or need for CNS prophylaxis in patients receiving infusional therapy with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-EPOCH) is not available. As R-EPOCH, is being increasingly used in pts with lymphoma, we sought to evaluate the role of IT chemotherapy when used with this regimen. Methods: We conducted a retrospective chart review analysis of patients with diffuse large B-cell lymphoma (DLBCL) who received R-EPOCH as frontline therapy, between 2005 and 2014. Use of IT ppx was at the discretion of the treating physician. We excluded patients under the age of 18, those receiving fewer than two cycles of R-EPOCH, those with CNS involvement at time of diagnosis, and those who received high-dose intravenous CNS ppx. Two-tailed Fisher's exact test was used to determine whether any of the following baseline features was associated with risk of CNS relapse: age 〉 60, ECOG PS 〉 1, LDH 〉 normal and/or 〉 3x ULN, presence of B symptoms, two or more EN sites, anatomic location of EN sites, international prognostic index (IPI) score 〉 1, bone marrow involvement, and HIV infection. In order to determine whether IT ppx was associated with any improvement in CNS and/or systemic control of disease, we compared, using Kaplan-Meier survival curves with log-rank analyses, the patterns of overall survival (OS), progression-free survival (PFS), and freedom from CNS progression (FFCP, in which death is not counted as an event) between patients receiving IT ppx and those not receiving it. Results: We identified 117 patients for analysis. Median age was 53 (range 19-80). 26% had ECOG PS 〉 1; 76% had LDH above upper limit of normal (ULN). 38% had two or more EN sites of disease, and 68% had stage III-IV disease. 62 patients received IT ppx, and 55 did not. Of those receiving IT ppx, 95% received MTX, with the remainder receiving cytarabine. Those receiving IT ppx were more likely to have 〉 1 EN site of disease, and IPI score 〉 1 (Table 1). A total of seven had observed CNS relapse, occurring at a median of 6 months from time of NHL diagnosis (range 2-24 months). At a median follow up of 18 months, the 24-month PFS and OS were 80% and 83%, respectively. Median PFS and OS were not reached. The only factors associated with increased risk of CNS relapse were genitourinary EN disease and LDH 〉 3x ULN (Table 2). There were no significant differences in OS, PFS, or FFCP among patients who did and did not receive CNS prophylaxis (Figure 1, panels A-C). Conclusions: The risk of CNS progression among DLBCL patients receiving R-EPOCH was similar to previous reports with R-CHOP, at 6%. GU location of EN disease and LDH 〉 3xULN were associated with increased risk of CNS relapse. IT ppx was not associated with improved outcomes. Despite the common use of IT PPX in pts treated with R-EPOCH, our data suggest that this practice might not impact CNS progression and/or relapse, though randomized studies would be needed to answer this. Such studies are warranted in order to better determine what factors are associated with CNS progression, and whom, if anyone, may benefit from IT ppx. Figure 2. Figure 2. Disclosures Nabhan: Celgene Corporation: Honoraria, Research Funding. Petrich:Seattle Genetics: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1500.1500

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 133, No. 18 ( 2019-05-02), p. 1964-1976

