ALBERT

Description: Background: Ibritumomab tiuxetan (IbT) is a radioimmunoconjugate linking rituximab with 90Y isotope. IbT is approved for treatment of relapsed/refractory indolent B-cell lymphomas, or for consolidation after chemotherapy in follicular lymphoma (FL), yet its use has been limited by concern about treatment-related myeloid neoplasms (tMDS/AML: acute myeloid leukemia and myelodysplastic syndrome). The risk of tMDS/AML may differ among older patients who experience significant competing mortality. Our objective was to use population-based data to examine real-life patterns of use of IbT, and associated incidence of tMDS/AML among older patients with B-cell lymphomas. Methods: From the SEER-Medicare registry, which covers about 28% of the United States population, we selected fee-for-service Medicare beneficiaries 〉60 years [y] old, with B-cell lymphomas diagnosed between 2001-2015, who received systemic therapy. We identified the use of IbT, purine analogues, alkylating agents, and rituximab. We defined tMDS/AML as myeloid neoplasms diagnosed 〉2 months from the start of first-line therapy for lymphoma, or use of tMDS/AML-directed chemotherapy. We estimated incidence rate and incidence rate ratio (IRR) for tMDS/AML after IbT exposure using a time-split survival model. By matching IbT recipients with non-recipients according to age, sex, lymphoma histology, and observation time from the start of lymphoma therapy, we compared the cumulative incidence function of tMDS/AML using competing risk models stratified by matched groups. We fitted the univariate model, and model adjusting for prior exposure to purine analogues or alkylators. Results: Among 43,945 Medicare beneficiaries (median age of 76 y) treated for diffuse large B-cell (DLBCL, 48%), FL (22%), mantle cell (7%), marginal zone (10%), or unspecified B-cell lymphoma (14%), 428 (1%) received IbT, at median 18 months from first-line chemotherapy (interquartile range [IQR], 8-34). IbT was used most frequently in FL (50%) and DLBCL (23%), and was applied as first-line treatment in 30 patients (7%). With median follow-up of 8.5 y, 618 cases of tMDS/AML were recorded (15 among IbT recipients, and 603 among non-recipients). Median latency from the start of first-line lymphoma therapy to tMDS/AML was 38 months (IQR, 18-65). The cumulative incidence rate of tMDS/AML after IbT exposure was 2.8% at 5y (95%CI, 1.2-4.4) and 3.9% at 10y (95%CI, 1.8-6.0). No tMDS/AML was observed among patients who received IbT as first-line treatment, before chemotherapy exposure. In the time-split survival analysis, the incidence of tMDS/AML was 0.39 per 100 person-years (95%CI, 0.18-0.60) without IbT exposure, and 1.02 (95%CI, 0.56-1.71) after IbT exposure, with an IRR of 3.22 (95%CI, 1.80-5.26). There was no significant heterogeneity in the IRR by lymphoma histology (Mantel-Haenszel test of homogeneity, P=.47). In the matched analysis (Fig A), the cumulative incidence of tMDS/AML was significantly higher among patients receiving IbT (subhazard ratio [SHR], 2.16; 95%CI, 1.32-3.55). However, the association became non-significant after adjusting for prior exposure to myelotoxic chemotherapy (SHR, 1.58; 95%CI, 0.93-2.68). Prior exposures to a purine analogue (SHR 3.83; 95%CI, 2.96-4.95) or an alkylator (SHR, 1.39; 95%CI, 1.11-1.75) remained significantly associated with increased risk of tMDS/AML. Median overall survival after tMDS/AML diagnosis was 0.6y (95%CI, 0.5-0.7), and it did not differ according to IbT exposure status (P=.62; Fig B). Conclusions: The cumulative incidence of secondary tMDS/AML in this large population-based cohort is similar to reports from clinical trials (Czuczman et al. J Clin Oncol. 2007), and lower than in some prior observational series (Epperla N, et al., Br J Haematol 2017). Our results support the use of IbT for older patients with indolent lymphomas. Exposure to IbT was associated with an increased incidence of tMDS/AML, but it was no longer significant after adjustment for prior exposure to myelotoxic chemotherapy. This result suggests that the increased incidence of tMDS/AML is a cumulative effect of IbT with other myelotoxic agents. Caution should thus be exercised when using IbT after exposure to chemotherapy. The fact that no tMDS/AML were observed in patients receiving IbT as first line therapy suggests that earlier use of IbT may be preferable from the point of view of the tMDS/AML risk. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding. OffLabel Disclosure: Ibritumumab tiuxetan - for treatment of any B-cell lymphoma in any setting

