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Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs) for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at four major US care centers. The most common treatment-related toxicity was rash (27% of patients). For most patients, disease was effectively managed at lower doses (0.5-1.0 mg trametinib daily). The response rate in the 17 evaluable patients was 71% (with 73% (8/11) without a detectable BRAF V600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, while median progression-free and overall survival had not been reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations); or alterations in other genes involved in the MAPK pathway, e.g., MAP2K1, NF1, GNAS or RAS. Most patients required lower than standard doses of trametinib but were responsive to the lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Introduction: The activity of immune checkpoint blockade including anti-cytotoxic T-lymphocyte associated protein-4 and anti-programmed cell death protein-1 monoclonal antibodies in hematologic malignancies is limited outside of classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Tumor mutational burden (TMB), programmed death ligand-1 (PD-L1) expression, and microsatellite instability-high (MSI-H) are well-established biomarkers predicting response to checkpoint blockade in solid malignancies. In addition, tumors with high TMB, defined as ≥10 mutations/megabase (mut/Mb), and/or MSI-H are Food and Drug Administration (FDA) approved tissue agnostic biomarkers for treatment with pembrolizumab. The frequencies of high TMB, MSI-H, and expression pattern of PD-L1 across specific hematologic malignancies are undefined. Methods: Patients with hematologic malignancies who had next generation sequencing (NGS) performed by Foundation One Heme were identified. TMB and MSI were measured by NGS. TMB was classified as high if ≥10 mut/Mb and low if Results: A total of 390 patients with hematologic malignancies with NGS were identified. Forty eight of the 390 samples (12%) had a high TMB (Table 1). Twenty five of 45 (56%) patients with DLBCL had a high TMB (Table 2). The TMB was low in all myeloid malignancies tested. None of the 302 samples tested were MSI-H. PD-L1 IHC was performed on 86 samples. Eleven (13%) had high expression, 26 (30%) had low expression, and 49 (57%) had no expression of PD-L1 on the tumor cells (Table 1). The majority of samples with PD-L1 expression were mature lymphomas (81%). TMB and PD-L1 score had a significant linear relationship (R = 0.22,p= 0.04, 95% CI 0.01 - 0.41) (Figure 1). Conclusion: This study provides detailed characteristics of TMB, MSI status, and PD-L1 expression for hematologic malignancies. Notably, a subset of lymphomas had high TMB and/or PD-L1 expression. Biomarker driven studies of checkpoint blockade in hematologic malignancies with high TMB and/or PD-L1 expression are warranted. Disclosures Sokol: Foundation Medicine:Current Employment;Roche:Current equity holder in publicly-traded company.Kurzrock:Medimmune:Research Funding;Foundation Medicine:Research Funding;Konica Minolta:Research Funding;IDbyDNA:Current equity holder in private company;Pfizer:Consultancy, Research Funding;Sequenom:Research Funding;Bicara Therapeutics, Inc.:Consultancy;Incyte:Research Funding;Takeda:Research Funding;TopAlliance:Research Funding;Boehringer Ingelheim:Research Funding;CureMatch Inc:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Grifols:Research Funding;Guardant:Research Funding;X Biotech:Consultancy;Neomed:Consultancy;Actuate Therapeutics:Consultancy;Roche:Consultancy;Merck Serono:Research Funding;Genentech:Research Funding;Debiopharm:Research Funding;CureMetrix:Membership on an entity's Board of Directors or advisory committees;OmniSeq:Research Funding;TD2/Volastra:Consultancy;Turning Point Therapeutics:Consultancy.Goodman:EUSA Pharma:Consultancy;Seattle Genetics:Consultancy.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Background: Activation of the MAPK pathway through BRAF mutations or other molecular alterations is a hallmark of the non-Lagerhans cell histiocytosis (non-LCH) such Erdheim-Chester disease (ECD) or Rosai-Dorfman disease (RDD). Conventional clinical molecular testing of tumor tissue fails to identify targetable molecular alteration in about one third of patients with non-LCH. Targeting the MAPK kinase pathway in non-LCH with small molecule inhibitors can be effective in patients with BRAF or other MAPK molecular alterations. Methods: Patients with non-LCH with any, unknown or pending molecular profile (tumor tissue targeted next generation sequencing [NGS], plasma cell-free [cf] DNA targeted NGS) were treated with trametinib, an oral inhibitor of MEK1/2 kinase. Treatment outcomes such as response per RECIST 1.1 or RANO in case of central nervous system involvement, time on therapy and adverse event (AE) were analyzed. Results: Total of 16 patients with ECD (n=12) or RDD (n=3) or ECD/LCH (n=1) were started on oral trametinib dose of 1 mg to 2 mg daily. Of these 16 patients, 3 patients were found to have BRAF V600E mutation in tumor and/or plasma cfDNA, 7 patients had other alteration(s) putatively activating the MAPK pathway (CAPZA2-BRAF fusion [n=1], RAF1 amplification [n=1], GNAS mutation [n=3], HMGA2 rearrangement [n=1], NF1 mutation [n=1], KRAS mutation [n=1] and MAP2K1 mutation [n=1]) and 2 patients had no results from molecular testing. Patients were treatment-naïve (n=9) or received 1 (n=3) or 2 (n=4) prior systemic therapies. To date, 5 (31%) patients had either partial (n=4) or complete response (n=1); 8 (50%) patients had stable disease (n=4) or non-CR/non-PD (n=4) in the absence of measurable disease and 3 (19%) did not have response assessed. At the median follow up of 10.1 months the median progression-free survival has not been reached as only two patients progressed on therapy while 14 remain progression-free for 1.1+ to 36+ months. The therapy was overall well tolerated with grade 1 rash being the most frequent AE. AE > grade 2 included mucositis (n=2), rash (n=2), dizziness (n=1), uveitis (n=1) and decrease in ejection fraction (n=1) and two patients discontinued therapy because of AEs. Conclusions: MEK inhibitor trametinib demonstrated encouraging activity in patients with non-LCH irrespective of underlying molecular profile. Further studies of trametinib in patients with non-LCH are warranted. Disclosures Janku: Ideaya: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees; Primmune Therapeutics: Consultancy; PureTech Health: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Deciphera: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Piqur: Research Funding; Bristol-Myers Squibb: Research Funding; IFM Therapeutics: Membership on an entity's Board of Directors or advisory committees; Synlogic: Membership on an entity's Board of Directors or advisory committees; Sotio: Consultancy; Astex: Research Funding; FujiFilm Corporation and Upsher-Smith Laboratories: Research Funding; Astellas: Research Funding; BioMed Valley Discoveries: Research Funding; Plexxikon: Research Funding; Symphogen: Research Funding; Bayer: Research Funding; Agios: Research Funding; Proximagen: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tovagene: Consultancy, Other: Ownership interests; Immunomet: Consultancy. OffLabel Disclosure: We will discuss trametinib (FDA approved for melanoma) to be used in non-LCH

The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. We describe 235 such patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%) and multiple myeloma (7.5%). Most patients (N = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. (Table 1) Altogether, 551 distinct alterations were seen, most commonly involving TP53 (9.3% of patients), TET2 (4.2%), DNMT3A (3.3%), ASXL1 (2.5%), MLL (2.5%), and KRAS (2.2%). (Figure 1 and Figure 2) The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents. Disclosures No relevant conflicts of interest to declare.

This multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.

The CD95 receptor, a member of the tumor necrosis factor (TNF) receptor superfamily, mediates signals for cell death on specific ligand or antibody engagement. It was hypothesized that interferon alpha (IFN-alpha) induces apoptosis through activation of the CD95-mediated pathway and that CD95 and ligands of the death domain may belong to the group of IFN-stimulated genes. Therefore, the effect of IFN-alpha on CD95-CD95L expression, on the release of TNF-alpha, and on TNF receptor 1 expression in an IFN-sensitive human Burkitt lymphoma cell line (Daudi) was investigated. After 5 days' incubation, apoptosis in 81% of IFN-alpha-treated Daudi cells was preceded by a release of TNF-alpha and an induction of CD95 receptor expression. Although supernatants of IFN-treated Daudi cells induced apoptosis of CD95-sensitive Jurkat cells, CD95L was undetectable on protein or on messenger RNA levels, and the weak initial expression of TNF receptor 1 increased only slightly during IFN treatment. Surprisingly, binding of TNF-alpha to CD95 was observed and confirmed by 3 different techniques-enzyme-linked immunosorbent assay using immobilized CD95:Fc-immunoglobulin G, immunoprecipitation assay using CD95 receptor precipitates of Daudi cells, and binding of sodium iodide 125-TNF-alpha to Daudi cells, which was strongly stimulated by IFN-alpha and inhibited by CD95L, CD95:Fc, unlabeled TNF-alpha, and anti-TNF-alpha antibody. Preincubation of Daudi cells with antagonists of the CD95-mediated pathway resulted in an inhibition of IFN-alpha-mediated cell death. The present investigation shows that IFN-alpha induces autocrine cell suicide of Daudi cells by a cross-talk between the CD95 receptor and TNF-alpha. The CD95 receptor can be considered a third TNF receptor, in addition to p55 and p75.

Erdheim-Chester disease is a rare non-Langerhans histiocytosis with multisystem involvement. To date, there is no standard treatment for this disorder, and more than half of the patients succumb within 3 years. Because interferon-α promotes the terminal differentiation of histiocytes and dendritic cells, we hypothesized that this molecule would be a useful therapy for Erdheim-Chester disease. We therefore treated 3 patients with advanced disease with interferon-α at a starting dose of 3 to 6 × 106 units, which was later reduced, during maintenance, to 1 × 106 units subcutaneous 3 times per week. Marked improvement was noted in all patients, with substantial retro-orbital disease regression within 1 month. Improvement in bone lesions, pain, diabetes insipidus, and other manifestations was gradual over many months. Responses were durable (3+ to 4.5+ years). Our observations suggest that this well-tolerated therapy has a significant effect on the course and outcome of Erdheim-Chester disease.

