Number Of Prior Therapies Research Articles

A phase 2 expanded access study of zanubrutinib (ZANU) in patients (pts) with Waldenström Macroglobulinemia (WM).

e19522 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. The next-generation BTK inhibitor ZANU (BGB-3111), designed to maximize BTK occupancy and minimize off-target inhibition of other kinases, is approved by the United States (US) Food and Drug Administration, Health Canada, and the European Union at a dose of 320 mg once daily (QD) or 160 mg twice daily (BID) for adult pts with WM. BGB-3111-216 is a single-arm expanded access study of ZANU in treatment-naïve (TN) pts who were unsuitable for standard chemoimmunotherapy or pts with relapsed refractory (R/R) WM. This study provides real-world experience with ZANU in pts with WM. Methods: Eligible pts with TN or R/R WM received ZANU 320 mg QD or 160 mg BID orally. Primary endpoint was the number of pts enrolled/treated and enrolling sites. Secondary endpoints included treatment-emergent adverse events (TEAEs) of special interest, disease response rate, progression-free survival (PFS), and overall survival (OS). Response was evaluated by investigator assessment according to the 6th International Workshop on WM ( Br J Haematol. 2013;160(2):171-6) every 6 mo at minimum. The study was closed by the sponsor in July 2021 and active pts were transitioned to commercial ZANU via a patient assistance program. Results: Fifty pts with WM (17, TN; 33, R/R) were enrolled between December 2019 and June 2021 across 10 academic and community medical centers in the US. Median age was 72 years, 54% had intermediate-, 40% had high-risk disease, and the median number of prior therapies for R/R pts was 2. Median treatment exposure was 9.2 mo (range, 1.4-20.0). Thirty-eight (76%) pts had ≥1 TEAE, and 36 (72%) had ≥1 TEAE of special interest. Grade ≥3 TEAEs of special interest were hypertension (8%), infection (8%), atrial fibrillation/flutter (2%), neutropenia (2%), and second primary malignancy (2%). No new safety signals were observed. In pts with ≥1 response evaluation, 39% achieved a best overall response (BOR) of very good partial response. Overall response rate was 85.4% and major response rate was 73.2% (Table). Of the 4 pts with BOR of progressive disease, 3 had IgM values that met partial response criteria before the 6-mo response assessment. PFS and OS were immature due to short follow-up, and the median was not met. Conclusions: These real-world expanded access study results were consistent with the established ZANU profile in WM or other B-cell malignancies when administered as oral monotherapy at 160 mg BID or 320 mg QD in pts with intermediate or high-risk R/R or TN WM. Clinical trial information: NCT04052854. [Table: see text]

Central nervous system (CNS) outcomes and progression patterns in patients with RET fusion-positive lung cancers treated with selpercatinib.

3109 Background: Selpercatinib, a potent/selective RET inhibitor, is approved for the treatment of RET fusion-positive non-small cell lung cancers. While the drug is known to have substantial intracranial activity (intracranial ORR 82%) in patients with existing brain metastases, (1) central nervous system (CNS) outcomes in patients without brain metastases and (2) CNS progression patterns in patients with brain metastases have not been explored. Methods: Patients with advanced RET fusion-positive lung cancers were prospectively treated with selpercatinib on the registrational LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 multi-center expanded access program (EAP, NCT03906331). Key overall and CNS eligibility criteria were previously presented. Patients with and without pre-selpercatinib brain metastases who underwent serial CNS and extracranial imaging were eligible for analysis. The data cutoff was November 24, 2020. Cumulative incidence rates (CIRs) were calculated using a competing risk model with systemic progression of disease (PD) or death as competing risks; patients with simultaneous CNS and systemic PD were treated as having had CNS PD. Results: Sixty-two patients (48 LIBRETTO-001, 14 EAP) were identified. Median age was 64. Thirty-two (52%) were female and 47 (76%) were never smokers. The most common 5’ fusion partner was KIF5B (68%). The median number of prior therapies was 2 (range 1-11); 34% received prior multikinase inhibitor therapy. The median time on treatment was 21.8 months. Thirty-one (50%) patients had no baseline brain metastases. In these patients, the CIR of CNS metastasis was 0% at 6 months and 12 months; none of these patients developed CNS metastasis during selpercatinib treatment. The 9 patients that progressed did so extracranially. Of the 31 patients with baseline brain metastases, 12 (39%) had prior CNS radiation and 3 (10%) had prior CNS surgery. At the time of data cut-off, 23 patients had some evidence of progression, including 8 in both the CNS and systemically, 6 only in the CNS, and 9 only systemically. Overall, 17 of the 31 patients with baseline brain metastasis did not develop evidence of CNS progression as of the data cut. Among patients with baseline brain metastasis, the CIR for evidence of CNS PD was 6.7% at 6 months and 27.4% at 12 months. Conclusions: In patients with RET fusion-positive lung cancers without baseline brain metastases, new CNS metastases were not observed during selpercatinib therapy. Among patients with baseline brain metastasis, a substantial number did not experience progression in the CNS on treatment.

Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcomes in patients with metastatic renal cell carcinoma (mRCC)?