Description: Background: Among many causes of thrombocytopenia acquired during hospitalization, heparin-induced thrombocytopenia (HIT), an immune complex-mediated thrombogenic state with high morbidity and mortality, is one of the most feared etiologies. The clinical '4T' score is an established method to assess risk for HIT and guide immediate management(Lo, Juhl et al. 2006). However, the 4T score is not consistently used by clinicians, leading to potential over-testing and suboptimal management of suspected HIT. Our objective in this Quality Improvement (QI) project was to implement a mandatory 4T calculator (4TC) into the electronic medical record (EMR) to improve the positive predictive value of HIT antibody (HITA) testing, decrease the incidence of testing of low-risk patients, and to improve clinical management of suspected HIT. Methods: We developed a 4TC that assisted clinicians by integrating EMR-derived data on heparin exposure and the five most recent platelet counts with a link to an online calculator as well as clinical suggestions (Figure). As a part of this QI project, clinicians were required to enter the calculated 4T score before ordering a polyspecific HITA assay, which serves as the screening test for HIT in our institution. We reviewed laboratory records for all HITA tests performed over a six-month period, including 3 months before and after the implementation of a "hard stop" for HITA order in the EMR. We extracted data on the ordering hospital service team, 4T score documented in notes (if any), as well as quality of care indicators including rates of clinically recommended heparin cessation and initiation of alternative anticoagulation in the subgroup of patients with intermediate or high 4T score at the time of HITA order. In this QI project, we refrained from any statistical testing and summarized pre-specified outcome measures: incidence of HITA testing, positive predictive value of the HITA assay, and quality of care indicators. Results: We identified 99 (53 prior to the 4TC and 46 post) cases of HITA orders in the study period, among which there were 4 cases of confirmed HIT (either with positive IgG or positive serotonin-release assay [SRA]). Three HIT cases occurred after the 4TC was implemented. After the implementation of the 4TC, the positive predictive value for the HITA assay increased from 9% to 21%. The rate of clinically appropriate heparin order discontinuation increased from 72% to 88%, as did the initiation of alternative anticoagulation from 14% to 27%. HITA assay was most commonly ordered by the internal medicine service (35% of tests), non-cardiac intensive care service (30%), coronary care and cardiothoracic surgery services (21%), neurology (5%), and general surgery/other services (9%). Implementation of the 4TC did not significantly change this distribution, but the overall incidence of HITA orders decreased from 4.0 to 3.4 per 1000 admissions. We observed a high frequency of confirmatory SRA testing requested (18%), which is the reflex confirmatory test performed at our institution, even in cases of negative polyspecific HITA or HIT IgG. Conclusions: Addition of a 4T score calculator into the EMR which provides immediate feedback on patient's prior heparin exposure and recent platelet counts allows clinicians to consistently use the 4T score when considering HIT. Importantly, it also helps to educate non-hematologists on the proper management of HIT. Improved predictive value of the HITA assay suggests that our 4TC led to ordering HITA in a more appropriate patient population. We also demonstrated improved quality of care for suspected HIT, with increased rates of heparin cessation and initiation of alternative anticoagulation in patients with intermediate or high pre-test probability. Identifying clinical teams that order a disproportionate number of HITA assays will help us to direct education to improve clinical management. This QI project has led to other areas of improvement, particularly with regard to rational ordering of the SRA. At only three months of review since implementation of the 4TC, we have noted an improvement in the management of suspected HIT and a slight reduction in the incidence of testing. With continued review, we hope to demonstrate further improvement, as practitioners continue to use the 4TC and rely on clinical rationale rather than reflexive laboratory testing when evaluating thrombocytopenia in the hospital. Disclosures Olszewski: TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding.