We administered liposome-encapsulated all-trans retinoic acid (L-ATRA) to 48 patients with refractory hematologic malignancies using an every- other-day schedule for 28 days and doses of 15 to 175 mg/m2. In 19 patients, pharmacology studies were conducted after the first (day 1) and seventh (day 15) doses. In contrast to the decline in tretinoin concentration seen within 3 to 4 days of administration of daily oral ATRA, there were no differences between the area under the curve (AUC) of tretinoin concentration versus time on day 1 and day 15 (P = .98, Wilcoxon signed-rank test). Peak day 1 concentrations after 15 mg/m2 were higher than those reported after 45 mg/m2 oral ATRA. Six patients with relapsed acute promyelocytic leukemia (APL) were treated. Three, each in first relapse and at least year from the last exposure to oral ATRA, achieved a complete response (CR). Disease recurred in two (one at 3 months despite maintenance L-ATRA and similarity in tretinoin AUC on days 1 and 85, and the other at 5 months, 2 months after discontinuation of L-ATRA) and the third was transplanted 1 month into CR. The three nonresponders were in at least a second relapse and failed to respond to oral ATRA before or immediately after receiving L- ATRA. Severe toxicity developed in three of eight patients treated at 175 mg/m2 (joint pains in two, skin in one). The maximum tolerated dose (MTD) was determined to be 140 mg/m2, at which dose grade 2 toxicity (primarily headache and skin) occurred in eight of eight patients, but grade 3 to 4 toxicity in none. Compared with oral ATRA, L-ATRA apparently results in greater exposure to tretinoin and for a longer time.

Introduction: The rapid technological advances in next generation sequencing (NGS) have allowed oncologists to sequence tumorexomesin a clinically meaningful period of time. NGS allows for identification of alterations that may be potentially targetable by already available Food and Drug Administration (FDA) approved drugs, providing a biologic rational for consideration of therapies and/or experimental treatments (clinical trials) that would not have otherwise been contemplated. Here we report our experience using NGS in a cohort of 60 patients with various lymphoid malignancies. Methods: We retrospectively reviewed the medical charts of 60 patients with various lymphoid malignancies who had undergone NGS. Patients were seen at the UCSD Moores Cancer Center (La Jolla, CA) from October 2012 until March 2016. We collected tumor samples from tissue (Table 1) or peripheral blood from 60 patients that were submitted for testing to Foundation Medicine, a clinical laboratory improvement amendments (CLIA)-certified lab. Hybrid capture based NGS (405 gene panel) was performed (http://www.foundationone.com/). The methods used in this assay have been described in detail in a previous report (He, J. et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016. 127:3004-3014.). Results: Sixty patients including 35 men (58%) and 25 women (42%), were identified with lymphoid malignancies (Table 1). A total of 224 alterations were found by NGS in the entire cohort of 60 individuals. Types of alterations identified included substitutions, indels, copy number alterations (CNAs), and gene fusions. Figure 1 demonstrates the 15 most frequent alterations among the cohort: TP53 mutations (10 patients), IGH rearrangements (9 patients), loss of CDKN2A/B (8 patients), and BCL2 mutations (8 patients). The median number of alterations detected per patient was 3 (range, 0 to 14). Shown in Figure 2, 7 patients (12%) had no reportable alterations, 10 patients (17%) had 1 alteration, and 43 (71%) patients had 2 or more alterations. The maximum number of alterations identified was 14, which occurred in two patients (3%), one with chronic lymphocytic leukemia (CLL) and the other with diffuse large B-cell lymphoma (DLBCL). A total of 49 patients (82%) had potentially actionable alterations using FDA approved drugs and/or experimental therapies (clinical trials) while 11 patients (18%) had no theoretically actionable alterations. Only 3 patientshad an alteration for which an approved drug in the disease is available (on-label) while 45 patients (75%) had an alteration for which an approved drug is available in another disease (off-label). Twenty-three patients (38%), 12 patients (20%), and 10 patients (17%) had 1, 2 and³ 3 FDA targetable alterations, respectively. The median number of theoretical FDA actionable alterations was 1. Conclusions:Most patients with lymphoid malignancies will have alterations that are potentially pharmacologically identified by NGS; however, only a minority of patients will have alterations for which an approved drug in the disease is available (on-label). Patients with lymphoid malignancies who have exhausted standard therapy or who are unable to tolerate chemotherapy may be excellent candidates for matched targeted therapies, ideally administered in the context of a clinical trial. Figure 1 The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 1. The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 2 Figure 2. Disclosures Goodman: Pfizer: Other: Fellowship funding. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurzrock:Serono: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Actuate Therapeutics: Research Funding; Sequenom: Research Funding; X Biotech: Research Funding; Genentech: Research Funding; Curematch: Equity Ownership; Novena: Equity Ownership.

Interleukin-10 (IL-10), also known as cytokine synthesis inhibitory factor, has multiple effects on lymphoid development. In addition, it has been previously reported that serum levels of IL-10 correlate with failure-free and overall survival in patients with non-Hodgkin's lymphoma. In this study, we used a sensitive enzyme-linked immunosorbent assay specific for human IL-10 (lower limit of sensitivity, 5 pg/mL) to measure serum levels in 52 newly diagnosed patients with diffuse large cell lymphoma and at least one adverse prognostic feature who were subsequently treated in a uniform way. Lymphoma patients had significantly higher serum levels of IL-10 (median, 7.98 pg/mL; range, < or = 5 to 27,143 pg/mL) than healthy volunteers (N = 50; median, < or = 5 pg/mL; range, < or = 5 to 19.21 pg/mL) (P = .0000012). Individuals with B symptoms had significantly higher serum levels of IL-10 than those without them (P = .03), but there was no correlation between IL-10 levels and any of the other prognostic variables analyzed, including age, lactic dehydrogenase, beta 2-microglobulin levels, performance status, bulky disease, Ann Arbor stage, or International Index score. More importantly, we found no correlation between IL-10 levels and the achievement of complete remission, nor with failure-free survival or overall survival. We conclude that in a uniform population of untreated patients with diffuse large cell lymphoma, serum levels of IL-10 do not appear to have any prognostic value.

We have recently demonstrated that interleukin (IL)-1 beta levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1 beta expression in CML, we analyzed IL-1 beta and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1 beta and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1 beta level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10(7) cells; range, 0 to 2,000 pg/2.4 x 10(7) cells) than the median level in 25 control samples (10.8 pg/2.4 x 10(7) cells; range, 0 to 95.5 pg/2.4 x 10(7) cells) (P < .01). IL-1 beta was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1 beta levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10(7) cells). The survival of the 44 patients with elevated IL-1 beta levels was significantly shorter than that of those who had low IL-1 beta levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1 beta and CML prognostic criteria shows that IL-1 beta levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10(7) cells) compared with patients in chronic phase (102.0 pg/2.4 x 10(7) cells) (P < .01), and that high IL-1 beta levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL-1RA levels did not differ between chronic-phase CML patients (median, 471.7 pg/2.4 x 10(5)) and healthy volunteers (median, 454.4 pg/2.4 x 10(5)), patients with accelerated/blast crisis disease had significantly lower levels of IL-1RA (median, 218.7 pg/2.4 x 10(5); P = .03). Finally, although IL-1 beta has been previously shown to increase IL-1RA levels, there was no correlation between IL-1 beta and IL-1RA levels in our CML patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B- cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T- cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.

A number of effective treatments are available for patients with hairy cell leukemia (HCL). 2-Chlorodeoxyadenosine (2-CdA) induces more than 80% complete responses, but is associated with profound suppression of CD4+ lymphocyte counts. However, the duration of each is uncertain. We have analyzed a previously reported cohort of 40 patients who had responded to 2-CdA. Eight patients (20%) have relapsed at a median of 16 months (range, 3 to 23 months). The remaining 32 patients were observed for a median of 30 months (range, 7 to 43 months). No patients have died. At 3 years, the actuarial disease-free survival rate is 77% (95% confidence interval, 70% to 84%). The median CD4+ lymphocyte count before therapy was 743/microL (range, 58 to 2,201/microL). The median CD4+ nadir after treatment was 139/microL (range, 25 to 580/microL). There was a single opportunistic infection and no second malignancies observed. Although there was evidence of some improvement in CD4+ lymphocyte counts on sequential testing, CD4+ counts remained significantly lower than baseline (P < .0001) at a median of 23 months after therapy (median, 237/microL; range, 25 to 514/microL), and were also lower than baseline (P < .002) in those patients with more than 1 year of follow-up (median, 27 months; range, 13 to 42 months). The median time to reach an absolute CD4+ lymphocyte count of 365/microL, the lower limit of the normal range, was 40 months. Although responses to 2-CdA are durable in the majority of patients with HCL, the uncertain long-term consequences of the observed CD4+ lymphocytopenia suggest caution in the broad application of this therapy.

We administered one course of 2-chlorodeoxyadenosine (2CdA) at 4 mg/m2 daily for 7 days by continuous intravenous infusion to 46 patients with hairy cell leukemia. Complete remissions occurred in 36 patients (78%; 95% confidence limits, 63% to 89%), partial remissions in five (11%), and a minor response in one. One patient died of candida sepsis 3 weeks after beginning treatment and three patients were clearly resistant to therapy. These three either had morphologically atypical hairy cells, less than 20% of which expressed Ig light chain on the cell surface, or had failed prior treatment with deoxycoformycin and interferon-alpha. At a median of 37 weeks since discontinuation of therapy, recurrent thrombocytopenia has developed in one patient, whose marrow remains normal, while a bone marrow relapse has occurred in another patient, whose blood counts remain normal. Treatment produced a greater than 50% decrease in neutrophil count in 26 patients, which lasted 3 to 4 weeks and was associated with an increased incidence of febrile episodes. These episodes occurred in 21 patients but were associated with documented infection in only four patients. Decreases in the number of CD4+ lymphocytes appeared to occur regularly after treatment and have persisted for a median of 18 weeks without obvious clinical significance. Although years of follow-up will be needed, our results confirm Piro et al's observation (N Engl J Med 322: 1117, 1990) that 2CdA appears to be highly effective in the treatment of hairy cell leukemia.

