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Melphalan at a dose of 200 mg/m(2) (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database (n = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32–62) in favor or the BuMelVel group (95% CI; 23–37) (p=0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44–0.97)(p=0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.

Context/Objective: Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective treatment for patients with MRD+ BCP-ALL.1 Blinatumomab is infused continuously (cIV) 28 days/cycle. Severe adverse events (AEs), e.g., cytokine release syndrome (CRS) and neurologic toxicity (NT), may occur; thus, hospitalization is recommended for cycle 1: days 1–3 (C1:D1–3) and C2:D1–2. However, the incidence of severe AEs is low (CRS: 2%, NT: 13%).1 We believe that with digital monitoring, blinatumomab can be safely administered as an outpatient. Design: Adult patients (n=45) with BCP-ALL in complete remission and MRD+ (≥0.1% blasts) are being enrolled at ≤25 sites, with endpoint: grade ≥3 AE (Amgen NCT04506086). Patient suitability and outpatient monitoring are established. Patients receive 2–4 blinatumomab cycles. Cycles are initiated in the outpatient setting, and digital monitoring devices are activated/attached. Once home, patients set up the home hub and real-time data transfer to the healthcare provider (HCP) begins. The devices are worn continuously, 24 hours/day, for C1:D1–3 and C2:D1–2 only. Devices: Current Health’s Wearable Monitoring System (CHWMS) is an FDA-cleared platform for wireless wearable health monitoring at home. The CHWMS provides continuous oxygen saturation, respiratory rates, and heart rates; an axillary sensor provides continuous temperature. Patients manually measure blood pressure every 3–6 hours around the clock. Patients have an integrated tablet to contact the HCP if needed. HCP/designee has a smartphone and receives vital signs constantly. The CHWMS platform generates a loud alert based on pre-specified vital sign thresholds or for data transfer interruption. Regardless of whether there is an alert, HCP may initiate direct audio/video contact with the patient, assess the patient’s condition, and make appropriate interventions. Patients are required to have a caregiver present during monitoring. Patients have a full set of replacement devices and a 24/7 support hotline. Trial enrollment is underway. This study may generate feasibility data on the effectiveness of home monitoring during blinatumomab infusion in patients with MRD+ BCP-ALL. 1Gokbuget, Blood, 2018. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved.

TPS7051 Background: The prognosis for adults with relapsed or refractory BCP-ALL is poor. MRD+ is the strongest predictor of relapse. Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective treatment for patients with MRD+.1 Blinatumomab is administered as a continuous intravenous infusion (cIV) 28 days per cycle. Severe adverse events (AEs) such as cytokine release syndrome (CRS) and neurologic toxicity (NT) may occur; thus, hospitalization is recommended for the first 3 days of cycle 1 and the first 2 days of cycle 2 for MRD+ patients. However, the incidence of severe AEs is low in MRD+ BCP-ALL patients (CRS: 2%, NT: 13%).1 We believe that with the use of effective digital monitoring devices, blinatumomab can be safely administered for the entire 28-day cIV cycle as an outpatient. Methods: Adult patients (n = 45) with BCP-ALL in complete remission and MRD+ (≥0.1% blasts) are being enrolled at 25 planned treatment sites, endpoint: grade ≥3 AE during monitoring (Amgen NCT04506086). Patient suitability for blinatumomab and outpatient monitoring is established. Patients will receive 2-4 cycles of blinatumomab. Cycles are initiated in the outpatient setting, digital monitoring devices activated and attached, and patients sent home. Once home, patients set up the home hub and real-time remote data transfer to the healthcare professional (HCP) begins. The devices are worn continuously, 24 hours a day for the first 3 days of cycle 1 and the first 2 days of cycle 2 only. Devices: Current Health’s Wearable Monitoring System (CHWMS) is an FDA-cleared platform for wireless and wearable health monitoring of patients at home. The CHWMS provides continuous oxygen saturation, respiratory rate, and heart rate; an axillary temperature sensor is worn and provides continuous temperature. Patients manually measure blood pressure every 3-6 hours around the clock. Patients have an integrated mobile device (tablet) to initiate contact with the HCP if needed. HCP/designee has a mobile device (smart phone) and receives vital signs as a constant live feed transmitted from the CHWMS device. The CHWMS platform generates a loud audible alert based on pre-specified vital sign alarming thresholds or if there is an interruption in data transfer. HCP may initiate direct audio and video contact with the patient, assess the patient’s condition, and make an appropriate intervention. HCP may also initiate patient contact in the absence of an alert. Patients are required to have a caregiver present during the entire period of outpatient monitoring. Patients have a full set of replacement devices as well as a 24/7 hotline for device support. Trial enrollment is underway. This study may generate feasibility data on the effectiveness of home monitoring during blinatumomab infusion in patients with MRD+ BCP-ALL. 1Gökbuget, Blood, 2018. Clinical trial information: NCT04506086.

The coronavirus disease 19 (COVID-19) pandemic has infected tens of millions across the world, but there is a significant gap in our understanding about COVID-19 in the hematopoietic stem transplant (HSCT) recipient population. Prolonged viral shedding is frequently observed with severe acute respiratory syndrome coronavirus-2 (SARSCoV-2), but studies suggest viral loads decline 10 days after symptom onset. Current CDC guidance suggests that severely ill and immunocompromised hosts are no longer infectious after 20 days from symptom onset. Cycle threshold (Ct) values are inversely proportional to the viral load and are used to detect SARS-CoV-2 RNA concentration. Specimens with reverse transcriptase PCR (RT-PCR) Ct values > 33–34 have been associated with inability to culture virus, and have been used as a surrogate for diminished infectivity. We report two cases of allogeneic peripheral blood stem cell transplant (PBSCT) recipients who had prolonged durations of infectivity with SARSCov-2, based on culture positivity and persistently low Ct values for greater than 50 days.

High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.

Umbilical cord blood (UCB) as an allogeneic transplant source is generally limited to units with pre-cryopreservation total nucleated cell (TNC) doses ⩾2.5 × 10(7) NC/kg. We prospectively investigated single UCB transplantation, with cord units as low as 1 × 10(7) NC/kg, all processed with post-thaw albumin-dextran dilution. We transplanted 104 adult patients with 84% having relapsed/refractory disease. The median TNC dose was 2.1 × 10(7) NC/kg (range: 1.0-4.4 × 10(7)) and median CD34+ cell dose was 1.0 × 10(5)/kg (range: 0.0-3.7 × 10(5)/kg). Post-manipulation cell recovery and viability were 96% and 99%, respectively. Median times to neutrophil and platelet engraftment were 16 and 43 days, respectively. Univariate factors predicting neutrophil engraftment included TNC (P=0.03) and CD34+ cell dose (P=0.01). CD34+ dose predicted platelet engraftment (P

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration–time curve (AUC) of 20,000 μM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m2) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.

Introduction: Multiple myeloma (MM) remains incurable when treated with novel myeloma therapies in combination with high dose chemotherapy and autologous stem cell transplantation (ASCT). In contrast to the accelerated development of effective new drugs for induction, maintenance, and relapse, single-agent melphalan remains the standard for conditioning before ASCT. Is this phase II trial, we prospectively evaluated a conditioning regimen consisting of high-dose intravenous busulfan and melphalan followed by bortezomib (BUMELVEL), an agent shown to be potentially synergistic in combination with alkylating agents. We report our 7 year long term follow up with direct comparison to a contemporaneous CIBMTR cohort with the primary aim of both long term progression-free (PFS) and overall survival (OS). Methods: This phase I/II study was conducted between July 2009 and May 2012 at Loyola University Medical Center. MM patients with any disease response following induction were enrolled at time of stem cell transplantation. 43 patients received BUMELVEL conditioning followed by ASCT on the phase II portion of this study. Busfulan was administered intravenously (i.v.) daily for 4 days with the first 2 days (days −6 and −5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (days −4 and −3) adjusted to achieve a target AUC total of 20,000 μM·min determined by pharmacokinetic (PK) analysis. Melphalan at 140 mg/m2 and bortezomib at 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Maintenance therapy was not planned. Patients received prophylaxis for oral mucositis with palifermin. Data from this phase II clinical trial were compared against a matched control cohort of contemporaneous North American MM patients from the CIBMTR database (n = 162) receiving conditioning with single agent iv melphalan at a dose of 200mg/m2. The primary objectives of this study were median PFS and toxicities. Results: Baseline patient characteristics are described in Table 1. More patients in the BUMELVEL arm received greater than one line of therapy prior to transplant (53 v 33%). There were more standard risk patients per Mayo Stratification (Kumar et al, Mayo Clin Proc 2009) in the MEL200 group (78%) v the BUMELVEL group (40%). There was no difference in response rates at day 100 (p=0.48) but a trend toward improved response at 1 year in the BUMELVEL arm with 77% achieving a VGPR or better versus 60% in the MEL200 group (p-0.09). No patients in the BUMELVEL group received planned maintenance therapy post-transplant whereas 112 (69.6%) in the MEL200 control arm received planned post-transplant maintenance. Non-relapse mortality was 2% (range 0-9%) in the BUMELVEL group and 10 (6%, range 3-11) in the MEL200 but this was not statistically significant in both univariate and multivariate modeling (p=0.25). There were no episodes of sinusoidal obstructive syndrome in the BUMELVEL group and 37% of patients experienced grade 3 mucositis with no grade 4 mucositis. After a median of more than seven years of follow up, the five year PFS was 47% (95% CI; 32-62) in the BUMELVEL group versus 30% (95% CI; 23-37) in the MEL200 group (p=0.05) (Figure 1). Notably the 7-year PFS in the BUMELVEL group was 32% (range 18-48). In multivariate analysis for PFS, BUMELVEL conditioning (HR 0.65; 95% CI 0.44-0.97)(p=0.036), time from diagnosis to transplant of greater than versus less than 12 months (HR 1.64; 95% CI 1.18 - 2.27), and disease status at transplant CR versus other (p=0.006) were all predictive of PFS (table 2). OS was not different between the two groups with a 7 year survival of 64% (95% CI; 48-79) in the BUMELVEL group versus 55% (95% CI; 46-64%) in the MEL200 group (Figure 1) which was confirmed on multivariate analysis (p=0.33). Discussion: Similar to recent reports in the literature comparing busulfan and melphalan to melphalan alone (Bashir et al, Lancet Hem 2019), we show that although depth of response was similar between the BUMELVEL group and the historical MEL200 comparator, the BUMELVEL group experienced an improved PFS. Importantly, we report no cases of SOS and a low non-relapse mortality of only 2% (v 6% in the historical control) reinforcing that the preparatory regimen in myeloma can be intensified safely with improved duration of unmaintained PFS. These long term results confirm a sustained benefit of novel combination conditioning in MM and the need for novel transplant preparative regimens. Disclosures D'Souza: EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Stiff:Unum: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Amgen: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding.

