ALBERT

Description: Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

Description: Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

Description: Key Points IRd was associated with a consistent PFS benefit vs placebo-Rd in RRMM patients with high-risk and standard-risk cytogenetics. The addition of ixazomib to Rd overcomes the poor PFS associated with high-risk cytogenetics in patients with RRMM.

Description: Introduction The treatment of MM patient has improved over the past 10 years, with median PFS approaching 4 years after autologous stem cell transplant (ASCT). Recently, Roussel et al reported a phase 2 trial combining melphalan and bortezomib as conditioning regimen. In this trial, 70% of patients attained VGPR or better with at least 32% of patients in CR after a single course of HDT prepared by the Bortezomib/Melphalan (Bor/MEL) conditioning regimen, regardless of the type of induction therapy. Methods We retrospectively reviewed all cases treated with bortezomib in combination with Melphalan 200 mg/m2 (Bor/MEL) as transplantation conditioning regimen in patients with MM. Bortezomib was administered intravenously at 1 mg/m2 -1.3 mg/m2 on days −5, −2, 1, and 4. Melphalan was administered intravenously at 200 mg/m2 and stem cells were infused on day 0. In an attempt to determine whether this Bor/MEL conditioning regimen was superior to Melphalan alone (MEL), we secondarily compared our cohort with patients treated at the same time where this strategy was not used. Two-sided Fisher exact test was used to test for differences between categorical variables. P value of

Description: Background: Cereblon (CRBN) is a substrate receptor of the Cullin 4 E3 ubiquitin ligase complex CRL4CRBN and is the molecular target of the IMiD® immunomodulatory drug lenalidomide. It has been shown that cereblon is required for the anti-proliferative activity of lenalidomide in multiple myeloma (MM) and that reduction of CRBN expression is associated with resistance to IMiD® compounds. Methods: RNA-seq analysis was performed on 12 paired MM patients samples of sorted CD138+ cells obtained prior to lenalidomide treatment initiation and after development of resistance. Transcriptome sequence data was generated on an Ion Torrent Proton sequencer with at least 70 million reads per sample. The STAR aligner was used to align raw reads to the Ensembl74 reference annotation. The HTseq and eXpress algorithms were used to quantify gene and transcript counts, respectively, and the Sailfish algorithm was used to validate eXpress transcript counts. The Deseq2 algorithm was used to determine differential expression at gene and transcript levels between paired samples. Results: Of 272 genes observed to change significantly in expression at relapse (FDR 〈 0.05), a majority (169) were up-regulated. Inter-pathway similarity analysis based on gene set enrichment analysis (GSEA; canonical pathways) suggested 4 distinct processes were down-regulated at relapse, including Notch Signaling, Interferon Signaling and G-coupled protein receptor signaling. Conversely, patients exhibited a single dominant up-regulated process associated with proliferation. Additional GSEA analysis on more specific gene categories revealed up-regulation of the Proliferation gene cluster described in the University of Arkansas for Medical Science (UAMS) classification for newly diagnosed MM (6 of 2599 gene sets tested; FDR

