ALBERT

Description: Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015]. A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.

Description: BACKGROUND: HIV-associated primary central nervous system lymphoma (HIV-PCNSL) is an AIDS-defining cancer. Tumors occur in patients with very low CD4+ counts, and tumors are almost always Epstein-Barr virus (EBV) infected. Overall survival (OS) has improved over time with antiretroviral therapy (ART)-associated immune reconstitution but is still generally less than 1 year. Treatment has traditionally included whole brain radiation, which can lead to devastating long-term neurotoxicity, including cognitive decline. ART has made it possible to treat patients with curative-intent, but radiation-sparing approaches have not been studied prospectively in HIV-PCNSL. METHODS: In a prospective phase II pilot study conducted in the HIV & AIDS Malignancy Branch at the National Cancer Institute, we evaluated curative-intent radiation-sparing immunochemotherapy in patients with untreated HIV-PCNSL (NCT00267865). Patients with HIV-PCNSL received ART, rituximab (375 mg/m2) and HD-MTX (6 g/m2) with leucovorin rescue (R-HD-MTX). Responses were evaluated by modified International Working Group Response Criteria for PCNSL after 6 cycles of induction R-HD-MTX and patients with a complete response (CR) received 2 consolidation cycles of R-HD-MTX. Patients with poor renal or cardiac function who were not eligible to receive HD-MTX at enrollment, received ART, rituximab and best-available radiation-sparing care. The primary objective of the study was to estimate the percentage of patients receiving ART and R-HD-MTX alive without recurrent lymphoma at two years. Response to treatment, immune reconstitution, and OS were evaluated using descriptive statistics and Kaplan-Meier methodology. RESULTS: Twelve patients were enrolled between September 2006 and June 2016. One enrolled patient was initially ineligible to receive HD-MTX due to renal dysfunction and received rituximab with temozolomide (TMZ) 150 mg/m2 for 5 days for one cycle followed by 6 cycles of R-HD-MTX + TMZ and 2 consolidation cycles of R-HD-MTX. Patient characteristics: 9 men, 3 women; median (med) age 33 years (range: 21-55); 8 African-American, 3 Hispanic, 1 white non-Hispanic; med Eastern Cooperative Oncology Group performance status 2 (1-3); med baseline Mini Mental State Examination (MMSE, maximum score = 30) was 22 (range: 5-29). Only 4 patients were on ART prior to diagnosis, and all but 1 had been on ART less than 4 months. Med time from HIV infection to PCNSL diagnosis was 30 weeks (range: 0-23 years). Med CD4+ T-cell count at PCNSL diagnosis was 16 cells/µL (0-409). Diagnosis of PCNSL was biopsy-confirmed (11) or made by 18fludeoxyglucose positron emission tomography/cerebral spinal fluid (CSF) EBV viral load criteria (1). 11/12 tumors were EBV positive. Flow cytometry showed leptomeningeal disease in 4 patients. Three had concurrent CNS infections, including Cryptococcus, histoplasmosis, and CMV retinitis. Ten were evaluable for response to R-HD-MTX induction. Two patients received only 1 cycle of therapy and were not evaluable due to treatment failure (TF). Responses after R-HD-MTX induction: CR (5), partial response (PR) (4) and progressive disease (PD) (1). Two patients with a PR received second-line TMZ at end of R-HD-MTX and obtained a subsequent CR. The patient with PD received second-line therapy with the Cancer and Leukemia Group B 50202 induction regimen and obtained a subsequent CR. There were 4 deaths on study: 1 pulmonary embolism, 1 CNS fungal infection in setting of PD, 2 TF. Eight patients (67%), including 3 patients who received second line therapy, obtained a durable CR. Med CD4+ T-cell increase following R-HD-MTX induction was +35 cells/uL (range: -54 - +369). In surviving patients, med MMSE after R-HD-MTX was 28 (27-30). For all patients, estimated 60-month OS was 66% (95% CI: 32-86%) with med potential follow-up of 82 months. Med OS was not reached. CONCLUSIONS:Treatment with ART and R-HD-MTX is associated with a high response rate, CD4+ immune reconstitution, preserved cognition, and improved OS, even in a high-risk patient population. Disclosures Uldrick: Celgene: Patents & Royalties: 10,001,483 B2; Celgene: Research Funding; Merck: Research Funding. Yarchoan:NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH.; Celgene Corp.: Research Funding.

