Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1554-1554

Abstract: Introduction: The majority of patients with classical Hodgkin lymphoma (cHL) will be cured with anthracycline-containing chemotherapy regimens. However, 10-20% of patients with early-stage disease and 30-40% of patients with advanced-stage cHL will relapse. The standard treatment for patients with relapsed cHL is salvage chemoimmunotherapy followed by high-dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) in chemotherapy-sensitive patients. Patients with primary treatment failure (PTF), i.e. patients who have progressive disease while on therapy or who fail to achieve complete remission (CR) at the end of initial therapy, or experience early relapse after CR1 are expected to have a worse prognosis than patients with late relapse. Since 2011 newer treatments, namely Brentuximab vedotin and PD1/PDL1 blockers have been introduced for the treatment of relapsed and refractory cHL. It is unknown whether changes in disease monitoring and management, including the availability of new agents, impacted survival of patients with cHL and PTF. Methods: Fifteen US academic medical centers contributed cases to the ECLIPSE study (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs). ECLIPSE retrospectively captured patient, disease and treatment characteristics and treatment response as assessed by treating physicians. Eligible patients were ≥ 15 years diagnosed with cHL on or after 2005, who received treatment with curative intent with anthracycline-containing chemotherapy regimens, and developed one of the 3 patterns of PTF: detection of progressive disease during or within 6 weeks of completion of chemotherapy (PP cohort, primary progression), partial response (PR) or stable disease (SD) by functional imaging at completion of chemotherapy (PR/SD cohort), or disease progression detected within 12 months of completion of chemotherapy after prior documentation of CR (ER cohort, early relapse). Patients were divided into two "eras" based on year of diagnosis, 2005-2010 (era1) and 2011-2018 (era2), with the latter expected to reflect changes in salvage therapy for cHL. Results: Patient characteristics for the 553 cases are summarized in Table. Median follow up of survivors was 58.7 and 31.2 months for patients diagnosed in era1 and era2, respectively. ABVD was the upfront treatment for 97.6% of cases. Nearly all patients (98.5%) received salvage therapy after PTF and 60.9% underwent auto-HCT. Patients who relapsed or progressed post auto-HCT received a median of 1 (range 0 to 3) salvage regimens. Five-year overall survival (OS) from time of PTF was 70.3% (95% CI=63.4-77.2%) for patients diagnosed in era1, and 77.6% (95% CI=70.3-84.8%, p = 0.018) for patients diagnosed in era2 (Figure A). While there was no difference in OS among the PP, PR/SD and ER cohorts in the era1 (Figure B), the PR/SD and ER cohorts had better OS than PP cohort in era2 (Figure C). On comparing the OS for each of the 3 cohorts between era1 and era2, there was an improvement in OS in the PR/SD (Figure E) and ER cohorts (Figure F) but no improvement among the PP cohort (D). Multivariable analysis of patients in era 2 identified only age (HR 1.05, 95% CI=1.03-1.07, P & lt;0.001) and PP pattern of PTF (HR 2.45, 95% CI=1.11-5.40, P=0.03) as predictors of worse survival. Conclusions: Though there has been an improvement in survival among cHL cases with PTF treated in the most recent years, the outcome of patients with PP did not change significantly across eras. Patients with PP disease should be prioritized for clinical trials incorporating newer agents and innovative cellular therapy to current available effective treatments. Disclosures Epperla: Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Costa:Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding. Cashen:Novartis: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Hamadani:Otsuka: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Medimmune: Consultancy, Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; 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. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Bello:Celgene: Speakers Bureau. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. 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. Glenn:BMS: Research Funding; Merck: Research Funding; Genentech: Research Funding. Cohen:Lymphoma Research Foundation: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; ASH: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Bristol-Meyers Squibb Company: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129199

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology

Abstract: In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase & gt;3x upper limit of normal, and a dual expressor immunophenotype. Age & gt;60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2023009731

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 455-455

Abstract: Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve & gt;1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-144308

