ALBERT

Description: Title: Collection and Processing Considerations in Haploidentical Stem Cell Transplantation Utilizing a 2-Step Methodology Background: Haploidentical transplantation is an active area of research because only about one-third of patients have an HLA-matched sibling and searching for an HLA-matched-unrelated donor can delay urgent need for alloBMT. However, nearly all patients have HLA-haploidentical related donors. The incidence of graft rejection, infection, and GVHD has been minimized by improving conditioning regimens and the use of cyclophosphamide-based T-cell tolerization. There are unique collection and processing considerations associated with such transplants. We describe the unique collection considerations for the Thomas Jefferson University 2 Step regimen (TJU2) (Grosso D, Blood 2011), where the donor lymphocyte infusion (DLI) precedes the CD34+ selected hematopoietic progenitor cell (HPC) transplant. The DLI target dose in this study is fixed at 2 x 10e8 CD3+/recipient kg. The HPC collection is CD34+ cell selected. The post-selection target cell doses/recipient kg are 2-10 x10e6 CD34+ cells and 〈 5 x 10e4 CD3+ cells. The points to consider in determining donor blood volume to be processed during apheresis collection are: 1. Although 0.14 x 10e8 CD3+/L processed/recipient kg is a median CD3+ dose collected with G-CSF mobilization (Korbling, JCA 2001), where the absolute lymphocyte count increases ~2-fold above its baseline (Holig, Blood 2009, Anderlini Transfusion 1996), the median dose for a non-mobilized collection is 0.07 x 10e8 CD3+/L processed/recipient kg (Korbling, JCA 2001). Therefore large volume DLI collection may need to be performed. 2. The collection facility's lymphocyte or CD3+ collection efficiency. Donor pre-collection peripheral blood CD3+ count is typically not available. 3. The collection facility's CD34+ cell collection efficiency. This can be calculated because the donor's peripheral blood CD34+ cell count is typically available. 4. Higher CD34+ cell doses appear to be beneficial in haploidentical transplant (Reisner, Blood 2011). Therefore we designed the HPC collection volume to obtain a post-CD34+ cell selection target dose of 7 x 10e6/recipient kg. 5. The processing facility's CD34+cell selection recovery. This typically varies from 30-100%. Methods: All procedures except one DLI (performed with the Spectra Optia CMNC) were performed using the Cobe Spectra MNC procedure (Terumo Corp). The following algorithms were used to estimate the donor blood volume ideally to be processed to ensure that target doses were reached: DLI: [(recipient kg x CD3 target/kg) / (0.6 x ALC)] / (median lymphocyte CE) 0.6 is the lower limit of a normal percentage of CD3+ lymphocytes ALC = donor absolute lymphocyte concentration on the day of collection CE = collection efficiency (facility-specific median = 0.58) HPC: [(recipient kg x post-selection CD34 target/kg) / PB CD34+] / (median CD34 CE) / (minimum CD34 selection recovery) Post-selection CD34 target/kg = 7 x 10e6/kg PB CD34+ = donor peripheral blood CD34+ concentration on day of collection CE = collection efficiency (facility-specific median = 0.45) Facility-specific minimal CD34+ selection recovery=0.31 CD 34+ cell enriched products were obtained by incubation of mobilized HPC, Apheresis products with Miltenyi CD34+ reagent and subsequent positive selection on the CliniMACS Plus (Milteyi Biotec GmbH) according to manufacturer's specifications. Results: Our results in 6 donor-recipient pairs were the following: Discussion: The variability in the predictive value is due to variabilities in lymphocyte CE (range 0.38-0.94), CD34+ CE (range 0.36-0.67), and CD34+ selection recovery (range 0.31-0.81). Nevertheless, the correlation coefficients are high and as the ranges of CEs and CD34+ selection recovery are optimized and narrowed, the predictive value of these formulas will increase. Of note, all collections except one were performed with the Cobe Spectra MNC procedure. With the transition to the Optia CMNC procedure, where the collection interface is controlled by the device, the CEs are expected to become more consistent. Table 1. Table 1. Table 2. Table 2. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Sickle cell disease (SCD) is an inherited autosomal recessive blood disorder associated with significant morbidity. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used in severely affected patients with SCD. These transplants result in mixed hematopoietic chimerism so accurate chimerism testing is important for monitoring the status of the transplant. Reconstitution of the erythroid compartment is essential. Since red cells lack a nucleus, DNA-based chimerism assays do not directly assess the chimerism in the erythroid compartment. Several studies have shown that the chimerism in the white cells and erythroid cells can be very different (W, C., etal. Exp. Hematol. 2003, 31:924; Andreanni, M., etal. Haematologica, 2011, 96:128). We developed a procedure for quantification of chimerism in the erythroid compartment of blood using RNA-based digital droplet PCR (ddPCR). The sensitivity and specificity of the assay was evaluated then tested post-transplant samples from sickle cell patients. Total RNA is reverse transcribed and amplified in a two-step RT-PCR approach. The PCR reaction containing allele-specific hydrolysis probes is partitioned into ~15,000 droplets then amplified. The copy number of HbA and HbS transcripts from cells of the erythroid lineage is determined with ddPCR (BioRad, QX-200). The %HbA and the %Donor can be calculated using the donor genotype (A/A or A/S). The assay is designed to have a sensitivity of 1% with donor genotype of A/A and 5% with donor genotype of A/S. Each post-transplant sample is tested in duplicate along with an AA control, SS control, AS control and 1% sensitivity controls (5 controls total). Thirty AA or SS samples were tested to assess assay specificity. The average %HbA detected in a SS sample was 0.03%; the average %HbS in a AA sample was as 0.02%. The background signal is significantly below the cutoff for 1% sensitivity. Using contrived samples with low, medium, and high %HbA, we demonstrate the assay is accurate and linear to 0-2%HbA across the reportable range of 0%HbA to 100%HbA. The % CV of the minor allele for samples in the range of 10%-90%HbA, were equal or below 15%. A total of 11 post-transplant samples from 7 transplanted sickle cell patients were tested, and the results were compared to DNA-based/FISH chimerism, if available. Our results were comparable with DNA-based chimerism (Table 1). Five of the samples had slightly higher %donor in the erythroid compartment compared to the white cell compartment. The erythroid chimerism reflected changes in chimerism status: the decrease then increase in chimerism (P2), stable chimerism (P5) and graft failure (P7). Abstract 563. Table 1: Erythroid chimerism status of post-transplant SCD patients Patient # Donor Genotype Sample # %HbA %Donor %Recipient %Donor by FISH/STR P1 AS 1 52 100 0 95 P2 AA 1 66 66 34 72 2 44 44 56 50 3 100 100 0 95 P3 AS 1 54 100 0 85 P4 AA 1 100 100 0 100 P5 AS 1 14 28 72 15 2 12 24 76 15 P6 AS 1 57 100 0 95 P7 AA 1 0 0 100 Rejecting graft 2 0 0 100 Rejecting graft Assessment of the chimerism in the erythroid lineage may be a better indicator of donor erythropoiesis. We describe an accurate and sensitive assay for monitoring erythroid chimerism and the effects of post-transplant therapies in sickle cell patients undergoing HSCT. This assay also demonstrates the feasibility measuring erythroid chimerism detection in other hematologic disorders, such as thalassemia. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 654 Background: Phase 2 clinical trials of DF in the treatment of severe VOD/MOF have demonstrated a complete response (CR) in 36-46% of patients (pts) with encouraging overall survival and tolerability (Richardson Blood 2002; Richardson ASH 2006). Given the life-threatening nature of VOD/MOF, a trial randomizing pts to placebo or best supportive care was considered but rejected. A phase 3 trial, comparing DF in the treatment of VOD/MOF post-SCT to a contemporaneous historical control (HC) was therefore performed. The HC was created using a sequential review of medical charts starting 6 months prior to use of DF at each center. Methods: Eligible pts met Baltimore VOD criteria by D+21 (total bilirubin ≥ 2.0 mg/dL with ≥ 2 of the following: hepatomegaly, ascites or 5% weight gain) and either renal and/or pulmonary failure by D+28. Exclusion criteria: severe GvHD involving liver or gut; clinically significant bleeding; or need for 〉1 pressors to maintain BP. As this is a non-randomized study, the primary efficacy analysis compared CR by D+100, adjusted by quintiles of propensity score based on 4 stratification variables, at an overall two-sided 0.01 significance level (Koch et al,1989). CR was defined as bilirubin 〈 2 mg/dL + resolution of MOF; stratification variables were allogeneic/autologous SCT, adult/pediatric, 1 or 2+ SCTs, and ventilator/dialysis dependence. A secondary endpoint was mortality at D+100. DF was given at 6.25 mg/kg IV q6h; treatment duration was recommended for at least 21d. To create the HC, 35 centers sequentially reviewed up to 266 cases. To determine HC eligibility, the Medical Review Committee (MRC, composed of 2 independent expert hematologists) assessed all pts who met VOD criteria with MOF. The MRC were provided data for each pt (a redacted medical chart or pt narrative, depending on the privacy laws for each center) only up to the date on which the pt met inclusion criteria. The MRC remained blinded to outcome data at all times. One interim analysis was planned. Results: For the HC, 6821 medical charts were screened, identifying 123 pts with features consistent with VOD in a setting of renal and/or pulmonary dysfunction that were reviewed for eligibility by the MRC. The MRC selected 32 cases as having an unequivocal diagnosis of VOD whose MOF was secondary to VOD, who met all protocol entry criteria; for all eligible pts, a confounding diagnosis of GvHD was ruled out. In the DF-treated group, 102 pts were enrolled. Following the interim analysis (comparing 61 DF pts to 32 HC pts), the DMC recommended an increase in HC sample size to 51 pts; given the large number of medical charts already reviewed, this was not considered feasible. In the final analysis (comparing 102 DF pts to 32 HC pts), the 2 groups were balanced regarding stratification variables. Baseline demographics (DF vs HC pts): median age 21 vs 18 yrs (43% and 44% pediatric); 63% vs 53% male, 88% vs 84% allogeneic SCT; 13% vs 3% with prior SCT; and 38% vs 38% ventilator/dialysis dependent. Median time post-SCT to VOD diagnosis was 13 and 11 days. Acute leukemia was the underlying diagnosis in 44% and 47%. Median duration of DF therapy was 22 days (range 1-60 days), with a median daily dose of 19 mg/kg/d. For the primary efficacy analysis, D+100 CR rate equaled 24% vs 9% (99%CI difference in CR rate: -1–35%; 95%CI difference in CR rate: 3–30%); p=0.015. D+100 mortality rate equaled 62% vs 75% (95%CI difference in rate -32–3%); p=0.051 by stratified log-rank. Consistent with prior studies, DF in children resulted in higher CR compared with HC (CR 36% vs 7%; p=0.04). Use of DF was associated with improved outcome in less sick pts (D+100 CR for pts without ventilator dependence equaled 40% vs 9%; p=0.051 and for pts without dialysis dependence equaled 34% vs 9 %; p=0.027). For pts receiving autologous SCT (n=12 and 5 pts in DF and HC arms), DF was associated with markedly improved CR (75% vs 0%, p=0.005). Hemorrhagic adverse events (any grade) were similar between the two groups (65% vs 69%); 18% of DF pts experienced a drug-related toxicity that led to discontinuation. D+100 CR strongly correlated with D+100 survival in both DF and HC groups (p

