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In: American Journal of Infection Control, Elsevier BV, Vol. 48, No. 4 ( 2020-04), p. 423-432

Type of Medium: Online Resource

ISSN: 0196-6553

URL: Article

DOI: 10.1016/j.ajic.2019.08.023

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2011724-3

In: American Journal of Infection Control, Elsevier BV, Vol. 44, No. 12 ( 2016-12), p. 1495-1504

Type of Medium: Online Resource

ISSN: 0196-6553

URL: Article

DOI: 10.1016/j.ajic.2016.08.007

Language: English

Publisher: Elsevier BV

Publication Date: 2016

detail.hit.zdb_id: 2011724-3

In: European Journal of Clinical Investigation, Wiley, Vol. 27, No. 3 ( 2003-11-14), p. 212-218

Type of Medium: Online Resource

ISSN: 0014-2972

URL: Article

DOI: 10.1046/j.1365-2362.1997.960643.x

Language: English

Publisher: Wiley

Publication Date: 2003

detail.hit.zdb_id: 2004971-7

In: Journal of Clinical Apheresis, Wiley, Vol. 11, No. 2 ( 1996), p. 61-70

Type of Medium: Online Resource

ISSN: 0733-2459 , 1098-1101

URL: Issue

URL: Journal

URL: Article

DOI: 10.1002/(SICI)1098-1101(1996)11:2〈〉1.0.CO;2-3

DOI: 10.1002/(ISSN)1098-1101

DOI: 10.1002/(SICI)1098-1101(1996)11:2〈61::AID-JCA2〉3.0.CO;2-8

Language: English

Publisher: Wiley

Publication Date: 1996

detail.hit.zdb_id: 2001633-5

In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 20 ( 1997-09-30), p. 10937-10942

Abstract: Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon–DNA adducts generate oncogenic mutations found in mouse skin papillomas ( Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E 1 ) and estradiol (E 2 ) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE 1 (E 2 )-1(α,β)-N7Gua at 59–213 μmol/mol DNA–phosphate whereas the level of stable adducts was 0.1 μmol/mol DNA–phosphate. In female Sprague–Dawley rats treated by intramammillary injection of E 2 -3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 μmol 4-OHE 2 -1(α,β)-N7Gua/molDNA–phosphate. When 4-OHE 1 (E 2 ) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87–440 μmol of 4-OHE 1 (E 2 )-1(α, β)-N7Gua was formed. After treatment with 4-OHE 2 , rat mammary tissue contained 1.4 μmol of adduct/mol DNA–phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.94.20.10937