Description: Background: Nodal and splenic marginal zone lymphomas (NMZL/SMZL) are rare, usually disseminated, and typically diagnosed in older patients (median age 69 years). They are increasingly treated with first-line bendamustine/rituximab (BR) based on phase 3 trials that pooled various B-cell indolent lymphomas (Rummel et al., Lancet 2013). However, NMZL and SMZL have unique biology and clinical course. In this context, without histology-specific evidence, the risk/benefit ratio of BR over single-agent rituximab (R) in SMZL/NMZL is uncertain. Our objective was to examine treatment patterns, and to compare survival and toxicity outcomes of BR versus (vs.) R, using population-based data. Methods: Using Medicare claims linked to cancer registry data covering ~34% of the US population (SEER-Medicare), we identified all SMZL/NMZL patients age ≥65 who received 1st line R or BR between 2009-2016 (after approval of bendamustine) and had complete Medicare records. We used a propensity score to generate "pseudo-randomized" cohorts (pooled, including NMZL and SMZL, and histology -specific for NMZL and SMZL), balancing patient and disease characteristics: age, sex, race, comorbidities (including kidney disease and heart failure), performance status, lymphoma stage, B symptoms, prior splenectomy, anemia (including autoimmune hemolytic), transfusions, hospitalizations, and time from diagnosis to therapy. In the balanced pseudo-randomized cohorts, we compared event-free survival (EFS, defined as 2nd line chemotherapy, splenectomy, hospice, or death) and overall survival (OS) from the start of therapy, risk of major toxicities (hospitalization, transfusions), and inflation-adjusted Medicare spending. Outcome models report hazard ratios (HR) or risk ratios (RR) with 95% confidence intervals (95%CI), and marginal means for costs. Results: Among 1,315 patients (901 with NMZL and 414 with SMZL), median age was 78 years [y], and there were 52% women. About half of patients received first-line R every year, but the proportion treated with BR increased from 4% in 2009 to 23% in 2016 (Fig. A). In the pooled NMZL/SMZL cohort of patients receiving BR or R (N=926), those treated with BR were on average younger, more likely to have NMZL, stage 2-4 lymphoma, and B symptoms. With median follow-up 3.8 y, median EFS was 4.3 y (95%CI, 3.5-5.1) for NMZL, and 4.5 y (95%CI, 3.8-6.5) for SMZL. Median OS was 5.7 y (95%CI, 4.9-6.7) in NMZL, and 5.2 y (95%CI, 4.4-6.7) in SMZL. After balancing the confounders, there was no significant difference in either EFS (HR for BR, 1.00; 95%CI, 0.76-1.30, P=.98) or OS (HR, 1.14; 95%CI, 0.85-1.53; P=.38). Toxicities were higher with BR, including hospitalizations (RR, 1.46; 95%CI, 1.14-1.87; P=.003) and transfusions (RR, 2.35; 95%CI, 1.55-3.56; P

Description: Background: CNS involvement in aggressive lymphomas (including diffuse large B-cell lymphoma, DLBCL) is associated with poor survival, requiring aggressive CNS-directed therapy to avert dismal outcomes. Early detection of clinically occult CNS invasion is thus critical. Clinical risk factors have low specificity to select patients for CNS prophylaxis, and routine evaluations of the CSF by cytology or flow cytometry have low sensitivity (Doolittle et al., Blood 2008). Moreover, most CNS recurrences of DLBCL occur in the brain parenchyma and remain occult on CSF examination. There is a high unmet need for an accurate method to identify subclinical CNS invasion and help non-invasively diagnose parenchymal disease. Clonotype-specific cell-free DNA (cfDNA) can be detected in the plasma of patients with DLBCL using high-throughput sequencing (HTS) combined with multiplex PCR, and cfDNA reappearance after therapy precedes systemic recurrence (Roschewski et al., Lancet Oncol. 