Objective.To describe characteristics ofClostridium difficileinfection (CDI) and markers of severe CDI among patients with hematologic malignancies.Design.Case-control study.Setting.Tertiary care teaching hospital.Patients and Methods.Inpatients with hematologic malignancies and CDI were age and time matched with 2 control inpatients without hematologic malignancies. Chart reviews were performed, andC. difficileisolates were strain typed.Results.Case patients (n= 41) and control patients (n= 82) patients were different in respect to receipt of immunosuppressive agents within 2 months (92.7% vs 25.6%;P< .0001); neutropenia within 2 months (75.6% vs 3.7%;P< .0001) and mean (± standard deviation) white blood cell (WBC) count at diagnosis (4.9 ± 14.1 vs 11.8 ± 6.8 × 103cells/mL;P= .0002); baseline mean creatinine level (0.89 ± 0.1 vs 1.6 ± 2.4 mg/dL;P= .003), mean creatinine level at diagnosis (0.83 ± 0.4 vs 1.85 ± 1.9 mg/dL;P= .004), and creatinine increases of 1.5 times over baseline (2.4% vs 15.1%;P= .02). Immunosuppressive agents and creatinine level remained significant in multivariable analysis (P= .03 for both variables). Severity correlated with mortality when measured by alternate severity criteria but not when measured by the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America criteria, which are based solely on WBC count and creatinine elevation. The prevalence of the epidemic BI/NAP1/027 strain was similar in both groups.Conclusions.Patients with hematologic malignancies had lower creatinine levels at the time of CDI diagnosis compared with control patients. WBC counts also tended to be lower in case patients. CDI severity criteria based on WBC count and creatinine level may not be applicable to patients with hematologic malignancies.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

Background: Approximately 9% to 27% of patients undergoing hematopoietic stem cell transplantation (HSCT) develop a cardiac arrhythmia (CA).[1] This complication correlates with longer length of stays, higher probability of ICU admission, and higher mortality compared to patients who do not develop CA. Moreover, post-transplant CA is associated with greater risk of death within a year of HSCT. Identification of predictive risk factors for CA in patients undergoing HSCT has been elusive. Traditional risk factors like male gender, smoking, hypertension, diabetes, hypercholesterolemia, or established coronary artery disease, have not been found to be predictive of pre or post-transplant CA in HSCT patients. Echocardiogram may help identifying patients at risk of post-surgical arrhythmias but this has not been the case in HSCT.[2] MUGA scan has not been able to identify patients at risk for developing cardiac events during HSCT either.[3] In view of the detrimental consequences associated with CA during HSCT and the lack of reliable predictive risk factors, we decided to analyze and identify potential risk factors for CA in patients transplanted at our institution. Objective: This study aims to determine risk factors for the development of CA in patients undergoing HSCT. Methodology: A retrospective analysis of 138 consecutive patients undergoing HSCT at our institution between January 1st, 2015 and December 31st, 2017 was performed. One patient was excluded due to lack of baseline EKG. Data from patients ≥ 18 y/o who underwent autologous or allogeneic HSCT was analyzed. Variables analyzed included: age, gender, ethnicity, prior HSCT, diagnosis, type of transplant (autologous vs allogeneic), prior anthracycline exposure, diabetes mellitus, chronic kidney disease, hypertension, coronary artery disease, congestive heart failure, hyperlipidemia, previous arrhythmias, amyloidosis, documented STEMI or NSTEMI, home medications continued during HSCT, prior cardiovascular procedures, left ventricular ejection fraction prior to HSCT, baseline QTc prior to HSCT, stem cell dose, conditioning regimen, graft-versus-host disease prophylaxis, number of prior acute kidney injuries using RIFLE criteria, documented infections, electrolyte abnormalities, and hemoglobin < 7.0 g/dL. Statistical Methods: The Statistical Analysis Software (SAS) System program V9.0 was used for analysis. To compare potential risk factors of categorized data by patients with a documented arrhythmia and patients without a documented arrhythmia, a univariate comparison was performed using chi-square or Fisher's Exact test. Variables that were collected and demonstrated, as per-patient means, were analyzed using a multivariable T Test linear regression. A difference in incidence of arrhythmias between variables with a P-value of < 0.05 were statistically significant. Results: 31 patients (23%) developed CA during their HSCT. The most common type was atrial fibrillation (n= 13; 42%). The incidence of CA was greater in patients with a diagnosis of Non-Hodgkin's Lymphoma (17/31; 54.8%) vs (7/106; 6.6%); (p < 0.001) and QTc greater than 500 msec at any time during transplantation (8/31; 25.8%) vs (6/106; 5.6%) (p= 0.0011). All other risk factors did not have an association with an increased risk of CA during HSCT. Mean length of hospital stay, incidence of ICU admission, and number of in-hospital deaths were not statistically different between groups. Conclusion: Our data suggests that a diagnosis of Non-Hodgkin's Lymphoma or QTc prolongation ≥ 500 msec at any time during HSCT may be risk factors for CA during HSCT. Our study has the limitation of being a single institution analysis however, most patients (70%) in this analysis were prospectively placed on cardiac telemetry making our assessment of the incidence of CA during HSCT reliably accurate. Prospective interventional studies are warrant. [1] Tonorezos, Emilys S; Stillwell, Elizabth E; Calloway, James J., et al., Bone Marrow Transplant. 2015 Sep; 50(9): 1212-1216. [2] Osranek M, Fatema K, Qaddoura F, et al. Left atrial volume predicts the risk of atrial fibrillation after cardiac surgery: a prospective study. J Am Coll Cardiol. 2006;48(4):779-786. [3] Garcia I., Rodriguez T.E., Davis S., et al.; The Necessity of MUGA Scans to Detect Risks for Cardiac Toxicity in Patients Considered for Bone Marrow Transplantation. Tandem IBMTR/ASBMT Meeting; Orlando, FL 2002. Disclosures No relevant conflicts of interest to declare.

Nonrandomized trials suggest that pegfilgrastim, a pegylated granulocyte colony-stimulating factor, could be used in lieu of filgrastim after autologus peripheral blood stem cell transplantation. This phase III, randomized, double-blinded, placebo-controlled trial compared the efficacy, costs, and safety of single-dose pegfilgrastim (single 6 mg dose) versus daily filgrastim (5 microg/kg/day) for this indication. Seventy-eight patients, matched for age, sex, underlying disease, stage, and CD34/kg transplant dose were enrolled. Cytokines were started on day +1 posttransplant and continued to an absolute neutrophil count (ANC) of 5x10(9)/L for 3 days or 10x10(9)/L for 1 day. The median time to neutrophil engraftment (ANC1.5x10(9)/L for 3 days or 5x10(9)/L for 1 day) was the same in both groups (12 days). No differences in platelet engraftment (11 versus 13 days), number of platelet transfusions (5 versus 4), percent with positive cultures for bacterial pathogens (23% versus 15%), days of fever (1 versus 2), deaths prior to engraftment (1 versus 1), or duration of hospital stay (19 versus 19 days) were seen between the pegfilgrastim and filgrastim groups, respectively. Using the average wholesale price for doses used in this trial, there was a per-patient savings of $961 for the pegfilgrastim group (P.001). This phase III study failed to demonstrate a difference in time to neutrophil engraftment or any clinical sequelae between pegfilgrastim and filgrastim when given post-APBSCT, with pegfilgrastim achieving a cost savings over filgrastim.

