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In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6547-6549

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-160234

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 233-233

Abstract: Introduction ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) represents standard frontline therapy for classical Hodgkin lymphoma (CHL) in North America. Substituting brentuximab vedotin for bleomycin in this regimen demonstrated improved efficacy in advanced stage patients (pts) but also increased toxicity (Connors et al NEJM 2017). PD-1 inhibitors are highly active in relapsed/refractory CHL, and the first-line setting may represent the ideal time for incorporating PD1 inhibition given the relatively intact host immunity and juxtaposition of malignant cells with T cells in the tumor microenvironment. Methods This was a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requiredECOG 0-1, adequate organ function, and measurable disease. The trial intended to enroll 30 pts. AVD was given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab (200 mg IV) was given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective was to estimate the safety of delivering 2 cycles of APVD. The secondary objective was to estimate the FDG-PET2 negative (Deauville score 1-3) rate after 2 cycles of APVD. Exploratory objectives included overall and progression free survival, predictive capacity of PET2 after APVD, analysis of ctDNA as well as assessments of metabolic tumor volume. After PET2 response assessment, subjects could continue APVD for up to 6 total cycles as deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy). Results All 30 subjects have enrolled and received at least 2 cycles of therapy. Median age was 32 years (range 18-69). Most pts had advanced stage (stage I n =1 (3%), stage II n=11 (37%), stage III n=7 (23%), stage IV n=11, (37%)). Thirteen (43%) pts had B symptoms at diagnosis and 5 (17%) had bulky disease. Among the 30 pts enrolled, 28 are evaluable for response (one pt declined interim-PET and further treatment and final patient will have PET2 shortly after abstract deadline.Nineteen (68%) pts were PET2 neg (5PS 1-3). No PET2+ pts have progressed to date. End of therapy (EOT) PET negativity (after 2-6 cycles) was 78% (18/23). Among the 5 pts with residual FDG uptake at EOT, only 1 (20%) has developed recurrent lymphoma. With median follow-up of 10.3 months, 1-year PFS and OS were 96% and 100%, respectively. Six (20%) pts required interruption of pembrolizumab due to toxicity, primarily grade ≥ 2 transaminitis (83%). Those with grade 2 transaminitis (2/6) completed chemotherapy prior to resolving to grade 1 and did not receive additional pembrolizumab. Those with grade ≥ 3 transaminitis (3/6) were required to permanently discontinue pembrolizumab. All transaminitis was transient and resolved with steroids and/or withholding pembrolizumab. No pneumonitis and no other grade ≥ 3 immune-related AEs were observed. Toxicities were otherwise similar to those expected with ABVD chemotherapy. No pt had a treatment delay of & gt; 21 days during the first 2 cycles, and no pt who interrupted pembrolizumab due to toxicity has relapsed. Updated efficacy and more detailed safety data will be presented at the meeting. Conclusion Pembrolizumab + AVD without a PD-1 lead-in is safe and effective therapy for frontline HL. In this study, PET2+ following APVD does not appear to be associated with high risk of disease relapse. Additional analyses of MTV and ctDNA are ongoing to better understand these results. Concurrent APVD, without an anti-PD-1 run-in, represents a well-tolerated, and efficacious backbone that can be further evaluated in all stages of CHL. Figure 1 Figure 1. Disclosures Lynch: Incyte: Research Funding; TG Therapeutics: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; SeaGen: Research Funding; Bayer: Research Funding; Juno Therapetics: Research Funding; Morphosys: Consultancy. Ujjani: ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Smith: Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Ignyta (spouse): Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Ayala (spouse): Research Funding; De Novo Biopharma: Research Funding; KITE pharm: Consultancy; Genentech: Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb (spouse): Research Funding; Incyte: Consultancy; Bayer: Research Funding; Beigene: Consultancy, Research Funding; Millenium/Takeda: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Shustov: Seagen Inc.: Research Funding. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Alizadeh: Gilead: Consultancy; Janssen Oncology: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Foresight Diagnostics: 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; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: 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. Gopal: Epizyme: Consultancy, Honoraria; MorphoSys: Honoraria; Gilead: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Teva: Research Funding; Beigene: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Acrotech: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Astra-Zeneca: Research Funding; Agios: Research Funding; Bristol Meyers Squibb: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Kite: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-144610

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 7, No. 11 ( 2023-06-13), p. 2449-2458