354 Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with < 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p=0.006) and more advanced age (median: 66 years vs 60 years, p=0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP and OS. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]

Abstract P2-14-17: A phase 1b study of PVX-410 vaccine in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC)

Abstract Background: Immunotherapy with checkpoint inhibition is active in mTNBC. Both pembrolizumab and atezolizumab are FDA approved for programmed cell death ligand 1 positive (PDL1+) mTNBC. Vaccines may further induce host immune response and enhance therapeutic activity of checkpoint inhibitors. PVX-410 (PVX) (OncoPep, Inc.) is a novel, HLA-A2 restricted, tetra-peptide vaccine, with 3 of its 4 antigens (XBP1[2 splice variants] and CD138) commonly overexpressed in TNBC. We present results from a phase 1b study evaluating the immune response, safety and tolerability, and clinical activity of PVX and pembrolizumab (PEM) in mTNBC. Methods: Eligibility for this phase 1b multi-center, single-arm study included HLA-A2+, PD-L1 unselected female patients (pts) ≥18 years with metastatic or inoperable locally advanced TNBC, measurable disease, and any number of prior therapies, including prior checkpoint inhibitor therapy. Pts received 6 doses of 800µg PVX emulsified in Montanide ISA 720 VG by subcutaneous injection co-administered with intramuscular Hiltonol weekly for 6 weeks (wks) followed by booster vaccine doses at wks 10 and 28, with concurrent intravenous 200 mg PEM every 3 wks starting with the second PVX dose. Therapy was given until progressive disease, unacceptable toxicity or a maximum of 24 months. Blood samples were scheduled for immune response assessment at baseline and at weeks 2, 5, 10, 28, and 52 post-treatment initiation. The primary objective was PVX- specific immune response at week 10. Immune response was defined as a ≥2-fold change over baseline in the proportion of CD3+CD8+ T cells that expressed IFNγ and the proportion of CD3+CD8+ T cells positive for PVX tetramers following an in vitro stimulation of PBMC with PVX peptides using a flow cytometric assay. Secondary objectives were immune response at wk 28, safety and tolerability, and clinical endpoints (RR, CBR, DCR, DoR, PFS, and OS). Results: Between 3/2018 and 8/2020, 19 pts enrolled. Median age was 62 yrs (range 46-79), with median 2 (range 0-9) lines of prior therapy for metastatic disease. Median disease-free interval among 16 pts with prior early TNBC was 3.3 years. Among 19 enrolled patients, 16 were available for analysis at the time of abstract submission. Among the 16, 10 pts were evaluable at week 10 and 7(70%) demonstrated a PVX specific immune response. There were 6 patients who progressed before week 10, of whom 3 (50%) had a positive immune response at the EOT visit. Immune response persisted in all evaluable pts assessed at week 28 (n=4). Immune response data for all evaluable patients will be updated at the presentation. Among 19 patients evaluable for safety analysis, the most common adverse events (AEs) attributable to PVX (grade ≥2) included: fatigue (21%), arthralgia (11%) injection site reaction (5 %) pain (5%) lymphocyte count decreased (5%), maculopapular rash (5%) and skin infection (5%) . There were two grade 3 AEs attributed to PEM (AST elevation, hyponatremia) and one grade 4 AE (ALT elevation). There were no grade 5 AEs. The clinical benefit rate (CR+PR+SD for ≥16 weeks) was 31.6% with no confirmed partial or complete responses. Best overall response was SD in 9 (47%) patients. Analysis of additional clinical endpoints including PFS and OS is ongoing and will be presented at the meeting. Conclusions: PVX plus PEM is safe with manageable toxicity in pts with mTNBC. No new unexpected adverse events were identified. Immune response data show PVX induces antigen-specific T cell expansion as observed by increases in PVX tetramer and IFN positive T cells. Clinical disease control was observed with a CBR of 31.6%. Based on these promising immune response results in this pretreated population, a phase 2 study with PVX+PEM in combination with standard chemotherapy in treatment naïve, PD-L1+ mTNBC is underway (NCT04634747). Citation Format: Steven J Isakoff, Nadine M. Tung, Jun Yin, Nabihah Tayob, Joanne Parker, Julie Rosenberg, Aditya Bardia, Laura Spring, Hannah Park, Maya Collins, William T. Barry, Mariano Severgnini, Doris Peterkin, Sara M. Tolaney. A phase 1b study of PVX-410 vaccine in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-17.

Abstract OT2-24-03: Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial

Abstract Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-03.

Phase 1/1b trial of fruquintinib in patients with advanced solid tumors: Preliminary results of the dose expansion cohorts in refractory metastatic colorectal cancer.

93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P < 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.

Assessing Romiplostim Dose and Platelet Response-Guided Titration to Support Use of Romiplostim in ITP Patients Less Than 12 Months from Diagnosis

Background: Romiplostim, a subcutaneous treatment for adult ITP, uses a platelet response-guided dose adjustment algorithm (USPI dosing, Table 1) to maintain patients' platelet count (PC). Romiplostim was recently approved for patients with ITP ≤ 12 months from diagnosis.Objectives: The primary objective of this analysis was to confirm the appropriateness of romiplostim dose and platelet response-guided titration for patients with ITP ≤ 12 months from diagnosis using a model based approach.Methods: Data from 268 adult patients with ITP ≤ 12 months from diagnosis was extracted from 7 previously conducted clinical studies and used to develop a model based on a previously published model of romiplostim dose-response in ITP patients (Perez-Ruixo et al, 2012). Following the model update, patient characteristics (time from diagnosis, PC at baseline, sex, age, weight, number of prior therapies, region, and use of rescue medications) were assessed to identify any potential factors influencing dose or platelet response in ITP patients ≤ 12 months from diagnosis. The model was qualified for simulation using standard methods modified to account for response-guided dosing. Additionally, observed and predicted platelet responses (incidence of durable response, sustained response, and duration of response) were compared for patients stratified by time from ITP diagnosis (<3, 3 to ≤ 6, and 6 to ≤ 12 months). Simulations were then conducted using prescribed dosing guidance to predict PC and romiplostim doses over 52 weeks of treatment in patients ≤ 6 months and > 6 to ≤ 12 months from diagnosis.Results: The analysis dataset included 7854 PC from 268 patients (with median baseline PC of 18 x 10 9/L and median time since diagnosis of 3 months) receiving romiplostim weekly for up to 3 years at doses ranging from 1 to 15 mg/kg.The updated model (Figure 1) consisted of a drug-sensitive progenitor cell compartment (Pre), 4 maturation compartments (Transit), and a peripheral blood compartment (Circ). Romiplostim increased production of platelet precursors in Pre in 2 ways: 1. linearly with romiplostim exposure (immediate response), and 2. as a function of cumulative administered dose. Response to romiplostim was bimodal with approximately 50% of patients more sensitive to romiplostim treatment with drug sensitivity proportional to time since diagnosis. In the other 50% of patients, immediate response was reduced and there was no cumulative effect of romiplostim dosing on platelet response over time. Age was associated with average platelet transit time where a patient of 30, 60, or 90 years would have a platelet transit time of 6.3, 7.5, and 8.3 days respectively. No other covariates were found to influence any model parameters.Model predicted and observed platelet responses were similar for ITP patients stratified by time from ITP diagnosis (<3, 3 to ≤ 6 and 6 to ≤ 12 months). Simulations (Figure 2) showed that romiplostim prescribed dosing is effective in maintaining PC of 50 - 250 x 10 9/L following titration (approximately 65% of subjects) and minimizing the proportion <20 or >400 x 10 9/L regardless of time since ITP diagnosis or sensitivity to romiplostim treatment. The predicted <35% of subjects above 400 x 10 9/L is consistent with what was observed in the adult ITP safety datasets.Conclusions: An updated model of romiplostim dose and platelet response was developed using data from ITP patients ≤12 months from diagnosis. Clinical trial simulations using the updated model predicted that weekly dosing of romiplostim according to the dose titration rules in the label adequately maintained platelet counts in patients with ITP ≤ 12 months from diagnosis. [Display omitted] DisclosuresGibiansky: Amgen: Consultancy. Serrano Castillo: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Chow: Amgen: Current Employment, Current equity holder in publicly-traded company. Doshi: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment.