Description: Background: Primary CNS lymphoma (PCNSL) is an aggressive B-cell lymphoma that relies on chronic active B-cell receptor (BCR) signaling. Patients with chemo-refractory PCNSL or relapsed 〈 1y have a median OS of only 2-4 mos. Ibrutinib targets BCR signaling through inhibition of BTK. In a phase 1 study, we showed tumor reductions after a 14-day ibrutinib window in 94%, including complete remissions (CR) (Lionakis et al. Cancer Cell 2017). Further, ibrutinib added to anthracycline-based chemotherapy (DA-TEDDi-R) achieved CR in 86% of evaluable patients. Routine use of DA-TEDDi-R, however, is limited by our observation of 7 presumed or proven cases of Aspergillus when no fungal prophylaxis was given and in conjunction with high dose steroids. Herein, we report the durability of CR and PFS in relapsed/refractory patients with extended follow-up. Methods: Patients with untreated or relapsed/refractory PCNSL, age 〉18, and adequate organ function were enrolled. Previous BTK inhibitor, EBV+, and active pregnancy were excluded. Patients had baseline MRI brain, PET/CT brain and body, Ommaya placed, CSF analysis with flow cytometry, and ophthamologic evaluation. A window of ibrutinib x 14d was given in 3 cohorts at escalating doses (560mg, 700mg, 840mg) then repeat MRI to assess activity. After ibrutinib window, patients received up to 6 cycles of ibrutinib + TEDD-R (temozolamide, etoposide, doxil, dexamethasone, rituximab) with ICV or IT cytarabine. No pt received maintenance or consolidation. All remissions by MRI were confirmed with PET/CT brain and repeat CSF analysis. Surveillance brain MRI after treatment q3mos for 1y, q4mos x 1y, q6mos x 1y, then annually. Results:18 PCNSL patients with a median age 66 (range 49-87) were enrolled between August 2014 and March 2016. 5 patients were untreated, 2 relapsed, and 11 chemo-refractory. After a median potential f/u of 38.9m, the median PFS for all patients who received DA-TEDDi-R is 15.2m (95% CI:3.8-undefined) and the 2-yr PFS is 43.8% (95% CI: 19.8-65.6). Of 13 relapsed/refractory patients, 2 died from Aspergillus infection during the ibrutinib window; neither had fungal prophylaxis and both had high-dose steroids. 11 patients received a median of 5 cycles (range 1-6) of DA-TEDDi-R. Nine (82%) of these patients achieved CR/CRu. Notably, none of the 6 patients with relapsed/refractory PCNSL (1 relapsed, 5 refractory) in CR at the time of publication have relapsed or died. The median duration of CR in relapsed/refractory PCNSL has not yet been reached (range 2-43m) and the 2-year durable CR rate is 66.7% (95% CI: 28.2-87.8) (Figure 1). Of the 11 relapsed/refractory patients who received DA-TEDDi-R, the median PFS has not yet been reached and the 2-yr PFS is 54.5% (95% CI: 22.9-78.0) (Figure 2). Conclusions: Ibrutinib + anthracycline-based chemotherapy (TEDDi-R) induces durable complete remissions in PCNSL without maintenance or consolidation, including patients with disease refractory to chemotherapy. Risk of Aspergillus infections mandates use of fungal prophylaxis and judicious use of steroids. Phase 1 study of escalating ibrutinib doses with concurrent isavuconazole is currently enrolling patients with relapsed and refractory PCNSL (NCT02203526). This work was supported by the Intramural Research Program of NCI at NIH Disclosures No relevant conflicts of interest to declare.

Description: Thirty-six patients with AIDS-associated Kaposi sarcoma (KS) requiring chemotherapy were treated for six 3-week cycles of pegylated liposomal doxorubicin (20 mg/m2) plus interleukin-12 (IL-12; 300 ng/kg subcutaneously twice weekly), followed by 500 ng/kg subcutaneous IL-12 twice weekly for up to 3 years. All received highly active antiretroviral therapy (HAART). Twenty-two had poor-prognosis KS (T1S1). Thirty patients had a major response, including 9 with complete response, yielding an 83.3% major response rate (95% confidence interval: 67.2%-93.6%). Median time to first response was 2 cycles. Median progression was not reached at median potential follow-up of 46.9 months. Of 27 patients with residual disease when starting maintenance IL-12, 15 had a new major response compared with this new baseline. The regimen was overall well tolerated; principal toxicities were neutropenia, anemia, transaminitis, and neuropsychiatric toxicity. Patients had increases in serum IL-12, interferon gamma, and inducible protein-10 (IP-10), and these remained increased at weeks 18 and 34. The regimen of IL-12 plus liposomal doxorubicin yielded rapid tumor responses and a high response rate in patients with AIDS-KS receiving HAART, and responses were sustained on IL-12 maintenance therapy. A randomized trial of IL-12 in this setting may be warranted. This study is registered at http://www.clinicaltrials.gov as no. NCT00020449.

