Multiple Lines Of Therapy Research Articles

Treatment patterns, healthcare resource utilization, and costs of patients diagnosed with primary mediastinal B-cell lymphoma in the United States

Aims With the advent of ICD-10-CM codes for PMBCL on 10/01/2015, assessment of treatment patterns and healthcare burden among US patients is possible. This study sought to describe the real-world treatment patterns and economic outcomes of patients with PMBCL. Methods Data from the Optum Clinformatics DataMart database was used (January 2013–March 2018). Patients with a first PMBCL ICD-10-CM diagnosis (with or without an antecedent ICD-10-CM diagnosis of DLBCL/other lymphoma, which may have been assigned before PMBCL confirmation) after 10/01/2015 (index date) and no ICD-9-CM diagnosis code for unspecified PMBCL/DLBCL were identified as incident patients. Those with PMBCL ICD-10-CM and unspecified ICD-9-CM diagnosis for PMBCL/DLBCL before 10/01/2015 (index date) were identified as prevalent patients. Patients were observed from the index date up to the earliest among death, end of data availability, or end of continuous health plan enrollment. An adapted algorithm was used to identify lines of therapy (LOT). Results Among 118 incident and 30 prevalent PMBCL patients, 14% and 20% of patients received ≥2 LOTs, respectively. In incident patients, 48% received ≥1 LOT, 14% ≥2, and 4% ≥3 LOTs. Among prevalent patients, 63% received ≥1 LOT and 20% ≥2 LOTs. The most frequently recorded 1 L therapy was R-CHOP both among incident and prevalent patients. Mean total healthcare costs for incident and prevalent patients were $149,340 and $92,799 per patient per year, respectively, with higher costs ≤12 months ($187,241 and $167,553). Outpatient costs were the main driver (accounting for 60.5% and 64.6% for incident and prevalent patients, respectively). Limitations Potential underuse of ICD-10-CM codes shortly after discontinuation of ICD-9-CM codes in 01/2015; regimens identified for each LOT using the claims-based algorithm may not reflect the regimen administered. Conclusion The multiple LOTs necessary for a sizeable minority of patients and the high costs of care highlight the significant unmet needs of PMBCL patients.

Tolerance to Bone Marrow Transplantation: Do Mesenchymal Stromal Cells Still Have a Future for Acute or Chronic GvHD?

Mesenchymal Stromal Cells (MSCs) are fibroblast-like cells of mesodermal origin present in many tissues and which have the potential to differentiate to osteoblasts, adipocytes and chondroblasts. They also have a clear immunosuppressive and tissue regeneration potential. Indeed, the initial classification of MSCs as pluripotent stem cells, has turned into their identification as stromal progenitors. Due to the relatively simple procedures available to expand in vitro large numbers of GMP grade MSCs from a variety of different tissues, many clinical trials have tested their therapeutic potential in vivo. One pathological condition where MSCs have been quite extensively tested is steroid resistant (SR) graft versus host disease (GvHD), a devastating condition that may occur in acute or chronic form following allogeneic hematopoietic stem cell transplantation. The clinical and experimental results obtained have outlined a possible efficacy of MSCs, but unfortunately statistical significance in clinical studies has only rarely been reached and effects have been relatively limited in most cases. Nonetheless, the extremely complex pathogenetic mechanisms at the basis of GvHD, the fact that studies have been conducted often in patients who had been previously treated with multiple lines of therapy, the variable MSC doses and schedules administered in different trials, the lack of validated potency assays and clear biomarkers, the difference in MSC sources and production methods may have been major factors for this lack of clear efficacy in vivo. The heterogeneity of MSCs and their different stromal differentiation potential and biological activity may be better understood through more refined single cell sequencing and proteomic studies, where either an “anti-inflammatory” or a more “immunosuppressive” profile can be identified. We summarize the pathogenic mechanisms of acute and chronic GvHD and the role for MSCs. We suggest that systematic controlled clinical trials still need to be conducted in the most promising clinical settings, using better characterized cells and measuring efficacy with specific biomarkers, before strong conclusions can be drawn about the therapeutic potential of these cells in this context. The same analysis should be applied to other inflammatory, immune or degenerative diseases where MSCs may have a therapeutic potential.

The Addition of IMiDs for Patients with Daratumumab-Refractory Multiple Myeloma Can Overcome Refractoriness to Both Agents

Introduction: Treatment options for patients with myeloma (MM) expand but development of refractoriness to major drug classes is inevitable in most patients. Management of disease refractory to proteasome inhibitors, IMiDs and antiCD38 monoclonal antibodies is challenging; but there is data to support that some drug combinations provide benefit even when there is resistance to individual drugs. This has been observed with anti-CD38-IMiD combinations and we have previously reported data in patients who have responded to the daratumumab-IMiD combination post refractoriness to both drug classes. These results may be related to the mechanisms of action of daratumumab, it acts both directly and through antibody mediated cytotoxicity, phagocytosis and immune modulation and of IMiDs which also enhance natural killer cell cytotoxicity and modify the immune microenvironment. Other mechanisms may also be involved but we need more clinical and biological data to understand this phenomenon. We present our experience with consecutive patients who were refractory to IMiD combinations and single agent daratumumab, who were retreated with the IMiD and daratumumab, following development of resistance to daratumumab. Methods: A total of 27 consecutive patients who were refractory to an IMiD (lenalidomide or pomalidomide) and progressed on single agent daratumumab, were enrolled. The more recent IMiD to which the patients were refractory prior to daratumumab treatment was added to daratumumab, without any intensification of either schedule (RESET). All patients were treated in the Department of Clinical Therapeutics, in Athens. Results: The median age was 74 years (range 52-86) and 70% were male. The median number of treatment lines prior to RESET was 4 (range 1-16). Eleven patients (41%) had undergone ASCT/HDM. All patients had previously received bortezomib and 60% were refractory, 37% (n=9) were carfilzomib-exposed and 30% refractory, 30% (n=8) were Ixazomib-exposed and 26% refractory; 82% had alkylating agent exposure and 52% were refractory. All patients had prior exposure and 93% of them were refractory to lenalidomide, while 52% (n=14) were pomalidomide-exposed and 48% refractory. The regimen prior to daratumumab monotherapy was IMiD-based in 48% (n=13), PI-based in 26% (n=7), both IMiD & PI containing in 18.5% (n=5), and other in 7% (n=2). At RESET, the IMiD added was lenalidomide in 48% (n=13) and pomalidomide in 52% (n=14). Median time from diagnosis to RESET was 72 months (25.6-135.3). The median time from the last IMiD dose to RESET was 13.2 months (2.13-41.3). The median duration of daratumumab monotherapy prior to RESET was 7.57 months (range 1.61 to 38.2) and the best response achieved was VGPR in 41% , PR in 33.3% a PR and 25.8% had stable disease, prior to progression. Median duration of treatment in RESET was 5.3 months (0.46 to 22.33) and best response distribution was VGPR in 7.4% (n=2), PR in 33.3% (n=9), for an ORR of 41% (n=11). Currently, 9 (33%) patients still receive treatment at RESET and 18 (67%) have progressed. Median PFS in RESET was 8.9 months (95% CI 4-13.7) and the median OS from start of RESET was 20 months (95% CI 6.4-33.6). Both PFS and response to RESET were independent of the type of IMiD added, whether IMiD at most recent line or added at RESET was administered at full or reduced dose, and the dose of dexamethasone at last regimen, Prior response to daratumumab monotherapy or to the most recent IMiD-based regimen and the median number of prior treatment lines also did not affect PFS or response at RESET. Following progression at RESET, 11 patients have received further therapy; the median number of treatment lines post RESET was 2 (1-5). Two patients responded to the subsequent therapy (at least PR). Conclusion: The combination of daratumumab with an IMiD can partly overcome resistance to both agents, even without intensification of either schedule. Importantly, this combination was associated with a 40% ORR and a PFS of 8.9 months, which is quite promising given the advanced refractoriness of these patients to individual treatments. These data also indicate the potential of an anti-CD38 backbone as part of a treatment strategy that extends over multiple lines of therapy, which should be explored in larger prospective trials. Our group is now investigating the impact of individual drugs and their combination to further understand the modulation in the immune environment. Disclosures Gavriatopoulou: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Terpos:Celgene: Honoraria; Medison: Honoraria; Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

