Minor Response Research Articles

A Phase Ib/II Trial of Selinexor Combined with Lenalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; IkB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. The combination of lenalidomide/dexamethasone (Rd) is an approved regimen in relapsed/refractory multiple myeloma (RRMM) with an overall response rate (ORR) of 70-76% and a low complete response rate. In combination with selinexor, the anticipated overlapping toxicities are fatigue, thrombocytopenia and neutropenia. We hypothesized that selinexor could be safely combined with Rd and improve efficacy.Methods - The objective of this phase 1b/2 dose escalation study (NCT02343042) was to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) of the combination of selinexor, lenalidomide (len) and dexamethasone (SRd) in RRMM. Patients (pts) with RRMM who received ≥ 1 prior therapy were enrolled. Selinexor was dosed escalated in two regimens once-weekly (QW) or twice weekly (BIW) with both dosing cohorts starting at 60 mg, len 25 mg PO daily and dexamethasone (dex) 20 mg BIW or 40 mg QW.Results - As of 15-Jul-2017, 18 pts (13 male / 5 female) were enrolled. The median age was 68 years and pts received a median of 1 (range, 1 - 7) prior treatment regimen. Thrombocytopenia was the most common side effect with 4 associated DLTs (2 pts each in the 60 mg BIW and 80 QW cohorts). One additional DLT of grade 3 anorexia was observed in the 60 mg BIW cohort. Common treatment-related grade 1/2 adverse events (AEs) included: nausea (67%), anorexia (44%), fatigue (28%), vomiting (28%), and constipation (28%). Grade 3/4 AEs include: thrombocytopenia (56%), neutropenia (39%), fatigue (11%) and anemia (6%). No DLTs were observed with selinexor 60 mg QW and long-term tolerability was observed. Fifteen pts were evaluable for response, of which 11 pts responded for an ORR of 73%. Among the len naïve pts (n=11), an ORR of 91% was seen, including 3 very good partial responses (VGPR), 7 partial responses (PR, 2 unconfirmed) and 1 unconfirmed minor response (MR). Of the len refractory/relapsed pts (n=4), there was 1 unconfirmed PR, 1 MR, and 2 stable disease (SD). Median PFS was 6.6 months with a median follow up of 4 months. Based on tolerability and anti-MM activity the RP2D of SRd is selinexor 60 mg QW, len 25 mg qd and dex 40 mg QW.Conclusions - The all oral combination of SRd has significant clinical activity in pts with MM. Importantly, in len naïve pts, the ORR was 91%. No new or unexpected toxicities were observed. The combination has no thrombotic, cardiac, pulmonary, liver or renal toxicity. The main DLT was thrombocytopenia. This phase 1 trial demonstrated that selinexor be can safely combined with Rd in RRMM with high ORR in len naïve pts. These results support the further studies in both newly diagnosed MM as well as in RRMM. DisclosuresBahlis:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Janssen, BMS, Celgene: Consultancy; Celgene: Research Funding. Sebag:Celgene, Janssen: Consultancy. Lentzsch:BMS: Consultancy; Amgen: Consultancy; Caelum Biosciences: Other: leadership position and stock. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Bayer: Research Funding. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment.

Patient-Reported Symptoms during Ibrutinib Holds: A Withdrawal Syndrome

Background:The Bruton tyrosine kinase (BTK) inhibitor ibrutinib recently became the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). The management of ibrutinib-related toxicities, such as bleeding and others, are often managed with temporary interruption of therapy. We observed that some WM patients who held ibrutinib developed symptoms during the time they were holding ibrutinib, which then resolved promptly after ibrutinib reinitiation. Our study aims at describing this “ibrutinib withdrawal” phenomenon.Methods: We identified patients seen at our institution between May 2012 and April 2017 who met clinicopathological criteria for WM, and received ibrutinib therapy. Medical files were manually reviewed to identify patients who reported new-onset symptoms occurring during a temporary hold of ibrutinib therapy. Pertinent clinical data were gathered. Patient characteristics are summarized descriptively. Univariate association with withdrawal symptoms was evaluated with logistic regression models.Results: A total of 189 patients with WM who started ibrutinib were identified; 100 patients (53%) have not held ibrutinib, and 89 (47%) held ibrutinib at some point during therapy. The median time on ibrutinib therapy in patients who held ibrutinib was 23 months (95% CI 13-30 months) and 10 months (95% CI 7-12 months) in patients who did not hold ibrutinib. There were no differences between the patients who held and did not hold ibrutinib with regards to age at WM diagnosis, age at ibrutinib initiation, sex, hemoglobin, platelet count, beta-2-microglobulin (B2M), serum IgM, bone marrow involvement, CXCR4 status, prior treatment and time between WM diagnosis and ibrutinib initiation (p≥0.05 for all factors). From the patients who held ibrutinib, 69 (78%) did not experience withdrawal symptoms and 20 (22%) did. Of the patients who experienced withdrawal symptoms, 17 (85%) were receiving ibrutinib in the relapsed/refractory setting. All patients were holding ibrutinib for the first time since treatment initiation. The median drug hold length was 7 days (range 3-33 days). Reasons for holding ibrutinib included: procedure/surgery (n=12; 60%), toxicity (n=6; 30%), drug interaction (n=1; 5%), and patient choice (n=1; 5%). The median time to symptom development was 2 days (range 0-5 days) from the start of the drug hold. Patient-reported symptoms included: fever (n=16; 80%), body aches (n=6; 30%), chills (n=5; 20%), night sweats (n=5; 20%), headache (n=4; 20%), fatigue (n=2; 10%), arthralgias (n=2; 10%), and weakness (n=1; 5%). There were no differences between patients who became symptomatic and remained asymptomatic during ibrutinib hold with regards to age at WM diagnosis, age at ibrutinib initiation, sex, hemoglobin, platelet count, B2M, bone marrow involvement, CXCR4 status, prior treatment, time from WM diagnosis and ibrutinib initiation and time on ibrutinib (p≥0.05 for all factors). Patients with serum IgM >4,000 mg/dl had a lower proportion of withdrawal symptoms than patients with serum IgM <4,000 mg/dl (9% vs. 30%; p=0.02). The rates of very good partial response (VGPR), partial response (PR), minor response (MR) and no response (NR) to ibrutinib were 16% (n=13), 57% (n=108), 22% (n=41) and 5% (n=9), respectively. No withdrawal symptoms were reported in patients with MR or NR. The proportion of patients with withdrawal symptoms was higher in patients who achieved VGPR (46%) than in patients who achieved PR (25%). Four patients with fever were admitted to the hospital; no infectious etiology was identified. All patients reported resolution of symptoms the same day ibrutinib was restarted following the drug hold. Nine patients had subsequent drug holds, and reported recurrence of the same symptoms during the hold period. Two patients known to develop these symptoms were treated with corticosteroids during a subsequent hold and reported symptomatic relief.Conclusion: We describe patient-reported symptoms that develop in about 20% of WM patients who held ibrutinib therapy. The rate of withdrawal symptoms is lower in patients who started ibrutinib with IgM levels >4,000 mg/dl (9%), and higher in patients who had achieved VGPR on ibrutinib (46%). Such symptoms ensue within 2 days of hold and resolve rapidly following reinitiation of therapy. Clinicians should be aware of this phenomenon which may represent an ibrutinib withdrawal syndrome. DisclosuresCastillo:Millennium: Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Phase I Trial of Regulatory T-Cell Donor Lymphocyte Infusion Plus Daily Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Versus-Host Disease

