Malecek, Mary‐Kate

Abstract The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.

Abstract We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale–Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

AbstractIntroductionWhile most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent‐behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy.MethodsOut of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high‐dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non‐intensive (n = 131).ResultsThere was no difference in progression‐free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non‐intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model.ConclusionsThese results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

Introduction Approximately 20% of patients (pts) with classical Hodgkin lymphoma (cHL) are age ≥ 60 years (yrs) at diagnosis (dx). Standard anthracycline-based therapies (ABTx) have historically shown lower efficacy and greater toxicity in this older population compared with younger pts, especially for unfit or frail pts. However, prior analyses have pre-dated the use of brentuximab vedotin (BV) and other novel targeted agents in the front-line setting and there remains no clearly defined or unified standard of care for this pt population. Studies in older lymphoma pts have also defined specific categories of pt fitness that may potentially guide therapy, although continued validation of these definitions in cHL are needed. We performed a large, multicenter retrospective study to identify current practice patterns in the US in older untreated cHL pts with specific attention to pt fitness using established definitions and to outcomes with ABTx versus non-ABTx. Methods Following IRB approval at each site, detailed pathologic and clinical data, including geriatric assessments (GAs) for the latter, were collected across 10 US academic medical centers. Eligible pts included: cHL dx on or after 1/1/2010, age ≥ 60 yrs at dx, and no preceding hematologic malignancy. Subjects with inadequate clinicopathologic and outcomes data or with dx other than cHL were excluded. A multivariable Cox proportional hazards model was developed to study the association of PFS and OS with various factors of interest, and survival rates were estimated by Kaplan-Meier using SPSS. Associations were considered significant for two-sided P values ≤ 0.05. Results Among 254 eligible older cHL pts with newly diagnosed disease, clinical features included: median age 67 yrs (range 60-90+), 54% male, 64% stage III/IV, 46% B symptoms, and 86.1% ECOG PS 0-1. 68.9% had nodular sclerosis, 18.9% mixed cellularity, and 12.2% other subtypes; EBV was detectable by IHC or peripheral blood in 39.3% of evaluable cases (n=98). In terms of geriatric measures, 31 pts (12.2%) had loss of at least one ADL; 40 (15.8%) had a geriatric syndrome; and 16 (6.3%) had both. Of note, only one pt underwent a comprehensive GA prior to treatment. Using established fitness definitions in lymphoma (Tucci et al, 2015), pts were classified as "Fit" (n=129; 50.8%), "Unfit" (n=8; 3.2%), or "Frail" (n=112 (44.1%); 5 (2%) were unclassifiable due to incomplete data (Table 1). Front-line regimens included ABVD (n=145; 57.1%), AVD (n=33; 13.0%), and CHOP (n=18; 7.1%). 6 pts (2.4%) received BV monotherapy; 21 (8.3%) received BV with AVD, the latter either concurrently (N=11) or sequentially (n=10). 11 pts did not receive systemic tx, of whom 9 received radiation alone; 58 pts received radiation with systemic tx. ABVD recipients received an average of 7.4 doses of bleomycin (range 1-14) and 18.4% (n=26) had pulmonary toxicity. In addition, 56.7% (n=130) of pts experienced at least one tx-related toxicity, which was similar across all fitness groups (Table 1). 15.1% (n=38) of pts stopped tx due to toxicity, which was noted more often in "frail" pts though it was relatively uncommon. 11 pts (4.3%) experienced treatment-related mortality (TRM). Compared with pts receiving non-ABTx, ABTx was associated with significantly improved PFS (HR 0.391, P=0.008) and OS (HR 0.195, P=0.0004). ECOG PS >1 was associated with inferior PFS (HR=1.96, P=0.017) and OS (HR=3.09, P=0.002). Pts defined as "frail" had no apparent difference in PFS compared with fit pts (Figure 1A;P=0.169), although decreased OS was seen (Figure 1B; P=0.01). Discussion To the best of our knowledge, these data represent one of the largest analyses of older cHL pts in the modern era. Our real-world analysis shows that in those who are able to receive them, anthracyclines provide meaningful survival benefit in this older cHL patient population and can be well-tolerated for many pts. The impact of dose intensity and backbone regimen are not yet known. In addition, current definitions of "fitness" incompletely identified pts at risk for poor outcomes or greater toxicity. Further studies are planned to better delineate fitness in this population. Disclosures Bartlett: Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Affimed: Research Funding; Merck: Research Funding; Janssen: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Genenetech: Research Funding; Bristol-Myers Squibb: Research Funding. Grover:Seattle Genetics: Consultancy. Bennani:Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board. Hill:Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Advani:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Kura: Research Funding; Janssen: Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Regeneron: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Cell Medica, Ltd: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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. Magarelli:Tevan Oncology: Speakers Bureau. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding. Cohen:Astra Zeneca: Research Funding; ASH: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Lymphoma Research Foundation: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Janssen Pharmaceuticals: Consultancy; Genentech, Inc.: Consultancy, Research Funding. Evens:Seattle Genetics: Consultancy, Honoraria, Research Funding; Tesaro: Research Funding; Epizyme: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Portell:AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding.

AbstractBackgroundCentral nervous system (CNS) relapse in non‐Hodgkin lymphoma (NHL) is a rare but serious complication that carries a poor prognosis. The use of infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH‐R) for frontline treatment of diffuse large B cell lymphoma (DLBCL) is increasing, though little is known about incidence of and risk factors for CNS relapse with this regimenPatients and methodsWe completed a chart review of patients with NHL who received EPOCH‐R as front line therapy. Data obtained included baseline and treatment characteristics including if patients received CNS directed therapy. We measured overall survival (OS), progression free survival (PFS), and progression to CNS involvement.ResultsWe identified 223 patients who met the inclusion criteria, 72% had DLBCL. Of all the patients, 5.8% experienced CNS relapse, and 38.6% were treated with CNS prophylaxis. There was no difference in rate of CNS relapse, OS, or PFS between patients who had and had not received CNS prophylaxis. Patients whose serum lactate dehydrogenase was greater than twice the upper limit of normal at diagnosis and those with extranodal disease were significantly more likely to have CNS relapse (P = .0247 and 0.022, respectively) than their counterparts.ConclusionsThe rate of CNS relapse in this patient population approaches 6%, not significantly different from reports on those receiving R‐CHOP. The results of this study suggest that CNS prophylaxis might be more selectively used among patients treated with EPOCH‐R with certain high‐risk features.