Successful Manufacturing of CAR T-Cells with Small Volume Peripheral Blood from Healthy Donors Using the Clinimacs Prodigy Device

Introduction In recent years, CAR T-cell therapy has emerged as a potentially curative intent treatment for some patients with relapsed, refractory hematologic malignancies. Despite the exciting results, not all patients are able to receive CAR T-cells due to manufacturing failures. T-cells for CAR products are typically autologous and isolated from heavily pre-treated patients, which might account for some of the manufacturing failures and suboptimal clinical efficacy. T-cells collected either early into cancer diagnosis or prior to diagnosis may improve CAR T-cell expansion and limit manufacturing failure. We evaluated the feasibility of generating a CAR T-cell product manufactured from 50 ml of healthy donor blood. Methods Collaborators at Cell Vault collected 50 ml of whole blood from 3 healthy donors, isolated peripheral blood mononuclear cells (PBMCs), and cryopreserved the cells in cryovials at 5e6/vial (1.05-1.35e8 total cells). The vials were shipped to the Medical College of Wisconsin and stored frozen in liquid nitrogen until use. All PBMC vials for a given donor were thawed and pooled. Thawed PBMCs (0.93-1.17e8 cells) were loaded onto a CliniMACS Prodigy device, CD4 and CD8 T cells enriched by immunomagnetic sorting, and T cells placed in the culture chamber with IL-7, IL-15 and TransAct reagent to induce proliferation. On the second day of manufacturing, T cells were transduced with a lentiviral CAR vector encoding anti-CD19, 4-1BB and CD3z. Final CAR T-cell products for these pre-clinical studies were harvested on day 8 of manufacture. Results Starting enriched T-cell numbers from the 3 healthy donors ranged from 4.0-4.8e7 cells, the cells were 74-79% CD4/8+, and the average CD4/CD8 ratio was 1.4. On the day of CAR T harvest (day 8), total cells in the chamber had expanded to 3.6-4.6e9 cells (74-115 fold expansion), the cells were >99% CD3+, and the average CD4/CD8 ratio was 2.9 (Table 1). Final cell numbers were similar to what previously published CAR T manufacturing runs on the CliniMACS Prodigy (Zhu et al., Cytotherapy, 2018), that started with 1x108 enriched T-cells obtained from apheresed mononuclear cells. Cell surface CD19 CAR expression on the final cell products varied from 19.2-48.1%. While more than 50% of the starting T cells had a naïve (CD62L+ CD45RO-) phenotype, the final cell products contained greater than 80% central-memory (CD62L+ CD45RO+) T cells. Finally, the number of CD19 CAR T cells obtained from these pre-clinical manufacturing runs ranged from 7.82e8 to 2.21e9 cells. Conclusions 50 ml of cryopreserved PBMCs was adequate to manufacture clinically relevant CAR T-cell therapy doses from healthy donors not previously exposed to chemotherapy. Sufficient numbers of CAR T-cells were obtained to dose an 80 kg individual with at least 9e6 cells/kg which is greater than prescribed commercial doses of CD19 CAR T-cells. Further studies are indicated to determine if T-cells collected prior to disease modifying chemotherapies result in an improved product. These results demonstrate feasibility for generating CAR T cells from small volumes of whole blood collected at a time point before a cancer patient has been treated with multiple lines of therapy that could negatively impact starting T cell numbers and function. Disclosures Hari: GSK: Consultancy; Amgen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy; Janssen: Consultancy. Shah:TG Therapeutics: Consultancy; Celgene: Consultancy, Honoraria; Incyte: Consultancy; Kite Pharma: Consultancy, Honoraria; Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Lily: Consultancy, Honoraria; Verastim: Consultancy. Johnson:Miltenyi Biotec: Research Funding; Cell Vault: Research Funding.

Daratumumab Plus Carfilzomib: An Optimistic Approach in Relapsed/ Refractory Multiple Myeloma

Abstract Background: Although with the introduction of novel agents, clinical outcomes have significantly improved in patients of multiple myeloma (MM); however, nearly all relapse, requiring subsequent treatment. Patients who have been heavily treated for relapsed/refractory MM (RRMM) have limited options and poor survival outcomes. Carfilzomib plus daratumumab combination have been evaluated in a phase 1b study in patients of RRMM progressing after 1–3 lines of therapies including bortezomib and an immune-modulatory drug. However, data are lacking evaluating the efficacy of this combination in RRMM patients who have progressed or have suboptimal response on either of these drugs (carfilzomib or daratumumab). Methods: Prospective analysis of data of 19 RRMM patients who progressed after multiple lines of therapy (including bortezomib and lenalidomide/pomalidomide) and had suboptimal response/stable/progressive disease after receiving carfilzomib or daratumumab based combination as last therapy. All patients received combination of carfilzomib plus daratumumab along with dexamethasone (DKd) after prior consent. Daratumumab (16 mg/kg IV) was administered weekly (days 1, 8, 15, and 22) during cycles 1 and 2, every 2 weeks (days 1 and 15) during cycles 3–6, and every 4 weeks thereafter. Carfilzomib was administered weekly on days 1, 8, and 15 of each 28-day cycle. Patients received an initial carfilzomib dose of 20 mg/m2 on day 1,2; 27 mg/m2 on day 8, 9, 15, 16 of cycle 1, which increased to 70 mg/m2 on day 1, 8, 15 from cycle 2 onwards if deemed tolerable. Dexamethasone was given as fixed-dose of 40 mg weekly. Results: Eighteen of 19 patients (including 3 high risk cytogenetics) to DKd (CR-4, very good partial response-10, partial response-02). After median follow-up of 16 months, progression-free survival (PFS) was 95%. Median PFS was not reached. Three patients who were transplant eligible received high-dose chemotherapy followed by autologous stem-cell transplantation and achieved minimal residual disease negativity. The most frequent all grade side effects were hematological, which included neutropenia 30%, anemia 70%, and thrombocytopenia 42%. Most frequent non hematological side effects were nausea 40%, vomiting, cough, respiratory tract infections, asthenia, and loss of appetite. Conclusion: Carfilzomib plus daratumumab based combination in RRMM patients has shown promising results in phase Ib study, where patients with prior exposure to either of these drugs were excluded. Our data show similar or better response of this combination in patients who had progressive disease/stable disease/minimal response to either of carfilzomib or daratumumab. This combination can be a better option in heavily treated RRMM (with prior exposure to either of carfilzomib or daratumumab) producing deeper and durable responses. A larger study may be required to prove this benefit.