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10904-10906

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-164959

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. 182-182

Abstract: Background: Despite advances in chemoimmunotherapy and stem cell transplantation, mantle cell lymphoma (MCL) has historically been difficult to treat. Patients with advanced age and high-risk features (e.g. blastoid/pleomorphic features, high MIPI score, complex karyotype, TP53 mutation) face particularly poor outcomes with standard chemoimmunotherapy. Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), was approved for second-line use in MCL in 2013. Other BTKis - acalabrutinib and zanubrutinib were approved in 2017 and 2019, respectively. BTKi provides a well-tolerated chemotherapy-free option for these hard-to-treat subgroups, especially the older patients. In this population-based study, we evaluated survival outcomes prior to and after the approval of ibrutinib, and hypothesized that survival benefit observed early after approval would be greatest in older patients not typically candidates for consolidative transplantation in the first-line setting. Methods: Using the Surveillance, Epidemiology, and End Results database, we included all adult patients diagnosed with MCL in the years 2007-2018 and followed them to the end of 2018 or death, whichever came first. The pre-BTKi era was defined by year of diagnosis 2007-2011, and the BTKi era was between 2014 and 2018. The years 2012-2013 were considered as a "washout" period to allow practice change related to the approval of ibrutinib. As age plays an important role in treatment decisions, including whether to use consolidative transplantation, patients were divided based on age at diagnosis: & lt;60, 60-69, 70-79, and ≥80 years. Outcomes of interest included all-cause mortality, and mortality from MCL (MFM). We applied multivariable Cox proportional hazards regression model for all-cause mortality, adjusting for age, sex, race, stage, and median household income at census level, and reported adjusted hazard ratio (HR) with 95% confidence interval (CI). We also conducted multivariable competing risk analyses for MFM, considering all other causes of death as the competing events, and reported subhazard ratio (sHR) with 95% CI. To eliminate potential confounding by duration of follow-up among patients diagnosed in different periods, we used only three-year follow-up data for primary analyses, and all available follow-up data for sensitivity analyses. Results: We identified 7,625 individuals diagnosed with MCL during our study period (3,424 and 4,201 diagnosed during 2007-2011 and 2014-2018, respectively). The majority were male (71%) and white (90%), with 49% of patients 70 years or older. The median follow-up was 9.2 and 2.4 years for patients diagnosed during 2007-2011 and 2014-2018, respectively. The 3-year all-cause mortality and 3-year MFM rates were 39.8% and 27.3%, respectively, in the overall population. Both the 3-year all-cause mortality and MFM increased as age increased. The 3-year all-cause mortality was lower in the BTKi era among all age groups, except patients & lt;60 years old, and the 3-year MFM was lower in the BTKi era among all age groups. The numeric difference of 3-year outcomes was more substantial in patients aged 70-79 for both all-cause mortality (pre-BTKi era: 47.8%, BTKi era: 40.4%) and MFM (pre-BTKi era: 33.9%, BTKi era: 27.5%) (Table, Figure A and B). In the multivariable analyses, risk of death was significantly lower during the BTKi era in the 60-69 (HR:0.85, 95% CI: 0.72-1.00) and 70-79 (HR: 0.80, 95% CI: 0.70-0.92) age groups. MFM was also significantly lower during the BTKi era in these two age groups (60-69: sHR: 0.78, 95% CI: 0.64-0.94; 70-79: sHR: 0.76, 95% CI: 0.65-0.90, Table). The results were largely unchanged in sensitivity analyses (results not shown). Conclusion: In this large population-based cohort analysis of individuals diagnosed with MCL, overall and lymphoma-specific survival improved in the BTKi era. At a median follow up of 2.4 years in our BTKi cohort, significant survival benefits were observed in those older than 60 but less than 80 years of age, and the observed benefits were greatest in the 70-79 age group. Future real-world studies should examine the impact of novel agents on treatment patterns and outcomes of MCL over a longer follow up period. Figure 1 Figure 1. Disclosures Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Zeidan: Amgen: Consultancy, Research Funding; Astellas: Consultancy; Jasper: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BeyondSpring: Consultancy; Acceleron: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Astex: Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Agios: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding. Podoltsev: PharmaEssentia: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria; Celgene: Honoraria; Blueprint Medicines: Honoraria; Pfizer: Honoraria. Neparidze: Janssen: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding. Huntington: AbbVie: Consultancy; TG Therapeutics: Research Funding; SeaGen: Consultancy; DTRM Biopharm: Research Funding; Flatiron Health Inc.: Consultancy; Novartis: Consultancy; Bayer: Honoraria; Pharmacyclics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy; Servier: Consultancy; Thyme Inc: Consultancy; Celgene: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146417