Low-dose daily Interleukin-2 (IL-2) therapy expands regulatory T cells (Treg) in vivo in patients with chronic graft-versus-host disease (cGvHD). Clinical improvement, primarily partial response, is seen in 50-60% of those treated. We hypothesized that infusion of fresh Tregs prior to low dose IL-2 may augment clinical and immune responses. In a Phase 1 study, we administered fresh Treg-enriched lymphocyte infusions (Treg-DLI) obtained from the original stem cell donor, without in vitro stimulation or expansion, followed by daily low-dose IL-2 as therapy for cGvHD. Methods: 24 recipients of 7-8/8 HLA-matched allogeneic hematopoietic stem cell transplants with steroid-refractory cGvHD on stable immune suppression received escalating doses Treg-DLI: 5 each at 0.1, 0.3, or 1x106 cells/kg plus an expansion cohort of 9 at 1x106/kg. Non-mobilized leukapheresis products were CD8/CD19 co-depleted, then positively selected for CD25+ Tregs via the CliniMACS system (Miltenyi). IL-2 was administered at 1x106 U/m2/day for 8 weeks after Treg-DLI infusion. Subjects: The first 22 subjects had a median age of 48 (range, 23-68), median of 3 cGvHD sites (range, 1-6), and median of 2 prior therapies in addition to steroids (range, 0 -5). Four had prior IL-2 exposure. Median time from cGvHD diagnosis to enrollment was 26 months (range, 7- 84). Manufacturing: All Treg-DLI products met release criteria. Median CD8 and CD19 log-depletions were 4.5 and 4.6, respectively. Released products contained a median of 92.6% CD4+CD25++ cells and 88.2% CD4+CD25+CD27low Tregs, a 24.8-fold enrichment (range, 12.7-43.4). At the highest targeted dose level, a median of 0.98x106 cells/kg were infused (range, 0.64-1.0). Safety: In the 21 subjects evaluable for safety, there were no infusional AEs, no DLTs, and no cases of relapse. 2 subjects underwent a 50% dose reduction of IL-2 for Grade 2 flu-like symptoms and injection site irritation, at provider discretion. Grade 3 AEs possibly related to therapy were dyspnea and edema in 1 subject. At median follow-up of 26 months, 17 subjects are alive. 2-year survival is 82% (95% CI, 54-95%). Response: At 8 weeks, 2 of 5 subjects in Cohort 1 (1 partial response (PR), 1 stable disease with minor response (SDMR)), 4 of 5 subjects in Cohort 2 (2 PR, 2 SDMR), and 8 of 11 subjects at the highest cell dose (1 complete response(CR), 3 PR, 4 SDMR) demonstrated clinical benefit. Response rate (CR+PR) was 33%; clinical benefit rate (CR+PR+SDMR) was 67%. 11 subjects opted to continue IL-2, for a median of 14.5 months (range, 3-39). Of 4 subjects previously on IL-2 alone, 2 were responders (CR, PR) and 1 each had mixed response and SDMR, respectively. Interestingly, 3 subjects with SDMR at 8 weeks manifested PR on extended IL-2. No impact of Treg-DLI dose was observed. At 6 months, median prednisone dose was 15mg (range, 5-40), down from 30mg daily at baseline (range, 5-80). Correlative Immunology: Treg counts and the ratio of Treg to conventional T cells (Tcon) rose over time. Higher Treg:Tcon ratios at baseline (p=0.08) and at 2 weeks into therapy (p=0.03) were associated with clinical response (Figure 1). Breadth of diversity within Treg T-cell receptor β (TCRβ) sequences (Shannon's entropy) and selective expansions of individual Treg clones (clonality) were low in cGvHD subjects at baseline, as compared to normal donors (p<0.01) and to Treg-DLI products (p<0.001). Treg TCRβ entropy increased in cGvHD subjects after 8 weeks of therapy (p<0.05), and resulting entropy was comparable to normal donors (n=16, Figure 2). This normalization was independent of clinical response and persisted through 6 months (n=8). Treg TCRβ clonality trended upwards at 8 weeks but did not reach levels seen in normal donors. Entropy and clonality of CD8 and Tcon TCRβ populations in cGvHD subjects were comparable to normal donors and did not change with therapy. Conclusions: GMP-grade manufacture ofCD25+ enriched Treg-DLI is feasible. In combination with low-dose IL-2, Treg-DLI is safe and has clinical efficacy in steroid-refractory cGvHD, including in those with inadequate responses to IL-2 alone. TCRβ population diversity specifically in Tregs is normalized with therapy. The incremental benefit of adding Treg-DLI to therapy with IL-2 alone on clinical responses, normalization of immunologic diversity, and functional suppressive activity, including at timepoints beyond 8 weeks, is the subject of ongoing analyses. [Display omitted] DisclosuresNikiforow:Kite Therapeutics: Membership on an entity's Board of Directors or advisory committees. Armand:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding; Genmab: Consultancy; Roche: Research Funding; Tensha: Research Funding; Pfizer: Consultancy, Research Funding; Sigma Tau: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Koreth:Millennium Pharmaceuticals: Research Funding; Prometheus Labs: Research Funding; Kadmon Corp: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy.

Individual Patient Dose-Escalated Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Vs.-Host Disease in Children and Adults: Safety, Efficacy and Immune Correlates

CD4+CD25+FoxP3+ regulatory T cells (Treg) are broadly suppressive and play a central role in the prevention of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT). Daily subcutaneous (SC) low-dose interleukin-2 (IL-2) at a fixed dose of 1x106 IU/m2/day in adult patients with refractory cGVHD induces selective Treg expansion and leads to clinical responses in 50-60% of evaluable participants (NEJM 2011, Blood 2016). During daily fixed-dose IL-2 therapy, plasma IL-2 levels rose rapidly by week 1, but subsequently decreased over time. The lower IL-2 levels were associated with a decline in Treg proliferation despite daily IL-2 administration (Sci Transl Med 2013), possibly due to IL-2 sequestration via binding to constitutively-expressed high affinity IL-2 receptors on Treg. We reasoned that IL-2 dose escalation at the time of anticipated fall in plasma IL-2 levels would avoid tachyphylaxis and maximize IL-2 induced Treg numbers in vivo.We conducted a phase 1 trial of individual patient IL-2 dose escalation over 8 weeks in adult and pediatric patients with steroid-refractory cGVHD. Daily SC IL-2 was initiated at 0.67x106 and 0.33x106 IU/m2/day in the adult and pediatric cohorts, respectively. Each participant had dose escalations at weeks 2 and 4 to a maximum dose of 2x106 IU/m2/day in adults and 1x106 IU/m2/day in children. We studied 18 HCT recipients (10 adult: 100% HLA-matched, 100% PBSC grafts, 40% prior aGVHD; 8 pediatric: 87.5% HLA-matched, 87.5% BM grafts, 28.6% prior aGVHD). Median age was 57 years (range, 33-71) in the adult cohort and 12 years (range, 5-22) in the pediatric cohort. The median time from HCT and from cGVHD onset to start of IL-2 treatment was 3 years (range, 1-12.1) and 597 days (range, 234-4336) respectively. Participants had a median of 2 cGVHD organ sites (range, 1-5) and 3 prior cGVHD therapies (range, 1-4) at enrollment. The cohorts did not differ in terms of time since cGVHD onset and number of failed therapies prior to enrollment.Individually dose-escalated IL-2 was well tolerated in children with 1 participant requiring dose reduction for electrolyte imbalances. In the adult cohort, 1 participant withdrew due to cGVHD progression, 1 required dose reduction for injection site reactions and 2 were unevaluable (1 IL-2 hold >1 month, 1 non-compliance). Seven grade 3 AEs were reported for six participants (electrolyte imbalance, vomiting, infection, increased ALT and soft tissue neoplasm); none relapsed. At week 8, objective cGVHD responses (PR) were seen in 7 of 8 pediatric participants (88%), but in only 1 of 8 evaluable adult participants (13%). cGVHD response sites included skin (n=4), joint/fascia/muscle (n=1), lung (n=4), and GI tract (n=2). Eight pediatric and 4 adult participants with clinical benefit (PR or SD with minor response) continued extended duration IL-2 therapy up to 120 weeks.Plasma IL-2 levels were higher in adults at weeks 1 and 2, but immune responses were similar between the 2 cohorts. Dose escalated IL-2 induced a >10-fold increase in median Treg count/µL that peaked at week 6. There were no significant changes in CD4 Tcon, CD8 T cell or B cell count. NK cell count increased >5-fold by week 8. The median Treg:Tcon ratio increased 6-fold from a baseline of 0.05 (Q1-Q3, 0.024-0.114) to a week 5 peak of 0.312 (Q1-Q3, 0.203-0.37). Compared with fixed daily dosing of IL-2 (Blood 2016), the individually dose escalated IL-2 schedule had a slower initial rise in Treg number and Treg:Tcon ratio (Figure 1). This likely reflects the lower starting doses in this study. The maximum IL-2 dose in the adults was twice the previously defined MTD but did not improve Treg expansion. Despite lower IL-2 doses, pediatric patients had a superior clinical response and a trend toward a better immunologic response compared with the adults.We demonstrate for the first time that low-dose IL-2 is safe in children with advanced steroid-refractory cGVHD and results in a high clinical response rate. A maximum dose of 1x106 IU/m2/day was well tolerated by pediatric patients in the extended duration phase and durably maintained Treg numbers above baseline. Five pediatric patients that continued IL-2 therapy for >20 weeks have reduced or discontinued steroid therapy. In adults, intrapatient dose escalation above fixed-dose MTD was not clinically tolerated and did not result in greater Treg expansion or clinical improvement relative to fixed daily dosing. [Display omitted] DisclosuresNikiforow:Kite Therapeutics: Membership on an entity's Board of Directors or advisory committees. Armand:Sequenta/Adaptive: Research Funding; Affimed: Research Funding; Roche: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Infinity: Consultancy; Genmab: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Otsuka: Research Funding; Pfizer: Consultancy, Research Funding; Tensha: Research Funding; Sigma Tau: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Koreth:Prometheus Labs: Research Funding; Amgen, Inc: Consultancy.