Efficacy and safety of cyclin dependent kinases 4/6 inhibitors in the treatment of metastatic breast cancer: a real-world experience

Background Randomized trials have shown survival gains for patients with metastatic breast cancer (BC) treated with CDK4/6 inhibitors (CDK4/6i) in combination with endocrine agents. It is not unlikely that there may be discrepancies between the generally fit clinical study population and the real-world setting that could affect adherence to treatment guidelines, tolerance to treatment and outcome. Material and methods Consecutive patients with metastatic or locally advanced and unresectable BC that were treated between July 2017 and January 2020 at Karolinska University Hospital, Stockholm, Sweden and that had received at least one dose of CDK4/6i were included in this retrospective study. The primary endpoint was safety, including toxicity according to CTCAE 5 and rates of treatment interruptions, dose reductions and discontinuations. The secondary endpoint was efficacy based on the treating physicians’ assessments in terms of progression free (PFS) and overall survival (OS), as well as the factors associated with patient outcome. Results Eighty-eight patients were included in the analysis, with a median age of 67.2 years. Grade 4 neutropenia occurred in 9.1% of patients and one episode of neutropenic infection was observed. Dose reductions were made in 38.6% of patients, while 11.4% discontinued treatment due to toxicity, most commonly non-hematologic. After a median follow-up of 18.33 months, median PFS was 13.30 months (95% CI, 11.39–15.21) and median OS could yet not be estimated. In multivariable analysis, number of prior chemotherapy lines was an independent predictor for shorter PFS (HR = 3.28, 95% CI 1.50–7.16, p = .003). Conclusions CDK4/6i administered in a real-world setting exhibits a similar toxicity profile but higher incidence of treatment discontinuation compared to randomized trials. Efficacy of CDK4/6i among patients pretreated with multiple therapy lines is markedly reduced.

The landscape of chromosome 11q13 amplification in Chinese solid tumor patients and hyperprogressive disease (HPD) clinical example.

e15222 Background: Multiple biomarkers are thought to be effective guides in selecting immune checkpoint inhibitors, such as Tumor mutational burden (TMB), PD-L1 and MSI/dMMR. Immunotherapy may be miraculous effective in some patients but many other patients experienced poor prognosis and even tumor overgrowth after immunotherapy in real practice. Previous studies have reported that 11q13 (CCND1, FGF3, FGF4, and FGF19) amplifications were associated with HPD. However, the characterization of chromosome 11q13 amplification in Chinese solid tumor patients are not clear. Methods: A total of 10167 Chinese solid tumor patients’ FFPE and matching blood samples sequenced by next-generation sequencing (NGS) targeting 450 cancer genes were included in this study. Genomic alterations including single nucleotide variants (SNV), insertions and deletions, copy number variations and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: Chromosome 11q13 amplifications were identified in 679 (6.7%) Chinese solid tumor patients. The top six tumor types with 11q13 amplification were esophageal carcinoma 43.8%, melanoma 17%, urothelial carcinoma 16%, breast carcinoma 13.4%, head and neck carcinoma 13.1% and hepatocellular carcinoma 9.4%. In 2257 patients with TMB-H (10muts/Mb) / PD-L1 expression / MSI samples, chromosome 11q13 copy number gain were identified in 184 (8.2%) patients. Chromosome 11q13 amplification and MSI were independent events and didn't occur simultaneously. In TMB-H patients, the detection rate of 11q13 amplification was 8.5%, while in PD-L1 positive patients, the amplification rate of 11q13 was 7.4%. In patients with TMB-H and PD-L1 positive, the detection rate of 11q13 amplification was 9.4%. In our clinical practice, we saw example of HPD exist in a lung squamous cell carcinoma patient who was treated with multiple lines of therapy and then used the Nivolumab. The patient underwent genetic testing and was found to be chromosome 11q13 amplified. Conclusions: The proportion of 11q13 amplification was different in different types of solid tumor. Esophageal carcinoma, melanoma and urothelial carcinoma were top three types of solid tumors with 11q13 amplification. The 11q13 amplification did not coincide with MSI but it overlapped with PD-L1 expression or TMB-H. Together, these results may provide immunotherapy guidance in clinical practice.

Evaluation of immune-related adverse events in patients treated with sequential immunotherapy and tyrosine kinase inhibitor treatment in non-small cell lung cancer.

e21562 Background: Immune-related adverse events (irAEs) have been frequently observed with non-small cell lung cancer (NSCLC) patients treated with immunotherapy (IO). The severity of irAEs in response to IO treatment may reflect antitumor response. The effect of irAEs with sequential IO and tyrosine kinase inhibitor therapies has not been fully characterized. This study aims to evaluate the irAEs in NSCLC patients who have received sequential IO and TKI treatment. Methods: A retrospective cohort of 387 NSCLC patients previously treated with IO was identified from the City of Hope Thoracic Registry (THOR) from February 2010 to January 2020. Patients had confirmed pathologic disease and received IO and TKI, either on clinical trial or as standard of care. IO-treated patients were classified into two groups: TKI vs non-TKI treated. The non-TKI IO-treated group was used to verify that outcomes are not dependent on the immunotherapy given, but rather TKI therapy. IrAEs were collected from treatment courses and assessed based on the treating physician diagnosis. Results: A total of 63 NSCLC patients received sequential IO and TKI treatment. Histology was nonsquamous in 59 (93.7%) and squamous in 4 (6.3%). Multiple lines of therapies were accounted for in each patient. IO therapies received included nivolumab (n = 30), pembrolizumab (n = 24) and atezolizumab (n = 11). Mostly frequently used TKI therapies were erlotinib (n = 43), osimertinib (n = 25), afatinib (n = 11), crizotinib (n = 10), gefitinib (n = 5), and alectinib (n = 4). IrAEs occurred in 23 patients (36.5%). 22/23 (95.7%) patients who reported irAEs received TKI treatment prior to receiving IO treatment. The most common irAEs were pneumonitis (n = 5), diarrhea (n = 4), fatigue (n = 3) and rash/pruritus (n = 3). Other irAEs included arthralgias & myalgias (n = 2), new onset diabetes (n = 1) and renal insufficiency (n = 1). Conclusions: The severity of irAEs and sequential IO and TKI treatment in NSCLC patients is still not well-defined. Overall and progression-free survival were considered in this cohort. Preliminary data suggested that EGFR-TKI treated patients have low response to immune checkpoint inhibitors, but outcomes vary by allele variation. Further prospective analyses are needed to investigate the correlation of irAEs and survival outcomes with TKI-resistant NSCLC patients treated with IO. Also, treating physician’s diagnosis of irAEs exposed a need to clarify grade and severity of irAEs.