Description: Expression of a viral interleukin-6 (vIL-6) has been detected in certain Kaposi sarcoma (KS)–associated herpesvirus positive (KSHV+) lesions. The release of vIL-6 systemically and its contribution to the pathogenesis of HIV-related malignancies was studied. Serum vIL-6 was detected in 13 (38.2%) of 34 HIV+ patients with KS, in 6 (85.7%) of 7 HIV+patients with primary effusion lymphoma (PEL) and/or multicentric Castleman disease (MCD), and in 18 (60.0%) of 30 HIV+, mostly homosexual, individuals without KS, MCD, or PEL. By contrast, serum vIL-6 was detected in only 3 (23.1%) of 13 patients with classic KS, 1 (2.5%) of 40 blood donors from the United States, and 4 (19.0%) of 21 blood donors from Italy. Circulating vIL-6 levels were associated with HIV+ status (P 

Description: Background: Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma that is largely curable with intensive therapy. Previously, a single-center study of 30 patients demonstrated that DA-EPOCH-R based therapy was highly effective in adults with BL (N Engl J Med 2013; 369:1915-1925). We set out to validate these results in a multi-center study and assess if a risk-adapted approach using DA-EPOCH-R is effective. Methods: Patients had newly diagnosed BL, age 18 years or older and HIV negative or positive. Low-risk (LR) patients (normal LDH, ECOG P.S. 0-1, stage I or II disease and a maximum tumor size 〈 7cm) received 3 cycles of DA-EPOCH-R (with no intrathecal prophylaxis) and all other patients (classified as high risk (HR)) received 6 cycles (with IT prophylaxis days 1 and 5 on cycles 3-6). Results: 77 patients were enrolled. Characteristics include median (range) age 45 (19-78) years; male sex 63 (82%); stage III or IV disease 49 (64%); elevated LDH 41 (53%); CNS involvement 7 (10%); HIV positive 20 (26%). Eleven (14%) and 66 (86%) were classified as LR and HR respectively. There were 2 deaths on treatment in the HR arm secondary to infection. Other toxicities were similar to previous reports of DA-EPOCH-R. At a median follow-up time of 25 months, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were 92% (95% CI: 82.9-96.8%), 87% (95% CI: 76.2-93%) and 88% (95% CI: 77.1-93.8%) respectively for all patients. TTP, PFS and OS were not significantly different for HR versus LR disease, HIV positive versus negative and age over versus under 40y. Conclusions: In a multicenter setting, both LR and HR patients have excellent outcomes with 3 and 6 cycles of therapy respectively. Risk group, HIV status and age are not associated with outcome (see table). Accrual to this study continues (NCT01092182). Table. TTP PFS OS Patients N=77 92% 87% 88% LR HR p 11 66 100% 91% 0.35 100% 85%0.22 100% 86%0.24 HIV - HIV + p 57 20 96% 84% 0.1 88% 84%0.66 90% 83%0.53 Age under 40 Age over 40 p 35 42 94% 91% 0.83 90% 84% 0.45 93% 83%0.24 Figure 1. Figure 1. Disclosures Link: Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

Description: Abstract 1573 Background: Multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder characterized by flares of severe inflammatory symptoms, including fever and cachexia, with cytopenias and biochemical abnormalities. In the idiopathic form, its pathogenesis is linked to overproduction of interleukin (IL)-6. A distinct form of MCD is caused by Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus [HHV]-8). KSHV encodes a viral homolog of IL-6, vIL-6, and this has been hypothesized to be central to KSHV-MCD pathogenesis. However, viral and human cytokines have not been examined together in KSHV-MCD, and their contribution to disease activity and symptoms is not known. Methods: Patients with pathologically-proven KSHV-MCD were enrolled on a prospective natural history study incorporating pilot evaluation of novel therapies (NCT00099073). Factors potentially important in pathogenesis were assayed at flare and complete clinical and laboratory remission: KSHV viral load (VL) in peripheral blood mononuclear cells, vIL-6, IL-1β, IL-5, human IL-6 (hIL-6), IL-8, IL-10, IL-12p70, IFN-γ and TNF-α. Paired analyses were performed for each patient comparing initial flare and remission. Associations between cytokines and individual disease manifestations were explored across all flares. Results: 21 patients had at least one flare for analysis (19 [90%] male; med age 44 [range 29–52]). 34 flares were observed (range 1–3 per patient) and followed to remission (20 patients) or death (1). All were HIV infected: CD4 med 252cells/μL (range 24–1319), HIV VL med