Acquired Von Willebrand Disease in Patients with Waldenström Macroglobulinemia

Introduction: Acquired von Willebrand disease (VWD) is uncommonly observed in patients with Waldenström Macroglobulinemia (WM), and necessitates treatment intervention. The clinical characteristics for WM patients with acquired VWD, as well as outcomes following therapy have not been well characterized.Methods: We carried a retrospective study in patients with new diagnosed diagnosed WM who were evaluated at our institution, and tested for the presence of VWD. The presence of any VWD was evaluated by measuring levels of VW factor antigen (VWFAG), VW factor activity (VWFACT) and factor VIII (FVIII). Low-level VWD was diagnosed if VWFAG, VWFACT and FVIII levels were between 30% and 50%. VWD was diagnosed if VFWAG, VWFACT and FVIII were <30%. Univariate and multivariate logistic regression models were fitted to evaluate association of clinical factors and presence of any VWD. We also evaluated the effect of response to therapy on VWFAG, VWFACT and FVIII levels.Results: A total of 320 patients with WM were tested for VWD, of whom 271 (85%) showed no evidence of deficiency, and 49 (15%) showed any VWD. Patients were tested because they provided a history of easy bruising or bleeding. Thirty patients had low-level VWD (61%) and 19 were VWD (39%). The median IgM level of patients with any VWD was 5,660 mg/dl (range 1,800-10,300 mg/dl) and 2270 mg/dl (95% CI 25-11,000 mg/dl) in patients without VWD. Patients with any VWD were more likely to have IgM levels 3,000-5,999 mg/dl and 6,000+ mg/dl (47% vs. 31%, and 45% vs. 6%, respectively; p<0.001) and less likely to have white blood cell count (WBC) >6 K/uL (29% vs. 50%; p=0.006) than patients without VWD. There were no differences in age, sex, hemoglobin levels, platelet count and bone marrow involvement between WM patients with any and without VWD. In the multivariate regression analyses, patients with IgM levels 3,000-5,999 mg/dl and 6,000+ mg/dl had OR 11.1 (95% CI 3.7-33.3; p<0.001) and OR 48.7 (95% CI 14.7-160.8; p<0.001), respectively, of having any VWD. WBC was not associated with presence of any VWD (p=0.34). In the subset of patients who had genomic testing performed (n=125), patients with any VWD were more likely to carry CXCR4 mutations (77% vs. 37%, p<0.001) than patients without VWD. There were no clinical or genomic differences between patients with low level VWD and actual VWD. Of 18 patients with any VWD who received therapy for WM, 6 patients (33%) received proteasome inhibitors + rituximab, 5 (28%) received alkylators + rituximab, 5 (28%) received ibrutinib and 2 (11%) received rituximab alone. Three patients (17%) achieved very good partial response (VGPR), 6 (33%) partial response, 8 (44%) minor response and 1 (11%) stable disease. At the moment of best response, the median IgM level had decreased from 6241 mg/dl to 2274 mg/dl, the median VWFAG level had increased from 21% to 64%, the median level VWFACT had increased from 23% to 58% and the median FVIII had increased from 21% to 57% (p<0.001 for all comparisons). Before therapy, 6 patients (33%) had low-level VWD and 12 (67%) had VWD. After therapy, 14 patients (78%) did not have VWD, 4 (22%) had low-level VWD and no patients had VWD. The depth of response to therapy (change in IgM) correlated with the percentage of change in VFWAG, VWFACT and FVIII (see Figure).Conclusion: Patients with WM can present with acquired VWD, which seems to strongly correlate with high serum IgM levels. VWD improves and in most cases resolves with response to WM therapy. The depth of response to therapy correlates with the degree of improvement in VWD. [Display omitted] DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Bendamustine and Bortezomib-Containing Regimens Produce Higher Response Rates and More Durable Responses Versus Cyclophosphamide-Based Therapy in Frontline Waldenstrom Macroglobulinemia