Murine studies using anti-T-cell antibodies for conditioning in allogeneic SCT demonstrate engraftment with low rates of GVHD. On the basis of this preclinical model, we conditioned 30 patients with advanced hematologic malignancies with rabbit antithymocyte globulin (ATG) and TBI, to reduce rates of fatal acute GVHD. Patients were enrolled in two sequential groups: cohort 1 received ATG 10 mg/kg in divided doses (days -4 to -1)+200 cGy TBI (n=16), and cohort 2 received ATG (days -10 to -7)+450 cGy TBI (n=14). Median donor blood chimerism for the combined group was 94, 93 and 93% in the first, second and third months after transplant. Only three developed grade II acute GVHD despite 43% of patients receiving unrelated donor transplants. One-year survival was 71+/-11 and 54+/-14%, respectively, in recipients of related and unrelated donor SCT. Donor lymphocyte infusions were needed in 12 patients for the management of relapse and for mixed donor-recipient chimerism in 4 patients. We conclude that 10 mg/kg ATG and TBI allows engraftment with a low risk of acute GVHD; however, further dose optimization of ATG is required to achieve a balance between GVHD and disease relapse.

We describe the clinical courses of 3 patients with hematologic malignancies (2 with acute myelogenous leukemia and 1 with multiple myeloma) who developed invasive fungal infections due to uncommon molds (Alternaria spp., Paecilomyces lilacinus, and Zygomycetes). Breakthrough invasive fungal infections of the sinus (n = 1), lung (n = 3), and pericardium (n = 1) developed despite fluconazole prophylaxis and failed to respond to treatment with other licensed antifungal therapies, including amphotericin B (n = 3), caspofungin (n = 2), and voriconazole (n = 3), and surgical intervention (n = 2). Salvage therapy with posaconazole oral suspension resulted in successful outcomes in all 3 patients, who subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) while on continued posaconazole therapy. The median duration of posaconazole treatment before HSCT was 5 months (range: 1.5-6 months). Posaconazole salvage therapy allowed successful allogeneic HSCT in 3 patients with refractory invasive mold infections.

Although autologous stem cell transplantation (ASCT) for patients with relapsed/refractory Hodgkin lymphoma (HL) appears to offer a survival advantage over conventional therapy, only approximately 25% to 35% of patients with primary progressive or poor-risk recurrent HL can achieve durable remission after ASCT, with disease progressive after transplant accounting for most of the treatment failures. We conducted a pilot study to evaluate the toxicities and efficacy of a tandem transplant approach in this subgroup of patients. Between April 1998 and March 2000, 46 patients were enrolled in the study. Eligibility criteria: primary progressive (n = 28) or recurrent HL (n = 18) with at least 1 of the following poor prognostic factors: first complete remission (CR)

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells (PBPCs) may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF ( (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (≥ 0.5 × 109/L) was similar between groups (13 vs. 13 days, P=0.69) while platelet engraftment (≥ 20 × 109/L) was slightly faster with CC+GF (19 vs. 18 days, P=0.006). Adjusted 3-years PFS was 43% (95% C.I. 38–48) in GF and 40% (95% C.I. 35–45) in CC+GF, P=0.33. Adjusted 3-years OS was 82% (95% C.I. 78–86) vs. 80% (95% C.I. 75–84), P=0.43 and adjusted 5-year OS was 62% (95C.I. 54–68) vs. 60% (95% C.I. 52–67), P=0.76, for GF and CC+GF respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Outpatient hematopoietic stem cell transplants (HSCT) are usually performed in patients receiving minimally mucotoxic preparative regimens; total body irradiation (TBI)-based regimens typically are excluded. To improve resource utilization and patient satisfaction, we developed a totally outpatient HSCT program for TBI regimens and compared outcomes for our first 100 such transplants to 32 performed as in-patients during the same interval, for caregiver or financial reasons. Symptoms were managed predominately with oral agents; pain management consisted of transdermal fentanyl and oral morphine solution. Except for more unmarried in-patients, the two groups were matched. Time to engraftment, severity of mucositis and transplant duration were identical for the two groups. Twenty-seven of the outpatients were admitted (median-6 days), primarily for progressing infection. Thus 92% of all transplant days were outpatient. There were no septic episodes or hospital admissions for pain management. There were no deaths to day 30 in either group and 100-day survival was identical. There was a mean cost savings of Dollars 16,000 per outpatient transplant and outpatient patient/caregiver quality of life was similar to that reported for in-patients. Patients undergoing severely mucotoxic regimens can be safely transplanted in an outpatient setting with a significant cost saving, with no increase in morbidity or mortality.

Both single and tandem cycles of high dose therapy and autologous peripheral blood stem cell transplantation (ASCT) have been shown to improve survival in multiple myeloma (MM) patients. We report outcomes in 104 MM patients undergoing a single transplant after conditioning with a conventional myeloablative regimen, busulphan and cyclophosphamide. The patients were either in a first (71%), or subsequent remission (29%). Peripheral blood stem cells were mobilized using cyclophosphamide and granulocyte colony stimulating factor. The conditioning regimen consisted of busulphan 0.85 mg/kg given orally every 6 h (16 doses) and cyclophosphamide 60 mg/kg/d given intravenously for 2 d. The entire conditioning, transplant and post-transplant course were in the outpatient setting for 45% patients. At a median follow-up of 26 months (range 2-98 months), the median overall and progression-free survival were 57 months [95% confidence interval (CI) 47-68] and 26 months (95% CI 20-32) respectively. Younger age and higher CD34+ cell dose infused were independently predictive of improved overall and progression-free survival. Busulphan and cyclophosphamide is an effective and well-tolerated preparative regimen for ASCT that can be given to MM patients in the outpatient setting.

10046 Background: The SIPAT is used to assess psychosocial risk in solid organ transplants but data in HSCT is lacking. We examined if pre-HSCT SIPAT scores predict mortality, morbidity, length of stay (LOS) and number of hospitalizations over a 1 year period. Methods: 89 adult HSCT (59% autologous, 38% allogeneic) pts from an academic medical center underwent the SIPAT pre-HSCT. Additional data were obtained on Day 0, and 3-, 6-, and 12-months. Univariable Cox proportional hazards models assessed the instantaneous risk of mortality at any given time after Day 0 as a function of baseline pt characteristics and the SIPAT score. Results: TheSIPAT categorized 28%, 66% and 5.7% respectively of the pts as excellent (E), good (G), and high risk (HR) candidates. One year post HSCT, 76% of E, 72% of G, and 40% of HR candidates were alive. Higher SIPAT scores were a significant predictor of mortality. Compared to E candidates, the HR candidates were 5.94 (95% CI: 1.31-26.81) times more likely to die any time after Day 0 – even after controlling for pts’ comorbidity index ( p = .02). Similarly, compared to G candidates, HR pts were 4.81 (95% CI: 1.33-17.47) times more likely to die even after controlling for pts’ comorbidity index ( p = .01). There was no difference between the G and E candidates on univariable ( p = .75) or multivariable analysis controlling for comorbidity index score ( p = .72). For every 1 point increase in pts’ adherence score, the risk of death was expected to decline by approximately 14% ( HR = 0.86, 95% CI: 0.78 – 0.96; p = .01). SIPAT items that predicted mortality were depression ( p = .02), deceptive behavior ( p < .001) and moderate alcohol abuse ( p < .001). In linear regression analysis, higher SIPAT score was associated with longer LOS ( p = .04) but not infection ( p = .23), GVHD ( p = .40), or number of hospitalizations ( p = .73). Because there were only 18 mortality events, multivariable analyses were limited. Future research will examine the effect of SIPAT on time to death controlling for other pt comorbidities. Conclusions: We found the SIPAT was able to predict mortality and LOS in HSCT pts. This finding if validated in a multi-center manner could be an important tool for HSCT pt selection.