Description: Background: PARP is overexpressed in many malignancies and protects against chemotherapy-induced genetic damage. The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. Bendamustine is an alkylator with activity in several lymphoid malignancies, multiple myeloma, and solid tumors. Bendamustine plus rituximab (BR) is highly active in indolent B-cell lymphomas, with overall (ORR) and complete response rates (CRR) of 90-92% and 41-60%, respectively. We therefore completed a phase 1b trial of veliparib plus bendamustine (VB) in patients with solid tumors, lymphoma and myeloma, as well as a cohort expansion of veliparib, bendamustine and rituximab (VBR) in patients with CD20+ B-cell lymphomas. We report here final response data with 10.5 months (median) of follow up for all patients with lymphoma included in this trial. Methods: Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for the dose escalation portion of this trial. We have previously reported the results of the dose escalation portion, wherein MTD was established at level 6 (veliparib 300mg PO BID plus bendamustine 90 mg/m2). In the cohort expansion, patients with CD20+ B-cell lymphoma (excluding Burkitt and Burkitt-like lymphoma) were treated with bendamustine 90mg/m2 IV days 1 and 2, veliparib 300 mg PO bid on days 1-7 and rituximab 375 mg/m2 on day 1 of each 28-day cycle, for a total 6 cycles. Results: Lymphoma histologies (n=15) were FL (7), DLBCL, transformed FL, or Richter's transformation (4), classical Hodgkin lymphoma (3) and MCL (1). Eight patients received VB in the dose escalation portion and 7 received VBR in the cohort expansion (all CD20+ NHL). Fourteen patients were evaluable for response. One patient with FL in the dose escalation cohort was withdrawn for inability to swallow study drug. Median age was 66 (26-82), median number of prior therapies was 3 (1-10), 7 were refractory to prior therapy, 3 received prior bendamustine, and all patients with CD20+ disease received prior rituximab. Among 7 patients who received VB in the dose escalation cohort, ORR and CRR were 5/7 (71%) and 4/7 (57%). Median PFS is 6.9 months (range 1.6 - 31.3), and 4 of 5 responding patients have progressed. Among 7 patients who received VBR in the cohort expansion, ORR and CRR were 6/7 (86%) and 5/7 (71%). Median PFS is not yet reached at 12.4 months (range 2.0-17.1), and 2 of 6 responding patients have progressed. All patients with FL achieved CR (including 1 VB, 5 VBR). Toxicities in the cohort expansion are similar to those from the dose escalation study. DLTs were grade 4 anemia and grade 3 nausea, hypertension and hyperhidrosis. No DLTs were seen in the cohort expansion. Among all 42 patients treated on study with either VB or VBR, grade ≥3 toxicities were lymphopenia (85.7%), anemia (19%), neutropenia (11.9%), thrombocytopenia (9.5%), leukopenia (7.1%), fatigue (4.8%), nausea (4.8%), sepsis (4.8%), anorexia (2.4%), transaminitis (2.4%), duodenal hemorrhage (2.4%) and hyperhidrosis (2.4%). Conclusions: VBR is tolerated and efficacious in patients with B-cell lymphoma, particularly among patients with follicular lymphoma. These data warrant further investigation of VBR in a phase II clinical trial. Disclosures No relevant conflicts of interest to declare.

Description: Human herpesvirus 8 (HHV-8) genomic sequences were recently detected by polymerase chain reaction (PCR) and in situ hybridization in bone marrow stromal cells grown from multiple myeloma (MM) patients, but not in cells from control subjects (Rettig et al, Science 276:1851, 1997). We sought to confirm these observations in our own group of MM patients (n = 30). DNA was extracted from adherent stromal cells grown under varying conditions and assayed for HHV-8 sequence using PCR to amplify the orf 26 (KS330) sequence (Chang et al,Science 266:1865, 1997), as initially reported. Samples from human control subjects (n = 25) were concurrently extracted and analyzed. After 30 cycles of amplification, we did not detect any positive samples. In a more sensitive nested PCR, samples from 18 of 30 (60%) MM patients were positive, at about the limit of detection, but orf 26 sequence was also amplified from 11 of 25 (44%) human control samples. However, PCR amplification from other regions of the viral genome (orf 72 and orf 75) was uniformly negative for all MM and control samples, despite equivalent sensitivity. Additionally, all sera from MM patients were negative for HHV-8 IgG by immunofluorescence. Our data do not support a role of HHV-8 in the etiology of MM but may suggest the presence of a related (KS330-containing) virus in MM patients and in some control subjects. This is a US government work. There are no restrictions on its use.