Description: Abstract 4052 Background: In patient (pts) with advanced MM, clinical parameters such as low platelet count and high serum creatinine levels carry poor prognosis (Kumar SK, et al. Mayo Clin Proc. 2004;79:867-74). At this disease stage, outcome of MM therapy should be assessed not only with the traditional parameters (progression-free survival, duration of response, and overall survival), but also by evaluating meaningful clinical parameters. POM a novel immunomodulatory agent, in combination with LoDEX, has demonstrated encouraging clinical activity and favorable tolerability in pts with RRMM in the multicenter, randomized, open-label MM-002 phase 1/2 study (Richardson PG, et al. Blood 2011;118:abs 634). This study evaluated changes in clinically important disease parameters with potential prognostic significance; data from the cut-off date of 30 March 2012 are presented. Methods: Pts with MM and ≥2 prior therapies including LEN and BORT, and disease progression during or within 60 days of their last treatment, were randomized to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle (C); LoDEX, 40 mg/week) or POM alone. At progression, patients receiving Pom alone could receive POM+LoDEX at the discretion of the investigatior. All pts received mandatory thromboprophylaxis (daily low-dose aspirin). We herein present the effect of POM+LoDEX on end-organ functional parameters, including platelet count, serum calcium, serum creatinine (SCr), albumin (Alb), residual nonaffected normal immunoglobulins (Ig) (other than M-protein), hemoglobin (Hgb), and ECOG performance status. Improvement from baseline parameters was assessed by evaluating the change in end-organ functional parameters from pre-therapy to best post-therapy levels. Improvement was defined as a shift from abnormal to normal, with a normal platelet count defined as 150–350 × 103/mm3; calcium level 8.3–10.6 mg/dL; SCr level 0.9–1.5 mg/dL; increase of serum Alb ≥0.5 g/dL; Ig levels: IgA 〉70 mg/dL, IgG 〉565 mg/dL, and IgM 〉40 mg/dL; Hgb increase ≥1 g/dL; and decrease in ECOG performance status of at least 1 score. No allowance was made for the possible confounding influence of the use of blood or platelet transfusions. Results: Of the 113 pts who were randomized to receive POM+LoDex, 112 pts were evaluable for safety. Median number of prior therapies was 5, median treatment duration with POM+LoDEX was 5.0 months, and median number of cycles was 5. A substantial number of pts had abnormal baseline platelet count, calcium, SCr, and Ig levels (Table). During POM+LoDEX treatment, platelet counts, calcium, and SCr levels improved in 62%, 93%, and 42% of pts with abnormal values at baseline, respectively. Most pts treated with POM+LoDEX (97%) had low IgA, IgG, or IgM at baseline. Of those pts, Ig levels improved into a normal range in 15% of pts. Hgb levels increased by ≥1 g/dL in 30% of pts by the end of C2, 41% by C4, and 50% by C8. Alb levels increased by ≥0.5 g/dL in 5% of pts by C2, 8% by C4, and 15% by C8. At baseline, 29 pts in the POM+LoDEX group had an ECOG score of 0, 66 pts had a score of 1 and 10 pts had a score of 2. During treatment, 2 of the 10 pts with a score of 2 improved to 1 and 1 improved to a score of 0; 6 pts maintained their baseline score of 2, 1 pt deteriorated from score 2 to 4. Of those with a baseline score of 1, 22 pts improved to a score of 0, 41 maintained their score of 1 and 3 pts deteriorated (2 to a score of 2 and 1 to a score of 5). Twenty-three pts maintained their ECOG score of 0; 6 pts deteriorated to a score of 1. Overall, there was no incidence of grade 3 or 4 peripheral neuropathy and there was a low overall incidence of hypercoagulable events 4% (2% DVT and 2% PE). Therefore disease parameters associated with these adverse events were not assessed. Conclusions: Treatment with POM+LoDEX is associated with an improvement in clinically important disease parameters including, platelet count, serum calcium, SCr, Alb, Ig, and Hgb. ECOG status also normalized or improved in 33% of pts. Improvements in end-organ functional parameters may improve the prognosis and facilitate clinical benefit for advanced RRMM pts, with the ability to continue effective therapy enhanced accordingly – an observation which warrants further clinical study, both comparatively and in combination with other active agents in this setting. Disclosures: Lonial: Millennium, Celgene, Novartis, BMS, Onyx, Merck; all 〈 $10,000 per year and disclosed to my institution: Consultancy. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Bahlis:Celgene: Honoraria; Johnson and Johnson: Honoraria, Research Funding. Chen:Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other.