The Philadelphia (Ph1) chromosome is present in greater than 90% of patients with chronic myelogenous leukemia (CML) and in 2% to 20% of those with acute leukemias, for which it is an important prognostic marker too. The chimeric BCR-ABL mRNAs resulting from the translocation encode either a 210-Kd or a 190-Kd protein. The techniques used to detect Ph1 chromosome include karyotyping, Southern analysis to demonstrate bcr rearrangement, and polymerase chain reaction to amplify the BCR-ABL transcripts. However, the routine performance of these methods by clinical laboratories is cumbersome, time consuming, and exposes laboratory personnel to radioisotopes. We describe here the clinical application of a new method, the hybridization protection assay (HPA), which uses chemiluminescent acridinium-ester-labeled probes in conjunction with PCR for detection of the amplified BCR-ABL sequences. The method is sensitive, specific, and can reliably distinguish between the transcripts for P190BCR-ABL and P210BCR-ABL. In contrast to the 2 days or longer required for conventional hybridization, HPA analysis can be completed in less than 30 minutes. We have successfully used this method to analyze 60 leukemia samples (34 from Ph1-negative acute leukemias; 6 from Ph1-positive acute leukemias; and 20 from CML) with complete correlation (of BCR-ABL positivity or negativity) with the results of karyotype or Southern Blot analysis of genomic DNA for bcr rearrangement. Therefore, the HPA, in conjunction with PCR, appears to provide a rapid and reliable test for the diagnosis of Ph1-positivity.

Fludarabine, a fluorinated analogue of adenine, was given to 11 patients with macroglobulinemic lymphoma, all but one having failed prior standard chemotherapy. Five patients (45%) responded with more than a 50% reduction of immunoglobulin M (IgM) tumor mass for a projected median duration of longer than 1 year. The onset of remission was usually slow, with a median tumor halving time of 5.2 months in responding patients, emphasizing the importance of repeated courses of treatment. Fludarabine is an important new agent effective against macroglobulinemic lymphoma, and should be evaluated further in combination with other active modalities.

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Background: Multicentric Castleman disease (MCD) describes a heterogeneous group of poorly-understood diseases involving proinflammatory hypercytokinemia that ultimately results in systemic inflammatory symptoms, generalized lymphadenopathy, multiple organ system dysfunction, and even death. HHV-8 is responsible for driving MCD in immunosuppressed patients (HHV-8-associated MCD). There is also a cohort of HHV-8-negative MCD cases, referred to as idiopathic MCD (iMCD), in which the etiology remains unknown. No formal diagnostic criteria exist for iMCD, and knowledge is limited to small case series and case reports. Objectives: We conducted a systematic literature review to describe demographic, clinical, and laboratory features of iMCD as well as the treatments currently used in practice. Methods: PubMed was queried using a comprehensive list of terms to identify all published cases of HHV-8-negative MCD. Criteria for study inclusion were as follows: (1) Pathology-confirmed Castleman disease in multiple lymph nodes; (2) Exclusion of another cause of Castleman-like histopathology, such as SLE or POEMS syndrome; (3) Negative testing for HHV-8 via PCR of blood, PCR of lymph node tissue, serum serologies, and/or IHC for LANA-1; (4) Written in English and published from January 1995 to July 2013; and (5) Availability of specified minimum data elements. HIV-positive cases were excluded. Inclusion criteria were confirmed by three independent investigators, who also extracted data into a standardized database. Case report authors were contacted to gather additional data in a standardized case report form. Results: 3,428 articles were identified on PubMed. Initial evaluation for exclusion criteria yielded 1,951 MCD cases; 629 patients were HIV-positive (32%). Of the 999 HIV-negative and 323 HIV-unknown MCD cases, 626 were HHV-8 negative (32% of total MCD), 517 were HHV-8-unknown (26%), and 179 were HHV-8-positive (9%).129 cases of HHV-8-negative MCD met all inclusion criteria and were included in the final analysis. 58% were male and median age was 50 years (range: 2-80). Frequently reported clinical features included: fever (51/64), enlarged liver and/or spleen (45/60), pleural effusion (29/38), edema (26/36), and weight loss (21/29). There were 43 plasmacytic, 26 mixed, and 23 hyaline vascular cases out of 108 cases that reported histopathological subtype. The most commonly reported laboratory abnormalities included elevated CRP (70/79), anemia (76/90), hypergammaglobulinemia (63/82), hypoalbuminemia (57/63), elevated IL-6 (57/63), and positive ANA (14/38). Of cases with abnormal platelet levels, 28 had thrombocytopenia and 14 had thrombocytosis. There were 19 reported cases with elevated soluble IL-2R levels and 15 with elevated VEGF. 27 patients were diagnosed with a malignancy before (5), concurrently with (12), or after (10) diagnosis. Most commonly employed first line therapies included corticosteroid monotherapy (36%), combinations of cytotoxic chemotherapies (36%) that included regimens with cytoxan (17%) and rituxan (12%), and anti-IL-6 therapies, such as siltuximab and tocilizumab, without a cytotoxic agent (10%). Thalidomide, bortezomib, anakinra, and IVIG were used less frequently. Patients experienced no response (21%), partial response (42%), and complete response (37%) to first-line therapies. Failure (relapse, death, additional treatment) of first line therapy occurred in 41% of patients, and median time to treatment failure was 6 months. Overall, 22% of patients died by the time of most recent follow up (median: 28 months) with median length of survival among fatal cases being 26 months (range: 1-120). The most common causes of death were septic shock, multi-organ failure, including renal and cardiac, pulmonary complications, and malignancy. Conclusion: This study identified a significant proportion of MCD patients who are HIV-negative and HHV-8-negative (iMCD). 45% of patients did not demonstrate the plasmacytic variant alone, which has been classically associated with MCD. It is striking that 22% of patients died by the time of most recent follow up, which had a median length of 26 months. Despite the many limitations of analyzing case reports, this study provides the most comprehensive data on HHV-8-negative MCD to date. A global natural history study and Castleman disease registry are urgently needed to gather more extensive data on MCD. Disclosures Fajgenbaum: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Cyclophosphamide, rituximab, tocilizumab, thalidomide, bortezomib, anakinra, and intravenous immunoglobulin will be presented as drugs used in HHV-8-negative MCD. It is very important to inventory the treatments that a physician has available when conventional therapies do not work, which is frequent in MCD. At the time that this data set was assembled, there were no FDA approved therapies for this orphan disease. van Rhee:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease characterized by fevers, night sweats, fatigue, anorexia, and wasting. Interleukin-6 (IL-6) plays a pivotal role in MCD and is involved in muscle wasting. Siltuximab (CNTO328) is a chimeric IgG1κ mab that binds IL-6 and prevents its interaction with IL-6 receptors. We analyzed prospectively collected computed tomography (CT) scans to determine siltuximab’s effects on muscle mass. Methods CT scans of MCD patients (pts) from a phase 1 siltuximab study were studied for changes in body composition from siltuximab treatment. Pts (n=37) were treated with CNTO328 q weekly, 2 wks or 3 wks at doses ranging from 2.8 to 11 mg/kg, and 34/37 pts had CT scans that were suitable for evaluating body composition. The median age was 49 (range 18-76) with 18 M/16 F. Median body weight was 78 kg (mean 87 kg, range 40 to 170 kg). Eleven pts had not received prior treatment; the other 23 pts had a median of 2 prior therapies, range 1 to 5. Pts’ histology was hyaline vascularity (n=17), plasmacytic (n=15), and mixed cellularity (n=2). CT scans for each pt at each time point in their treatment were landmarked at the axial 3rd lumbar vertebra (L3). L3 images were then tissue cross sectional area analyzed using Slice-O-Matic® (Tomovision, Montreal, Canada) with Hounsfield units (HU) set at different levels for each tissue: skeletal muscle within the range of -29 HU to 150 HU, visceral adipose tissue within -150 HU to -50 HU, intramuscular adipose tissue within -190 HU to -30 HU, and subcutaneous adipose tissue within -190 HU to -30 HU. Tissue areas were used to estimate tissue mass Shen et al. 2004 J Appl Physiol 97:2333-2338). Results The median duration of treatment in this phase I study was 703 days (range 21 to 1843 days). During siltuximab treatment 38% of pts gained > 1 kg of muscle, mean 2.3 kg ± 1.1 kg (all mean values reported as mean±SD), 47% of pts had a stable muscle mass, muscle gain or loss less than 1 kg, mean 0.2 kg ± 0.5 kg and 15% of pts lost more than 1 kg, mean loss 3.1 ± 1.7 kg. Over the entire patient population (n=34) the mean gain in muscle was 0.5 kg (median 0.6 kg, range -5.5 to 4.4 kg); and the mean gain in adipose tissue was 3.1 kg (median 3.05, range -13.8 to 35.8 kg). By MCD histology the gain in muscle was 0.25 kg for hyaline vascular, 0.33 kg for mixed cellularity, and 0.85 kg for plasmacytic. Changes in fat mass by MCD histology was 5.1 kg for hyaline vascular, 5.8 for mixed cellularity, and 3.8 kg for plasmacytic. By Cheson radiologic disease response criteria the change in muscle mass was 0.9 kg for pts with partial response (PR, n=11), 0.5 kg for patients with stable disease (SD, n=22), and -3.7 kg for the one patient with progressive disease (PD). The change in fat mass was 8.5 kg for patients with PR (n=11), 2.85 kg for patients with SD (n=22) and -0.6 kg for the one patient with PD. At the recommended phase II dose of 11mg/kg q 3 wks (n=17), the mean gain in muscle mass was 0.6 kg (median 0.9 kg, range -5.5 kg to 4.4 kg). The pattern of muscle and fat mass gain was interesting in that the fat mass increased first followed by a delay and then muscle gains occurred. Pts who continued to respond to siltuximab continued to gain muscle mass up to the time that they were censored. Conclusions In addition to objective responses that were durable in MCD (median duration of response was not reached at follow-up of 29.4 months), siltuximab caused reversal of muscle wasting in 38% of patients, stabilization of muscle wasting in another 47% and in only 15% of patients did muscle wasting worsen. This stabilization and improvement in muscle wasting could lead to functional status improvements in MCD patients. Disclosures: Kurzrock: Janssen Research & Development: Research Funding. van Rhee:Janssen Research & Development: Research Funding. Ming:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.

Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease driven by interleukin (IL)-6 overproduction. There is no established standard of care for MCD, and patients are usually managed by a variety of strategies with only modest success. Treatment with siltuximab, an anti-IL-6 mAb, demonstrated clinical and radiologic responses in MCD patients in a phase 1 study (Kurzrock et al. Clin Cancer Res 2013;19:3659-70). A phase 2 extension study to assess the safety of long-term treatment with siltuximab in MCD patients is currently ongoing. We report the interim analysis results based on 19 patients who had sustained disease control on siltuximab in the phase 1 study and continued to receive siltuximab 11 mg/kg q3w IV in the phase 2 extension study. Safety monitoring focused on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, and liver function based on the potential risks from the mechanism of action of IL-6 blockade. Investigator assessed disease control and survival status were also collected. When these 19 patients started the phase 1 study, median age was 44 (range 18, 76) yrs, 63% were male, median disease duration was 4.8 mos (37% newly diagnosed), 53% had hyaline vascular and 47% had plasmacytic histological type, all were HIV- and HHV-8-negative, 32% were therapy-naïve, and 68% had prior therapy (including 21% with prior cancer-related surgery and 63% with prior systemic therapy for MCD). At the data cutoff for this interim analysis of the extension study (January 2013), patients had received in total a median of 81 doses (maximum 129) of siltuximab during a median treatment duration of 5.1 (range 3.4, 7.2) yrs, with 74% of patients treated >4 yrs. All 19 patients are alive and continuing siltuximab treatment. Over the entire treatment duration (ie, both studies), upper respiratory tract infection (89%); nausea (63%); vomiting (58%); diarrhea (53%); hypercholesterolemia (47%); hypertriglyceridemia, pain in extremities, headache, rash, and hepatic function abnormal (each 42%) were most commonly reported. The incidence of AEs reported in the different system-organ classes was similar or lower in the treatment periods of 2 to 4 yrs and more than 4 yrs compared with the treatment period of 0 to 2 yrs. 63% of patients reported at least one grade ≥3 AE (mostly grade 3, none grade 5) during the entire treatment period, most commonly in the following system-organ classes: gastrointestinal (32%); infections (26%); and blood/lymphatic system disorders or general disorders/administration-site conditions (each 21%). Grade ≥3 hypertension was reported in 3 patients; grade ≥3 nausea, cellulitis, and fatigue in 2 patients each; other grade ≥3 AEs were reported in single patients. Two patients had at least one serious infection during phase 1, and none were reported during phase 2 extension study (overall incidence 0.0226 per pt-yr). Eight patients had low-grade hypertriglyceridemia in phase 1, with no additional cases reported during extension study (overall incidence 0.1250 per pt-yr). No patient had grade ≥3 thrombocytopenia, and only 1 patient had grade ≥3 neutropenia during the entire treatment period (overall incidence 0.0103 per pt-yr). Only 1 case of grade ≥3 abnormal hepatic function was reported (in phase 1). No GI perforations occurred. No patient developed infusion-related reactions during the extension study. Only 3 patients had SAEs during the extension study, including unrelated syncope and dyspnea. One patient developed grade 3 polycythemia (Hb 18.8 g/dL), which was controlled without complications. Based on independent radiologic review of images from the phase 1 study, 1 patient had CR, 11 had PR, and 7 had SD at initiation of extension study. All 19 patients have sustained disease control (SD or better) by investigator assessment, including 8 patients who had their dosing interval increased to q6w after established prolonged PR/CR (median q6w treatment duration 11 mos). After a median follow-up of 5.1 yrs, the OS rate in these 19 patients is 100%. In conclusion, the 19 patients with MCD in this extension study have received siltuximab for a prolonged period of time (median 5.1 yrs, up to 7.2 yrs). All patients are alive and maintain disease control. Prolonged siltuximab treatment is well tolerated, with no evidence of new or cumulative toxicity or treatment discontinuations and with a low rate of serious adverse events including serious infections. Disclosures: Van Rhee: Janssen Research & Development: Research Funding. Casper:Janssen Research & Development: Research Funding. Voorhees:Janssen Research & Development: Research Funding; Abbott: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Membership on an entity’s Board of Directors or advisory committees; MedImmune: Membership on an entity’s Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qin:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Tromp:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Kurzrock:Janssen Research & Development: Research Funding.

Background Preclinical models have suggested that HDAC and mTOR inhibitors have synergistic antineoplastic activity in Hodgkin lymphoma and other cancers by reducing the activity of AKT, mTOR and HDAC. Methods We designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1mg-5mg PO daily q 28 days) and HDAC inhibitor vorinostat (100mg-400mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4mg and vorinostat 300mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints. Results A total of 16 patients (men, n=8; women, n=8), median age 33 years, median of 6.5 prior therapies (including autologous SCT [n=15], autologous and allogeneic SCT [n=4]) were enrolled in dose escalation (n=1) or RP2D (n=15) cohorts. At the median follow-up of 3.2 months, 15 (94%) patients demonstrated decreased FDG uptake including 2 CRs (13%) and 5 PRs (31%) using CHESON criteria, with a total CR+PR rate of 44%. The median reduction of tumor was -27% (-100% to +20%, Figure). The estimated median time-to-treatment failure has not been reached and 63% of the patients continued on therapy with further improvement in their level of disease response. Major grade 3-4 treatment-related toxicities included grade 3 thrombocytopenia (4 patients, 25%), grade 4 thrombocytopenia (6, 38%), grade 3 anemia (1, 6%), febrile neutropenia (1, 6%) and led to treatment interruptions and/or dose modifications in 10 (63%) patients. Five (31%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR. This patient has had a continuing response to therapy (-56%) for 8.4+ months. PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis continue. Conclusion The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Enrollment continues. Disclosures: Off Label Use: sirolimus - mTOR inhibitor vorinostat - HDAC inhibitor.

Abstract 1365 Introduction Siltuximab (CNTO 328) is a chimeric, murine-human, monoclonal antibody that specifically binds human interleukin (IL)-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity, i.e., reductions in CRP suggest inhibition of systemic IL-6. A population mechanistic pharmacokinetic (PK)/PD model was developed to describe the relationship between siltuximab serum concentrations and CRP suppression in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). Simulation was used to support the dose selection in the CD registration study and future clinical studies. Methods PK/PD data were obtained from a phase 1 clinical study examining multiple dosing regimens of siltuximab administered intravenously in patients with NHL, MM, or CD. Dosing regimens included siltuximab 2.8, 5.5, or 11 mg/kg every 2 weeks; 11 mg/kg every 3 weeks; or 5.5 mg/kg every week. Serial samples to determine serum concentration of siltuximab and serial CRP samples were collected following the first dose. NONMEM 7 was used to simultaneously fit a two-compartment PK model and an inhibitory indirect-response PD model to the observed data. Simulation of 1000 replications was then used to identify siltuximab dosage regimens that would maintain CRP suppression below the lower limit of quantification (LLOQ) of 1 mg/L. Results The mechanistic PK/PD model was able to describe the serum siltuximab and CRP concentration-time profiles. Volume of distribution and systemic clearance rate constant of siltuximab were estimated at 68.42 mL/kg and 0.0584/day, respectively. The PD parameter estimates (Kin and Kout of CRP) were 5.03 mg/L/day and 0.457/day, respectively, and were similar between the three disease types in this study. IC50was estimated at 9.73 μg/mL and was also similar between disease types. For all disease types, simulations showed that siltuximab 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks after the second dose would reduce serum CRP to below the LLOQ throughout the entire treatment period. However, lower dose intensive schedules, including a dose of 5.5 mg/kg every 2 weeks, would not reduce CRP to below the LLOQ at any time point during the treatment period. Conclusion The population PK/PD modeling and simulation support using a siltuximab dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks in future clinical development studies. This dosing recommendation is supported by the observed efficacy dose-response relationship in patients with CD (J Clin Oncol 2010;28:3701–8). Disclosures: Xie: Johnson & Johnson: Employment, Equity Ownership. Li:Johnson & Johnson: Employment, Equity Ownership. Kurzrock:Johnson & Johnson: Honoraria, Research Funding. van Rhee:Johnson & Johnson: Research Funding. Qin:Johnson & Johnson: Employment, Equity Ownership. Reddy:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Davis:Johnson & Johnson: Employment, Equity Ownership. Zhou:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership.