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 21-22

Abstract: Introduction While the approved dose of brentuximab in T cell lymphomas has been every 3 weeks on a 1.8 mg/kg schedule, earlier studies exploring weekly dosing showed that a dose of 1.2 mg/kg on a weekly dosing (every 3 out of 4 weeks) in pts with Hodgkin's lymphoma and hematologic malignancies may improve cancer response rates while still having manageable side effects3. We explored the weekly dosing schedule in 37 pts (pts) with mycosis fungoides/Sezary syndrome (MF/SS) and aggressive T cell lymphomas and compared to our experience with every 3 week dosing in 36 pts to evaluate tolerability and efficacy of the weekly schedule.. Methods We reviewed charts of 67 pts, 36 received dosing q 3 weeks and 37 received a dose weekly for 3 consecutive weeks on a 4-week schedule. Pts included MF/SS (n=35), gamma delta T cell lymphoma (n=2), anaplastic large cell lymphoma (n=12), Peripheral T cell Lymphoma (n=10), angioimmunoblastic T cell lymphoma (n=4), adult T cell leukemia (n=2), and NK-T cell lymphoma. Pts were treated with brentuximab vedotin at a dose of either 1.8 mg/kg every 3 weeks or 1.2 mg/kg weekly x 3 every 4 weeks. CD30 expression was scored by the pathologist in tumor biopsies as high ( & lt;50%), low (5-10%), or intermediate ( & gt;10%-49%). Toxicity data was recorded from the medical records and data analyzed descriptively. Results Of 67 pts in this study, the average age was 61. Doses were 1.8 mg/kg for the q 3 week schedule and 0.75 to 1.2 mg/kg for the weekly x 3 schedule. Cycles were 3-47 for q 3 weeks and 1-9.7 for weekly dosing. CD30 expression was high in 13% of pts, low in 43%, and absent in 6% with equal distribution between the weekly and q 3 week cohorts, as shown in Table 1. Dose adjustments were made in 67% of q 3 week and 61% of weekly pts for neurotoxicity (n=28), with a higher incidence in the q 3 week pts compared to those with weekly dosing (75% vs 53%, p=0.01) . Discontinuation for progression (25% vs 30%) was similar for both groups. In the weekly group, 8 pts had a stem cell transplant, including allogeneic transplantation in 3. Conclusion In the Phase II registration trial of brentuximab vedotin 1.8 mg/kg q3 weeks, 41% of pts had neuropathy (severe in 12%). 1 Forty two percent of discontinuations were for neuropathy. In our weekly schedule, incidence of neuropathy was lower and led to fewer treatment discontinuations. Our retrospective data shows that Brentuximab vedotin is well tolerated on a weekly dosing schedule and has activity in pts with MF/SS and aggressive T cell lymphomas. As in prior studies, responses were seen with low CD30 expression4, 5. Prospective clinical trials with a self-reported neurotoxicity scale and quality of life instruments should be performed address the impact of more frequent, lower doses of brentuximab vedotin on patient outcomes. 1 Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T et al.J Clin Oncol 2012; 30(18): 2190-2196. doi: 10.1200/JCO.2011.38.0402 2 Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P et al.Lancet 2017; 390(10094): 555-566. doi: 10.1016/S0140-6736(17)31266-7 3 Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA et al.Clin Cancer Res 2012; 18(1): 248-255. doi: 10.1158/1078-0432.CCR-11-1425 4 Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. J Clin Oncol 2015; 33(32): 3759-3765. doi: 10.1200/JCO.2014.60.3787 5 Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S et al.J Clin Oncol 2015; 33(32): 3750-3758. doi: 10.1200/JCO.2014.60.3969 Figure Disclosures Huntington: Pharmacyclics: Honoraria; DTRM: Research Funding; Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Astrazeneca: Honoraria. Xu:Seattle Genetics: 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-2020-139790