Patient characteristics and treatment patterns in relapsed/refractory multiple myeloma patients after exposure to a proteasome inhibitor, an immunomodulatory agent and daratumumab.

e20540 Background: Many novel agents, such as a Chimeric Antigen Receptor T-Cell (CAR-T) therapy, are under investigation for the treatment of relapsed/refractory multiple myeloma (RRMM) patients (pts) who have been exposed to a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and daratumumab (triple-exposed). However, limited data are available on treatment patterns in these pts. Here, we aim to study characteristics and treatment patterns after triple-exposure in RRMM pts. Methods: Data from triple-exposed RRMM pts from the Flatiron MM core registry (Jan 1, 2011 - Oct 2019) who received ≥3 prior lines of therapy (LOT) were used for the analyses. Descriptive statistics for pt characteristics and treatment patterns were assessed at end of triple exposure LOT (time T0) and after triple exposure by LOT. Results: Of the 10,011 MM pts in the Flatiron registry, 1,029 were triple-exposed; of these, 362 had a LOT after triple-exposure. Median age at T0 was 68 years and time to triple-exposure was 3.5 years from index MM diagnosis (Table). 52% were male, 81% (of 250 with available ECOG data) had ECOG status < 2, and 54% had a stem cell transplant. In 96% of pts, daratumumab was part of the triple-exposure regimen. Median follow-up from triple-exposure (LOT end date) was 7.4 months. 49% and 23% of pts had ≥2 LOTs and ≥3 LOTs after triple-exposure. Pomalidomide-, carfilzomib-, or daratumumab-containing regimens accounted for 71% and 49% of all LOT1-post-triple and LOT3 post-triple treatments, respectively; non-novel treatments accounted for 18% and 30% of LOT1 post-triple and LOT3 post-triple treatments. Conclusions: Triple-exposed RRMM pts accounted for approximately 10% of the population in the Flatiron MM core registry. Triple-exposed RRMM pts progress to multiple LOT in which they continue to be treated with PIs, IMiDs, and daratumumab; therefore, there is a need for new treatments with novel mechanisms of action for this pt population. [Table: see text]

Disease characteristics and outcome of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received a beta emitter (177Lu-PSMA) after an alpha emitter (radium-223).

e17592 Background: Ra-223, a targeted alpha therapy, showed an overall survival (OS) benefit and favorable safety profile in mCRPC pts in a phase 3 trial. 177Lu-PSMA radioligand is an investigational agent for mCRPC. REASSURE (NCT02141438) is a global, prospective, observational study investigating Ra-223 safety in routine clinical practice over 7 years’ follow-up in mCRPC pts. Data from the second prespecified interim analysis (IA) were used to investigate safety and outcomes of pts who received 177Lu-PSMA after Ra-223 therapy. Methods: Data cut-off for the second prespecified IA was March 2019, and included pts who had subsequent 177Lu-PSMA after the last Ra-223 dose. Disease characteristics, adverse events (AEs) after last Ra-223 dose, and OS are described. Results: Of 1465 pts overall, 26 received 177Lu-PSMA subsequent to Ra-223. In this subgroup, pts received multiple anticancer therapies prior to 177Lu-PSMA. 13 pts (50%) received Ra-223 as combination therapy at second line (metastatic setting). Pts received a median of six Ra-223 doses. After Ra-223 treatment ended, 3 pts (12%) had drug-related serious AEs, 9 pts (35%) had grade 3/4 bone marrow suppression-relevant hematologic AEs. Median duration of 177Lu-PSMA treatment was 3.5 months. 19 pts (73%) received 177Lu-PSMA as fourth-line therapy or onwards. OS was 28.0 months from start of Ra-223 and 13.2 months from start of 177Lu-PSMA. Conclusions: In this select population receiving a sequence of multiple lines of therapy with different modes of action, grade 3/4 hematologic AEs after Ra-223 were low. Treatment with subsequent 177Lu-PSMA seems feasible, based on duration of 177Lu-PSMA and survival. Clinical trial information: NCT02141438 . [Table: see text]

Pharmacogenomic blood-based assay to predict chemotherapy response and survival in pancreatic cancer.

738 Background: Pancreatic adenocarcinoma (PDAC) is for most patients a refractory disease. Modern cytotoxic chemotherapeutics (C) are not yet optimal for inducing responses and extending life. We are developing a blood-based pharmacogenomic (PGx) assay profiling circulating tumor and invasive cells (CTICs) to predict sensitivity and resistance to C. Methods: The PGx assay was studied in two cohorts of patients (pts) presenting for frontline C therapy of metastatic PDAC. Cohort 1 is from an ongoing prospective study (planned n=80); pts are enrolled prior to receiving either FOLFIRINOX or gemcitabine (Gem)/nab-paclitaxel (Nab-P). Cohort 2 (n=50) consists of pts enrolled prior to receiving bespoke combinations of C agents informed by the assay. 6 mL of peripheral blood was collected from pts at baseline and while on C therapy. CTICs were isolated by previously described collagen invasion assay, total RNA was extracted and gene-expression analysis was performed. PGx models for seven C agents used in PDAC were applied, and correlated to treatment received. Pts were classified as sensitive if C received were predicted to be effective and resistant if not. Objective endpoints were PFS and OS. Results: Cohort 1 patients who received sensitive first-line C combinations experienced significantly longer time to progression (TTP) v resistant (Table). In Cohort 2, the PGx assay was predictive of TTP and OS when used across multiple lines of therapy, with a two-year survival of 38%. Greater OS was observed in Cohort 2 pts receiving heterogenous C regimens more highly correlated to those predicted by the PGx assay. Conclusions: The PGx assay has promising predictive performance in both standard and personalized C regimens. A prospective, directed trial comparing these approaches is warranted. Clinical trial information: NCT03033927. [Table: see text]

Efficacy and safety of albumin-bound paclitaxel in the treatment of advanced malignant tumors