Background: Waldenstrom macroglobulinemia (WM) is an incurable IgM-secreting lymphoplasmacytic lymphoma. Primary therapy for symptomatic WM patients often consists of combination therapy with an alkylating agent or proteasome inhibitor with rituximab. However, randomized studies comparing these treatment regimens are lacking in WM patients.Methods: We retrospectively searched our database for WM patients who received primary therapy with bendamustine-rituximab (Benda-R), bortezomib-dexamethasone-rituximab (BDR), or cyclophosphamide-dexamethasone-rituximab (CDR) between 2005 and 2016. Pertinent clinical data were collected. Response was assessed based on current criteria. Univariate and multivariate regression models were fitted to evaluate the association between clinical variables and response. Time to events was estimated using the Kaplan-Meier method. The Cox regression method was used to fit univariate and multivariate models for progression-free (PFS) and overall survival (OS). P<0.05 was considered statistically significant.Results: 182 patients with WM were identified who received frontline therapy with Benda-R (n=57), BDR (n=88), and CDR (n=37). No differences in sex, hemoglobin level, platelet count, B2M, bone marrow involvement, IPSSWM, and MYD88 and CXCR4 mutational status were observed between treatment groups (p>0.05 for all comparisons). Patients treated with BDR were more likely <65 years, have serum IgM >4,000 mg/dl, and receive treatment for symptomatic hyperviscosity versus patients treated with Benda-R and CDR. Patients with extramedullary disease and peripheral neuropathy were more likely to be treated with Benda-R and CDR, respectively (p<0.01 for all comparisons). 116 patients (64%) received maintenance rituximab, and did not differ between treatment regimens (p=0.68). Rates of CR, VGPR, PR, minor response and no response to therapy were 12% (n=22), 27% (n=48), 47% (n=84), 6% (n=10), and 8% (n=14), respectively. The rate of major response (PR+) was 86%, and the rate of deep response (VGPR+) was 39%. No difference in response was observed between treatment regimens (p=0.45). In the multivariate logistic analysis, patients with serum IgM >4,000 mg/dl had lower odds of major response to therapy (OR 0.3, 95% CI 0.1-0.8; p=0.02), whereas patients who received maintenance rituximab had higher odds of both a major response (OR 13.9, 95% CI 4.4-44.1; p<0.001) and deep response (OR 2.1, 95% CI 1.1-4.0; p=0.02). For patients treated with Benda-R, BDR, and CDR, the median PFS was 5.5 years (95% CI 4.9-not reached [NR]), 5.8 years (95% CI 4.4-7.4), and 4.9 years (95% CI 2.8-7.0), respectively. In the multivariate regression analysis, an increased risk of progression was associated with B2M >3 mg/l (HR 2.33, 95% CI 1.37-3.96; p=0.002) and serum IgM level >4,000 mg/dl (HR 1.85, 95% CI 1.08-3.20; p=0.02). A decreased risk of progression was associated with both Benda-R (HR 0.2, 95% CI 0.1-0.5; p<0.001) and BDR (HR 0.6, 95% CI 0.3-1.0; p=0.05) when compared to CDR. Maintenance rituximab was also associated with a decreased risk of progression (HR 0.11, 95% CI 0.06-0.21; p<0.001), and the median PFS for patients who did and did not receive maintenance rituximab was 6.8 years (95% CI 5.9-NR) versus 2.8 years (95% CI 2.1-4.1), respectively. No difference in the risk of progression was observed between BDR and Benda-R (p=0.13). The estimated 5- and 10-year OS for all patients was 92% and 79%, respectively; median OS has not been reached. The estimated 5-year OS among patients treated with Benda-R, BDR, and CDR was 95%, 96%, and 81%, respectively; p=0.06). For patients treated with BDR and CDR, the estimated 10-year OS was 87% and 61%, respectively, and was not evaluable for patients treated with Benda-R. Treatment with BDR (HR 0.16, 95% CI 0.04-0.59; p=0.006) and maintenance rituximab (HR 0.17, 95% CI 0.05-0.61; p=0.006) were independently associated with a decreased risk of death.Conclusions: Primary therapy with Benda-R, BDR, and CDR produces high response rates and durable PFS in patients with WM. The risk of progression is lower in patients treated with Benda-R and BDR when compared to CDR. Maintenance rituximab is associated with both major and deep responses to therapy as well as superior PFS and OS. DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

A Phase I/II Study of Pomalidomide and Dexamethasone with Growth Factor Support in Patients with Relapsed/Refractory Multiple Myeloma

A Phase I/II Study of Pomalidomide and Dexamethasone with Growth Factor Support in Patients with Relapsed/Refractory Multiple Myeloma

Haplo-Identical Stem Cell Transplantation for Patients with Multiple Myeloma Who Relapsed after Autografting. a Study from the Cmwp of EBMT

IntroductionHaploidentical stem cells are becoming an alternative stem cell source for patients lacking an HLA-identical sibling or 10/10 HLA-matched donor. While an increasing number of studies for patients with acute leukemia, malignant lymphoma, and MDS are reported there are only very few results of haploidentical stem cell transplants in myeloma patients.Method and patientsIn EBMT registry 50 MMpatients with a median age of 55 y (r: 37 - 73) with relapse after autograft who received a mismatched related stem cell graft after myeloablative (n = 12, 25%) or reduced intensity conditioning (n = 37, 75%) between 2004 and 2014 were reported. The median time to relapse after single (n = 28, 56%) or tandem (n = 18, 36%) autologous stem cell transplantation was 6.2 months (r: 0.1 - 30.5) and the median time between last autograft and allograft was 17.4 months (r: 2 = 74 months).At time of allograft 4 (8%) of the patients were in CR, 21 (42%) in PR, 9 (18%) had stable disease or minor response, and 15 (30%) had progressive disease. The majority (84%) received peripheral blood stem cells as graft source and GvHD prophylaxis with ex- or in-vivo T-cell depletion (CD34 selection or ATG) (Cyclophosphamide post transplant) was performed in 37% of the patients while 63% did not receive any in-vivo or ex-vivo T-cell depletion.ResultsAfter a median follow-up of 52 months (95% CI: 12-112) the cumulative incidence of non-relapse mortality at 1 year was 20% (95% CI: 9 - 31%) and the cumulative incidence of relapse at 3 years was 56% (95% CI: 42 - 70%) resulting in an estimated 3-year PFS and OS of 15% (95% CI: 5 - 26%) 31% (95% CI: 7 - 45%), respectively. Significant factor for improved OS in a univariate analysis was only the use of BM (3 y OS: 71% (95% CI: 38 -100%) vs. 24% (95% CI: 11 - 38%), p = 0.02) and for relapse a higher but not significant incidence for ex-vivo T-cell depletion was observed (p = 0.07). The use of cyclophosphamide post transplantation as GvHD prophylaxis did not influence NRM, relapse incidence, PFS, OS, or chronic GvHD.ConclusionHaploidentical stem cell transplantation after relapse to an autograft is feasible for MMpatients. Major treatment failure is the high incidence of relapse. Post-transplant cyclophosphamide had no major impact on outcome in this limited number of patients. DisclosuresDreger:medac: Other: Travel grants; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Jansen: Consultancy; Jansen: Consultancy; medac: Other; medac: Other: Travel grants; medac: Other: Travel grants; medac: Other; Gilead: Consultancy, Speakers Bureau; medac: Other; medac: Other; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Jansen: Consultancy; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Jansen: Consultancy; Riemser: Consultancy, Research Funding; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; medac: Other: Travel grants; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau. Corradini:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Zuckerman:BioSight Ltd.: Consultancy. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Petersen:Sanofi: Membership on an entity's Board of Directors or advisory committees. Schönland:Sanofi: Research Funding; prothena: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Speakers Bureau. Garderet:Amgen: Honoraria; Takeda: Honoraria.