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2942-2942

Abstract: Background: At the molecular level, mantle cell lymphoma (MCL) is characterized by the deregulation of Bcl-2 family members (Mcl-1, BIM) and cell cycle (cyclin D1) regulatory proteins. Perhaps related to this, the clinical outcome of MCL continues to be poor specially for those patients with disease progression after high dose chemotherapy and autologous stem cell rescue and/or BTK inhibitors, stressing the need to develop novel therapeutic strategies or optimize current available options. Venetoclax (V), a highly selective Bcl-2 inhibitor, has shown modest activity against relapsed/refractory MCL. Over-expression of Mcl-1 has been postulated to be a mechanism of resistance to V limiting its anti-tumor activity in subtypes of lymphoma including MCL. The lethality by proteasome inhibitors (PIs) has been associated with changes in the Bcl-2 family members (Bax, Noxa, Mcl-1 and Bcl-XL) in lymphoma pre-clinical models, making them ideal agents to combine with V. To this end, we studied the anti-tumor activity of combining PIs with V in MCL pre-clinical models. Materials and Methods: A panel cytarabine sensitive (Rec-1, Jeko, Granta, HBL-2, Z-138 and Mino) and resistant (araC) cell lines (Jeko araC, HBL-2 araC, and Mino araC) were exposed to V, Bortezomib (BTZ), carfilzomib (CFZ), or ixazomib (IXZ) for 24, 48 and 72 hours. Cell viability was calculated measuring the ATP content. IC50 drug concentrations were calculated for each agent. Subsequently, MCL cell lines were exposed to escalating doses of V (0.001uM-5uM) and CFZ (1.5625nM-50nM), BTZ (3.125nM-100nM) or IXZ (3.125nM-100nM). In addition, primary tumor cells isolated from B-cell lymphoma patients (N=21) including MCL patients were exposed to V +/- BTZ or CFZ for 48 hrs. Cell viability was determined by Cell Titerglo. Coefficient of synergy were calculated using CalcuSyn software program. Induction of apoptosis was detected by Annexin V/Propidium iodine staining and PARP cleavage. Changes in Bcl-2 and cell cycle regulatory proteins were evaluated by Western blotting in HBL-2 cells. For in vivo experiments, 6-8 weeks old severe combined immunodeficiency (SCID) mice were inoculated with 10x106 HBL-2 cells via tail vein injection (IV). Subsequently, SCID mice were treated with V (100mg/kg/dose via gastric lavage on days 3-7, 10-14 and 17-21) or IXZ (6mg/kg/dose IV days 3, 6, 10, 13, 17 and 20) or combination of both agents. A group of untreated animals was used as a control. Differences in survival were evaluated between treatment groups. Results: In vitro exposure of MCL cell lines to either V, BTZ, CFZ, and IXZ induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed by combining both V with CFZ or IXZ at known sub-therapeutic and therapeutic doses of individual agents measured by ATP content and apoptosis potential. Anti-tumor activity was observed in cytarabine sensitive and resistant cell lines. Similar findings were observed in primary tumor cells isolated from B-cell lymphoma patients. In vitro exposure of MCL cell lines with the lowest IC50 (HBL-2) to V and PIs (BTZ, CFZ, or IXZ) resulted in the upregulation of Noxa, BIM, Mcl-1 cleavage form (pro-apoptotic) and downregulation of Bcl-XL leading to PARP cleavage and apoptosis. In vivo treatment of MCL bearing SCID mice with V resulted in significant anti-tumor activity when compared to single agent IXZ treated or control animals. Of interest, MCL bearing SCID animals treated with V and IXZ exhibited a better disease control and the survival was longer than SCID animals treated with V or IXZ single agent (P 〈 0.05). Conclusion: Our data suggests that V exhibits strong synergistic activity with PIs, especially with CFZ (in vitro) or IXZ (in vitro and in vivo). Together, our data supports the evaluation of V in combination with readily available novel PIs (IXZ or CFZ) in relapsed/refractory MCL. (Supported by LRF grant 555463, an NIH grant R01 CA136907-01A1 and a grant from The Roswell Park Cancer Institute Alliance Foundation) Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116510

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 3839-3841

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157105

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. 132, No. Supplement 1 ( 2018-11-29), p. 451-451