Abstract 3959 Introduction: Interleukin (IL)-6 serves as a growth factor for B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Castleman's disease (CD). Siltuximab (CNTO 328) is a chimeric monoclonal antibody that neutralizes the biological activity of human IL-6. We have previously reported interim safety and efficacy of siltuximab, which is highly notable in CD (van Rhee et al, Blood 2008;112:1008; Kurzrock et al, Blood 2008;112:1009). We now report the long-term safety of siltuximab in the 29 patients who were treated for more than 1 yr. Methods: An open-label, dose-finding, phase 1 trial of siltuximab in patients with B-cell NHL, MM, or CD was conducted. Five dose-escalation cohorts with increasing total dose exposure [3 mg/kg q 2 weeks (n=6), 6 mg/kg q 2 weeks (n=7), 12 mg/kg q 3 weeks (n=10), 6 mg/kg q 1 week (n=6), 12 mg/kg q 2 weeks (n=6)] were studied initially. Two additional cohorts were subsequently added: 12 mg/kg q 3 weeks as a 1-hour infusion (n=12) and a CD extension cohort with exploratory biomarkers (9 mg/kg q 3 weeks, n=12; 12 mg/kg q 3 weeks, n=8). Between Jun 2005 and Sep 2009, 67 patients (37 CD, 13 MM, 17 NHL) with median age 54 (range 18–82) yrs were enrolled. Results: Twenty-nine patients (24 CD, 3 MM, 2 NHL) were treated for at least 1 yr, including 19 and 15 patients treated for >2 and >3 yrs, respectively, with maximum duration of therapy up to 5 yrs. The grade ≥3 AEs most commonly reported between yrs 1 and 2 (irrespective of attribution to siltuximab) were infections (n=7, 24%), including device-related infection and bacteraemia (n=1), staph bacteraemia (n=1), wound abscess and pneumonia (n=1), limb and vulval abscesses (n=1), rectal abscess (n=1), bronchitis (n=1), and herpes zoster (n=1). Other common grade ≥3 AEs were blood and lymphatic system disorders (14%, most were neutropenia [10%]), and gastrointestinal disorders (10%, most were nausea [7%]). Incidence of AEs in these system-organ classes did not increase with longer duration of treatment. AEs of all grades reported in >10% of patients between yrs 1 and 2 were: nausea (31%); diarrhea, upper respiratory tract infection (each 28%); leukopenia, hepatic function abnormal, hypertriglyceridemia (each 21%); anemia, neutropenia, thrombocytopenia, sinusitis, hypercholesterolemia (each 14%). However, the majority of these AEs were low grade and tended to decrease with time. SAEs did not increase over time (n=5 between yrs 1–2, n=2 between yrs 2–3, n=4 at >3 yrs), and no specific SAE was reported in more than 1 patient. No patient discontinued therapy due to an AE during the long-term follow-up period, and there were no treatment-related deaths. Although some patients experienced clinically significant laboratory-related AEs, the laboratory results showed that mean levels of creatinine and triglycerides remained stable over time. In the 15 patients treated for ≥3 yrs, the following laboratory parameters showed modest trends of increase in mean value at 36 mos: hemoglobin increased to 13.9 g/dL from 12.4 g/dL at baseline, cholesterol increased to 201.07 mg/dL from 160.73 mg/dL at baseline, and bilirubin increased to 0.76 mg/dL from 0.49 mg/dL at baseline. On the other hand, at 36 mos in these 15 patients, the mean neutrophil count decreased to 3.70 x103/μL from 6.65 x103/μL at baseline, and the mean platelet count decreased to 216.0 x103/μL from 381.8 x103/μL at baseline. No severe infusion-related reactions were reported. At the time of database lock, 20 patients (1 MM, 19 CD) were still receiving study treatment. All 24 CD patients treated for ≥1 yr had sustained clinical responses, and half (n=12) also had an objective radiologic response, including 1 CR and 11 PR based on central radiology review. Ten of the 12 responders were treated with the highest dose of siltuximab (12 mg/kg), including 1 patient who responded after switching to 12 mg/kg. In addition, 3 unconfirmed PR were seen in the CD patients. Five patients with MM or NHL treated for ≥1 yr also had clinical benefit, including 2 CR and 1 prolonged SD in 3 MM patients and durable PR (>4 mos) in 2 NHL patients. Conclusion: Siltuximab appears to have a favorable safety profile suitable for chronic dosing and shows clinical activity as a single agent, especially in treating Castleman's disease. Phase 2 and 3 studies are ongoing to further evaluate the safety and efficacy of siltuximab in patients with multicentric Castleman's disease and in combination with other agents in patients with multiple myeloma. Disclosures: Kurzrock: Centocor Ortho Biotech Research & Development: Research Funding. Voorhees:Pfizer: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Centocor Ortho Biotech: Consultancy, Research Funding; Celgene: Research Funding; MedImmune: Consultancy, Research Funding. Casper:Johnson & Johnson: Research Funding. Fayad:Centocor Ortho Biotech Research & Development: Research Funding. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Borghaei:Genetech: Honoraria; Amgen: Honoraria; Eli Lilly: Honoraria. Jagannath:Educational Concepts Group: Teaching/Lectures; Envision Communication: Membership on an entity's Board of Directors or advisory committees, Teaching/Lectures; Imedex, LLC: Teaching/Lectures; Japanese Society of Hematology: Teaching/Lectures; Medical Learning Institute: Teaching/Lectures; Becker Pharmaceutical: Questionnaire regarding drug usage; Clinical Care Options, LLC: Teaching/Lectures; American Society of Clinical Oncology (ASCO): Editorial Board – Cancer.net; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Investigator's Meeting; Janssen Pharmaceuticals: Teaching/Lectures; Johnson & Johnson Pharmaceutical: Member, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Teaching/Lectures; MMRF: Teaching/Lectures; PER Group: Teaching/Lectures; Prime Oncology: Teaching/Lectures; South Carolina Oncology Society: Teaching/Lectures; CIG Media Group: Editor for Clinical Lymphoma Myeloma Leukemia Journal; Research to Practice: Teaching/Lectures. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Qin:Ortho Biotech Oncology Research & Development: Employment. Qi:Ortho Biotech Oncology Research & Development: Employment. Cornfeld:Janssen Pharmaceuticals: Employment, Equity Ownership. van Rhee:Johnson & Johnson Pharmaceuticals: Consultancy, Research Funding.

Abstract 5150 Introduction: Siltuximab is a chimeric monoclonal antibody with high affinity for the inflammatory cytokine, IL-6, which is currently being studied in hematologic, solid malignancies and multicentric Castleman's disease (MCD). In addition to representing a therapeutic target, IL-6 is reported to play a key role in the etiology and symptoms of anemia of cancer. A possible mechanism is through up-regulation of hepatic production of hepcidin, the central iron-regulatory hormone. Siltuximab treatment has previously been shown to be associated with clinically significant Hb increases in MCD (a disorder caused by deregulated IL-6 production) and renal cell carcinoma. We have prospectively studied the Hb response in the context of a phase I study with siltuximab in patients with advanced solid tumors. Patients and Methods Siltuximab was administered intravenously to patients with any advanced solid tumor at increasing dose levels (2.8 or 5.5 mg/kg every 2 weeks, 11 or 15 mg/kg every 3 weeks). Hepcidin (C-ELISA), Hb, CRP (marker for inflammation) and iron status (serum iron, ferritin, transferrin saturation, total iron binding capacity) were measured at baseline and serially during treatment. IL-6 was not measured since interference of the drug with assay performance prevents accurate measurement of bioactive IL-6. The relationships between these biomarkers and Hb response (defined as a maximum Hb increase of ≥1 g/dL during treatment) were evaluated. Results: Forty-four pts (18 colorectal, 12 ovarian, 5 pancreatic, 9 other) received a median of 3 siltuximab cycles (range 1 – 25). Eight patients were excluded from analysis because they received blood transfusions or ESAs. There were no objective tumor responses (CR or PR). Baseline Hb ranged from 9.4–15.3 g/dL (median 12.2). All 36 evaluable patients had an increase in Hb (median 1.35 g/dL; range 0.1–3.2). Eleven (31%) patients had a maximum increase of ≥2 g/dL. Maximum Hb levels did not exceed the upper limit of normal. Baseline hepcidin (median 118.6 ng/mL; range 9.5–493.3) was positively correlated with baseline CRP (median 13.6 mg/L; range 0.42–152.0) (p Conclusion: Siltuximab treatment was associated with clinically meaningful Hb response in this moderately anemic refractory cancer population. The exact mechanism of action remains uncertain, however correlation with additional markers (e.g., soluble transferrin receptor, inflammatory markers such as IL-6) might also be important to identify patients most likely to respond to treatment and should be evaluated further in randomized trials. Disclosures: Kurzrock: Johnson & Johnson: Research Funding. Angévin:Johnson & Johnson: Research Funding. Cohen:Johnson & Johnson: Research Funding. Van Laethem:Johnson & Johnson: Research Funding. Rijnbeek:Johnson & Johnson: Employment. Vermeulen:Johnson & Johnson: Employment. Tromp:Johnson & Johnson: Employment. Li:Johnson & Johnson: Employment. Reddy:Johnson & Johnson: Employment. Cornfeld:Johnson & Johnson: Employment. Tabernero:Johnson & Johnson: Research Funding.