Introduction: Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HCT). The most widely used aGVHD prophylaxis regimen is a combination of a calcineurin inhibitor and a short course of methotrexate. Results of studies on the optimal blood levels of the calcineurin inhibitor tacrolimus to prevent aGVHD are mixed, with some showing no correlation and others indicating that trough levels between 7-15 ng/mL required to adequately prevent aGVHD. Currently, the established target trough level for this agent is 10 to 20 ng/mL. We retrospectively evaluated the relationship between tacrolimus blood concentration and the incidence of grade II-IV aGVHD in a large cohort of adult patients following allogeneic HCT from either an HLA-matched related or matched unrelated donors. Methods: We evaluated all related/unrelated allografts between January 2004 and December 2012 at the Cardinal Bernardin Cancer Center at Loyola University. Inclusion criteria included age 18 years or older, first allogeneic HCT for a hematological malignancy, and use of tacrolimus and short term methotrexate for aGVHD prophylaxis. Donors included human leukocyte antigen (HLA) identical sibling (Allo-Sib) or unrelated donors (MUD) either fully matched or 1 antigen mismatched (10%). Both myeloablative and non-myeloablative conditioning regimens were included. Disease risk was defined by the ASBMT classification and Co-Morbidity Index by Sorror et al (HCT-CI). Infusional tacrolimus was initiated on day -2 of HCT at dose of 0.03 mg/kg/d and AM trough blood concentrations measured every other day during the entire hospital stay with the goal of maintaining a level of 10-15 ng/ml and then twice weekly after discharge. Dose adjustments or withholds were based primary on serum creatinine and trough levels per a set protocol that withholds for levels greater than 20 ng/ml or creatinine greater than 2.0 mg/dl. Acute GVHD was graded based on the International Bone Marrow Transplant Registry System. Univariate and multivariate analyses exploring all risk factors for aGVHD were performed. Results: A total of 428 patients met the inclusion criteria. Median age was 48.5 years with a male predominance (60.6%). HCT-CI was evenly distributed with 121 (28.2%) low risk, 151 (35.3%) intermediate risk, and 156 (36.4%) high risk. Per ASBMT disease risk classification, more patients had high disease risk (n=211, 49.3%); 64 (15%) with intermediate risk, and 153 (35.7%) with low risk. Acute GVHD II-IV developed in 186 (43%) patients in this largely myeloablative patient population (89%), with donor source split nearly evenly between MUD (45%) and Allo-sib (55%). An extensive univariate analysis for the factors associated with the development of aGVHD was developed (Table 1). The strongest predictor of aGVHD was a level of tacrolimus < 5 ng/ml in weeks 3 and 4 after transplant: of those with no aGVHD only 16.9% had a level < 5 ng/ml during these weeks vs 27.4% with aGVHD (p = .009). Other tacrolimus trough cut points, i.e. 10 ng/ml, 2.5 ng/ml and the mean (13.4 ng/ml in each group) were not associated with a higher rate of aGVHD. In the univariate analysis, AML and allo-sib grafts were noted to be associated with lower risk of aGVHD. In multivariate analysis (Table 2), tacrolimus levels less than 5 ng/ml in weeks 3 or 4 was found to be the most statistically significant factor in predicting aGVHD incidence (Odds ratio 82 95% CI 1.13-2.94; p = .01); other significant factors include HCT-CI (p = .02) and graft source (p = .04). Conclusion: In one of the largest retrospective studies examining the correlation of early tacrolimus blood concentrations and acute GHVD incidence, we show that trough tacrolimus levels less than 5 ng/ml in weeks 3-4 following Allo-Sib or MUD HCT is a strong predictor for an increased risk of aGVHD. We affirm that higher HCT-CI and donor source are risk factors for aGVHD after allografts. This not only helps define more accurately the lower limits of acceptable tacrolimus levels, but appears to emphasize the importance for close monitoring and dose adjustment of these levels at a time when patients are typically discharged to the outpatient setting. Disclosures No relevant conflicts of interest to declare.

Although bone marrow transplantation has been recognized as an effective therapy for malignant and nonmalignant blood disorders, the modality has also been associated with side-effects and complications. Among these adverse events, neurologic complications emerged as an important and frequent source of treatment-related morbidity and mortality. The survival of patients who died from complications related to central nervous system abnormalities appears to be shorter compared to those who died from non-neurological complications. The incidence of neurologic complications appears to correlate with the degree of human leukocyte antigen (HLA) disparity and the risk status of the underlying disease. Nonrelapse mortality associated with reduced intensity regimens is lower compared to myeloablative conditioning regimens. However, reduced intensity regimens are still associated with significant incidence of complications, including graft-versus-host disease, opportunistic infections, organ toxicity, and neurologic complications. Complications of sepsis-related encephalopathy in mechanically ventilated patients are frequently either overlooked or misdiagnosed. Obtaining a microbiological diagnosis through body fluid cultures or tissue identification is important in order to identify the source of infection and guide an effective antimicrobial therapy. However, pursuing a microbiological diagnosis must not delay the administration of antibiotics and resuscitation of a patient with septic shock.

Allogeneic transplant using reduced intensity conditioning is a therapeutic option for patients with Hodgkin lymphoma (HL) who relapse after an autograft. This was a prospective study of 31 consecutive eligible patients with HL who relapsed after an autograft and underwent an allograft using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning. At a median follow-up of 7 years the progression-free survival (PFS) was 36% (95% confidence interval [CI] 19-54%) and overall survival (OS) was 42% (95% CI 23-59%). In multivariate analysis only residual disease at the time of transplant predicted outcome, with a 4-year PFS and OS of 62% and 75% for patients with minimal residual disease versus 8% and 8% for patients with gross residual disease, respectively (p = 0.005 and p = 0.001, respectively). This benefit seemed to be irrespective of chemosensitivity, with an OS for patients with chemorefractory yet minimal disease of 71% at 4 years. BEAM allogeneic transplant is effective in producing long-term remissions after autograft failure. Regardless of chemosensitivity, minimizing tumor burden pre-transplant may improve long-term outcome.

Graft-versus-host disease (GVHD) causes most non-relapse mortality (NRM) after alternative donor (unrelated and mismatched related) hematopoietic cell transplant (HCT). We previously showed that increases in day +7 TNF-receptor-1 (TNFR1) ratios (posttransplantation day +7/pretransplantation baseline) after myeloablative HCT correlate with outcomes including GVHD, NRM, and survival. Therefore, we conducted a phase II trial at 2 centers, testing whether the addition of the TNF-inhibitor etanercept (25 mg twice weekly from start of conditioning to day +56) to standard GVHD prophylaxis would lower TNFR1 levels, reduce GVHD rates, and improve NRM and survival. Patients underwent myeloablative HCT from a matched unrelated donor (URD; N = 71), 1-antigen mismatched URD (N = 26), or 1-antigen mismatched related donor (N = 3) using either total body irradiation (TBI)-based conditioning (N = 29) or non-TBI-based conditioning (N = 71). Compared to historical controls, the increase in posttransplantation day +7 TNFR1 ratios was not altered in patients who received TBI-based conditioning, but was 40% lower in patients receiving non-TBI-based conditioning. The latter group experienced relatively low rates of severe grade 3 to 4 GVHD (14%), 1-year NRM (16%), and high 1-year survival (69%). These findings suggest that (1) the effectiveness of TNF-inhibition with etanercept may depend on the conditioning regimen, and (2) attenuating the expected rise in TNFR1 levels early posttransplantation correlates with good outcomes.

Uncontrolled delayed nausea and vomiting remains a problem after high-dose preparative regimens used for autologous and allogeneic hematopoietic stem cell transplants. Recently, aprepitant was approved for highly and moderately emetogenic chemotherapy, and, in particular, is effective for decreasing delayed emesis. To evaluate its safety and efficacy in the transplantation setting, we performed a randomized, placebo-controlled, phase 3 trial of aprepitant in combination with ondansetron and dexamethasone in patients treated with ablative preparative regimens. Patients were randomized to receive oral aprepitant or placebo daily with oral ondansetron and dexamethasone during and for 3 days after the completion of the preparative regimen in this prospective randomized, double-blind study. The primary objective was complete response (CR) rate, defined as no emesis with no or mild nausea. Other endpoints included number of emetic episodes, nausea severity assessed using a 100-mm visual analog scale (VAS), the need for rescue antiemetics, and transplantation outcome, including regimen-related toxicity. One hundred eighty-one patients were randomized and 179 patients were eligible for analysis. Overall, CR rates were 81.9% for the aprepitant and 65.8% for the placebo arms (P < .001). Percentages of patients with no emesis all days were 73.3% for aprepitant and 22.5% placebo (P < .001). Mean VAS scores were 16.6 mm aprepitant and 16.9 mm placebo (NS), and there were no differences in the amount of rescue antiemetics used, regimen related toxicity, engraftment, or transplantation outcome. Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, whereas not increasing RRT or affecting short-term survival but had no significant impact on the use of PRN antiemetics, or overall VAS nausea scores.

Steroid refractory graft versus host disease (GVHD) presents a significant therapeutic challenge due to the limited efficacy and safety of second-line treatments. Three patients with extensively pretreated, refractory GVHD were treated with a targeted anti-T-cell agent, alefacept, and demonstrated rapid and clinically significant improvement in their GVHD, facilitating tapering of corticosteroids. The pathological and immunohistochemical findings of GVHD also improved, validating our clinical impression. These preliminary findings indicate that alefacept may have beneficial activity in GVHD warranting further study.

A 55-yr-old woman with a history of B-cell lymphoma of the nasopharynx diagnosed in March 1999 eventually underwent submyeloablative allogeneic stem cell transplantation from a sibling donor in December 2002 after conventional treatment options were exhausted. The treatment approach was somewhat altered by the fact that the patient was a practicing Jehovah's Witness and refused blood-blood product transfusion. The course of her treatment was unremarkable until around day 100 posttransplant when she developed graft failure, leading to severe anemia. Blood transfusions were refused. Donor cells were re-infused. During this treatment period, the patient's hemoglobin dropped to a low of 2.7 g/dL, with the patient experiencing severe fatigue, dyspnea on exertion, headaches, and blurred vision. Polymerized human hemoglobin (pyridoxylated) (Poly- Heme, Northfield Laboratories Inc., Evanston, IL) was given under an emergency, compassionate use protocol and successfully bridged the patient's hemoglobin and relieved symptoms during her marrow recovery period.

Patients referred for hematopoietic stem cell transplantation (HSCT) often have knowledge deficits about their disease and overestimate their prognosis making it difficult initially to discuss potentially life-threatening transplant options. To determine patients' understanding of their disease and the adequacy of a 3-h consultation at our center, we developed a survey that measured perceived knowledge deficits of disease, prognosis, and emotional status before and after their initial consultation. Ninety nine consecutive eligible patients completed the survey. Although 76.7% claimed adequate information about their disease pre-HCST visit, 51.5 and 41.4% respectively lacked knowledge about their 1-year prognosis with and without any therapy. After the visit, 66.7% of the patients had obtained enough information to make an informed decision regarding HSCT versus 23.2% pre-visit, and a significant reduction in the need for further information was reported by 53.5% of patients (P

s / Biol Blood Marrow Transplant 19 (2013) S178eS193 S186 may be warranted to discern if DM pts may benefit from different methods of mobilization or if long term transplant outcomes are impacted.