Abstract: Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-11-880526

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3990-3990

Abstract: Background: MCL carries a poor overall prognosis despite high response rates to induction chemotherapy. Maintenance strategies have impacted survival in MCL but optimal strategies have yet to be defined. Despite profound activity of ibrutinib, a selective BTK inhibitor, in relapsed/refractory MCL, ibrutinib maintenance (I-M) following induction for treatment-naive MCL has not been explored. We report preliminary results of a multicenter phase II trial assessing efficacy and safety of I-M for MCL after frontline induction. Methods: Patients (pts) with MCL with complete or partial response (CR/PR) to frontline chemo-immunotherapy +/- autologous stem cell transplantation (autoSCT) received I-M 560 mg daily for up to 4 years. The primary objective was 3 year PFS rate with I-M. Secondary objectives were PR to CR conversions, median OS after 4 years and toxicity. Measurable residual disease (MRD) assessments using an NGS-MRD Assay (detection resolution of 〈 1 cell per million; Adaptive Biotechnologies) on peripheral blood and/or PBMCs were planned at 4 time points: prior to I-M initiation and at 1, 6 and 18-24 mo(s) after initiation of I-M. Results: Accrual is complete (n=36). Median age was 60 (range 46-90), 28 pts (78%) were males, 28 (78%) had advanced stage and 9 (25%) had extranodal disease. 18 (50%), 7 (19%) and 11 (31%) had low vs intermediate vs high risk MIPI respectively. For induction, 17 (47%) received bendamustine-rituximab (BR), 18 (50%) a cytarabine-based regimen, and 1 (3%) R-CHOP. 18 (50%) had autoSCT in CR1 prior to enrollment. 33 (92%) and 3 (8%) had CR and PR with induction respectively with 1 PR to CR conversion on I-M. Median follow-up from initiation of induction therapy was 33 mos. With a median follow-up of 24.5 mos from initiation of I-M, 1 pt had disease progression (PD) and 2 others died, 1 from hepatic cholangiocarcinoma 2 years after I-M discontinuation for toxicity (atrial fibrillation) and 1 from unknown cause. 20/36 (56%) pts remain on I-M (median 24 cycles, range 1-52). Sixteen pts discontinued ibrutinib, including 3 for completion of 4 years of I-M. Of the remaining 13 who discontinued, TRAEs accounted for 10 (77%) and the other 3 were for uterine cancer (n=1), PD (n=1), and death of unknown cause (n=1) (Table 1). Atrial fibrillation/atrial flutter accounted for 50% (n=5) of TRAEs that led to I-M discontinuation. 9 (25%) pts required permanent dose reductions for TRAEs with neutropenia (n=3), myalgias (n=2), and fatigue (n=2) being the most common. Collectively, TRAEs led to dose reductions/ interruptions/ discontinuations in 25 (69%) pts. At time of data cut-off, (July 2019), using a trackable dominant clone identified from tissue at diagnosis, MRD was assessed in 12 patients at varying time points (Figure 1). In these 12 pts, 6 were induced with BR, 5 with a cytarabine-based regimen, and 1 with R-CHOP and 5 were consolidated with autoSCT prior to enrollment. Prior to I-M initiation, 9 pts were MRD (-) and 3 had indeterminate MRD status. Indeterminate results corresponded with total cell counts below the level of detection and quantification with our assay. Those with indeterminate MRD status were confirmed to be MRD (-) with subsequent evaluation after 1 month of I-M. 3 of 12 (25%) pts became MRD (+) on I-M. The first reverted back to MRD (-) status and remains MRD (-) with clinical CR on 〉 3 years of I-M. The second pt was treated with hyperCVAD with PR prior to I-M. This patient required several dose interruptions for neutropenia just prior to MRD detection with clinical PD leading to discontinuation of therapy after 9 months of I-M. The third pt was treated with R-CHOP + autoSCT with PR prior to I-M and maintains a PR despite MRD conversion on 〉 2 years of I-M. Further analysis of dynamic changes in dominant and non-dominant clones associated with I-M is ongoing. Conclusions: I-M is feasible in MCL pts who respond to frontline chemo-immunotherapy +/- autoSCT with manageable toxicities consistent with the known safety profile of ibrutinib. Guidelines to discontinue I-M for atrial fibrillation were strictly upheld in this protocol though not typical of current practice. NGS can be used to assess MRD with induction and maintenance therapy and demonstrates that most pts are MRD negative after intensive induction. Longer follow-up, evaluation of dynamic changes in MRD, and PFS and OS data are needed to assess clinical relevance of I-M and importance of MRD status, and may support larger, controlled studies. Disclosures Karmali: Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Winter:Merck: Consultancy, Research Funding. Ma:Genentech: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Speakers Bureau; Kite: Consultancy; Juno: Research Funding; Xeme: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding; Bioverativ: Consultancy; Novartis: Research Funding. Petrich:Abbvie: Employment, Equity Ownership. Kuhr:Adaptive Biotechnologies: Employment, Other: shareholder. Gordon:Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Gilead: Other: Advisory Board. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. OffLabel Disclosure: We will discuss results of our trial looking at ibrutinib maintenance in frontline MCL