Objective To investigate the efficacy and safety of albumin-bound paclitaxel in the treatment of advanced malignant tumors. Methods Patients in advanced stage of cancer who had had drug-resistant relapse after receiving multiple-line treatment received chemotherapy with albumin-bound paclitaxel from May 2016 to April 2018 in Daxing Hospital of Capital Medical University. Their clinical data were collected to evaluate the treatment efficacy and safety profile. Results 36 patients who had advanced treatment-resistent tumors with evaluable data were enrolled. Of 36 patients, 55.56% (20) had previously received chemotherapy with paclitaxel. The objective response rate (ORR) was 8.33%, the disease control rate (DCR) was 25.0%, the median progression free survival (PFS) was 106 days, and the median overall survival (OS) was 183 days. The main adverse reactions of grade 3-4 were hematological toxicity, including neutropenia [36.11% (13/36)], anemia and thrombocytopenia [5.56% (2/36) and 16.67% (6/36)] in patients without neutropenia fever. Adverse effects of 3-4 degrees related to non-hematologic toxicity were not observed. Conclusions Chemotherapy regimen with albumin-bound paclitaxel has certain efficacy for advanced malignant tumors resistant to multiple lines of therapy and the adverse effects could be generally tolerated. Key words: Albumin-bound paclitaxel; Antineoplastic combined chemotherapy protocols; Drug resistance, neoplasm

Novel Drugs and Clinical Trial-Based Treatments Prolong Survival of Peripheral T-Cell Lymphomas (PTCL) Patients: Single Institution Retrospective Analysis

Introduction Peripheral T-cell lymphomas (PTCL) are a group of rare and heterogeneous diseases associated with unfavorable prognoses. Conventional chemotherapy has been the standard of care, but is considered marginally effective. This outcome has been attributed to the fact that most PTCL treatments are derived from the management of aggressive B-cell lymphomas. While relapse is common, subsequent line therapies are heterogeneous, and can include many lines of non-specific chemotherapy. Recently approved novel agents, such as pralatrexate and histone deacetylase (HDAC) inhibitors, and clinical trials however, tend to either not be used or used too late in the natural history of the disease. Herein, we compared the efficacy of chemotherapy and novel therapies, in first line, second line and third line, to identify factors that might influence the outcome of PTCL patients in a single institutional cohort. Methods A search of the electronic medical record and clinical trial databases from January 1, 1994 to May 31, 2019 was performed to identify patients with PTCL. Only patients 18 years and older with pathology-confirmed PTCL and complete clinical data were included. Due to substantially different disease characteristics, behavior, and treatment, we excluded patients with T/NK large granular lymphocytic leukemia and primary cutaneous T-cell lymphoma, with the exception of transformed mycosis fungoides. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Kaplan-Meier curves were generated and compared based on the log-rank test. Cox proportional hazard models were used to investigate the association by adjusting for the type of treatments and the lines of therapy. Statistical analyses were performed with SAS version 9.4. Results There were 213 patients (1.2 males:1 female) included in the analysis with a median age of diagnosis of 56.9 years (range 18.1-90.3). Front-line therapies typically consisted of chemotherapy, including CHOP, CHOEP, and EPOCH. The use of clinical trials and novel agents increased as patients progressed through multiple lines of therapy. Figure 1A showed that patients who achieved a CR with first line chemotherapy had a better overall survival than patients who did not (median 8.9 years vs 0.83 years, p<0.0001), with trends suggesting improvement in survival with novel combinations and single agents. Although limited by small numbers, patients with primary refractory or relapsed disease were generally given additional lines of chemotherapy, and the percentage of patients who achieved CR trended down more drastically (42% first line in Figure 1A, 16% second line in Figure 1D, 21% third line in Figure 1G) than patients who received novel combinations (50% first line in Figure 1B, 23% second line in Figure 1E, 30% third line in Figure 1H) or single agents (27% first line in Figure 1C, 40% second line in Figure 1F, 20% third line in Figure 1I). There were no significant differences in the frequency of radiotherapy or autologous stem cell transplantation over the study period. Our data demonstrate that exposure to novel agents (p=0.002) in Figure 2A and novel combinations (p=0.003) in Figure 2B, especially histone deacetylase inhibitors (HDACI, p=0.045) in Figure 2D, during the treatment course of PTCL patients, was associated with prolonged overall survival. Pralatrexate had a trend toward improving outcomes in the first ten years as shown in Figure 2C, but this was not statistically significant. Conclusions Clinical trials and novel therapies improve outcomes and should be considered earlier in the therapy of patients with PTCL. Patients who obtain CR early have the best overall survival. Our findings suggest that patients with R/R PTCL who fail chemotherapy should be enrolled in clinical trials or be given novel approved agents rather than repeated rounds of non-specific cytotoxic therapy. Disclosures Marchi: Spectrum Pharmaceuticals, Verastem Oncology: Research Funding. O'Connor:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding; TG Therapeutics: Other: Travel Support, Research Funding. OffLabel Disclosure: Drugs that are approved for the treatment of patients with relapsed and refractory peripheral T-cell lymphoma, such as pralatrexate (a novel antifolate) and histone deacetylase inhibitors, were used in the front line setting when patients were not candidates for chemotherapy or enrolled in clinical trials. Outcomes are also described for non-FDA approved drugs used as monotherapy or in combination in clinical trials as well as FDA approved drugs for other indications used in clinical trials are described though not explicitly listed.

A Discrete Event Simulation Model to Evaluate the Impact of Treatment Sequences on Long-Term Patient Outcomes in Multiple Myeloma (MM)