A second allogeneic hematopoietic stem cell transplant (HSCT) for relapsed hematologic malignancies is an option in select patients after an initial allograft has failed. If the original donor is not available, a different donor may have to be considered. We report our experience of performing a second allogeneic HSCT using a different donor in patients with relapsed leukemia and lymphoma. In a 5-year period, six patients underwent a second allograft with myeloablative conditioning using a different donor. Four of these were retransplanted using a matched-unrelated donor. Four of the patients (67%) remain progression-free at a median follow-up of 32 months (range 3-72). There were no cases of transplant-related mortality. We conclude that a second allogeneic HSCT using a different donor is a viable option for selected patients relapsing after an allograft if the original donor is not available.

Although acute myeloid and lymphoid leukemia initially respond to conventional chemotherapy, most patients relapse and succumb from their disease. For the past 30 years, efforts at intensifying induction or postremission conventional chemotherapy have met with limited success. Of all the therapies examined, allogeneic hematopoietic stem cell transplantation has achieved the best outcomes, with the first reports of cure 25 years ago. Most phase III studies have failed to demonstrate a clear advantage of allografting over chemotherapy because of significant risk of transplant-related mortality. However, there is reason for optimism based on the identification of high-risk groups and from improvements in the prevention and management of transplant-related complications. These accomplishments, along with a recent increase in the donor pool through the availability of unrelated donors and cryopreserved umbilical cord blood stem cells, continue to make allografting the most promising curative modality for acute leukemias.

Background Progression free and overall survival (PFS/OS) for Multiple Myeloma (MM) have improved over the past 20 years largely as a result of ASCT as well as novel conventional dose therapeutic agents. However, since the 1990s improvements in PFS and OS due to ASCT have improved minimally due to continued reliance on single agent melphalan (MEL). In order to improve PFS and OS, better transplant regimens should be investigated. The combination of Busulfan (BU) and MEL delivers better PFS compared to MEL alone (Lahuerta, et al) with similar toxicity rates to MEL alone. Furthermore, in vitro and in vivo studies indicate synergy between MEL and proteasome inhibitors such as Botezomib (BTZ). Superior response rates and PFS were seen when BTZ is combined with MEL when compared with historical controls using MEL in a recent IFM study. (Roussel et al. Blood 2010). We hypothesize that IV BU and MEL followed by BTZ (BuMelVel) could be an effective preparative regimen with acceptable toxicity for patients with MM. Methods Between July 2009 and June 2013 57 patients with Multiple Myeloma who had already undergone induction therapy and were eligible for ASCT were enrolled. Patients received IV BU administered as a daily intravenous infusion for a total of 4 days with the first 2 days (day -6, -5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (day -4, -3) adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 mM* min. Pharmacokinetic (PK) analysis performed after the first dose of IV Bu was used to determine Bu AUC and individualized Bu PK-directed dosing for later doses (d-4 and -3). MEL was administered at 140 mg/ m2 IV over 15-30 minutes on D-2. BTZ 1.6 mg/m2 was administered IV push on D-1. Palifermin was given for mucoprotection at a dose of 6.25 mg IV for two consecutive days before the first busulfan dose (days -8 and -7). A third dose of 6.25 mg was give on day 0 after stem cell transplantation. Results Of the 57 patients enrolled 56 are evaluable for toxicity and 54 for response at D +100. Median age is 61 (31 - 72). 49 % of patients had received ≥ 2 induction regimens (range 1-4) and 69% were DS stage III. 38% of patients had achieved at least a VGPR after induction with 9% of those achieving a CR. After transplantation, 70% of patients had at least a VGPR including 37% CR or sCR. All but 4 patients had a PR or better to induction therapy (three had stable and one progressive disease). The most common grade ≥ 3 toxicities were neutropenic fever (n = 42) and mucositis (n=21). No VOD or treatment related deaths at D+100 were observed and all patients engrafted. Median time to engraftment was 10 days (range 10-12) and median hospital stay was 20 days ( 15-31). Median PFS at 2 years was 78%. Conclusion BuMelVel is an effective novel preparative regimen with ≥ VGPR and CR/sCR of 70% and 37% respectively which compare favorably to responses previously reported with MEL 200 alone (43% and 11%, respectively) by Roussel et al. At the time of reporting, 12 patients had relapsed; 2 and 3-year PFS rates were 78% and 60% respectively. The regimen of BuMelVel is well tolerated and may lead to improvements in PFS and OS in patients with multiple myeloma. Disclosures: Rodriguez: Otsuka: Research Funding; Millennium: Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

Introduction Non-Hodgkin’s Lymphoma (NHL) is the most common hematologic malignancy in the United States with 69,700 new cases and 19,000 deaths predicted in 2013. The majority of patients diagnosed with NHL respond well to conventional chemotherapy, however, patients with relapsed or refractory NHL usually have poor long-term outcomes. While autologous stem cell transplantation (auto-SCT) is a mainstay for patients with relapsed or refractory disease that are chemotherapy-sensitive, allogeneic stem cell transplantation (allo-SCT) has been used to treat NHL in patients who have relapsed after auto-SCT, are chemotherapy-resistant, or have adverse risk factors. While some evidence has suggested that chemotherapy-resistant disease status prior to allo-SCT is associated with a poor prognosis, limited data exists to guide evidence-based transplant paradigms. We sought to determine if disease status prior to allo-SCT in patients with relapsed or refractory NHL impacts outcomes. Methods A retrospective chart review identified 154 patients diagnosed with relapsed or refractory NHL who underwent an allo-SCT at Loyola University Medical Center between January 1998 and January 2012. Fifteen patients were excluded for lack of data yielding 139 patients over a 14-year period. Of our patients with relapsed or refractory disease, chemotherapy-sensitive patients were defined as patients with partial or complete response to chemotherapy at time of transplant. Chemotherapy-resistant patients were defined as patients that either had progressive disease or were refractory to chemotherapy at time of transplant. Data on age, sex, type of NHL, stage at diagnosis, chemotherapy regiment, previous auto-SCT, disease status prior to allo-SCT, overall survival, and cause of death were collected. Results Of the 139 patients, the median age was 48 years with a male to female ratio of 1.4:1. The majority of patients had stage 3 or 4 disease (74%). Breakdown of NHL subtype revealed 31% diffuse large B-cell (DLBCL), 31% follicular, 13.7% mantle cell, 8% T-cell, 3.6% Burkitt’s, 2.1% marginal cell, and 10.7% other category that included small lymphocytic, anaplastic, natural killer cell, mixed cellularity, and unspecified NHL. A total of 44 patients (31%) underwent auto-SCT prior to allo-SCT. Subtypes of allo-SCT included matched sibling (45.3%), matched unrelated donor (MUD, 39.6%), and cord blood transplant (15.1%). Matched sibling allo-SCT had an improved 2 year overall survival of 57.1% when compared to MUD and cord allo-SCT (33% and 30%, respectively). Overall survival after allo-SCT for all patients was 41% at 3 years and 33.1% at 5 years. Disease status prior to transplant was divided into two categories: (1) chemotherapy-resistant (97 patients, 69.7%) and (2) chemotherapy-sensitive (42 patients, 30.2%). There was no statistical difference in overall survival between the chemotherapy-resistant and chemotherapy-sensitive groups at 6 months (60.8% and 78.5% respectively, p=0.066) and at 3 years (40.2% and 42.8% respectively, p=0.91). In a subgroup analysis, DLBCL patients with chemotherapy-resistant disease had similar 3 year survival as compared to patients with chemotherapy-sensitive disease (22.2% and 23%, respectively, p=0.93). Similar results were observed for both subgroups of patients with follicular lymphoma, with 55.2% survival in the chemotherapy-resistant group as compared to 64.2% in the chemotherapy-sensitive group at 3 years (p=0.81). Conclusion Our data suggest that disease status at the time of transplant does not impact survival outcomes in patients with relapsed or refractory NHL. This finding extended into a sub-group analysis of DLBCL, representative of an aggressive NHL subtype, and follicular cell lymphoma, representative of an indolent NHL subtype. We hypothesize that the comparable survival outcomes between chemotherapy-sensitive and chemotherapy-resistant disease states at transplant may be a result of graft versus lymphoma effect and use of a disease free graft. As no survival advantage was incurred in patients with chemotherapy sensitive disease, these data imply that the lymphoma burden at time of transplant is not prognostic. This potentially highlights the utility of earlier time to transplant in patients with chemotherapy-resistant disease, and perhaps suggest limiting the duration of attempted salvage chemotherapy after disease relapse. Disclosures: No relevant conflicts of interest to declare.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin’s lymphoma (NHL) characterized by the chromosomal translocation t (11;14) (q13;q32). It comprises approximately 6% of all NHL, but has a highly aggressive clinical course. While 60-90% of patients achieve complete remission (CR) with augmented induction regimens, approximately 85% will eventually relapse with a median overall survival (OS) of 3-4 years with less than 15% of patients alive at 5 years. Optimal initial therapy for this disease usually includes for those in first CR autologous hematopoietic stem cell transplant (HSCT), with allogeneic HSCT reserved for those who relapse. Patients who are non-responsive to first-line chemotherapy are increasingly being considered for an allogeneic HSCT. Methods After obtaining IRB approval, a retrospective chart review was performed on all patients with a diagnosis of MCL (confirmed by histology) at LUMC to compare the outcome of transplants vs. non-transplants patients. Primary end points were overall survival (OS) and progression-free survival (PFS) after stem cell transplant. A total of 104 patients were evaluated from 1999 to 2013, of whom 63 underwent a transplant after induction therapy and 13 an allograft after first relapse. Results The induction chemotherapy regimens used for the 104 patients were CHOP(R) in approximately 50% and Hyper-CVAD in 25%. A total of 51 patients received a first remission autologous HSCT, of these 20 patients were in CR1 at the time of transplant. A total of 25 patients received an allogeneic transplants (15 were sibling and 10 unrelated grafts); 12 underwent first-line allogeneic transplant with 65% receiving a reduced intensity regimen. In the group of 13 patients who relapsed after autologous HSCT, 90% received a reduced intensity regimen. Survival analysis by treatment modality was as follows: median OS for the non-transplant and transplant cohorts respectively were 29 months and 63.5 months (p=0.007). Median OS was not reached for patient who received first-line allogeneic HSCT while median OS for patient failing a prior autologous HSCT who received an allogeneic transplant was 28 months. Of the 12 patients who underwent first-line allogeneic transplant, despite all having chemo-resistant disease after induction therapy, no patient died of relapse; the only patient who relapsed received bortezomib and rituximab and achieved complete remission. Of the 13 patients who received an allogeneic transplant after prior autologous transplant, only two patients died of relapsed disease but nine patients died of transplant-related complications, largely related to their poor performance status due to multiple chemotherapy regimens associated with their refractory lymphoma. Conclusions Our results for autografts are consistent with the data available in the literature confirming the benefit of this strategy as part of induction treatment. However this analysis suggests a significant benefit for early allografts for those failing induction therapy, presumably due to a potent graft vs. lymphoma effect despite chemotherapy resistance. Such an effect also occurs for allografts performed after autograft failure, but the frailty of patients does impact its benefit. Based on our data, patients in CR1 should be considered for ASCT after initial therapy, however those in less than CR after initial therapy should be considered for an early allogeneic transplant. Disclosures: No relevant conflicts of interest to declare.