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126920

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3924-3924

Abstract: Background: Apoptotic cell death can be triggered by activation of extrinsic and intrinsic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, binds to its death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) to selectively activate the extrinsic apoptotic pathway in cancer cells. ABBV-621 is a second-generation TRAIL receptor agonist with antitumor activity as monotherapy (621-mono) in preclinical models of AML and DLBCL. The intrinsic apoptotic pathway is regulated by the BCL2 protein family, commonly overexpressed in hematologic malignancies. Venetoclax (VEN), a highly selective small-molecule BCL2 inhibitor, has shown antitumor activity in combination therapy in AML and DLBCL. In preclinical and xenograft models of AML and DLBCL, the ABBV-621 and VEN combination (621-VEN) had antitumor activity superior to either agent alone. This first-in-human study evaluated ABBV-621 as single agent and in combination in pts with advanced solid tumors and hematologic malignancies (NCT03082209). Safety and tolerability of ABBV-621 in advanced solid tumors have previously been presented (Ratain et al. J Clin Oncol 2019;37[suppl]: abstr 3013). Here, we report preliminary data for 621-mono in pts with RR AML and for 621-VEN in pts with RR AML and DLBCL. Methods: Adult pts with RR AML or DLBCL (ECOG 0-2) were enrolled. Pts with AML received ABBV-621 at 1.25-, 3.75-, 7.5-mg/kg doses in the 621-mono and at 3.75-mg/kg dose in the 621-VEN arms. Pts in the DLBCL 621-VEN arm received ABBV-621 at 3.75- and 7.5-mg/kg doses. ABBV-621 was administered intravenously on D1, 8, and 15 of a 21-D cycle; in 621-VEN cohorts pts received 400 mg oral VEN daily, and could be escalated to 800 mg. The primary endpoint was safety. In addition, preliminary antitumor efficacy and ABBV-621 binding to decoy receptors on neutrophils from peripheral blood were assessed. Results: As of Jun 2019, 17 pts were enrolled. Pts in AML 621-mono arm (1.25 [1], 3.75 [1] , 7.5 [2] mg/kg): 1 male; median (med) age, 75 yr (range 71-82); med prior treatments, 2.5 (range 1-4); med time on treatment, 15 D (range 1-70). Pts in AML 621-VEN arm (3.75 mg/kg [7] ): 5 male; med age, 71 yr (60-79); med prior treatments, 2 (1-2); med time on treatment, 26 D (1-77). Pts in DLBCL 621-VEN arm (3.75 [3], 7.5 [3] mg/kg): 4 male; med age, 57 yr (40-75); stage 4 (3); med prior treatments, 2.5 (1 to ≥5); med time on treatment, 26 D (8-36). One pt in the AML 621-VEN 3.75-mg/kg dose cohort had increases in alanine aminotransferase, aspartate aminotransferase and bilirubin as dose-limiting toxicities. Sixteen pts experienced adverse events (AEs) irrespective of causality. A summary of AEs is shown in