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 1997

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1606-1606

Abstract: Background: Two commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are currently approved by the FDA for r/r aggressive B-cell lymphomas: axicabtagene ciloleucel (approved in October 2017) and tisagenlecleucel (tisa-cel, approved in May 2018). In published clinical trials, CART19 therapy results in long term remissions in 30-40% of patients (pts). While most CART19 protocols use cyclophosphamide/fludarabine (Cy/Flu) for lymphodepleting chemotherapy (LDC) prior to CART19 infusion, the phase 2 JULIET trial (NCT02445248) with tisa-cel allowed investigator's choice of Cy/Flu or bendamustine. LDC was not required for pts with WBC & lt;1000 cells/μL within one week prior to tisa-cel infusion. In JULIET, 75 (73%) pts received Cy/Flu, 21 (20%) pts received bendamustine, and 7 (7%) pts received no LDC (Schuster et al, NEJM 2019). Grade 3 or 4 cytopenias not resolved by Day 28 following tisa-cel included thrombocytopenia (40%) and neutropenia (25%) among JULIET pts (FDA package insert). Many r/r lymphoma pts are Cy-resistant and bendamustine is not cross-resistant with Cy. Prolonged cytopenias can be seen with Cy/Flu in addition to lymphopenia. In an effort to reduce tumor volume and minimize cytopenias, bendamustine is frequently used for LDC at our institution. We report our experience with bendamustine as LDC before commercially supplied tisa-cel. Methods: We conducted a single center, retrospective, IRB-approved analysis of r/r lymphoma pts receiving commercial tisa-cel at the University of Pennsylvania. Responses were based on treating physician's assessment utilizing Revised Response Criteria for Malignant Lymphoma (Cheson et al, JCO 2014). Unless the pt had signs or symptoms of progressive lymphoma, response assessment was generally performed at 3 months from tisa-cel infusion per our institutional practice and based on evidence that 3-month response outcomes are more predictive of long-term efficacy than 1-month outcomes. Cytokine release syndrome (CRS) was assessed using Penn criteria (Porter et al, J Hematol Oncol 2018). Neurotoxicity was graded using CARTOX-based scale (Neelapu et al, Nat Rev Clin Oncol 2018). Cytopenias were graded using Common Terminology Criteria for Adverse Events, version 5. Results: We identified 28 pts with DLBCL or transformed lymphoma who received commercially supplied tisa-cel between June 2018 and June 2019 with bendamustine as LDC and a follow-up of at least 30 days from the infusion. Pt characteristics are described in Table 1. Median age was 65.5 years (range: 38-81). Bendamustine dose was 90 mg/m2 intravenously daily for 2 days in 23/28 (82%) pts with remaining 5/28 (18%) pts receiving lower doses at the discretion of the treating physician. Twenty-four of 28 pts received bendamustine for LDC and had at least 3-month follow-up or progression prior to 3 months. The 3-month overall response rate was 11/24 (46%) with complete response rate 9/24 (38%). With median follow-up 5.5 months, 3-month progression-free survival estimate was 52% (95%CI: 30%-70%). In terms of toxicities in this cohort, there were no deaths related to tisa-cel. CRS was experienced by 8/28 (29%) of pts with no grade 3 or 4 events by Penn scale. Neurotoxicity was seen in 2/28 (7%) pts with 1 (4%) experiencing transient grade 3 by CARTOX-based grading. At day 28 post tisa-cel infusion, 3/28 (11%) pts had grade 3 or higher neutropenia and 3/28 (11%) had grade 3 or higher thrombocytopenia. Most pts were treated as outpatients with only 2/28 (7%) receiving tisa-cel infusion as inpatient. Conclusion: Three-month complete response rates are considered reasonably predictive of outcome for CART19 therapies. Although our follow-up is short, our experience shows that bendamustine as LDC for tisa-cel performs well outside of a clinical trial, is an option for LDC before tisa-cel therapy for pts with r/r aggressive B-cell lymphomas treated in the outpatient setting, and may have an improved safety profile with regard to cytopenias. Disclosures Svoboda: Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Hughes:Genzyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:Millenium/takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Triphase: Research Funding; Takeda: Research Funding. Barta:Bayer: Consultancy, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Ruella:Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees; Nanostring: Consultancy, Speakers Bureau. Frey:Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees. Schuster:Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131482

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. 130, No. Suppl_1 ( 2017-12-07), p. 653-653