Efficacy Outcomes of Isatuximab with Pomalidomide and Dexamethasone Are Comparable to (ICARIA-MM) Trial Data: Initial Results of a UK-Wide Real-World Study of Relapsed Myeloma Patients

Efficacy Outcomes of Isatuximab with Pomalidomide and Dexamethasone Are Comparable to (ICARIA-MM) Trial Data: Initial Results of a UK-Wide Real-World Study of Relapsed Myeloma Patients

Updated Phase I/II Safety and Efficacy Results for Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed/Refractory Immune Thrombocytopenia

Updated Phase I/II Safety and Efficacy Results for Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed/Refractory Immune Thrombocytopenia

P-212: DREAMM-5 platform trial: Belantamab mafodotin (belamaf; GSK2857916) in combination with five different novel agents in patients with relapsed/refractory multiple myeloma (RRMM)

<h3>Background</h3> Single-agent belamaf, a B-cell maturation antigen-targeting antibody-drug conjugate, induced durable responses with a manageable safety profile in patients with RRMM at 13 months of follow-up (DREAMM-2; NCT03525678). The unique multimodal mechanisms of action (MoAs) of belamaf, in combination with MoAs of selected agents, have the potential to achieve synergistic effects in RRMM to further enhance the benefit-risk profile. Belamaf is being evaluated in DREAMM-5 in various lines of treatment, as monotherapy or in combination with other agents. <h3>Methods</h3> DREAMM-5 (NCT04126200) is a phase 1/2 platform study that utilizes a master protocol with separate sub-studies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases to identify effective belamaf combinations compared with a shared single-agent belamaf control arm (CE phase only). In the DE phase, patients will be assigned to one of the multiple belamaf dosing combination cohorts by a predetermined algorithm (N≤10 per cohort). A recommended phase 2 dose (RP2D) for each combination will be identified based on safety and preliminary efficacy in the DE phase. An interim analysis of safety, pharmacokinetic, biomarker, and efficacy data will be performed for each combination to determine if it should move forward to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a sub-study, and within a sub-study, to either the combination arm or belamaf control arm. Patients will also be stratified by number of prior therapies; eligible patients will have received ≥3 prior lines, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. All patients will provide informed consent for participation. Primary objectives of the study are to identify the RP2D (DE phase), the overall response rate (≥partial response, CE phase), and safety and tolerability for each combination. Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment. Sub-study 5 (combination with isatuximab [Sanofi], CD38 antagonist antibody) will be open to enrollment soon. Additional sub-studies will be explored based on scientific rationale and/or available preclinical combination data. <h3>Funding</h3> GSK (208887; NCT04126200). Belamaf drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Nirogacestat and isatuximab produced by and used in collaboration with SpringWorks Therapeutics and Sanofi, respectively <h3>Encore Statement</h3> ©2021 European Hematology Association, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 EHA Annual Meeting. All rights reserved.

ABCL-289: Matching-Adjusted Indirect Comparison (MAIC) of Axicabtagene Ciloleucel (Axi-Cel) and Lisocabtagene Maraleucel (Liso-Cel) in Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL) After Two or More Prior Lines of Therapy

