Steven M. Bair's research while affiliated with University of Colorado and other places

Except for anaplastic large cell lymphoma, five-year progression free survival (PFS) for peripheral T-cell lymphomas (PTCLs) with anthracycline-based chemotherapy is ~25%. Dose adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is an anthracycline based regimen for PTCLs. The programmed death (PD) pathway is an inhibitory immune checkpoint that downregulates T-cell activation and proliferation. PD-1 or PD-L1 expression on neoplastic T-cells and stromal or innate immune cells is common in T-cell neoplasms. Checkpoint blockade (CPB) with anti-PD1 monoclonal antibodies produced an overall response rate (ORR) of ~30% in pre-treated PTCLs. Cytotoxic chemotherapy has additive efficacy when combined with CPB; however, the immune-enhancing effect of CPB in untreated PTCL patients may lead to excessive toxicity or hyper-progression. To assess the safety and preliminary efficacy of front-line CPB-chemotherapy in PTCLs, we conducted a Phase I trial of nivolumab (Nivo) in combination with DA-EPOCH.

Introduction The cornerstone for management of newly diagnosed patients (pts) with cHL is an anthracycline (AC) based chemotherapy (chemo) regimen. There are a paucity of data available regarding treatment patterns and outcomes for cHL pts with low EF. Furthermore, cHL pts with low EF are typically excluded from clinical trials limiting our understanding on management of these pts. Methods This was a multicenter retrospective cohort study evaluating pts with newly diagnosed cHL with low EF from 16 US medical centers. Eligible pts included adults diagnosed after 1/1/2010 with pretreatment EF of <50% on echocardiogram. Pts who developed reduced EF during or after first-line treatment were excluded. Based on EF, pts were divided into 2 groups (gp): <45% (gp 1) and 45-49% (gp 2). First-line treatment was categorized into AC based and non-AC based therapies. Primary outcome was progression-free survival (PFS). Secondary outcomes included response rates to first-line therapy and overall survival (OS). Time to event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results The study included 69 pts with a median age of 55 yrs (21-88), 74% males, and performance status (PS) of ECOG 0-1 in 65%. There were 37 (54%) pts in gp 1 and 32 (46%) in gp 2. 39 pts received AC and 30 received non-AC based therapies. Pts in the AC group were significantly younger (median age, 46 vs 64 yrs), had higher proportion with EF of 45-49% (72% vs 13%) & ECOG PS of 0-1 (82% vs 54%) compared to non-AC based therapies. Among the 30 pts who received non-AC based therapies, 26 were in gp 1 and 4 in gp 2. Non-AC based therapies included BV monotherapy (n=6), non-AC BV-based therapies (n=11), and other non-AC chemo (n=13). The most common BV based therapy was BV+dacarbazine (n=4) followed by BV+bendamustine (n=3), while the most common other non-AC chemo was MOPP (n=4) followed by ChlVPP (n=3). The overall response rate (ORR) and complete response rate (CRR) to AC based therapy was 77% (30/39) and 69% (27/39), respectively. Among the non-AC therapies, the ORR/CR rates for BV monotherapy, BV based therapies, and other non-AC chemo were 33%/17%, 55%/27%, and 61%/54%, respectively. The median PFS for the entire cohort was 2.7 yrs (95%CI= 0.80-5.01). The median PFS for gp 1 vs gp 2 was 1.55 yrs and 4.20 yrs, respectively (p=0.26). The median PFS was significantly longer in pts receiving AC based compared to non-AC therapies (5.01 yrs vs 0.55 yrs, <0.001, Figure 1) with 3- and 5-yr PFS estimates of 62% vs 27%, and 54% vs 16%, respectively. Among the recipients of non-AC therapies, the 3-year PFS estimates for BV monotherapy, BV based therapies, and other non-AC chemo was 20%, 34%, and 42%, respectively (p=0.25). The median OS for the entire cohort was 5.6 yrs (95% CI=3.47-NR). The median OS for gp 1 vs gp 2 was 5.41 yrs and 5.73 yrs, respectively (p=0.82). The median OS was