Background High dose melphalan (MEL) preceding autologous hematopoietic cell transplantation (HCT) for MM continues to be the standard of care. No regimen has been clearly proven superior to MEL 200 mg/m2 (MEL 200). The combination of Busulfan (Bu) and MEL was shown to improve progression free survival (PFS) (Lahuerta, et al; Haematologica. 2010 Nov; 95 (11):1913-20). The combination of bortezomib (Vel) with MEL also demonstrated superior PFS vs. MEL alone using historical controls (Roussel et al; Blood. 2010; 115:32-7). We studied a conditioning regimen combining Bu, MEL and Vel (BuMelVel) in an open label phase II study aimed at improving PFS after HCT for MM. To assess the potential value of this novel regimen, we performed a comparative analysis between BuMelVel and a cohort of patients conditioned with MEL 200 from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Methods Between July 2009 and May 2012, 43 eligible patients received BuMelVel conditioning followed by HCT. Bu was administered daily intravenous (IV) for a total of 4 days with the first 2 days (day -6, -5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (day -4, -3) adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 mM* min by performing pharmacokinetic (PK) analysis after the first dose of IV Bu. Mel 140 mg/m2 and Vel 1.6 mg/m2 were administered IV on Day-2 and Day -1 respectively. Outcomes were compared with a contemporaneous North American cohort (n=162) receiving single agent MEL 200 conditioning from the CIBMTR database. Controls were matched on age, sex, Karnofsky performance status (KPS), stage and interval from diagnosis to HCT. Multivariate analysis of Relapse, PFS, and overall survival (OS) was performed. Median follow up of survivors was 25 months. Planned maintenance therapy was not used. Results Age, gender, KPS, isotype, and stage were similar between groups (Table 1.). The MEL 200 cohort had more standard risk patients per Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) (78% vs. 40% in BuMelVel, p Conclusion PK directed dosing of Bu can be safely combined with Mel 140 followed by bortezomib without higher risk of VOD or NRM and in the absence of maintenance therapy. Within the constraints of a short follow up and uncontrolled post-transplant salvage therapies on both groups, no difference in OS has yet been observed. This novel conditioning regimen is safe and was associated with superior PFS compared with similarly matched controls and warrants further testing. Disclosures: Rodriguez: Otsuka: Research Funding; Millennium: Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Vesole:Millennium: Speakers Bureau.

Background Allogeneic hematopoietic stem cell transplantation (HDT) in the elderly patient with acute myeloid leukemia (AML) or myelodysplasia (MDS) continues to pose a challenge due to treatment failure and treatment related toxicity. TBI/Cy, allows for engraftment and tolerance while maximizing anti-tumor activity, but can be a difficult regimen in elderly patients due to its associated toxicity profile. The introduction of reduced intensity conditioning regimens (RIC) and improved supportive care has led to decreased mortality following HDT in the elderly. However, for patients at high risk for relapse, RIC may not achieve prolonged disease control. For these patients, an ablative HDT with reduced toxicity (RT-SCT) may be beneficial by controlling disease with acceptable toxicity while allowing a GVL effect. We evaluated a novel conditioning regimen in an open label phase II study consisting of Bu/Pent aimed at improving toxicity, relapse rate, and overall survival (OS) in elderly patients with AML or MDS, and compared them with an elderly group who received TBI/Cy. Methods We treated 54 patients with AML/MDS over the age of 55, who were recipients of HDT from fully matched related donor (MRD), umbilical cord donor, or matched unrelated donor (MUD). We defined elderly as greater than 55 years of age. The median age in the Bu/Pent group was 64, 61% had adverse prognostic features including cytogenetics, relapsed, treatment related or transformed disease, or high IPSS score, 39% were in the intermediate group. There were 60% MRD and 40% unrelated HDT. In the TBI group median age was 59, 48% had adverse features and 52% intermediate, 48% MRD and 52% unrelated HDT. The Bu/Pent group (n=23) was conditioned with intravenous busulfan 1.6mg/kg every 12 hours day -7 to -4 and pentostatin 4mg/m2 on day -3 and day-2 prior to SCT on day 0. GVHD prophylaxis was methotrexate 10mg/m2 on day 1 and 5mg/m2 on days 3 and 6. Tacrolimus was started on day -2 and tapered over 1 month after day +100. Relapse, survival and toxicity data was compared with a historical control group at our institution who received 12 Gy TBI/Cy (60 mg/kg x 2) (n=31). Controls were selected by retrospective chart review of patients with a diagnosis of MDS or AML who had received an allogeneic transplant with a TBI/Cy based conditioning regimen after the age of 55. There was no graft failure reported in either group. The OS at 100 days and 1-year post HDT was significantly better for the Bu/Pent group vs. TBI group (82.6% vs. 51.6% and 43.5% vs. 25.8% respectively; p value= 0.029). Progression free survival (PFS) was also significantly better in the elderly population receiving Bu/Pent; 43.5% at 1 year versus 22.6% in the TBI group with a p value of .021. The rate of relapse was comparable regardless of conditioning regimen with 34% in the Bu/Pent group (8/23) and 29% in the TBI/Cy group (9/31) relapsing. Transplant related mortality (TRM) accounted for 13% (3/23) of the deaths in the Bu/Pent group, and 38% (12/31) in the TBI/Cy group. Of the three deaths in the Bu/Pent group, 2 were due to GVHD and 1 was secondary to sepsis within 100 days. Other significant nonfatal toxicities such as mucositis and nausea/vomiting were medically managed and rates of GVHD were similar in the two groups; 10/23 (43%) in the Bu/Pent group and 14/31 (45%) in the TBI group. Of the 10 GVHD patients in the Bu/Pent group, 7 had chronic (cGVHD) (30%). None of the patients in the Bu/Pent group and 3/31 in the TBI group developed VOD. Upon sub-group analysis, elderly CIBMTR high-risk AML/MDS patients who received Bu/Pent had an 86% 100 day survival versus 60% in the TBI/Cy group; 1 year survival was 43% and 33% respectively. In the elderly CIBMTR intermediate risk group, Bu/Pent 100 day survival was 78% vs. 44% in the TBI group. At 1 year, patients in the intermediate group who received Bu/Pent had 45% survival vs. 19% in the TBI group. Conclusion We found that OS and PFS at 100 days and 1 year were significantly better in the Bu/Pent group due to a much lower TRM. The Bu/Pent based regimen appears to be superior for patients over the age of 55 with MDS or AML undergoing HDT when compared with TBI based regimens. With a low toxicity profile, Bu/Pent patients had a lower incidence of TRM when compared with a prospective study of patients receiving RIC-SCT busulfan/fludarabine (20%) and a lower incidence of cGVHD(53%) (Valcarcel et al). This regimen warrants further prospective evaluation. p value= 0.029 p value= 0.021 Disclosures: Smith: Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Rodriguez:otsuka: Honoraria, Research Funding.