2015). However, clonotypic cfDNA has not been systematically evaluated in the CSF compartment. Because of the blood-brain barrier that isolates CSF from plasma, clonotypic cfDNA might hold promise as a sensitive method of CNS lymphoma detection. Therefore, we sought to evaluate the ability of HTS-based cfDNA assay in the CSF to detect CNS invasion. Methods: We collected CSF samples from consenting patients with aggressive lymphomas who either had clinically overt CNS disease, or who were newly diagnosed and without evident CNS disease, but at high clinical risk. Genomic DNA from primary tumors (formalin-fixed paraffin-embedded [FFPE] tissue; Fig. A) was analyzed for tumor-specific clonotype using a quantitative HTS of rearranged IGK, IGH (VJ or DJ), or IGL loci, as previously described (Carlson CS et al., Nat Commun. 2013). Clonotypes in each primary tumor were selected for subsequent tracking in the CSF based on frequency relative to other B cells and all nucleated cells, as well as distribution. HTS of B-cell receptor (BCR) was performed on 5 mL CSF centrifuged at 1000x for 5 min at 4°C and separated into acellular portion for cfDNA, and a cell pellet suspension. Clonotype copy numbers are expressed per mL for acellular fluid, and per 106 cells for cell pellets. Results: The HTS assay identified median 3 (range, 2-6) dominant immunoglobulin sequences in each primary FFPE lymphoma sample (N=9), with median dominant clonotype frequency 39.0% (range, 22.0-97.9%) and median copy count 753,618 per 106 cells (range 47,455-1,407,748). In the CSF, the HTS/ASO-PCR assay detected the dominant clonotype in 5 out of 9 samples (Table), including all cases (N=3) with overt CNS disease, and 2 without known CNS invasion (sensitivity=100% and specificity=67% for clinically overt disease). Of note, the cfDNA assay detected tumor-specific clonotype in the CSF of a patient with primary CNS lymphoma (PCNSL) who had negative CSF evaluations by flow cytometry and IGH PCR. In the cell-free CSF, median detectable cfDNA clonotype copy count was 1,649/mL (range, 2-5,620), and in the CSF cell suspension it was 389,558 per 106 cells (range, 10,373-1,181,171). Copy counts were significantly higher (P=.004 for cfDNA in CSF fluid, P=.004 for cell suspension) in patients with overt leptomeningeal involvement (positive CSF cytology) than those with parenchymal or clinically occult disease (Fig. B). The 2 cases with positive CSF cfDNA but negative clinical staging and CSF cytology were notable for high risk of CNS dissemination due to ruptured epidural tumor with spinal cord compression, or double-hit histology (MYC-IGH and BCL2-IGH rearrangements) with extensive extranodal invasion of kidneys, pleura, and liver. Both patients were recommended CNS-directed prophylaxis based on clinical risk. Conclusions: HTS of BCR loci in the CSF of patients with aggressive lymphomas can identify intraparenchymal CNS or leptomeningeal disease with high sensitivity. More importantly, it can detect intraparenchymal involvement not identifiable using traditional means of CSF analysis (flow cytometry, standard IGH PCR). Detection of cfDNA in CSF of some high-risk patients without overt CNS disease will be further explored in a larger sample. It suggests that pre-treatment HTS of BCR loci could be prospectively tested to predict the risk of CNS recurrence, with a future potential to enable more sensitive and specific selection of patients for CNS prophylaxis therapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Research Funding. Reagan:Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Mullins:Adaptive Biotechnologies: Employment.