significantly longer in pts receiving AC based compared to non-AC therapies (7.43 yrs vs 3.20 yrs, p=0.003) with 3- and 5-yr OS estimates of 80% vs 60% and 80% vs 30%, respectively. Among the recipients of non-AC therapies, the 3-year OS estimates for BV monotherapy, BV based therapies and other non-AC chemo were 44%, 78% and 51%, respectively. Univariable Cox models tested baseline pt and disease variables and found increasing age, ECOG PS ≥2, and the presence of geriatric syndrome to be prognostic of inferior PFS and OS but not EF gp. Only increasing age remained associated with significantly inferior PFS and OS in multivariable analysis ( Table 1). After adjusting for these variables together with the inclusion of first-line treatment (AC vs non-AC based therapies), we found first-line treatment with AC-based therapy was associated with superior PFS (aHR= 0.39, 95% CI=0.15-0.97, p=0.04) but not OS (aHR= 0.51 (95% CI=0.16-1.65, p=0.26, Table 1). With inclusion of treatment, only age remained associated with inferior OS in the multivariable adjustment (aHR=1.27, 95%CI=1.04-1.54). Conclusion This first RWE of cHL pts with low EF found that a majority of pts with EF of 45-49% were treated with AC-based therapies. Furthermore, PFS was improved for pts who received AC-based therapies. However, outcomes appeared modest for pts compared with expectant outcomes. Collectively, these data underscore the critical need for prospective interventional studies in this challenging pt population. Further data on AC dosing, safety, risk of AC-induced heart failure, etc. will be presented at the meeting.

Background: In the LOTIS-2 study, patients (pts) with relapsed/refractory (R/R) DLBCL treated with loncastuximab-tesirine (lonca), a CD19 directed antibody-drug conjugate, demonstrated an overall response rate (ORR) and complete response rate (CRR) of 48.3 % and 24.1%. However, there is a paucity of data evaluating outcomes with lonca in the real-world setting (RWS). Hence, we performed a multicenter retrospective study to describe pt characteristics and clinical outcomes in R/R DLBCL pts receiving lonca in this setting. Methods: This retrospective study included pts with R/R DLBCL treated with commercial lonca at 21 academic centers in USA. Clinicopathologic data, treatment outcomes and adverse event (AE) data were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method and characteristics associated with survival and CR calculated using Cox proportional hazards model and logistic regression. Response was assessed per institutional standards. Results: 187 pts were analyzed with a median follow-up of 12.5 months (mo). Median age was 68 years (range 22-95), 64% male, and 85% white ( Table 1). Most common histology was DLBCL (55% de novo, 22% transformed from low-grade) and 19% were double hit (DH). Thirty-two percent (n=59) had primary refractory disease, 17% (n=31) prior autologous transplant, and 60% (n=112) prior CAR T-cell therapy (CART). Median number of treatment lines before lonca was 4 (1-11) with 81% (n=151) receiving lonca in 4 th line (4L) or later and 8 pts treated off-label in 2 nd line. More pts receiving lonca in ≥4L had prior CART (72% vs 8%, p <0.001). CD19 status was confirmed prior to lonca in 128 pts (68%) with 109 (58%) confirmed CD19+. The ORR/CRR were 33% and 14%, respectively. Median PFS was 2.1 mo (95%CI=1.8-2.6) and median OS 4.6 mo (95%CI=3.7-5.8). 