ALBERT

Description: Background: Primary central nervous system lymphoma (PCNSL) is a rare type of extranodal non-Hodgkin lymphoma (NHL). Most cases occur in the immunocompetent population. Despite advances in therapy, the prognosis of PCNSL remains poor, with 5-year overall survival (OS) rates at 30-50% (Ferreri 2011). The standard of care treatment regimen includes high-dose methotrexate (HD-MTX), often in combination with other multiagent CNS penetrating chemotherapies. Although the addition of rituximab in systemic aggressive B-cell NHLs has shown improvement in OS, the benefit of this agent in PCNSL has not been confirmed in a prospective dataset (Bromberg 2017). The majority of PCNSLs are classified as diffuse large B-cell lymphomas (DLBCL), and the outcomes based on treatment and cell of origin (germinal center B-cell (GCB) vs. non-GCB subtype) have yet to be fully elucidated. In this review, we report our findings from a series of PCNSL patients based on treatment regimen and cell of origin. Methods: This is a retrospective study of patients with PCNSL diagnosed and treated at the University of Colorado Hospital from 1995 to 2017. Chart abstraction included demographics, DLBCL subtype by Hans algorithm (Hans 2004), treatment details, and outcomes. OS was examined using Kaplan Meier methods, while bootstrap resampling and a z-test was used to compare median survival times across strata. Fisher's exact test was used to determine whether treatment responses were different between those that received treatment withHD-MTX and rituximab versus HD-MTX without rituximab. A significance level of 0.05 was used for all tests. When assessing differences by subtype, treatment type, relapse, and treatment response the data was subset to include only patients without a prior HIV diagnosis. Results: 71 patients with PCNSL were identified. 13 patients were HIV positive (the HIV status of 1 patient was unknown). Of the remaining 57 immunocompetent patients, 39 patients were treated with HD-MTX, of which 29 patients received rituximab in combination therapy. The most commonly received regimen was rituximab with methotrexate, procarbazine, and vincristine (R-MPV) (43.6%, 17 of 39). Median age in the HD-MTX subgroup was 65 years, with 83% of patients with KPS〉70 at diagnosis. EBV positivity was noted in only 4 of 39 samples (10.2%), while 25 of 39 (64.1%) tested negative; the remaining patients' data was not available. Median OS was 29.9 months for all 71 patients (Figure 1). There was no significant difference in median OS between those with and without HIV (p=0.127). 22 of 29 (75.9%) patients in the HD-MTX with rituximab group achieved a complete response (CR) while no patients (0%; 0 of 10) in the HD-MTX without rituximab group achieved a CR. The number of patients with a CR was significantly higher for those that received HD-MTX with rituximab compared to those that received HD-MTX without rituximab (p

Description: Key Points Checkpoint blockade via anti–PD-1 mAbs was associated with a high overall response rate in relapsed Hodgkin lymphoma allo-HCT patients. Checkpoint blockade via anti–PD-1 mAbs after allo-HCT can be complicated by rapid onset of severe and treatment-refractory GVHD.