Abstract: The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]–EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] ) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2022009145

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 2876449-3

In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 6 ( 2022-10), p. 26-27

Type of Medium: Online Resource

ISSN: 2572-9241

URL: Article

DOI: 10.1097/01.HS9.0000890796.34979.cc

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2022

detail.hit.zdb_id: 2922183-3

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7546-7546

Abstract: 7546 Background: The phase 3 POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the R-CHOP regimen for large B-cell lymphomas. However, it is unknown if Pola can be safely incorporated into intensified regimens typically utilized for the highest risk histologies. To address this question, we conducted a prospective trial (NCT04231877) evaluating Pola with dose adjusted etoposide, cyclophosphamide, doxorubicin, and rituximab (Pola-DA-EPCH-R). Methods: This is a single center, open label, investigator-initiated clinical trial of 6 cycles of Pola-DA-EPCH-R in aggressive large B-cell lymphomas where DA-EPOCH-R is considered standard (eg. HGBCL, PMBCL, and select DLBCL-NOS). Pola is given at 1.8 mg/kg on day 1 without intra-patient dose escalation. All other components of the regimen including escalation of chemotherapy dosing based on neutrophil and platelet nadirs from the previous cycle are given according to Dunleavy et al NEJM 2013. The primary objective is to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with pre-specified suspension rules if the lower limit of an 80% confidence interval cannot exclude a DLT rate of 〉 20%. Efficacy, survival, and correlative analyses will also be performed. Results: 18 patients enrolled on study and as of Feb 15, 2022, 3 patients remain on study treatment. Median age was 64 years (range 41-74). With only 3 DLTs, the study met its primary endpoint for safety. Five SAEs were observed, including one grade 5 sepsis/typhlitis (during cycle 1), 3 episodes of febrile neutropenia, and a grade 3 perforation of a colonic diverticula which required a treatment delay of 12 days before completing all expected study therapy. Other grade 3+ non-heme AEs in more than one pt. include hyperglycemia (17%), oral mucositis (17%), incidental asymptomatic pulmonary embolism (17%), abdominal pain (11%), and hypokalemia (11%). Grade 1 peripheral sensory neuropathy was uncommon (22%), no grade 2+ neuropathy was observed. One patient required a decrease in Pola dosing due to a platelet nadir at dose level 1. Among those with at least 2 cycles of treatment, 94% were able to increase chemotherapy to at least dose level 2 (Table). Post cycle 2 interim overall response rate (ORR) and complete response (CR) rate was 88% and 24%, respectively. EOT ORR and CR was 93% and 71%, respectively, with one PD. Updated data will be presented at the meeting. Conclusions: Using Pola at 1.8 mg/kg to replace vincristine in the DA-EPOCH-R regimen appears feasible and met its primary safety endpoint. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. Clinical trial information: NCT04231877. [Table: see text]

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2022.40.16_suppl.7546

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2022

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, ( 2023-03-13)

Abstract: Concurrent administration pembrolizumab with chemotherapy in untreated classical Hodgkin lymphoma (CHL) has not previously been studied. To investigate this combination, we conducted a single arm study of concurrent pembrolizumab with AVD (APVD) for untreated CHL. We enrolled 30 patients (6 early favorable, 6 early unfavorable, and 18 advanced stage, median age 33 years (range 18-69 years)) and met the primary safety endpoint with no observed significant treatment delays in the first two cycles. Twelve patients experienced grade 3-4 non-hematologic adverse events (AEs) most commonly febrile neutropenia (5, 17%) and infection/sepsis (3, 10%). Grade 3-4 immune-related AEs were seen in 3 patients, including ALT elevation (3, 10%) and AST elevation (1, 3%). One patient experienced an episode of grade 2 colitis and arthritis. Six (20%) patients missed at least one dose of pembrolizumab due to adverse events, primarily grade 2 or higher transaminitis (5, 17%). Among 29 response-evaluable patients, the best overall response rate was 100% and CR rate of 90%. With median follow up of 2.1 years, 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who withheld or discontinued pembrolizumab due to toxicity has progressed. Clearance of ctDNA was associated with superior PFS when measured after cycle 2 (p=0.025) and at end of treatment (EOT, p=0.0016). None of the 4 patients with persistent disease by FDG-PET at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy, but may yield spurious PET findings in some patients. Trial Registration Number: NCT03331341

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2022019254

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7