Abstract: Background: Cellular therapy using anti-CD19 autologous chimeric antigen receptor modified T (CART19) cells demonstrates promising outcomes in several hematologic malignancies of B-cell origin, but this therapy has not been studied in HL patients (pts). While neoplastic HL Reed-Sternberg (HRS) cells are considered CD19 negative, circulating CD19 positive clonal HRS cell precursors and CD19 positive reactive cells within the HRS tumor microenvironment represent potential therapeutic targets for CART19 in HL. Methods: We designed companion pediatric (NCT02624258) and adult (NCT02277522) open-label pilot studies to estimate the feasibility, safety, and efficacy of CART19 cell infusions in pts with relapsed/refractory HL lacking curative treatment options. To allow transient CD19 targeting and limit the window for acute toxicity and B cell aplasia, we used autologous T-cells electroporated with mRNA encoding chimeric anti-CD19 immunoreceptor scFv (RNA CART19) cells in lieu of permanently modified cells engineered by viral transduction. The scFv is derived from a murine monoclonal antibody. Following pheresis and manufacturing of RNA CART19 cells, pts undergo up to 6 infusions of 8x105-1.5x106 RNA CART19 cells/kg/dose for pts & lt;80kg and 1x108 RNA CART19 cells/dose (±20%) for pts ≥80kg. Intravenous cyclophosphamide (30mg/kg) is administered prior to the first and fourth infusion to enhance engraftment. Safety, response assessments (Cheson 2007 criteria), and ancillary studies are measured at defined time points. The primary objective is to describe manufacturing feasibility, safety, and persistence of RNA CART19 cells in HL. Secondary objectives are to estimate efficacy by overall response rates (ORR) and the effect of RNA CART19 on immune factors. Results: To date, 5 pts have been enrolled and had RNA CART19 manufactured. Four pts were infused with RNA CART19 and are evaluable for toxicity/response. Characteristics of the 5 pts include: median age 24 years (range 21-42), 4 (80%) with stage IV, median number of previous therapies 5 (range 4-9), 4 (80%) had stem cell transplant (SCT): 3 had auto SCT, 1 had both auto and allo SCT. Three pts previously progressed on PD-1 inhibitor. All 5 pts underwent successful manufacturing of RNA CART19. One pt developed MDS prior to RNA CART19 infusions and was taken off study. Four patients who underwent RNA CART19 infusions were treated with cyclophosphamide as per protocol. The median number of infused CART19 cells/kg/dose was 1.5x106 (range 7.3x105 -1.5x106). Each patient (pt) received 6 infusions over 2 weeks. Using qRT-PCR, RNA CART19 was detected in 80% of peripheral blood samples drawn within 2 hours after each infusion (Figure 1). RNA CART19 was also detected in 20% of samples drawn immediately prior each infusion reflecting persistence of RNA CART19 from previous infusion at 48 or more hours ago. No pt had RNA CART19 detected by Day (D) 21. There were no study related deaths or grade (G) 3/4 non-hematologic toxicities. Most common G1/2 toxicities at least possibly related to the RNA CART19 therapy occurring in & gt; 1 pt included transient headache in 3 and insomnia in 2. There was no evidence of cytokine release syndrome or significant elevation in cytokines at any point. The ORR at D28 was 50%: 1 complete (CR) and 1 partial response (PR). One pt had stable disease (SD) and one pt had progressive disease (PD). The CR pt (#3) was noted to have persistent RNA CART19 cells in 3 samples drawn at about 48 hours after the prior infusion compared with the PD pt (#1) who had no RNA CART19 detected by this time point on any measurement. In 2 pts who responded (#3 and #4), number of CD19-positive B-cells by flow cytometry as % of total leukocytes declined by 50% on D28 when compared to baseline. There was no evidence of B cell aplasia. The pt in CR progressed at 3 months and the pt in PR was taken off study. As part of routine clinical care, the 2 responding pts (#3 and #4) are currently in CR on PD-1 inhibitor (one underwent auto SCT). The pt with SD is in PR on lenalidomide and the pt with PD died of disease progression. Conclusion: Targeting CD19 positive cells with non-viral, RNA-electroporated, transiently expressed CART19 cells is a feasible and safe strategy in pts with relapsed/refractory HL. We saw encouraging responses, but these were short-lived. We are planning a study for HL pts utilizing virally transduced CART19 cells that are capable of in vivo expansion in combination with PD-1 inhibitors. Disclosures Svoboda: Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Pharmacyclics: Research Funding. Gill: Novartis Pharmaceuticals: Patents & Royalties, Research Funding. Grupp: Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant. Lacey: Novartis: Research Funding; Genentech: Honoraria. Melenhorst: Novartis: Research Funding. Mato: DTRM: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Portola: Research Funding; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Dwivedy Nasta: Takeda: Research Funding; Incyte: Research Funding; Immunogen: Research Funding. Landsburg: Takeda: Research Funding; Curis: Consultancy, Research Funding. Levine: GE Healthcare: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; Brammer Bio: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding. Porter: Immunovative Therapies: Other: Member DSMB; Novartis: Honoraria, Patents & Royalties, Research Funding; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Servier: Honoraria, Other: Travel reimbursement; Incyte: Honoraria. June: Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schuster: Genentech: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.653.653