Description: Abstract 813FN2 Introduction: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib. Carfilzomib has demonstrated durable anti-tumor activity and an acceptable tolerability profile in patients with multiple myeloma (MM). Final results will be presented for the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Herein we report the most recent data analysis available at time of abstract submission. Updated final results for the bortezomib-naïve group of PX-171-004, including OS data, will be presented at the meeting. Methods: Patients received either 20 mg/m2 for all treatment cycles (Cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter (Cohort 2). Carfilzomib was administered over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 of every 28-day cycle, for a maximum of 12 cycles. The primary endpoint was the best overall response rate (ORR; [CR + VGPR + PR]) determined according to the IMWG Uniform Response Criteria. Secondary endpoints included the clinical benefit response rate (CBR; [ORR + MR per EBMT criteria]), progression-free survival (PFS), time to progression (TTP), duration of response (DOR), OS, and safety. The result of efficacy analysis from disease assessment by the Independent Review Committee is presented in this abstract. Results: 127 of 129 enrolled bortezomib-naïve patients were evaluable for response. Prior therapies included thalidomide (59%), lenalidomide (59%), alkylating agents (81%), and stem cell transplant (73%). Patients had received a median of 2 prior regimens (1 in 54 patients, 2 in 40 patients, 3 in 28 patients, and ≥4 in 7 patients). 84 patients (65%) were disease refractory to their most recent therapy, defined as ≤25% response or progression during or within 60 days after completion of therapy. The median duration of carfilzomib treatment is 7 cycles (range 1−12) in Cohort 1; 8 patients were receiving drug as of February 2011 in Cohort 2 with a median treatment of 6.5 cycles (range 1−13) at that time. Best ORR was 42% in Cohort 1 and 52% in Cohort 2. Median TTP was 8.3 months and median DOR was 13.1 months in Cohort 1. The median TTP and DOR for Cohort 2 have not been reached at the time of this interim analysis; the lower bound of the 95% CI for the median TTP was 10.2 months, and 84% were estimated to have DOR ≥1 year at the time of data cutoff. Higher response rates for Cohort 2 compared with Cohort 1 do not appear to be associated with higher toxicities. Patients with unfavorable cytogenetic characteristics (≥1 abnormality) per mSMART criteria had an ORR of 37% and CBR of 42% compared with 50% and 65%, respectively, for patients with no abnormality. The most common treatment-emergent adverse events (AEs), regardless of relationship to carfilzomib in Cohorts 1 and 2, respectively, were fatigue (71%, 54%), nausea (54%, 43%), anemia (46%, 37%), and dyspnea (49%, 33%). These were primarily ≤Grade 2 in severity. The most common Grade 3/4 AEs were anemia (15%), lymphopenia (15%), thrombocytopenia (13%), pneumonia (12%) and neutropenia (12%). Treatment-emergent peripheral neuropathy (PN) was mild and infrequent (16%). Only 1 case of Grade 3 PN (0.8%) was observed. Overall, 38 patients (30%) completed 12 cycles and 22 of these patients continued to receive carfilzomib therapy under a safety extension protocol (PX-171-010), an ongoing, multicenter, open-label phase 2 study to monitor long-term use of single-agent carfilzomib. Conclusions: To date we have seen robust and durable single-agent activity for carfilzomib in bortezomib-naïve patients with relapsed and often refractory MM with an ORR of 42−52% and a CBR of 59−63% from 2 separate dose cohorts in a population wherein 92% received an immunomodulatry drug and 73% had undergone an autologous stem cell transplant previously. These data are suggestive of a dose–response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007. Carfilzomib was associated with minimal PN and excellent long-term tolerability, with nearly one-third of patients completing 12 cycles and 22 of these continuing treatment beyond 1 year in the extension protocol PX-171-010. Disclosures: Vij: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Kaufman:Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Wang:Onyx Pharmaceuticals: Research Funding. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Belch:Celgene: Research Funding; Onyx: Research Funding. Gabrail:Millennium: Research Funding. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Description: The outcome of conventional therapy in MM is highly heterogeneous and appears to be largely dictated by the presence of recurrent genomic aberrations. Among these t(4;14), deletion 17p13 (TP53 locus), maf gene translocations and to a lesser extent del13q define a subgroup of patients with high risk disease. We here report on the efficacy (RR, PFS and OS) of lenalidomide and dexamethasone (len-dex) in relapsed MM patients according to their del13q, t(4;14) and del17p13 status. The MM016 is a multicenter single arm open label expanded access program for len in relapsed and refractory MM. Pts received dex orally (40mg, days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and len 25mg orally on days 1–21 of a 28 days cycle. FISH studies with commercially available probes detected the presence or absence of del13q, t(4;14)(p16;q32) and del17p13 on the interphase bone marrow aspirates. Blade criteria were used to define RR. PFS and OS were defined according to the international uniform response criteria. 159 patients with FISH results available for a least one of the genomic aberrations were included in this analysis: median age was 61 yrs (32–85), 50.3% had ISS stage II or III, median beta2-microglobulin was 3.055 mg/L (0.69–17.5), median number of prior treatments was 3 (1–6) with 50.3% previously treated with thalidomide, 43.7% with bortezomib and 73% with SCT. Del13q, t(4;14) and del17p13 were detected in 57 (37.3%), 21(19.1%) and 11 (11.6%) of patients, respectively. The overall response RR (CR+PR) to len-dex was 77.3% (14.4% CR and nCR) and 64.9% for the del13q, 76.2% for t(4;14) and 63.6% for del17p patients. The median PFS was 10.56 months (95%C.I.[6.65–14.48]). The median OS was not reached at the time of this analysis with 55.4% alive at a median follow-up of 16 months. PFS and OS were also similar when results were analyzed according to the presence or absence of del13q, t(4;14), ISS stage and prior SCT. In univariate analysis, prior thalidomide or bortezomib exposure, number of prior lines of therapy, depth of response (CR vs PR) and the presence of del17p13 by FISH did result in lower PFS and OS. However in multivariate analysis only the presence of 17p13 deletion and the depth of response correlated with PFS and OS (Table). Treatment with len-dex overcomes the poor prognosis conferred by t(4;14), high beta2-microglobulin and del13q in relapsed and refractory MM. Patients with deletion of the TP53 locus still fare very poorly despite a rapid initial response to len-dex. Confirmation of these results in patients with del17p13 with a larger prospective study is clearly warranted. Variable PFS OS HR, 95% CI p value HR, 95% CI p value t(4;14) 0.92(0.29–2.13) 0.920 1.26(0.46–3.42 0.641 Del 13 0.90 (0.44–1.83) 0.783 0.56 (0.25–1.29) 0.179 Del17p13 6.26 (2.48–15.77) 0.000 3.83(1.34–10.93) 0.012 ISS III 2.03 (0.42–9.82) 0.376 1.72 (0.39–11.33) 0.378 Prior Thal 1.12 (0.51–2.44) 0.768 1.22 (0.53–2.82) 0.633 Prior Bortez 1.29 (0.61–2.74) 0.501 1.66 (0.74–3.71) 0.215 Response ≤ PR vs CR 3.031 (2.14–4.27) 0.000 2.17 (1.50–3.12) 0.000