12-month PFS and OS were 12% and 20%. The CRR in 2L/3L, 4L, and >4L were 15%, 13%, and 15% with ORR of 44%, 26%, and 33%, respectively. Figure 1 shows PFS stratified by response with median PFS not reached in those achieving CR. Patients with a CR to last therapy prior to lonca had superior median PFS (8.8 vs 2.0 mo, p<0.01) and OS (10.8 vs 4.5 mo, p =0.01). Factors associated with achieving CR to lonca included CR to last prior therapy (OR 8.3, p<0.01) and nonGCB subtype (OR 3.9, p=0.02). No pts with bulky disease (>10 cm) had objective response. In multivariable analysis (MVA) including factors in Table 1, elevated LDH (HR 1.8, p=0.02; 95%CI=1.1-2.9) and bulky disease (HR 1.7, p=0.03; 95%CI=1.1-2.6) were associated with inferior PFS while CR to last therapy was associated with superior PFS (HR 0.2, p=0.02; 95%CI=0.05-0.76). Bulky disease (HR 2.3, p<0.01; 95%CI=1.4-3.5), HGBL histology (HR 6.1, p<0.01; 95%CI=2.6-14.5), and elevated LDH (HR 2.0, p<0.01; 95%CI=1.2-3.3) were associated with inferior OS, while CR to last therapy (HR 0.4, p=0.05; 95%CI=0.13-0.98) was associated with superior OS in MVA. Neither CD19 status nor prior CART were associated with PFS, OS, or CR. In pts receiving lonca after CART, ORR/CRR were 31% and 15%, respectively, and median PFS/OS were 2.0mo (95%CI=1.6-2.7) and 4.6mo (95%CI=3.2-6.1). In pts who received tafasitamab (n=15) and CART (n=7) after lonca, CR was 13% and 29%, respectively. The most commonly documented AE was cytopenias (45%), followed by peripheral edema, and rash (27% and 27% respectively). Infection was seen in 5% and AEs led to lonca discontinuation in 14%, including peripheral edema (24%) and rash (28%). Conclusions: In this heavily pre-treated population enriched with prior CART exposure, HGBL, and DHL, ORR and CRR to lonca were lower than previously reported. Nonetheless, we found that pts who achieve a CR to lonca have favorable outcomes and factors associated with achieving a CR include lack of bulky disease, nonGCB subtype, and achieving a CR to most recent therapy prior to lonca. Receipt of prior CART did not negatively impact outcomes to lonca. Furthermore, responses were seen with CD19-directed therapies following lonca failure, suggesting sequencing of CD19 therapy pre and post lonca was successful.

Background: One-third of patients (pts) with newly diagnosed DLBCL are 70 and older. Although a standard of care for first-line (1L) DLBCL is anthracycline-based chemoimmunotherapy with R-CHOP, in elderly DLBCL pts treatment approaches vary and outcomes of these are poorly understood. In this study, we aimed to evaluate long-term outcomes among elderly pts with DLBCL across 1L regimens with a focus on those who received reduced dose (RD) R-CHOP, standard dose (SD) R-CHOP, and non-anthracycline alternative regimens (AR). Methods: We evaluated a cohort of pts from the Flatiron Health electronic health record (EHR)-derived, de-identified database with DLBCL diagnosis (dx) after 1/1/2011, age 70 or greater at dx, and with no evidence of prior indolent lymphoma or other malignancy within 2 years of 1L therapy. RD R-CHOP was defined as <80% SD doxorubicin or cyclophosphamide. Time-to-event analysis was performed with the Kaplan-Meier method and differences were evaluated using the log rank test. Real world overall survival (rwOS) was defined as the interval, in months (mos), from DLBCL dx to death or last follow-up. Real world progression free survival (rwPFS) was defined as the interval, in mos, from initiation of 1L therapy to progression, death, or last follow-up. Multiple imputation was performed (m = 50). Multivariate Cox regression analysis (MVA) was conducted within each imputed dataset and pooled. MVA was additionally performed across age strata. Results: There were 434 pts included in the complete cohort. Eighty-six percent (N=372) received 1L therapy and 62 pts (14%) had no therapy documented. Among treated pts, 47% were female, median age was 79 (IQR 75-82), and median CCI score 7 (IQR 6-9). Twenty-six percent and 47% had limited and advanced stage at dx, respectively; stage was unknown in 27%. Cell of origin was germinal center (GCB), non-GCB, and unknown in 34%, 24%, and 43%, respectively. Forty-eight percent of pts (N=212) received R-CHOP as 1L. Best real world response (rwR), defined as either complete response (CR) or partial response (PR) to 1L, was 89.0%, 89.5%, and 81.6% (p = 0.20) in pts who received SD R-CHOP, RD R-CHOP, and AR, respectively. CR rates were 78.0%, 58.1%, and 60.2% (p = 0.008) among these