Description: Background: Recent studies (Maurer et al., JCO 2018, Olszewski et al., BJH 2018) have identified short diagnosis-to-treatment interval (DTI) of less than 15 days as a high-risk feature in B-cell lymphomas, independently of other clinical factors. T-cell lymphomas (TCL) pose a challenge because of their heterogeneity, rarity, and poor outcomes. Patients who respond to initial induction chemotherapy frequently proceed to consolidative high-dose chemotherapy with stem cell transplantation (SCT). Our objective was to examine the association between short DTI, receipt of SCT, and survival in 4 most common types of aggressive NK/TCL: peripheral TCL not otherwise specified (PTCL), angioimmunoblastic TCL (AITL), anaplastic large-cell TCL (ALCL), and extranodal NK-/T-cell lymphoma, nasal type (ENKTL). Methods: From the National Cancer Data Base, a registry containing 〉80% of lymphomas diagnosed in the US, we selected patients age 18 to 70, diagnosed with PTCL, AITL, ALCL, or ENKTL in 2004-2014, who received multi-agent chemotherapy within 120 days of diagnosis. Short DTI was defined as less than 15 days from diagnosis to start of chemotherapy. We analyzed the use of SCT as part of first course of treatment (before relapse) in a hierarchical logistic model adjusting for age, sex, race/ethnicity, TCL histology, stage, extranodal origin, and type of hospital (academic or community), reporting adjusted odds ratios (OR) with 95% confidence intervals (CI). Overall survival (OS) from start of chemotherapy was examined using Cox models adjusting for the same variables, reporting adjusted hazard ratios (HR). To investigate the differential impact of early mortality, we conducted sensitivity analyses in pre-specified subgroups excluding patients who died within 3 or 6 months of starting chemotherapy, and in the subset who underwent SCT (after presumably favorable response to initial chemotherapy). Results: Among 8,194 patients (Table; median age 54 years, 38% women), median DTI was 22 days (interquartile range, 11 to 38). The proportion undergoing SCT (11% overall) varied by histology, and was higher in academic centers (17%) compared with other types of hospitals (7%, P3 months from the start of chemotherapy (OR, 0.78; 95%CI, 0.65-0.94, P=.012). With a median follow-up of 10.1 years, survival varied by histology, and was significantly worse for patients with short DTI in PTCL, ALCL and ENKTL, but not in AITL (Fig. A-D). Worse prognosis with short DTI persisted in the subsets patients who survived 〉3 months (overall HR, 1.32; 95%CI, 1.14-1.33; P6 months (overall HR, 1.14; 95%CI, 1.04-1.25; P=.005) from the start of chemotherapy. However, in the subgroup of patients who successfully underwent SCT, a short DTI was no longer prognostic (Fig. E; HR, 0.91; 95%CI, 0.66-1.26; P=.57). Conclusions: Patients with TCL who need to start chemotherapy within 15 days of diagnosis have a lower likelihood of undergoing subsequent SCT. This association is not fully explained by early mortality, and may reflect a more aggressive biology, including worse response to standard chemotherapy-a hypothesis supported by the fact that achievement of SCT nullifies the poor prognostic value of short DTI. Short DTI is thus a novel risk factor in TCL that identifies a high-risk population well suited to experimental treatment strategies, and clinical researchers should strive to enroll these patients. Outcomes from clinical trials in which subjects start therapy after a screening period lasting 〉15 days from diagnosis should not be uncritically extrapolated to patients who start urgent chemotherapy in general practice. Further research should examine molecular characteristics and response rates to chemotherapy among patients with TCL who require immediate treatment upon diagnosis. Disclosures Reagan: Takeda Oncology: Research Funding; Alexion: Honoraria; Pfizer: Research Funding. Olszewski:Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding.

Description: Background: Allogeneic stem cell transplant (allo-SCT) is a cornerstone in the treatment of Acute Myeloid Leukemia (AML) exerting much of its therapeutic efficacy through the graft-versus-leukemia effect. The administration of immunoregulatory cells via engrafted donor lymphocytes is essential to the eradication of residual malignancy and long-term survival. Many patients, however, either do not have an allo-SCT donor or cannot withstand the toxicity of allo-SCT. Previous studies have shown durable responses in AML patients following donor lymphocyte infusions in the absence of engraftment in both the frontline and relapsed setting (Dey et al, BJH 2005, Colvin et al, BBMT 2009, Ai et al, Blood 2010). In this clinical trial we propose a role for donor leukocyte infusions (DLI) in the absence of engraftment. Without the need for