Table. One pt in the AML 621-mono 7.5-mg/kg dose cohort died due to AML progression, unrelated to ABBV-621. Antitumor activity was observed in 1 pt in the AML 621-VEN arm (with complex cytogenetics and TP53 mutation) who reached complete remission (CR). One pt in the DLBCL 621-VEN 3.75-mg/kg cohort had stable disease, 2 with AML had resistant disease (1 in 621-mono [7.5 mg/kg] and 1 in 621-VEN), and 7 had progressive disease (PD; 1 in AML 621-mono [1.25 mg/kg] , 2 in AML 621-VEN, and 4 in DLBCL 621-VEN [2 each in 3.75- and 7.5-mg/kg] cohorts). Using flow cytometry, saturation of ABBV-621 binding to decoy receptors on neutrophils was observed at 2 h postdosing, followed by dose-dependent desaturation of receptors in pts with DLBCL at 48-168 h. In AML 621-VEN pts, ABBV-621 remained bound to decoy receptors for up to 168 h; in DLBCL 621-VEN pts, the duration of binding was higher at ABBV-621 7.5 mg/kg compared with 3.75 mg/kg. In AML, the baseline frequency of myeloblasts was higher in pts with PD than CR, while that of myelomonocytes was higher in the pt with CR. The f requency of myeloblasts and myelomonocytes expressing DR4 and DR5 at baseline was highest in the pt with CR (Figure). Conclusions: ABBV-621 was tolerated and showed antitumor activity in combination with VEN in pts with RR AML. Disclosures de Jonge: Faron Pharmaceuticals Ltd.: Consultancy. Carneiro:Actuate Therapeutics: Research Funding; Bayer: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; Medimmune: Research Funding; Astellas: Research Funding; AbbVie: Research Funding. Devriese:MSD: Consultancy. Penugonda:AbbVie: Employment, Other: Stock/stock options. Petrich:Abbvie: Employment, Equity Ownership. Nuthalapati:AbbVie: Employment, Other: Stock/stock options. Motwani:AbbVie: Employment, Other: Stock/stock options. Modi:AbbVie: Employment, Other: Stock/stock options. Chang:AbbVie: Employment, Other: Stock/stock options. Calvo:Celgene: Consultancy; Roche/Genentech: Consultancy, Other: travel/accommodations/expenses; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; PsiOxus: Consultancy; Amcure: Consultancy; START: Other: stock/ownership interests, Research Funding; Janssen-Cilag: Consultancy; EUSA Pharma: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Oncoart Associated: Other: stock/ownership interests; Guidepoint Global: Consultancy; Nanobiotix: Consultancy; HM Hospitales Group: Honoraria; AbbVie: Consultancy; BeiGene: Research Funding; Servier: Consultancy; International Cancer Consultants: Other: stock/ownership interests; Foundation INTHEOS: Other: president and founder; Gerson Lehrman Group: Consultancy; Pfizer: Consultancy. Moreno:Puma Biotechnology: Consultancy; Sanofi/Regeneron: Other: travel/accommodations/expenses.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129783