Description: Introduction Tenalisib (RP6530) is a next generation, oral, selective, PI3Kδ/g inhibitor with nanomolar inhibitory potency. Besides its apoptotic and anti-proliferative activity, Tenalisib modulates the tumor microenvironment resulting in reprogramming of tumor associated-macrophages (TAMs) from a protumor M2 phenotype to an antitumor M1 phenotype and a marked reduction of angiogenesis in pre-clinical models. Tenalisib has demonstrated activity in patients with relapsed/refractory lymphoid malignancies (Carmelo, ASH 2016 and Oki, ASCO 2018). Since there are concerns over long-term safety of PI3K δ or PI3K dual δ/g inhibitors with respect to immune-mediated toxicities (e.g. transaminitis, colitis and pneumonitis), cytopenias, and infections, a pooled safety analysis across two Phase I studies in patients treated with Tenalisib was performed. Methods Safety data was pooled from two Phase I Tenalisib monotherapy trials (NCT02017613 and NCT02567656) with similar key eligibility criteria. Patients had R/R lymphoid malignancies with ≥1 prior therapy. Responses were evaluated in lymphoid malignancies using IWG criteria (Cheson et al., 2007) and in CTCL using the modified Severity Weighted Assessment Tool (mSWAT). Adverse events were graded according to CTCAE v4.03. Results A total of 93 patients were included in the analysis. Among these patients, 34% were PTCL, 32% CTCL, 16% HL, 6% DLBCL and 12% were other lymphomas. Patients received a median of 5 prior therapies. 53 % of patients received Tenalisib for ≤ 3 months, 21% for 3-6 months and 26% for 〉 6 months. The overall incidence of related AEs and ≥G3 AEs were 58% and 29% respectively (Table 1). Very few AEs were seen with exposures 〉6 months and mainly included single cases of diarrhea, anemia, edema, and abdominal pain. There were no incidences of late onset toxicities such as colitis and pneumonitis and most of the AEs happened during the initial three months of therapy. No treatment discontinuations due to AE's were seen in patients exposed to 〉 6 months of treatment. Efficacy response assessments of the 66 evaluable patients demonstrated an ORR of 45% in TCL (44% in PTCL (8/18, 3 CR, 4 PR) & 45% in CTCL (9/20, 9 PR)), 29% (4/14; 1CR; 3PR) in HL, and 13% (1/6; 1CR) in DLBCL. Conclusion In this pooled safety analysis with long term follow-up, Tenalisib exhibited an improved safety profile when compared to other investigational/marketed PI3K inhibitors. The incidence of transaminitis was low and occurred within the first two to three cycles of therapy. In particular, there were no occurrences of pneumonitis or colitis in patients that had been on treatment for 〉 3 months and beyond. Incidence of neutropenia/thrombocytopenia and infections was limited. Tenalisib can therefore be safely combined with a diverse array of other agents active in lymphoid malignancies. Tenalisib is currently being studied in combination with Pembrolizumab and Romidepsin and as a monotherapy in a Phase II trial in indolent NHL. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ramchandren:Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Devata:Affimed: Research Funding. Routhu:Rhizen Pharmaceuticals SA: Employment. Barde:Rhizen Pharmaceuticals SA: Employment. Nair:Rhizen Pharmaceuticals SA: Employment. Carlo-Stella:Boehringher Ingelheim Italia: Consultancy; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; AstraZeneca: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Genenta Science: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Amgen: Speakers Bureau.

Description: BACKGROUND: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare complication of solid organ transplant, with no standard therapy. Epstein-Barr virus (EBV) is ubiquitous making the virus a candidate therapeutic target. For virus targeted therapy to be effective, antiviral agents must be phosphorylated by lytic-phase kinases BXLF1 and BGLF4. We hypothesized that lytic kinases would be constitutively expressed in PCNS-PTLD and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based regimens in patients who often have impaired organ function and poor performance status. METHODS: We investigated the safety and efficacy of EBV-kinase targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS-PTLD. Patients with biopsy-proven PCNS-PTLD following solid organ transplantation were eligible for treatment. Immune suppression was reduced in all patients prior to treatment. Induction therapy consisted of 14 days of AZT 1500 mg IV BID, GCV 5 mg/kg IV BID, dexamethasone 10 mg IV BID and rituximab 375 mg/m2 once weekly for four weeks. Maintenance antiviral therapy was initiated on day 15 with valganciclovir 450 mg and AZT 300 mg, both twice daily. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of BGLF4 and BXLF1 by in situ hybridization or immunohistochemistry. To test the hypothesis that expression of EBV kinases conferred sensitivity to antiviral therapy, 293T cells were transfected with cDNAs (or control vectors) encoding for full length BXLF1 and/or BGLF4. Transiently transfected cells were tested for expression by immunoblot and drug sensitivity to AZT/GCV was performed by MTS and flow cytometry assays. RESULTS: Twelve patients (7 M, 5 F) with a median age of 49 were treated from 1998-2014. Transplant history included kidney (N=11), pancreas (N=2), and liver (N=1). Histology data included diffuse large B-cell lymphoma (N=7) and grade III lymphomatoid granulomatosis (N=5). EBV positivity (EBER-ISH) and CD20 expression were documented in all cases. All patients completed induction therapy. Median follow-up time and median duration of maintenance therapy were 28 months (range 2 - 143). The mean progression free survival (PFS) was 33.8 months. Overall response rate (ORR) was 83.3%. Eight patients achieved a complete response (CR) within a median time of 2 months (range 0.75 – 6 months). Two patients had a partial response (PR) with an average time to response of 1.25 months. Two patients (2/12) had progressive disease (PD). Causes of death included septic shock (n=3), pulmonary embolism (n=1), and poor functional status requiring hospice (n=1). One patient had PD at the time of death. Median overall survival (OS) was 29 months (range 2 – 143 months). Grade 3-4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=2), and neutropenia (N=5). Toxicity in the maintenance phase was generally reversible with holding therapy. Three patients required discontinuation of AZT during maintenance treatment for transfusion-dependent anemia persisting after holding AZT for 7 days or neutropenia coinciding with systemic infection. One patient had AZT discontinued due to nausea and vomiting that led to acute kidney injury. Evaluation of BXLF1, BGLF4 and LMP1 was completed in 7 patients and found to be positive in all cases. LMP1 and kinase expression occurred in mutually exclusive regions of the tumor. Expression of BXLF1 and BGLF4 led to enhanced sensitization of 293T cells to antiviral-induced growth inhibition and apoptosis. CONCLUSIONS: EBV-kinase targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be effective treatment for patients with EBV+ PCNS-PTLD. We demonstrated durable responses without disease recurrence and minimal toxicity. Expression of BXLF1 and BGLF4 kinases provides a mechanistic rationale for an antiviral approach to this disease and an attractive option to replace high dose chemotherapeutic regimens with less toxic targeted therapy in patients with compromised transplant organ function. A multi-center phase II trial is in development to further investigate this regimen in patients with immune deficiency-related CNS EBV-LPD. Figure 1 Figure 1. Disclosures Porcu: Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees.

Description: INTRODUCTION: Acute graft-versus-host disease (aGVHD) remains a significant cause of morbidity and mortality following allogeneic stem cell transplantation (allo-SCT). CD74, also known as the HLA class II invariant chain, is expressed on the surface of antigen presenting cells (APCs) and involved in pro-survival signaling. Milatuzumab is a humanized IgG1K monoclonal antibody that interacts with CD74 leading to rapid internalization and cytotoxicity independent of antibody crosslinking. Milatuzumab, therefore, has potential to inhibit APC-mediated T-cell proliferation and decrease the risk of aGVHD. In a xenogeneic SCID mouse model, milatuzumab administered prior to SCT prevented the