Description: Background: HIV infection is associated with increased risk of non-Hodgkin (NHL) and Hodgkin lymphoma (HL). Historically HIV-infected patients had inferior outcomes and increased treatment-related morbidity and mortality over uninfected patients. Highly active antiretroviral therapy (HAART) improved the prognosis for patients with HAL and permitted treatment identical to that in uninfected patients. The role of AHCT in HIV-infected patients, however, remains under investigation. This BMT CTN 0803/ AMC-071 trial, sponsored by the National Heart, Lung and Blood Institute and National Cancer Institute, was designed to prospectively assess overall survival (OS) after AHCT in patients with CSRR HAL. Methods : Patients with treatable HIV-1 infection, age 〉 15 years, adequate organ function and CSRR aggressive NHL or HL were included. Mobilization and collection followed institutional guidelines. Patients underwent AHCT using the BEAM regimen [carmustine 300 mg/m2 (day -6), etoposide 100 mg/m2 twice daily (days -5 to -2), cytarabine 100 mg/m2 (days -5 to -2), melphalan 140 mg/m2 (day -1)]. Patients received AHCT on day 0 and standard supportive care through discharge. HAART was withheld during the preparative regimen and until therapy-related GI toxicity resolved. The primary trial objective was estimation of one-year OS. Secondary objectives included lymphoma response post-transplant, progression-free survival (PFS), transplant-related mortality (TRM), infection-related complications and recovery of hematological function (RHF) post-AHCT. RHF was defined as ANC 〉 1500/µl, untransfused hemoglobin 〉 10 gm/dL and platelet 〉 200,000/µl. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results : Between July 2010 and May 2013, 43 patients were enrolled; 3 progressed prior to AHCT and were excluded from analysis. Forty patients underwent AHCT (5 female, 35 male). Median age was 46.9 years (range, 22.5-62.2). Lymphoma subtypes included diffuse large B-cell lymphoma (40%), plasmablastic lymphoma (5%), Burkitt/Burkitt-like lymphoma (17.5%) and HL (37.5%). All patients received 〈 2 salvage regimens. Prior to transplant, 30 patients (75%) were in complete remission (CR), 8 (20%) were in partial remission (PR) and 2 (5%) had relapsed/progressive disease (RPD). Pre-HCT HIV viral load (VL) was undetectable in 31 patients (77.5%) and detectable in 9 (22.5%) with a median VL of 84 copies/mL (interquartile range [IQR], 58-234). Median CD4 count was 250.5/µL (range 39-797, IQR 175-307). All 40 patients completed BEAM and underwent HCT. At day 100 post-HCT, 39 patients were assessed for disease response (1 inevaluable due to early death): 36 (92.3%) were in CR, one (2.6%) in PR and two (5.1%) had RPD. By one-year post-HCT, 5 patients died (3 from recurrent/persistent disease, 1 from organ failure [cardiac arrest] and 1 from invasive fungal infection). Cumulative incidence of TRM was 5.2% (95% confidence interval [CI]: 0.9%-15.7%). With a median follow-up of 24 months post-AHCT, estimated probability of one-year OS was 86.6% (95% CI: 70.8%-94.2%) (Figure 1). By one-year, 5 patients relapsed post-HCT, 3 of whom subsequently died. The cumulative incidence of relapse/progression at one-year post-HCT was 12.5% (95% CI: 4.5%-24.8%). Estimated probability of one-year PFS was 82.3% (95% CI: 66.3%-91.1%) (Figure 2). Within one-year of HCT, 13 patients experienced grade 3 and 2 patients grade 4 toxicities (1 patient with mucositis and 1 patient with dyspnea/hypoxia/ cardiac arrhythmia/hypotension). Seventeen patients (42.5%) developed a total of 42 episodes of infection within one-year post-HCT, including 9 with an infection severity grade of severe. Median time to neutrophil engraftment (〉 500/µl) was 11 days (range, 9-32).Median time to platelet transfusion-independent engraftment 〉20,000/µl was 18 days (range, 9-176); 1 patient died prior to platelet recovery. Eleven (28.9%) of 38 evaluable patients and 24 (75%) of 32 evaluable patients achieved RHF by 100 days and 1-year post-HCT, respectively. Discussion : Patients with HAL may successfully undergo AHCT with favorable outcomes. AHCT should be considered the standard of care for patients with relapsed/refractory HAL who meet standard eligibility criteria. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.