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4380-4380

Abstract: Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.4380.4380

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2996-2996

Abstract: Studies of EBV positive (+) and negative (-) classical Hodgkin lymphoma (cHL) have shown the importance of the immune microenvironment in affecting Reed-Sternberg (hRS) cell survival, proliferation, and biologic behavior. For example, macrophage infiltrates may correlate with inferior disease outcome and survival and proliferation of the hRS cells depends on trophic signals from various inflammatory cells, including CD4+ T cells. The latter finding may explain why HIV-cHL patients (pts) usually present with higher circulating CD4+ T-cell counts (cCD4) compared to HIV-related non-Hodgkin lymphoma. Pathobiologically, HIV-cHL differs from HIV negative cHL (cHL) in that it is nearly always EBV+, has higher numbers of hRS cells, presents with more advanced median stage, exhibits more commonly the mixed cellularity (MC) pattern, and some studies suggest it is more clinically aggressive. To investigate the microenvironment of HIV-cHL and its influence on cHL biology, we assessed the immune cell composition and clinical characteristics of HIV-cHL and compared the findings to those of EBV+ and EBV- cHLs. Methods 31 HIV-cHL and 40 cHL (8 EBV+/32 EBV-) cases were identified and corresponding tissue microarrays (TMAs) created. TMAs were evaluated for EBV (EBER), CD30, and microenvironment-associated antigens: PAX5, CD3, CD4, CD8, CD68, CD163 (% positive), TIA1, FOXP3 (relative number 0-4+); the hRS-macrophage microenvironment was evaluated by assessing the number of hRS where 〉 50% of the circumference of the neoplastic cell was associated with CD68+ cells. Results were compared based on HIV status, EBV status (in HIV negative pts), demographics, cCD4 and histology; each was correlated with overall survival. Analyses were performed using non-parametric Fisher's exact test, Kaplan-Meier method and Cox Proportional Hazards model. Results M:F ratio was 9:1 in the HIV group vs. 1.3:1 in the HIV negative pts (p 〈 0.001). The median cCD4 in the HIV+ pts at HIV-cHL diagnosis was 248 cells/mm3. No differences in age, stage, B symptoms, bulky disease, IPS score, and hRS concentration were found between HIV+ and HIV negative cHLs pts. 7% of cHLs and 33% of HIV-cHLs were classified as MC (p 〈 0.01). 90% of HIV-cHLs were EBV+ compared to 20% of the cHL cases. Statistically significant differences were seen in the number of CD4+ and CD8+ cells between the EBV+ and EBV- cHLs irrespective of HIV status. The only difference among all the immune microenvironment markers observed between EBV+ HIV-cHL and EBV+ cHL cases was that of peri-hRS CD68 cells, which were more abundant in the EBV+ HIV-cHL (Table 1; 51% vs. 30% p 〈 0.005). Similar differences in peri-hRS CD68 staining were observed between the HIV-cHL and all cHL pts. The only deaths in HIV-cHL pts occurred when CD68 was 〉 15% (p 〈 0.05). No statistical differences were noted for OS with respect to cCD4, histologic subtype, race, gender, or HIV status. Conclusions No significant differences were observed between HIV-cHL and cHL pts with respect to stage, B symptoms, bulky disease, IPS score, or overall survival, but there were more MC cases in the HIV-cHL cohort. The microenvironment of HIV-cHL and EBV+ cHL is similar, but different from EBV- cHL with respect to percentages of CD163+, PAX5+, CD4+ and CD8+ cells. The location of CD68+ macrophages was the only discordant result between the EBV+ HIV-cHL and EBV+ cHL cohorts. The differences in location of the CD68+ cells, which may be dependent on HIV status, suggests greater influence of these cells on the biologic behavior of the neoplastic process, correlating with poor survival. However, the similarity in the microenvironments in HIV-cHL and EBV+ cHL with respect to CD4, CD8, and CD163 staining implies an important role for EBV on disease biology, as well. Thus, these data suggest that EBV as well as HIV, play prominent roles in determining the immune response and disease behavior in HIV-cHL, warranting further study Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2996.2996