Abstract 3080 Background: Salvage therapeutic options are limited for multiple myeloma (MM) patients who relapse after autologous hematopoietic stem cell transplantation (ASCT). A second ASCT using a different conditioning regimen may provide long-term disease control. We report efficacy and safety of daily intravenous busulfan (IV Bu) conditioning given with bortezomib for second ASCT. Materials and Methods: In this prospective, multicenter, Phase IIa study, thirty MM patients who relapsed ≥ 1 year after initial ASCT and were candidates for second ASCT were enrolled at eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between Days -12 and -9 prior to ASCT. Pharmacokinetic (PK) analysis from test dose determined Bu exposure as area under the concentration-time curve (AUC). This analysis was used to determine individualized Bu PK-directed dosing for the conditioning regimen in order to achieve a total regimen AUC of 20,000 mM*min. IV Bu was administered over 3 hours once daily from Day -5 to Day -2. Confirmatory PK analysis was conducted in all patients on Day -5. Bu doses were adjusted on Days -3 and -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. Disease response was evaluated prior to the ASCT and at 3 and 6 months post-transplant, based on the International Myeloma Working Group uniform response criteria in 2006. Results: Patient Demographics: Median age at second ASCT was 59 years (range: 48–73). All patients had previously been treated with bortezomib (86.7%), thalidomide (46.7%), and/or lenalidomide (66.7%). All subjects underwent first ASCT with high-dose melphalan. Median time from first ASCT to second ASCT was 28.0 months (range: 12–119). The disease status at second ASCT was seven very good partial response (VGPR; 23.3%), twelve partial response (PR; 40.0%), two stable disease (SD; 6.7%); and nine progressive disease (PD; 30.0%). Safety: The most common grade 3 or 4 adverse event (CTCAE v3.0) was febrile neutropenia in 15 patients (50.0%), followed by stomatitis in 13 patients (43.3%), nausea in four (13.3%) and hypokalemia in three (10.0%). One transplant-related death due to pulmonary complications was reported for a patient with Parkinsonism on post-transplant Day 20. There was no instance of seizure, worsening neuropathy, or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria. Efficacy: 28 patients had evaluable disease response at least at one time point after second ASCT. Disease response at 3 months were two complete responses (CR; 6.7%), five VGPR (16.7%), four PR (13.3%), eight SD (26.7%), nine PD (30.0%), and two cases without evaluable assessment (6.7%). Two patients who achieved CR at 3 months had PD and VGPR prior to ASCT, respectively. Disease response at 6 months were one stringent CR (sCR; 3.3%), one CR (3.3%), four VGPR (13.3%), seven SD (23.3%), fourteen PD (46.7%), and three cases without evaluable assessment (10.0%). Median progression-free survival was 191 days, while median overall survival has not been reached yet. PK: 40.0% (n=12/30) of patients had AUC outside the expected range from pre-transplant test dose, 0.8 mg/kg of IV Bu: eleven cases with AUC 1,500 μM*min. If only weight was used (e.g. 3.2 mg/kg daily) to determine the dose without considering difference in individual busulfan metabolism, this 40% would have been dosed outside the total target AUC range. Based on test PK, IV Bu dosing for conditioning was individualized ranging between 1.99 and 4.73 mg/kg, which resulted in 93.3% of patients (n=28/30) falling between 16,000 and 24,000 μM*min as a total target AUC without any further dose alteration during conditioning. Only 2 patients (6.7%) needed dose reduction on Days -3 and -2. Mean Bu clearance for test dose and on Day -5 were comparable, 3.00 and 2.92 ml/min/kg, respectively. Conclusions: Disclosures: Stadtmauer: Millenium: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: IV busulfan and bortezomib-based conditioning regimen prior to transplant for myeloma. Freytes:Otsuka Pharmaceuticals: Research Funding. Shaughnessy:Otsuka: Honoraria, Speakers Bureau. White:Otsuka: Honoraria, Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmaceutical Development & Commercialization, Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialisation., Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millinneum Pharmaceuticals: Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Abstract 813 Background: Published reports indicate that oral or intravenous (IV) busulfan in combination with cyclophosphamide and VP-16 (BuCyVP-16) is an effective conditioning regimen with acceptable safety profile for lymphoma patients prior to autologous hematopoietic stem cell transplantation (ASCT). Since the therapeutic window of Bu is narrow, it is important to standardize the systemic exposure during conditioning. Although the IV formulation of Bu eliminates the problem of variable drug absorption, unpredictable systemic exposure can still occur due to interpatient differences in Bu clearance. Therefore, tighter control of systemic Bu exposure using pharmacokinetics (PK) may lead to improved efficacy and further decrease in toxicity. The aim of this multi-center, single-arm, Phase II study was to prospectively evaluate the safety and efficacy of IV BuCyVP-16 regimen in lymphoma patients undergoing ASCT, after optimizing Bu exposure using PK-directed dosing. Methods: Patients with chemosensitive, relapsed or primary-refractory Hodgkin and B-cell non-Hodgkin lymphoma undergoing the first ASCT received a test dose of IV Bu (0.8 mg/kg) given as a 2-hour infusion 11 to 14 days before transplant. Bu exposure was determined as area under the concentration-time curve (AUC) using six serial blood samples after the test dose administration. Doses for the conditioning regimen were then calculated to result in total AUC (conditioning + test) of 20,000 mM*min. One-fourth of the resulting calculated Bu dose was given as a 3-hour infusion on Day -8, followed by a second, confirmatory PK analysis. The same daily Bu dose was administered on the next 3 days, unless the confirmatory PK analysis showed that this would result in total AUC outside the target range (>24,000 mM*min or Results: A total of 202 subjects with Hodgkin (n=65) and non-Hodgkin lymphoma (n=137) were enrolled from 32 centers in the US and Canada. 196 subjects had both test PK and confirmatory PK results. Test PK demonstrated that 36.2% (n=71) of the patients had exposure outside of expected range (1,250 μM*min ± 20%): higher AUC (>1,500 μM*min) in five patients (2.6 %) and lower AUC ( An early subset-analysis by age in June 2011 revealed that 4 of 18 subjects older than 65 years suffered TRM. Consequently, the protocol was amended to lower the inclusion age limit to 65. The final TRM at day 100 was 4/18 (22.2% [95%CI; 6.4–47.6%]) for patients older than 65 years and 5/184 (2.7% [95%CI; 0.9–6.2%]) for those 65 years old or younger. PK results indicated no extraordinary Bu exposure in TRM cases. The most frequently observed grade ≥ 3 adverse events (CTCAE ver. 3.0) were febrile neutropenia 55.1 % (Grade 3: 52.2%; Grade 4: 2.9%; no Grade 5), stomatitis 37.7% (all Grade 3 events) and nausea 9.7% (all Grade 3 events). No case of hepatic veno-occlusive disease (HVOD) meeting Baltimore criteria was reported. Conclusions: A pre-conditioning test dose estimated individual PK parameters and accurately predicted Day-8 PK in 95% of the subjects. This strategy personalized the dosing for optimal Bu exposure preventing the Bu overexposure or underexposure that would have occurred in over a third of patients. The toxicity of PK-guided IV BuCyVP-16 preparative regimen was low for patients younger than 66 years of age. This approach resulted in no incidence of HVOD. Disclosures: Costa: Otsuka: Research Funding. Off Label Use: Off label use of busulfan in non hodgkin and hodgkin lymphoma. Waller:Outsuka: Research Funding. Freytes:Otsuka Pharmaceuticals: Research Funding. Shea:Otsuka : Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka America Pharmaceuticals Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Vaughan:Pierre Fabre: Honoraria.

Abstract 3131 Patients with relapsed or refractory Hodgkin's Lymphoma (HL) who fail autologous transplantation seldom survive long term and most have exhausted effective therapeutic options. Preliminary data however suggests a role for allogeneic transplantation (allo-SCT) using reduced intensity conditioning (RIC), with 2–5 year progression free survival (PFS) and overall survival (OS) of 20–36% and 28–64%, respectively. Allo-SCT for HL is still uncommon however with CIBMTR data indicating a median of only 2 allografts/center/year (range: 1–13) at US centers. Methods We report 7 year outcome on 31 consecutive patients with HL who failed an autograft who were prospectively enrolled in a single institution trial and treated with BEAM RIC regimen (BCNU 300mg/m2 day -6, Etoposide 100mg/m2 daily and Cytarabine 100mg/m2 BID days -5 to -2, and Melphalan 140mg/m2 day -1). Graft vs host disease (GVHD) prophylaxis was with tacrolimus (0.03mg/kg/day starting day -2) and methotrexate (5mg/m2 days +1,+3,+6). Antithymocyte globulin (ATG 1.5mg/kg/day on days -4, -3) was used in 17 patients who underwent matched unrelated donor (MUD) transplantation and had no cytotoxic chemotherapy in the preceding three months. Results Median time from diagnosis to allo-SCT was 51 months (range: 17–172) and median age was 36 (range: 21–55 years). Patients were heavily pretreated with a median number of 5 prior regimens (including autograft; range: 4–9). Thirteen patients received stem cells from an HLA-matched sibling, 12 MUDs, 5 mismatched unrelated and 1 had mismatched related stem cells. All patients engrafted promptly at a median of 15 days (range: 12–26) defined as an absolute neutrophil count of >0.5 × 109/L and a median of 26 days (range: 10–76) for unsupported platelets >20 × 109/L. 100-day chimerism results were available for 26 patients: 23 (88%) were full donor chimeras (>98% donor DNA), 1 was a mixed chimera at 96% donor DNA, and one patient had graft rejection. The incidence of grade 1–2 acute GVHD was 29% and grade 3–4 was 7%. Incidence of limited stage chronic GVHD (cGVHD) was 56% and extensive stage was 9%. At a median follow up of 7 years the PFS is 36% (95% CI 19–54%) and OS is 42% (95% CI 23–59%), with no relapses seen after 36 months. Non-relapse mortality at one year was 13% (95% CI 5–32%). Significant predictors of improved survival in univariate analysis included chemosensitivity, bulk of disease Conclusion RIC BEAM allogeneic transplantation is safe and effective in producing long term remissions in patients with advanced HL who fail autografts. Bulk of disease is the only significant prognostic factor for a successful outcome regardless of chemosensitivity, thus patients with chemorefractory disease should be offered an allo-SCT after additional therapy has been given to achieve a minimal residual disease state, e.g with brentuximab vedotin and/or involved field radiation. While very preliminary, brentuximab vedotin also appears promising in the treatment of relapsed HL after allograft failure and thus should be further explored as maintenance therapy after engraftment to reduce early relapses while awaiting a potential graft vs Hodgkin's effect. Disclosures: Rodriguez: Seattle Genetics, Inc: Research Funding. Smith:Seattle Genetics, Inc: Consultancy, Research Funding. Stiff:Seattle Genetics, Inc: Research Funding.