<h3>Context</h3> Axi-cel and liso-cel are autologous, anti-CD19, chimeric antigen receptor T-cell therapies for the treatment of R/R LBCL. Both have demonstrated high and durable responses in single-arm trials, but comparative evidence is lacking. <h3>Objective</h3> To estimate relative treatment effects with axi-cel <i>versus</i> liso-cel for the treatment of R/R LBCL. <h3>Methods</h3> A logistic propensity score model was used to estimate weights for the individual patient data in ZUMA-1 (axi-cel) to match the mean baseline characteristics observed in TRANSCEND-NHL-001 (liso-cel). The following variables were matched: ECOG score, best response to last therapy, use of bridging therapy, LBCL subtype, number of prior therapies, prior autologous stem cell transplant, tumor burden, age, and lactate dehydrogenase. Relative treatment effects (with 95% confidence interval [CI]) were estimated using outcomes from TRANSCEND-NHL-001 and the weighted population in ZUMA-1. Outcomes included response rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), and neurological events (NEs). Base–case analyses were conducted using ZUMA-1 pivotal cohorts 1 and 2 (N=101) and published outcomes for liso-cel. Scenario analyses included ZUMA-1 additional safety management cohorts 4 (N=41) and 6 (N=40). <h3>Results</h3> In the base–case analysis, the estimated odds ratios (ORs) for objective response (2.18 [0.96–4.98]) and complete response (1.84 [0.97–3.50]) were higher with axi-cel, but these differences were not statistically significant. Axi-cel was associated with a statistically significant improvement in OS (hazard ratio [HR]: 0.53 [0.34–0.83]) and PFS (HR: 0.61 [0.40–0.93]). DoR results were in favor of axi-cel, although not statistically significant (HR: 0.63 [0.37–1.06]). Compared to liso-cel, axi-cel was associated with a higher rate of grade ≥3 CRS (OR: 3.64 [1.04–12.76]) and grade ≥3 NEs (OR: 3.45 [1.65–7.19]), but differences were smaller in scenarios including the expanded safety management cohorts (OR: 1.71 [0.47–6.19] and 2.90 [1.54–5.47], respectively). Differences in OS and grade ≥3 CRS did not reach statistical significance in the scenario analysis. <h3>Conclusions</h3> Our findings suggest that axi-cel safety outcomes have improved over time, but grade ≥3 NEs remained higher than liso-cel. Although we found no difference in response rates, axi-cel showed higher OS and PFS.

CLL-115: First Results of a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia

Context: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib versus ibrutinib may improve tolerability. Objective: To compare acalabrutinib versus ibrutinib in patients with chronic lymphocytic leukemia (CLL). Design: Open-label, randomized, noninferiority, phase 3 trial. Patients: Previously treated CLL patients with del(17p) or del(11q) by central lab. Interventions: Oral acalabrutinib 100 mg twice daily (BID) or ibrutinib 420 mg once daily (QD) (stratified by del(17p) status, Eastern Cooperative Oncology Group performance status [2 vs ≤ 1], and number of prior therapies [1–3 vs ≥4]) until progression or unacceptable toxicity. Main Outcome Measures: Primary endpoint was progression-free survival (PFS), as assessed by independent review committee; secondary endpoints of all-grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order. Results: 533 patients (acalabrutinib, n=268; ibrutinib, n=265) were randomized (median age 66 years; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 months (range 0.0–59.1), acalabrutinib was noninferior to ibrutinib with a median PFS of 38.4 months in both arms (HR: 1.00; 95% CI: 0.79–1.27). Acalabrutinib was statistically superior to ibrutinib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among other secondary endpoints, incidences of grade ≥3 infection (acalabrutinib: 30.8%, ibrutinib: 30.0%) and Richter transformation (acalabrutinib: 3.8%, ibrutinib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR: 0.82; 95% CI: 0.59–1.15), with 63 (23.5%) deaths in the acalabrutinib arm and 73 (27.5%) in the ibrutinib arm. Among any-grade adverse events (AEs) in ≥20% of patients in either arm, acalabrutinib was associated with lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of acalabrutinib- versus 21.3% of ibrutinib-treated patients. Any-grade AEs of clinical interest that were less frequent with acalabrutinib included cardiac (24.1% vs 30.0%), hypertension (above), and bleeding events (38.0% vs 51.3%). Conclusions: In this first head-to-head trial of BTKis in CLL, acalabrutinib demonstrated noninferior PFS with less cardiotoxicity and fewer discontinuations due to AEs versus ibrutinib.

Lack of impact of type and extent of prior therapy on outcomes of mogamulizumab therapy in patients with cutaneous T cell lymphoma in the MAVORIC trial

Patients with mycosis fungoides (MF) and Sézary syndrome (SS) often require multiple lines of systemic therapy. In the phase 3 MAVORIC study (NCT01728805), mogamulizumab demonstrated superiority to vorinostat in median progression-free survival (PFS) and confirmed overall response rate (ORR) in patients with MF/SS. This post hoc analysis examined the effects of number and type of prior systemic therapies on mogamulizumab response. MAVORIC patients randomized to mogamulizumab (1.0 mg/kg intravenously weekly) or vorinostat (400 mg orally daily) were grouped by number of prior therapies and immunomodulatory activity of immediate prior systemic therapy while also considering time elapsed since treatment. ORR, PFS, and duration of response (DOR) did not vary with number of prior therapies. ORR and DOR remained consistent regardless of immediate prior therapy type. Additionally, immunomodulatory activity of the last prior therapy and time from prior treatment generally did not affect the ORR or PFS observed in response to mogamulizumab.

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer

Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC. To determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC. The Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021. Nivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects. The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Of 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P = .34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P = .09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab. In this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC. ClinicalTrials.gov Identifier: NCT02785952.

Ofatumumab, Very Late Antigen 4 (VLA4), and Dendritic Cells in Patients Undergoing Autologous Peripheral Blood Stem Cell (PBSC) Mobilization and Transplantation (ASCT) for Relapsed b-Cell Non-Hodgkin's Lymphomas (NHL)