Description: Background Deregulation of ribosome biogenesis is associated with carcinogenesis and in MM two of the most common recurrent mutations (DIS3 and FAM46C) are implicated in ribosomal decay and translational control. Beside its role in the regulation of protein synthesis, the importance of ribosome biogenesis is underscored by the observation that the impairment of this process leads to a ribosomal stress response with induction of p53, inhibition of c-Myc and cell cycle arrest. These effects are mediated by the direct binding of ribosomal proteins (RPs), particularly RPL11 and RPL5 to Mdm2 and c-Myc. Immunomodulatory drugs (IMiDs) anti-MM effects require their binding to Cereblon (CRBN), an adaptor protein of the Cul4A-DDB1-ROC1 ubiquitin E3 ligase complex with an ensuing down-regulation of c-Myc and up-regulation of p21. In the present study, we delineated the mechanisms through which IMiDs mediate these effects in MM cells. Methods and Results In order to identify ubiquitylated substrates that are modified by lenalidomide (Len) treatment, we performed a ubiquitin-proteome pull-down using Tandem Ubiquitin Binding Entity (Lifesensors) coupled with quantitative mass-spectroscopy proteomics (iTRAQ) in OPM2 cells exposed to Len (10 μM). Several ribosomal proteins (RPs) - S25, S26, S20 & S28 - were increased in Len treated samples suggesting that the Cul4a-CRBN complex may regulate RPs stability and hence IMiDs binding to cereblon may trigger a ribosomal stress response. Immunoblot analysis of MM cells exposed to Len lead to a rapid decrease in c-Myc expression (within 30 min) that significantly preceded the downregulation of IRF4 consistent with an IRF4-independent mechanism for c-Myc down-regulation. Furthermore, Len treatment transiently stabilised and subsequently down-regulated MDM2 expression with up-regulation of p53 and its down-stream targets (p21, PUMA). Under ribosomal stress conditions, polysome-free RPs are released into the nucleoplasm where they bind Mdm2 and suppress its E3 ligase activity. Consistent with this effect, in Len treated cells MDM2 co-immunoprecipitated with RPL11 and RPL5 with p53 protein stabilization (no change in p53 mRNA). In addition, an increase in the interaction between RPL11 and c-Myc was also observed consistent with the reported role for RPL11 in the post-transcriptional regulation and suppression of c-Myc. Furthermore, treatment with Lenalidomide supressed ribosomal RNA (rRNA) transcription with inhibition of pre-rRNA (47S) processing. The examination of polysome fractions (sucrose gradients) in Len treated MM cells (OPM2 and MM1S) revealed a striking reduction of 60S and 80S as well as polysomes fractions, an effect similar to that Actinomycin D (5 nM), a known RNA PolI inhibitor and potent ribosome stress inducer. Furthermore Len treatment significant reduced RPL11 within the 60S and 80S ribosome fractions. Of note, CRBN knockdown abrogated all these effects suggesting that Len binding to CRBN is upstream of this ribosome stress response. In order to investigate whether the down-regulation of c-Myc is the primary event leading to the disruption of ribogenesis, we transiently and stably silenced RPL11 in MM cells. RPL11 silencing nearly fully protected MM cells from the effects of Len and importantly it completely reversed Len-induced Mdm2 E3 ligase inhibition with up-regulation of p53, p21 and suppression of c-Myc and IRF4. Conclusion Taken together our data indicate that treatment with lenalidomide suppresses ribogenesis and induces a ribosomal stress response downstream of Cul4a-CRBN but upstream of c-Myc suppression and p53 induction. These effects likely result from the IMiDs-induced modification of the Cul4a-CRBN ubiquitome and the regulation of RPs integration into ribosomal subunits. These findings also explain the observed clinical activity of IMiDs in other ribosomopathies like 5q- MDS and Diamond-Blackfan anemia Disclosures: No relevant conflicts of interest to declare.