development of GVHD, suppressed circulating cytokines, and reduced the mortality of the SCID mice (Chen, BBMT, 2013). METHODS: We are performing an open-label, single-center phase 1 dose escalation trial to determine the maximum tolerated dose of milatuzumab when added to standard GVHD prophylaxis in the setting of reduced-intensity conditioning (RIC) for HLA matched (≥8/8) sibling or unrelated donor SCT. Patients are premedicated with dexamethasone and receive milatuzumab intravenously on Days -7, -4, -1, and +7. The initial starting dose was 8 mg/kg with continued dose escalation to 16 mg/kg and 20 mg/kg in cohorts of 3-6 until unacceptable toxicity. Dose limiting toxicities are defined as graft failure, any ≥ grade 4 organ toxicities, or ≥ grade 4 infusion reactions attributable to milatuzumab (CTCAE v4.0). Expected hematologic toxicities from SCT were excluded from this definition. Acute and chronic GVHD was recorded according to Consensus and NIH criteria, respectively. RESULTS: Seven patients have been treated on trial with median follow up of 53 days post SCT (average 105 days; range 13-234). The median age is 59 years (range 26-70). Patients had a variety of hematologic malignancies (3 AML, 1 MDS, 1 ALL, 1 HD, & 1 MCL). Median Sorror comorbidity score (CMI) was 1 (range 0-8). Patients were in complete remission prior to SCT except for one MCL patient with partial response to prior therapy. Recipients received RIC with fludarabine (30 mg/m2 days -7 to -3) and busulfan (0.8 mg/kg Q6 hours days -4 & -3 x8 doses) along with standard GVHD prophylaxis including tacrolimus and methotrexate (D+ 1, 3, 6, & 11). Donors were 8/8 HLA-matched siblings (UPNs 2, 4, & 7) or matched unrelated (UPNs 1, 3, 5, & 6). All patients received four doses of milatuzumab. Three individuals were initially treated with 8 mg/kg (DL1) and 3 received 16 mg/kg (DL2). At DL2, two of 3 patients had grade 5 sepsis with one having grade 4 respiratory failure. As a result, three more patients will be enrolled to DL1 to further assess safety; one has been treated thus far. The most common toxicities attributable to milatuzumab were grade 1-2 including GI complaints, nasal congestion, fever, parathesia, and urticaria. One patient had grade 1-2 infusion reactions on two occasions. Four of 7 patients had cutaneous aGVHD with 2 of 4 experiencing grade 1, one with grade 2, and one with grade 4 (table 1). One patient experienced grade 1 GI aGVHD. The grade 4 aGVHD (UPN 6) was histologically and phenotypically indistinguishable from toxic epidermal necrolysis/Stevens-Johnson syndrome and that patient was treated with brentuximab for steroid-refractory cutaneous GVHD. He subsequently died due to polymicrobial sepsis. Two other patients died, one from relapsed AML (UPN 4) and one from staphylococcal aureus sepsis (UPN 5). CONCLUSIONS: While the grade 5 events in DL2 (16 mg/kg) were not considered specifically attributable to milatuzumab, DL1 has been expanded to further evaluate safety of this dose. Four patients have been enrolled at DL1 with only grade 1 and 2 aGVHD reported, either cutaneous or upper GI. We will continue to accrue at DL1 and pending tolerability may amend the protocol to test an intermediate dose of 12 mg/kg. Milatuzumab remains an intriguing potential agent to prevent aGVHD. Abstract 1168. Table 1: Matched RIC allo-SCT recipients treated prophylactically with milatuzumab for prevention of aGVHD UPN Age Disease CMI Dose Level aGVHD Follow up 1 59 AML 4 1 D+20 (grade 2/stage 3 cutaneous) Alive D+234 2 70 AML 0 1 D+22 (grade 1/stage 2 GI & cutaneous) Alive D+181 3 26 HD 1 1 D+35 (grade 1/stage 1 cutaneous) Alive D+186 4 51 AML 1 2 none Relapse D+26 (Death D+53) 5 66 MDS 8 2 none Death D+13 6 57 ALL 0 2 D+16 (grade 1/stage 2); D+34 (grade 4/stage 4) cutaneous Death D+48 7 59 NHL (MCL) 0 1 none Alive D+22 Disclosures Goldenberg: immunomedics: Employment. Wegener:immunomedics: Employment.

Description: PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). Although single-agent anti-PD-1 monoclonal antibodies (mAb’s) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAb’s, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again, PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained.