▪Background: The in-vivo use of anti-CD20 monoclonal antibodies during PBSC mobilization has the potential to decrease the relapse rates following ASCT in patients with b-cell NHL (Khouri et al. J Clin Oncol 2005). We studied the feasibility of PBSC mobilization with G-CSF following ofatumumab with ifosfamide/etoposide (a standard chemo-regimen at our center). In addition to mobilizing CD34+ PBSCs, G-CSF mobilizes naïve T cells (CD3+ VLA4 low) and myeloid dendritic cells (mDC), as well as activates and matures the latter to become efficient antigen presenting cells. Patients and Methods: Eligibility criteria included patients with chemosensitive NHL with <5% marrow involvement at study entry, a platelet count of > 100,000/mm3 and an ANC > 1500/mm3. Ofatumumab was given at 1000 mg on day 1 and 2000 mg on day 8. Chemotherapy (days 2-4) and G-CSF were used per standard protocols at our center. Each patient provided a PB sample prior to mobilization and an aliquot of leukapheresis product (LP) after mobilization for detection of leukocyte subsets including T-, B-, - and DC-subsets, and VLA-4 and VLA-6 molecules on CD34+ PBSC by multicolor FACS analyses. Differences in values of leukocyte subsets between LP and PB were determined using the Wilcoxon Signed Rank test. Results: Fifty patients were studied; median age was 55 years (range, 25-70). Histologies included: diffuse large cell (n=33; 66%), including 9 double-hit; mantle cell (n=12; 24%) and indolent lymphoma (n=5; 10%). Median number of prior chemotherapies received was 2 (range, 1-5). Forty (80%) patients were in either first complete remission (CR1, n=18; 36%) or >CR1 (n=22; 44%); 9 (18%) in partial remission (5 of 7 were PET+), and 1 (2%) had stable disease. Forty-six (92%) patients mobilized PBSC after a median of 1.5 (range, 1-6) apheresis. Median WBC count at day one of collection was 17.7 k/μL (range, 3.6-52.3). Four (8%) patients failed collection of at least 2x106 CD34+cells/kg but then mobilized successfully after receiving Plerixafor. All patients were able to receive an ASCT. Median number of CD34 infused was 6.3 x10^6/kg (range, 3.2-16.9). Median times to recovery of ANC > 500/mm3 and a platelet count of >20,000/mm3 were 10 days (range, 9-12) and 12 days (range, 0-25), respectively, following transplantation. With a median follow-up time of 14.4 months (range, 1.2-50) post-transplant, the median overall survival (OS) and progression-free survival (PFS) rates have not been reached. The OS and PFS at the median follow-up time were 85% and 75%, respectively. Correlative studies have shown significantly higher percentages of CD3+ cells (82.2% vs. 74 % p<0.0001), CD4+ T cells (45.3% vs 34.2%; p<0.0001), and total DC (1.78% vs 0.41%; p<0.0001), in LP than paired PB samples, respectively. Differences in OS and PFS were evaluated for disease characteristics (histology, disease status, PET, number of prior therapies) and apheresis products. Whereas a significantly better OS rate was observed in patients who had apheresis products that contained naïve T cells (CD3+ VLA4 low) [p= 0.017 at the optimal cutoff value (figure) and 0.047 at the median], a better PFS was associated with apheresis products containing a higher percentage of mDCs (p=0.049). We were unable to confirm earlier reports of a positive association between the expression of VLA-4 on CD34+ CD38dim cells and time to engraftment.Conclusions:PBSC mobilization with ofatumumab is feasible with minimal toxicity, and resulted in a leukopheresis product with an increase in the recruitment of CD3+, CD4+ T cells, and DC, compared with levels in PB. Whereas superior OS is associated with naïve CD3+ VLA4 low T cells, better PFS was associated with higher percentage of mDCs. Since these observations were obtained with a small sample size, additional studies are warranted to validate our findings [Display omitted] DisclosuresKhouri:Novartis: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy.

Age Is Not Important for Autologous Peripheral Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Introduction: High-dose melphalan followed by autologous hematopoietic cell transplantation (auto HSCT) has become the standard procedure for patients with symptomatic multiple myeloma (MM). Retrospective analyses suggest that the benefit of HDT extends to elderly myeloma patients, which is an important finding considering that the median age at diagnosis is 69 years (range: 65-74) for MM in United States, using 2010-2014 US SEER data. The aim of our study was to determine the effect of age on stem cell collection and engraftment in patients with MM.Materyal and Methods: From January 2010 through April 2016, data from 260 myeloma patients below the age of 65 were compared to 41 myeloma patients above 65 years of age who were eligible for auto HSCT according to geriatric assessment (GA), depending on the results of IMWG report in 2015. All these data were obtained from the Ankara University Faculty of Medicine Center for Therapeutic Apheresis and written informed consent was signed according to our institution regulations. Mostly bortezomib based regimens were given as induction therapy to our patients. Ninety two percent of the patients received only GCSF at a dose of 5 µg/kg BW twice-daily s.c. until stem cell procurement. Patients underwent further PBSC collections until we obtained the target dose >20 CD34+ cells/µL blood. A maximum of 3 collections were performed in the first mobilization; if the cell dose was not achieved, we submitted patients to a second mobilization.Results: Forty-one of 301 patients were above 65 years of age (median age 68, range 65-75) and 260 patients were below the age of 65 (median age 56, range 29-64). Baseline characteristics of the older and younger patient cohorts are summarized in Table-1. The median follow-up was 48.5 months (range 1-90) for age <65 years old patients and 46 months (range 1-90) for age ≥65 years old patients. Mobilization regimens for the younger patient population were G-CSF only (n:241), cyclophosphamide based (n:12) and +plerixafor (n:7). Mobilization in the older population was with cyclophosphamide based (n:4), G-CSF only (n:36) and +plerixafor (n=1) in whom poor mobilization had been predicted. The chemotherapy regimens were not statistically different between both age groups (chi square p value 0.37). There were no significant statistical differences in time from diagnosis to mobilization, number of prior therapies or disease status between both patient groups. The number of CD34-positive circulating cells before scheduled leukapheresis was mean 23.26 cells/μL in all patients (including patients who failed mobilization). Neutrophil engraftment was seen faster in elderly group (mean 10.4±3.1 vs. 11.5±1.8; p=0.008) but platelet engraftment was similar compared the younger patients with older ones (Table-2). In The probability of 5-year progression free survival (PFS) and overall survival (OS) in elderly patients with ISS-3 was 82.4%±12.1% and 48.5±16.5%. No statistical significance was observed for mean estimated 5-year OS in terms of patient age (<65 and ≥65 years; 82.5%±2.8% and 74.3%±8.7% p=0.29) (Figure-1). Less relapse was occurred in elderly cohort (17.5% vs. 35.4%) but the number of patients in this group does not provide enough statistical power to confirm whether the differences in PFS were statistically significant.Conclusion: To date, accepted approach for elderly patients with MM is not only improving survival, also their quality of life. Based on this single center study, auto-HSCT is safe and efficient in the treatment of elderly myeloma patients but no statistical difference was demonstrated in respect to age groups. [Display omitted] DisclosuresIlhan:Novartis: Consultancy.