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

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. 2905-2905

Abstract: Introduction Novel agents such as ibrutinib, lenalidomide, and venetoclax are increasingly used in patients with relapsed/refractory lymphoma. A number of patients on these oral agents require radiation therapy (RT) either for palliation of their lymphoma symptoms or for management of another malignancy. There is no available information regarding the safety and outcomes of patients receiving RT and a novel agent concurrently. There is some theoretical concern for overlap in toxicities, yet there is no consensus on holding or continuing the oral agent during RT. Our goal was to characterize toxicities in patients with lymphoma receiving both RT and a novel agent. Methods We conducted a retrospective study of patients with lymphoma who received RT and either ibrutinib, lenalidomide, or venetoclax at the University of Pennsylvania between 1/2009 and 6/2018. Those who received one of these agents within one month of RT were included in the study and were required to have at least one encounter at least 14 days after completing RT to assess for toxicities. Patients who received the agent for less than 7 days and those also receiving chemotherapy were excluded. Toxicities that developed during and up to 3 months following radiation were recorded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4. Concurrent administration of the novel agent was defined as receiving the agent within 5 days or less of RT, whereas sequential administration was defined as having greater than a 5-day interval between RT and the agent. Rates of grade 3/4 adverse events (AEs) were compared between the concurrent and sequential groups using Fisher's exact test. Results A total of 80 patients with lymphoma received one of the novel agents within one month of RT. After excluding cases where the novel agent was received for less than 7 days as well as those with inadequate follow up post-RT, a total of 69 patients with a corresponding 74 radiation courses were included (Table 1). The most common agent received was ibrutinib (61%), followed by lenalidomide (31%), and venetoclax (8%). The novel agent was administered concurrently with RT in 47 instances and sequentially in the remaining 28. Sixty-three (85%) of the RT courses were for treatment of lymphoma and the remaining 11 (15%) for other malignancies. The most common lymphoma diagnoses were DLBCL (46%), mantle cell lymphoma (23%), and CLL/SLL (13%). The median age was 68 (range: 27-86), and 79% were male. The median radiation dose was 30 Gy (range: 2-79) and the median fractions delivered was 14 (range: 2-44). Twenty-one of 69 patients experienced acute (within 30 days of RT) grade 3/4 AEs (Table 2a and 2b). Overall, we observed similar rates of hematologic grade 3/4 AEs in our cohort as compared to historical studies of these novel agents in lymphoma patients (Barr et al., Haemotologica, 2018; Wiernik et al. J. Clin. Oncol, 2008). However, the rate of grade 3/4 neutropenia in patients receiving ibrutinib concurrently with RT (N=29) was significantly higher than in those receiving therapy sequentially (N=16) (24% vs 0%, p=0.04). There was otherwise not a significant difference in the prevalence of grade 3/4 hematologic or non-hematologic AEs in patients receiving any of the novel agents concurrently vs sequentially. Notable non-hematologic AEs in the entire cohort was infection (9%) and atrial fibrillation (4%), with the latter occurring only in the ibrutinib group. The novel agent was held or discontinued due to AEs in 15% of cases (8 patients on ibrutinib, 3 on lenalidomide) with no significant difference in rates between concurrent vs sequential administration. 59 of the 69 patients had follow-up within 30-90 days of completing RT, and only 4 of those experienced grade 3/4 AEs in that time period. Twenty patients transitioned to comfort-focused care or hospice within 2 months of completing RT. Conclusion To our knowledge, this is the first study to describe the safety of using novel oral agents in lymphoma patients receiving RT. Our data suggests that the use of ibrutinib with concurrent RT may be associated with an increased incidence of neutropenia, but the use of lenalidomide, and venetoclax with concurrent RT is not associated with significantly increased toxicities compared to sequential administration. Although concurrent therapy appears tolerated, further work is needed to corroborate our findings as our study is limited by the small size and heterogeneity of our cohort. Disclosures Hughes: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Triphase: Research Funding; Takeda: Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Dwivedy Nasta:Roche: Research Funding; 47 (Forty Seven): Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Pharmacyclics: Research Funding; ATARA: Research Funding; Aileron: Research Funding. Gerson:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy. Schuster:Merck: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria; Loxo Oncology: Honoraria; Acerta: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria; Nordic Nanovector: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124195

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. 124, No. 21 ( 2014-12-06), p. 1260-1260