Purpose: Many new therapies have been approved for the treatment of multiple myeloma (MM) in recent years. In June 2019, daratumumab (Darzalex®), a CD38-directed monoclonal antibody, in combination with lenalidomide and dexamethasone (DRd), received FDA approval for the treatment of newly diagnosed MM (NDMM) patients ineligible for stem cell transplantation. This approval provides NDMM patients with a new option as first-line therapy, however, with many options for MM treatment available, identification of the optimal sequence of treatments becomes of critical importance to healthcare providers and payers. Objective: To develop a treatment sequencing discrete event simulation (DES) model that compares unique treatment sequences and estimates the impact of first-line DRd on longer-term outcomes (i.e. survival through multiple lines of therapy) in a general population of MM patients. Methods: A DES model of MM treatment sequences was developed. FDA approved and NCCN recommended non-transplant therapies were included. Treatment efficacy was estimated by digitizing and extrapolating progression-free and overall survival (OS) Kaplan-Meier (KM) data, using established methods (Guyot et al., 2012). Five common parametric functions were fit, and the curve-of-best-fit was determined by standard statistics (i.e., Akaike & Bayesian information criterion) and visual inspection. The model was developed to allow patients to go through up to 6 lines of treatment. The time of progression and death events were randomly assigned based on the estimated parametric functions. All-cause mortality data (US Census 2016) were considered in the simulation of survival. Where data were not available, previous therapies were assumed not to impact the efficacy of subsequent therapies. Model survival predictions were validated against published real-world estimates of survival from: 1) a retrospective analysis of a large American electronic medical record database, Humedica (Hari et al., 2018) and 2) a retrospective analysis of the Dutch PHAROS registry (Verelst et al., 2017). The Humedica and PHAROS datasets reported on the effects of three and four lines of treatment, respectively, starting with newly diagnosed patients. From the Humedica dataset, first-line therapy consisted of proteasome inhibitor- (PI), immunomodulatory- (IMiD), and PI + IMiD-based regimens in 42%, 34% and 18% of patients, respectively, with other regimens used in 7% of cases. Treatment was primarily doublets (63%) rather than triplets (37%). From the PHAROS registry, first-line therapy was primarily thalidomide-based (66%), bortezomib-based (15%), or lenalidomide-based (7%). Statistically, validation was quantified through the calculation of the mean absolute percent error (MAPE), a commonly used statistic to assess the accuracy of forecasts. To estimate the impact of first-line DRd, a hypothetical analysis was simulated wherein all first-line treatments described within both the Humedica and PHAROS datasets were replaced with DRd. Following DRd, patients received subsequent treatment as described within those datasets. Results: Restriction of the modeled treatment algorithm to treatment patterns described within the Humedica database and PHAROS registry led to valid simulated OS estimates that were in line with the published data (MAPE values of 9% and 19% for Humedica and PHAROS, respectively). Utilization of DRd as first-line treatment was estimated to increase OS in scenario analyses (Table 1). The DES model estimated 5-year survival rates for frontline DRd with subsequent therapy based upon the Humedica and PHAROS datasets were 62% and 57%, respectively. In contrast, the estimated 5-year survival for the Humedica and PHAROS datasets without DRd frontline was 40% and 26% respectively, highlighting a 22-31% incremental survival benefit due to DRd at 5-years. Conclusions: The MM DES model validated well to the published estimates of real-world OS. Preliminary results indicate that first-line treatment with DRd may improve OS in MM compared with historical treatment sequences, that include PI+IMiD based triplets as first-line treatment. The model is being further developed to describe the impact of sequencing other MM treatment regimens to estimate the optimal treatment pathways. Disclosures Liu: Janssen Scientific Affairs, LLC: Employment, Equity Ownership. Moldaver:Janssen Scientific Affairs, LLC: Consultancy. Zhu:Janssen Scientific Affairs, LLC: Other: contractor for Janssen. Zhou:Janssen Scientific Affairs, LLC: Consultancy. Maiese:Janssen: Employment, Equity Ownership. Hollmann:Janssen Scientific Affairs, LLC: Consultancy.

Novel Immunotherapeutic Approaches for Hodgkin Lymphoma

The outcome of patients with relapsed/refractory Hodgkin Lymphoma (HL) for whom salvage therapy or stem cell transplant have failed is poor. HL tumor cells (HRS) cells universally express CD30, which is an excellent target for directed therapy such as the antibody drug conjugate brentuximab vedotin (BV). Patients with relapsed HL can also respond to checkpoint inhibitors, emphasizing the susceptibility of this tumor to T-cell-mediated immune control. The adoptive transfer of chimeric antigen receptor T (CAR-T) cells, which combine antibody-mediated antigen specificity with the effector function and replication potential of T lymphocytes, offers the opportunity to infuse large numbers of T cells with defined antigen-specificity and MHC-independent tumor targeting. In two parallel and simultaneously conducted phase 1/2 dose-escalation studies, we administered CD30-specific CAR-T (CD30.CAR-T) cells after lymphodepletion to patients with HL that had relapsed after multiple lines of therapy, including BV, checkpoint inhibitors and stem cell transplant. We observed an excellent safety profile, with modest and self-limited cytokine release syndrome and no neurologic toxicity. The overall response rate was 78%, including 18 patients (67%) with complete responses, and the 1 year progression free survival was 47% (95% CI: 25% - 67%). Despite these promising results, unsolved obstacles include CAR-T cell trafficking and persistence in the tumor site. HL is characterized by a unique tumor microenvironment that creates a physical barrier and a hostile niche for CD30.CAR-T cells. Expression of PD-1 on CD30.CAR-T cells indicates that these cells likely remain susceptible to inhibition by PD-L1 in the tumor, and suggests that the combination of CD30.CAR-T cells with checkpoint blockade should be investigated. Enhancing CAR-T cell trafficking to tumor sites should also tip the delicate balance between effector and inhibitory mechanisms towards the former. Since the tumor microenvironment of HL is rich in TARC (thymus and activation regulated chemokine/CC chemokine ligand 17), we have initiated a clinical study in which CD30.CAR-T cells are further modified to co-express the cognate receptor (CCR4) for TARC to improve their tumor homing (NCT03062157). Disclosures Savoldo: Baylor College of Medicine: Patents & Royalties: CAR.CD30 patent; Bluebirdbio: Other: research agreement; Cell Medica: Other: Research Agreement; Bellicum: Other: Research Agreement. Grover:Seattle Genetics: Consultancy. Ramos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding.

Health Economic Burden and Treatment-Based Survival for Current Follicular Lymphoma Treatment Practice in Japan Using a Nationwide Retrospective Claims Database