Evidence of Targetable Immune Dysfunction in the Bone Marrow of Patients with Intermediate/High-Risk Myelodysplastic Syndrome Refractory to Hypomethylating Agents

Background Growing evidence indicates that a dysfunctional adaptive immune response contributes to the pathogenesis of myelodysplastic syndrome (MDS). Intermediate/high (I/H)-risk MDS is associated with immunosuppression, and median overall survival in hypomethylating agent (HMA)-refractory patients (pts) remains poor at < 6 months. Thus, new immune checkpoint-targeting therapies may be important for restoring effective anti-tumor T-cell mechanisms in these pts. Here we aim to evaluate the relationship between immunomodulatory and regulatory targets in lymphocytes and CD34+ blasts, cytogenetics and prior treatment regimens to inform future novel immunotherapy combinations.Methods Bone marrow aspirates from HMA-refractory, I/H-risk pts (n = 18) and normal donors (NDs; n = 20) were assessed by flow cytometry (FC), immunohistochemistry and RNA sequencing (RNAseq). An independent cohort of treatment-naive, I/H-risk pts (n = 9) was assessed for regulatory T-cell (Treg) counts by FC. T-cell subsets (Treg, T-naive, T-effector memory, T-central memory, T-late effector memory) were identified by FC based on established markers (CD3, CD4, CD8, CD197, CD45RO, CD127, CD25, FOXP3). Activation/proliferation status of T-cell subsets was measured by HLA-DR and Ki-67. MDS blasts were identified by CD45, CD34 and CD117. Immune checkpoint markers programmed death-1 (PD-1) and programmed death-ligands 1 and 2 (PD-L1/2) were measured on T cells and CD34+ blasts. T-cell immunoglobulin and ITIM domain (TIGIT) was also measured on CD4 and CD8 T cells. T cells (CD4, CD8) and PD-L1 were identified in decalcified bone marrow biopsies by immunohistochemistry. Whole transcriptome gene expression analysis was performed using the Illumina TruSeq RNA Access Library Prep Kit on bulk bone marrow aspirates.Results T cells were detected in bone marrow aspirates from HMA-refractory, I/H-risk pts at levels comparable to those in NDs. Treg counts (cells/µL) were increased in HMA-refractory vs treatment-naive pts (P= 0.017), with the highest Treg count associated with complex cytogenetic karyotypes (≥ 3 abnormalities). We observed increased T-cell activation and proliferation in these pts compared with NDs (MDS vs ND medians [% positive cells]; HLA-DR−/Ki-67+: 1.23 vs 0.75; HLA-DR+/Ki-67+: 1.71 vs 0.33; HLA-DR+/Ki-67−: 14.14 vs 4.80). No trends were seen in CD4-naive and memory subsets, whereas CD8-naive cells were lower and late effector memory cells were higher than in NDs (P= 0.035 each). We observed higher expression of immune checkpoint and regulatory molecules (PD-L1, PD-1, TIGIT) in MDS except for PD-L2, which was minimally detected (< 5%). Frequency (%) of PD-L1 on CD34+ blasts was higher in pts with MDS than in NDs (P= 0.02) and was associated with complex karyotype (P= 0.026) and Treg frequency (P= 0.021). PD-1+ T cells were higher in pts with MDS than in NDs (CD4, P= 0.004; CD8, P= 0.012), with a trend toward increased PD-1 expression associated with number of prior therapies. TIGIT expression on CD4 T cells correlated with PD-1 (P= 0.008) and Treg frequency (P= 0.022). Lymphocyte-activation gene 3 expression by RNAseq was also higher in MDS vs ND marrow (P < 0.001). Some signals, such as PD-L1 and Tregs, correlated by FC and RNAseq.Conclusions Bone marrow in pts with I/H-risk MDS demonstrate evidence of prolonged T-cell activation, an increase in suppressive immune cell populations (i.e., Tregs) and expression of immune checkpoint molecules (PD-L1, TIGIT) compared with normal bone marrow. Patients with complex karyotype had subtle differences, potentially relevant for identifying subsets responsive to checkpoint inhibitors. These data provide new insight into the immune landscape of HMA-refractory I/H-risk MDS. DisclosuresGreen:Genentech, Inc.: Employment. Yan:F. Hoffmann-La Roche Ltd: Employment. Nalle:Genentech, Inc.: Employment; Roche: Equity Ownership. Ma:Genentech, Inc.: Employment. Robert:Genentech, Inc.: Employment. Zhong:F. Hoffmann-La Roche Ltd.: Employment. Krishnan:Genentech, Inc.: Employment. Phuong:Genentech, Inc.: Employment. Byon:Genentech, Inc.: Employment. Woodard:Genentech, Inc.: Employment, Equity Ownership. Adamkewicz:Genentech Inc.: Employment. Venstrom:Genentech, Inc.: Employment. Dail:Genentech, Inc.: Employment.