Abstract: Background: The most common cause of treatment failure after reduced intensity conditioned allogeneic stem-cell transplantation (RIC alloSCT) is disease relapse. The curative potential of RIC transplants relies primarily on the immunologic graft-versus-tumor (GvT) effect. We hypothesized that graft T-cell doses correlate with relapse and survival outcomes, and that the graft T-cell content could be predicted according to donor characteristics. Methods: We retrospectively studied 218 consecutive patients (pts) who underwent a first peripheral blood alloSCT after fludarabine (120 mg/m2) and busulfan (6.4 mg/kg) conditioning between 2006 and 2014, of whom 190 pts had available graft T-cell content data. CD3, CD4, CD8 and CD34 doses were analyzed. Cox regression was used to evaluate correlations between cell doses and time-to-relapse, relapse-free survival (RFS), overall survival (OS), and acute and chronic graft-versus-host disease (GvHD). Standard variables and the Disease Risk Index (DRI) were used for adjustment in multivariate models. A Classification and Regression Tree (CART) procedure was used to identify optimal cutoffs for continuous variables that correlated with outcome. Finally, we studied 23 alloHSCT donor blood samples to identify clinical and immunophenotypic characteristics that correlate with graft T cell content. Results The median follow-up was 29.6 mo. (range 0.4 – 81.5). The median age was 62 (range 21-76) and diseases included AML (79), MDS (42), NHL (31), CLL (8), ALL (10) and others (20). Pts were allografted from HLA-matched (86%) or mismatched (14%), sibling (43%) or unrelated (57%) donors. There was significant variability in T-cell doses: CD3 - mean 2.3x108/kg (range 0.2 – 8.1), CD8 - mean 0.5x108/kg (range 0.03 – 2.2), CD4 - mean 1.3x108/kg (range 0.1 – 5.4). Relapse and survival: A high CD8 cell dose correlated with a decreased risk of relapse and improved RFS and OS. The univariate hazard ratios (HR) per 1 x 108/kg CD8 cells were: relapse 0.44 (95% CI [0.24 – 0.83]), p = 0.01; RFS 0.50 (95% CI [0.30 – 0.83] ), p = 0.008; OS 0.63 (95% CI [0.37 – 1.08]), p = 0.09. After adjustment for DRI, GvHD prophylaxis and age, the CD8 cell dose remained significantly correlated with relapse, RFS and OS (Table 1). There were no significant correlations between the CD34, CD3 or CD4 doses and these outcomes. Using CART, we identified a cutoff of 0.72 x 108/kg CD8 cells that predicted OS. We found that pts who received a CD8hi graft had improved OS (adjusted HR = 0.53, 95% CI [0.33 – 0.84], p = 0.007; Fig. 1). Engraftment: Donor T-cell engraftment correlated with higher CD8 but not CD4 cell doses. Donor T-cell chimerism levels were higher in pts who received a higher CD8 cell dose (day 30: r = 0.27, p = 0.002; day 60: r = 0.28, p = 0.005; day 100: r = 0.22, p = 0.01). Time to neutrophil or platelet engraftment was not affected by CD3, CD4 or CD8 doses although a high CD34 dose predicted faster neutrophil recovery (r = -0.19, p = 0.01). GvHD: There were no significant correlations between T cell doses and GvHD. A trend was observed between acute GvHD and high CD4 but not CD8 cell doses (adjusted HR = 1.29, 95% CI [0.97 - 1.71], p = 0.08). A trend was also observed between moderate-severe chronic GvHD and high CD8 cell doses (adjusted HR = 1.93, 95% CI [0.90 - 4.10] , p = 0.09). Donors: We investigated whether a high CD8 cell content could be predicted during donor screening. Not surprisingly, we found that donors whose grafts contained a high CD8 cell dose could be identified in a screening blood sample by having higher %CD8 cells (r = 0.69, p = 0.0004; Fig. 2), lower CD4/8 ratio (r = -0.55, p = 0.008) and higher %CD3 cells (r = 0.37, p = 0.09). There were no correlations between the graft content and other immunophenotypic parameters or clinical variables such as donor age, weight, gender or viral serologies. Conclusion: A high CD8 cell dose correlates with improved RFS and OS after RIC alloSCT through a reduction in relapse without a significant increase in GvHD. Donor screening can potentially be optimized by selecting donors from whom a CD8-high graft can be collected. Targeting CD8 cell doses should be considered in prospective trials of RIC alloSCT. Table 1: Adjusted HRs of graft T-cell doses and outcomes Relapse RFS OS Variable HR p HR p HR p CD8 dose 0.43 0.011 0.49 0.006 0.57 0.046 CD4 dose 0.91 0.53 0.93 0.57 1.05 0.68 CD3 dose 0.85 0.15 0.87 0.12 0.94 0.49 Figure 1 The impact of graft CD8 cell dose on overall survival Figure 1. The impact of graft CD8 cell dose on overall survival Figure 2 Prediction of graft CD8 content Figure 2. Prediction of graft CD8 content Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1260.1260

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cellular and Molecular Life Sciences, Springer Science and Business Media LLC, Vol. 79, No. 11 ( 2022-11)

Type of Medium: Online Resource

ISSN: 1420-682X , 1420-9071

URL: Article

DOI: 10.1007/s00018-022-04583-w

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 1458497-9

SSG: 12