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 351-351

Abstract: Background: Immunocompromised patients (pts) face an approximate 6-fold increase in lifetime risk of lymphoid malignancies compared with immunocompetent counterparts. Additionally, up to 80% of post-transplant lymphoproliferative disease (PTLD) cases are driven by EBV-associated mechanisms of tumorigenesis. Approximately 70% will express CD30 and over 80% will express CD20. Recent studies of chemoimmunotherapy (CIT) have reported median overall survival (OS) of 2-4 years and treatment-related mortality (TRM) rates of 13-50%. Moreover, solid organ transplant (SOT) pts are at significant risk of graft rejection when CIT is employed, possibly due to "off target" depletion of regulatory T-cell populations. R monotherapy induction, followed by response-stratified use of CIT, has been evaluated (Trappe, et al, JCO, 2016). However, ~75% of pts had an inadequate response to R alone and required subsequent CIT; 2-yr OS for the population as a whole was ~70%. BV is an anti-CD30 antibody-drug conjugate that received accelerated FDA approval for previously untreated CD30+ T-cell lymphoma and Hodgkin lymphoma. We hypothesized that a combination of BV and R would yield improved breadth and depth of response compared with R monotherapy induction, would spare pts subsequent exposure to CIT, and result in favorable OS. Methods: We report here results of a phase I/II multicenter study investigating the efficacy and safety of BV+R as frontline therapy in pts diagnosed with immunosuppression-associated CD30+ and/or EBV+ lymphoid malignancies. Induction consisted of R 375 mg/m2 given days 1, 8, 15, 22 and BV 1.2 mg/kg given days 1, 8, 15, of a 28-day cycle, followed by restaging. Those with progression were removed from study. Pts with stable disease were offered study discontinuation or completion of one consolidation cycle followed by repeat disease assessment. Pts with partial response or complete response (CR) could receive either consolidation followed by maintenance therapy (MT) or move directly to MT without consolidation. Consolidation was identical to induction dosing; MT consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to 1 year of therapy. Toxicity was defined using CTCAE 4.0 and response (Cheson, 2007) was assessed at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. Results: A total of 22 pts were entered in the trial. Toxicity and response data are available for 20 pts. Median age was 67 years (range, 30-79) and 14 pts (64%) were male (range, 30-79 years). Fourteen pts (64%) had received either a SOT or hematopoietic allograft requiring immunosuppression, 3 pts required immunosuppression for underlying rheumatologic conditions, and 3 pts were found to have EBV-associated lymphoid malignancies in the absence of iatrogenic immunosuppression (Table 1). Overall response rate was 70%, including a CR rate of 60%. With median follow-up of 26.1 month, the probability of progression-free survival at 1 year was 75.2% and 67.6% at 3 years (Fig 1). Probability of OS was 89.2% at both 1-year and 3-year follow-up (Fig 1). Median time to best response was 28 days. Three pts withdrew consent after induction, 2 pts died (1 death related to treatment), and 1 patient was lost to follow-up. Seven pts (31%) required dose adjustments or delay of medication administration during induction therapy and 45% required discontinuation of therapy due to toxicity within 1 year. The most frequent grade 3/4 toxicities were peripheral neuropathy, neutropenia, lymphopenia, and pancreatitis. The most frequent adverse events of any grade were fatigue, nausea, abdominal pain, pancytopenia, and peripheral neuropathy (Table 2). Conclusions: The combination of BV + R had an acceptable safety profile and appeared effective in achieving early remissions when used as frontline therapy for PTLD and other immunosuppression-related lymphomas. Specifically, over half of pts achieved CR, and 75% have been spared exposure to multi-agent cytotoxic chemotherapy. Furthermore, survival and PFS data were encouraging compared with historical controls. However, nearly half of pts discontinued therapy within 1 year due to toxicity suggesting poor long-term tolerance of the regimen and that earlier cessation of therapy may be warranted. Further studies are needed to confirm these efficacy results and to determine optimal BV+R dosing regimens and durations. Disclosures Pro: Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria. Gordon:Gilead: Other: Advisory Board; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Winter:Merck: Consultancy, Research Funding. Ma:Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Xeme: Research Funding; Bioverativ: Consultancy; Beigene: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy; Abbvie: Research Funding; Incyte: Research Funding; Juno: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Novartis: Research Funding. Behdad:Pfizer: Other: Speaker; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees. Petrich:AbbVie: Employment, Equity Ownership. Smith:Portola Pharmaceuticals: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-127390

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer, Wiley, Vol. 120, No. 24 ( 2014-12-15), p. 3884-3895

Abstract: The co‐presence of MYC and BCL2 , termed double hit lymphomas, occurs in up to one‐third of diffuse large B‐cell lymphomas via immunohistochemistry and has a very poor prognosis. There is limited data on clinical management, but increased awareness of this entity will help define criteria for future clinical trial development.

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v120.24

DOI: 10.1002/cncr.28899

Language: English

Publisher: Wiley

Publication Date: 2014

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1