Abstract 3102 Identifying the optimal patients and timing for allogeneic hematopoietic stem cell transplant (HSCT) is an ongoing challenge for transplant centers that requires assessment of more than just the disease status and stage. Pre-existing co-morbidities also independently impact both 100 day and 1 year non-relapse mortality (NRM) as well as long term overall survival. Additionally, the CIBMTR has also shown that Hispanic patients have an inferior survival after allogeneic HSCT, although why ethnicity is linked to a higher mortality, e.g. is it higher risk/timing of transplant, lower socioeconomic status, increased co-morbidities, etc. however, is still undetermined. A survival analysis of allogeneic HCT outcomes that includes ethnicity, co-morbidity, insurance payor, as well as traditional risk factors such as age, disease risk at transplant, and remission status would be helpful to clarify the outcome disparities found in different ethnic subgroups and more importantly lead to strategies to minimize the effect. Methods: We performed a retrospective analysis of the outcome of 363 consecutive adult allogeneic transplants at Loyola University Hospital of whom approximately 10% were Hispanics (34) from January 1, 2003 to June 30, 2010. We use a focused approach to optimize care of non-English speaking Hispanics which involves native speakers at all levels, written materials in Spanish, and an IRB approved method to permit all non-English speaking patients to enroll in all clinical trials is present. Traditional prognostic data as well as the Sorror co-morbidity index and socioeconomic and ethnicity status were determined for each patient. The surrogate we used for socioeconomic status was insurance payor (i.e. indigent + Medicaid vs. third party insurance/Medicare). Survival analysis was calculated using Kaplan Meier plots considering each patient at 100 days, 1 year, and 3 years. Results: The median age for the 363 patients was 47.1 years with 48.7% being in the High Risk CIBMTR category, and 74.1% being in remission at transplant. The median co-morbidity index was 2.0. No differences were seen in remission status or the co-morbidity index for Hispanic vs. non-Hispanic patients, while fewer Hispanic patients were in the High CIBMTR Risk group (27.3 vs. 50.9%; p = .048). Survival for Hispanics (34) vs. non-Hispanics (329) showed no difference in overall survival at three years (42.1 vs. 42.8%). Based on payors, we found no statistical difference in 100 day overall mortality after HSCT for those with Medicaid (n = 35) vs. non-Medicaid (n = 328) payors with Hispanic non-Medicaid and non-Hispanic non-Medicaid survivals at 100 days of 82.8 and 87.9%. However despite the relatively small number, both the non-Hispanic and Hispanic patients with Medicaid showed a significantly decreased survival after 100 days with 3 year survivals of 20.0 and 30.0% for Hispanic and non-Hispanic Medicaid patients vs. 51.7 and 56.7% of the Hispanic and non-Hispanic non-Medicaid groups respectively (p = .002). Conclusions: Unlike prior reports, and perhaps by using a focused approach for our non-English speaking Hispanic patients, we found no difference in survival between Hispanics and non-Hispanics in our series of 363 consecutive allografts at 100 days, 1, or 3 years, although they may have been predicted to have had a slightly better prognosis based on a better Risk Group status. We did however find that payor was an important prognostic variable for outcome after the first 100 days regardless of ethnicity. Whether this is simply due to the financial toll of such a chronic illness and therapy remains to be seen, but this suggests that closer follow-up after day 100 may be of significant benefit for this subgroup of patents which may grow due to health care reform. Disclosures: No relevant conflicts of interest to declare.

Abstract 4509 BACKGROUND: Once multiple myeloma (MM) relapses after a first autologous hematopoietic stem cell transplantation (HSCT), long-term disease control is challenging because of limited therapeutic options. A second autologous HSCT is one of the options although the choice of conditioning regimens has not been thoroughly investigated. Past studies demonstrated that adding oral busulfan (Bu) to melphalan for conditioning regimen prior to a first HSCT resulted in better disease control of MM than melphalan single administration [Lahuerta et al, Haematologica. 2010;95:1913]. Nonetheless, the risk of hepatic veno-occlusive disease (VOD) hinders the use of oral Bu as a part of the conditioning regimen. Intravenous (IV) Bu eliminates the unpredictable bioavailability of the oral drug, whereas pharmacokinetic (PK)-directed dose optimization reduces inter-individual variability in the metabolism of Bu, resulting in decreased incidence of VOD and improvement in the control of hematologic malignancies [Andersson et al, Biol Blood Marrow Transplant 2002;8:477]. In addition, a proteasome inhibitor like bortezomib may have synergy with an alkylating agent for conditioning prior to HSCT in myeloma [Lonial et al, Clin Cancer Res 2010; 16: 5079], but the safety of a combination with Bu has not been investigated to date. Here we report results from a multicenter, prospective Phase 2 study to examine the pharmacokinetics of IV Bu and safety with bortezomib as a conditioning regimen for a second autologous HSCT. METHODS: 30 patients with relapsed MM who had a first autologous HSCT ≥1 year prior to the planned HSCT were enrolled from eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between days 12 and 9 prior to HSCT. Serial blood samples were drawn up to 360 min after the start of the infusion. A central laboratory measured Bu concentrations, determined Bu exposure as area under the concentration-time curve (AUC) using WinNonlin software, and recommended individualized PK-directed dosing in order to achieve a total regimen AUC of 20,000 μM·min. Using the patient-specific PK-directed dose, IV Bu was administered over 3 hours once daily from Day -5 to Day -2. In all patients, a second PK analysis was conducted on Day -5 to confirm the PK-directed dose. Bu doses were adjusted on Day -3 and Day -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. RESULTS: All 30 patients who enrolled in this study had been treated with high dose melphalan before a first HSCT. The median time from the first to second HSCT was 31.4 months (range 12.0 – 119.2 months). Disease status prior to the second HSCT was VGPR (n=6), PR (n=12), SD (n=2), and PD (n=10). Test PK revealed that 40.0 % (n=12/30) of the patients had doses outside of target range (1,250 μM·min +/− 20%), based on expected exposure using a fixed dose of 0.8 mg/kg. Specifically, infusion of the test dose resulted in 1,500 μM·min or higher AUC in 3.3% (n=1/30) and 1,000 μM·min or lower AUC in 36.7% (n=11/30) of patients. In order to achieve the target AUC, daily PK-directed dose of IV Bu when conditioning started on Day -5 ranged between 1.99 mg/kg and 4.73 mg/kg: lower than 3.2 mg/kg in 12 subjects and higher than 3.2 mg/kg in the remaining 18. Confirmatory PK on Day -5 demonstrated that mean Bu clearances were comparable to that from test PK: 3.03 ml/min/kg for test dose and 2.93 ml/min/kg for Day - 5. Consequently, using a test dose followed by PK-directed Bu dosing, 93.3% of patients (n=28/30) fell within the target range (AUC, 20,000 μM·min +/−20%). Only two patients (6.7%) needed subsequent daily dose adjustment on Day -3 and Day -2. No instances of VOD, seizure, or worsening neuropathy have been reported to date. One death was reported by Day 30 after transplant in a patient with Parkinsonism who died of pulmonary complications. CONCLUSION: This multicenter, prospective study reveals that a pre-transplant test dose PK allows accurate targeting of busulfan dosing. The conditioning regimen of bortezomib and IV busulfan with PK-directed dose optimization is well tolerated in patients with relapsed MM who undergo second autologous HSCT. Disclosures: Freytes: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfex and bortezomib as conditioning regimen for autologous transplant in patients with multiple myeloma. Yeh:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Shaughnessy:Otsuka: Consultancy, Honoraria, Speakers Bureau. White:Otsuka: Consultancy, Honoraria. Rodriguez:Millennium: Research Funding, Speakers Bureau; Otsuka: Research Funding. Yu:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka Pharmaceutical Development and Commercialization, Inc.: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Johnson & Johnson: Research Funding.