Abstract: Introduction: Patients (pts) with limited stage (LS) aggressive large B-cell lymphoma (ALBCL) comprise 30-40% of ALBCLs and are usually treated with R-CHOP with or without consolidative involved field radiation therapy (IFRT). In pts with ALBCL, cytogenetic studies have identified a subset with high-risk disease who harbor MYC rearrangement (MYC-R) with or without BCL2 (BCL2-R) and/or BCL6 (BCL6-R) rearrangements. This has led to the adoption of intensive induction strategies in this population; however, it is unclear if such an approach is necessary in limited stage disease. Methods: We conducted a multi-center (15 US academic centers) retrospective study of MYC-R LS-ALBCL pts with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) morphology. LS was defined by stage I and II confined to a single radiation field as determined by the treating center. Pts diagnosed between 1/1/2005 and 3/1/2017 were included. All pts received either R-CHOP or more intensive immuno-chemotherapy (IIC) (i.e. R-DA-EPOCH, R-hyperCVAD/MA, or R-CODOX-M/IVAC) with or without IFRT. Baseline demographic, clinical, laboratory, pathology and outcomes data was collected by retrospective chart review. Stage-modified IPI (sm-IPI) score was calculated [stage II (vs 1), age 〉 60, elevated LDH, and ECOG performance status ≥ 2]. Differences in overall response rate (ORR), complete remission (CR) rate, 2-year progression-free survival (PFS) and overall survival (OS) were compared in pts treated with R-CHOP vs IIC and in pts treated with IFRT vs no IFRT. Results: A total of 142 pts with MYC-R LS-ALBCL were identified, of which 105 fulfilled the inclusion criteria. Baseline characteristics included: median age 65 yrs (range 21-85), 66% male; 14% stage I, 32% stage IE, 28% stage II, 26% stage IIE disease; 17% bulky, 58% extra-nodal, 15% transformed disease, 40% elevated LDH. The majority of pts (70%) had germinal center B-cell phenotype. Eighty-two pts had data on BCL2-R and BCL6-R, of which 41 (50%) had double-hit lymphoma (DHL), including 4 pts with triple-hit lymphoma. Forty-five pts (43%) received R-CHOP, of which 56% had IFRT. Sixty pts (57%) received IIC, of which 42% had IFRT. R-DA-EPOCH was the most common IIC regimen used (85%), followed by R-hyperCVAD/MA (12%). Age (p=0.38), stage (p=0.32), extra-nodal disease (p=0.84), LDH (p=0.09), sm-IPI (p=0.24), morphology (p=0.44) and double-hit status (p=1.00) were similar between pts receiving R-CHOP and IIC. Median no. of cycles (NOC) (6 vs 6) and proportion of pts who received IFRT (56% vs 42%, p=0.17) did not differ in the 2 groups. Median NOC were lower in IFRT vs no IFRT group (4 vs 6; p=0.02). Pts receiving IIC (vs. R-CHOP) were more likely to undergo CNS prophylaxis (CNS-P) (75% vs 29%, p 〈 0.001). No. of pts receiving CNS-P were similar in DHL vs MYC-R only (64% vs 49%; p=0.23). ORR was 90% (83% CR, 7% PR). Pts with DHL were less likely to achieve a CR compared to pts with MYC-R only (73% vs 98%; p=0.011). CR rate was higher in the IFRT vs no-IFRT group (92% vs. 75%, p=0.028). In the 27 pts who had relapsed/refractory disease, distant relapses were more common in the IFRT vs no-IFRT group (87% vs 33%, p=0.007). Median follow-up was 3.2 yrs; 35 (33%) pts progressed or died. Of the 23 deaths, 15 were due to progressive lymphoma, 1 due to treatment-related toxicity and 7 due to unrelated causes. 2-year PFS and OS were 78% and 86% for the entire cohort and 72% and 82% respectively for DHL pts. Sm-IPI ≥ 2 (HR: 2.81, p=0.02) and age ≥ 70 (HR: 4.07, P 〈 0.001) were associated with inferior OS. Stage, extra-nodal disease, morphology, LDH and double hit status did not affect survival. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort (Figures 1 and 2) and in DHL pts (Figures 3 and 4). Use of CNS-P was not associated with improved PFS (HR: 0.57 [95% CI: 023, 1.43]) or OS (HR 0.98 [95% CI: 0.34, 2.85] ). Conclusions: Outcomes of MYC-R LS-ALBCL pts are excellent with 2-year PFS and OS of 78% and 86% respectively. There was no benefit of choosing IIC over R-CHOP or using CNS prophylaxis in pts with MYC-R LS-ALBCL and LS-DHL in our study. While IFRT was effective in inducing CRs and preventing local relapses, distant relapses limited its benefit. Pts with LS-DHL had lower CR rates with similar PFS and OS when compared to those with MYC-R as the sole cytogenetic abnormality. Longer follow up is needed to assess the impact of upfront treatment strategies on late relapses. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Maddocks:Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Millenium: Other: Institutional Research Support. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Vose:Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Roche: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Legend Pharmaceuticals: Honoraria. Cohen:Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Mehta:Seattle Genetics: Research Funding; Kite: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Merck: Research Funding; Spectrum: Consultancy; Epizyme: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Incyte: Research Funding; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Olszewski:Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, 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-2018-99-111530

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 6, No. 11 ( 2022-06-14), p. 3339-3342

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2021006934

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 2876449-3