Pilot Study of Pembrolizumab for Immunoprevention in Smoldering Multiple Myeloma

Background: The current management of patients with smoldering multiple myeloma (SMM) is watchful waiting. However, a fraction of these patients are at significant risk of progression to symptomatic multiple myeloma (MM). In a recent study, expression of PD-L1 on tumor cells correlated with increased risk of progression from SMM to MM (Dhodapkar et al Blood. 2015; 126(22): 2475-2478) suggesting a role for immune checkpoint blockade for immunoprevention of MM. Pembrolizumab is a humanized monoclonal antibody against programmed death receptor-1 (PD-1) and blocks the interaction between PD-1 and PD-L1. Here, we report the results of a pilot study evaluating the safety and efficacy of pembrolizumab in intermediate- and high-risk SMM patients (I-HR-SMM). Methods: Patients with I-HR-SMM by PETHEMA, Mayo or SWOG criteria were eligible. Permbrolizumab was administered at a dose of 200 mg IV every 21 days for up to 8 cycles. Patients were eligible to continue treatment for up to 24 cycles if they achieved ≥ minor response after 8 cycles. The primary objective was the overall response rate (ORR) after 8 cycles. The target ORR was 25%. The trial was conducted by the Simon's Minimax design and the ORR was estimated accordingly (Simon, 1989). Twelve patients were planned for the first stage. If at least one patient had ≥ partial response, 4 more patients could enroll for a total of 16 patients. Serial peripheral blood mononuclear cells and bone marrow samples were collected for comprehensive immunophenotyping using multiparametric flow cytometry, and molecular profiling with gene expression profiling (GEP) and exome sequencing. Results: Twelve patients with I-HR-SMM were dosed on the first stage between 08/2016 and 06/2017 (Table 1a/b). Median age was 67.5 years (range 49-74). Median number of cycles received was 8 (range 3-8) and all 12 were evaluable for safety and efficacy. Median follow up was 8.54 months (4.7 to 9.6 months). One patient achieved a stringent complete remission (sCR) (8%), ten patients had stable disease (83%), and one patient had progressive disease (8%). The patient with sCR had HR-SMM by GEP70 and FISH (deletion 17p and amplification of CKS1B) and 50% plasma cells infiltration in the bone marrow at study entry. The sCR with negative flow cytometry on bone marrow was noted in this patient after only 3 cycles of therapy and response is ongoing 8 months after the end of treatment. Five patients discontinued therapy due to related adverse events: grade 2 elevation in LFT (n=2), grade 3 myalgia (n=1), and grade 3 acute kidney injury (AKI) due to tubulo-interstitial nephritis (n=2) [all resolved with discontinuation of treatment or prednisone administration]. There were no grade 4/5 adverse events. Enrollment on second stage is ongoing. Imunophenotyping of paired baseline and end of treatment bone marrow samples showed that the patient who achieved sCR had high levels of PD-1 expression on CD4+ and CD8+ T cells at baseline and showed evidence of CD8+ T-cell activation after therapy with greater upregulation of CD69, CTLA-4, PD-1, TIM-3, 4-1BB, and ICOS relative to non-responders. In contrast, expression of other immune checkpoint molecules such as TIM-3, LAG-3, and CD244 were greater on T cells in non-responders at baseline relative to the responder suggesting greater exhaustion of T cells in non-responders. Molecular profiling including GEP, exome sequencing, and neoantigens analysis is ongoing and will be presented at the meeting. Conclusions: This pilot study of pembrolizumab monotherapy showed that it is tolerable and can induce sCR in patients with SMM. More importantly, it suggested that immunoprevention to prevent progression of SMM to MM is possible. Additional biomarker studies are needed to identify patients that are most likely to respond to this approach. Our correlative studies also provide insights into potential future combination approaches to further improve efficacy of immunoprevention strategies in SMM. [Display omitted] DisclosuresManasanch:takeda: Consultancy; celgene: Consultancy; sanofi: Research Funding; quest diagnostics: Research Funding; merck: Research Funding; adaptive biotechnologies: Consultancy. Lee:Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Pimera Inc: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Research Funding; Takeda: Consultancy. Patel:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy; Celgene: Consultancy. Thomas:Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Neelapu:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karus: Research Funding; Cellectis Inc.: Research Funding; Poseida Therapeutics, Inc: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Extra-Corporeal Photopheresis Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Vs.-Host Disease: Efficacy, Safety and Immune Correlates

CD4+CD25+FOXP3+ regulatory T cells (Treg) are dominant suppressors of innate and adaptive immune effector cells that enhance tolerance. Treg augmentation can control immune activation underlying chronic graft-versus-host disease (cGVHD). In prior studies, daily subcutaneous (SC) low-dose interleukin-2 (IL-2) therapy for 8-12 weeks induced preferential Treg expansion in-vivo, with objective clinical responses in over half of evaluable participants (NEJM 2011, Blood 2016). Alternative immunomodulatory approaches like extra-corporeal photopheresis (ECP) also have efficacy in cGVHD and may function via Treg augmentation. Combining ECP plus IL-2 could offer therapeutic synergy.We report on a prospective single arm phase 2 trial of twice-weekly ECP (weeks 1-16) plus sequential low-dose IL-2 (1x106 IU/m2/d SC, weeks 9-16) for treatment of steroid-refractory cGVHD. The study enrolled 25 participants (48% male, 88% HLA-matched, 100% PBSC grafts, 52% prior aGVHD). Median participant age was 62 years (range, 34-76). Median time from HSCT and from cGVHD onset to start of treatment was 919 days (range, 177-2842) and 524 days (range, 58-2697) respectively. Participants had a median of 3 cGVHD organ sites (range, 2-5). The median follow-up time in survivors is 16 months (range, 2.1-26).ECP plus IL-2 was well tolerated: 1 participant withdrew due to IL-2 adverse effects (AE) (myalgia, fatigue), and 3 were additionally unevaluable (1 cardiac arrest; 1 parainfluenza infection, 1 still undergoing treatment). None required IL-2 dose reduction. There were four grade 3 AEs during the 16-week study (1 participant had dehydration/hypotension/syncope, possibly IL-2-related;1 had ECP-related anemia). None experienced relapse. At week 16, cGVHD objective partial responses (PR) were documented in 14 of 21 evaluable participants (67%). None had cGVHD progression. Response sites included skin (n=9/18), joint/fascia/muscle (n=7/16), liver (n=1/1), lung (n=2/9), and GI tract (n=3/5). 18 participants with clinical benefit (PR, and stable disease with minor response) proceeded to extended ECP plus IL-2 therapy.Immunologically, 8 weeks of ECP alone did not induce significant changes in buffy coat WBC or absolute lymphocyte count (ALC). Peripheral blood CD3 T cell counts/µL fell, with a median CD8 and CD4 conventional T cell (Tcon) decrement of -109 (Q1, Q3: -220, -13; p<0.001) and -68 (Q1, Q3: -244, -19; p=0.023), respectively, at week 8 (Figure 1A). There was an early fall in Treg cell counts/µL, with a median decrement of -4 (Q1, Q3: -9, 0; p=0.033) at week 4, without change in NK or B cell counts or Treg:Tcon ratio. The addition of low-dose IL-2 thereafter induced a >5-fold increase in median Treg count/µL (p<0.001), from a baseline of 9 (Q1, Q3: 5, 17) at week 8 to a peak of 72 (Q1, Q3: 22, 186) at week 10, plateauing at 50 (Q1, Q3: 33, 71) at week 16 (Figure 1A). No significant change in CD4 Tcon or B cell count was noted. NK cell count increased 1.7-fold (p=0.009). The median Treg:Tcon ratio increased 4-fold (p<0.001): from a baseline of 0.06 (Q1, Q3: 0.03, 0.08) at week 8 to a peak of 0.26 (Q1, Q3: 0.12, 0.42) at week 12, and remained elevated at 0.17 (Q1, Q3: 0.14, 0.34) at week 16 (Figure 1B). Treg count and Treg:Tcon ratio remained elevated in responders during extended ECP plus IL-2 therapy.Immunologically, clinical responders had a higher median Treg count/µL vs. non-responders after 1 and 6 weeks of IL-2 therapy (21 vs. 11, p<0.001; 73 vs. 29, p=0.016 respectively). Treg:Tcon ratio at week 2 and 6 after IL-2 therapy was also higher in responders (0.29 vs. 0.15, p=0.038; 0.28 vs. 0.13, p=0.016 respectively). Applying our previous cutoffs (Blood 2016), Treg:Tcon ratio ≥0.2 after 1 week of IL-2 was also predictive of clinical response (p=0.05).In summary, in steroid-refractory cGVHD, ECP was associated with a fall in peripheral CD8, CD4 Tcon, and Treg counts. The addition of low-dose IL-2 thereafter induced profound Treg and NK cell augmentation. Clinical responses (PR) to combination ECP plus IL-2 therapy were documented in 67% of the evaluable participants. Those with early rise in Treg count and Treg:Tcon ratio after the addition of IL-2 were likelier to benefit. However, the overall clinical efficacy of ECP plus IL-2 did not appear markedly higher than low-dose IL-2 alone. [Display omitted] DisclosuresKoreth:Prometheus Labs: Research Funding; Kadmon Corp: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding; Affimed: Research Funding; Roche: Research Funding; Pfizer: Consultancy, Research Funding; Genmab: Consultancy; Infinity: Consultancy; Otsuka: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma

Introduction - Elevated expression of XPO1 (Exportin 1) increases the nuclear export / inactivation of tumor suppressor proteins (e.g. p53, IkB, p21, FOXO) and promotes the export / translation of eIF4E-bound oncoprotein mRNAs (e.g. c-MYC, BCL-2, Cyclin D). Selinexor, the first oral Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 and has shown promising anti-cancer activity across hematological and solid tumors in Phase 1 and 2 clinical trials, including in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Considering the breadth of knowledge on selinexor ± dexamethasone (dex) in RRMM, eltanexor (KPT-8602), a second-generation oral SINE compound, was evaluated for safety and tolerability in this pt population. The primary objectives were to determine the safety, preliminary anti-MM activity, and the recommended Phase 2 dose (RP2D) of eltanexor ± dex.Methods - In this Phase 1/2 study, using a 3+3 dose escalation design, eltanexor is dosed orally (QDx5 or QoDx3 weekly) for a 28-day cycle with a starting dose of 5 mg. Pts with less than a minor response (MR) after 1 cycle or partial response (PR) after 2 cycles were permitted to add low dose dex. In some pts, dex was added from day 1. The pharmacokinetic (PK) and pharmacodynamic (XPO1 mRNA) profiles of eltanexor were evaluated.Results - As of 31-July-2017, 36 pts (23 M/13 F; median prior therapies: 7; median age: 66) with RRMM were enrolled; most with quad- or penta-refractory MM. Median duration of treatment is 76 days (range: 10 - 441). Most common drug related adverse events (AEs; >30%, any grade) are thrombocytopenia, nausea, neutropenia, anemia, leukopenia, fatigue, diarrhea, and dysgeusia. Grade ≥3 related AEs include thrombocytopenia (43%), neutropenia (26%), leukopenia (14%), and anemia (11%). Although 2 dose limiting toxicities (DLTs; >4 missed doses and Grade 4 thrombocytopenia) were observed in different cohorts, the protocol-defined maximum tolerated dose (MTD) was not reached. Further evaluation of 20 or 30 mg eltanexor QDx5 + dex is ongoing in expansion cohorts. The preliminary efficacy of eltanexor (Table 1) shows that eltanexor ± dex can induce responses and disease stabilization. A dose proportional PK profile without accumulation has been observed. Mean Cmax and AUC0-inf values for eltanexor doses of 5 - 60 mg ranged from 36.6 - 284 ng/mL and 164 - 2,581 ng*h/mL, respectively. Tmax and t½ ranged from 0.5 - 8.0 h and 4.0 - 7.1 h, respectively. For all cohorts evaluated, the fold-change maximum (Fmax) of XPO1 mRNA expression was achieved 4 - 8 h post-dose (tmax). The Fmax for XPO1 mRNA was roughly dose proportional to the Cmax of eltanexor. As expected, based on observations with other SINE compounds, the plateau for Fmax of XPO1 mRNA in treated pts was ~6 - 10-fold change and was achievable at 40 - 60 mg of eltanexor.Conclusions - Based on preliminary data, eltanexor is well tolerated and demonstrates promising activity in this heavily pre-treated RRMM population. The gastrointestinal and constitutional toxicities observed with <40 mg eltanexor QDx5 are low grade, transient, and do not limit dosing. Thrombocytopenia (with minimal clinical impact) was the most common hematologic toxicity and was expected in this population. As with selinexor, addition of low-dose dex (20 mg) twice weekly (BIW) to the eltanexor treatment regimen appeared to improve efficacy while maintaining tolerability. Of the 31 evaluable pts, 25 received dex with their eltanexor regimen. Therefore, both 20 and 30 mg eltanexor QDx5 + 20 mg dex BIW are being evaluated to clearly define the RP2D. Based on these results and anti-tumor activity previously observed with selinexor, pts with advanced colorectal cancer, castration resistant prostate cancer, and myelodysplastic syndrome are being enrolled. [Display omitted] DisclosuresRossi:Thrassos: Consultancy; Celgene: Consultancy. Baz:Sanofi: Research Funding; BMS: Research Funding; merck: Research Funding; takeda: Research Funding; celgene: Honoraria, Research Funding; karyopharm: Research Funding. Hofmeister:Roche: Research Funding; Celgene: Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding. Shustik:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Richter:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Vogl:Teva: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; GSK: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Calithera: Research Funding. Baloglu:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

PD-1 Blockade with Pembrolizumab in Relapsed Low Grade Non-Hodgkin Lymphoma

Background: The natural history of low grade non-Hodgkin lymphoma (NHL) typically includes multiple relapses and short responses to therapy after each relapse. The development of novel therapies for NHL patients with multiple relapses is therefore clinically needed. In previous studies, we demonstrated the presence of PD-1 positive exhausted T cells in the nodal tissue of low grade NHL patients. We therefore hypothesized that blocking PD-1 will activate tumor infiltrating T cells to induce effector cell-mediated cytotoxicity. To test this hypothesis, we performed a phase 2 trial (MC1485) to test the efficacy of the PD-1 blocking antibody pembrolizumab in relapsed/refractory low grade NHL.Methods: Relapsed/refractory low grade NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL) who had ECOG performance 0-2 and normal organ function were included in arm B of the MC1485 trial. Patients with prior allogeneic stem cell transplant were excluded. Pembrolizumab 200 mg was administered intravenously every 3 weeks until progression, excessive toxicity, or completion of 2 years of therapy. The primary end point of this study was overall response rate. Tumor T cell infiltration and expression of PD-1 and PD-L1 were assessed with standard immunohistochemical (IHC) staining.Results: 23 patients including 18 FL, 2 MZL and 3 LPL were enrolled and the median age was 67 years (47-82). The median number of prior therapies was 4 (1-20). 17 out of 23 (74%) patients had received more than 2 prior therapies. 100% of patients had received an anti-CD20 antibody and 22/23 (96%) had received chemoimmunotherapy. 6 (26%) had a prior autologous stem cell transplant. 10 (43%) had received prior novel agents including lenalidomide or idelalisib or other experimental therapies. The median number of pembrolizumab doses received was 4 (range, 1 to 16), administered over a median treatment duration of 13.9 weeks (range, 2.6 to 50.8). Drug-related adverse events (AE) occurred in 17 patients (74%) with the common ones being thrombocytopenia in 6 (26%), neutropenia in 5 (22%), anemia in 5 (22%), nausea in 5 (22%), diarrhea in 4 (17%), lymphocyte decrease in 4 (17%), nausea, vomiting and cough each in 3 (13%), and dyspnea in 2 (8%) patients. Drug-related grade 3 or above AE occurred in 9 (39%) patients with most common ones being thrombocytopenia (3, 13%), anemia (3, 13%), neutropenia (2, 8%) and dyspnea (2, 8%). One possibly related death occurred in a patient who had baseline obstructive sleep apnea and developed respiratory failure after two doses of therapy without clear cause. He eventually refused to receive further supportive care. Based on the investigator assessment, 2 FL patients had partial responses (PR, 9%). One LPL patient had minor response using LPL/Waldenstrom macroglobulinemia response criteria (MR, 4%). 11 patients (48%) had stable disease (SD). These two responders had durations of response of 5.5 and 4.9 months respectively (Figure). One MZL patient had ~40% tumor reduction with ongoing therapy. 7 patients (30%) had progressive disease. With a median follow-up being 6.5 months (1.6-24.7), the median progression free survival is 3.4 months (95% CI: 2.1-5.7). The median overall survival has not been reached.Conclusion: Pembrolizumab had an acceptable safety profile in low grade NHL patients. In selected NHL patients, pembrolizumab has activity as single-agent therapy. Biomarker evaluation is needed to select patients who can benefit from this therapy. Further combination therapy will be required to improve efficacy. [Display omitted] DisclosuresDing:Merck: Research Funding. Witzig:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Kura: Research Funding; Novartis: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Abbvie: Consultancy; celgene: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Genetech: Consultancy, Research Funding; pharmacyclics: Consultancy; Nanostring: Research Funding. Reeder:Millennium: Research Funding; Celgene: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Kapoor:Takeda, Celgene and Amgen: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Merck: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding.