Description: Abstract 3481 Background: Two prospective studies have investigated DF in the treatment of severe VOD/MOF post-SCT. Protocol 99–118 (a Phase 2 trial of DF; n=150) compared two doses of DF (25 and 40 mg/kg/day) and produced a similar complete response (CR) rate: 46% and 42% of patients (pts), respectively (Richardson et al BBMT 2010). Protocol 2005-01 (a Phase 3 trial enrolling pts with more severe VOD/MOF) demonstrated a CR of 24%. For the Phase 3 trial, a historical control (HC) had been created by review of 6864 medical charts at 35 BMT centers; up to 266 SCT pts were sequentially reviewed for symptoms of possible VOD/MOF with pts selected by an independent Medical Review Committee (MRC). The MRC was provided a redacted medical chart or pt narrative up to the date on which the pt met entry criteria, but remained blinded to outcome. Compared to this HC, the Phase 3 trial demonstrated that use of DF in pts with severe VOD/MOF resulted in a significantly higher CR rate (p=0.0148; Richardson et al ASH 2009). In order to assess consistency of DF treatment effect across these trials, a meta-analysis was undertaken. Methods: Data for the subset of Phase 2 pts who had received a dose of 25 mg/kg/day and met eligibility criteria for the Phase 3 trial were combined with all 102 Phase 3 pts. Pts were required to have a diagnosis of VOD based upon Baltimore criteria (bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF as defined in the Phase 3 trial (renal and/or pulmonary dysfunction). CR was defined as bilirubin 〈 2 mg/dL + resolution of MOF. CR and mortality were assessed at D+100. DF (6.25 mg/kg IV q6h) was recommended for at least 21d. As the Phase 3 trial was not a prospectively randomized study, the primary efficacy analysis compared CR by D+100, adjusted by quintiles of propensity score based on 4 stratification variables of age, allogeneic SCT, prior SCT and ventilator/dialysis dependence at study entry. Results: This meta-analysis identified 31 Phase 2 pts treated at a dose of 25 mg/kg/day who met eligibility for the Phase 3 trial. Baseline characteristics were similar (n=31 and n=102, respectively); 61% vs 63% were male with median age (years) 20 vs. 22; acute leukemia in 52% and 44%; allogeneic SCT in 90% and 88%; and prior SCT in 9% and 13%. The 31 Phase 2 pts had less ventilator and dialysis dependence at study entry (6% and 3% vs 25% and 21%, respectively). For the HC, the MRC had selected 32 cases as having an unequivocal diagnosis of severe VOD, whose MOF was secondary to VOD and who met all entry criteria. DF treatment duration was shorter for the Phase 2 pts: a median of 15 vs 22 days of DF, respectively. Of the 133 pts, 38 (29%) achieved a CR by D+100, compared to 9% in the HC (p=0.0021 by propensity adjusted score). When comparing 133 pts with the HC, CR by D+100 rate was 43% for pediatric pts compared with 7% (p = 0.0001; n=58 and 14 pts, respectively). For pts with only 1 prior SCT and those with ≥2 prior SCTs, the CR rate was improved with DF (29% vs 10%, p=0.0008 with only 1 prior SCT; 25% vs 0%, p=0.0143 with 2+ prior SCTs). The CR rate was higher in pts not on dialysis/ventilator at study entry (35% vs 10%; p=0.0006). For those pts who were on dialysis/ventilator at study entry, the CR rate was 14% vs 8% (p=0.362). D+100 mortality rate equaled 60% vs 75% (p=0.0408 using Kaplan Meier estimates by log-rank analysis). Hemorrhage (any grade regardless of relationship to DF) was lower in the DF-group (61% vs 72% in the HC). Similar to the observation of decreased GvHD in a recent randomized prophylactic study (Corbacioglu et al, EBMT 2010), the incidence of GvHD (any grade) was lower (6% vs 25%) in the DF group. Conclusions: This meta-analysis of DF-treated pts, pooling data from two separate clinical trials, confirmed improvement in CR and survival by D+100 compared to HC. The incidence of CR and D+100 survival was similar to that observed in prior phase 2 single-arm trials investigating DF in the treatment of this life-threatening condition. DF was well tolerated with less hemorrhage vs HC. A prospective sub-analysis suggests that DF results in a higher CR rate in pts who have not progressed to ventilator/dialysis dependence. GVHD was less common in DF treated pts compared to HC; this potentially important observation warrants further study. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Grupp:Gentium: Membership on an entity's Board of Directors or advisory committees. Hume:Gentium: Employment. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment.