ABSTRACT Introduction: Follicular lymphoma (FL) is an indolent form of non-Hodgkin lymphoma (NHL), which accounts for 20-30% of all NHL cases. In most patients, FL is diagnosed in advance stages, mild disease progression and long treatment period that may incur a great burden to patients and healthcare system. However, to our knowledge there is no comprehensive analysis which have been done in the real world setting in Japan. Therefore, we conducted a retrospective claim database study to elucidate the lines of treatment patterns as well as the associated healthcare resource utilization (HCRU), and 3- and 5-year overall survival (OS) among 3,593 Japanese patients with a median age of 65.0 years. Methods: This retrospective study analyzed data from the Medical Data Vision (MDV) database for patients diagnosed with FL (ICD-10: C82). The MDV database is an electronic health records-based database comprised of anonymized inpatient and outpatient data covering over 25 million patients and over 374 Japanese hospitals, approximately 22% of acute phase hospitals, including 187 cancer therapeutic facilities. Patients who received treatment during the identification period from 1 October 2008 to 31 December 2017 were selected. Patients were required to have data for at least 6 months before the first treatment date (ie, patient index date) and at least 12 months after the index date (unless they died). Costs were converted from Japanese yen to US dollars using the exchange rate based on January of each year of service. For 3- and 5-year OS, patients who had a record of death in their hospital discharge were counted as an event, otherwise they were censored at the latest of: end of patient record, end of data availability, or end of the 3- or 5- year period. Results: A total of 3,593 patients with FL met the inclusion criteria of which 51.2% was female patients. Of these 3,593 patients who met the inclusion criteria, 3,004 patients (83.6%) received rituximab-based (R) therapy as index treatment, of which 1309 (36.4%) of patients received R-CHOP. During the subsequent lines of therapies, patients received heterogeneous treatment regimens (fig 1). Overall, the average healthcare cost during follow-up period was $67,557.40 for all FL patients, ranging from $39,340 (immunotherapy, targeted therapy, or hormone therapy without R) to $ 95,095 (other R-based chemotherapy). The average number of outpatient visits during follow-up for all FL patients was 51, ranging from 44.6 to 55.1 for each treatment group. There were 3,394 (94.5%) patients who had at least one hospitalization during follow up period. Among those who had at least one hospitalization, the average number of hospitalizations was 3.8 for all FL patients, ranging from 2.5 to 4.6 for each treatment group. The average number of days of hospitalization during follow-up was 74.5 for all FL patients, ranging from 31 to 110.4 for each treatment group. 85 (2.4%) FL patients received a stem cell transplant (SCT) during follow-up at the age under 79 years, with other R-based therapies having the highest percentage (7.6%). There were 346 (9.7%) FL patients receiving radiation therapy, ranging from 8.1% (other treatment groups) to 24.1% (immunotherapy, targeted therapy, or hormone therapy without R). There were 337 deaths (9.4%) recorded within 3 years and 400 (11.1%) within 5 years of index treatment. The median Kaplan-Meier OS was not reached for most analysis groups due to the overall high survival rates. When comparing overall survival by index regimen group, chemotherapy without R consistently had worse survival, especially compared to R-based regimens (fig. 2). Conclusions: Patients with FL in Japan received diverse treatment regimens and multiple lines of therapy with relatively high survival rates. Majority of patients have received R-based therapies and have shown longer survival rates compared to those who have received chemotherapy without R. This is the first study to clarify lines of treatment patterns using retrospective claims database and treatment group-based OS in FL patients in Japan, which will give clinical insights of the landscape of daily practices and the associated real world health economic burden for patients, clinicians and healthcare providers to support their better decision makings. Disclosures Tsutsue: Celgene: Employment. Tobinai:Solasia: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Yakult: Honoraria; AbbVie: Research Funding; Meiji Seika: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; HUYA Bioscience: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Verastem: Honoraria; Kyowa Kirin: Honoraria, Research Funding. Yi:Celgene: Consultancy. Crawford:Celgene: Consultancy.

Similar Survival with Deferred Versus Salvage Autologous Stem Cell Transplant in Light Chain Amyloidosis

Background: Light chain (AL) amyloidosis is characterized by deposition of misfolded monoclonal immunoglobulin light chains leading to organ dysfunction. AL amyloidosis has traditionally been treated with agents used in multiple myeloma, primarily alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and high-dose melphalan/autologous stem cell transplantation (ASCT). A retrospective study comparing patients with AL amyloidosis who underwent ASCT as frontline therapy ('upfront ASCT') to those undergoing ASCT following induction ('deferred ASCT') revealed that deferred ASCT was associated with prolonged overall survival (OS) compared to upfront ASCT (Afrough et al, Biol Blood Marrow Transplant, 2018). Given the number of effective new therapies for AL amyloidosis, the potential to delay ASCT after one or more lines of therapy ('salvage ASCT') is feasible. To our knowledge, transplant outcomes of AL amyloidosis patients undergoing deferred vs salvage ASCT following at least one relapse have not been reported. A retrospective chart review was conducted to compare AL amyloidosis patients receiving deferred vs salvage ASCT for progression-free survival (PFS) and overall survival (OS). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: Twenty-four patients with AL amyloidosis who underwent deferred or salvage ASCT between 2000-2018 were included in the analysis. Patients who underwent upfront ASCT without induction chemotherapy were excluded. Demographics and clinical parameters were extracted from the electronic medical record. PFS was calculated from date of ASCT to first relapse and OS was calculated both from date of diagnosis and date of ASCT to death. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS as well as OS of patients who underwent deferred vs salvage ASCT were compared. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using deferred ASCT as the reference treatment. Results: Among the 24 patients included in this analysis, 13 underwent deferred ASCT with 1 prior line of chemotherapy (e.g., induction), and 11 underwent salvage ASCT with a median of 3 prior lines (Table 1). Ten patients had cardiac amyloidosis, 15 had renal amyloidosis, and 6 had multi-organ involvement. Induction regimens received in the deferred group are included in Table 1. Neither PFS nor OS was significantly different between patients receiving deferred vs salvage ASCT. After median follow-up of 2.9 years, median PFS in patients who received deferred ASCT was 6.5 years and not reached in those who received salvage ASCT (P=0.47), with a HR of 1.74 (95% CI, 0.38-7.85) (Figure 1A). Median OS from date of ASCT was not reached in either group after a median follow-up of 2.8 years (P=0.52), with a HR of 2.16 (95% CI, 0.19-24.04) (Figure 1B). Similarly, median OS calculated from date of diagnosis was not significantly different between deferred vs salvage ASCT (P=0.79) (Figure 1C). Conclusions: In this cohort of 24 AL amyloidosis patients, no significant differences in PFS or OS were seen between patients undergoing deferred ASCT following induction vs salvage ASCT following multiple lines of therapy. Unlike the superior OS seen with deferred vs upfront ASCT, our findings show that either deferred or salvage ASCT may be associated with comparable outcomes and suggest similar OS despite timing of transplant. However, it is important to note the small sample size and that none of our patients received daratumumab-based regimens which may have improved PFS/OS in either or both groups. There were also small differences between groups in use of maintenance (1 vs 3 patients in the deferred and salvage groups, respectively) and proportion of patients receiving higher doses of melphalan 200mg/m2 vs 140 mg/m2 (69% vs 55% in deferred and salvage groups, respectively). Nevertheless, the lack of difference seen in PFS and OS between the two groups suggests that eventual hematologic relapse and organ progression with death occur at similar time intervals despite timing of ASCT. This speaks to the point that in newly diagnosed AL amyloidosis as well as later in the disease, achieving deep responses to prevent organ progression and death regardless of timing of ASCT remains an important treatment goal. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Pharmacyclics: Speakers Bureau; Merck: Research Funding; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health.