An Integrated Analysis of Darbepoetin Alfa (DAR) in the Treatment of Anemia in Patients with Low- or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS)

An Integrated Analysis of Darbepoetin Alfa (DAR) in the Treatment of Anemia in Patients with Low- or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS)

Renal Response in Relapsed Refractory Multiple Myeloma Patients with Severe Renal Impairment at treatment Initiation: Intermediate Data of a Large, Observational, Prospective Study

Introduction: Renal impairment (RI) is a common complication of multiple myeloma (MM) that causes significant morbidity and mortality. Approximately 20%-30% of patients (pts) at diagnosis and more than 50% of pts with advanced disease present RI. Moreover, pts with Acute Kidney Injury (AKI) are more likely to suffer advanced mortality and have worse prognosis. Thus, reverting renal dysfunction is critical for the management of these pts. However, there is little information on the renal evolution of pts with relapsed refractory MM (RRMM) receiving treatment with novel agents in clinical practice.Aims: This is an observational, prospective, multicenter study aimed to evaluate the renal response to the administered therapy in pts with RRMM and moderate (clearance [CrCl] 30-50 mL/min) or severe (CrCl<30 mL/min) RI. We present results focused on the subgroup of pts with severe RI from an intermediate analysis 15 mos) after completion of the inclusion period (cut-off: May 8, 2017).Methods: Renal and MM responses were evaluated according to International Myeloma Working Group criteria. eGFR by the Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were compared to analyse renal response. Descriptive statistics have been used for response rates and Kaplan Meier estimates for Progression-Free Survival (PFS) and overall survival (OS).Results: A total of 327 pts were recruited and 99 pts with severe RI at study entry were included in the current analysis (mean ± SD age 75 ± 10 years, 49% male, 58% in first relapse). Main comorbidities were arterial hypertension (59%) and diabetes (27%). At diagnosis, 46% of pts had ISS stage III. Median time (range) from MM diagnosis was 2.5 (0.2-10.4) years. Main MM types were Ig G (50%), Bence Jones (20%), and Ig A (13%); 13% of pts with severe RI presented with high risk cytogenetic abnormalities. Main anti-myeloma therapies were: lenalidomide (LEN; 37%), bortezomib (BORT; 31%), and other treatments (OT; 32%: different chemotherapy regimens, 20%; and other non-chemotherapy treatments, 12%).The mean baseline eGFRs according to CG, MDRD and CKD-EPI formulas were 20.0/19.9/19.1 (± 7.5/9.4/9.0) mL/min,with a strong correlation between them (coefficients: CG/MDRD = 0.91; CG/CKD-EPI = 0.93; MDRD/CKD-EPI = 0.99). Using RIFLE classification, the proportion of pts with AKI during the MM treatment was 51.5%. Overall, 26.3% (95% CI, 16.7%-33.8%) of patients had a renal response (2.1% renal complete response [renalCR], 2.1% renal partial response [renalPR], and 22.1% renal minor response [renalMR]) according to the CG formula while responses measured by the MDRD formula, were 24.0% (3.1% renalCR, 2.1% renalPR, and 18.8% renalMR). Median time to best renal response was 1.7mos (range, 0.5-8.9 mos). After adjusting by demographic and clinical characteristics (52 evaluable pts), ISS stage III was statistically significantly associated with poor renal response. There were no significant differences in GFR improvement between pts according to the administered treatment (P = 0.306). The overall MM efficacy response rate (≥ PR) was 35.4%. The overall response rates were 48.4% and 38.9% for pts receiving BORT and LEN, respectively whereas only 11.5% of pts receiving OT achieved at least PR. PFS was 14.9 mos with LEN-based, 6.5 mos with BORT-based, and 2.6mos with OT (P=0.0003). OS was 24.6mos with LEN-based, 14.6 mos with BORT-based, and 4.6mos with OT (P < 0.0001).Conclusions: This observational study shows that LEN- and BORT-based treatments are the regimens most commonly used in the clinical practice in RRMM pts with severe RI. These therapies can improve RI in approximately 26% of pts, with no differences between treatments. Despite this, there are still many pts who develop AKI during the course of treatment. DisclosuresMorales:Alexion: Other: Personal fees; Celgene: Other: Personal fees. de la Rubia:Amgen: Other: Honoraria; Janssen: Other: Honoraria; Celgene: Other: Honoraria.

Chimeric Anti CD-20 Monoclonal Antibody-Rituximab in Refractory Childhood Idiopathic Thrombocytopenic Purpura: An Indian Experience.

The treatment of chronic idiopathic thrombocytopenic purpura (ITP) continues to be a challange. A significant proportion of patients continue to be symptomatic despite all available means of therapy. Recently Rituximab, a chimeric anti CD-20 monoclonal antibody has been shown to be an effective mode of therapy in such patients with an overall response rate of appx 50 %.We studied the efficacy and side effects of this therapeutic modality in 10 children (6 girls) with chronic ITP. The patients belonged to pediatric age group (median age: 9 years, range 4–18 years) with 4 children less than 10 years of age. All the patients were screened for systemic illnesses and different secondary causes leading to thrombocytopenia. They all had been treated with standard therapies using conventional and high dose steroids, ciclosporin cyclophosphamide, vincristine, periodic use of high dose IVIG and splenectomy in 6 patients, but had continued to be symptomatic with recurrent mucocutaneous bleeds and markedly low platelet counts (< 20x 109/L). All patients received intravenous Rituximab at a dose of 375 mg/M2 as weekly dose for 4 consecutive weeks. The infusion related side effects were a few (n= 3) and minor. They included urticarial rash (1) and fever(2) that responded to antipyretics. None of these were severe enough to interrupt the treatment. A complete response was defined as a platelet count > 100 x 109/L, partial response (PR) as count > 50x109/L and a minor response as a count < 50x109/L but without the need of continued treatment. Patients showing no significant rise in platelet count were marked as showing no response. Of the 10 evaluable children, 9 (90%) showed overall response; 4 (40%) showed complete response and 4 (40 %) showed partial response. Two (20%) patients showed minor responses. Patients have been under follow up for last 3 years. The patients with CR and PR have been in remission for longer periods (as much as 150 weeks ).The side effects due to the therapy have been few and very mild. Besides infusional reactions in 3 patients (Transient fever in 2 and mild rash in 1) there were no significant toxicities. No correlation could be found between clinical/laboratory parameters with the responsiveness or the duration of response except that patients showing a higher degree of response continued to be in remission for a longer period as compared to the ones with lesser degree of response. The high percentage of response in our patients as compared to the ones in other studies could be due to the fact that our patients belonged to a younger age group. Probably children show a better response.In conclusion, Rituximab offers a safe and convenient modality of treatment in symptomatic children with refractory ITP. Its use is certainly cost effective even in a developing country in view of the good degree of a sustained response in these refractory patients wherein all modalities of treatment have failed.