Description: Introduction: Lenalidomide (len) is an immunomodulatory agent with single agent activity in relapsed and refractory peripheral T-cell lymphoma (PTCL). CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) is a common initial regimen. Herein, we report the completed phase II results of the combination of len-CHOEP. Methods: Eligible patients (pts) had newly diagnosed PTCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. Based on phase I results [Lunning et al. T-cell Forum 2018] 10 mg of len was chosen for phase II. CHOEP was administered at standard doses with len given on days 1-10 of 21-day cycle for six planned cycles. Mandatory prophylaxis included aspirin (ASA) or alternative thromboprophylaxis and growth factor support per institutional guidelines with each cycle. A PET/CT after two cycles (PET-2) for interim response assessment was required per protocol. The primary endpoint was complete response (CR) by PET/CT after 6 cycles (PET-6) of len-CHOEP utilizing the revised Cheson 2007 criteria with secondary endpoints to include toxicity, overall response rate (ORR), progression free survival (PFS), 2-year PFS, and overall survival (OS). Pts who had CR or partial response (PR) at the end of therapy had the option of len maintenance (10 mg/day for 21 out of 28 days) for 1-year or consolidative autologous stem cell transplant (ASCT) without len maintenance. Per protocol pts dosed at 10 mg in phase I (N=8) were included in the phase II analysis. Results: Forty pts with PTCL-NOS (23), ALK negative ALCL (5) and AITL (12) enrolled into the phase II portion. Median age was 62 years (range 24-79) and 21 were male. Thirty (75%) pts completed all 6 cycles. Reasons for discontinuing len-CHOEP early were toxicity (n=6) and progressive disease (PD; n=4). PET-2 was not done in 4/40 pts (n=2 each either not performed or PD). In an intent to treat (ITT) analysis the CR rate at the end of treatment was 48% (19/40; 95CI-32-64%) with an ORR of 68%. In pts who completed 6 cycles (n=30) the CR/ORR rate was 63%/87% respectively. Seven pts (18%) experienced primary treatment failure. Of the 19 pts in CR at end of initial therapy, 14 were in a CR at PET-2 assessment. Two pts in a PET-2 CR discontinued prior to cycle 6 due to toxicity and have not progressed. Five pts converted from a PR to CR after PET-2, but 7 of 13 PRs remained PRs. Responding pts (CR/PR; n=30) proceeded either to an ASCT (n=18), len maintenance (n=10) or neither (investigator/pts preference; n=2). At a median follow up of 13 months (range: 4-23 months), the 1-year estimated PFS and OS is 68% [95% CI--50-80%] and 89% [95%CI--73-96%] respectively. There were five grade (G) 5 events including PD (n=1), secondary malignancy (n=1; AML), sepsis (n=2), and cardiac arrest (n=1). Serious or recurrent adverse events (SAEs or AEs) of interest occurring during any cycle included 38% G 3-4 febrile neutropenia despite mandated GCSF use, 43% G 3-4 anemia, 43% G 3-4 thrombocytopenia (without report of G 3-4 bleeding or bruising despite ASA use), 3% G3-4 rash (all G 23%), and 8% G 3-4 diarrhea (all G 43%). Conclusions: The phase II portion of the study in an ITT population noted an unexpectedly modest 48% CR rate and a high discontinuation rate (15%) due to AEs or SAE. The utility of response at PET-2 and post initial therapy strategy (len maintenance vs ASCT) continue to be monitored for PFS and OS in this limited cohort. Improving frontline outcomes for pts with PTCL remains an unmet need. Disclosures Lunning: Celgene: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Spectrum: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Astra-Zeneca: Consultancy; Genzyme: Consultancy; Juno: Consultancy; Genentech: Consultancy; Verastem: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Portola: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Corvus: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Advani:Janssen Pharmaceutical: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Agensys: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role. Vose:Epizyme: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics, Inc.: Research Funding; Abbvie: Honoraria; Acerta Pharma: Research Funding; Kite Pharma: Research Funding; Merck Sharp & Dohme Corp.: Research Funding. Mehta-Shah:Verastem: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Spectrum: Consultancy. Haverkos:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Takeda: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Regeneron: Research Funding.