Ibrutinib for Chronic Pulmonary Graft-Versus-Host-Disease after Progression on Prior Therapy

Introduction: Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Pulmonary cGVHD consists of both obstructive and restrictive pulmonary changes, and as such, represents a broad spectrum of disease. While corticosteroids are a mainstay of treatment, there is no established standard-of-care for second line therapy. The Bruton's tyrosine kinase inhibitor ibrutinib was recently approved for treatment of cGVHD after failure of 1 or more lines of systemic therapy. However, the role of ibrutinib in patients with pulmonary cGVHD is not well understood. Here we report an institutional experience of ibrutinib as non-first-line therapy for pulmonary cGVHD. Methods: We performed a retrospective study of adult patients with steroid-dependent or steroid-refractory pulmonary cGVHD treated with ibrutinib as non-first line therapy between 2014 and 2018. Patients were diagnosed with pulmonary cGVHD if they met the 2014 National Institutes of Health cGVHD Consensus Panel criteria or were diagnosed based on expert opinion. All patients received appropriate GVHD prophylaxis at the time of transplant. The severity of pulmonary cGVHD was assessed by pulmonary function testing (PFT) done prior to and 180 days after initiation of ibrutinib therapy. The primary clinical outcome was absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) over 180 days. Patients were identified as having a complete response (normalization of %FEV1), partial response (≥10% increase in %FEV1), stable disease (<10% change in %FEV1), or progression (≥10% decrease in %FEV1). Results: A total of 17 patients received ibrutinib for pulmonary cGVHD (mean age 46 ± 11 years, 59% male), with a mean duration of 34 ± 17 weeks from transplant to diagnosis of cGVHD (31% de novo, 31% progressive, 38% interrupted). On average, patients had 5 involved organs, received 4 treatments for cGVHD prior to ibrutinib, and 14/17 (82%) were on at least 0.25 mg/kg/day of prednisone (or an equivalent dose of corticosteroid) at the time of ibrutinib initiation. The median %FEV1 at time of ibrutinib initiation was 50 ± 24%. At 180 days after initiation, 14/17 patients (82%) continued receiving ibrutinib (1 patient each discontinued therapy for lack of symptomatic improvement, oral ulcers, and enrollment in a clinical trial). Among the 14 patients who completed 180 days of therapy, only 3 had disease progression (Figure 1). Conclusions: Ibrutinib was generally well tolerated as a non-first line therapy for pulmonary cGVHD. In this cohort of patients with steroid-dependent or steroid-refractory disease who had progression on multiple lines of therapy, most had stable or improved pulmonary function by %FEV1 while on ibrutinib. Given the heterogeneity of pulmonary cGVHD, further studies can help clarify which patients are most likely to demonstrate response. Disclosures Miklos: Becton Dickinson: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Celgene-Juno: Consultancy; AlloGene: Consultancy; Janssen: Consultancy; Precision Bioscience: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Miltenyi: Consultancy, Research Funding; Novartis: Consultancy.

The Prognostic Factors for Early Fatal Outcome in Patients with Multiple Myeloma

Introduction: Survival of Multiple Myeloma (MM) patients has improved in recent decades due to the advent of novel agents and broader utilization of stem cell transplant. Fatal outcomes occur mostly after multiple lines of therapy due to increasingly resistant disease. Indeed, early mortality after diagnosis is unusual in front line treatment MM trials, where patients are often selected on the basis of good performance status and absence of organ dysfunction. The real world incidence of early deaths is largely unknown. Hereby, we analyze the factors impacting early mortality in the National Cancer Database (NCDB) which covers more than 70% of MM patients in United States. Methods: Patients with MM diagnosed from 2005-2014 were identified in the NCDB. Early mortality (EM) was defined as death within six months of MM diagnosis. The effect of demographic and clinical factors, insurance type, distance to treatment facility, medical facility and facility volume on the probability of EM was estimated by univariate logistic model. The effect of these factors on the probability of EM was further estimated by multivariable logistic regression. The overall performance of multivariable logistic regression was evaluated using the receiver operating characteristic curve (ROC) analysis. The difference of continuous measurements between groups was examined using t-test. The association between categorical variables was examined using Chi-square test. All tests are two-sided and p-value ≤ 0.05 were considered statistically significant. Results: 90,258 patients with ICD-O 9732 were included. 49949 (55%) were male. EM was reported in 15729 (17%) within the first 6 months after MM diagnosis. Median age at diagnosis was 67 years (19-90). 15729 patients (17%) died in the first 6 months after diagnosis. There was no significant change in the percentage of EM over the years from 2005-2014. 11963 (76%) of patients with EM were older than 65 years while 3766 (23%) patients were less than 65 years. 12300 (78.1%) of the patients with EM were white and 2822 (17.9%) were African American. In a multivariable analysis, variables that confer the worst prognosis were increasing age, higher charlson co-morbidity score, lower annual median income of less than 30,000, and being treated in a community hospital. Controlling the effects of other factors (charlson co-morbidity score, hospital type and transplant), the odds ratio of EM was 1.04 per year increase of age (p<0.0001), 0.52 with treatment in academic center compared to community hospital (p<0.0001). Conclusion: Taken together our data suggest almost 1 out of 6 MM patients died at the first 6 months after diagnosis. Therefore, EM remains high in MM and a major barrier for continued improvement in survival outcomes. In addition to well-known MM-specific determinants of survival, socioeconomic factors were significantly associated with early mortality. Disclosures Malek: Adaptive: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Sanofi: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Amgen: Speakers Bureau.

2666 Disseminated Renal Cell Carcinoma Presented as Obscure Gastrointestinal Bleeding

INTRODUCTION: Metastatic disease to the gastrointestinal tract is frequently observed in patient with known disseminated malignancies. Among those, melanoma, breast and lung cancer are commonly reported. Renal cell carcinoma (RCC) metastasis to small bowel is rare and the presentation varies from obstructive symptoms, intussusception, as well as, gastrointestinal bleeding. CASE DESCRIPTION/METHODS: A 85 years old male with medical history of pulmonary embolism on apixaban and progressive stage IV RCC despite multiple lines of therapy on lenvatinib, presented with progressive fatigue and melenic stools. Denied abdominal pain, change in bowel habits, prior episodes of bleeding, or NSAIDs use. Vital signs were unremarkable. Physical exam was pertinent for non-tender abdomen, no distention, active bowel sounds, no rebound or guarding, and a rectal exam that revealed melenic stools. Labs: Hemoglobin of 6.8 g/dL (Baseline 10.3 g/dl), electrolytes, kidney and liver function tests were unremarkable. Computerized tomography (CT) of the abdomen and pelvis revealed multiple hepatic, retroperitoneal and mesenteric metastases. He received two units of packed red blood cells with appropriate response. Apixaban was held and he was admitted for workup of gastrointestinal bleeding. Esophagogastroduodenoscopy was unrevealing, while colonoscopy showed a few non-bleeding colonic and rectal angioectasias. A subsequent capsule endoscopy demonstrated an actively bleeding jejunal lesion (Figure 1). He continued to have large melenic bowel movements, and his hemoglobin decreased to 5.5 g/dL. A computed tomography angiography showed a blush of contrast in the jejunum, near the site of a tumor implant (Figures 2 and 3). An interventional radiology embolization was performed, with successful hemostasis. DISCUSSION: One autopsy series reported that only 2 out of 44 metastatic tumors to the small intestine were duodenal implants of RCC. In recent years, however, the number of published reports of RCC small bowel metastasis has been increasing. Retrograde venous spread to the paravertebral vessels has been propose as the route of dissemination of RCC to the intestine and solitary, bulky hypervascular lesions might be diagnostic if seen on CT scan. Luminal evaluation may localize the bleeding and offer potential treatment, however, angiography with embolization is the preferred therapeutic approach for small intestine lesions. Small bowel metastases must be considered as an etiology of bleeding when patients with RCC present with melena.