cohorts, respectively. Median rwOS and rwPFS among all treated pts was 39.0 mos (32.4-47.3) and 15.2 mos (12.3-23.4), respectively. Among patients who received SD R-CHOP, RD R-CHOP, and AR, median age (IQR) was 72 (71-77), 81 (79-83), and 80 (77-81), respectively (p<0.001). Median Charlson comorbidity index (CCI) score (IQR) was 6 (5-8), 8 (6-9), and 7 (6-9) across these groups, respectively (p<0.001). SD R-CHOP was associated with better rwPFS and rwOS in the entire treated cohort. Real world OS and rwPFS were 95.6 mos (67.0-NE) and 77.3 mos (40.3-NE) for SD R-CHOP, 37.6 mos (27.9-NE) and 15.8 mos (11.9-35.8) RD R-CHOP, and 25.7 mos (16.0-32.6) and 9.6 mos (8.1-12.0) for AR, respectively. When stratifying by age, pts 70-79 years had PFS of 77.3 mos (41.2-NE), 22.4 mos (9.86-NE), and 11.0 mos (8.6-23.4) with SD R-CHOP, RD R-CHOP, and AR, respectively (p <0.0001), whereas pts >=80 had PFS 6.14 mos (4.21-NE), 14.7 mos (8.87-NE), and 7.3 mos (4.47-12.0) with these regimens (p=0.03). In Cox regression MVA, CCI was associated with rwPFS in pts >=80 (HR 1.18, p=0.004). High-risk IPI score was associated with rwPFS (HR 2.13, p=0.05) and rwOS (HR 2.51, p=0.033), but only in pts age 70-79. When stratifying by age and adjusting for comorbidities, IPI, and MYC alteration, treatment with RD R-CHOP and AR were associated with inferior rwPFS and rwOS compared to SD R-CHOP among pts age 70-79, however, there was no association between treatment intensity and outcome among pts >=80 (Table). Conclusions: This study represents one of the largest real-world studies evaluating contemporary outcomes among elderly pts with DLBCL receiving 1L therapy. In MVA, SD R-CHOP is significantly associated with improved rwPFS and rwOS compared to RD-RCHOP and AR, but only among pts aged 70-79. There was no effect of treatment intensity or regimen on either rwPFS or rwOS among pts aged >=80. Other covariates significantly associated with outcome included CCI among pts >=80 and high-risk IPI in pts 70-79. These results suggest that pts aged 70-79 should receive SD R-CHOP whenever feasible, but that treatment intensity is not the primary determinant of outcomes among pts aged >=80. CCI should be part of routine evaluation in elderly DLBCL pts.

In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A+AVD) demonstrated superior efficacy compared to bleomycin+AVD (ABVD) for the treatment of advanced-stage classic Hodgkin's lymphoma (cHL). However, there is minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 stage III and IV cHL patients treated with frontline A+AVD from January 2010 through April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median age was 37 years, and high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received six cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% CI: 24.8 - 29 months), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% confidence interval [CI], 85.9-95.0). The impact of CDB on PFS was not significant (p-value=0.15), nor was high CDB significantly associated with increased adverse events (AE). In real-world experience, A+AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Introduction: Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a non-trial setting, where clinicians may have different strategies for managing it. Methods: We conducted a multi-site retrospective study to characterize PN in patients who received BV+AVD for newly diagnosed cHL. Results: 153 patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients due to PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow up of 24 months, PN resolution was documented in 36% and improvement in 33% at last follow up. 2-year progression-free survival (PFS) for the advanced stage patients was 82.7% (95% CI 0.76-0.90) and overall survival (OS) was 97.4% (95% CI 0.944-1.00). Patients who discontinued BV due to PN did not have inferior PFS. Conclusions: In the non-trial setting, BV+AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable.