Description: Background: Myeloablative hematopoietic cell transplantation (HCT) provides a cure for children with hemoglobinopathies, but transplant related early and late morbidity remains a challenge. Toxicities associated with myeloablative chemotherapy include early complications such as mucositis, hemorrhagic cystitis, seizures, and hepatic injury. Late effects such as infertility and compromised linear growth impair long-term quality of life, often decreasing enthusiasm for the procedure. Reduced intensity preparative regimens are especially attractive in children with non-malignant disorders to mitigate these toxicities but have been associated with increased risk of graft rejection. The primary objective of this study was to determine the toxicity and efficacy of a non-myeloablative preparative regimen using alemtuzumab, fludarabine, and melphalan followed by HCT from HLA matched related donors (MRD) in children with hemoglobinopathies. Methods: Following institutional review board approval, and parent and/or patient consent, participants were enrolled at 18 centers. Children 〈 21 years of age with severe sickle cell disease (SCD) manifestations, or transfusion dependent (〉 8 red blood cell transfusions per year) thalassemia with a MRD and a performance status 〉 40 were eligible for inclusion. The preparative regimen included alemtuzumab (total dose 48 mg) IV (between days –22 and –19), fludarabine (30 mg/m2/day) (days –8 to –4) and melphalan (140 mg/m2) on day -3. Graft versus host disease (GVHD) prophylaxis included a calcineurin inhibitor (tapered after day 100, and methotrexate (7.5 mg/m2 on days 1, 3 and 6) or mycophenolate mofetil. Five patients also received methylprednisone (1 mg/kg/day) between days 1 and 28; this practice was discontinued in 2007. Results: A total of 52 children (43 with SCD and 9 with thalassemia), median age 11 years (range, 10m - 20y) underwent HCT between March 2003 and July 2014. Of these, 46 received bone marrow, 5 received marrow and cord blood (CB), and 1 received CB alone. Median follow up was 35.5 months (range, 3 – 136). Forty-nine children were alive at last follow up (Figure 1); 48 were symptom-free; one CB recipient had disease recurrence following graft rejection and successfully underwent a 2nd HCT. No hepatic veno-occlusive disease was noted. Three deaths 6, 11 and 21 months post HCT were from GVHD related causes [bronchiolitis obliterans (n=1); infection with GVHD (n=2)]. The cumulative incidence of graft failure and transplant related mortality was 1.9% and 5.7% respectively. The mean time to engraftment of neutrophils (ANC 〉500/cu mm) and platelets (〉50,000/cu mm) was 13.0 (range 5-21) and 25.9 (range 8-120) days respectively. Three patients had neurologic toxicity (seizures/PRES) post HCT. At the time of last follow up, 35 patients (67%) were complete donor chimera (〉90% donor) and 16 (31%) were mixed chimera (28-89% donor). Acute GVHD (grade 1-3) was noted in 30.8%. Four had grade I, 6 had grade II, and 6 had grade III GVHD. No patient developed grade IV aGVHD. Chronic GVHD was noted in 13%. Of 43 patients that were alive without disease and 〉6 months post HSCT, 38 had successfully discontinued all immune suppression and maintained donor chimerism post withdrawal. Immune reconstitution was robust by the end of the first year post transplant; infectious complications (23 of 30 CMV+ recipients had reactivation) were noted primarily in the first 3 months post HSCT. Conclusions: Children with hemoglobinopathies undergoing MRD HCT tolerated this non-myeloablative preparative regimen well, with minimal early toxicities. The event-free survival rate was comparable to those achieved with myeloablative regimens. Withdrawing immunosuppression was not associated with graft loss or recurrent GVHD. GVHD complications resulted in a low mortality rate. Alternative GVHD prophylaxis may further improve event-free survival. No gonadal toxicity (determined by hormone levels) has been identified to date in 15 HCT recipients of pubertal age (〉13 years). Follow up however is early and in progress to determine long-term toxicities. These results support consideration of reduced intensity conditioning regimens for HCT in children with hemoglobinopathies as an alternative to standard myeloablative regimens. Figure 1: Overall/Event-free survival following non-myeloablative conditioning andMRD transplants for hemoglobinopathy Figure 1:. Overall/Event-free survival following non-myeloablative conditioning andMRD transplants for hemoglobinopathy Disclosures No relevant conflicts of interest to declare.