Preliminary Results of a Phase II Study of CC-5013 (Lenalidomide, Revlimid®) in Patients with Cutaneous T-Cell Lymphoma.

Background: Mycosis fungoides (MF)/Sézary syndrome (SS) represent the most common type of cutaneous T-cell lymphoma (CTCL) comprising 50% of cutaneous lymphomas. No treatment cures patients with CTCL and patients ultimately develop advanced or relapsed disease that is refractory to standard treatment options. The direct antitumor effects associated with potent anti-angiogenic, anti-inflammatory and T-cell co-stimulatory activity and favorable toxicity profile of lenalidomide provided the rationale to use this agent in patients with MF/SS. Preliminary results of this ongoing phase II trial indicate encouraging early signs, responses and manageable toxicity.Methods: The study is designed to accrue 29 evaluable patients. Nine patients have been enrolled between April and August 2005. Eight patients are evaluable for response and toxicity. Lenalidomide was administered orally on an outpatient basis. Patients received 25 mg daily for 21 days with 7 days rest of a 28-day cycle. Patients with stable disease and partial response will continue treatment with a maximum of 2 years if tolerated or unless unforeseen toxicities occur. Response was assessed after every cycle using Composite Assessment (CA) of Index Lesion Disease Severity for skin lesions, absolute Sézary cell count for quantification of circulating malignant lymphocytes and/or CT scans for evidence of adenopathy or visceral disease.Results: The median patient age was 60 years (range, 47–69) and patients had received a median of 6 prior treatment regimens (range, 2–9). Preliminary results indicate that a total of 3 patients (38%) have already experienced an objective response (defined as a CA ratio less than or equal to 0.5 with no new clinically abnormal lymph nodes, no progression of existing clinically abnormal lymph nodes, and no new cutaneous tumors) after 1 to 3 cycles of therapy. Four patients have achieved a minor response such as regression of cutaneous tumor lesions and cervical lymphadenopathy in one patient each, and skin improvement from initial generalized erythroderma to less severe erythema with less scaling and remain on therapy. The most common side effects were fatigue (4 patients-grade I) and lower leg edema (3 patients-grade II). GI symptoms (grade I) and anemia (grade II) was noted in one patient each. One patient discontinued treatment after one cycle because of neurological symptoms (slurred speech) possibly related to the study drug and one patient for progressive disease after 3 cycles following a minor response.Conclusions: In our study lenalidomide has shown encouraging activity in heavily pretreated patients with advanced MF/SS and a mild toxicity profile. Accrual is ongoing. Revlimid® is a registered trademark of Celgene Corporation.

Re-established grasslands on farmland promote pollinators more than predators

Agricultural intensification is among the major threats to farmland biodiversity and associated ecosystem services. Agri-environment schemes in Europe aim to counteract the continuous decrease of permanent grassland habitat and related decline of biodiversity in agricultural landscapes. We established new grasslands adjacent to permanent old grasslands to study effects on arthropod pollinators and predators. Over three years, we assessed the effects of newly established grasslands on activity density, species richness and assemblages of pollinators (syrphids, bumblebees, solitary bees) and ground-dwelling predatory arthropods (carabids, spiders, ants). Pollinator activity density and species richness of all three pollinator groups approximately doubled in newly established grasslands compared to old grasslands, indicating suitability of new grasslands as pollinator feeding habitat. Predator responses were less consistent. Species richness and activity density of carabids and ants did not increase in new grasslands, indicating slower adaptation to new habitats. Spider activity density increased in the newly established grasslands and in adjacent cereal fields, but no significant differences in species richness compared to old grasslands were observed. Bumblebees and solitary bees showed distinct distance decays in cereal fields. Syrphid activity density declined in cereal fields far away from the newly established grasslands, but not nearby. Carabids increased and ants decreased in species richness and activity density with increasing distance from old grasslands in cereal fields and newly established grasslands alike. In contrast, spider species richness and activity density decreased with increasing distance from old grasslands in cereal fields only, but there was no distance decay in newly established grasslands. While pollinators utilized the additional floral resources within the whole area of newly established grassland quickly, predators reacted much slower. Even after three years, there was no measurable response of carabid and ant activity density and only a minor response of spiders. This clearly shows that short-term measures are not sufficient to sustainably conserve farmland biodiversity. The conservation of permanent grassland and landscape heterogeneity should be prioritized. However, the restoration of new grassland should also be encouraged by agri-environment schemes as a supplement, to enhance functional biodiversity in agricultural landscapes.

Effect of Adding Bevacizumab to Chemotherapy on Pathologic Response to Preoperative Systemic Therapy for Resectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis

BackgroundLiver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM. MethodsWe systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. ResultsOf the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P < .001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P < .001), in the bevacizumab group. The analyses showed a low level of heterogeneity (I2 = 0% to 6%). Publication bias was not found. ConclusionsThis meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials. MicroAbstractThe benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.

Contesting racist talk in families: strategies used, and effects on family practices and social change

ABSTRACT Differences of opinion between family members are familiar narratives for many people. When family tensions involve racist talk, how do family members navigate this? This paper asks: (1) What strategies do family members use to challenge racist talk within their own family? and (2) What effects do these strategies have on (a) on-going racist talk, (b) family practices and (c) broader social change around racism? In Australia, where this project was based, anti-racism campaigns often advocate for individual contestations of racism, but their effects on the structures of racism are not well known. This paper identifies four strategies used to challenge racist talk in families including (1) undertaking safe critique, (2) humour, (3) direct confrontation or violence and (4) reference to personal / familial experiences of racism. I found that individual contestations of racist talk within families may, at times, shift family practices (Morgan 2011) away from expressions of racism, or further the development of race literacy amongst some family members. However, this was very much a minority response to individual contestations of racist talk. To create social change, this paper highlights the critical need for activity that much more broadly seeks to dismantle racist structures and institutionalized racism.

Efficacy of naxitamab in patients with refractory/relapse (R/R) high-risk neuroblastoma (HR-NB) by bone/bone marrow (BM) evaluation, potential sites of residual disease.

10022 Background: NB is the most common extracranial solid tumor in children and half of patients present with high-risk disease. Bone and BM are frequent sites of metastatic disease and can serve as a reservoir for residual disease driving relapse. Naxitamab, a GD2-binding monoclonal antibody, was recently approved in the United States in combination with GM-CSF for the treatment of pediatric patients ≥1 year of age and adult patients with R/R HR-NB in the bone/BM who have demonstrated a partial response (PR), minor response (MR), or stable disease (SD) to prior therapy. Here we describe outcomes from the registrational Trial 201 (NCT03363373) detailed by bone/BM involvement. Methods: HR-NB patients with primary refractory disease or incomplete response to salvage treatment following relapse or progressive disease (PD) (in both cases including SD, MR and PR) with disease limited to bone and/or BM were eligible. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3 mg/kg/infusion (9 mg/kg/cycle) in combination with GM-CSF at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles were repeated every 4 weeks. Response was assessed after Cycle 2 and then every 2-3 months by revised International Neuroblastoma Response Criteria (INRC) using BM biopsies/aspirates and 123I-MIBG scintigraphy or FDG-PET. Effectiveness was concluded if the lower limit of the Clopper-Pearson exact 95% confidence interval (CI) of overall response rate (ORR) was &gt;20%. We report efficacy data on 22 patients and safety data on the first 25 patients enrolled. Results: 13 (59%) patients had NB in bone, 2 (9%) had NB in BM, and 7 (32%) had NB in both bone and BM. Summary of overall response and response by compartment. Conclusions: Naxitamab provided clinically meaningful activity in both bone and BM with ORR of 68% and had a manageable AE profile. Clinical trial information: NCT03363373. [Table: see text]