Interleukin (IL)-6 is a multifunctional cytokine that serves as a growth factor for B-cell non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and Castleman’s Disease (CD). CNTO 328 is a chimeric monoclonal antibody that binds with both high specificity and high affinity while neutralizing the biological activity of human IL-6. Interim results are presented here from an ongoing open-label, dose-finding, phase I trial to assess the safety, pharmacokinetics, pharmacodynamics and clinical activity of CNTO 328 in patients with B-cell NHL (including Waldenstrom’s macroglobulinemia [WM]), MM, and CD. Evaluation of six dose cohorts with the following infusion schedules: 3 mg/kg q 2 weeks, 6 mg/kg q 2 weeks, 12 mg/kg q 3 weeks, 6 mg/kg q 1 week, 12 mg/kg q 2 weeks, 12 mg/kg q 3 weeks has been completed. A seventh cohort evaluating CNTO 328 9-mg/kg administered with a tri-weekly infusion schedule in CD patients is also ongoing. Fifty-two patients (NHL n=17, MM n=13, CD n=22) have been enrolled. The median age is 56 years (range 21–82). Patients received an average of 15 doses (up to 87 doses) of CNTO 328 with a median exposure of 131 days (up to 1051 days). Preliminary pharmacokinetic data from cohorts 1 through 5 show that serum concentrations declined in a bi-exponential manner with a terminal half-life of ~15 days. Dose-proportional increases in Cmax and AUC (0–14 days) were observed. No apparent differences in pharmacokinetics were observed when comparing patients with NHL, MM or CD. The median baseline C-reactive protein (CRP) level, a surrogate for IL-6 activity (n=47) was 9.21 mg/L (range 1–260 mg/L). Of patients with post-baseline CRP values, 83% of patients demonstrated complete suppression of CRP (a surrogate for IL-6 activity) on at least one follow up assessment (median baseline level of 13.6 mg/L (range 1–260 mg/L). CNTO 328 was well tolerated with no doselimiting toxicity observed in any of the study cohorts. Forty-nine (94%) of 52 patients had one or more adverse events. Of these 49 patients, 23 (47%) had adverse events with a maximum toxicity grade of grade 2 or less . The following adverse events were observed in more than 15% of patients: upper respiratory or urinary tract infection, thrombocytopenia, neutropenia, leukopenia, anemia, elevated ALT, hypertriglyceridemia, nausea, diarrhea, fatigue, headache. Adverse events of Grade 3 or higher, observed in more than 5% of patients overall, were limited to neutropenia (21%, none febrile), thrombocytopenia (8%), anemia (6%), cellulitis (8%), and pleural effusion (6%); most were not attributable to CNTO 328. Clinical activity has been seen in all diseases types, particularly CD and WM. Among patients with NHL, 1 patient with MALT lymphoma, 1 with follicular lymphoma and 1 with mantle cell lymphoma demonstrated stable disease for more than 6 months. Among patients with WM, 2 demonstrated partial response (1 not yet confirmed) and the remaining 3 showed stable disease. Among patients with MM, 3 had at least partial response (the low baseline serum M-protein levels of 2 patients became undetectable during treatment) and 2 patients had long-lasting stable disease (1 patient for 224 days, 1 patient for more than 533 days). A high response rate was observed in patients with CD; whose results are presented in a separate abstract. In summary, these interim results show that CNTO 328 appears to have a favorable safety profile and demonstrate clinical activity as a single agent in the treatment of MM, NHL, WM and CD.

Castleman’s disease is a rare lymphoproliferative disorder in which overproduction of interleukin (IL)-6 causes a polyclonal B cell proliferation resulting in lymph node enlargement and debilitating symptoms, including autoimmune phenomena, systemic inflammatory manifestations (e.g., fever, fatigue, and weight loss) and markedly abnormal laboratory findings (e.g., anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis and increases in acute-phase proteins like CRP, ESR and fibrinogen). There is no satisfactory systemic treatment for Castleman’s disease. CNTO 328 is a chimeric monoclonal antibody that binds with both high specificity and high affinity while neutralizing the biological activity of human IL-6. In an ongoing phase 1 study of CNTO 328, 22 patients with Castleman’s disease (9 newly diagnosed) were treated according to the following schedule: 3 mg/kg q 2 weeks (n= 1), 6 mg/kg q 2 weeks (n=2), 12 mg/kg q 2 weeks (n=3), 9 mg/kg q 3 weeks (n=5), 12 mg/kg q 3 weeks (n=8), or 6 mg/kg weekly (n=3). Disease types included hyaline vascular (9), plasmacytic (11), mixed (1) and undetermined (1). No patients are known to be either HIV+ or HHV−8+. The average number of infusions received was 23 with median drug exposure of 295 days (up to 1015 days). CNTO 328 was well tolerated with 10 patients (45%) having no drug-related toxicity greater than grade 1 and three patients (14%) with drug-related toxicity of grade 3 or higher (anemia, vomiting, herpes zoster). The most common drug related side effects, seen in more than 10% of patients were elevated ALT, hypertriglyceridemia, hypercholesterolemia and upper respiratory tract infection. There were no deaths attributed to CNTO 328. Most patients (18/22 or 82%) experienced clinical benefit response, defined as improvement in at least one of the 6 measures (hemoglobin, fatigue, anorexia, fever/night sweats, weight, or size of largest lymph node) with all other measures stable or better on at least one assessment. Additional evidence of clinical benefit included increased hemoglobin [median maximum increase of 2.15 g/dL (range: 0.3–7.2 g/dL)]. A high frequency of tumor response (both complete response [CR] and partial response [PR]) as per modified International Working Group criteria was confirmed by independent radiological review. Seven of 11 evaluable patients [64%, 95% CI (31%, 89%)] treated with 12mg/kg on either the q 2 week or q 3 week schedule responded (1 CR, 5 PR, 1 unconfirmed PR), with time to initial response ranging from 9 to 36 weeks. No radiologic response was seen at doses lower than 12mg/kg. All 6 patients who required steroids at study entry were able to discontinue steroid use. Complete suppression of CRP (a surrogate for IL-6 activity) on at least one follow up assessment was observed in 83% of patients with post-baseline CRP values (median baseline level of 13.6 mg/L (range 1-260 mg/L). These interim results appear to demonstrate substantial benefit of CNTO 328 in Castleman’s disease, which merits further investigation.

Venous thromboembolism (VTE) is common in patients with advanced cancer and may influence patient eligibility for clinical studies, quality of life, and survival. We reviewed the records of 220 consecutive patients seen in the Phase I Program at M. D. Anderson Cancer Center to determine the frequency of VTE, associated characteristics and clinical outcomes. Of 220 patients, 23 (10.5%) presented to the Phase I clinic with a history of VTE. Twenty-six patients (11.8%) subsequently developed a venous thromboembolic event, with a median follow-up of 8.4 months. These included 9 of 23 patients (39%) with and 17 of 197 (8.6%) without a history of VTE (p < 0.0001). The median time from the first visit to the Phase I clinic to a new thromboembolic episode in the 26 patients was 5.1 months (range, 0 to 27 months). The respective times to development of new thromboembolic events for patients with and without a history of thromboembolism were 3.1 months (n = 9) and 5.3 months (n = 17). Four (15%) of the 26 patients developed venous thromboembolism within one month after their first visit to the Phase I clinic. Among the remaining 22 patients, 18 (69%) developed venous thromboembolism within the first year following their initial visit to the Phase I clinic, and 4 patients developed it after 2.5 years. Fifteen patients developed DVT, seven pulmonary embolism (PE), and one patient each developed one of the following thromboembolic episodes: concurrent DVT and PE; right atrial thrombus; thrombus in the abdominal aorta and DVT; and isolated thrombus in an abdominal aortic aneurysm. The median survival in patients with and without a history of VTE were 4.7 and 10.9 months, respectively (p = 0.0002). Multivariate analysis demonstrated that a history of VTE (hazard ratio 6.2; 95% C.I. 2.6–14.7; p < 0.0001), diagnosis of pancreatic cancer (hazard ratio 4.0; 95% C.I. 1.5–11.2; p=0.007) and platelet count >440 × 109/L (hazard ratio 3.1; 95% C.I. 1.1–8.2; p = 0.026) predicted the development of new venous thromboembolic episodes. These three parameters were used to design a predictive model. Based on the relative risks of the independent covariates, the relative risk of a new thromboembolic episode could be characterized by summing the weighted number of risk factors present at first visit to the Phase I clinic. History of venous thromboembolism was given a score of 2 because the hazard ratio was 6.3, whereas the diagnosis of pancreatic cancer and elevated platelet counts had hazard ratios of 4.7 and 3.0, respectively, and were each given a score of 1. Therefore, patients could have a score ranging from 0 to 4 (no patients had a score of 4). Patients were assigned to one of three risk groups on the basis of their weighted number of presenting risk factors: 0, low risk; 1, medium risk; 2–3, high risk. At 6 months, the rates of a new thromboembolic episode were 3.5%, 12.5%, and 28% for patients with scores 0, 1, or 2–3, respectively (p

NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity in multiple myeloma, lymphoma, leukemia and solid tumor models. Phase 1 dose escalation studies are ongoing in patients with myeloma, lymphomas and solid tumors. Data from the Phase 1 study in patients with lymphomas or solid tumors are presented herein to examine the endpoints of pharmacodynamics (proteasome inhibition), pharmacokinetics and safety at doses below the MTD. Patients in this study were treated with NPI-0052 administered as a weekly IV bolus, for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. In addition to weekly safety monitoring, proteasome inhibition and pharmacokinetics were assayed after the 1st and 3rd dose and with intrapatient dose escalations. Sixteen patients have been treated at doses ranging from 0.0125 mg/m2 to 0.112 mg/m2 for up to 7 cycles without reaching an MTD. Although, one SAE of MRSA sepsis and renal failure was reported at a dose of 0.1 mg/m2, drug related adverse events have not been reported at 0.112 mg/m2. Proteasome inhibition in whole blood has been assayed from 0.0125 mg/m2 through 0.075 mg/m2, with results ranging from no inhibition to 63% inhibition of CT-L activity and indication of a correlation of inhibition with dose, inclusive of intrapatient dose increases. Preliminary pharmacokinetic data demonstrate a rapid elimination half-life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L. No responses have been confirmed, however, 4 patients have had stable disease for 4 or more months, including patients with hepatocellular carcinoma (6 months), adenoid cystic carcinoma (4 months and 4 months), and cervical carcinoma [7 months with investigator reported complete resolution of target (lymph node) lesion(s) to palpation]. These data suggest that NPI-0052 is affecting parameters relevant to pharmacodynamics, pharmacokinetics and potentially clinical benefit at doses below the MTD. Dose escalation continues to define a recommended phase 2 dose and further investigate the relevance of these outcomes in larger Recommended Phase 2 Dose Cohorts.

Background: Tissue necrosis factor (TNF)-α is a naturally occurring cytokine involved in the pathogenesis of several hematologic malignancies, but an independent prognostic role for TNF-α in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) has not been established. The purpose of this study was to determine the association between TNF-α levels and pretreatment characteristics and clinical outcomes in these diseases. Methods: From 9/94 through 1/01, serum levels of TNF-α were prospectively measured in 198 patients with AML or high-risk MDS. Serum TNF-α was quantified using commercially available ELISA kits (R&D Systems, Minneapolis, MN) (lower limits of sensitivity were 4.4 pg/mL). The appropriate recombinant cytokine was used to create a standard curve for each cytokine, and serum level was ascertained using the appropriate standard curve. All values represent the means of 3 sets of duplicate experiments. Results: The median patient age of the 198 patients with serum TNF-α measurements was 65 years (range, 21–84 years); 62% were ≥ 60 years. Cytogenetics were favorable in 6% of patients, intermediate in 53%, poor-risk in 38%, and 3% of patients had insufficient metaphases or unknown cytogenetics. Zubrod performance status (PS) was 0–1 in 66% of patients, 2 in 25%, and 3–4 in 9%. Forty-nine percent had a history of an antecedent hematologic disorder (AHD), and 93% received ara-C-based therapy. High TNF-α levels were associated with poor Zubrod PS (cor= .28); high levels of β2 microglobulin (cor=.50), creatinine (cor=.35), uric acid (p=.35), or LDH (p=.32); low albumin levels (cor=−.22); and longer duration of AHD (cor=.74) (p TNF-α (pg/mL_ TNF-α In multivariate analysis, independent factors predicting response to therapy were younger age (p=.03), shorter duration of AHD (p=.007), higher hemoglobin levels (p=.04), lower TNF-α levels (p=.038), and better PS (p=.02). Factors independently prognostic of longer survival were younger age (p=.0008), better-risk cytogenetics (p=.049), lower TNF-α levels (p=.049), lower leukocyte counts (p=.003), higher hemoglobin levels (p=.03), lower β2-microglobulin levels (p=.03), female gender (p=.02), no history of chemotherapy or radiotherapy (p=.02), and race other than African American (p=.02). Factors independently prognostic of longer event-free survival (EFS) were better-risk cytogenetics (p=.002), lower β2-microglobulin levels (p=.008), lower leukocyte counts (p=.03), and younger age (p=.04). Conclusions: These data indicate that an elevated serum TNF-α level is associated among others with poorer Zubrod PS and higher levels of β2 microglobulin and it is an independent adverse prognostic factor for response and survival in the context of established prognostic factors for AML.

Background: IL-6 is a pleiotropic cytokine, the dysregulation of which plays an etiological role in many diseases. Multicentric Castleman’s disease (CD) is a polyclonal lymphoproliferative disorder in which IL-6, overproduced by enlarged lymph nodes, is responsible for B-cell proliferation, auto-immune phenomena, systemic inflammatory manifestations (eg, fever, fatigue, and weight loss) and abnormal laboratory findings, including anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis and increases in acute-phase proteins (eg, CRP, ESR and fibrinogen). The inflammatory syndrome can be severe and refractory to steroids, chemotherapy and even autologous stem cell transplantation. CNTO 328 is a chimeric mAb that specifically binds and neutralizes human IL-6 with high affinity. A phase I trial is being conducted to assess the safety and PK of CNTO 328 in subjects with CD and other hematological diseases. Methods: This trial enrolls subjects with non Hodgkin’s B-cell lymphoma, multiple myeloma, or CD in cohorts exploring doses ranging from 3 to 12mg/kg given intravenously repeated either weekly, or every 2, or 3 weeks. Dose limiting toxicity (DLT) is defined as a ≥Grade 3 event (excluding hematologic toxicity), or ≥Grade 2 allergic reaction/hypersensitivity by NCI CTCAE attributed to CNTO 328 after the first administration. Clinical benefit assessment is based on improvements in Hb, fatigue, anorexia, fever/night sweats, weight, and size of target lymph node. Results: Results from the first 7 CD subjects enrolled in Cohorts 1 (n=1, CNTO 328 3mg/kg q 2 weeks), 2 (n=2, CNTO 328 6mg/kg q 2 weeks) and 3 (n=4, CNTO 328 12mg/kg q 3 weeks) are currently available. At present time, subjects have received a median number of 4 (range 3 to 21) doses. CNTO 328 alone was well tolerated and no DLTs were observed. Non-related to CNTO 328 Grade 3 AEs such as anemia, thrombocytosis, fatigue and one possibly-related AE (ie, vomiting, grade 3) were observed. In addition, 3 subjects experienced Grade 3 SAEs that were deemed either unrelated or unlikely related to CNTO 328. Six evaluable subjects with CD showed a response by clinical benefit assessment including improvement in Hb and in severe thrombocytosis, and fatigue, reduction of fever, resolution of rash, improvement in skin tumors, or decrease in lymphadenopathy. PK and PD analysis from these subjects is currently ongoing and data from these analyses will be presented. Conclusions: Treatment with CNTO 328 has been well tolerated in CD subjects at doses up to 12mg/kg q 3 weeks, and no allergic reactions have been observed after repeated dosing. Preliminary results suggest that CNTO 328 can abrogate the effects of IL-6 and induce both clinical and biochemical responses in CD.

BACKGROUND: There is preclinical data suggesting pro-apoptotic synergy between the proteosome inhibitor bortezomib, doxorubucin and gemcitabine. Therefore, we are currently conducting a Phase I dose finding trial of this combination. As a part of this trial, high response rates with excellent tolerance were noted in advanced cutaneous T- cell lymphoma, and are presented here. METHODS: A 3+ 3 design was used. There were two cohorts of patients: < 65 and ≥65 years of age. The older cohort was dose escalated after the younger cohort demonstrated safety at a dose level. Initial dose escalations were in bortezomib alone, followed by gemcitabine, and then by liposomal doxorubicin. RESULTS: There were 33 patients who were treated on this trial to date. We are reporting the results of 7 patients with cutaneous T cell lymphoma. These patients had been heavily pretreated with a median of 6 prior therapies (range 1–12). All six of six evaluable patients (100%) achieved a partial remission (PR). Some of these responses are ongoing and the patients are still improving. The most common toxicities were grade 2 thrombocytopenia (50% of patients), grade 1–2 fatigue (44% patients), grade1–2 mucositis (14% patients), and myelosuppression (12% patients). Four patients needed hospitalization early in the course for sepsis. All of these patients had advanced disease with ulcerating skin lesions. Dose limiting toxicity has not been seen. CONCLUSIONS: The above combination is safe up to the doses tested so far- (dose level 5 = doxil 24mg/m2 on day1, gemcitabine 800 mg/m2 on days 1 and 8 and bortezomib 1.0 mg/m2 on days 1,4,8,11) and has activity in heavily pretreated, advanced cutaneous T-Cell lymphoma. Responses in Cutaneous T Cell Lymphoma Age Sex Stage Number of prior therapies Dose Level Response Duration of therapy in months 71 F IV 12 1 PR 4 32 F IV 6 1 PR 3 (sent to BMT) 61 F IV 8 2 Lost to follow up after 2 doses 72 M IV 2 2 PR 7+ 73 M IV B 6 2 PR 4+ 53 M II B 1 5 PR 7+ 60 F IV 5 5 PR 8+

Purpose: The Epstein-Barr virus (EBV) is implicated in the development of Richter’s transformation in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The objective of this study was to assess the incidence and the clinical significance of EBV in patients with CLL/SLL. Patients and Methods: Patients with CLL/SLL who presented at The University of Texas M. D. Anderson Cancer Center over a two-year period, and had available marrow paraffin blocks were studied for evidence of EBV infection using a highly specific in-situ hybridization assay for detection of EBV encoded RNA (EBERs). Results were analyzed in relation to other presenting characteristics and outcome. Results: Thirty-two patients were examined. EBERs were detected in 12 of 32 (38%) CLL/SLL marrows versus 0 of 20 normal marrows (p = 0.002). EBERs were observed in sporadic granulocytes alone or in addition to its presence in lymphocytes in nine of the twelve EBV-positive patients. EBERs were detected less frequently in patients with Rai stage 0-1 disease (20%) compared with Rai stage 2–4 (66%; p=0.008); EBER-positive patients tended to have higher lactate dehydrogenase (LDH) levels (p=0.053). The 10-year survival rate was 22% versus 58% for patients with and without discernible EBERs (log-rank, p=0.08). Figure Figure Conclusions: Evidence of EBV infection was found in 38% of CLL/SLL patients assessed. Despite the small number of patients tested, discernable EBERs were significantly more common in individuals with more advanced Rai stage, and there was a trend toward shorter survival in patients in whom EBV EBERs were discerned. Larger studies are needed to determine the prognostic value and role of EBV infection in patients with CLL/SLL.

Tipifarnib (ZARNESTRA®, R115777), an oral selective inhibitor of farnesyltransferase (FTase), demonstrates potent antiangiogenic, antiproliferative, and apoptotic effects. This phase 1 study assessed the tolerability and response rate in patients with myelodysplastic syndrome (MDS) receiving tipifarnib on an alternate week (1 week on/1 week off) schedule. Starting dose of tipifarnib was 100 mg BID, for a total initial treatment period of 8 weeks, with a standard 3+3 design. Dose escalation was 100 mg PO BID until grade 2 nonhematologic toxicity was observed, then 100 mg total dose per day escalation until the maximum tolerated dose (MTD) was reached. Sixty-three patients were treated (median age 68 years; range, 35–84 years) with RA (n = 15), RARS (n = 6), RAEB (n = 26), RAEB-t (n = 8), and CMMoL (n = 8). Five patients (8%) had IPSS score low, 27 (43%) INT-1, 23 (36%) INT-2, and 8 (13%) high. Three patients had an N-Ras mutation and one had a K-Ras mutation. A total of 63 patients were evaluable for toxicity and 61 were evaluable for response (1 noncompliant, 1 ineligible). This alternate week regimen of tipifarnib was well tolerated; the most common toxicity was myelosuppression (all grades, 60% of patients). No side effects were reported by 20% of patients. Nonhematologic toxicities (all grades) included fatigue (20%), skin rash (9%), diarrhea (16%), increase in SGPT (14%), increase in bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), insomnia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib 1,300 mg/day to 1,500 mg/day. The MTD of tipifarnib in this patient population was 1,200 mg/day. Fifteen of 61 (25%) evaluable patients responded (3 CRs and 12 hematologic improvements). Major platelet responses were most common; they were observed in 11 of 15 responders. There was no obvious dose-response relationship and three of the fifteen patients (20%) at the lowest dose level (100 mg bid) responded including one CR. Only one patient among the responders (hematologic improvement) had a Ras (N-Ras) mutation. Median time to response was eight weeks (range, 4–32 weeks). In conclusion, an alternate week regimen of tipifarnib was well tolerated and a response rate of 25% was achieved in this phase 1 study in MDS patients. Responses were seen at all dose levels, and major platelet responses were most common. This schedule is therefore conducive to combination regimens as well as to maintenance therapy.

R115777 is an oral selective inhibitor of farnesyltransferase with potent antiangiogenic, antiproliferative, and apoptotic effects. The current study assesses the tolerance and response rate in patients (pts) with myelodysplastic syndrome (MDS) receiving R115777 on a one-week on/one-week off schedule. Starting dose was 100 mg bid with a standard 3+3 design for a total initial treatment period of eight weeks. Escalation was 100 mg po bid until grade 2 non-hematologic toxicity was observed, then 100 mg total dose per day escalation until MTD. Fifty-three pts were treated (median age 68.5 yrs; range 35–83) with RA (n=12), RARS (n=4), RAEB (n=22), RAEBt (n=7), and CMMoL (n=8). Three pts (5%) had IPSS score low; 24 (45%), INT-1; 19 (36%), INT-2; and 7 (13%) high score. Three patients had an N-RAS mutation and one had a K-RAS mutation. Fifty-three patients are evaluable for toxicity and 51 are evaluable for response (1 non-compliant, 1 ineligible). This regimen was well tolerated. The most common toxicity was myelosuppression (60% of the patients). Twenty percent reported no side effects. Non-hematologic toxicities included mild skin rash (15%), diarrhea (13%), increase in SGPT (13%), increase in bilirubin (10%), and nausea (8%). DLTs of ataxia (n=1) and fatigue (n=1) occurred at doses of 1300 mg/day. The MTD appears to be 1200 mg/day. Fifteen of 51 evaluable patients responded (3 CRs and 12 hematologic improvements). Interestingly, 3 of 6 pts at the lowest dose level (100 mg bid) responded, including a CR. Major platelet responses were most common; 11 of the 15 responders had a platelet response. Only one patient among the responders (hematologic improvement) had a RAS (N-RAS) mutation. Median time to response is eight weeks (range: 4–32 weeks). In conclusion, alternate week therapy with R115777 is well tolerated and a response rate of 29% is achieved in the Phase I setting. This intermittent schedule would lend itself well to combination or maintenance regimens.

RAD001 (everolimus, Novartis) is an orally bioavailable derivative of rapamycin with demonstrated anti-proliferative activity against a broad panel of tumor cell lines and antitumor activity in experimental animal models of human cancer. RAD001 inhibits the mammalian target of rapamycin (mTOR) signaling pathway, which is involved in regulating many aspects of cell growth and cell cycle progression. Several lines of evidence implicate the importance of the PI3K/Akt/mTOR pathway in hematological malignancies. As there has been extensive experience with this agent in the solid organ transplantation setting, two dose levels (5 and 10 mg/day) were evaluated in the Phase I portion of this study to determine the maximum tolerated dose (MTD) to be used in the Phase II portion. RAD001 was administered orally once a day at the starting dose level of 5 mg. Fifteen patients have been enrolled, of which 14 (3 B-CLL, 4 MDS, 1 MF, 1 NK/T cell lymphoma/leukemia, 1 MCL, 3 AML, 1 T-PLL) were evaluable for safety and toxicity. Median age was 65 years (range, 56 to 76 years). Twelve patients (86%) had received prior therapy (median, 2 regimens; range, 0 to 6 regimens). Median time on study was 29 days (range, 12 to 105 days). No dose-limiting toxicities were observed in the 6 patients enrolled in the Phase I portion of the study (cohorts of 3 patients per dose level). The most common adverse events were grade ≥ 2 and consisted of hyperglycemia, hyperlipidemia, hypocalcemia, hypomagnesemia, hypophosphatemia and hypokalemia, transaminitis, diarrhea, dermatitis, and mucositis. Grade 3 toxicities consisted of asymptomatic hypophosphatemia (2), and hyperglycemia (3). No patient experienced grade 4 toxicities or death from RAD001. Of the 14 evaluable patients, 2 patients with B-CLL had a 33% and 65% reduction in the size of lymph nodes, respectively, and 1 patient with MDS had decreased transfusion requirements. At the time of analysis, only 1 patient had discontinued therapy due to disease progression. These preliminary findings indicate that RAD001 is well tolerated at a daily dose of 10 mg/day and may have clinical activity in patients with hematologic malignancies. Enrollment is ongoing.

R115777 is an oral selective inhibitor of farnesyltransferase which disrupts critical signaling pathways resulting in antiangiogenic, antiproliferative and apoptotic effects. Single-agent activity of R115777 in patients (pt) with MDS, with manageable toxicity, was previously reported in single-institution studies. The current multicenter study assesses the response rate (IWG-criteria) and survival of R115777 in pt with high-risk MDS, defined by FAB classification as RAEBt and RAEB or CMML with ≥10% bone marrow (BM) blasts. Starting dose of R115777 was 300 mg bid for the first 21 days of every 28-day cycle. Eighty-two pt were enrolled (median age 67 yrs; range 39–86) with RAEBt (n=23), RAEB (n=40) and CMML (n=19). Thirty-six pt (44%) had IPSS score high, 32 (39%) int-2 and 14 (17%) int-1. Fifty-two pt were therapy-naïve, while 30 (37%) had received prior therapy for MDS. Pt were treated for a median of 3 cycles (range: 6 to 553+ days), with 78% relative dose intensity. Pt discontinued treatment primarily for progressive disease (n=37) or for adverse event (n=20), with 6 pt still on therapy. Responses were seen in 28 pt (33%; 6 CR, 2 CR with incomplete platelet recovery, 2 PR, 18 hematological improvement-HI), both in therapy-naïve and pre-treated pt. Responses were durable, with median duration of 14+ months (mo) for CR-PR (11+ to 20+ mo) and 6.7 mo for HI (3–15 mo). In 68 pt with at least 1 on-study BM assessment, BM response (either normalization or ≥50% decrease in BM blast count) was observed in 35 pt (51%). Median time to leukemic transformation (mTTL) was 14.1 mo, median time to leukemia or death (mTTLorD) was 6.4 mo and median overall survival (mOS) was 11.9 mo. Results (in mo) by risk-group are tabulated. by FAB class by IPSS score RAEBt RAEB CMML high int-2 int-1 n = 23 40 19 36 32 14 mOS 9.2 12.2 15.0 10.4 15.0 15.1 mTTLorD 3.3 7.4 10.8 3.7 7.4 11.9 mTTL 3.7 median was not reached 7.6 median was not reached Myelosuppression was the most common side effect, with 24% grade (G) 3–4 neutro-penia and 37% G3–4 thrombocytopenia. Non-hematological toxicity was mostly G1–2, rarely G3–4. Most frequently reported were nausea (35%; 4% G3), fatigue (35%; 2% G3), diarrhea (34%; 1% G3), fever (23%, 10% G3), dyspnea (20%; 2% G3–4), purpura (20%; 4% G3) and rash (19%; 2% G3). Conclusion: In a large cohort of pt with high-risk MDS as defined by FAB and IPSS, clinical activity with durable responses and limited toxicity is confirmed for R115777. Further study is warranted.

Recently, we reported that recombinant interferon-alpha (rIFN-alpha) can induce hematologic remissions and cytogenetic improvement in newly diagnosed Philadelphia (Ph)-positive chronic myelogenous leukemia (CML) patients. Although IFN-gamma is a structurally distinct molecule, this agent suppresses in vitro hematopoietic progenitor cells in a fashion similar to that of IFN-alpha. Therefore, we initiated a study of rIFN- gamma at doses of 0.25 to 0.5 mg/m2/d intramuscularly in patients with Ph-positive benign-phase CML. Twenty-six of 30 patients entered in the study were evaluable. Six patients have achieved a complete hematologic response; four, a partial hematologic response. The median follow-up period of patients who are in complete remission is 7.5 months (range, 5 to 12 months). No relapses have occurred among the complete responders. So far, five patients have had cytogenetic improvement with emergence of 5% to 45% diploid cells in the bone marrow. Fever and flulike symptoms were the most common side effects, with partial tolerance often developing after about 1 week. The majority of patients tolerated therapy with minimal change in performance status. In conclusion, rIFN-gamma has demonstrated clinical activity in CML. On the basis of these observations and the in vitro synergistic growth- inhibitory effects of IFN-alpha and IFN-gamma, we have started trials of combination IFN therapy in CML patients.

The identical cytogenetic marker, t(9;22)(q34;q11) (Philadelphia [Ph] translocation), is found in approximately 90%, 20%, and 2% of adult patients with chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML), respectively. In CML, the molecular events resulting from the Ph translocation include a break within the bcr locus on chromosome 22, transfer of the c-abl protooncogene from chromosome 9 to 22, and formation of an aberrant 210- kD bcr-abl fusion protein (p210bcr-abl). Recently, the absence of bcr rearrangement and expression of a distinct aberrant 190-kd abl protein (p190c-abl) has been described in Ph-positive ALL, with the suggestion that the two abl variants may be pathogenetically associated with myeloid v lymphoid leukemogenesis. Here we report that the genomic configuration and translation product of Ph-positive AML can be similar to that of Ph-positive ALL: the break at 22q11 may occur outside the 5.8 kb bcr region and result in expression of a 190-kD abl protein lacking these bcr sequences. Phosphokinase enzymatic activity, a fundamental property of p210bcr-abl, was also associated with AML- derived p190c-abl. Our current observations indicate that p190c-abl can be found in cells of lymphoid or myeloid lineage and is therefore unlikely to play a specific role in the development of lymphoid leukemias. Formation of p190c-abl instead of p210bcr-abl appears to be a characteristic of the acute rather than the chronic Ph-positive leukemic state.