Description: Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), is a rare and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Severe cases, historically defined by multi-organ dysfunction (MOD), may be associated with mortality rates of 〉80%. There is no FDA-approved treatment for VOD/SOS. Defibrotide (DF) has a proposed mechanism of action that includes stabilization of endothelial cells and restoration of thrombo-fibrinolytic balance. Earlier analyses of a pivotal phase 3 trial of DF in VOD/SOS plus MOD (Richardson et al. Blood. 2009;114:Abstract 654) underpinned approval of DF in the EU to treat severe hepatic VOD/SOS after HSCT. Additional data were obtained at the request of US health authorities. Here we present the final analysis: day +100 survival (primary endpoint) and complete response (CR; secondary). Methods This was a multicenter, open-label, phase 3 historical control (HC) study assessing DF. Eligible patients met Baltimore VOD/SOS criteria (total bilirubin ≥2.0 mg/dL with ≥2 of: hepatomegaly, ascites, or 5% weight gain) by day +21 post-HSCT, plus MOD (renal [trebling of creatinine levels, reduced creatinine clearance, or dialysis] and/or pulmonary [oxygen saturation ≤90%, need for oxygen supplementation/ventilator dependence]) by day +28 post-HSCT. Exclusion criteria included severe graft-versus-host disease (GvHD) of liver or gut, clinically significant bleeding, or need for ≥2 pressors. HC patients were reviewed for inclusion/exclusion criteria in a sequential review of medical charts starting 6 months prior to use of DF at each site; a blinded medical review committee made the final determination of HCs unequivocally meeting criteria for VOD/SOS with MOD. DF dose was 25 mg/kg/d in 4 divided 2-hour IV infusions q6h; recommended treatment duration was ≥21 days. Primary endpoint was day +100 survival. CR by day +100 was a secondary endpoint. Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival (ie, ventilator and/or dialysis dependency at entry, age ≤/〉16 years, transplant type, and prior HSCT). Analyses included patients treated with DF and HCs. Results There were 102 patients in the DF group and 32 cases selected as HCs. Baseline characteristics were similar in the DF and HC groups: mean age (26 and 25 years; 43% and 44% ≤16 years), allogeneic graft (88% and 84%), prior HSCT (13% and 9%), ventilator- and/or dialysis-dependent at study entry (33% and 22%), myeloablative conditioning (87% and 94%), and the most common underlying diseases (acute leukemias: 45% and 47%), respectively. In the DF-treated group, common GvHD medications included tacrolimus (49%), methotrexate (41%), and cyclosporine (38%); in the HC group, common medications were cyclosporine (72%) and methotrexate (63%). Survival at day +100 in the DF and HC groups was 38% and 25%, respectively. The propensity-stratified difference in survival was 23.0% (95.1% CI, 5.2-40.8, P = .0109). Respective observed CR rates by day +100 were 25.5% and 12.5%, and the propensity-stratified difference in CR was 19.0% (95.1% CI, 3.5-34.6, P = .0160). Comparing the earlier EU and final analyses, the survival rates at day +100 in each group did not vary; however, the propensity adjusted final analysis provided a different level of statistical significance. Day +100 CR rates in the original analysis were slightly lower in both arms at 24% and 9% due to increased data capture to investigate CR; the P value was essentially unchanged. For the DF group, 45% had an adverse event (AE) at least possibly related to study drug, and 21% had a serious AE at least possibly related to study drug. In this very sick population, percentages of patients with ≥1 AE leading to death were similar between DF and HC patients (64% and 69%), as were hemorrhagic AEs (64%, 75%) and hypotension (39%, 50%). Conclusions Based on observed study data and using a propensity-adjusted rate difference estimator, patients treated with DF had a 23% reduction in risk of death by day +100 and 19% improvement in CR rate. Overall incidence of hemorrhage and fatal AEs were similar between groups with AEs consistent with those expected in this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Marizomib, pmalidomide, and low dose dexamethasone in RR MM. Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. . Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Guinan:Gentium SpA/Jazz Pharmaceuticals: Other: My institution received fees for research.. Martin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Steinbach:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Krishnan:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Jazz: Consultancy; Millenium: Speakers Bureau. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding. Rodriguez:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Doyle:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. D'Agostino:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Massaro:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Iacobelli:Gentium SpA: Employment. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Gentium SpA: Other: Personal fees during conduct of the study.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Key Points Defibrotide improves day +100 survival and CR in patients with VOD and MOF compared with a historical control. The historical control selection methodology offers a novel approach for investigation of a life-threatening orphan disease.