Description: Background: Cobomarsen (MRG-106) is an inhibitor of miR-155, a microRNA with a strong link to cutaneous T cell lymphoma (CTCL) pathogenesis. The goals of this first in human study are to evaluate the safety, tolerability, pharmacokinetics, and efficacy of cobomarsen in mycosis fungoides (MF) patients. Methods: This Phase 1 trial evaluated cobomarsen given via intralesional injection (75 mg/dose), subcutaneous (SC), IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Patients must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Patients received 6 doses, either subcutaneous or intravenous, in the first 26 days of the study followed by weekly or bi-monthly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of cobomarsen on quality of life was assessed by Skindex-29. Results: 38 subjects receiving IV or SC treatment (25 male/13 female, median age 59 years) have been on study for up to 22 months. As of the data cut off, no serious AEs have been attributed to cobomarsen. The most common AEs reported in greater than 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed dose limiting toxicities (DLTs): Grade 3 worsening pruritus and Grade 3 tumor flare. The maximum tolerated dose (MTD) has not yet been reached. In the subcutaneous and IV cohorts, 29 out of 32 (91%) evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). The best improvements were observed after more than 1 month of treatment. Eleven out of twenty-one (52%) patients receiving more than one month of dosing (6 doses) achieved greater than 50% reduction in mSWAT score. The mean duration of response (n=11) was 213 days, as of data cut off. Eight patients achieved a partial response meeting the criteria for ORR4, an objective response rate lasting at least four months in duration. The overall skin response in patients who received cobomarsen as monotherapy or cobomarsen with concurrent stable therapy were not significantly different. Improvement in quality of life (QOL), as measured by the Skindex-29 total score, correlated with reductions in mSWAT score during the treatment phase. Conclusions: These results demonstrate that cobomarsen is well-tolerated, has clinical activity, and has the potential to impact MF quality of life. These encouraging data support the continued investigation of cobomarsen in the CTCL population. The study is expanded to enroll patients with other hematologic malignancies in which miR-155 is elevated and relevant, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and adult T cell lymphoma/leukemia (ATLL). Final safety and efficacy data on CTCL mycosis fungoides will be presented. Disclosures Foss: Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Mallinkrodt: Consultancy.

Description: Background: Cytomegalovirus (CMV) infection remains an important cause of morbidity and cost following umbilical cord blood transplantation (UCBT). While the introduction of letermovir represents a novel approach to CMV prophylaxis, optimal CMV management strategies remain controversial. An intensive strategy to prevent CMV disease including one week of pre-transplant ganciclovir followed by high-dose acyclovir or high-dose valacyclovir through day 100 reduced post-transplant CMV reactivation (Milano et al, Blood 2011), but this approach is costly and potentially challenging to administer. Insurance approval for outpatient high-dose valacyclovir is variable, and the pill burden of high-dose acyclovir for post-transplant patients may be unmanageable. A recent study demonstrates that the removal of pre-transplant ganciclovir does not decrease CMV reactivation rates (Hill et al, BBMT 2018). At our center we have attempted to implement the high intensity strategy described above, but for patients who are unable to obtain high-dose valacyclovir at hospital discharge, we have transitioned to standard dose 800 mg acyclovir twice daily. Additionally, in November 2016, we discontinued pre-transplant ganciclovir. To examine the efficacy of these approaches, we compared CMV outcomes among these patients. Methods: All consecutive adult CMV seropositive (CMV R+) patients who received their first double UCBT from December 2009 to January 2018 were reviewed. Patients were excluded if they had initial CMV reactivation prior to day 0 or after day 100, graft failure, death or relapse before day 100, or participated in a CMV prophylaxis trial. Starting the day of transplant, CMV R+ patients received either valacyclovir 2 grams orally 3 times daily or acyclovir 500 mg/m2 intravenously every 8 hours until able to tolerate oral medication. At hospital discharge, patients for whom valacyclovir was authorized by insurance received valacyclovir 2 grams orally 3 times daily through day 100. All others received acyclovir 800 mg orally twice a day through day 100. No patients received anti-thymocyte globulin with conditioning. All patients transplanted prior to November 2016 received pre-transplant ganciclovir, after which pre-transplant ganciclovir was discontinued. CMV reactivation was defined as any detectable PCR positive whole blood sample (checked twice weekly through day 100). Thresholds for treatment with ganciclovir or foscarnet evolved over time, but required high initial copies levels, persistent or rising DNAemia, or evidence of end-organ involvement. Acute graft-versus-host-disease (aGVHD) treatment was based on institutional guidelines and uniform for all patients. Results: Demographics of the 101 patients studied are provided in table 1. Forty-one patients received prophylaxis with high-dose valacyclovir until post-transplant discharge only (median 23 days) and 60 received valacyclovir through day 100. Between day 0 and day 100, fewer patients in the high-dose valacyclovir group (n= 20, 36%) had CMV reactivation compared to those in the acyclovir group (n= 23, 57%), p= 0.025 (figure 1). Nine patients (9%) in the acyclovir group and 6 (6%) in valacyclovir group received CMV directed treatment (p= 0.1). Patients who did or did not received pre-transplant ganciclovir had similar rates of CMV reactivation (p= 0.55 in acyclovir arm, p= 0.15 in valacylcovir arm). Overall survival (p= 0.64), neutrophil and platelet engraftment time, and incidence of grade 2-3 (p= 0.7) and grade 3-4 aGVHD (p= 0.3) were comparable between groups. Conclusions: High-dose valacyclovir through day 100 post-transplant as compared to through the day of hospital discharge post-transplant reduced CMV reactivation rates. While threshold for treatment will vary according to institutional protocol, high-dose valacyclovir through day 100 likely reduces treatment episodes. One week of pre-transplant ganciclovir does not reduce CMV reactivation rates. These data provide important baselines for future comparisons of outcomes following letermovir prophylaxis in this population. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoeitic stem cell transplant (allo HSCT) despite current prophylactic regimen. It is fueled by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), leading to damage of host tissues. Front-line treatment with glucocorticoids provide 30-40% complete response. Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody that binds to both soluble and membrane-expressed IL-6R, inhibiting IL-6–mediated proinflammatory activity. A case report and a recent small series (8 patients) with steroid refractory GVHD(SR GVHD) showed encouraging single agent activity of tocilizumab(Gergis et al, 2010; Drobyski et al, 2011). We report our experience on 9 patients who had SR aGVHD and received tocilizumab therapy. Method Tocilizumabwas administered intravenously at a dose of 8 mg/kg every 2 to 3 weeks. aGVHD grading and responses were based on consensus criteria (Przepiorka et al, 1995). Patients were monitored for toxicities and infections. Results The median age at transplant was 48 years (range 25-61). Four patients had double cord allo HSCT, 2 had matched related, 2 unrelated (with one 9/10 matched) and 1 haploidentical after a failed cord HSCT. Six patients had received myeloablative and 3 reduced intensity allo HSCT. All but one patient received tacrolimus and methotrexate for aGVHD prophylaxis, and all were in complete remission of their underlying disease at time of aGVHD. Table 1 includes responses and outcomes to tocilizumab therapy. All patients had GI involvement and 6 patients had two organs involved. Median aGVHD grade was 3 (range 3-4). The median time from first aGVHD onset to tocilizumab administration was 44 days (range 14-176). The median number of infusions was 2(1-6). There were no allergic or infusion-related events. Two patients (22%) had a complete response (CR), and two had mixed responses with CR in one organ, but no response in another. Only one of nine patients survived. Six patients (67%) died from aGVHD and its complications, one from CMV and one from septic shock. The median survival from start of tocilizumab was 26 days (range 13-759). Conclusions While the few tocilizumab treated patients with SR aGVHD reported in the literature have experienced a high response rate of 67%(CR and PR), our limited experience showed a less impressive 22% CR. Although tocilizumab has some activity in the treatment of SR aGVHD, it may not be significantly better than other available agents. Disclosures: Off Label Use: There is currently no standard of practice of steroid-refractory GVHD, every treatment option besides steroids are considered off-label. However, there is evidence to support its use. Tocilizumab Tocilizumab is a humanized anti–IL-6 receptor (anti–IL-6R) monoclonal antibody that binds both soluble and membrane-expressed IL-6R, inhibiting IL-6–mediated proinflammatory activity. In this study, we report our experience with the administration of tocilizumab, an anti-interleukin 6 receptor antibody, in the treatment of steroid refractory GVHD.