engraftment patients will not need to receive high dose chemotherapy or radiation and the toxicities that accompany these therapies. Instead, allogeneic donor cells are infused into patient with relapsed/refractory (R/R) AML to serve as a potent immune stimulator. Prior to DLI, patients will receive fractionated dosing of gemtuzumab ozogamicin (GO). GO is an anti-CD-33 antibody drug conjugate approved in combination with induction therapy for de novo AML and in R/R disease. Patients who demonstrate a CR or CRi to therapy will go on to have up to 2 additional GO + DLI treatments. Bone marrow and blood samples will be obtained from patients before, during, and after treatment to determine immune effector cells (both donor and patient), cytokine release profiles, and extracellular vesicle components. Study Design and Methods: Our study, BrUOG 345 [NCT03374332], evaluates the combination of fractionated GO with non-engraftment DLI in the treatment of patients with R/R AML. Adults patients 18 years of age and older with histologically confirmed R/R AML who have had recurrence or progression after at least 1 prior standard treatment are eligible. Enrollees must have no active systemic infections and have adequate lung, liver, cardiac, and renal function with an ECOG PS 0-1. Fractionated GO 6-9mg/m2 will be administered on days 1, 4, and 7 followed by infusion of 1-2x108 CD3 cells/kg from a 0-3/6 HLA mismatched related donor cell. Patients that are in CR or CRi can receive up to 2 additional treatments with GO+DLI (Figure 1). The primary objective of the phase 1 portion is to determine the maximum tolerated dose (MTD) of DLI in combination with GO while the primary objective of Phase 2 portion is to assess the response rate after one cycle of fractionated GO followed by non-engraftment DLI in patients with relapsed/refractory AML. The study will initially utilize a 3+3 design in Phase 1 to determine if 1-2x108 CD3 cells/kg can be safely administered with GO. This study will target a response rate of 57% considered to be interesting enough to warrant further study in a randomized setting. With this hypothesis in mind, the phase 2 portion of the study will use Simon's two-stage design. The null hypothesis that the true response rate (CR and CRi) is only 29% will be tested against a one-sided alternative. In the first stage, 9 subjects will be accrued. Patients treated at MTD in the Phase 1 portion of the study will be included in this cohort. If there are 3 or fewer responses in these 9 patients, the study will be stopped for futility. Otherwise, 6 additional subjects will be accrued for a total of 15. The null hypothesis will be rejected if 7 or more responses are observed in 15 patients. This design yields a type I error rate of 0.1 and power of 80% if the true response rate is 57%. A continuous assessment of toxicity will be utilized for the Phase 2 portion of this study. Sequential boundaries will be used to monitor dose-limiting toxicity rate for patients after the initial MTD is determined. Accrual will be halted if excessive numbers of dose-limiting toxicities are seen. The primary outcome of the Phase 2 portion is the CR/CRi rate following GO and non-engraftment DLI. Secondary outcomes will include survival, both progression-free (PFS) and overall (OS) until two years post treatment, and dose limiting toxicities until 16 weeks post-infusion. Additional lab correlative studies will be performed including CD33 expression before, during, and after GO infusion and T-cell activation markers, antigen presenting cell/macrophage amounts, cytokine release profiles, and extracellular vesicle measurements (Figure 1). Disclosures Olszewski: TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Research Funding. Reagan:Pfizer: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

Description: Background: The combination of bendamustine and rituximab (BR) is frequently used as treatment for indolent B-cell lymphomas (iBCL; Rummel et al, Lancet 2013; Olszewski et al, Am J Hematol 2019). Its relatively low adverse effect profile and lack of overlapping toxicities suggest the potential for adding vincristine - another highly active anti-lymphoma agent. However, a prior trial found high rates of thrombocytopenia when standard vincristine was combined with full-dose bendamustine (Herold M, et al. J Cancer Res Clin Oncol. 