Introduction:Dose-adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a frequently used first line chemotherapy regimen for peripheral T-cell lymphomas (PTCLs), but relapses are common and long-term outcomes are poor. Checkpoint blockade (CPB) immunotherapy has shown modest single agent efficacy in relapsed PTCLs. In other hematologic malignancies the combination of CPB and cytotoxic chemotherapy is promising. Methods: We conducted a Phase I trial to assess safety, spectrum of immune-related toxicity, and efficacy of nivolumab (Nivo) in combination with DA-EPOCH as front-line therapy for PTCLs. Patients received Nivo (360 mg) followed by DA-EPOCH every 21 days for six cycles. Patients were allowed to receive one cycle of standard-of-care chemotherapy prior to enrollment. Results:18 patients were enrolled: 7 PTCL-not otherwise specified (NOS), 6 nodal T-cell lymphomas with a T-follicular helper phenotype, 2 primary cutaneous gamma/delta T-cell lymphoma, 2 ALK negative anaplastic large cell lymphoma, and 1 subcutaneous panniculitis like T-cell lymphoma. Fifteen had an intermediate or high-risk International Prognostic Index. Immune related (ir) adverse events (AEs) of all grades occurred in 14 and 7 patients experienced ≥ grade 3 irAEs. Eight patients required discontinuation of Nivo due to irAEs. Of the 6 patients who received a cycle of anthracycline-based combination chemotherapy prior to enrollment, none experienced an irAE resulting in Nivo dose hold or discontinuation, compared to 8 of 12 patients whose first cycle was Nivo+DA-EPOCH. There were no hyperprogression events. Interim and end of therapy overall response rates were 94% and 89%, respectively (11 complete responses, 5 partial responses, and 2 progressive diseases). With a median follow up of 707 days, median progression free and overall survival is 434 and 714 days, respectively. Conclusions: Front-line Nivo + DA-EPOCH showed good feasibility and acceptable safety when Nivo was started after chemotherapy but was associated with frequent dose-limiting irAEs when administered synchronously. Efficacy was encouraging with lengthy responses in very high risk PTCL subtypes. Further investigation of front-line line CPB-chemotherapy combinations in PTCL is warranted using a sequential approach. The trial is registered with ClinicalTrials.gov, NCT 03586999.

7542 Background: Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is the new standard of care for newly diagnosed stage III/IV cHL. In the pivotal ECHELON-1 trial, peripheral neuropathy (PN) was the most common toxicity, seen in 67% of patients (pts) and leading to discontinuation of BV in 6.6%. However, PN from BV+AVD in cHL has not been studied in a non-trial setting, where clinicians may have different strategies for managing it. Methods: We conducted a multi-site, retrospective study to characterize PN in pts who were planned to receive 6 cycles of BV+AVD for newly diagnosed cHL before 9/2022. Data was obtained from medical records and PN was graded retrospectively using CTCAE v5.0 criteria. Multivariable logistic regression was used to assess factors associated with PN. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. A Cox proportional hazards model was used to test the effect of discontinuation on PFS. Results: 153 pts from 10 US institutions were eligible. Median age was 35 years (range 18-76) with 22% of pts over 60 years old. Thirty-four pts (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage (8% stage I/II), performance status (3% ECOG 3+), preexisting PN (6%), or other comorbidities including HIV and other malignancies (10%). Of advanced stage pts, 41% had IPS 4-7. Median no. BV+AVD cycles was 6 (range 1-6). PN was reported by 80% of pts during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of pts due to PN leading to BV discontinuation in 23% with median no. of doses omitted of 4 (range 1-10), dose reduction in 17% and temporary dose hold in 4%. Vinblastine was modified in 17% of pts due to PN including discontinuation or temporary hold in 10% and dose-reduction in 7%; in 35% of pts with vinblastine modification, BV was continued. None of the factors assessed (age, sex, baseline PN, diabetes mellitus) predicted development of any grade PN. However, higher initial dose of BV in mg (based on weight) was associated with increased risk of grade 2+ PN (OR 1.03, 95% CI 1.01-1.05, p = 0.002). With median follow up of 24 months (range 0.33-87), PN resolution was documented in 36% and improvement in 33% at last follow up. Ongoing G2+ PN was present in 13% of pts at last follow up. 2-year PFS for the advanced stage patients was 82.7% (95% CI 0.76-0.90) and OS was 97.4% (95% CI 0.944-1). Discontinuation of BV due to neuropathy did not affect PFS (HR 1.1, 95% CI 0.45-2.5). Conclusions: In the non-trial setting, BV+AVD was associated with a high incidence of PN. In our cohort, which includes pts who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable; discontinuation of BV was not associated with inferior PFS.