Collaborative Physician-Pharmacist Multiple Myeloma Clinic Improves Guideline Adherence and Prevents Treatment Delays

Although survival of patients with multiple myeloma (MM) has improved in the last decade, achieving optimal outcomes requires timely delivery of anti-myeloma therapy as well as adherence to supportive care guidelines and patient education. We hypothesized that a multidisciplinary approach of a collaborative physician-pharmacist MM clinic would have a positive impact on clinical measures such as guideline adherence as well as improve the workflow process and prevent treatment delays.From March 2014 to February 2015, we initiated a collaborative MM clinic at our institution, whereby in addition to normal physician care, a dedicated board-certified oncology pharmacist provided consultation on all new and continuing patients. The pharmacist provided education and medication lists, completed medication reconciliation, monitored for adherence and side effects, recommended management of toxicity and supportive care, and navigated issues involving enrollment and access to oral specialty medications. All consultations were documented in the patient's medical chart using a template addressing these key components. Outcomes were compared to those of patients being treated by the same physician during the previous year, when ad-hoc pharmacist consultation was available (traditional model). We compared clinical measures related to guideline adherence and analyzed delays in obtaining immunomodulator drugs (IMiDs) using available dispensing records.Patient characteristics were similar between the collaborative and traditional models including age, sex, race, ISS stage, protein subtype, treatment type, and prior number of therapies. During the 12-month study period when a collaborative model was implemented, 399 pharmacist consultations occurred during 551 physician visits (n=57 patients). During the prior year when a traditional model existed, there were 26 pharmacist consultations on 355 physician encounters (n=44 patients) (7.3% versus 72.4%, p<0.0001).We observed improved adherence to bisphosphonates (BP) in the collaborative clinic (55 (96%) versus 30 (68%) patients, p=0.0002). Among patients receiving BP, the time to initiation from diagnosis and re-initiation after autologous stem cell transplant (ASCT) was 5.5 versus 97.5 days (p<0.001) and 12.5 versus 135 days (p<0.001) among the collaborative and traditional clinic, respectively. One hundred percent of patients in the collaborative clinic versus 41% of patients in the traditional clinic received concomitant calcium and vitamin D (p<0.001). In patients receiving IMID-based regimens, appropriate VTE prophylaxis was prescribed in 52 (100%) versus 29 (76%) patients in the collaborative and traditional clinic, respectively (p<0.0002). Appropriate use of acyclovir prophylaxis in patients receiving proteasome inhibitor-based treatment was observed more frequently in the collaborative clinic (98% versus 56%, p=0.004). Although the number of patients receiving Pneumocystis Jirovecii pneumonia prophylaxis post-ASCT was similar (93 versus 100 percent, p=0.4), the time to initiation of prophylaxis was shorter in the collaborative clinic (11 versus 40.5 days, p<0.0001). Finally, influenza vaccination administration was higher in the collaborative clinic (76 versus 24 percent, p<0.001). When analyzing delays in obtaining IMiD therapy, we found that the median time from when the treatment plan was noted in the medical chart to when the IMiD was first filled was 7 (range: 0-32) vs. 15 (range: 3-62) days in the collaborative and traditional clinic, respectively (p=0.002). Finally, there was a significant reduction in treatment delays observed in the collaborative compared to the traditional clinic (21% vs. 85% of patients undergoing a delay, p<0.0001).Here we pilot a multidisciplinary approach that leads to increased guideline adherence and prevents delay in anti-myeloma treatment. The collaborative clinic model could be applied to several different practice sites in order to establish an improved and more systematic approach in the management of MM patients. Prospective studies analyzing clinical outcomes, patient satisfaction and cost effectiveness of this approach are warranted. DisclosuresWirth:Celgene: Consultancy, Honoraria. Patel:Celgene: Consultancy, Honoraria.

Retrospective Analysis of Adult Relapsed and Refractory Acute Leukemia Patients Treated with FLAG at a Comprehensive Cancer Center

IntroductionRelapsed and Refractory (R/R) Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) have poor outcomes. No uniform consensus has been made on a preferred treatment regimen for R/R AML & ALL. FLAG, comprised of fludarabine, cytarabine, granulocyte colony-stimulating factor (GCSF), with or without Idarubicin, is an induction and salvage chemotherapy regimen for these diseases. Studies reviewing FLAG-/+Ida are decades-old with small populations. CR rates in R/R-AML historically range from 52-63% and in R/R-ALL from 30-39%. Here, we retrospectively review the outcomes for R/R-AML/ALL patients recently treated with FLAG-/+Ida at the UC Davis Comprehensive Cancer Center (UCDCCC).MethodsAdult patients (≥18 years) with R/R-AML and R/R-ALL who received FLAG or FLAG-Ida from January 1, 2012 to October 31, 2016 were eligible. Patient charts were generated from a pharmacy electronic medical record report and retrospectively reviewed. Baseline data included demographics, performance status, number of prior therapies, disease status, and pre-treatment peripheral blood and marrow biopsy data, including cytogenetic and molecular studies. Disease status was defined as “relapsed” if patients experienced recurrence of disease after previously obtaining CR with another chemotherapy regimen and “refractory” if they failed to obtain CR with another regimen prior to receiving FLAG. Primary outcomes were complete remission (CR) and overall survival (OS). Secondary outcomes included overall response rate [ORR: defined as number of patients achieving CR plus CR with incomplete count recovery (CRi)], disease-free survival (DFS), and adverse events.ResultsOf the 57 patients identified, 42 had AML, 14 had B-Cell ALL and 1 had T-Cell ALL. The median age was 51 (range 22-74). Twenty-two (38.5%) patients were relapsed, 31 (54.4%) refractory, and 4 (7%) relapsed and refractory. The median number of chemotherapy regimens prior to FLAG was 2, with range from 1 to 5. Seventy-seven percent of patients had an ECOG score of 0 to 1 at treatment initiation. For AML patients, 4 (9.5%) were European Leukemia Network (ELN) Favorable Risk, 20 (47.6%) were ELN Intermediate-1, 15 (35.7%) were ELN Intermediate-2, and 3 (7.1%) were ELN Adverse Risk. No patients with ALL were Philadelphia chromosome positive, 10 (66%) were older than age 35, and 5 (33%) had a WBC count higher than 30k at start of therapy. For AML, responses were CR in 20 (47.6%), CRi in 5 (11.9%), and partial response in 1 (2.4%). In ALL, responses were CR in 7 (46.7%) and no patients achieved CRi or PR. ORR (CR+CRi) was 59.5% for AML and 46.7% for ALL. Ten (23.8%) patients with AML received FLAG within 100 days prior to allogeneic hematopoietic stem cell transplant (HSCT; n=3) or donor lymphocyte infusion (DLI, n=7). Two (4.8%) AML patients received FLAG within 100 days after HSCT. Two (13.3%) patients with ALL received FLAG within 100 days prior to HSCT(n=1) or DLI (n=1). Median OS in AML was 10 months and Median DFS was 8.8 months. When censored for HSCT, Median OS and DFS in AML were both 7.8 months. Median OS and DFS in ALL were both 4.7 months, and censoring for HSCT did not change this duration. Patients experienced the following notable adverse events: febrile neutropenia 40 (70.2%), culture-positive bacteremia 14 (24.6%), pneumonia 3 (5.3%), colitis 6 (10.5%), port/line infection 1 (1.8%), hemorrhage/thrombus/DIC 5 (8.8%), and renal injury 3 (5.3%). Eight died within 30 days (14%) and 5 additional died within 60 days (8.8%) of treatment. Three died within 1 day of treatment, respectively from intracranial hemorrhage, blast crisis, and DIC. One died of STEMI on day 26. The remaining 9 early deaths were attributed to febrile neutropenia with septic shock. The most common primary cause of death over the course of treatment was refractory leukemia, 30 (52.6%).ConclusionOutcomes of FLAG +/- Ida in patients with R/R-AML and R/R-ALL at UCDCCC are similar to historical controls, confirming its role as a salvage regimen in these poor risk patients. As expected, adverse events were common in this population, and comparable to historical controls. Although supportive care advances, such as improved treatments for infection, have been developed since earlier publications of the FLAG regimen, our study suggests treatment outcomes remain similar. This further encourages the investigation of novel regimens for relapsed and refractory AML and ALL. [Display omitted] DisclosuresRosenberg:Amgen: Speakers Bureau. Jonas:Rigel: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding.