2006). VSLI is a liposome-encapsulated formulation of vincristine designed to improve its activity, therapeutic index, and pharmacokinetic profile. VSLI at an uncapped dose of 2.0 mg/m2 has been successfully combined with cyclophosphamide, doxorubicin, and prednisone (Hagemeister et al., Br J Haematol 2013). The objective of this phase 1 study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of VSLI in combination with standard doses of BR for treatment of iBCL. Methods: Patients with iBCL otherwise appropriate for BR therapy were eligible for this phase 1 study. Bendamustine was given at 90 mg/m2 on Day 1, 2, and rituximab at 375 mg/m2 on Day 1 of each 28-day cycle, for 6 cycles. VSLI was given on Day 2 of each cycle at a patient-specific dose ranging from 1.8 mg/m2 up to maximum 2.3 mg/m2, as determined by the Escalation with Overdose Control (EWOC) model-based design (Babb et al., Stat Med, 2001). EWOC allows for rapid identification of the MTD using a small sample size and single-subject dose cohorts. Model parameters for this study included target probability of DLT (q) of 0.33 and starting probability of exceeding MTD (a) of 0.25. There was no intra-patient dose escalation. Simulations indicated that n=10 subjects would be sufficient to determine the MTD, and this sample size was set for the study by design. MTD was defined as median of the Bayesian 95% confidence interval (CI) for the VSLI dose, calculated from the model at the end of the study. DLT was defined during cycle 1 only, as grade (G) 4 neutropenia lasting 〉7 days (or G3 with fever / infection), G4 thrombocytopenia (or G3 requiring transfusion), or any G3/4 non-hematologic toxicity. Secondary objectives included cumulative rates of adverse effects (AE, particularly VSLI-related neuropathy), completion rate of 6 cycles of therapy, overall response rate (ORR), and complete response (CR) rate. This study (BrUOG-326) was conducted by Brown University Oncology Research Group (BrUOG) and registered on clinicaltrials.gov as NCT02257242. Results: Ten patients received BR+VSLI as first-line therapy. The VSLI dose was escalated from 1.80 to 2.24 mg/m2 (see Table). Median age was 59.5 years; there were 6 (60%) women. Patients had follicular (n=4), marginal zone (n=3), mantle cell (n=2), and small lymphocytic lymphoma (n=1). There was 1 observed DLT (G3 ileus) at VSLI dose 2.04 mg/m2. So far, six patients have completed 6 cycles of BR+VSLI, while two discontinued VSLI and continued on 6 cycles with BR alone (one for DLT in cycle 1, and one for G2 neuropathy after cycle 3). The most common AE included lymphopenia (100%), constipation (60%), nausea, infusion reaction, neutropenia (each 50%), and peripheral neuropathy (40%). The only G3/4 AE were lymphopenia (90%), neutropenia (20%) and ileus (10%). Four patients developed neuropathy: two G1 and two G2. Only one patient (10%) had treatment-related rash (G2 during cycle 5). Using data from all 10 subjects, the MTD for VSLI in combination with BR was estimated to be 2.25 mg/m2 (Bayesian 95% CI, 2.00-2.40 mg/m2). All patients who completed therapy (n=8) achieved a response, with 50% achieving CR at the end of therapy (i.e. after 6 cycles of BR+VSLI or BR if VSLI was discontinued early). With median follow-up 18 months (range, 2-29), one patient experienced recurrence of a blastoid mantle cell lymphoma, while others remain in remission (see Figure). Estimated 2-year progression-free survival is 80.0% (95% CI, 20.4-96.9%), and all patients remain alive. Conclusions: VSLI at 2.25 mg/m2 can be safely combined with BR as first-line treatment for iBCL. In this study, the efficient phase 1 EWOC design enabled MTD determination for VSLI in a small cohort. Considering low rate of G3/4 toxicity, BR+VSLI may provide a platform for further combinations in treatment of B-cell lymphomas (including with an anthracycline for aggressive NHL). Disclosures MacKinnon: Brown University Oncology Research Group: Current Employment. Margolis:Brown University Oncology Research Group: Current Employment. Olszewski:TG Therapeutics: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; Spectrum Pharmaceuticals: Research Funding. OffLabel Disclosure: Vincristine sulfate liposome injection (Marqibo) is indicated for the treatment of adult patients with Philadelphia chromosomeâ€'negative (Phâ€') acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following 2 or more anti-leukemia therapies. Bendamustine is indicated for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Description: Introduction: Treatment of older patients (pts) with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). The optimal induction CT and consolidation regimens for older PCNSL pts is unknown. Moreover, there are few large scale prognostication studies available, including analysis of geriatric assessments (GA). We analyzed detailed characteristics, treatment patterns and outcomes with prognostication across 17 academic centers. Methods: We conducted a large, RW retrospective study of newly diagnosed PCNSL pts (1/2008-1/2019) ages ≥ 60 years (yrs). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. We detailed Cumulative Index Rating Scale-Geriatric (CIRS-G) scores & other GAs. Univariate associations were derived via Cox model with variables p