Description: Background BK virus (BKV) is a polyomavirus that carries up to a 90% sero-prevalence in the general population. After infection the virus enters a latent phase in the renourinary epithelium. In hematopoietic stem cell transplant patients, BKV reactivation may lead to hemorrhagic cystitis with an incidence of 7%-70%. Aside from BKV, hemorrhagic cystitis (〉72 h) has been linked to patient age, conditioning regimen, graft versus host disease (GVHD), and unrelated/mismatch donor. Symptoms range from dysuria to severe hemorrhage leading to clot formation, urinary obstruction and renal impairment. These complications have been shown to impact length of hospitalization, cost of care, and mortality. The incidence and impact of hemorrhagic cystitis in patients receiving fludarabine (Flu), busulfan (Bu)and anti-thymocyte globulin (ATG) conditioning is unknown. We carried out this study to determine the incidence and its effect on patient outcomes including overall survival, relapse, GVHD, and health care resource use. Patient Selection and Methods We reviewed the medical records of 661 consecutive patients undergoing allogeneic stem cell transplant from January 1, 2003 to January 1, 2013. Hemorrhagic cystitis was diagnosed with symptoms (cystitis with microscopic or macroscopic hematuria, in the absence of other causes such as bacterial/fungal infection or nephrolithiasis) of at least 1 week following stem cell transplant. Microbiological confirmation was obtained routinely after 2005. Controls were matched to cases in a 2:1 ratio in the following priority: age (+/- 10 years), donor type, disease type, GVHD prophylaxis and disease status. All cases received FluBuATG +/- total body irradiation (400 cGy), and all except two received methotrexate (MTX) and cyclosporine (CsA) for GVHD prophylaxis (only received CsA). Results Hemorrhagic cystitis was identified in 117/661 transplant recipients over ten years, for an incidence of 17.7%. After removing cases with a previous transplant, unsuitable matched controls, and incomplete data, 94 evaluable cases were matched to 188 controls. The cohort median age was 50.25 years. Diagnoses included AML (38.3%), ALL (21.3%), MDS (11.7%), CLL (13.8%), NHL (6.4%) and myeloproliferative syndromes (6.4%). Disease statuses included CR1 (31.9%, CR2 (19.1%), untreated (14.9%), PR (13%) and primary refractory (4.3%). Of the cases, 77 of 83 (92.8%) tested positive for BKV in urine by PCR. Median onset was 45 days (range 12 – 279 days). Median BK viral copies was 2242.5 x 106copies/mL (range 0.285 to 4530000). Cases had higher proportions of significant (Grade 2-4) acute GVHD (43.6% vs 27.0%, P=0.0052) and chronic GVHD (cGVHD) requiring steroids (34.9% vs 18.6%, P=0.004). The median onset of significant acute GVHD (aGVHD) was 27 days (range 11 – 103 days), and for cGVHD was 108 days (range 29 – 236 days). Out of 41 aGVHD cases, 8 occurred after BKV hemorrhagic cystitis diagnosis while 23 occurred prior. In 30 cGVHD cases, 23 occurred after BKV hemorrhagic cystitis diagnosis while 7 occurred prior. Cases also had longer hospital stays in the 6 months following transplant (65.5 days vs 40.5 days, P