Impact of Ibrutinib Dose Intensity on Patient Outcomes in Previously Treated Waldenström Macroglobulinemia

Introduction: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib recently became the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Temporary interruption of therapy is recommended to manage treatment-related toxicities and when patients undergo invasive procedures. However, the impact of interrupted therapy with ibrutinib has not been evaluated in patients with WM. We therefore examined the clinical implications of dose intensity in previously treated WM patients treated with ibrutinib in the multicenter phase 2 trial supporting regulatory approval.Methods: Patient charts were retrospectively analyzed and pertinent clinical data were collected surrounding ibrutinib drug holds. Treatment adherence to ibrutinib was documented during the clinical trial, and was measured by overall dose intensity (DIoverall). DI was defined as the proportion of administered versus planned doses from initiation of therapy until last dose received. Response was assessed based on current criteria. Time to events was estimated using the Kaplan-Meier method and comparisons between groups were made using the log-rank test.Results: Sixty-three patients with WM were enrolled and began therapy with ibrutinib 420 mg once daily. Fifty patients (79%) held ibrutinib at least once, and there were 102 drug-hold events in total. The median drug hold length was 6 days (range, 2-50 days). An increase in serum IgM level was observed on 63 occasions at the next response assessment after a drug hold. The median increase in serum IgM level was 50% (range, 4-555%), and 37 increases (59%) met criteria for progressive disease (PD). Following the reinitiation of ibrutinib, the median time to a response of stable disease (SD) or better was 125 days (95% CI 109-186 days) for patients who met PD criteria, and was significantly longer for patients with the MYD88MUTCXCR4WHIM versus MYD88MUTCXCR4WT tumor genotype (207 vs. 101 days; p<0.0001). The mean DIoverall was 97% after a median 3.9 years of ibrutinib therapy. Eighteen patients (29%) had a DIoverall below the mean (low DI), and 45 patients (71%) had a DIoverall above the mean (high DI). Patients with low DIoverall versus high DIoverall had no difference in age at ibrutinib initiation, sex, number of prior therapies, beta-2-microglobulin, serum IgM, hemoglobin level, bone marrow involvement, adenopathy, splenomegaly, and MYD88 and CXCR4 mutational status (p>0.05 for all comparisons). Overall PFS was significantly shorter in patients with low DIoverall versus high DIoverall (median, 22 months vs. not reached [NR]; p=0.008). The mean DIoverall for patients with MYD88MUTCXCR4WT (n=37), MYD88MUTCXCR4WHIM (n=21), and MYD88WTCXCR4WT (n=5) tumor genotype was 99%, 95%, and 99%, respectively. A subgroup analysis demonstrated a significant difference in PFS for MYD88MUTCXCR4WHIM patients with low DIoverall versus high DIoverall (median, 9.4 months vs. NR; p=0.0003), whereas no difference was observed in MYD88MUTCXCR4WT and MYD88WTCXCR4WT patients (p>0.05 for both comparisons). Twenty-five patients missed ³8 consecutive days of ibrutinib therapy. Among patients who held ibrutinib, those who missed doses for ³8 consecutive days experienced a shorter PFS compared to patients who missed <8 consecutive days (median, 35 months vs. NR; p=0.005). This was observed for patients with both the MYD88MUTCXCR4WT (median, 48 months vs. NR; p=0.01) and MYD88MUTCXCR4WHIM (median, 22 months vs. NR; p=0.03) tumor genotype. No patients with MYD88WTCXCR4WT held ibrutinib for ³8 consecutive days.Conclusion: Temporary interruption of ibrutinib therapy is associated with transient increases in serum IgM level which appear to persist longer for patients with the MYD88MUTCXCR4WHIM tumor genotype. Patients with DI higher than 97% had longer PFS, and holding ibrutinib >1 week during the entire treatment duration was associated with increased PFS events. These findings suggest ibrutinib holds should be minimized and ibrutinib restarted as soon as clinically indicated to achieve optimal patient outcomes. DisclosuresTreon:Pharmacyclics: Consultancy, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding.