ALBERT

Description: Background : DLBCL is an aggressive non-Hodgkin lymphoma (NHL) with poor outcomes in the R/R setting; overall survival (OS) is 28% at 1 year and 20% at 2 years in refractory patients (Crump, Blood 2017). Outcomes are particularly poor for patients ineligible for stem cell transplant (SCT). Ibrutinib is the only once-daily inhibitor of Bruton's tyrosine kinase and is approved for the treatment of various B-cell malignancies. Based on preclinical models, ibrutinib and lenalidomide, an immunomodulator that downregulates the MYD88 pathway, may synergize when combined (Yang, Cancer Cell 2012). Rituximab, an anti-CD20 antibody, has shown activity combined with ibrutinib in NHL (Wang, Lancet Onc 2016). PCYC-1123 is a multicenter, open-label phase 1b/2 study (NCT02077166) evaluating the combination of ibrutinib, lenalidomide, and rituximab (iR2) in R/R DLBCL. Methods : Patients ≥18 years of age with R/R non-GCB DLBCL ineligible for SCT received lenalidomide 20 or 25 mg orally on Days 1-21 of each 28-day cycle plus ibrutinib 560 mg orally once daily and rituximab 375 mg/m2 IV on Day 1 of Cycle 1-6. Treatment was continued until progressive disease (PD) or unacceptable toxicity. Immunohistochemistry (IHC) was performed by central laboratory per the Hans algorithm. The primary endpoint was overall response rate (ORR); secondary endpoints were complete response (CR), duration of response (DOR), progression-free survival (PFS), OS, and safety. Response was determined by investigator assessment per Cheson (J Clin Oncol 2014) every 3 treatment cycles for the first 24 months (mos) and then every 6 cycles thereafter. Results: In total, 89 patients were enrolled and treated in phase 2 (n=55 and n=34 in the lenalidomide 20 mg and 25 mg cohorts, respectively). The median patient age was 64 years; 58% were male. At study entry, 53% of patients were refractory to their last therapy and 16% were primary refractory, 47% had relapsed, and 63% had stage IV disease. Median number of prior DLBCL therapies was 2 (range 1-5), with the most common being R-CHOP (73%), RICE (26%), and R-DHAP (13%). Twenty patients had prior SCT. All patients were non-GCB by IHC; for the 47 patients with tumor tissue available for nanostring testing by GEP, there was 84% concordance in non-GCB status (activated B-cell [ABC] or unclassified). The median time on study was 16 mos (range 30% of patients) were diarrhea (53%), fatigue (42%), neutropenia (40%), cough (34%), anemia (33%), peripheral edema (33%), and maculopapular rash (31%). The most common Grade 3/4 AEs were neutropenia (36%) and maculopapular rash (18%); Grade 3/4 atrial fibrillation occurred in 2% of patients. Grade 5 TEAEs occurred in 12 patients; of these, 7 were due to worsening of DLBCL, and 5 were not related to PD (pneumonia [n=3], sepsis [n=1], and cardiac arrest [n=1]). AEs led to discontinuation in 17% of patients (n=15) overall (those occurring in ≥2 patients were worsening of DLBCL [n=4], pneumonia [n=2], and thrombocytopenia [n=2]). Conclusions : The iR2 combination of ibrutinib, lenalidomide, and rituximab showed an ORR of 47% in patients with follow-up response assessment, with 28% CRs, including durable CRs of up to 22 mos. The safety profile was manageable in this phase 2 study of patients with R/R non-GCB DLBCL ineligible for SCT. Further evaluation of the iR2 regimen is ongoing. Disclosures Ramchandren: Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Johnson:Boehringer Ingelheim: Honoraria; Incyte: Honoraria; Epizyme: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Kite: Honoraria. Ghosh:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; Forty Seven Inc: Research Funding; Bristol-Myers Squibb: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding. Ruan:Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy. Ardeshna:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Johnson:Takeda: Other: Travel, accomodations, expenses; Roche: Consultancy, Honoraria, Speakers Bureau. Cunningham:Clovis: Research Funding; Eli Lilly: Research Funding; 4SC: Research Funding; Bayer: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Merck: Research Funding; Merrimack: Research Funding. de Vos:Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy; Bayer: Consultancy. Radford:Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Research Funding; GSK: Equity Ownership; Novartis: Consultancy, Honoraria; AstraZeneca: Equity Ownership, Research Funding; BMS: Consultancy, Honoraria. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership; Novo Nordisk: Equity Ownership; Pfizer: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership. Munoz:Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Ping:Pharmacyclics LLC, an AbbVie company: Employment; AbbVie: Equity Ownership. Kwei:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie company: Employment; AbbVie: Equity Ownership. Eckert:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. Neuenburg:Pharmacyclics LLC, an AbbVie company: Employment, Other: Travel, accomodations, expenses. Goy:University of Nebraska: Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants outside of the submitted work, Research Funding; Hackensack University Medical Center, RCCA: Employment; Hakensackumc: Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Ibrutinib in combination with lenalidomide and rituximab is not approved by the FDA for treatment of diffuse large B-cell lymphoma (DLBCL)

Description: Background : Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have poor treatment outcomes, especially patients who are ineligible for stem cell transplantation (SCT). Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US for various B-cell malignancies. Preclinical data suggest potential synergy when combining ibrutinib with lenalidomide, a thalidomide analogue that disrupts signaling downstream of B-cell receptor and MYD88. An open-label, multicenter, phase 1b/2 study (NCT02077166) was initiated to evaluate the iR2 regimen of ibrutinib, lenalidomide, and rituximab in R/R DLBCL. Results from the ongoing phase 2 portion of the study evaluating the safety and activity of the iR2 regimen in SCT-ineligible adults aged ≥18 y with R/R non-germinal center B-cell-like (non-GCB) DLBCL per Hans method are presented here. Methods : The iR2 regimen was administered at the recommended phase 2 dose (RP2D) of once-daily 560 mg PO ibrutinib with 20 mg PO lenalidomide on Days 1-21 and 375 mg/m2 IV rituximab on Day 1 of Cycles 1-6 in 28-day cycles (additional 25-mg cohort ongoing). The primary phase 2 efficacy endpoint was ORR; the null hypothesis of an ORR of 40% will be tested against the alternative hypothesis of an ORR 〉60%. Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Response was based on investigator assessments and performed using CT or MRI scans after every 3 treatment cycles for the first 24 mo and every 6 mo thereafter. For rash and neutropenia, if clinically indicated, study medication was withheld until resolution or improvement to grade 1, and treatment with oral corticosteroids and antihistamines (for rash) or hematopoietic growth factors (for neutropenia) was initiated. Results : A total of 55 patients were enrolled and treated at the RP2D with 20 mg PO lenalidomide in phase 2. The median age was 63 y; 58% were male; 64% had stage IV disease; 24% had primary refractory disease; 53% were refractory to the last therapy. Patients had received a median of 2 (range: 1-5) prior systemic therapies for DLBCL; the most common regimens were R-CHOP (71%), RICE (29%), and R-DHAP (16%). Among the 44 response-evaluable patients with follow-up imaging, the ORR was 55% (95% CI: 39%-70%; n=24) and included CR in 30% (n=13) and PR in 25% (n=11); 5 patients (11%) had stable disease. The median DOR was 9 mo for all responders and 10 mo for those who achieved a CR. The median maximum percent change from baseline in the size of the target lesion(s) was −61%. Among all 55 treated patients, the median duration of iR2 treatment was 4 mo (range: 0-13), and almost half (45%) of patients were still receiving iR2 treatment at the time of analysis (Figure 1A). Progressive disease was the most common reason for treatment discontinuation (45%). Median PFS was 5 mo (95% CI: 3-12; Figure 1B), with 6-mo and 12-mo PFS rates of 44% and 28%, respectively. Median OS was 17 mo (95% CI: 8-17), with 6-mo and 12-mo OS rates of 85% and 58%, respectively. For the 24 responders, median PFS was 12 mo (95% CI: 6-12), and median OS was 17 mo (95% CI: not evaluable). The majority (85%) of patients experienced a grade 3-4 TEAE; events reported in ≥5% of patients included neutropenia (33%), maculopapular rash (15%), anemia (11%), diarrhea, dyspnea, fatigue, and hypokalemia (5% each). Neutropenia, maculopapular rash, and anemia were the only grade 3-4 TEAEs in 〉2 patients considered related to either ibrutinib or lenalidomide. Of the 8 patients with grade 3/4 maculopapular rash, 7 received concomitant corticosteroids. Grade 5 TEAEs were experienced by 6 patients and included worsening of DLBCL (n=3), pneumonia (n=2), and sepsis (n=1). Doses of study treatment were temporarily interrupted or reduced due to TEAEs in 62% and 29% of patients, respectively. Discontinuation due to TEAEs occurred in 11% of patients (worsening of DLBCL [5%], pneumonia [4%], and sepsis [2%]). No cases of febrile neutropenia were reported. Conclusions : The iR2 combination regimen of 560 mg ibrutinib, 20 mg lenalidomide, and 375 mg/m2 rituximab demonstrated promising activity with a manageable safety profile in these difficult-to-treat R/R non-GCB DLBCL patients ineligible for SCT. Evaluation of the iR2 regimen using a dose of 25 mg lenalidomide and biomarker analyses, including GEP, are ongoing. Disclosures Ramchandren: Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Johnson:Genmab: Consultancy; Novartis: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Janssen: Consultancy, Research Funding; Kite: Consultancy; Incyte: Consultancy; Boeringher Ingelheim: Consultancy; Bristol-Myers Squibb: Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Eisai: Research Funding. Ghosh:Forty seven Inc: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Spectrum: Consultancy; F. Hoffman-La Roche Ltd: Research Funding. Ardeshna:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Johnson:Takeda Pharma: Other: Funded an educational place for me to attend the Lugano Lymphoma conference in June 2017. Cunningham:Roche pharmaceuticals: Research Funding. Kassam:AbbVie: Equity Ownership. Radford:Pfizer: Research Funding; BMS: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership; Celgene: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau. Bailly:Abbvie: Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Takeda: Other: Travel, Accommodations, Expenses. Munoz:Bayer: Consultancy, Speakers Bureau; Janssen: Consultancy; Kite Pharmaceuticals: Consultancy, Speakers Bureau; Juno: Consultancy; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Alexion: Consultancy; Pharmacyclics LLC, an ABBVIE Company: Consultancy. Ping:Pharmacyclics, an Abbvie company: Employment; Abbvie: Equity Ownership. Co:Abbvie: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Neuenburg:Pharmacyclics, an Abbvie company: Employment.

Description: Background CD123 (IL-3 receptor alpha-chain) is a therapeutic target for hematological malignancies based on high expression levels in acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and other cancers. The anti-CD123 antibody-drug conjugate (ADC), IMGN632, comprises a humanized monoclonal antibody covalently linked to a DNA - alkylating cytotoxic payload which is currently in phase 1 evaluation for relapsed/refractory CD123-positive hematological malignancies (NCT03386513). Novel approaches to enhance the efficacy of ADCs are of significant therapeutic interest. Our laboratory has previously demonstrated that the Poly ADP Ribose (PARP) inhibitor, olaparib, synergistically enhances the activity of the CD33-targeted ADC, IMGN779, in preclinical AML models (Portwood S et al, ASH 2016). Based on the hypothesis that PARP inhibition will synergize with DNA damaging mechanism of IMGN632, we investigated the ability of olaparib and other PARP inhibitors (PARPi) in clinical development (talazoparib, niraparib, rucaparib, and veliparib) to enhance the therapeutic efficacy of IMGN632 across diverse human AML cell lines and primary relapsed/refractory AML samples. Materials and Methods CD123 expression on human AML cell lines (HEL, HL60, MV411, Molm13, EOL-1, THP-1, and Kasumi-1) was quantified by flow cytometry using QuantriBrite beads. AML cells were continuously cultured for 72-96 hours with varying doses of IMGN632 (range 100pM - 100nM) and specific PARP inhibitors (range 100pM -15μM) alone and in combination. Cell viability was measured using a WST-8 colorimetric assay. Primary clinically annotated CD123+ AML cells from patients with relapsed/refractory disease were obtained under IRB-approved protocols from the Roswell Park Hematologic Procurement Shared Resource and cultured short-term in the presence of multiple cytokines plus IMGN632 +/- PARP inhibitors. Apoptosis (Annexin V/PI), cell cycle, and DNA damage (H2AX) were evaluated by flow cytometry. Additive vs. synergistic effects were determined by combination indices using Compusyn software. PARP trapping was evaluated by Western blot analysis in nuclear lysates obtained from IMGN632 +/- PARP inhibitors treated AML cells. Results High expression levels of CD123 (range 937 - 2231 CD123 molecules/cell) were detected on multiple human AML cell lines (HEL-luc, MV411, Molm13, EOL-1, and THP-1) relative to unstained negative controls. Western blot analysis of nuclear lysates from AML cells demonstrated that all PARP inhibitors had varying degrees of PARP trapping on DNA. Continuous single agent 5-day treatment with all tested PARP inhibitors resulted in dose dependent in vitro inhibition of AML cell line growth with IC50 values ranging from 360 nM (talazoparib, most potent) to 78uM (veliparib, least potent). Combination therapy using PARP inhibitors (doses ranging from 300nM - 15uM) and IMGN632 (10nM) consistently resulted in enhanced anti-leukemic effects over monotherapy (Figure 1 for example). Synergistic anti-proliferative effects were obtained across all tested AML cell lines (n=5) with combination indexes ranging from 0.3-0.7 by Compusyn analysis. Combination therapy correlated with enhanced DNA damage, tumor cell apoptosis, and cell cycle arrest of AML cells. Moreover, IMGN632 and PARPi (olaparib or talazoparib) resulted in single agent activity against clinically annotated primary relapsed/refractory AML patient samples with evidence of synergistic effects when combined in vitro. Conclusions Addition of PARP inhibitors to IMGN632, a novel anti-CD123 antibody-drug conjugate, further enhances DNA damage effects and consistently results in synergistic in vitro anti-leukemic effects across multiple CD123+ AML cell lines and primary AML patient samples. Further studies investigating this novel combinatorial approach in specific molecular subtypes of AML with variable baseline sensitivities to PARPi are currently ongoing. Our results strongly support future investigation of PARPi as a novel class of agents with the potential to significantly enhance the efficacy of DNA-alkylating ADCs and/or cytotoxic chemotherapy for hematological malignancies. Figure. Figure. Disclosures Sloss: ImmunoGen: Employment. Watkins:ImmunoGen Inc.: Employment. Kovtun:ImmunoGen Inc.: Employment. Adams:ImmunoGen Inc.: Employment. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: CTLA-4 is a critical inhibitory “checkpoint” molecule of immune activation. Several recent reports have described patients with immune dysregulation and lymphoproliferative disease resulting from 2 different genetic diseases that directly or indirectly cause CTLA-4 deficiency. Numerous articles have also been published describing CTLA-4 blockade in cancer immunotherapy and its side effects, which are ultimately the consequence of treatment-induced CTLA-4 deficiency. Here, we review these 2 diseases and CTLA-4 blockade therapy, emphasizing the crucial role of CTLA-4 in immune checkpoint regulation.

Description: Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) occurs primarily in older patients (pts) who often have increased comorbidities and cannot tolerate aggressive treatments, which leads to poorer outcomes (Balducci, Cancer Control 2015; Thurmes, Leuk Lymphoma 2008). Alkylating agents, such as chlorambucil (clb), have been commonly used to treat these pts (Eichhorst, Blood 2009). Ibrutinib (ibr), a first-in-class, once-daily, inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. RESONATE-2 (PCYC-1115) is a randomized phase 3 trial designed to compare the efficacy and safety of ibr vs clb in pts with treatment-naïve (TN) CLL/SLL (Tedeschi, ASH 2015). Primary results, as assessed by an independent review committee (IRC), demonstrated with a median follow-up of 18.4 mo that ibr significantly reduced the risk of progression or death by 84% (P

Description: Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Autologous T cells transduced to express chimeric antigen receptors (CAR) directed against CD19, a B cell antigen, are reported to induce complete remission in patients with leukemia or lymphoma of the B cell lineage. Although potentially very effective, this treatment strategy has major drawbacks. First, CAR therapy is based on autologous T cells and therefore dependent on the nature and quality of T cells present in the peripheral blood of these patients at the time of treatment. Poor quality of the T cells may cause treatment failure in some patients. In addition, therapy based on autologous cells is tailor-made i.e. CAR+ T cells have to be generated de novo for every patient. Finally, autologous cell therapy requires different, more complicated logistics than conventional therapy. We therefore investigate whether a general purpose, allogeneic CAR therapy based on HLA-matched cord blood obtained from cord blood banks can be devised. Here, we investigated whether functional CAR+ T cells can be generated in vitro that do not express an endogenous T cell receptor to avoid alloreactivity causing graft versus host reactions. We compared carcino-embryonic antigen (CEA)- specific CARs of the first generation (intracellular CD3ζ signaling chain), of the 2nd generation (intracellular CD3ζ and CD28 signaling chain) and of the 3rd generation (intracellular CD3ζ, CD28 and OX40 signaling chain). CD34+ progenitor cells were isolated from human cord blood or postnatal thymus and subsequently transduced with one of the three green fluorescent protein (GFP)-encoding CAR constructs. Transduced cells were subsequently co-cultured on OP9DL1 in the presence of stem cell factor, Flt3-ligand and interleukin-7. Unlike T cell receptor transduced precursors (1), expansion was not enhanced by transduction of the chimeric receptor. Expansion was highest with first generation CARs whereas second and third generation CARs displayed only restricted expansion. Similar to T cell receptor transduced progenitors, CAR transduced cells show an accelerated differentiation during co-culture compared to the non-transduced cells: first committed CD5+ CD7+ T precursors appear, then CD4+ CD8+ double positive cells (DP) and finally CD1- CD27- single positive or double negative (DN) mature T cells. In cultures transduced with 2nd and 3rd generation CARs, few transduced cells passed through the proliferative DP pathway but rather differentiated to mature CD1- CD27- non-proliferative DN cells without passing through the DP stage. This phenomenon is responsible for the limited expansion seen with precursors transgenic for 2nd or 3rd generation CARs. However, in all cultures CAR+ DP cells were generated and, as shown for TCR transgenic cells (1), we were able to induce CEA specific maturation after co-culturing these DP cells with a cell line expressing CEA or by antibody-induced cross-linking of the CAR, giving rise to CD1- CD27+ matured cells. The observations described above are compatible with data obtained in mice showing that strong T cell receptor (TCR) activation during thymocyte differentiation inhibits the generation of DP cells and induces maturation to DN cells. Both the spontaneously and induced mature CAR+ cells were TCR and CD3 negative, suggesting that the expression of a CAR in early T cell precursors shuts down rearrangements of the endogenous TCR chains. Moreover, these cells lack NK marker expression (CD56, NKG2D) and show expression of T cell markers (CD5, CD7, CD2), confirming their T cell nature. In conclusion, the CAR+ CD3/TCR negative cells are T cells as these are derived from T cell precursors (CD5+, DP cells) and express various membrane and nuclear T cell markers. Mature CD1- CD27- CAR+ cells can be expanded to large cell numbers using T cell expansion protocols. They displayed cytokine production specific for CEA+ tumor lines as well as specific cytotoxicity. Moreover, the 2nd and 3rd generation CAR expressing cells showed increased specific cytokine production when compared to the first generation CAR expressing cells. These results show that the cord blood-derived CAR+ cells have potent functional activity similar to peripheral blood derived CAR+ T cells. We believe that these in vitro generated CAR+ cells developed from HLA-matched cord blood progenitors may be ideal as an adjunct to cord blood transplantation. (1) Snauwaert et al, Leukemia, 2014 Disclosures No relevant conflicts of interest to declare.

Description: Introduction MCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed or refractory (R/R) MCL who had received ≥1 prior rituximab-containing therapy. Methods Patients were randomized at a 1:1 ratio to receive oral ibrutinib (560 mg once-daily) or intravenous temsirolimus (175 mg: Days 1, 8, and 15 of Cycle 1; 75 mg: Days 1, 8, and 15 of subsequent cycles). Stratification factors were number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index (sMIPI) risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was PFS, as assessed by an independent review committee (IRC). Secondary end points included ORR, overall survival (OS), time to next treatment (TTNT), time to worsening of lymphoma symptoms (measured by FACT-Lym lymphoma subscale), and safety. Results Overall, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141). Baseline disease characteristics and demographics were generally well balanced. Median age (range) was 68 years (34-88) and median number (range) of prior lines of therapy was 2 (1-9). Approximately two-thirds of the patients had intermediate- or high-risk disease. At the time of this analysis, median follow-up was 20.0 months. Ibrutinib was superior to temsirolimus for the primary end point of IRC-assessed PFS, with a statistically significant 57% reduction in the risk of progression or death (Figure 1). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm, respectively. At a landmark of 2 years, the PFS rate is 41% in the ibrutinib arm vs 7% in the temsirolimus arm. PFS results were consistent across most assessed subgroups. Investigator-assessed PFS was consistent with the IRC results. IRC-assessed ORR was significantly higher for ibrutinib vs temsirolimus (71.9% vs 40.4%; p 〈 0.0001) with a CR rate of 18.7% vs 1.4%, respectively. Median OS was not reached with ibrutinib vs 21.3 months with temsirolimus, showing a positive trend toward patients in the ibrutinib arm (reduced risk of death by 24% [HR, 0.76; 95% CI, 0.53-1.09]). However, these results may have been confounded by 23% of patients that initially received temsirolimus crossing over to receive ibrutinib. A greater proportion of patients treated with ibrutinib vs temsirolimus avoided worsening of lymphoma symptoms throughout the study; 27% of ibrutinib patients had worsening vs 52% of temsirolimus patients. Median TTNT was not reached with ibrutinib vs 11.6 months with temsirolimus. Median treatment duration was 14.4 months for ibrutinib and 3.0 months for temsirolimus. Overall, 6.5% of subjects discontinued treatment due to AEs in the ibrutinib arm and 25.5% of subjects discontinued treatment due to AEs in the temsirolimus arm. The most common TEAEs with ibrutinib were diarrhea, fatigue, and cough, whereas with temsirolimus, thrombocytopenia, anemia, and diarrhea were most commonly observed (Table 1). Grade ³3 TEAEs were reported for 67.6% of ibrutinib patients vs 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia. When adjusted for exposure, TEAE incidence was consistently lower for the ibrutinib arm vs the temsirolimus arm. Conclusions Ibrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability. The results of this phase 3 trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase 2 studies. Future concepts will investigate ibrutinib-based combination approaches for patients with R/R MCL. Disclosures Rule: Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement. Rusconi:Roche: Honoraria. Joao:Celgene, Novartis: Consultancy; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Hess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Balasubramanian:Janssen: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Bandyopadhyay:Janssen: Employment. Sun:Janssen/J&J: Employment, Equity Ownership. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Traina:Janssen: Employment. Enny:Janssen: Employment. Rizo:Janssen: Employment. Vermeulen:Janssen: Employment.

Description: BACKGROUND: Prophylaxis of invasive fungal infections in children treated for malignant hematologic disease has traditionally been based on the widespread use of fluconazole. With the awareness of increasing rates of invasive mould infections, new agents have been developed and offered to patients at highest risk. METHODS: We compared the tolerance and outcome of different antifungal prophylaxis in 198 childhood patients treated for acute myeloid and lymphoblastic leukemia in a pediatric cancer center. Until 2011 antifungal prophylaxis with fluconazole was offered to all patients, resulting in 15.2-19.4% of invasive mould infections. As the burden of fungal infections was restricted to high risk patients only (i.e. acute myeloid leukemia, leukemia relapse, high risk acute lymphoblastic leukemia and patients after stem cell transplant) and no infection with candida was registered, antifungal prophylaxis was replaced with liposomal amphotericin and offered to this particular patient group. RESULTS: Liposomal amphotericin was well tolerated; there was no occurrence of infusion-related reaction and/or glomerular-associated nephrotoxicity. The development of vincristine-induced neurotoxicity was significantly reduced, as stool frequency was increased up to 38% in patients treated with liposomal amphotericin (p = 0.024). Importantly, there was a marked shift in the percentage of patients with severe constipation (15.5% versus 4.2%, fluconazole versus liposomal amphotericin respectively, p = 0.010). Notably, with limitation of prophylactic treatment to high risk patients a major group of patients did not receive any antifungal prophylaxis (48.81%) and most importantly, the occurrence of invasive fungal infection was completely prevented (p = 0.021). In comparison, 10 patients in the fluconazole group developed proven invasive pulmonary infections. Of these, 6 patients developed disseminated disease, and 4 patients died. Aspergillus was isolated in 40% and rhizopus in 30% of biopsy specimens. CONCLUSION: Polyene prophylaxis offers effective antifungal activity with improved tolerability compared to older agents. The potential impact of this treatment should be included in current prophylaxis guidelines of antileukemic treatment. Disclosures No relevant conflicts of interest to declare.

Description: Authors 1 -3: Contributed equally to this work Authors 8-9: Shared last author Background Genetic material from aggressive B-cell lymphoma is typified by recurrent multiple somatic alterations. Given some of the disease's most profound characteristics-large tumor cell turnovers and its evident physical relation to the cardiovascular system-it presents itself as an excellent candidate for cell-free DNA (cfDNA) based research through liquid biopsies. Recent studies on cfDNA mainly focus on targeted sequencing for single nucleotide variation and translocation detection. This technique remains expensive, requires targeted panels and is yet to be clinically standardized. In contrast, the much cheaper shallow whole genome sequencing (sWGS) for copy number variation (CNV) detection, is operative at most hospitals that offer noninvasive prenatal testing (NIPT). Despite these benefits, the potential of this approach for lymphoma remains insufficiently explored. Methods Between May 2016 and June 2019, 129 patients (pts; median age of 59; Ann Arbor stage I (4%), II (21%), III (20%) and IV (55%)) with confirmed lymphoma (86 diffuse large B-cell lymphoma (DLBCL), 39 Hodgkin lymphoma (HL) and 4 grey zone lymphoma (GZL)) were recruited. Ultimately, 236 samples were collected, including liquid biopsies at initial diagnosis; follow-up liquid biopsies at relapse or surveillance (25 pts); and paired formalin-fixed paraffin-embedded (FFPE) tissue samples (35 pts). Follow- up samples were collected during the following evaluations: DLBCL pts were evaluated by Lugano 2014 criteria after 4 cycles of R- CHOP and at the end of treatment. HL pts were subject to an early interim evaluation after only 2 cycles of ABVD. cfDNA was analyzed by sWGS (0.5x coverage), where resulting reads were mapped to both human and viral reference genomes, aiming at identifying nuclear CNVs and viral fragments, respectively. Additionally, the cohort was extended with 60 NIPT (liquid negative control) and 9 benign FFPE (tissue negative control) samples in order to statistically determine cancerous copy number profiles and abnormal viral titers. Results At staging, 36/44 (82%) of HL and 67/96 (70%) of DLBCL liquid biopsies had detectable CNVs. The remainder possibly had no structural aberrations, or, more likely, had an insufficient fraction of cell-free tumor DNA. Notably, no CNVs could be detected in 87% of HL FFPE samples, suggesting HL tumor DNA is more abundant in plasma. For DLBCL however, liquid copy number profiles were well-represented by their solid equivalent, indicated by an average Pearson correlation of 0.82. In order to quantify copy number abnormality, we developed a statistic that increases with rising deviance from the overall healthy diploid state. This score, named the copy number profile abnormality (CPA) score, positively and significantly correlates with Ann Arbor stage (p=0.044), the International Prognostic Index (IPI; p=0.038) and metabolic tumor volume (MTV; p=0.0004), derived from PET/CT scans. In 15 HL (34%), 18 DLBCL (19%) and 2 GZL (50%) samples, a statistically (q